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CN100338031C - Compounds and methods for synthesis and therapy - Google Patents

Compounds and methods for synthesis and therapy Download PDF

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Publication number
CN100338031C
CN100338031C CNB2005100876596A CN200510087659A CN100338031C CN 100338031 C CN100338031 C CN 100338031C CN B2005100876596 A CNB2005100876596 A CN B2005100876596A CN 200510087659 A CN200510087659 A CN 200510087659A CN 100338031 C CN100338031 C CN 100338031C
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group
alkyl
nhr
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CN1733707A (en
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诺伯特·毕乔夫伯格
金正恩
威勒德·雷
刘洪涛
马修·威廉斯
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Gilead Sciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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Abstract

Novel compounds are described. The compounds generally comprise an acidic group, a basic group, a substituted amino or N-acyl and a group having an optionally hydroxylated alkane moiety. Pharmaceutical compositions comprising the inhibitors of the invention are also described. Methods of inhibiting neuraminidase in samples suspected of containing neuraminidase are also described. Antigenic materials, polymers, antibodies, conjugates of the compounds of the invention with labels, and assay methods for detecting neuraminidase activity are also described.

Description

Compounds, its synthetic method and therepic use
The present invention is to be the dividing an application of Chinese patent application 01124714.2 on February 26th, 1996 applying date, and the denomination of invention of original bill is " compounds, its synthetic method and a therepic use ".
Background of invention
Invention field
Neuraminidase (also being called sialidase, acylneuraminate base hydrolase, and EC3.2.1.18) is a common enzyme in animal and the many microorganisms.It is a kind of glycosylhydrolase, and from glycoprotein, glycolipid and oligosaccharides decompose the sialic acid of terminal α-ketoside bond.Many microorganisms that contain neuraminidase are pathogenic to human and other animals (comprising poultry, horse, pig and sea dog).These pathogenic organisms comprise influenza virus.
Neuraminidase is pathogenic relevant with influenza virus.It is considered to deviate from infected cells with helping firm synthetic virus particle, and helps virus to move (by its hydrolytic enzyme activities) in respiratory mucus.
Description of Related Art
Itzstein, people such as M.von be at " Nature ", and 363 (6428): the Design Theory that discloses the sialidase base inhibitor that influenza virus duplicates among the 418-423 (1993).
Colman, P.M. (Int.App.No.PCT/AU 90/00501 at International Patent Publication No.WO 92/06691 to wait the people, on April 30th, 1992 is open) in, Itzstein, people such as L.M.von are at European Patent Publication No 0539 204A1 (EP App.No.92309648.6, on April 28th, 1993 is open) in, and Itzstein, (Int.App.No.PCT/AU 91/00161 at International Publication No.WO 91/16320 for people such as L.M.von, on October 31st, 1991 is open) in disclose and neuraminidase bonded compound, and claim that it has the interior resisting virus activity.
Goal of the invention
Main purpose of the present invention is the inhibition of the inhibition, particularly influenza virus of virus.Special purpose is to suppress glycolytic enzyme such as neuraminidase, and selectivity particularly viral or bacillary neuraminidase suppresses.
Another purpose of the present invention is to provide neuraminidase inhibitor, it has inhibition to the speed of urinating, can enter nose or pulmonary secretions from systemic circulation, having is enough to treat effective oral biological available rate (bioavailability), has efficient, acceptable clinically toxicity curve (profiles), and other required pharmaceutical properties.
Another purpose is to provide the synthetic method of improved more cheap neuraminidase inhibitor.
Another purpose is to provide uses improving one's methods of known and novel neuraminidase inhibitor.
A purpose is for being provided for preparing polymkeric substance, tensio-active agent or immunogen and the composition that is used for other commercial runs and goods again.
Above-mentioned these purposes and other purposes will be easy to be understood by those of ordinary skill after integral body is considered the present invention.
Summary of the invention
The invention provides have formula (I) or compound (II) or composition
Wherein
A 1For-C (J 1)=, or-N=;
A 2For-C (J 1) 2-,-N (J 1)-,-N (O) (J 1)-,-N (O)=,-S-,-S (O)-,-S (O) 2-or-O-;
E 1For-(CR 1R 1) M1W 1
G 1Be N 3,-CN ,-OH ,-OR 6a,-NO 2, or-(CR 1R 1) M1W 2
T 1For-NR 1W 3, heterocycle, or and U 1Or G 1Form group together with following structure:
Figure C20051008765900162
U 1For H or-X 1W 6
J 1With J 1aBe R independently 1, Br, Cl, F, I, CN, NO 2Or N 3
J 2With J 2aBe H or R independently 1
R 1Be H or C independently 1-C 12Alkyl;
R 2Be R independently 3Or R 4, each R wherein 4Use 0 to 3 R independently 3Group replaces;
R 3Be F independently, Cl, Br, I ,-CN, N 3,-NO 2,-OR 6a,-OR 1,-N (R 1) 2,-N (R 1) (R 6b) ,-N (R 6b) 2,-SR 1,-SR 6a,-S (O) R 1,-S (O) 2R 1,-S (O) OR 1,-S (O) OR 6a,-S (O) 2OR 1,-S (O) 2OR 6a,-C (O) OR 1,-C (O) R 6c,-C (O) OR 6a,-OC (O) R 1,-N (R 1) (C (O) R 1) ,-N (R 6b) (C (O) R 1) ,-N (R 1) (C (O) OR 1) ,-N (R 6b) (C (O) OR 1) ,-C (O) N (R 1) 2,-C (O) N (R 6b) (R 1) ,-C (O) N (R 6b) 2,-C (NR 1) (N (R 1) 2) ,-C (N (R 6b)) (N (R 1) 2) ,-C (N (R 1)) (N (R 1) (R 6b)) ,-C (N (R 6b)) (N (R 1) (R 6b)) ,-C (N (R 1)) (N (R 6b) 2) ,-C (N (R 6b)) (N (R 6b) 2) ,-N (R 1) C (N (R 1)) (N (R 1) 2) ,-N (R 1) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 1)) N (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 6b) C (N (R 1)) (N (R 6b) 2) ,-N (R 1) C (N (R 6b)) (N (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 6b) 2) ,=O ,=S ,=N (R 1) or=N (R 6b);
R 4Be C independently 1-C 12Alkyl, C 2-C 12Alkenyl, or C 2-C 12Alkynyl;
R 5Be R independently 4, each R wherein 4Be 0 to 3 R 3Group replaces;
R 5aBe C independently 1-C 12Alkylidene group, C 2-C 12Alkylene group, or C 2-C 12Alkynylene, arbitrary alkylidene group, alkylene group or alkynylene are by 0 to 3 R 3Group replaces;
R 6aBe H or one-tenth ether or the group that becomes ester independently;
R 6bBe H independently, the residue of amino protecting group or carboxylated compound;
R 6cBe H or the residue that contains aminocompound independently;
W 1For containing the group of acidic hydrogen, the acidic-group of protection, or contain the R of the group of acidic hydrogen 6cAcid amides;
W 2For containing the alkaline heteroatomic group of alkaline heteroatoms or protection, or should the heteroatomic R of alkalescence 6bAcid amides;
W 3Be W 4Or W 5
W 4Be R 5Or-C (O) R 5,-C (O) W 5,-SO 2R 5Or-SO 2W 5
W 5Be carbocyclic ring or heterocycle, wherein W 5Independently by 0 to 3 R 2Group replaces;
W 6For-R 5,-W 5,-R 5aW 5,-C (O) OR 6a,-C (O) R 6c,-C (O) N (R 6b) 2,-C (NR 6b) (N (H) (R 6b)) ,-C (NR 6b) (N (R 6b) 2) ,-C (N (H) (N (R 6b) 2) ,-C (S) N (R 6b) 2, or-C (O) R 2
X 1Be a key ,-O-,-N (H)-,-N (W 6)-,-N (OH)-,-N (OW 6)-,-N (NH 2)-,-N (N (H) (W 6))-,-N (N (W 6) 2))-,-N (H) N (W 6)-,-S-,-SO-, or-SO 2-; With
Each m 1Be 0 to 2 integer independently; But condition is not comprise following compounds, wherein;
(a) A 1For-CH=or-N=and A 2For-CH 2-;
(b) E 1Be COOH, P (O) (OH) 2, SOOH, SO 3H, or tetrazolium;
(c) G 1Be CN, N (H) R 20, N 3, SR 20, OR 20, guanidine radicals ,-N (H) CN
Figure C20051008765900181
(d) T 1For-NHR 20
(e) R 20Be H; C 1-C 4Acyl group; C 1-C 6Line style or cyclic alkyl, or the analogue of its halogen replacement; Allyl group or unsubstituted aryl, or by halogen, OH group, NO 2Group, NH 2The aryl that group or COOH group replace;
(f) J 1Be H and J 1aBe H, F, Cl, Br or CN;
(g) J 2Be H and J 2aBe H, CN or N 3
(h) U 1Be CH 2YR 20a, CHYR 20aCH 2YR 20a, or CHYR 20aCHYR 20aCH 2YR 20a
(i) R 20aBe H or C 1-C 4Acyl group;
(j) Y is O, S, H or NH;
(k) 0 to 2 YR 20aBe H, and
(l) U 1Each Y partly is identical or different in the group, and when Y is H, R 20aBe covalent linkage, and if condition is G 1Be N 3U then 1Be not-CH 2OCH 2Ph,
With and pharmaceutically acceptable salt and solvate;
With and salt, solvate, the enantiomorph of parsing and the diastereomer of purifying.
Another concrete example of the present invention relates to following formula: compound:
Figure C20051008765900191
Wherein
E 1For-(CR 1R 1) M1W 1
G 1Be N 3,-CN ,-OH ,-OR 6a,-NO 2, or-(CR 1R 1) M1W 2
T 1For-NR 1W 3, heterocycle, or and U 1Or G 1Form group together with following structure:
Figure C20051008765900192
U 1For H or-X 1W 6And if be-X 1W 6, U then 1Be branched chain;
J 1With J 1aBe R independently 1, Br, Cl, F, I, CN, NO 2Or N 3
J 2With J 2aBe H or R independently 1
R 1Be H or C independently 1-C 12Alkyl;
R 2Be R independently 3Or R 4, each R wherein 4Use 0 to 3 R independently 3Group replaces;
R 3Be F independently, Cl, Br, I ,-CN, N 3,-NO 2,-OR 6a,-OR 1,-N (R 1) 2,-N (R 1) (R 6b) ,-N (R 6b) 2,-SR 1,-SR 6a,-S (O) R 1,-S (O) 2R 1,-S (O) OR 1,-S (O) OR 6a,-S (O) 2OR 1,-S (O) 2OR 6a,-C (O) OR 1,-C (O) R 6c,-C (O) OR 6a,-OC (O) R 1,-N (R 1) (C (O) R 1) ,-N (R 6b) (C (O) R 1) ,-N (R 1) (C (O) OR 1) ,-N (R 6b) (C (O) OR 1) ,-C (O) N (R 1) 2,-C (O) N (R 6b) (R 1) ,-C (O) N (R 6b) 2,-C (NR 1) (N (R 1) 2) ,-C (N (R 6b)) (N (R 1) 2) ,-C (N (R 1)) (N (R 1) (R 6b)) ,-C (N (R 6b)) (N (R 1) (R 6b)) ,-C (N (R 1)) (N (R 6b) 2) ,-C (N (R 6b)) (N (R 6b) 2) ,-N (R 1) C (N (R 1)) (N (R 1) 2) ,-N (R 1) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 1)) (N (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 6b) C (N (R 1)) (N (R 6b) 2) ,-N (R 1) C (N (R 6b)) (N (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 6b) 2) ,=O ,=S ,=N (R 1) or=N (R 6b);
R 4Be C independently 1-C 12Alkyl, C 2-C 12Alkenyl, or C 2-C 12Alkynyl;
R 5Be R independently 4, each R wherein 4Be 0 to 3 R 3Group replaces;
R 5aBe C independently 1-C 12Alkylidene group, C 2-C 12Alkylene group, or C 2-C 12Alkynylene, and this alkynylene is by 0 to 3 R 3Group replaces;
R 6aBe H or one-tenth ether or the group that becomes ester independently;
R 6bBe H independently, the residue of amino protecting group or carboxylated compound;
R 6cBe H or the residue that contains aminocompound independently;
W 1For containing the group of acidic hydrogen, the acidic-group of protection, or contain the R of acidic hydrogen group 6cAcid amides;
W 2For containing the alkaline heteroatomic group of alkaline heteroatoms or protection, or should the heteroatomic R of alkalescence 6bAcid amides;
W 3Be W 4Or W 5
W 4Be R 5Or-C (O) R 5,-C (O) W 5,-SO 2R 5Or-SO 2W 5
W 5Be carbocyclic ring or heterocycle, wherein W 5Be 0 to 3 R independently 2Group replaces;
W 6For-R 5,-W 5,-R 5aW 5,-C (O) OR 6a,-C (O) R 6c,-C (O) N (R 6b) 2,-C (NR 6b) (N (R 6b) 2) ,-C (S) N (R 6b) 2Or C (O) R 2
X 1Be a key ,-O-,-N (H)-,-N (W 6)-,-N (OH)-,-N (OW 6)-,-N (NH 2)-,-N (N (H) (W 6))-,-N (N (W 6) 2)-,-N (H) N (W 6)-,-S-,-SO-, or-SO 2-; With
Each m 1Be 0 to 2 integer independently;
With and salt, solvate, the enantiomorph of parsing and the diastereomer of purifying.
Another concrete example of the present invention relates to the compound of following formula:
Figure C20051008765900211
Wherein
E 1For-(CR 1R 1) M1W 1
G 1Be N 3,-CN ,-OH ,-OR 6a,-NO 2, or-(CR 1R 1) M1W 2
T 1For-NR 1W 3, heterocycle, or and U 1Or G 1Form group together with following structure:
U 1For H or-X 1W 6
J 1With J 1aBe R independently 1, Br, Cl, F, I, CN, NO 2Or N 3
J 2With J 2aBe H or R independently 1
R 1Be H or C independently 1-C 12Alkyl;
R 2Be R independently 3Or R 4, each R wherein 4Independently by 0 to 3 R 3Group replaces;
R 3Be F independently, Cl, Br, I ,-CN, N 3,-NO 2,-OR 6a,-OR 1,-N (R 1) 2,-N (R 1) (R 6b) ,-N (R 6b) 2,-SR 1,-SR 6a,-S (O) R 1,-S (O) 2R 1,-S (O) OR 1,-S (O) OR 6a,-S (O) 2OR 1,-S (O) 2OR 6a,-C (O) OR 1,-C (O) R 6c,-C (O) OR 6a,-OC (O) R 1,-N (R 1) (C (O) R 1) ,-N (R 6b) (C (O) R 1) ,-N (R 1) (C (O) OR 1) ,-N (R 6b) (C (O) OR 1) ,-C (O) N (R 1) 2,-C (O) N (R 6b) (R 1) ,-C (O) N (R 6b) 2,-C (NR 1) (N (R 1) 2) ,-C (N (R 6b)) (N (R 1) 2) ,-C (N (R 1)) (N (R 1) (R 6b)) ,-C (N (R 6b)) (N (R 1) (R 6b)) ,-C (N (R 1)) (N (R 6b) 2) ,-C (N (R 6b)) (N (R 6b) 2) ,-N (R 1) C (N (R 1)) (N (R 1) 2) ,-N (R 1) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 1)) (N (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 6b) C (N (R 1)) N (R 6b) 2) ,-N (R 1) C (N (R 6b)) (N (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 6b) 2) ,=O ,=S ,=N (R 1) or=N (R 6b);
R 4Be C independently 1-C 12Alkyl, C 2-C 12Alkenyl, or C 2-C 12Alkynyl;
R 5Be R independently 4, each R wherein 4Be 0 to 3 R 3Group replaces;
R 5aBe C independently 1-C 12Alkylidene group, C 2-C 12Alkylene group, or C 2-C 12Alkynylene, and this alkynylene is by 0 to 3 R 3Group replaces;
R 6aBe H or one-tenth ether or the group that becomes ester independently;
R 6bBe H independently, the residue of amino protecting group or carboxylated compound;
R 6cBe H or the residue that contains aminocompound independently;
W 1For containing the group of acidic hydrogen, the acidic-group of protection, or contain the R of acidic hydrogen group 6cAcid amides;
W 2For containing the alkaline heteroatomic group of alkaline heteroatoms or protection, or should the heteroatomic R of alkalescence 6bAcid amides;
W 3Be W 4Or W 5
W 4Be R 5Or-C (O) R 5,-C (O) W 5,-SO 2R 5Or-SO 2W 5
W 5Be carbocyclic ring or heterocycle, wherein W 5Be 0 to 3 R independently 2Group replaces;
W 6For-R 5,-W 5,-R 5aW 5,-C (O) OR 6a,-C (O) R 6c,-C (O) N (R 6b) 2,-C (NR 6b) (N (R 6b) 2) ,-C (S) N (R 6b) 2, or C (O) R 2
X 1For-O-,-N (H)-,-N (W 6)-,-N (OH)-,-N (OW 6)-,-N (NH 2)-,-N (N (H) (W 6))-,-N (N (W 6) 2)-,-N (H) N (W 6)-,-S-,-SO-, or-SO 2-; With
Each m 1Be 0 to 2 integer independently;
With and salt, solvate, the enantiomorph of parsing and the diastereomer of purifying.
Another concrete example of the present invention relates to the compound of following formula:
Figure C20051008765900231
Wherein
E 1For-CO 2R 1
G 1For-NH 2,-N (H) (R 5) or-N (H) (C (N (H)) (NH 2));
T 1For-N (H) (C (O) CH 3);
U 1For-OR 60
R 1For H or have 1,2,3,4,5,6,7,8, the alkyl of 9,10,11 or 12 carbon atoms; With
R 60For having 3,4,5,6,7,8,9,10, the branched-alkyl of 11 or 12 carbon atoms; With and salt, solvate, the enantiomorph of parsing and the diastereomer of purifying.
Another concrete example of the present invention relates to formula (VII) or (VIII) compound:
Wherein
E 1For-(CR 1R 1) M1W 1
G 1Be N 3,-CN ,-OH ,-OR 6a,-NO 2, or-(CR 1R 1) M1W 2
T 1For-NR 1W 3, heterocycle, or and G 1Form group together with following structure
Figure C20051008765900233
U 1For-X 1W 6
J 1With J 1aBe R independently 1, Br, Cl, F, I, CN, NO 2Or N 3
J 2With J 2aBe H or R independently 1
R 1Be H or C independently 1-C 12Alkyl;
R 2Be R independently 3Or R 4, each R wherein 4Be 0 to 3 R independently 3Group replaces;
R 3Be F independently, Cl, Br, I ,-CN, N 3,-NO 2,-OR 6a,-OR 1,-N (R 1) 2,-N (R 1) (R 6b) ,-N (R 6b) 2,-SR 1,-SR 6a,-S (O) R 1,-S (O) 2R 1,-S (O) OR 1,-S (O) OR 6a,-S (O) 2OR 1,-S (O) 2OR 6a,-C (O) OR 1,-C (O) R 6c,-C (O) OR 6a,-OC (O) R 1,-N (R 1) (C (O) R 1) ,-N (R 6b) (C (O) R 1) ,-N (R 1) (C (O) OR 1) ,-N (R 6b) (C (O) OR 1) ,-C (O) N (R 1) 2,-C (O) N (R 6b) (R 1) ,-C (O) N (R 6b) 2,-C (NR 1) (N (R 1) 2) ,-C (N (R 6b)) (N (R 1) 2) ,-C (N (R 1)) (N (R 1) (R 6b)) ,-C (N (R 6b)) (N (R 1) (R 6b)) ,-C (N (R 1)) (N (R 6b) 2) ,-C (N (R 6b)) (N (R 6b) 2) ,-N (R 1) C (N (R 1)) (N (R 1) 2) ,-N (R 1) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 1)) (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 6b) C (N (R 1)) (N (R 6b) 2) ,-N (R 1) C (N (R 6B)) (N (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 6b) 2) ,=O ,=S ,=N (R 1) or=N (R 6b);
R 4Be C independently 1-C 12Alkyl, C 2-C 12Alkenyl, or C 2-C 12Alkynyl;
R 5Be R independently 4, each R wherein 4Be 0 to 3 R 3Group replaces;
R 5aBe C independently 1-C 12Alkylidene group, C 2-C 12Alkylene group, or C 2-C 12Alkynylene, arbitrary alkylidene group, alkylene group or alkynylene are by 0 to 3 R 3Group replaces;
R 6aBe the blocking group of H or hydroxyl or sulfydryl (thio) independently;
R 6bBe H independently, the residue of amino protecting group or carboxylated compound;
R 6cBe H or the residue that contains aminocompound independently;
W 1For containing the group of acidic hydrogen, the acidic-group of protection, or contain the R of acidic hydrogen group 6cAcid amides;
W 2For containing the alkaline heteroatomic group of alkaline heteroatoms or protection, or should the heteroatomic R of alkalescence 6bAcid amides;
W 3Be W 4Or W 5
W 4Be R 5Or-C (O) R 5,-C (O) W 5,-SO 2R 5Or-SO 2W 5
W 5Be carbocyclic ring or heterocycle, wherein W 5Be 0 to 3 R independently 2Group replaces;
W 6For-R 5,-W 5,-R 5aW 5,-C (O) OR 6a,-C (O) R 6c,-C (O) N (R 6b) 2,-C (NR 6b) (N (R 6b) 2) ,-C (NR 6b) (N (H) (R 6b)) ,-C (N (H) (N (R 6b) 2) ,-C (S) N (R 6b) 2, or C (O) R 2
X 1Be a key ,-O-,-N (H)-,-N (W 6)-,-S-,-SO-, or-SO 2-; With
Each m 1Be 0 to 2 integer independently;
But condition is not comprise wherein U 1For H or-CH 2CH (OH) CH 2(OH) compound;
With and salt, solvate, the enantiomorph of parsing and the diastereomer of purifying.
Compound or the composition that comprises pharmaceutical acceptable carrier in addition is provided in another concrete example of the present invention.
In another concrete example of the present invention, comprise the activity that the method for step that may contain the sample of neuraminidase with The compounds of this invention or compositions-treated suppresses neuraminidase with one.
Another concrete example of the present invention provides and suppresses the active method of neuraminidase, and it comprises the step that allows the sample that may contain neuraminidase contact with the present composition.
Another concrete example of the present invention is treatment or a prophylaxis of viral infections in the host, the method that infects of influenza virus particularly, it comprises via the path of topical application to the respiratory tract and is applied to the WO 91/16320 that this host treats effective dose, WO 92/06691 or United States Patent (USP) 5360817 described antiviral activity compounds.
In other concrete examples, provide the novel synthesis method of The compounds of this invention.In this concrete example, the method for using compound 281 is provided, wherein this method comprises and uses formula R 5-X 1-H compound treatment compound 281 forms compound 281.1:
Figure C20051008765900251
Wherein
X 1With R 5As above definition;
R 51For protecting group is stablized in the acid of carboxylic acid;
R 54Be the aziridine activating group.
The method of using following formula: compound is provided in another concrete example
Figure C20051008765900261
Quinic acid
Wherein this method comprises using together with (geminal) dialkoxy alkane or together with dialkoxy naphthenic hydrocarbon and acid and handles quinic acid, to form following formula: compound:
Figure C20051008765900262
Handle compound 274 with metal alkoxide and alkanol,, form following formula: compound:
Figure C20051008765900263
Handle compound 275 with sulfonic acid halide and amine, form following formula: compound:
Figure C20051008765900264
Handle compound 276 with dewatering agent, then handle with acid and alkanol again, form following formula: compound:
Figure C20051008765900271
Wherein
R 50Be 1,2-glycerol protection base;
R 51For protecting group is stablized in the acid of carboxylic acid; With
R 52Be the hydroxyl activating group.
The simple declaration of accompanying drawing
Fig. 1 and Fig. 2 explanation are subjected to the arterial oxygen saturation (SaO of influenza-A mice infected 2); this mouse is through the following compounds treatment of various i.p. dosage: GG167 (4-guanidine radicals-2,4-dideoxy-2,3-dehydrogenation-N-acetyl neuraminic acid); it emits virus compound (Fig. 1) for known influenza; The compounds of this invention 203 (Fig. 2): each is with 50,10, and 2 and test compounds and the saline control group of 0.5mpk (mg/kg/ days); among the figure respectively with square; solid rim, trilateral, rhombus and open circle are represented.In all figure, compare with the saline control group, *P＜0.05, *P＜0.01.
Fig. 3-5 is the SaO in influenza A mice infected relatively 2Level, its each ribavirin (trilateral) through p.o. dosage, compound 203 (square) and GG167 (solid rim) treatment, the saline control group is an open circle.Fig. 3: compound 203 respectively is 150mpk with GG167, and ribavirin is 100mpk; Fig. 4: compound 203 respectively is 50mpk with GG167, and ribavirin is 32mpk; Fig. 5: compound 203 respectively is 10mpk with GG167, and ribavirin is 10mpk.
Fig. 6-8 explanation is subjected to the SaO of influenza-A mice infected 2Level, its each compound 262 (circle) through hanging down p.o. dosage is handled with GG167 (trilateral) with 260 (solid squares); The saline control group is an open circle, is square hollow and do not infect control group.Fig. 6: each test compounds is mpk; Fig. 7: each test compounds is 1mpk; Fig. 8: each test compounds is 0.1mpk.
Describe in detail
Invention forms
The compounds of this invention does not comprise hitherto known compound. But can find out as following other concrete examples, for antiviral purpose is only known before using as the known compound of antiviral compound intermediate also within the scope of the present invention. In the U.S., the compound of this paper or composition do not comprise compound or the 35USC ξ 103 apparent compounds that 35USC ξ 102 expects. Especially, claims of the application have been got rid of WO 91/16320, and WO 92/06691, United States Patent (USP) 5360817 or Chandler, M. wait people's J.Chem.Soc.Perkin Trans.1, that 1995,1189-1197 expects or do not have a compound of novelty.
But in the present invention's one concrete example, comprised at WO 91/16320, WO 92/ 06691, or the compound in the United States Patent (USP) 5360817 upperseat concept scopes, the formula Ia of ' 320 application that it has (a), (b) ' be used for the carbon of group " A " in 320 applications, and (c) R of ' 320 and ' 691 application5Be " CH2YR 6，-CHYR 6CH 2YR 6Or-CHYR6CHYR 6CH 2YR 6", YR wherein6Not can be the OH (wherein this protecting group hydrolyzable in human gi-tract produces free OH) of OH or protection, namely this compound in intestines and stomach to hydrolysis-stable. So the compound that concrete example is got rid of is R wherein5Be acetyl group or other C1-C 4The compound of carbonylic ' 320 or ' 691 application.
The method of measuring the stability of compound in substituting gastrointestinal secretion thing is known. So-calledly refer at the stable compound of intestines and stomach: cultivate after 1 hour in 37 ℃ of alternative intestinal juice or gastric juice, de-protected protecting group is less than about 50mol%. This compounds is suitable for use in the above-mentioned concrete example. Should notice that compound stable in intestines and stomach does not represent that it can not be hydrolyzed in vivo. Usually, prodrug (prodrug) is stable in digestive system, but at gastrovascular cavity, liver or other metabolism organs, or in general cell, can be hydrolyzed into female medicine (parental drug).
But should be understood that other concrete example imagination uses of the present invention WO 91/ 16320 that hereinafter describes in detail, the compound that WO 92/06691 or United States Patent (USP) 5360817 disclose comprises those its YR6For free hydroxyl group or by the hydroxyl of facile hydrolysis group (such as acetyl group) protection. Yet in this example, these compounds are used by novel method of administration.
In another concrete example, the compound of this paper is got rid of following compound, wherein:
(a)E 1For-CO2H，-P(O)(OH) 2，-NO 2，-SO 2H，-SO 3H, tetrazole radical ,-CH2CHO ,-CHO, or-CH (CHO)2；
(b)G 1For-CN, N3，-NHR 20，NR 20，-OR 20, guanidine radicals, SR20，-N (R 20)→O，-N(R 20)(OR 20)，-N(H)(R 20)N(R 20) 2, unsubstituted pyrimidine radicals, or unsubstituted (pyrimidine radicals) methyl;
(c)T 1For-NHR20，-NO 2 And R20Be H; C1-C 4Acyl group; C1-C 6Line style or cyclic alkyl, or the congener of its halogen replacement; Pi-allyl or unsubstituted aryl, or through halogen, OH group, NO2Group, NH2The aryl that group or COOH group replace;
(d) each J1Be H; With
(e)X 1Be a key ,-CH2-or-CH2CH 2-；
In this example, W6Be not H, W7Or-CH2W 7, W wherein7Be H ,-OR6a，-OR 1，-N(R 1) 2，-N(R 1)(R 6b)，-N(R 6b) 2，-SR 1, or-SR6a。
In another concrete example, The compounds of this invention is U wherein1Be not-CH2OH，- CH 2OAc or-CH2OCH 2Those of Ph.
In another concrete example, The compounds of this invention is E wherein1Be not-CH2OH，- CH 2OTMS, or-those of CHO.
In another concrete example, The compounds of this invention is U wherein1Not directly via the carbon atom bond to nuclear ring, or U1Do not replaced by hydroxyl or hydroxy ester, particularly U1Be not polyhydroxyalkanes, particularly-CH (OH) CH (OH) CH2Those of OH. In another concrete example, U1Be branched group R as described below5, or use at least one radicals R5The carbocyclic ring that replaces.
In another concrete example, the present invention gets rid of following formula: compound:
Figure C20051008765900291
Wherein:
1. in formula (V):
A 2For-O-or-CH2-；
E 1For-CO2H；
G 1For-N (H) (C (NH) (NH2))；
T 1For-N (H) is (Ac); With
U 1Have following formula:
2. in formula (V):
A 2For-O-or-CH2-；
E 1For-CO2H；
G 1For-NH2；
T 1For-N (H) is (Ac); With
U 1For-CH2OH；
3. in formula (V):
A 2For-CH2-；
E 1For-CH2OH or-CH2OTMS；
G 1For-N3；
T 1For-N (H) is (Ac); With
U 1For-CH2OCH 2Ph；
4. in formula (V):
A 2For-CH2-；
E 1For-CO2H or-CO2CH 3；
G 1For-N3；
T 1For-N (H) is (Ac); With
U 1For-CH2OH；
5. in formula (V):
A 2For-CH2-；
E 1For-CO2H ,-CHO, or-CH2OH；
G 1For-N3：
T 1For-N (H) is (Ac); With
U 1For-CH2OCH 2Ph；
6. in formula (VI):
A 2For-CH2-；
E 1For-CO2H；
G 1For-OCH3；
T 1For-NH2 With
U 1For-CH2OH; With
7. in formula (VI):
A 2For-CH2-；
E 1For-CO2H；
G 1For-OCH3；
T 1For-N (H) is (Ac); With
U 1For-CH2OAc。
When compound described herein by same group (for example, " R1" or " R6a") when repeatedly replacing, should understand this group can be identical or different, namely each group is independently selected.
" heterocycle " comprise in this article, as an example but and unrestricted, Paquette, Leo A.; " Principles of Modern Heterocyclic Chemistry " (W.A.Benjamin, New York, 1968), particularly the 1st, 3,4,6,7 and 9 chapters; " The Chemistry of Heterocyclic Compounds, A series of Monographs " (1950 so far for John Wiley ﹠ Sons, New York), particularly the 13rd, 14,16,19 and 28 volumes; And the described heterocycle of " J.Am.Chem.Soc., " 82:5566 (1960).
The example of heterocycle comprises, as an example but and unrestricted, pyridine radicals, thiazolyl; the tetrahydrochysene thiophenyl, thio-oxidizing tetrahydrochysene thiophenyl, pyrimidine radicals, furyl; thienyl, pyrrole radicals, pyrazolyl, imidazole radicals; tetrazole radical, benzofuranyl, thia naphthyl, indyl; indolinyl (in-dolenyl), quinolyl, isoquinolyl; benzimidazolyl, piperidyl, 4-piperidone base; pyrrolidinyl, 2-Pyrrolidone base, pyrrolinyl; tetrahydrofuran base, tetrahydric quinoline group, tetrahydro isoquinolyl; + hydrogen quinolyl, octahydro isoquinolyl, azocine base; triazine radical, 6H-1,2; 5-thiadiazine base, 2H, 6H-1; 5,2-dithiazine base, thienyl; thianthrene group, pyranose, isobenzofuran-base; benzopyranyl, xanthyl, phenoxathiin; the 2H-pyrrole radicals, isothiazolyl, different _ the azoles base; pyrazinyl, pyridazinyl, indolizine base; isoindolyl, 3H-indyl, 1H-indazolyl; purine radicals, 4H-quinolizine base, 2; the 3-phthalazinyl, 1,5-phthalazinyl; quinoxalinyl, quinazolyl, 1; the 2-phthalazinyl, pteridyl, 4aH-carbazyl; carbazyl, B-carboline base, phenanthridinyl; acridinyl, acridinyl, pyrimidine radicals; the phenanthroline base, phenazinyl, phenothiazinyl; the furazan base, fen _ piperazine base, isochroman base; dihydro pyranyl, imidazolidinyl, imidazolinyl; pyrazolidinyl, pyrazolinyl, piperazinyl; indolinyl, isoindolinyl, the peaceful cyclic group of quinoline; morpholinyl, _ oxazolidinyl, BTA base; benzisoxa _ azoles base, hydroxyindole base, benzo _ azoles quinoline base and isatin acyl group (isatinoyl).
As an example also unrestricted, carbon bond knot heterocycle bond is at 2,3,4,5 or 6 of pyridine, 3,4,5 of pyridazine, or 6,2 of pyrimidine, 4,5 or 6,2,3,5 or 6 of pyrazine, furans, oxolane, thio-furan, thiophene, 2 of pyrroles or nafoxidine, 3,4, or 5, azoles, 2 of imidazoles or thiazole, 4, or 5, different _ azoles, 3 of pyrazoles or isothiazole, 4 or 5,2 or 3 of aziridine, 2,3 or 4 of azetidine, 2,3,4,5 of quinoline, 6,7 or 8,1,3 of isoquinolin, 4,5,6,7 or 8. More particularly, carbon bond knot heterocycle comprises the 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, the 5-pyridine radicals, 6-pyridine radicals, 3-base, 4-pyridazinyl, the 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidine radicals, the 4-pyrimidine radicals, 5-pyrimidine radicals, 6-pyrimidine radicals, the 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.
As an example also unrestricted, nitrogen bond heterocycle bond is at aziridine, azetidine, pyrroles, pyrrolidines, 2-pyrrolin, 3-pyrrolin, imidazoles, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazoles, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidines, piperazine, indoles, indoline, 1 of 1H-indazole, benzazine or isodihydroazaindole 2,4 of morpholine, carbazole or B-carboline 9. Clearer and more definite nitrogen bond heterocycle comprises the 1-aziridine, 1-azetidinyl (azetedyl), 1-pyrrole radicals, 1-imidazole radicals, 1-pyrazolyl and 1-piperidyl.
Used in the literary composition " alkyl " unless otherwise, just referring to contain, the second month in a season, the C of uncle or ring carbon atom1-C 12Alkyl. Example has methyl (Me ,-CH3), ethyl (Et ,-CH2CH 3), 1-propyl group (n-Pr, n-pro-pyl ,-CH2CH 2CH 3), 2-propyl group (i-Pr, isopropyl ,-CH (CH3) 2), 1-butyl (n-Bu, normal-butyl ,-CH2CH 2CH 2CH 3), 2-methyl-1-propyl group (i-Bu, isobutyl group ,-CH2CH(CH 3) 2), 2-butyl (s-Bu, sec-butyl ,-CH (CH3)CH 2CH 3), 2-methyl-2-propyl (t-Bu, the tert-butyl group ,-C (CH3) 3), 1-amyl group (n-pentyl ,-CH2CH 2CH 2CH 2CH 3), 2-amyl group (CH (CH3)CH 2CH 2CH 3), 3-amyl group (CH (CH2CH 3) 2), 2-methyl-2-butyl (C (CH3) 2CH 2CH 3), 3-methyl-2-butyl (CH (CH3)CH (CH 3) 2), 3-methyl isophthalic acid-butyl (CH2CH 2CH(CH 3) 2), 2-methyl isophthalic acid-butyl (CH2CH(CH 3)CH 2CH 3), 1-hexyl (CH2CH 2CH 2CH 2CH 2CH 3), 2-hexyl (CH (CHx) CH2CH 2CH 2CH 3), 3-hexyl (CH (CH2CH 3)(CH 2CH 2CH 3), 2-methyl-2-amyl group (C (CH3) 2CH 2CH 2CH 3), 3-methyl-2-amyl group (CH (CH3)CH(CH 3) CH 2CH 3), 4-methyl-2-amyl group (CH (CH3)CH 2CH(CH 3) 2), 3-methyl-3-amyl group (C (CH3)(CH 2CH 3) 2), 2-methyl-3-amyl group (CH (CH2CH 3)CH(CH 3) 2), 2,3-dimethyl-2-butyl (C (CH3) 2CH (CH 3) 2), 3,3-dimethyl-2-butyl (CH (CH3)C(CH 3) 3). The group 2-5 of the example of alkyl such as table 2,7,9 and 100-399.
The present composition comprises the compound of one of following formula:
Figure C20051008765900331
In typical concrete example, selecting type I compound.
J 1With J1aBe R independently1，Br，Cl，F，I，CN，NO 2Or N3, typically be R1Or F, more typically be H or F, more preferably H.
J 2With J2aBe H or R independently1, typically be H.
A 1For-C (J1)=, or-N=, typically be-C (J1)=, more typically is-CH=.
A 2For-C (J1) 2-，-N(J 1)-，-N(O)(J 1)-，-N(O)＝，- S-，-S(O)-，-S(O) 2-or-O-, typically be-C (J1) 2-，-N (J 1)-,-S-or-O-, more typically be-C (J1) 2-, or-O-, more typically be-CH2-or-O-, more typically be-CH2-。
E 1For-(CR1R 1) m1W 1。
Typically, R1Be H or C1-C 12Alkyl is generally H or C1-C 4Or C5-C 10Alkyl is more typically for H or have the alkyl of 1,2,3,4,5,6,7,8,9,10,11 or 12 carbon atoms, more typically for H or be selected from methyl, ethyl, the C of n-pro-pyl and isopropyl1-C 6Alkyl. The most typical R1Be H.
M1 is 0 to 2 integer, typically is 0 or 1, more typically is 0.
M2 is 0 to 1 integer.
M3 is 1 to 3 integer.
W 1For containing the group of acidic hydrogen, the acidic-group of protection, or contain the R of acidic hydrogen group6cAcid amides, it refers to have the hydrogen atom that can be removed by alkali and produces the group of anion or corresponding salt or solvate in this article. Acid or the alkaline General Principle of organic substance is known, and defines W with this1, no longer describe in detail herein. Yet can be with reference to Streitwieser, A. and Heathcock, C.H.; Introduction to Organic Chemistry, Secocnd Edition " (Macmillan, New York, 1981), the 60-64 page or leaf. Usually, the pk value that acidic groups of the present invention has is littler than water, and is usually less than pk=10, better is lower than pk=8, is preferably lower than PK=6. They comprise tetrazolium and carbon, sulphur, and the acid of phosphorus and nitrogen typically is carboxylic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid and phosphonic acids, and the R of these acids6cAcid amides and R6bEster (R6aWith R6cAs give a definition). W1Example have-CO2H，-CO 2R 6a，- OSO 3H，-SO 3H，-SO 2H，-OPO 3H 2，-PO 3(R 6a) 2，-PO 3H 2，- PO 3(H)(R 6a) and-OPO3(R 6a) 2，W 1Typically be E1，E 1Typically be-CO2H，-CO 2R 6a，-CO 2R 4Or CO2R 1, typically be CO most2R 14, R wherein14For just or terminal secondary C1-C 6Alkyl.
W 1Also can be the acidic-group of protection, it refers to be used in one of the group that is usually used in the art protecting acidic-group protection and below will be at R in this article6aThe above-mentioned acidic-group of lower explanation. More typically, the W of protection1For-CO2R 1，-SO 3R 1，-S(O) OR 1，-P(O)(OR 1) 2，-C(O)NHSO 2R 4, or-SO2NHC(O)-R 4, R wherein1As above definition.
More typically, E1Be selected from-C (O) O (CH2) bCH((CH 2) cCH 3) 2, wherein b=0 to 4, c=0 to 4, and b+c=1 to 4, or be selected from following groups:
Figure C20051008765900351
Group E1Example be listed in the table 3a to 3b in.
G 1Be N3，-CN，-OH，OR 6a，-NO 2Or-(CR1R 1) m1W 2, R wherein1As above define with m1. Common G1For-(CR1R 1) m1W 2。
W 2For containing the alkaline heteroatomic group of alkaline hetero atom or protection, or should the heteroatomic R of alkalescence6bAcid amides. W2Usually comprise alkaline hetero atom, it refers in this article not for carbon and can (be had above-mentioned W by acidic hydrogen1Acid range) protonated atom. The basic principle of alkalescence and makes alkaline hetero atom one word have the meaning of the art those of ordinary skill understanding as described in Streitwieser and the Heathcock (as above citation). Usually, the used alkaline heteroatomic corresponding protonated form of The compounds of this invention has above-mentioned W1The pK value of scope. The alkalescence hetero atom includes hetero atom common in the organic compounds, and it does not have shares, bond not, the duplet of n-type etc. And unrestricted, typical alkaline hetero atom comprises alcohol as an example, amine, and amidine, guanidine, the oxygen of sulfide etc., nitrogen and sulphur atom are generally amine, amidine and guanidine. Common W2Be amino or aminoalkyl (normally low alkyl), for example, aminomethyl, aminoethyl or aminopropyl; Amidino groups or amidino groups alkyl, such as the amidino groups methyl, amidino groups ethyl or amidino groups propyl group; Or guanidine radicals or guanidine alkyl, such as the guanidine methyl, guanidine ethyl or guanidine propyl group (in each example, alkyl is used for this alkali subtituent is bridged to carbocyclic ring). More typically, W2Be amino, amidino groups, guanidine radicals, heterocycle, the heterocycle that replaces through 1 or 2 amino or guanidine radicals (normally 1), or the C that replaces through amino or guanidine radicals2- C 3Alkyl, or through the C of amino with second the group replacement that is selected from hydroxyl and amino2-C 3Alkyl. Can be used as W2Heterocycle typically comprise 5 or 6 yuan of rings that contain N or S, wherein the ring on contain 1 or 2 hetero atom. This type of heterocycle is substituted at ring carbon atom usually. It can be saturated or unsaturated and can via low alkyl (m1=1 or 2) or-NR1-bond is to the core cyclohexene. More typically, W2For-NHR1，-C(NH)(NH 2)，-NR 1-C (NR 1)(NR 1R 3)，-NH-C(NH)(NHR 3)，-NH-C(NH) (NHR 1)，-NH-C(NH)NH 2，-CH(CH 2NHR 1)(CH 2OH)，-CH (CH 2NHR 1)(CH 2NHR 1)，-CH(NHR 1)-(CR 1R 1) m2-CH(NHR 1) R 1，-CH(OH)-(CR 1R 1) m2-CH(NHR 1)R 1, or-CH (NHR1)- (CR 1R 1) m2-CH(OH)R 1，-(CR 1R 1) m2-S-C(NH)NH 2，-N＝C (NHR 1)(R 3)，-N＝C(SR 1)N(R 1) 2，-N(R 1)C(NH)N(R 1) C=N, or-N=C (NHR1)(R 1); Wherein each m2 is generally 0, usually R1Be H, R3Be C (O) N (R1) 2。
W 2Can be arbitrarily the alkaline hetero atom of protection, it refers to use R in this article6bAbove-mentioned alkaline hetero atom such as the protection of one of this area group commonly used. This type of group is specified in (this paper quotes from) among the Greene. But also unrestricted, this type of group comprises acid amides, carbamate, amido-acetal, imines as an example; enamine, N-alkyl or N-aryl oxide phosphino-, N-alkyl or N-aryl sulfonyl kia or sulfonyl, N-alkyl or N-aryl silicyl; thioether, thioesters, disulphide, sulfinyl etc. In some concrete example, R6bProtecting group can disconnect under physiological condition, and typically it disconnects in vivo, wherein, and for example should the alkalescence hetero atom and organic acid or amino acid such as naturally occurring amino acid or R hereinafter6aDescribed in polypeptide form acid amides.
Typically, G1Be selected from following:
Figure C20051008765900371
G 1Other example is listed in the table 4.
T 1For-NR1W 3Or heterocycle, or and U1Or G1Form together the group with following structure:
Figure C20051008765900381
R wherein6bAs give a definition R1With W1As above definition. Common T1Be selected from following:
Figure C20051008765900382
T 1Example list in the table 5.
W 3Be W4Or W5, W wherein4Be R1Or-C (O) R5，-C(O)W 5，- SO 2R 5Or-SO2W 5。W 3Typically be-C (O) R5Or W5。
R 2Be independently as undefined R3Or R4, condition is each R4Independently by 0 to 3 R3Group replaces;
R 3Be F independently, Cl, Br, I ,-CN, N3，-NO 2，-OR 6a，-OR 1，- N(R 1) 2，-N(R 1)(R 6b)，-N(R 6b) 2，-SR 1，-SR 6a，-S(O)R 1，-S (O) 2R 1，-S(O)OR 1，-S(O)OR 6a，-S(O) 2OR 1，-S(O) 2OR 6a，-C (O)OR 1，-C(O)R 6c，-C(O)OR 6a，-OC(O)R 1，-N(R 1)(C(O) R 1)，-N(R 6b)(C(O)R 1)，-N(R 1)(C(O)OR 1)，-N(R 6b)(C(O) OR 1)，-C(O)N(R 1) 2，-C(O)N(R 6b)(R 1)，-C(O)N(R 6b) 2，-C (NR 1)(N(R 1) 2)，-C(N(R 6b))(N(R 1) 2)，-C(N(R 1))(N(R 1) (R 6b))，-C(N(R 6b))(N(R 1)(R 6b))，-C(N(R 1))(N(R 6b) 2)，-C (N(R 6b))(N(R 6b) 2)，-N(R 1)C(N(R 1))(N(R 1) 2)，-N(R 1)C(N (R 1))(N(R 1)(R 6b))，-N(R 1)C(N(R 6b))(N(R 1) 2)，-N(R 6b)C(N (R 1))(N(R 1) 2)，-N(R 6b)C(N(R 6b))(N(R 1) 2)，-N(R 6b)C(N (R 1))(N(R 1)(R 6b))，-N(R 1)C(N(R 6b))(N(R 1)(R 6b))，-N(R 1)C (N(R 1))(N(R 6b) 2)，-N(R 6b)C(N(R 6b))(N(R 1)(R 6b))，-N(R 6b) C(N(R 1))(N(R 6b) 2)，-N(R 1)C(N(R 6b))(N(R 6b) 2)，-N(R 6b)C(N (R 6b))(N(R 6b) 2)，＝O，＝S，＝N(R 1) or=N (R6b)。R 3Be typically F, Cl ,-CN, N3，NO 2，-OR 6a，-OR 1，-N(R 1) 2，-N(R 1)(R 6b)，-N (R 6b) 2，-SR 1，-SR 6a，-C(O)OR 1，-C(O)R 6c，-C(O)OR 6a，-OC (O)R 1，-NR 1C(O)R 1，-N(R 6b)C(O)R 1，-C(O)N(R 1) 2，-C(O) N(R 6b)(R 1)，-C(O)N(R 6b) 2Or=O. More typically, comprise R6bRadicals R3Comprise-C (O) N (R6b) 2，-C(O)N(R 6b)(R 1)，-C(S)N(R 6b) 2, or-C (S) N (R6b)(R 1). More typically, R3Be F, Cl ,-CN, N3，-OR 1，-N (R 1) 2，-SR 1，-C(O)OR 1，-OC(O)R 1, or=O. More typically, R3Be F ,-OR1，-N(R 1) 2Or=O. In this application, "=O " expression is with the oxygen atom (oxo) of two key bonds, "=S ", "=N (R6b) " and "=N (R1) " expression sulphur and nitrogen analog.
R 4Be C1-C 12Alkyl, C2-C 12Alkynyl or C2-C 12Alkenyl. Typically, alkyl R4Have 1,2,3,4,5,6,7,8,9,10,11 or 12 carbon atoms, alkenyl and alkynyl R4Have 2,3,4,5,6,7,8,9,10,11 or 12 carbon atoms. R4Be generally alkyl (as above definition). Work as R4During for alkenyl, be generally vinyl (CH=CH2), 1-third-1-thiazolinyl (CH=CHCH3), 1-third-2-thiazolinyl (CH2CH＝CH 2), 2-third-1-thiazolinyl (C (=CH2)(CH 3)), 1-but-1-ene base (CH=CHCH2CH 3), 1-but-2-ene base (CH2CH＝CHCH 3), 1-fourth-3-thiazolinyl (CH2CH 2CH＝CH 2), 2-methyl isophthalic acid-third-1-thiazolinyl (CH=C (CH3) 2), 2-methyl isophthalic acid-third-2-thiazolinyl (CH2C(＝CH 2)(CH 3)), 2-but-1-ene base (C (=CH2)CH 2CH 3), 2-but-2-ene base (C (CH3)＝ CHCH 3), 2-fourth-3-thiazolinyl (CH (CH3)CH＝CH 2), 1-penta-1-thiazolinyl (CH=CHCH2CH 2CH 3), 1-penta-2-thiazolinyl (CHCH=CHCH2CH 3), 1-penta-3-thiazolinyl (CHCH2CH＝CHCH 3), 1-penta-4-thiazolinyl (CHCH2CH 2CH＝CH 2), 2-penta-1-thiazolinyl (C (=CH2) CH 2CH 2CH 3), 2-penta-2-thiazolinyl (C (CH3)＝CH 2CH 2CH 3), 2-penta-3-thiazolinyl (CH (CH3)CH＝CHCH 3), 2-penta-4-thiazolinyl (CH (CH3) CH 2CH＝CH 2) or 3-methyl isophthalic acid-but-2-ene base (CH2CH＝C (CH 3) 2). More typically, R4Alkenyl has 2,3 or 4 carbon atoms. Work as R4During for alkynyl, typically be acetenyl (CCH), 1-third-1-alkynyl (CCCH3), 1-Propargyl (CH2CCH), 1-fourth-1-alkynyl (CCCH2CH 3), 1-fourth-2-alkynyl (CH2CCCH 3), 1-fourth-3-alkynyl (CH2CH 2CCH), 2-fourth-3-alkynyl (CH (CH3) CCH), 1-penta-1-alkynyl (CCCH2CH 2CH 3), 1-penta-2-alkynyl (CH2CCCH 2CH 3), 1-penta-3-alkynyl (CH2CH 2CCCH 3) or 1-penta-4-alkynyl (CH2CH 2CH 2CCH). More typically, R4Alkynyl has 2,3 or 4 carbon atoms.
R 5Be R4(as above definition), or through 0 to 3 R3The R that group replaces4 Typically, R5Be the C that replaces through 0 to 3 fluorine atom1-C 4Alkyl.
R 5aBe C1-C 12Alkylidene, C2-C 12Alkylene group, or through 0 to 3 R3The C that group replaces2-C 12Alkynylene. Such as R4In define R5aFor having 1,2,3,4,5,6,7,8, the alkylidene of 9,10,11 or 12 carbon atoms; Have 2,3,4,5,6,7,8,9, the alkylene group of 10,11 or 12 carbon atoms or alkynylene. Each typical R4Group is typical R5aGroup, condition are described R4Hydrogen atom is removed and forms the open valency (open valence) of carbon atom in the group, by second key of this carbon atom and R5aLink to each other.
R 10For through 0 to 3 R2The C that replaces1-C 12Alkyl, alkenyl, alkynyl.
R 11Be H or R independently10。
R 12Be C3-C 10Cycloalkyl, or C4-C 10Cycloalkenyl group.
R 14For just or terminal secondary C1-C 6Alkyl.
W 5Be carbocyclic ring or heterocycle, condition is each W5Independently through 0 to 3 R2Group replaces. W5Carbocyclic ring and T1And W5Heterocycle is stable chemical constitution. These structures can be separated with the productive rate that can measure from-78 ℃ to 200 ℃ reactant mixture, and have measurable purity. Each W5Independently by 0 to 3 R2Group replaces. Typically, T1With W5Saturated for the carbocyclic ring that contains monocycle or dicyclo or heterocycle, unsaturated or aromatic ring. More typically, T1Or W5Have 3 to 10 annular atomses, more typically, 3 to 7 annular atomses, and 3 to 6 annular atomses normally. T1With W5Ring be saturated when containing 3 annular atomses; Be saturated or monounsaturated when containing 4 annular atomses; Be saturated when containing 5 annular atomses, cholesterol or two undersaturated; Be saturated, monounsaturated when containing 6 annular atomses, two is undersaturated, or be aromatics.
Work as W5During for carbocyclic ring, typically be the monocycle of 3 to 7 carbon or two rings of 7 to 12 carbon. More typically, W5The monocycle carbocyclic ring has 3 to 6 annular atomses, more preferably 5 or 6 annular atomses. W5Two ring carbocyclic rings have 7 to 12 annular atomses, and they line up two rings (4,5), and (5,5), (5,6) or (6,6) system is more typically for lining up 9 or 10 annular atomses of two ring (5,6) or (6,6) systems. Example comprises cyclopropyl, cyclobutyl, cyclopenta, 1-ring penta-1-thiazolinyl, 1-ring penta-2-thiazolinyl, 1-ring penta-3-thiazolinyl, cyclohexyl, 1-hexamethylene-1-thiazolinyl, 1-hexamethylene-2-thiazolinyl, 1-hexamethylene-3-thiazolinyl, phenyl, spiryl and naphthyl.
T 1Or W5Heterocycle typically is and has 3 to 7 ring memberses the monocycle of (2 to 6 carbon atom and 1 to 3 be selected from N, O, P, the hetero atom of S), or has two rings of 7 to 10 ring memberses (4 to 9 carbon atom and 1 to 3 be selected from N, O, P, the hetero atom of S). More typically, T1With W5The heterocycle monocycle has 3 to 6 annular atomses (2 to 5 carbon atom and 1 to 2 be selected from N, O, the hetero atom of S), more typically 5 or 6 annular atomses (3 to 5 carbon atoms and 1 to 2 hetero atom that is selected from N and S). T1With W5Heterocycle two ring has 7 to 10 annular atomses (6 to 9 carbon atom and 1 to 2 be selected from N, O, the hetero atom of S), they line up two rings (4,5), (5,5), (5,6) or (6,6) system, 9 to 10 annular atomses (8 to 9 carbon atoms and 1 to 2 hetero atom that is selected from N and S) more typically, they line up two ring (5,6) or (6,6) systems.
Typically, T1With W5Heterocycle is selected from: pyridine radicals, and pyridazinyl, pyrimidine radicals, pyrazinyl, cyanuro, _ azoles base, imidazole radicals, thiazolyl, different _ the azoles base, pyrazolyl, isothiazolyl, furyl, thio-furan base, thienyl or pyrrole radicals.
More typically, T1With W5Heterocycle comes bond via its carbon atom or nitrogen-atoms. More typically, T1Heterocycle by its nitrogen-atoms with stable covalent bonds to the cyclohexene ring of The compounds of this invention, W5Heterocycle by its carbon or nitrogen-atoms with stable covalent bonds to the cyclohexene ring of The compounds of this invention. Stable covalent bond refers to above-mentioned chemically stable structure.
W 5Be selected from arbitrarily following:
Figure C20051008765900411
Figure C20051008765900421
U 1For H or-X1W 6, but typically be the latter.
X 1Be a key ,-CR5R 5-，-(CR 5R 5) 2-，-O-，-N(H)，-N (W 6)-，-N(OH)-，-N(OW 6)-，-N(NH 2)，-N(N(H) (W 6))-，-N(N(W 6) 2)-，-N(H)N(W 6)-,-S-,-SO-, or-SO2-; Typically, X1Be a key ,-CR5R 5-，-(CR 5R 5) 2-，-O-，- N(H)-，-N(R 5)-，-N(OH)-，-N(OR 5)-，-N(NH 2)-，- N(N(H)(R 5))-，-N(N(R 5) 2)-，-N(H)N(R 5)-,-S-,-SO-, or-SO2-, X more typically1Be a key ,-CR1R 1-，- (CR 1R 1) 2-，-O-，-NR 1-，-N(OR 1)-，-N(NR 1R 1)-,-S-,-SO-, or-SO2-. Common X1For-O-,-NH-,-S-,-SO-, or-SO2-；
W 6For-R5，-W 5，-R 5aW 5，-C(O)OR 6a，-C(O)R 6c，-C(O) N(R 6b) 2，-C(NR 6b)(N(R 6b) 2)，-C(NR 6b)(N(H)(R 6b))，-C(N (H)(N(R 6b) 2)，-C(S)N(R 6b) 2, or-C (O) R2, typically be-R5，- W 5, or-R5aW 5 In some concrete example, W6Be R1，-C(O)-R 1，- CHR 1W 7，-CH(R 1) aW 7，-CH(W 7) 2, (wherein a is 0 or 1, but works as W7Then be 0 during for divalence) or-C (O) W7 In some concrete example, W6For-CHR1W 7Or-C (O) W7, or W6For-(CH2) m1CH((CH 2) m3R 3) 2，-(CH 2) m1C ((CH 2) m3R 3) 3；-(CH 2) m1CH((CH 2) m3R 5aW 5) 2；-(CH 2) m1CH ((CH 2) m3R 3)((CH 2) m3R 5aW 5)；-(CH 2) m1C((CH 2) m3R 3) 2(CH 2) m3 R 5aW 5)，(CH 2) m1C((CH 2) m3R 5aW 5) 3Or-(CH2) m1C((CH 2) m3R 3) ((CH 2) m3R 5aW 5) 2 Wherein m3 is 1 to 3 integer.
W 7Be R3Or R5, but typically be through 0 to 3 R3The C that group replaces1-C 12Alkyl, R3Typically be selected from-NR1(R 6b)，-N(R 6b) 2，-OR 6a, or SR6a More typically, W7For-OR1, or through OR1The C that replaces3-C 12Alkyl.
Usually, U1Be R1O-，-OCHR 1W 7，
Figure C20051008765900431
U 1The example of group is listed in the table 2.
The present invention's one concrete example comprises following formula: compound:
Figure C20051008765900432
E wherein2Be E1, but typically be selected from:
Figure C20051008765900433
G wherein2Be G1, but typically be selected from:
Figure C20051008765900434
T wherein2Be R4Or R5 Common T2Be the C that replaces through 0 to 3 fluorine atom1- C 2Alkyl.
U 2For one of following:
Figure C20051008765900441
R wherein7Be H ,-CH3，-CH 2CH 3，-CH 2CH 2CH 3，-OCH 3，- OAc(-O-C(O)CH 3)，-OH，-NH 2, or-SH, typically be H ,-CH3Or-CH2CH 3。
Radicals R6aWith R6bBe not important functional group, so can change widely. When being not H, its function is the intermediate as female medicine, but this does not represent that it does not have biologically active. On the contrary, the major function of these groups is for to change into prodrug with female medicine, and this prodrug is transformed in vivo and disengages this mother's medicine. Because the more female medicine of active prodrug easily is absorbed, so in fact, in vivo, the more female medicine of the usefulness of prodrug is high. R6aWith R6bCan in external (in the example at chemical intermediate) or body, (in the example at prodrug) remove. When as chemical intermediate, sense (pro-functionality) product before the gained, for example, whether alcohol is that physiology can be accepted not particular importance, although normally better with the harmless person of pharmacy.
R 6aGroup for H or one-tenth ether or one-tenth ester. " group of one-tenth ether " refers to form the group of stable covalent bond between parent molecule and following formula group:
Figure C20051008765900442
V whereinaBe tetrad, usually be selected from C and Si; VbBe triad, usually be selected from B, Al, N and P, more preferably N and P; VcBe bivalent, usually be selected from O, S and Se, more preferably S; V1For to stablize the covalent single bond bond to Va，V bOr VcGroup, better V1Be W6Group, H more preferably, R2，W 5Or-R5aW 5, be preferably H or R2；V 2For to stablize the double covalent bonds bond to VaOr VbGroup, condition is V2Not can be=O ,=S or=N-, V2Be preferably=C (V1) 2, V wherein1As mentioned above; V3For to stablize covalency triple bond bond to VaGroup, better V3Be ≡ C (V1), V wherein1As mentioned above.
" group of one-tenth ester " refers to form the group of stable covalent bond between parent molecule and following formula group:
Figure C20051008765900452
V whereina，V bWith V1As mentioned above; VdBe pentavalent atom, better be selected from P and N; VeBe hexad, be preferably S; V4For to stablize the double covalent bonds bond to Va，V b，V dOr VeGroup, condition are at least one V4Be=O ,=S or=N-V1, when not being=O ,=S or=during N-, be preferably=C (V1) 2, V wherein1As mentioned above.
The protecting group of-OH official energy (no matter be hydroxyl, acid or other senses) is the object lesson of " group that becomes ether or one-tenth ester ".
Become in the group of ether or one-tenth ester, special good person is can be as protecting group person in synthetic reaction scheme described herein. Yet to understand as the one skilled in the art, some hydroxyl is not into ether with sulfhydryl protected base or becomes the group of ester, and is included in following R6cAcid amides in. R6cCan protect hydroxyl or sulfydryl, thereby make the parent molecule hydrolysis generate hydroxyl or sulfydryl.
Play into ester and do the time spent, typically, R6aBond to any acidic-group (for example, as an example and unrestricted ,-CO2H or-C (S) OH group, thereby formation-CO2R 6a For example, R6aCan derive the many ester groups from WO 95/07920.
R 6aExample comprise:
C 3-C 12Heterocycle (as above-mentioned) or aryl. These aryl arbitrariness ground are many rings or monocycle. Example has phenyl, spiryl, 2-and 3-pyrrole radicals, 2-and 3-thienyl, 2-and 4-imidazole radicals, 2-, 4-and 5-_ azoles base, 3-and 4-be different _ the azoles base, and 2-, 4-and 5-thiazolyl, 3-, 4-and 5-isothiazolyl, 3-and 4-pyrazolyl, 1-, 2-, 3-and 4-pyridine radicals, and 1-, 2-, 4-and 5-pyrimidine radicals.
C through the following groups replacement3-C 12Heterocycle or aryl: halogen, R1，R 1-O-C 1- C 12Alkylidene, C1-C 12Alkoxyl, CN, NO2, OH, carboxyl, carboxyl ester, mercaptan, thioesters, C1-C 12Haloalkyl (1-6 halogen atom), C2-C 12Alkenyl or C2-C 12Alkynyl. This type of group comprises 2-, 3-and 4-alkoxyphenyl radical (C1-C 12Alkyl), 2-, 3-and 4-anisyl, 2-, 3-and 4-ethoxyphenyl, 2; 3-, 2,4-, 2,5-, 2; 6-, 3,4-and 3,5-diethoxy phenyl, 2-and 3-carbethoxyl group-4-hydroxyphenyl, 2-and 3-ethyoxyl-4-hydroxyphenyl; 2-, 3-and 4-O-acetylphenyl, 2-, 3-and 4-dimethylamino phenyl, 2-, 3-and 4-methyl mercapto phenyl; 2-, 3-and 4-halogenophenyl (comprising 2-, 3-and 4-fluorophenyl and 2-, 3-and 4-chlorphenyl), 2; 3-, 2,4-, 2,5-, 2; 6-, 3,4-and 3,5-xylyl, 2,3-; 2,4-, 2,5-, 2,6-; 3,4-and 3,5-, two carboxyethyl phenyls, 2,3-; 2,4-, 2,5-, 2; 6-, 3,4-and 3,5-dimethoxy phenyl, 2; 3-, 2,4-, 2,5-; 2,6-, 3,4-and 3,5-dihalogenated phenyl (comprise 2; 4-difluorophenyl and 3,5-difluorophenyl), 2-, 3-and 4-haloalkyl phenyl (1 to 5 halogen atom, C1-C 12Alkyl comprises the 4-trifluoromethyl), 2-, 3-and 4-cyano-phenyl, 2-, 3-and 4-nitrobenzophenone, 2-, 3-and 4-haloalkyl benzyl (1 to 5 halogen atom, C1-C 12Alkyl comprises 4-trifluoromethyl benzyl and 2-, 3-and 4-trichloromethyl phenyl and 2-, 3-and 4-trichloromethyl phenyl), 4-N-methyl piperidine base, 3-N-methyl-piperidyl, 1-ethyl piperazidine base, benzyl, alkylated salicylamide base phenyl (C1-C 4Alkyl comprises 2-, 3-and 4-ethyl salicyl phenyl), 2-, 3-and 4-acetylphenyl, 1,8-dihydroxy naphthyl (C10H 6-OH) with fragrant oxygen ethyl (C6-C 6Aryl (comprising benzene oxygen ethyl)), 2,2 '-the dihydroxy xenyl, 2-, 3-and 4-N, N-dialkylamino phenol ,-C6H 4- CH 2-N(CH 3) 2, trimethoxy benzyl, three ethoxy benzyls, 2-Alkylpyridyl (C1-C 4Alkyl);
Figure C20051008765900461
The C of 2-carboxyl phenyl4-C 8Ester; And C1-C 4Alkylidene-C3-C 6Aryl (comprises benzyl ,-CH2-pyrrole radicals ,-CH2-thienyl ,-CH2-imidazole radicals ,-CH2-_ azoles base ,-CH2-different _ azoles base ,-CH2-thiazolyl ,-CH2-isothiazolyl ,-CH2-pyrazolyl ,-CH2-pyridine radicals and-CH2-pyrimidine radicals), its aryl moiety is selected from following atom by 3 to 5 halogen atoms or 1 to 2 or group replaces: halogen, C1-C 12Alkoxyl (comprising methoxyl group and ethyoxyl), cyano group, nitro, OH, C1-C 12Haloalkyl (1 to 6 halogen atom; Comprise-CH2，CC l3)，C 1-C 12Alkyl (comprising methyl and ethyl), C2-C 12Alkenyl or C2-C 12Alkynyl;
Alkoxyl oxygen alkyl ethyl (C1-C 6Alkyl comprises-CH2-CH 2-O-CH 3(methoxyethyl));
Substituting group (particularly OH) or 1 to 3 alkyl (CH that halogen atom replaces through above-mentioned aryl3，-CH(CH 3) 2，-C(CH 3) 3，-CH 2CH 3，- (CH 2) 2CH 3，-(CH 2) 3CH 3，-(CH 2) 4CH 3，-(CH 2) 5CH 3，- CH 2CH 2F，-CH 2CH 2Cl，-CH 2CF 3, and-CH2CCl 3)；
Figure C20051008765900471
-N-2-propyl group morpholinyl, 2,3-dihydro-6-hydroxyl indenes, sesamol, catechol monoesters ,-CH2-C(O)-N(R 1) 2，-CH 2-S(O)(R 1)，-CH 2-S(O) 2 (R 1)，-CH 2-CH(OC(O)CH 2R 1)-CH 2(OC(O)CH 2R 1), cholesteryl, enol pyruvate (HOOC-C (=CH2)-), glycerine;
The monose of 5 or 6 carbon, disaccharide or oligosaccharides (3 to 9 monosaccharide residues);
Triglycerides, as via the glyceryl oxygen atom bond of this triglycerides to this paper parent compound acyl group α-(aliphatic acid that wherein consists of lipid glyceride is generally naturally occurring saturated or unsaturated C to the D-3-diglyceride6-26，C 6-18Or C6-10Aliphatic acid, linoleic acid for example, laurate, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic acid, the aliphatic acid such as leukotrienes);
Phosphatide, via the phosphate bond of this phosphatide to carboxyl;
Phthalidyl (people such as Clayton, Antimicrob.Agents Chemo.5 (6): 670-671[1974] shown in Figure 1);
Cyclic carbonate, such as (5-Rd-2-oxo-1,3-dioxole-4-yl) methyl esters (people such as Sakamoto, Chem.Pharm.Bull.32 (6) 2241-2248 [1984]), wherein Rd is R1，R 4Or aryl; And
Figure C20051008765900472
The hydroxyl of The compounds of this invention is arbitrarily through WO 94/21604 disclosed group III, one of IV or V, or isopropyl replaces.
As another concrete example, Table A is listed R6aEster example partly, its can via the oxygen bond to as-C (O) O-with-P (O) (O-)2Group. Also list in addition several R6cAmidate, its direct bond to-C (O)-or-P (O)2 Structure 1 to 5,8 to 10 and 16,17, the compound and corresponding halide (chloride or acyl chlorides etc.) and N of 19 to 22 ester by having free hydroxyl group, N-dicyclohexyl-N-morpholine carboxylic carbonamidine (or other alkali, such as DBU, triethylamine, CsCO3, N, N-dimethylaniline etc.) and reaction and synthesizing in DMF (or other solvents, such as acetonitrile or 1-METHYLPYRROLIDONE). Work as W1During for phosphonate ester, structure 5 to 7,11,12,21 with 23 to 26 ester by alcohol or alkoxide (or corresponding amine, in the example such as compound 13,14 and 15) with monochloro phosphonate ester or dichloro phosphonate ester (or other activation phosphonate ester) reaction and synthesize.
Table A
1.-CH 2-C(O)-N(R 1) 2 *                10.-CH 2-O-C(O)-C(CH 3) 3
2.-CH 2-S(O)(R 1)                      11.-CH 2-CCl 3
3.-CH 2-S(O) 2(R 1)                    12.-C 6H 5
4.-CH 2-O-C(O)-CH 2-C 6H 5             13.-NH-CH 2-C(O)O-CH 2CH 3
5.3-cholesteryl 14.-N (CH3)-CH 2-C(O)O-CH 2CH 3
6.3-pyridine radicals 15.-NHR1
7.N-ethyl morpholine base 16.-CH2-O-C(O)-C 10H 15
8.-CH 2-O-C(O)-C 6H 5                  17.-CH 2-O-C(O)-CH(CH 3) 2
9.-CH 2-O-C(O)-CH 2CH 3                18.-CH 2-C#H(OC(O)CH 2R 1)-CH 2-
                                           -(OC(O)CH 2R 1) *
Figure C20051008765900481
The # chiral centre is (R), (S) or racemoid
The ester class description that other this paper are suitable for is in EP 632 048.
R 6aThe preceding functional group who also comprises formation " dibasic acid esters " (double ester), for example
-CH 2OC (O) OCH 3,
Figure C20051008765900482
-CH 2OCON (CH 3) 2, or structure-CH (R 1Or W 5) O ((CO) R 37) or-CH (R 1Or W 5) ((CO) OR 38) alkyl-or aryl-acyloxy alkyl (bond is to the oxygen of acidic-group), wherein R 37With R 38Be alkyl, aryl, or alkaryl (seeing United States Patent (USP) 4968788).Usually, R 37With R 38Be macoradical, as branch's alkyl, the ortho position substituted aryl, a position substituted aryl, or its combination just comprise, the second month in a season, different-with uncle C 1-C 6Alkyl.Example has pivalyl oxygen methyl.It is used in the oral prodrugs especially.This type of useful R 6aThe example of group has alkyl acyl-oxygen methyl ester and derivative thereof, comprises-CH (CH 2CH 2OCH 3) OC (O) C (CH 3) 3,
Figure C20051008765900491
-CH 2OC (O) C 10H 15,-CH 2OC (O) C (CH 3) 3,-CH (CH 2OCH 3) OC (O) C (CH 3) 3,-CH (CH (CH 3) 2) OC (O) C (CH 3) 3,-CH 2OC (O) CH 2CH (CH 3) 2,-CH 2OC (O) C 6H 11,-CH 2OC (O) C 6H 5,-CH 2OC (O) C 10H 15,-CH 2OC (O) CH 2CH 3,-CH 2OC (O) CH (CH 3) 2,-CH 2OC (O) C (CH 3) 3With-CH 2OC (O) CH 2C 6H 5
When as prodrug, selected ester is used for the antibiotic medicine before being preferably person, particularly cyclic carbonate, dibasic acid esters, or phthalidyl ester, aryl ester or alkyl ester.
Should note R 6a, R 6cWith R 6bGroup can be used for preventing in the synthesis step side reaction with the group of protection arbitrarily, so it can be as protecting group (PRT) in synthetic.
Determine which group to want that character protected and PRT is common must look the reactive chemistry (for example, acidity, alkalescence, oxidisability, reductibility or other conditions) that will protect antagonism and the synthetic direction that will carry out and determine.If when having in the compound a plurality of PRT to replace, this PRT group needn't, and be not usually, identical.Generally speaking, PRT will be used for protecting carboxyl, hydroxyl or amino.Go to protect the order that draws free group decide on synthetic direction and the reaction conditions that carries out, and any the occurring in sequence that can those skilled in the art determines.
Unusual Duo R 6aHydroxyl protecting group and R 6cAcid amides forms group and corresponding chemical disconnection reaction is described in " Protective Groups in Organic Chemistry ", TheodoraW.Greene (John Wiley ﹠amp; Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (" Greene ").Also can be with reference to Kocienski, Philip J.; " Pro-tecting Groups " (Georg Thieme Verlag Stuttgart, New York, 1994), it is for referencial use that its integral body is incorporated this paper into.Particularly Chapter 1, ProtectingGroups:An Overview, 1-20 page or leaf, Chapter 2, Hydroxyl Protect-ing Groups, 21-94 page or leaf, Chapter 3, Diol Protecting Groups, 95-117 page or leaf, Chapter 4, Carboxyl Protecting Groups, the 118-154 page or leaf, Chapter 5, Carbonyl Protecting Groups, the 155-184 page or leaf.For R 6aCarboxylic acid, phosphonic acids, phosphonic acid ester, sulfonic acid and W 1Other protecting group of acid can be with reference to following Greene.This type of group comprises, as an example and unrestricted, and ester, acid amides, hydrazides etc.
In some concrete example, through R 6aThe acidic-group of protection is the ester of this acidic-group, and R 6aResidue for the hydroxyl functional group.In other concrete examples, R 6cAminocompound is used to protect the acid functional group.Suitable hydroxyl or contain amino functional group's residue as mentioned above, or be found in WO 95/07920.Useful especially is amino acid, amino acid ester, polypeptide or fragrant and mellow residue.Typical amino acid, the amino-acid residue of polypeptide and carboxyl esterification is described in the 11-18 page or leaf and associated viscera of WO 95/07920, as group L 1Or L 2WO 95/07920 instruction phosphonic amidate forms with amino-acid residue shown in any acidic-group described herein and the WO 95/07920 but should understand these amidates.
Be used to protect W 1The typical R of acid functional groups 6aEster also is described among the WO 95/07920, and similarly, the acidic-group that should understand with this paper also can form and the identical ester of the usefulness disclosed phosphonic acid ester in ' 920.Typical case's ester group is defined in WO 95/07920 89-93 page or leaf at least (at R 31Or R 35Down), in the 105th page the table, and 21-23 page or leaf (R).Special good person is the ester of following groups: the aryl that is unsubstituted, and as phenyl or aralkyl (as benzyl), or through hydroxyl, halogen, alkoxyl group, the aryl or the alkaryl of carboxyl and/or alkyl ester carboxyl substituted, particularly phenyl, adjacent phenelyl, or C 1-C 4Alkyl ester carboxyl phenyl (Whitfield's ointment C 1-C 12Alkyl ester).
The acidic-group W of protection 1, when particularly using the ester of WO 95/07920 or acid amides, can be used as oral prodrugs.Yet W 1Acidic-group might not get the protected The compounds of this invention that just can allow and use effectively with oral.When (particularly amino acid amide thing or the aryl ester that is substituted and is unsubstituted) whole body of the The compounds of this invention with protecting group or oral administration, it can be hydrolyzed fracture in vivo and draw free acid.
One or more acid hydroxy groups can be protected.If more than one acid hydroxy group is protected, available identical or different protecting group, for example, ester can be identical or different, or available blended amidate and ester.
Typical R 6aHydroxyl protecting group is described among the Greene (14-118 page or leaf), comprises ether (methyl); The methyl ether that is substituted (methoxyl methyl, first thiomethyl, uncle's fourth thiomethyl, (phenyl dimetylsilyl) methoxyl methyl, benzyloxymethyl is to methoxyl group benzyloxy methyl, (4-methoxyl group phenoxy group) methyl, hydroxyanisole methyl, uncle's fourth oxygen methyl, 4-amylene oxygen ylmethyl, siloxy-methyl, 2-methoxyl group ethoxymethyl, 2,2,2-trichlorine ethoxymethyl, two (2-chloroethoxy) methyl, 2-(trimethyl silyl) ethoxymethyl, THP trtrahydropyranyl, 3-bromine THP trtrahydropyranyl, tetrahydrochysene sulfo-pyranyl, 1-methoxyl group cyclohexyl, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydrochysene sulfo-pyranyl, 4-methoxyl group tetrahydrochysene sulfo-pyranyl S, S-two oxo bridges (dioxido), 1-((2-chloro-4-methyl) phenyl)-4-methoxyl group piperidin-4-yl, 35,1,4-two _ alkane-2-base, tetrahydrofuran base, tetrahydrochysene thio-furan base, 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethylammonium-4,7-methylene radical benzo furans-2-yl)); The ethyl ether (1-ethoxyethyl, 1-(2-chloroethene oxygen) ethyl, the 1-methyl isophthalic acid-methoxyethyl that replace, 1-methyl isophthalic acid-benzyloxy ethyl, 1-methyl isophthalic acid-benzyloxy-2-fluoro ethyl, 2,2,2-three chloroethyls, 2-trimethyl silyl ethyl, 2-(phenyl selenyl) ethyl, the tertiary butyl, allyl group, rubigan, p-methoxyphenyl, 2, the 4-dinitrophenyl, benzyl); The benzylic ether that is substituted (to methoxybenzyl, 3, the 4-veratryl, adjacent nitrobenzyl is to nitrobenzyl, to halogeno-benzyl, 2, the 6-dichloro benzyl is to the cyano group benzyl, to phenylbenzyl, 2-and 4-picolyl, 3-methyl-2-picolyl N-oxo bridge, diphenyl-methyl, P, P '-dinitrobenzene diphenyl-methyl, 5-dibenzo suberyl, trityl, Alpha-Naphthyl diphenyl-methyl, the p-methoxyphenyl diphenyl-methyl, two (p-methoxyphenyl) phenmethyl, three (p-methoxyphenyl) methyl, 4-(4 '-bromobenzene formyl methoxyl group) the phenyl diphenyl-methyl, 4,4 ', 4 " three (4,5-dichloro phthalimido phenyl) methyl, 4; 4 ', 4 " three (levulinic acyl-oxygen phenyl) methyl, 4,4 ' 4 " three (benzoyl oxygen phenyl) methyl, 3-(imidazoles-1-ylmethyl) two (4 ', 4 " dimethoxy phenyl) methyl, 1,1-two (4-methoxyphenyl)-1 '-pyrenyl methyl, 9-anthryl, 9-(9-phenyl) xanthenyl, 9-(9-phenyl-10 1 oxo) anthryl, 1,3-benzo dithiane-2-base, benzisothiazole base S, S-two oxo bridges); Silyl ether (trimethyl silyl, triethylsilyl, triisopropyl silyl, dimethyl sec.-propyl silyl, diethyl sec.-propyl silyl, ethylhexyl dimethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, the tribenzyl silyl, three p-Xylol base silyls, triphenyl silyl, the diphenylmethylsilane base, tertiary butyl p-methoxy-phenyl silyl); Ester (manthanoate, benzoyl formiate, acetic ester, chloracetate, dichloro acetic acid ester, trichloroacetic esters, trifluoro-acetate, methoxyacetic acid ester, triphenyl methoxyacetic acid ester, the phenylium ester, parachlorophen-oxyacetic acid ester, p-poly-phenyl yl acetate, 3-phenylpropionic acid ester, 4-oxopentanoie acid ester (levulinate), 4,4-(ethylene sulfo-) valerate, pivalate, adamantate, crotonate, 4-methoxyl group crotonate, benzoic ether, to phenylbenzoate, 2,4,6-trimethylbenzoic acid ester; Carbonic ether (methyl, 9-fluorenyl methyl, ethyl, 2,2,2-trifluoroethyl, 2-(trimethyl silyl) ethyl, 2-(phenyl sulfonyl) ethyl, 2-(triphenyl phosphorus _ yl) ethyl, isobutyl-, vinyl, allyl group, p-nitrophenyl, benzyl, to methoxybenzyl, 3, the 4-veratryl, adjacent nitrobenzyl is to nitrobenzyl, S-benzyl thiocarbonic ester, 4-oxyethyl group-1-naphthyl, dithiocarbonic acid methyl esters); Group (2-iodobenzoic acid ester with the fracture of helping, 4-azido-butyric ester, 4-nitro-4-methyl valerate, adjacent (two brooethyls) benzoic ether, 2-formyl radical benzene sulfonate, carbonic acid 2-(methylthio group methoxyl group) ethyl ester, 4-(methylthio group methoxyl methyl) butyric ester, 2-(methylthio group methoxyl group) benzoic ether); Other esters (2,6-two chloro-4-methylenedioxy phenoxy yl acetates, 2,6-two chloro-4-(1,1,3, the 3-tetramethyl butyl) phenylium ester, 2,4-two (1, the 1-dimethyl propyl) phenylium ester, chloro diphenyl acetic acid ester, isobutyrate, the monosuccinic acid ester, (E)-2-methyl-2-butene acid esters (tigliate), adjacent (methoxycarbonyl) benzoic ether, the p-poly-phenyl manthanoate, α-naphthoic acid ester, nitric ether, alkyl N, N, N ', N '-tetramethyl phosphorodiamidite, the N-phenylcarbamate, boric acid ester, dimethyl sulphide phosphino-, 2,4-dinitrophenyl sulfenic acid ester); And sulphonate (sulfuric ester, methanesulfonates, benzyl sulfonic acid ester, tosylate).
More typically, R 6aHydroxyl protecting group comprises the methyl ether that is substituted, the benzylic ether that is substituted, and silyl ether, and the ester class that comprises sulphonate are preferably trialkylsilyl ethers, tosylate and acetic ester.
Typical 1,2-glycerol protection base (so, this two OH base and R usually 6aProtecting group merges) as Greene as described in the 118-142 page or leaf, comprise cyclic acetal and ketal (methylene radical, ethylidene, 1-tertiary butyl ethylidene, 1-phenyl ethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-three chlorethylidenes, acetone solvate (isopropylidene), cyclopentylidene, cyclohexylidene, inferior suberyl, benzylidene, to the methoxyl group benzylidene, 2, the 4-dimethoxybenzylidenegroup group, 3,4-dimethoxybenzylidenegroup group, 2-nitro benzylidene); Cyclic ortho ester (methoxyl group methylene radical, oxyethyl group methylene radical, dimethoxy methylene radical, 1-methoxyl group ethylidene, 1-oxyethyl group ethylidene, 1,2-dimethoxy ethylidene, α-methoxyl group benzylidene, 1-(N, N-dimethylamino) ethidene derivant, α-(N, the N-dimethylamino) benzylidene derivatives, 2-oxa-cyclopentylidene); The silyl derivative (the di-t-butyl silylene, 1,3-(1,1,3,3-tetra isopropyl two inferior siloxaness), and four tert.-butoxy sily oxide-1,3-two subunits), cyclic carbonate, ring-type boride (Boronate), ethyl boride and phenyl boride.
More typically, 1,2-glycerol protection base comprises those shown in the table B, more preferably epoxide, acetone solvate, cyclic acetal and aryl acetal.
Table B
Figure C20051008765900531
R wherein 9Be C 1-C 6Alkyl.
R 6bBe H, the residue of amino protecting group or carboxylated compound, particularly H ,-C (O) R 4, amino acid, polypeptide, or be not-C (O) R 4, amino acid, the protecting group of polypeptide.Form the R of acid amides 6bGroup G for example 1Shown in.Work as R 6bDuring for amino acid or polypeptide, its structure is R 15NHCH (R 16) C (O)-, R wherein 15Be H, amino acid or polypeptid residue, or R 5, and R 16As give a definition.
R 16Be low alkyl group or the C that replaces through following groups 1-C 6Low alkyl group: amino, carboxyl, acid amides, carboxyl ester, hydroxyl, C 6-C 7Aryl, guanidine radicals, imidazolyl, indyl, sulfydryl, sulfoxide and/or alkyl phosphate.R 10Also can merge and form proline residue (R with amino acid whose α-N 10=-(CH 2) 3-).But R 10Be generally naturally occurring amino acid whose side group, H for example ,-CH 3,-CH (CH 3) 2,-CH 2-CH (CH 3) 2,-CHCH 3-CH 2-CH 3,-CH 2-C 6H 5,-CH 2CH 2-S-CH 3,-CH 2OH ,-CH (OH)-CH 3,-CH 2-SH ,-CH 2-C 6H 4OH ,-CH 2-CO-NH 2,-CH 2-CH 2-CO-NH 2,-CH 2-COOH ,-CH 2-CH 2-COOH ,-(CH 2) 4-NH 2With-(CH 2) 3-NH-C (NH 2)-NH 2R 10Also comprise 1-guanidine radicals third-3-base, benzyl, 4-acrinyl, imidazol-4 yl, indol-3-yl, methoxyphenyl and phenelyl.
In the time of most of, R 6bBe carboxylic acid residues, but also available any Greene is at the described typical amino protecting group of 315-385 page or leaf.They comprise carbamate (methyl, ethyl, 9-fluorenyl methyl, 9-(2-sulfo group) fluorenyl methyl, 9-(2, the 7-dibromo) fluorenyl methyl, 2, the 7-di-t-butyl-(9-(10,10-dioxo-10,10,10,10-tetrahydrochysene sulfo-xanthenyl)), methyl, 4-methoxybenzoyl methyl); The ethyl that is substituted (2,2,2-three chloroethyls, 2-trimethyl silyl ethyl, the 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-halogenated ethyl, 1,1-dimethyl-2,2-two bromotrifluoromethanes, 1,1-dimethyl-2,2,2-three chloroethyls, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-(3, the 5-di-tert-butyl-phenyl)-1-methylethyl, 2-(2 '-with 4 '-pyridyl) ethyl, 2-(N, N-dicyclohexyl carboxamido) ethyl, the tertiary butyl, 1-adamantyl, vinyl, allyl group, 1-sec.-propyl allyl group, cinnamyl, 4-nitro cinnamyl, 8-quinolyl, N-hydroxy piperidine base, alkane disulfide group, benzyl, to methoxybenzyl, to nitrobenzyl, to bromobenzyl, p-chlorobenzyl, 2, the 4-dichloro benzyl, 4-methanesulfinyl benzyl, 9-anthryl methyl, diphenyl methyl); Group (2-methylmercaptoethyl, 2-methyl sulphonyl ethyl, 2-(p-toluenesulfonyl) ethyl with the fracture of helping, (2-(1,3-dithiane base)) methyl, 4-methylthio group phenyl, 2,4-diformazan sulfenyl phenyl, 2-phosphorus _ basic ethyl, 2-triphenyl phosphorus _ basic sec.-propyl, 1,1-dimethyl-2-cyanoethyl, between chloro-to the acyloxy benzyl, to (dihydroxyl boryl) benzyl, 5-benzisoxa _ azoles methyl, 2-(trifluoromethyl)-6-chromone ylmethyl); Light degradable group (m-nitro base, 3,5-dimethoxy-benzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl (ortho-nitrophenyl base) methyl); Urea type derivative (phenothiazinyl-(10)-carbonyl, N '-tolysulfonyl aminocarboxyl, N '-phenyl amino thiocarbonyl); Other carbamates (tert-pentyl, S-benzyl thiocarbamate is to the cyano group benzyl, cyclobutyl, cyclohexyl, cyclopentyl, the cyclopropyl methyl, to oxy-benzyl in the last of the ten Heavenly stems, the di-isopropyl methyl, 2,2-dimethoxycarbonyl vinyl, adjacent (N, N-dimethyl carboxamido) benzyl, 1,1-dimethyl-3-(N, N-dimethyl carboxamido) propyl group, 1, the 1-alkynyl dimethyl, two (2-pyridyl) methyl, 2-furyl methyl, 2-iodine ethyl, isobornyl, isobutyl-, different nicotinoyl, to (p-methoxyphenyl azo-group) benzyl, 1-methyl cyclobutyl, 1-methylcyclohexyl, 1-methyl isophthalic acid-cyclopropyl methyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo phenyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, phenyl is to (phenylazo) benzyl, 2,4,6-tri-tert phenyl, 4-(TMA (TriMethylAmine)) benzyl, 2,4, the 6-trimethyl benzyl); Acid amides (N-formyl radical, N-ethanoyl, N-chloracetyl, N-tribromo-acetyl base, the N-TFA base, N-phenyl acetyl, N-3-phenyl propionyl, N-picoline acyl group, N-3-pyridyl carboxylic acid amides, N-benzoyl phenylalanyl, the N-benzoyl, N-is to the phenyl benzoyl); Acid amides (N-ortho-nitrophenyl ethanoyl with the fracture of helping, N-ortho-nitrophenyl oxygen base ethanoyl, the N-acetoacetyl, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, N-3-(p-hydroxybenzene) propionyl, N-3-(ortho-nitrophenyl base) propionyl, N-2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, N-2-methyl-2-(adjacent phenylazo phenoxyl) propionyl, the N-4-chlorobutyryl, N-3-methyl-3-nitro butyryl radicals, the adjacent nitro cinnamoyl of N-, N-ethanoyl methionine(Met), the N-o-nitrobenzoyl, N-neighbour's (benzoyloxy methyl) benzoyl, 4,5-phenylbenzene-3-_ azoles quinoline-2-ketone); Cyclic imide derivative (N-phthalimide, N-dithio succinyl, N-2,3-phenylbenzene maleoyl, N-2,5-dimethyl pyrrole, N-1,1,4,4-tetramethyl-dimethyl silanyl aza-cyclopentane affixture, 1 of 5-replacement, 3-dimethyl-1,3,5 ,-Trianacyclohexane-2-ketone, 1 of 5-replacement, 3-dibenzyl-1,3,5-Trianacyclohexane-2-ketone, 3 of 1-replacement, 5-dinitrobenzene-4-pyriconyl); N-alkyl and N-arylamines (N-methyl, N-allyl group, N-(2-(trimethyl silyl) oxyethyl group) methyl, N-3-acetyl oxygen propyl group, N-(1-sec.-propyl-4-nitro-2-oxo-3-pyrroline-3-yl), quaternary ammonium salt, the N-benzyl, N-two (4-p-methoxy-phenyl) methyl, N-5-dibenzo suberyl, the N-trityl group, N-(4-p-methoxy-phenyl) diphenyl methyl, N-9-phenyl fluorenyl, N-2,7-two chloro-9-fluorenes methylene radical, N-ferrocenyl methyl, N-2-picolyl amine N '-oxide compound), imine derivative (N-1,1-methyl-sulfide methylene, N-benzylidene, N-be to the methoxyl group benzylidene, N-phenylbenzene methylene radical, N-((2-pyridyl) _ yl) methylene radical, N-(N ', N '-dimethylamino) methylene radical, N, N '-isopropylidene, N-is to the nitro benzylidene, N-salicylidene, N-5-chlorine salicylidene, N-(5-chloro-2-hydroxyphenyl) phenylmethylene, the N-cyclohexylidene); Enamine derivates (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)); N-metal derivative (N-borane derivative, N-phenylbenzene boric acid (borinic acid) derivative, N-(phenyl (pentacarbonyl chromium or tungsten)) carbene base, N-copper or N-chelates of zinc); N-N derivative (N-nitro, N-nitroso-group, N-oxide compound); N-P derivative (N-two phenenyl phosphinyl, N-diformazan sulfenyl phosphinyl, N-hexichol sulfenyl phosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N-diphenylphosphine acyl group); The N-Si derivative; The N-S derivative; N-sulfinyl derivative (N-benzenesulfinyl, N-ortho-nitrophenyl sulfinyl, N-2,4-dinitrobenzene sulfinyl, N-pentachlorobenzene sulfinyl, N-2-nitro-4-anisole sulfinyl, N-trityl group sulfinyl, N-3-nitropyridine sulfinyl); And N-sulfonyl-derivatives (N-p-toluenesulfonyl, N-benzenesulfonyl, N-2; 3,6-trimethylammonium-4-anisole alkylsulfonyl, N-2; 4,6-trimethoxy benzenesulfonyl, N-2; 6-dimethyl-4-anisole alkylsulfonyl, N-pentamethylbenzene alkylsulfonyl, N-2; 3,5,6-tetramethyl--4-anisole alkylsulfonyl; N-4-anisole alkylsulfonyl, N-2,4; 6-Three methyl Benzene alkylsulfonyl, N-2,6-dimethoxy-4 '-Methyl benzenesulfonyl base; N-2,2,5; 7,8-pentamethyl-benzo dihydropyrane-6-alkylsulfonyl, N-methylsulfonyl; N-β-trimethyl silyl ethylsulfonyl, N-9-anthracene alkylsulfonyl, N-4-(4 '; 8 '-the dimethoxy menaphthyl) benzenesulfonyl; N-benzyl alkylsulfonyl, N-trifluoromethyl sulfonyl, N-phenacyl alkylsulfonyl).
More typically, the amino of protection comprises carbamate and acid amides, more preferably-and NHC (O) R 1Or-N=CR 1N (R 1) 2Another kind of protecting group also can be used as G 1The prodrug of position, especially for amino or-NH (R 5), for:
Figure C20051008765900561
Reference, for example, Alexander, people such as J.; J.Med.Chem.1996,39,480-486.
R 6cFor H or contain the residue (particularly amino acid, polypeptide) of aminocompound, protecting group ,-NHSO 2R 4, NHC (O) R 4,-N (R 4) 2, NH 2Or-NH (R 4) H, thus, W 1Carboxyl or the reaction of phosphonate group and above-mentioned amine form acid amides, as at-C (O) R 6c,-P (O) (R 6c) 2Or-(OH) (R of P (O) 6c) in.Common R 6cHas R 17C (O) CH (R 16) structure of NH-, wherein R 17Be OH, OR 6a, OR 5, amino acid or polypeptid residue.
Amino acid is low-molecular weight compound, less than about 1000MW, and comprises at least one amino or imino-and at least one carboxyl.Usually this amino acid is present in nature, that is, can be in biological substance such as bacterium or other microorganisms, plant detects among the animal or human.Suitable amino acid typically is a-amino acid, and promptly an one amino or imino nitrogen atom are separated by the carbon atom of a single replacement or a unsubstituted alpha-carbon atom and a carbonyl in the compound.The preferably is a hydrophobic residue, as single-or two-alkyl or aryl amino acid, cycloalkylamino acid etc.These residues help cell permeability by the partition ratio that improves female medicine.Typically, this residue does not contain sulfydryl or guanidine radicals substituting group.
The natural amino acid residue is plant, the residue of natural discovery in animal or the microorganism, particularly its protein.Polypeptide typically is made up of the naturally occurring amino-acid residue of this class substantially.These amino acid are glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, Serine, Threonine, halfcystine, methionine(Met), L-glutamic acid, aspartic acid, Methionin, oxylysine, arginine, Histidine, phenylalanine, tyrosine, tryptophane, proline(Pro), l-asparagine, glutamine and oxyproline.
Work as R 6bWith R 6cDuring for monamino acid residue or polypeptide, it is usually in R 3, W 6, W 1And/or W 2Last replacement, but better only in W 1Or W 2Last replacement.These conjugates are by carboxyl and W at this amino acid (or for example the carbon teminal amino acid of polypeptide) 2Between form amido linkage and form.Similarly, also can be in W 1And form conjugate between the amino of amino acid or polypeptide.Usually, have only an amino acid amide that the position is as described herein in the parent molecule, yet introduce amino acid also within the scope of the present invention in more than one position.Common W 1The carboxyl amino acid amide.Usually; the functional group that the terminal amino group of this amino acid whose alpha-amino group or alpha-carbonyl or polypeptide or carboxyl are connected to parent compound; promptly the carboxyl on the amino acid side chain or amino be not used for usually forming and parent compound between amido linkage (though these groups may when conjugate is synthetic, be protected, as mentioned below).
About the carboxylic side-chain that contains of amino acid or polypeptide, should understand this carboxyl can be protected arbitrarily, for example, uses R 6a, use R 5Esterification, or use R 6cAmidation.Similarly, amino side-chain R 16Can use R arbitrarily 6bProtect or use R 5Replace.
Ester or amido linkage that these and side chain amino or carboxyl form, as the ester or the amido linkage that form with parent molecule, can be at random in body or hydrolysis under external acidity (pH＜3) or alkalescence (pH＞10) condition.In addition, they can be basicly stable in human gi-tract, but can be by enzymic hydrolysis in blood or intracellular environment.Intermediate when these esters or amino acid or polypeptide amidate also can be used as the parent molecule that contains free amine group or carboxyl and prepare.The free acid of parent compound or alkali can be easily made via routine hydrolysis by ester of the present invention or amino acid or polypeptide conjugate.
When amino-acid residue contains one or more chiral centre, available any D, L, meso, Soviet Union or red (if suitably) racemoid, crystallization isomer (scalemates) or its mixture.Usually, if desire to make the non-enzymatically hydrolyse of intermediate (for example with the chemical intermediate of this acid amides as free acid or unhindered amina), the D isomer is useful.On the other hand, the L isomer is more general, because it can urge or non-enzymatically hydrolyse through enzyme, and can more effectively be shifted by amino acid or dipeptides transfer system in gi tract.
(its residue is with R for suitable amino acid 6bWith R 6cExpression) example comprises following:
Glycine;
The aminopolycanboxylic acid, for example, aspartic acid, the beta-hydroxy aspartic acid, L-glutamic acid, BOG, the Beta-methyl aspartic acid, Beta-methyl L-glutamic acid, β, the beta-dimethyl-aspartic acid, γ-Qiang Jiguansuan, β, γ-dihydroxyl L-glutamic acid, beta-phenyl L-glutamic acid, γ-methylene radical L-glutamic acid, the 3-aminoadipic acid, 2-diaminopimelic acid, amino suberic acid of 2-and the amino sebacic acid of 2-;
Amino acid amide is as glutamine and l-asparagine;
Polyamino-or polynary monocarboxylic acid, as arginine, Methionin, beta-amino L-Ala, gamma-amino butyrin, ornithine, citrulline, homoarginine, Homocitrulline, oxylysine, allohydroxylysine and DAB;
Other alkaline amino acid residues are as Histidine;
The diamino dicarboxylic acid, as, α, α '-diaminosuccinic acid, α, α '-diamino pentanedioic acid, α, α '-diamino hexanodioic acid, α, α '-diaminopimelic acid, α, α '-diamino-beta-hydroxy pimelic acid, α, α '-diamino suberic acid, α, α '-diamino nonane diacid, with α, α '-diamino sebacic acid;
Imino-acid, as proline(Pro), oxyproline, other hydroxyl proline, γ-methylproline, piperidines-2-formic acid, 5-hydroxyl are sent pyridine-2-formic acid, with azetidine-2-carboxylic acid;
Single-or dialkyl group (be preferably C 1-C 8Side chain or straight chain) amino acid, as L-Ala, Xie Ansuan, leucine, allylglycine, butyrin, norvaline, nor-leucine, propylhomoserin in heptan (heptyline), the Alpha-Methyl Serine, alpha-amino group-Alpha-Methyl-γ-hydroxypentanoic acid, alpha-amino group-Alpha-Methyl-δ-hydroxypentanoic acid, alpha-amino group-Alpha-Methyl-ε-hydroxycaproic acid, isovaline, Alpha-Methyl L-glutamic acid, α-An Jiyidingsuan, the alpha-amino group diethylacetic acid, alpha-amino group di-isopropyl acetate, alpha-amino group di acetate, alpha-amino group diisobutyl acetate, the alpha-amino group di-n-butylacetic acid, alpha-amino group ethyl sec.-propyl acetate, alpha-amino group n-propyl acetate, alpha-amino group diisoamyl acetate, the Alpha-Methyl aspartic acid, Alpha-Methyl L-glutamic acid, 1-amino-cyclopropane-1-carboxylic acid, Isoleucine, alloisoleucine, Terleu, the Beta-methyl tryptophane is with pantonine-ethyl-beta-phenyl propionic acid;
The beta-phenyl seryl;
Aliphatic series pantonine-alcohol acid, as, Serine, the beta-hydroxy leucine, the beta-hydroxy nor-leucine, the beta-hydroxy norvaline is with pantonine-oxystearic acid;
Alpha-amino group, α-, γ-, δ-or ε-alcohol acid, as, homoserine, γ-hydroxynorvaline, δ-hydroxynorvaline is with ε-hydroxyl nor-leucine residue; Canavanine and canaline; γ-hydroxyl ornithine;
2-hexose propylhomoserin is as D-glucose propylhomoserin or D-semi-lactosi propylhomoserin;
Pantonine-mercaptan, as Trolovol, β-mercaptan norvaline or β-mercaptan butyrin;
The amino-acid residue of other sulfur-bearings comprises halfcystine; Homocystine, beta-phenyl methionine(Met), methionine(Met), S-allyl group-L-halfcystine sulfoxide, 2-mercaptan Histidine, cystathionine, and the mercaptan ether of halfcystine or homocysteine;
Phenylalanine, tryptophane and cyclosubstituted a-amino acid, as, phenyl-or cyclohexyl amino acid, alpha aminophenylacetic acid, alpha-amino group cyclohexyl acetic acid and pantonine-cyclohexylpropionic acid; Contain aryl, low alkyl group, hydroxyl, guanidine radicals, oxyalkyl ether, nitro, the phenylalanine congener of the phenyl that sulphur or halogen replace and derivative are (for example, tyrosine, methyltyrosine and adjacent chloro-are to chloro-, 3,4-two chloro-, adjacent-, between-or right-methyl-, 2,4, the 6-trimethylammonium, 2-oxyethyl group-5-nitro-, 2-hydroxyl-5-nitro-with to nitro-phenylalanine); Furyl-, thienyl-, pyridyl-, pyrimidyl-, purine radicals-or naphthyl-L-Ala; And tryptophane analogue and derivative, comprise kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxyl tryptophane;
The amino acid that alpha-amino group replaces comprises sarkosine (sarcosine), N-benzyl glycine, N-methylalanine, N-benzyl L-Ala, N-aminomethyl phenyl L-Ala, N-benzyl phenyl L-Ala, N-methylvaline and N-benzyl Xie Ansuan;
The Alpha-hydroxy amino acid of Alpha-hydroxy and replacement comprises Serine, Threonine, allothreonine, phosphoserine and phosphothreonine.
Polypeptide is a polymer of amino acid, and the carboxyl of one of them amino acid monomer and the amino of another amino acid monomer or imino-combine with amido linkage.Polypeptide comprises dipeptides, low molecular weight polypeptide (about 1500-5000MW) and protein.Protein can comprise 3,5,10,50,75,100 or more a plurality of residue arbitrarily, and preferably with the mankind, animal, the protein of plant or microorganism has basic similarly sequence.It comprises enzyme (as, hydroperoxide are dark) and immunogen (as KLH), or antibody, or produce the protein of immunoreactive any kind because of antagonism.The character of these polypeptide and identification feature can extensively change.
The polypeptide amidate can be used as immunogen and the antibody of epitope on this polypeptide that creates antagonism (if in the animal body of medication and non-immunogenic) or the antagonism The compounds of this invention remainder.
The antibody that can be bonded on the parent compound of non-peptidyl can be used to isolate this parent compound from mixture, for example, and in diagnosis or when parent compound prepares.The conjugate of parent compound and polypeptide can have more immunogenicity than this polypeptide usually in similar animal, institute is so that this polypeptide has more immunogenicity, and its antibody promotes to create antagonism.So this polypeptide or protein can be immunogenicity in the animal that is commonly used to produce antibody (for example, rabbit, mouse, horse and rat), and as long as final conjugation product is an immunogenicity at least a this animal.This polypeptide contains peptide arbitrarily on the peptide bond between contiguous acid heteroatomic first and second residue separates the enzymatic breaking position.This fracture position is attacked by the enzyme recognition structure laterally, and for example, specific residue sequence is separated enzyme by peptide and discerned.
It is known that the peptide that is used for cutting off polypeptide conjugate of the present invention is separated enzyme, particularly comprises carboxypeptidase.Carboxypeptidase decomposes polypeptide by removing the carbon teminal residue, and in many examples, the particular carbon terminal sequence is had specificity.This fermentoid and its matrix demand are generally known.For example, dipeptides (having specific a pair of residue and free carboxyl end group) is covalently bond on the phosphorus or carbon atom of this paper compound with its alpha-amino group.At W 1In the example for phosphonic acid ester, expect that this peptide will be separated enzyme by suitable peptide and cut off, stay the carboxyl of near-end (proximal) amino-acid residue and autocatalysis ground cuts off the phosphonic amide key.
Two suitable peptidyls (with its single-letter representation) are
AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, D E, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, IS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YE, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV.
Tripeptide residue also can be used as R 6bOr R 6cWork as W 1During for phosphonic acid ester, (wherein X4 is any amino-acid residue to sequence-X4-pro-X5-, and X5 is an amino-acid residue, the carboxyl ester of proline(Pro), or hydrogen) can be cut into X4 by versomnal (luminal) carboxypeptidase, it has free carboxy, and its expection can be cut off the phosphonic amide key in autocatalysis ground.The carboxyl of X5 is arbitrarily through the benzyl esterification.
According to known transfer character and/or the susceptibility (it can influence to the transfer of intestinal mucosa or other cellular fories) of peptase is selected the kind of dipeptides or tripeptides.Lacking alpha-amino dipeptides or tripeptides is that the peptide of finding in the brush shape boundary film of intestinal mucosa cells shifts sub transfer medium (Bai, J.P.F., " Pharm Res. " 9:969-978 (1992)).The peptide that is fit to shift can be used for strengthening the biological available rate of this amide compound.Having amino acid whose dipeptides of one or more D configurations or tripeptides also is suitable for peptide and shifts and can be used in the amide compound of the present invention.D configuration amino acid also can be used to reduce dipeptides or tripeptides by the possibility of protease hydrolysis, and this proteolytic enzyme is common for brush shape border, for example aminopeptidase N (EC 3.4.11.2).In addition, also can be according to dipeptides or tripeptides to the relative antagonism of the protease hydrolysis found in the enteric cavity and select it.For example, tripeptides or the polypeptide of shortage asp and/or glu are the bad matrix of aminopeptidase A (EC 3.4.11.7); Hydrophobic amino acid (leu, tyr, phe, val, distolateral dipeptides or the tripeptides of going up the lack amino acid residue of nitrogen trp) is the bad matrix of phthalein chain restriction endonuclease 24.11 (EC 3.4.24.11); The peptide class that lacks the pro residue in free carboxy end penult position is the bad matrix of carboxypeptidase P (EC 3.4.17).But also consider like the application class to select than difficulty or more easily by cytosol kidney, liver, the peptide of serum or the hydrolysis of other peptases institute.It is immunogen or can be used to be bonded to makes immunogen on the protein that this kind is difficult for cut polypeptide amidate.
Another concrete example of the present invention relates to formula (VII) or composition (VIII):
Figure C20051008765900621
E wherein 1, G 1, T 1, U 1, J 1, J 1a, J 2With J 2aAs above definition, but different be:
T 1For-NR 1W 3, heterocycle, or and G 1Form group together with following structure
Figure C20051008765900622
X 1Be a key ,-O-,-N (H)-,-N (R 5)-,-S-,-SO-, or-SO 2-; But condition is not comprise U 1For H or-CH 2CH (OH) CH 2(OH) compound;
And salt, solvate, the enantiomorph of parsing and purified diastereomer.
Above the typical case of the formula of Xiang Shuing (I)-(VI) or general concrete example also are formula (VII) and typical concrete example (VIII).
Many formulas (VII) and (VIII) compound (U wherein 1For H or-CH 2CH (OH) CH 2(OH) synthetic sees people such as Nishimura, Y.; J.Antibiotics, 1993,46 (2), 300; 46 (12), 1883; And Nat.Prod.Lett.1992,1 (1), 39.With U of the present invention 1Described in the method such as this article that group connects.
Steric isomer
The compounds of this invention is the optically active isomer for being rich in (enriched) or resolving on arbitrary or all asymmetric atoms.For example, conspicuous chiral centre is chiral isomer or racemic mixture in explanation.Racemic mixture or non-enantiomer mixture, and separated or each optically active isomer (being substantially free of its enantiomorph or diastereomer) of synthesizing is all within the scope of the present invention.Racemic mixture is separated into according to known technology and is essentially optically pure each isomer, for example, will be separated with the diastereoisomeric salt that optical activity auxiliary (as acid or alkali) forms, and then transforms back original optically active substance.In most example, make desired optically active isomer synthesize, to expect that the suitable steric isomer of initiator begins reaction with stereospecific reaction.
The stereochemistry example of The compounds of this invention shows as among the following table C.
Table C
Figure C20051008765900631
Formula (I)
E 1 J 1a J 1b U 1 T 1 G 1
- - α β α α
- - β α α α
- - α β β α
- - α β α β
- - β α β α
- - β α α β
- - α β β β
- - β α β β
Formula (I)
E 1 J 1a J 1b J 2 U 1 T 1 G 1
- α β α β α α
- β α α β α α
- α β β α α α
- α β α β β α
- α β α β α β
- β α β α α α
- β α α β β α
- β α α β α β
- α β β α β α
- α β β α α β
- α β α β β β
- β α β α β α
- β α β β α β
- β α α β β β
- α β β α β β
- β α β α β β
The compounds of this invention also can be tautomer in some example.For example, imidazoles, guanidine, amidine and tetrazolium system can be alkene-amine tautomer, and all possible tautomer is all within the scope of the invention.
Example compound
Examples for compounds as an example and unrestricted, is listed with forms mode (table 6).Usually, each compound is expressed as the nuclear (nuclear is represented with capitalization) that is substituted, and each substituting group is then in regular turn with lowercase or numeral.Table 1a and 1b are the table of each nuclear, the character of unsaturated position and substitution in ring base on the ring that its main difference part is each nuclear.Each nuclear gives a digital code in table 1a and 1b, and this code name is the 1st word of each compound name.Similarly, table 2a-av, 3a-b, 4a-c and 5a-d list selected Q 1, Q 2, Q 3, Q 4Substituting group similarly, is used the letter or number code name.Therefore, will be expressed as by each compound of being named: capitalization is represented the nuclear among the 1a-1b, then is expression Q 1Substituent numeral, expression Q 4Substituent lowercase, expression Q 3Substituent numeral, expression Q 4Substituent lowercase.So A.49.a.4.i the structure 8 in the reaction scheme 1 is expressed as.Should understand Q 1-Q 4Be not group or atom, just relevant representation.
Table 1a
Figure C20051008765900651
Table 1b
Figure C20051008765900661
Table 2a
Figure C20051008765900671
Table 2b
Figure C20051008765900681
Table 2c
Table 2d
Figure C20051008765900701
Table 2e
Table 2f
Figure C20051008765900721
Table 2g
Table 2h
Table 2i
Figure C20051008765900751
Table 2j
Figure C20051008765900761
Table 2k
Figure C20051008765900771
Table 2l
Figure C20051008765900781
Table 2m
Table 2n
Figure C20051008765900801
Table 2o
Figure C20051008765900811
Table 2p
Table 2q
Figure C20051008765900831
Table 2r
Figure C20051008765900841
Table 2s
Figure C20051008765900851
Table 2t
Figure C20051008765900861
Table 2u
Figure C20051008765900871
Table 2v
Figure C20051008765900881
Table 2w
Figure C20051008765900891
Table 2x
Table 2y
Figure C20051008765900911
Table 2z
Figure C20051008765900921
Table 2aa
Table 2ab
Figure C20051008765900941
Table 2ac
Figure C20051008765900951
Table 2ad
Figure C20051008765900961
Table 2ae
Figure C20051008765900971
Table 2af
Table 2ag
Figure C20051008765900991
Table 2ah
Table 2ai
Figure C20051008765901011
Table 3a
Figure C20051008765901021
Table 3b
Table 4a Q 3-OH Q 3-N 3Q 3-NO 2Q 3-NH 21234
Figure C20051008765901041
Table 4b
Figure C20051008765901051
Table 4c
Figure C20051008765901061
Table 5a
Figure C20051008765901071
Table 5b
Figure C20051008765901081
Table 5c
Figure C20051008765901091
Table 6-example compound
A.17.a.4.i；A.17.a.4.v；A.17.a.6.i；A.17.a.6.v；A.17.a.11.i；A.17.a.11.v；A.17.a.14.i； A.17.a.14.v；A.17.a.15.i；A.17.a.15.v；A.17.a.18.i；A.17.a.18.v；A.17.a.25.i； A.17.a.25.v；A.17.e.4.i；A.17.e.4.v；A.17.e.6.i；A.17.e.6.v；A.17.e.11.i；A.17.e.11.v； A.17.e.14.i；A.17.e.14.v；A.17.e.15.i；A.17.e.15.v；A.17.e.18.i；A.17.e.18.v； A.17.e.25.i；A.17.e.25.v；A.17.g.4.i；A.17.g.4.v；A.17.g.6.i；A.17.g.6.v；A.17.g.11.i； A.17.g.11.v；A.17.g.14.i；A.17.g.14.v；A.17.g.15.i；A.17.g.15.v；A.17.g.18.i； A.17.g.18.v；A.17.g.25.i；A.17.g.25.v；A.17.l.4.i；A.17.l.4.v；A.17.l.6.i；A.17.l.6.v； A.17.l.11.i；A.17.l.11.v；A.17.l.14.i；A.17.l.14.v；A.17.l.15.i；A.17.l.15.v；A.17.l.18.i； A.17.l.18.v；A.17.l.25.i；A.17.l.25.v；A.17.m.4.i；A.17.m.4.v；A.17.m.6.i； A.17.m.6.v；A.17.m.11.i；A.17.m.11.v；A.17.m.14.i；A.17.m.14.v；A.17.m.15.i； A.17.m.15.v；A.17.m.18.i；A.17.m.18.v；A.17.m.25.i；A.17.m.25.v；A.17.o.4.i； A.17.o.4.v；A.17.o.6.i；A.17.o.6.v；A.17.o.11.i；A.17.o.11.v；A.17.o.14.i； A.17.o.14.v；A.17.o.15.i；A.17.o.15.v；A.17.o.18.i；A.17.o.18.v；A.17.o.25.i； A.17.o.25.v；A.33.a.4.i；A.33.a.4.v；A.33.a.6.i；A.33.a.6.v；A.33.a.11.i；A.33.a.11.v； A.33.a.14.i；A.33.a.14.v；A.33.a.15.i；A.33.a.15.v；A.33.a.18.i；A.33.a.18.v； A.33.a.25.i；A.33.a.25.v；A.33.e.4.i；A.33.e.4.v；A.33.e.6.i；A.33.e.6.v；A.33.e.11.i； A.33.e.11.v；A.33.e.14.i；A.33.e.14.v；A.33.e.15.i；A.33.e.15.v；A.33.e.18.i； A.33.e.18.v；A.33.e.25.i；A.33.e.25.v；A.33.g.4.i；A.33.g.4.v；A.33.g.6.i；A.33.g.6.v； A.33.g.11.i；A.33.g.11.v；A.33.g.14.i；A.33.g.14.v；A.33.g.15.i；A.33.g.15.v； A.33.g.18.i；A.33.g.18.v；A.33.g.25.i；A.33.g.25.v；A.33.l.4.i；A.33.l.4.v；A.33.l.6.i； A.33.l.6.v；A.33.l.11.i；A.33.l.11.v；A.33.l.14.i；A.33.l.14.v；A.33.l.15.i；A.33.l.15.v； A.33.l.18.i；A.33.l.18.v；A.33.l.25.i；A.33.l.25.v；A.33.m.4.i；A.33.m.4.v； A.33.m.6.i；A.33.m.6.v；A.33.m.11.i；A.33.m.11.v；A.33.m.14.i；A.33.m.14.v； A.33.m.15.i；A.33.m.15.v；A.33.m.18.i；A.33.m.18.v；A.33.m.25.i；A.33.m.25.v； A.33.o.4.i；A.33.o.4.v；A.33.o.6.i；A.33.o.6.v；A.33.o.11.i；A.33.o.11.v；A.33.o.14.i； A.33.o.14.v；A.33.o.15.i；A.33.o.15.v；A.33.o.18.i；A.33.o.18.v；A.33.o.25.i； A.33.o.25.v；A.49.a.4.i；A.49.a.4.v；A.49.a.6.i；A.49.a.6.v；A.49.a.11.i；A.49.a.11.v； A.49.a.14.i；A.49.a.14.v；A.49.a.15.i；A.49.a.15.v；A.49.a.18.i；A.49.a.18.v； A.49.a.25.i；A.49.a.25.v；A.49.e.4.i；A.49.e.4.v；A.49.e.6.i；A.49.e.6.v；A.49.e.11.i； A.49.e.11.v；A.49.e.14.i；A.49.e.14.v；A.49.e.15.i；A.49.e.15.v；A.49.e.18.i； A.49.e.18.v；A.49.e.25.i；A.49.e.25.v；A.49.g.4.i；A.49.g.4.v；A.49.g.6.i；A.49.g.6.v； A.49.g.11.i；A.49.g.11.v；A.49.g.14.i；A.49.g.14.v；A.49.g.15.i；A.49.g.15.v； A.49.g.18.i；A.49.g.18.v；A.49.g.25.i；A.49.g.25.v；A.49.l.4.i；A.49.l.4.v；A.49.l.6.i； A.49.l.6.v；A.49.l.11.i；A.49.l.11.v；A.49.l.14.i；A.49.l.14.v；A.49.l.15.i；A.49.l.15.v； A.49.l.18.i；A.49.l.18.v；A.49.l.25.i；A.49.l.25.v；A.49.m.4.i；A.49.m.4.v； A.49.m.6.i；A.49.m.6.v；A.49.m.11.i；A.49.m.11.v；A.49.m.14.i；A.49.m.14.v； A.49.m.15.i；A.49.m.15.v；A.49.m.18.i；A.49.m.18.v；A.49.m.25.i；A.49.m.25.v； A.49.o.4.i；A.49.o.4.v；A.49.o.6.i；A.49.o.6.v；A.49.o.11.i；A.49.o.11.v；A.49.o.14.i； A.49.o.14.v；A.49.o.15.i；A.49.o.15.v；A.49.o.18.i；A.49.o.18.v；A.49.o.25.i； A.49.o.25.v；B.17.a.4.i；B.17.a.4.v；B.17.a.6.i；B.17.a.6.v；B.17.a.11.i；B.17.a.11.v； B.17.a.14.i；B.17.a.14.v；B.17.a.15.i；B.17.a.15.v；B.17.a.18.i；B.17.a.18.v；B.17.a.25.i； B.17.a.25.v；B.17.e.4.i；B.17.e.4.v；B.17.e.6.i；B.17.e.6.v；B.17.e.11.i；B.17.e.11.v； B.17.e.14.i；B.17.e.14.v；B.17.e.15.i；B.17.e.15.v；B.17.e.18.i；B.17.e.18.v；B.17.e.25.i； B.17.e.25.v；B.17.g.4.i；B.17.g.4.v；B.17.g.6.i；B.17.g.6.v；B.17.g.11.i；B.17.g.11.v；B.17.g.14.i；B.17.g.14.v；B.17.g.15.i；B.17.g.15.v；B.17.g.18.i；B.17.g.18.v；B.17.g.25.i； B.17.g.25.v；B.17.l.4.i；B.17.l.4.v；B.17.l.6.i；B.17.l.6.v；B.17.l.11.i；B.17.l.11.v； B.17.l.14.i；B.17.l.14.v；B.17.l.15.i；B.17.l.15.v；B.17.l.18.i；B.17.l.18.v；B.17.l.25.i； B.17.l.25.v；B.17.m.4.i；B.17.m.4.v；B.17.m.6.i；B.17.m.6.v；B.17.m.11.i； B.17.m.11.v；B.17.m.14.i；B.17.m.14.v；B.17.m.15.i；B.17.m.15.v；B.17.m.18.i； B.17.m.18.v；B.17.m.25.i；B.17.m.25.v；B.17.o.4.i；B.17.o.4.v；B.17.o.6.i；B.17.o.6.v； B.17.o.11.i；B.17.o.11.v；B.17.o.14.i；B.17.o.14.v；B.17.o.15.i；B.17.o.15.v； B.17.o.18.i；B.17.o.18.v；B.17.o.25.i；B.17.o.25.v；B.33.a.4.i；B.33.a.4.v；B.33.a.6.i； B.33.a.6.v；B.33.a.11.i；B.33.a.11.v；B.33.a.14.i；B.33.a.14.v；B.33.a.15.i；B.33.a.15.v； B.33.a.18.i；B.33.a.18.v；B.33.a.25.i；B.33.a.25.v；B.33.e.4.i；B.33.e.4.v；B.33.e.6.i； B.33.e.6.v；B.33.e.11.i；B.33.e.11.v；B.33.e.14.i；B.33.e.14.v；B.33.e.15.i；B.33.e.15.v； B.33.e.18.i；B.33.e.18.v；B.33.e.25.i；B.33.e.25.v；B.33.g.4.i；B.33.g.4.v；B.33.g.6.i； B.33.g.6.v；B.33.g.11.i；B.33.g.11.v；B.33.g.14.i；B.33.g.14.v；B.33.g.15.i；B.33.g.15.v； B.33.g.18.i；B.33.g.18.v；B.33.g.25.i；B.33.g.25.v；B.33.l.4.i；B.33.l.4.v；B.33.l.6.i； B.33.l.6.v；B.33.l.11.i；B.33.l.11.v；B.33.l.14.i；B.33.l.14.v；B.33.l.15.i；B.33.l.15.v； B.33.l.18.i；B.33.l.18.v；B.33.l.25.i；B.33.l.25.v；B.33.m.4.i；B.33.m.4.v；B.33.m.6.i； B.33.m.6.v；B.33.m.11.i；B.33.m.11.v；B.33.m.14.i；B.33.m.14.v；B.33.m.15.i； B.33.m.15.v；B.33.m.18.i；B.33.m.18.v；B.33.m.25.i；B.33.m.25.v；B.33.o.4.i； B.33.o.4.v；B.33.o.6.i；B.33.o.6.v；B.33.o.11.i；B.33.o.11.v；B.33.o.14.i；B.33.o.14.v； B.33.o.15.i；B.33.o.15.v；B.33.o.18.i；B.33.o.18.v；B.33.o.25.i；B.33.o.25.v；B.49，a.4.i； B.49.a.4.v；B.49.a.6.i；B.49.a.6.v；B.49.a.11.i；B.49.a.11.v；B.49.a.14.i；B.49.a.14.v； B.49.a.15.i；B.49.a.15.v；B.49.a.18.i；B.49.a.18.v；B.49.a.25.i；B.49.a.25.v；B.49.e.4.i； B.49.e.4.v；B.49.e.6.i；B.49.e.6.v；B.49.e.11.i；B.49.e.11.v；B.49.e.14.i；B.49.e.14.v； B.49.e.15.i；B.49.e.15.v；B.49.e.18.i；B.49.e.18.v；B.49.e.25.i；B.49.e.25.v；B.49.g.4.i； B.49.g.4.v；B.49.g.6.i；B.49.g.6.v；B.49.g.11.i；B.49.g.11.v；B.49.g.14.i；B.49.g.14.v； B.49.g.15.i；B.49.g.15.v；B.49.g.18.i；B.49.g.18.v；B.49.g.25.i；B.49.g.25.v；B.49.l.4.i； B.49.l.4.v；B.49.l.6.i；B.49.l.6.v；B.49.l.11.i；B.49.l.11.v；B.49.l.14.i；B.49.l.14.v； B.49.l.15.i；B.49.l.15.v；B.49.l.18.i；B.49.l.18.v；B.49.l.25.i；B.49.l.25.v；B.49.m.4.i； B.49.m.4.v；B.49.m.6.i；B.49.m.6.v；B.49.m.11.i；B.49.m.11.v；B.49.m.14.i； B.49.m.14.v；B.49.m.15.i；B.49.m.15.v；B.49.m.18.i；B.49.m.18.v；B.49.m.25.i； B.49.m.25.v；B.49.o.4.i；B.49.o.4.v；B.49.o.6.i；B.49.o.6.v；B.49.o.11.i；B.49.o.11.v； B.49.o.14.i；B.49.o.14.v；B.49.o.15.i；B.49.o.15.v；B.49.o.18.i；B.49.o.18.v； B.49.o.25.i；B.49.o.25.v；E.17.a.4.i；E.17.a.4.v；E.17.a.6.i；E.17.a.6.v；E.17.a.11.i； E.17.a.11.v；E.17.a.14.i；E.17.a.14.v；E.17.a.15.i；E.17.a.15.v；E.17.a.18.i；E.17.a.18.v； E.17.a.25.i；E.17.a.25.v；E.17.e.4.i；E.17.e.4.v；E.17.e.6.i；E.17.e.6.v；E.17.e.11.i； E.17.e.11.v；E.17.e.14.i；E.17.e.14.v；E.17.e.15.i；E.17.e.15.v；E.17.e.18.i；E.17.e.18.v； E.17.e.25.i；E.17.e.25.v；E.17.g.4.i；E.17.g.4.v；E.17.g.6.i；E.17.g.6.v；E.17.g.11.i； E.17.g.11.v；E.17.g.14.i；E.17.g.14.v；E.17.g.15.i；E.17.g.15.v；E.17.g.18.i；E.17.g.18.v； E.17.g.25.i；E.17.g.25.v；E.17.l.4.i；E.17.l.4.v；E.17.l.6.i；E.17.l.6.v；E.17.l.11.i； E.17.l.11.v；E.17.l.14.i；E.17.l.14.v；E.17.l.15.i；E.17.l.15.v；E.17.l.18.i；E.17.l.18.v； E.17.l.25.i；E.17.l.25.v；E.17.m.4.i；E.17.m.4.v；E.17.m.6.i；E.17.m.6.v；E.17.m.11.i； E.17.m.11.v；E.17.m.14.i；E.17.m.14.v；E.17.m.15.i；E.17.m.15.v；E.17.m.18.i； E.17.m.18.v；E.17.m.25.i；E.17.m.25.v；E.17.o.4.i；E.17.o.4.v；E.17.o.6.i；E.17.o.6.v； E.17.o.11.i；E.17.o.11.v；E.17.o.14.i；E.17.o.14.v；E.17.o.15.i；E.17.o.15.v；E.17.o.18.i； E.17.o.18.v；E.17.o.25.i；E.17.o.25.v；E.33.a.4.i；E.33.a.4.v；E.33.a.6.i；E.33.a.6.v； E.33.a.11.i；E.33.a.11.v；E.33.a.14.i；E.33.a.14.v；E.33.a.15.i；E.33.a.15.v；E.33.a.18.i； E.33.a.18.v；E.33.a.25.i；E.33.a.25.v；E.33.e.4.i；E.33.e.4.v；E.33.e.6.i；E.33.e.6.v；E.33.e.11.i；E.33.e.11.v；E.33.e.14.i；E.33.e.14.v；E.33.e.15.i；E.33.e.15.v；E.33.e.18.i； E.33.e.18.v；E.33.e.25.i；E.33.e.25.v；E.33.g.4.i；E.33.g.4.v；E.33.g.6.i；E.33.g.6.v； E.33.g.11.i；E.33.g.11.v；E.33.g.14.i；E.33.g.14.v；E.33.g.15.i；E.33.g.15.v；E.33.g.18.i； E.33.g.18.v；E.33.g.25.i；E.33.g.25.v；E.33.l.4.i；E.33.l.4.v；E.33.l.6.i；E.33.l.6.v； E.33.l.11.i；E.33.l.11.v；E.33.l.14.i；E.33.l.14.v；E.33.l.15.i；E.33.l.15.v；E.33.l.18.i； E.33.l.18.v；E.33.l.25.i；E.33.l.25.v；E.33.m.4.i；E.33.m.4.v；E.33.m.6.i；E.33.m.6.v； E.33.m.11.i；E.33.m.11.v；E.33.m.14.i；E.33.m.14.v；E.33.m.15.i；E.33.m.15.v； E.33.m.18.i；E.33.m.18.v；E.33.m.25.i；E.33.m.25.v；E.33.o.4.i；E.33.o.4.v；E.33.o.6.i； E.33.o.6.v；E.33.o.11.i；E.33.o.11.v；E.33.o.14.i；E.33.o.14.v；E.33.o.15.i；E.33.o.15.v； E.33.o.18.i；E.33.o.18.v；E.33.o.25.i；E.33.o.25.v；E.49.a.4.i；E.49.a.4.v；E.49.a.6.i； E.49.a.6.v；E.49.a.11.i；E.49.a.11.v；E.49.a.14.i；E.49.a.14.v；E.49.a.15.i；E.49.a.15.v； E.49.a.18.i；E.49.a.18.v；E.49.a.25.i；E.49.a.25.v；E.49.e.4.i；E.49.e.4.v；E.49.e.6.i； E.49.e.6.v；E.49.e.11.i；E.49.e.11.v；E.49.e.14.i；E.49.e.14.v；E.49.e.15.i；E.49.e.15.v； E.49.e.18.i；E.49.e.18.v；E.49.e.25.i；E.49.e.25.v；E.49.g.4.i；E.49.g.4.v；E.49.g.6.i； E.49.g.6.v；E.49.g.11.i；E.49.g.11.v；E.49.g.14.i；E.49.g.14.v；E.49.g.15.i；E.49.g.15.v； E.49.g.18.i；E.49.g.18.v；E.49.g.25.i；E.49.g.25.v；E.49.l.4.i；E.49.l.4.v；E.49.l.6.i； E.49.l.6.v；E.49.l.11.i；E.49.l.11.v；E.49.l.14.i；E.49.l.14.v；E.49.l.15.i；E.49.l.15.v； E.49.l.18.i；E.49.l.18.v；E.49.l.25.i；E.49.l.25.v；E.49.m.4.i；E.49.m.4.v；E.49.m.6.i； E.49.m.6.v；E.49.m.11.i；E.49.m.11.v；E.49.m.14.i；E.49.m.14.v；E.49.m.15.i； E.49.m.15.v；E.49.m.18.i；E.49.m.18.v；E.49.m.25.i；E.49.m.25.v；E.49.o.4.i； E.49.o.4.v；E.49.o.6.i；E.49.o.6.v；E.49.o.11.i；E.49.o.11.v；E.49.o.14.i；E.49.o.14.v； E.49.o.15.i；E.49.o.15.v；E.49.o.18.i；E.49.o.18.v；E.49.o.25.i；E.49.o.25.v；H.17.a.4.i； H.17.a.4.v；H.17.a.6.i；H.17.a.6.v；H.17.a.11.i；H.17.a.11.v；H.17.a.14.i；H.17.a.14.v； H.17.a.15.i；H.17.a.15.v；H.17.a.18.i；H.17.a.18.v；H.17.a.25.i；H.17.a.25.v； H.17.e.4.i；H.17.e.4.v；H.17.e.6.i；H.17.e.6.v；H.17.e.11.i；H.17.e.11.v；H.17.e.14.i； H.17.e.14.v；H.17.e.15.i；H.17.e.15.v；H.17.e.18.i；H.17.e.18.v；H.17.e.25.i； H.17.e.25.v；H.17.g.4.i；H.17.g.4.v；H.17.g.6.i；H.17.g.6.v；H.17.g.11.i；H.17.g.11.v； H.17.g.14.i；H.17.g.14.v；H.17.g.15.i；H.17.g.15.v；H.17.g.18.i；H.17.g.18.v； H.17.g.25.i；H.17.g.25.v；H.17.l.4.i；H.17.l.4.v；H.17.l.6.i；H.17.l.6.v；H.17.l.11.i； H.17.l.11.v；H.17.l.14.i；H.17.l.14.v；H.17.l.15.i；H.17.l.15.v；H.17.l.18.i；H.17.l.18.v； H.17.l.25.i；H.17.l.25.v；H.17.m.4.i；H.17.m.4.v；H.17.m.6.i；H.17.m.6.v； H.17.m.11.i；H.17.m.11.v；H.17.m.14.i；H.17.m.14.v；H.17.m.15.i；H.17.m.15.v； H.17.m.18.i；H.17.m.18.v；H.17.m.25.i；H.17.m.25.v；H.17.o.4.i；H.17.o.4.v； H.17.o.6.i；H.17.o.6.v；H.17.o.11.i；H.17.o.11.v；H.17.o.14.i；H.17.o.14.v； H.17.o.15.i；H.17.o.15.v；H.17.o.18.i；H.17.o.18.v；H.17.o.25.i；H.17.o.25.v； H.33.a.4.i；H.33.a.4.v；H.33.a.6.i；H.33.a.6.v；H.33.a.11.i；H.33.a.11.v；H.33.a.14.i； H.33.a.14.v；H.33.a.15.i；H.33.a.15.v；H.33.a.18.i；H.33.a.18.v；H.33.a.25.i； H.33.a.25.v；H.33.e.4.i；H.33.e.4.v；H.33.e.6.i；H.33.e.6.v；H.33.e.11.i；H.33.e.11.v； H.33.e.14.i；H.33.e.14.v；H.33.e.15.i；H.33.e.15.v；H.33.e.18.i；H.33.e.18.v； H.33.e.25.i；H.33.e.25.v；H.33.g.4.i；H.33.g.4.v；H.33.g.6.i；H.33.g.6.v；H.33.g.11.i； H.33.g.11.v；H.33.g.14.i；H.33.g.14.v；H.33.g.15.i；H.33.g.15.v；H.33.g.18.i； H.33.g.18.v；H.33.g.25.i；H.33.g.25.v；H.33.l.4.i；H.33.l.4.v；H.33.l.6.i；H.33.l.6.v； H.33.l.11.i；H.33.l.11.v；H.33.l.14.i；H.33.l.14.v；H.33.l.15.i；H.33.l.15.v；H.33.l.18.i； H.33.l.18.v；H.33.l.25.i；H.33.l.25.v；H.33.m.4.i；H.33.m.4.v；H.33.m.6.i； H.33.m.6.v；H.33.m.11.i；H.33.m.11.v；H.33.m.14.i；H.33.m.14.v；H.33.m.15.i； H.33.m.15.v；H.33.m.18.i；H.33.m.18.v；H.33.m.25.i；H.33.m.25.v；H.33.o.4.i； H.33.o.4.v；H.33.o.6.i；H.33.o.6.v；H.33.o.11.i；H.33.o.11.v；H.33.o.14.i；H.33.o.14.v；H.33.o.15.i；H.33.o.15.v；H.33.o.18.i；H.33.o.18.v；H.33.o.25.i； H.33.o.25.v；H.49.a.4.i；H.49.a.4.v；H.49.a.6.i；H.49.a.6.v；H.49.a.11.i；H.49.a.11.v； H.49.a.14.i；H.49.a.14.v；H.49.a.15.i；H.49.a.15.v；H.49.a.18.i；H.49.a.18.v； H.49.a.25.i；H.49.a.25.v；H.49.e.4.i；H.49.e.4.v；H.49.e.6.i；H.49.e.6.v；H.49.e.11.i； H.49.e.11.v；H.49.e.14.i；H.49.e.14.v；H.49.e.15.i；H.49.e.15.v；H.49.e.18.i； H.49.e.18.v；H.49.e.25.i；H.49.e.25.v；H.49.g.4.i；H.49.g.4.v；H.49.g.6.i；H.49.g.6.v； H.49.g.11.i；H.49.g.11.v；H.49.g.14.i；H.49.g.14.v；H.49.g.15.i；H.49.g.15.v； H.49.g.18.i；H.49.g.18.v；H.49.g.25.i；H.49.g.25.v；H.49.l.4.i；H.49.l.4.v；H.49.l.6.i； H.49.l.6.v；H.49.l.11.i；H.49.l.11.v；H.49.l.14.i；H.49.l.14.v；H.49.l.15.i；H.49.l.15.v； H.49.l.18.i；H.49.l.18.v；H.49.l.25.i；H.49.l.25.v；H.49.m.4.i；H.49.m.4.v； H.49.m.6.i；H.49.m.6.v；H.49.m.11.i；H.49.m.11.v；H.49.m.14.i；H.49.m.14.v； H.49.m.15.i；H.49.m.15.v；H.49.m.18.i；H.49.m.18.v；H.49.m.25.i；H.49.m.25.v； H.49.o.4.i；H.49.o.4.v；H.49.o.6.i；H.49.o.6.v；H.49.o.11.i；H.49.o.11.v；H.49.o.14.i； H.49.o.14.v；H.49.o.15.i；H.49.o.15.v；H.49.o.18.i；H.49.o.18.v；H.49.o.25.i； H.49.o.25.v；I.17.a.4.i；I.17.a.4.v；I.17.a.6.i；I.17.a.6.v；I.17.a.11.i；I.17.a.11.v； I.17.a.14.i；I.17.a.14.v；I.17.a.15.i；I.17.a.15.v；I.17.a.18.i；I.17.a.18.v；I.17.a.25.i； I.17.a.25.v；I.17.e.4.i；I.17.e.4.v；I.17.e.6.i；I.17.e.6.v；I.17.e.11.i；I.17.e.11.v； I.17.e.14.i；I.17.e.14.v；I.17.e.15.i；I.17.e.15.v；I.17.e.18.i；I.17.e.18.v；I.17.e.25.i； I.17.e.25.v；I.17.g.4.i；I.17.g.4.v；I.17.g.6.i；I.17.g.6.v；I.17.g.11.i；I.17.g.11.v； I.17.g.14.i；I.17.g.14.v；I.17.g.15.i；I.17.g.15.v；I.17.g.18.i；I.17.g.18.v；I.17.g.25.i； I.17.g.25.v；I.17.l.4.i；I.17.l.4.v；I.17.l.6.i；I.17.l.6.v；I.17.l.11.i；I.17.l.11.v；I.17.l.14.i； I.17.l.14.v；I17.l.15.i；I.17.l.15.v；I.17.l.18.i；I.17.l.18.v；I.17.l.25.i；I.17.l.25.v； I.17.m.4.i；I.17.m.4.v；I.17.m.6.i；I.17.m.6.v；I.17.m.11.i；I.17.m.11.v；I.17.m.14.i； I.17.m.14.v；I.17.m.15.i；I.17.m.15.v；I.17.m.18.i；I.17.m.18.v；I.17.m.25.i； I.17.m.25.v；I.17.o.4.i；I.17.o.4.v；I.17.o.6.i；I.17.o.6.v；I.17.o.11.i；I.17.o.11.v； I.17.o.14.i；I.17.o.14.v；I.17.o.15.i；I.17.o.15.v；I.17.o.18.i；I.17.o.18.v；I.17.o.25.i； I.17.o.25.v；I.33.a.4.i；I.33.a.4.v；I.33.a.6.i；I.33.a.6.v；I.33.a.11.i；I.33.a.11.v； I.33.a.14.i；I.33.a.14.v；I.33.a.15.i；I.33.a.15.v；I.33.a.18.i；I.33.a.18.v；I.33.a.25.i； I.33.a.25.v；I.33.e.4.i；I.33.e.4.v；I.33.e.6.i；I.33.e.6.v；I.33.e.11.i；I.33.e.11.v； I.33.e.14.i；I.33.e.14.v；I.33.e.15.i；I.33.e.15.v；I.33.e.18.i；I.33.e.18.v；I.33.e.25.i； I.33.e.25.v；I.33.g.4.i；I.33.g.4.v；I.33.g.6.i；I.33.g.6.v；I.33.g.11.i；I.33.g.11.v； I.33.g.14.i；I.33.g.14.v；I.33.g.15.i；I.33.g.15.v；I.33.g.18.i；I.33.g.18.v；I.33.g.25.i； I.33.g.25.v；I.33.l.4.i；I.33.l.4.v；I.33.l.6.i；I.33.l.6.v；I.33.l.11.i；I.33.l.11.v；I.33.l.14.i； I.33.l.14.v；I.33.l.15.i；I.33.l.15.v；I.33.l.18.i；I.33.l.18.v；I.33.l.25.i；I.33.l.25.v； I.33.m.4.i；I.33.m.4.v；I.33.m.6.i；I.33.m.6.v；I.33.m.11.i；I.33.m.11.v；I.33.m.14.i； I.33.m.14.v；I.33.m.15.i；I.33.m.15.v；I.33.m.18.i；I.33.m.18.v；I.33.m.25.i； I.33.m.25.v；I.33.o.4.i；I.33.o.4.v；I.33.o.6.i；I.33.o.6.v；I.33.o.11.i；I.33.o.11.v； I.33.o.14.i；I.33.o.14.v；I.33.o.15.i；I.33.o.15.v；I.33.o.18.i；I.33.o.18.v；I.33.o.25.i； I.33.o.25.v；I.49.a.4i；I.49.a.4.v；I.49.a.6.i；I.49.a.6.v；I.49.a.11.i；I.49.a.11.v； I.49.a.14.i；I.49.a.14.v；I.49.a.15.i；I.49.a.15.v；I.49.a.18.i；I.49.a.18.v；I.49.a.25.i； I.49.a.25.v；I.49.e.4.i；I.49.e.4.v；I.49.e.6.i；I.49.e.6.v；I.49.e.11.i；I.49.e.11.v； I.49.e.14.i；I.49.e.14.v；I.49.e.15.i；I.49.e.15.v；I.49.e.18.i；I.49.e.18.v；I.49.e.25.i； I.49.e.25.v；I.49.g.4.i；I.49.g.4.v；I.49.g.6.i；I.49.g.6.v；I.49.g.11.i；I.49.g.11.v； I.49.g.14.i；I.49.g.14.v；I.49.g.15.i；I.49.g.15.v；I.49g.18.i；I.49.g.18.v；I.49.g.25.i； I.49.g.25.v；I.49.l.4.i；I.49.l.4.v；I.49.l.6.i；I.49.l.6.v；I.49.l.11.i；I.49.l.11.v；I.49.l.14.i； I.49.l.14.v；I.49.l.15.i；I.49.l.15.v；I.49.l.18.i；I.49.l.18.v；I.49.l.25.i；I.49.l.25.v； I.49.m.4.i；I.49.m.4.v；I.49.m.6.i；I.49.m.6.v；I.49.m.11.i；I.49.m.11.v；I.49.m.14.i；I.49.m.14.v；I.49.m.15.i；I.49.m.15.v；I.49.m.18.i；I.49.m.18.v；I.49.m.25.i； I.49.m.25.v；I.49.o.4.i；I.49.o.4.v；I.49.o.6.i；I.49.o.6.v；I.49.o.11.i；I.49.o.11.v； I.49.o.14.i；I.49.o.14.v；I.49.o.15.i；I.49.o.15.v；I.49.o.18.i；I.49.o.18.v；I.49.o.25.i； I.49.o.25.v；L.17.a.4.i；L.17.a.4.v；L.17.a.6.i；L.17.a.6.v；L.17.a.11.i；L.17.a.11.v； L.17.a.14.i；L.17.a.14.v；L.17.a.15.i；L.17.a.15.v；L.17.a.18.i；L.17.a.18.v；L.17.a.25.i； L.17.a.25.v；L.17.e.4.i；L.17.e.4.v；L.17.e.6.i；L.17.e.6.v；L.17.e.11.i；L.17.e.11.v； L.17.e.14.i；L.17.e.14.v；L.17.e.15.i；L.17.e.15.v；L.17.e.18.i；L.17.e.18.v；L.17.e.25.i； L.17.e.25.v；L.17.g.4.i；L.17.g.4.v；L.17.g.6.i；L.17.g.6.v；L.17.g.11.i；L.17.g.11.v； L.17.g.14.i；L.17.g.14.v；L.17.g.15.i；L.17.g.15.v；L.17.g.18.i；L.17.g.18.v；L.17.g.25.i； L.17.g.25.v；L.17.l.4.i；L.17.l.4.v；L.17.l.6.i；L.17.l.6.v；L.17.l.11.i；L.17.l.11.v； L.17.l.14.i；L.17.l.14.v；L.17.l.15.i；L.17.l.15.v；L.17.l.18.i；L.17.l.18.v；L.17.l.25.i； L.17.l.25.v；L.17.m.4.i；L.17.m.4.v；L.17.m.6.i；L.17.m.6.v；L.17.m.11.i； L.17.m.11.v；L.17.m.14.i；L.17.m.14.v；L.17.m.15.i；L.17.m.15.v；L.17.m.18.i； L.17.m.18.v；L.17.m.25.i；L.17.m.25.v；L.17.o.4.i；L.17.o.4.v；L.17.o.6.i；L.17.o.6.v； L.17.o.11.i；L.17.o.11.v；L.17.o.14.i；L.17.o.14.v；L.17.o.15.i；L.17.o.15.v；L.17.o.18.i； L.17.o.18.v；L.17.o.25.i；L.17.o.25.v；L.33.a.4.i；L.33.a.4.v；L.33.a.6.i；L.33.a.6.v； L.33.a.11.i；L.33.a.11.v；L.33.a.14.i；L.33.a.14.v；L.33.a15.i；L.33.a.15.v；L.33.a.18.i； L.33.a.18.v；L.33.a.25.i；L.33.a.25.v；L.33.e.4.i；L.33.e.4.v；L.33.e.6.i；L.33.e.6.v； L.33.e.11.i；L.33.e.11.v；L.33.e.14.i；L.33.e.14.v；L.33.e.15.i；L.33.e.15.v；L.33.e.18.i； L.33.e.18.v；L.33.e.25.i；L.33.e.25.v；L.33.g.4.i；L.33.g.4.v；L.33.g.6.i；L.33.g.6.v； L.33.g.11.i；L.33.g.11.v；L.33.g.14.i；L.33.g.14.v；L.33.g.15.i；L.33.g.15.v；L.33.g.18.i； L.33.g.18.v；L.33.g.25.i；L.33.g.25.v；L.33.l.4.i；L.33.l.4.v；L.33.l.6.i；L.33.l.6.v； L.33.l.11.i；L.33.l.11.v；L.33.l.14.i；L.33.l.14.v；L.33.l.15.i；L.33.l.15.v；L.33.l.18.i； L.33.l.18.v；L.33.l.25.i；L.33.l.25.v；L.33.m.4.i；L.33.m.4.v；L.33.m.6.i；L.33.m.6.v； L.33.m.11.i；L.33.m.11.v；L.33.m.14.i；L.33.m.14.v；L.33.m.15.i；L.33.m.15.v； L.33.m.18.i；L.33.m.18.v；L.33.m.25.i；L.33.m.25.v；L.33.o.4.i；L.33.o.4.v；L.33.o.6.i； L.33.o.6.v；L.33.o.11.i；L.33.o.11.v；L.33.o.14.i；L.33.o.14.v；L.33.o.15.i；L.33.o.15.v； L.33.o.18.i；L.33.o.18.v；L.33.o.25.i；L.33.o.25.v；L.49.a.4.i；L.49.a.4.v；L.49.a.6.i； L.49.a.6.v；L.49.a.11.i；L.49.a.11.v；L.49.a.14.i；L.49.a.14.v；L.49.a.15.i；L.49.a.15.v； L.49.a.18.i；L.49.a.18.v；L.49.a.25.i；L.49.a.25.v；L.49.e.4.i；L.49.e.4.v；L.49.e.6.i； L.49.e.6.v；L.49.e.11.i；L.49.e.11.v；L.49.e.14.i；L.49.e.14.v；L.49.e.15.i；L.49.e.15.v； L.49.e.18.i；L.49.e.18.v；L.49.e.25.i；L.49.e.25.v；L.49.g.4.i；L.49.g.4.v；L.49.g.6.i； L.49.g.6.v；L.49.g.11.i；L.49.g.11.v；L.49.g.14.i；L.49.g.14.v；L.49.g.15.i；L.49.g.15.v； L.49.g.18.i；L.49.g.18.v；L.49.g.25.i；L.49.g.25.v；L.49.l.4.i；L.49.l.4.v；L.49.l.6.i； L.49.l.6.v；L.49.l.11.i；L.49.l.11.v；L.49.l.14.i；L.49.l.14.v；L.49.l.15.i；L.49.l.15.v； L.49.l.18.i；L.49.l.18.v；L.49.l.25.i；L.49.l.25.v；L.49.m.4.i；L.49.m.4.v；L.49.m.6.i； L.49.m.6.v；L.49.m.11.i；L.49.m.11.v；L.49.m.14.i；L.49.m.14.v；L.49.m.15.i； L.49.m.15.v；L.49.m.18.i；L.49.m.18.v；L.49.m.25.i；L.49.m.25.v；L.49.o.4.i； L.49.o.4.v；L.49.o.6.i；L.49.o.6.v；L.49.o.11.i；L.49.o.11.v；L.49.o.14.i；L.49.o.14.v； L.49.o.15.i；L.49.o.15.v；L.49.o.18.i；L.49.o.18.v；L.49.o.25.i；L.49.o.25.v；B.93.a.4.i； B.93.a.4.v；B.93.a.6.i；B.93.a.6.v；B.93.a.11.i；B.93.a.11.v；B.93.a.14.i；B.93.a.14.v； B.93.a.15.i；B.93.a.15.v；B.93.a.18.i；B.93.a.18.v；B.93.a.25.i；B.93.a.25.v；B.93.e.4.i； B.93.e.4.v；B；93.e.6.i；B.93.e.6.v；B.93.e.11.i；B.93.e.11.v；B.93.e.14.i；B.93.e.14.v； B.93.e.15.i；B.93.e.15.v；B.93.e.18.i；B.93.e.18.v；B.93.e.25.i；B.93.e.25.v；B.93.g.4.i； B.93.g.4.v；B.93.g.6.i；B.93.g.6.v；B.93.g.11.i；B.93.g.11.v；B.93.g.14.i；B.93.g.14.v； B.93.g.15.i；B.93.g.15.v；B.93.g.18.i；B.93.g.18v；B.93.g.25.i；B.93.g.25.v；B.93.l.4.i； B.93.l.4.v；B.93.l.6.i；B.93.l.6.v；B.93l.11.i；B.93.l.11.v；B.93.l.14.i；B.93.l.14.v；B.93.l.15.i；B.93.l.15.v；B.93.l.18.i；B.93.l.18.v；B.93.l.25.i；B.93.l.25.v；B.93.m.4.i； B.93.m.4.v；B.93.m.6.i；B.93.m.6.v；B.93.m.11.i；B.93.m.11.v；B.93.m.14.i； B.93.m.14.v；B.93.m.15.i；B.93.m.15.v；B.93.m.18.i；B.93.m.18.v；B.93.m.25.i； B.93.m.25.v；B.93.o.4.i；B.93.o.4.v；B.93.o.6.i；B.93.o.6.v；B.93.o.11.i；B.93.o.11.v； B.93.o.14.i；B.93.o.14.v；B.93.o.15.i；B.93.o.15.v；B.93.o.18.i；B.93.o.18.v； B.93.o.25.i；B.93.o.25.v；B.94.a.4.i；B.94.a.4.v；B.94.a.6.i；B.94.a.6.v；B.94.a.11.i； B.94.a.11.v；B.94.a.14.i；B.94.a.14.v；B.94.a.15.i；B.94.a.15.v；B.94.a.18.i；B.94.a.18.v； B.94.a.25.i；B.94.a.25.v；B.94.e.4.i；B.94.e.4.v；B.94.e.6.i；B.94.e.6.v；B.94.e.11.i； B.94.e.11.v；B.94.e.14.i；B.94.e.14.v；B.94.e.15.i；B.94.e.15.v；B.94.e.18.i；B.94.e.18.v； B.94.e.25.i；B.94.e.25.v；B.94.g.4.i；B.94.g.4.v；B.94.g.6.i；B.94.g.6.v；B.94.g.11.i； B.94.g.11.v；B.94.g.14.i；B.94.g.14.v；B.94.g.15.i；B.94.g.15.v；B.94.g.18.i；B.94.g.18.v； B.94.g.25.i；B.94.g.25.v；B.94.l.4.i；B.94.l.4.v；B.94.l.6.i；B.94.l.6.v；B.94.l.11.i； B.94.l.11.v；B.94.l.14.i；B.94.l.14.v；B.94.l.15.i；B.94.l.15.v；B.94.l.18.i；B.94.l.18.v； B.94.l.25.i；B.94.l.25.v；B.94.m.4.i；B.94.m.4.v；B.94.m.6.i；B.94.m.6.v；B.94.m.11.i； B.94.m.11.v；B.94.m.14.i；B.94.m.14.v；B.94.m.15.i；B.94.m.15.v；B.94.m.18.i； B.94.m.18.v；B.94.m.25.i；B.94.m.25.v；B.94.o.4.i；B.94.o.4.v；B.94.o.6.i；B.94.o.6.v； B.94.o.11.i；B.94.o.11.v；B.94.o.14.i；B.94.o.14.v；B.94.o.15.i；B.94.o.15.v； B.94.o.18.i；B.94.o.18.v；B.94.o.25.i；B.94.o.25v；E.93.a.4.i；E.93.a.4.v；E.93.a.6.i； E.93.a.6.v；E.93.a.11.i；E.93.a.11.v；E.93.a.14.i；E.93.a.14.v；E.93.a.15.i；E.93.a.15.v； E.93.a.18.i；E.93.a.18.v；E.93.a.25.i；E.93.a.25.v；E.93.e.4.i；E.93.e.4.v；E.93.e.6.i； E.93.e.6.v；E.93.e.11.i；E.93.e.11.v；E.93.e.14.i；E.93.e.14.v；E.93.e.15.i；E.93.e.15.v； E.93.e.18.i；E.93.e.18.v；E.93.e.25.i；E.93.e.25.v；E.93.g.4.i；E.93.g.4.v；E.93.g.6.i； E.93.g.6.v；E.93.g.11.i；E.93.g.11.v；E.93.g.14.i；E.93.g.14.v；E.93.g.15.i；E.93.g.15.v； E.93.g.18.i；E.93.g.18.v；E.93.g.25.i；E.93.g.25.v；E.93.l.4.i；E.93.l.4.v；E.93.l.6.i； E.93.l.6.v；E.93.l.11.i；E.93.l.11.v；E.93.l.14.i；E.93.l.14.v；E.93.l.15.i；E.93.l.15.v； E.93.l.18.i；E.93.l.18.v；E.93.l.25.i；E.93.l.25.v；E.93.m.4.i；E.93.m.4.v；E.93.m.6.i； E.93.m.6.v；E.93.m.11.i；E.93.m.11.v；E.93.m.14.i；E.93.m.14.v；E.93.m.15.i； E.93.m.15.v；E.93.m.18.i；E.93.m.18.v；E.93.m.25.i；E.93.m.25.v；E.93.o.4.i； E.93.o.4.v；E.93.o.6.i；E.93.o.6.v；E.93.o.11.i；E.93.o.11.v；E.93.o.14.i；E.93.o.14.v； E.93.o.15.i；E.93.o.15.v；E.93.o.18.i；E.93.o.18.v；E.93.o.25.i；E.93.o.25.v；E.94.a.4.i； E.94.a.4.v；E.94.a.6.i；E.94.a.6.v；E.94.a.11.i；E.94.a.11.v；E.94.a.14.i；E.94.a.14.v； E.94.a.15.i；E.94.a.15.v；E.94.a.18.i；E.94.a.18.v；E.94.a.25.i；E.94.a.25.v；E.94.e.4.i； E.94.e.4.v；E.94.e.6.i；E.94.e.6.v；E.94.e.11.i；E.94.e.11.v；E.94.e.14.i；E.94.e.14.v； E.94.e.15.i；E.94.e.15.v；E.94.e.18.i；E.94.e.18.v；E.94.e.25.i；E.94.e.25.v；E.94.g.4.i； E.94.g.4.v；E.94.g.6.i；E.94.g.6.v；E.94.g.11.i；E.94.g.11.v；E.94.g.14.i；E.94.g.14.v； E.94.g.15.i；E.94.g.15.v；E.94.g.18.i；E.94.g.18.v；E.94.g.25.i；E.94.g.25.v；E.94.l.4.i； E.94.l.4.v；E.94.l.6.i；E.94.l.6.v；E.94.l.11.i；E.94.l.11.v；E.94.l.14.i；E.94.l.14.v； E.94.l.15.i；E.94.l.15.v；E.94.l.18.i；E.94.l.18.v；E.94.l.25.i；E.94.l.25.v；E.94.m.4.i； E.94.m.4.v；E.94.m.6.i；E.94.m.6.v；E.94.m.11.i；E.94.m.11.v；E.94.m.14.i； E.94.m.14.v；E.94.m.15.i；E.94.m.15.v；E.94.m.18.i；E.94.m.18.v；E.94.m.25.i； E.94.m.25.v；E.94.o.4.i；E.94.o.4.v；E.94.o.6.i；E.94.o.6.v；E.94.o.11.i；E.94.o.11.v； E.94.o.14.i；E.94.o.14.v；E.94.o.15.i；E.94.o.15.v；E.94.o.18.i；E.94.o.18.v；E.94.o.25.i； E.94.o.25.v；I.93.a.4.i；I.93.a.4.v；I.93.a.6.i；I.93.a.6.v；I.93.a.11.i；I.93.a.11.v； I.93.a.14.i；I.93.a.14.v；I.93.a.15.i；I.93.a.15.v；I.93.a.18.i；I.93.a.18.v；I.93.a.25.i； I.93.a.25.v；I.93.e.4.i；I.93.e.4.v；I.93.e.6.i；I.93.e.6.v；I.93.e.11.i；I.93.e.11.v； I.93.e.14.i；I.93.e.14.v；I.93.e.15.i；I.93.e.15.v；I.93.e.18.i；I.93.e.18.v；I.93.e.25.i； I.93.e.25.v；I.93.g.4.i；I.93.g.4.v；I.93.g.6.i；I.93.g.6.v；I.93.g.11.i；I.93.g.11.v；I.93.g.14.i；I.93.g.14.v；I.93.g.15.i；I.93.g.15.v；I.93.g.18.i；I.93.g.18.v；I.93.g.25.i； I.93.g.25.v；I.93.l.4.i；I.93.l.4.v；I.93.l.6.i；I.93.l.6.v；I.93.l.11.i；I.93.l.11.v；I.93.l.14.i； I.93.l.14.v；I.93.l.15.i；I.93.l.15.v；I.93.l.18.i；I.93.l.18.v；I.93.l.25.i；I.93.l.25.v； I.93.m.4.i；I.93.m.4.v；I.93.m.6.i；I.93.m.6.v；I.93.m.11.i；I.93.m.11.v；I.93.m.14.i； I.93.m.14.v；I.93.m.15.i；I.93.m.15.v；I.93.m.18.i；I.93.m.18.v；I.93.m.25.i； I.93.m.25.v；I.93.o.4.i；I.93.o.4.v；I.93.o.6.i；I.93.o.6.v；I.93.o.11.i；I.93.o.11.v； I.93.o.14.i；I.93.o.14.v；I.93.o.15.i；I.93.o.15.v；I.93.o.18.i；I.93.o.18.v；I.93.o.25.i； I.93.o.25.v；I.94.a.4.i；I.94.a.4.v；I.94.a.6.i；I.94.a.6.v；I.94.a.11.i；I.94.a.11.v； I.94.a.14.i；I.94.a.14.v；I.94.a.15.i；I.94.a.15.v；I.94.a.18.i；I.94.a.18.v；I.94.a.25.i； I.94.a.25.v；I.94.e.4.i；I.94.e.4.v；I.94.e.6.i；I.94.e.6.v；I.94.e.11.i；I.94.e.11.v； I.94.e.14.i；I.94.e.14.v；I.94.e.15.i；I.94.e.15.v；I.94.e.18.i；I.94.e.18.v；I.94.e.25.i； I.94.e.25.v；I.94.g.4.i；I.94.g.4.v；I.94.g.6.i；I.94.g.6.v；I.94.g.11.i；I.94.g.11.v； I.94.g.14.i；I.94.g.14.v；I.94.g.15.i；I.94.g.15.v；I.94.g.18.i；I.94.g.18.v；I.94.g.25.i； I.94.g.25.v；I.94.l.4.i；I.94.l.4.v；I.94.l.6.i；I.94.l.6.v；I.94.l.11.i；I.94.l.11.v；I.94.l.14.i； I.94.l.14.v；I.94.l.15.i；I.94.l.15.v；I.94.l.18.i；I.94.l.18.v；I.94.l.25.i；I.94.l.25.v； I.94.m.4.i；I.94.m.4.v；I.94.m.6.i；I.94.m.6.v；I.94.m.11.i；I.94.m.11.v；I.94.m.14.i； I.94.m.14.v；I.94.m.15.i；I.94.m.15.v；I.94.m.18.i；I.94.m.18.v；I.94.m.25.i； I.94.m.25.v；I.94.o.4.i；I.94.o.4.v；I.94.o.6.i；I.94.o.6.v；I.94.o.11.i；I.94.o.11.v； I.94.o.14.i；I.94.o.14.v；I.94.o.15.i；I.94.o.15.v；I.94.o.18.i；I.94.o.18.v；I.94.o.25.i； I.94.o.25.v；L.93.a.4.i；L.93.a.4.v；L.93.a.6.i；L.93.a.6.v；L.93.a.11.i；L.93.a.11.v； L.93.a.14.i；L.93.a.14.v；L93.a.15.i；L.93.a.15.v；L.93.a.18.i；L.93.a.18.v；L.93.a.25.i； L.93.a.25.v；L.93.e.4.i；L.93.e.4.v；L.93.e.6.i；L.93.e.6.v；L.93.e.11.i；L.93.e.11.v； L.93.e.14.i；L.93.e.14.v；L.93.e.15.i；L.93.e.15.v；L.93.e.18.i；L.93.e.18.v；L.93.e.25.i； L.93.e.25.v；L.93.g.4.i；L.93.g.4.v；L.93.g.6.i；L.93.g.6.v；L.93.g.11.i；L.93.g.11.v； L.93.g.14.i；L.93.g.14.v；L.93.g.15.i；L.93.g.15.v；L.93.g.18.i；L.93.g.18.v；L.93.g.25.i； L.93.g.25.v；L.93.l.4.i；L.93.l.4.v；L.93.l.6.i；L.93.l.6.v；L.93.l.11.i；L.93.l.11.v； L.93.l.14.i；L.93.l.14.v；L.93.l.15.i；L.93.l.15.v；L.93.l.18.i；L.93.l.18.v；L.93.l.25.i； L.93.l.25.v；L.93.m.4.i；L.93.m.4.v；L.93.m.6.i；L.93.m.6.v；L.93.m.11.i； L.93.m.11.v；L.93.m.14.i；L.93.m.14.v；L.93.m.15.i；L.93.m.15.v；L.93.m.18.i； L.93.m.18.v；L.93.m.25.i；L.93.m.25.v；L.93.o.4.i；L.93.o.4.v；L.93.o.6.i；L.93.o.6.v； L.93.o.11.i；L.93.o.11.v；L.93.o.14.i；L.93.o.14.v；L.93.o.15.i；L.93.o.15.v；L.93.o.18.i； L.93.o.18.v；L.93.o.25.i；L.93.o.25.v；L.94.a.4.i；L.94.a.4.v；L.94.a.6.i；L.94.a.6.v； L.94.a.11.i；L.94.a.11.v；L.94.a.14.i；L.94.a.14.v；L.94.a.15.i；L.94.a.15.v；L.94.a.18.i； L.94.a.18.v；L.94.a.25.i；L.94.a.25.v；L.94.e.4.i；L.94.e.4.v；L.94.e.6.i；L.94.e.6.v； L.94.e.11.i；L.94.e.11.v；L.94.e.14.i；L.94.e.14.v；L.94.e.15.i；L.94.e.15.v；L.94.e.18.i； L.94.e.18.v；L.94.e.25.i；L.94.e.25.v；L.94.g.4.i；L.94.g.4.v；L.94.g.6.i；L.94.g.6.v； L.94.g.11.i；L.94.g.11.v；L.94.g.14.i；L.94.g.14.v；L.94.g.15.i；L.94.g.15.v；L.94.g.18.i； L.94.g.18.v；L.94.g.25.i；L.94.g.25.v；L.94.l.4.i；L.94.l.4.v；L.94.l.6.i；L.94.l.6.v； L.94.l.11.i；L.94.l.11.v；L.94.l.14.i；L.94.l.14.v；L.94.l.15.i；L.94.l.15.v；L.94.l.18.i； L.94.l.18.v；L.94.l.25.i；L.94.l.25.v；L.94.m.4.i；L.94.m.4.v；L.94.m.6.i；L.94.m.6.v； L.94.m.11.i；L.94.m.11.v；L.94.m.14.i；L.94.m.14.v；L.94.m.15.i；L.94.m.15.v； L.94.m.18.i；L.94.m.18.v；L.94.m.25.i；L.94.m.25.v；L.94.o.4.i；L.94.o.4.v；L.94.o.6.i； L.94.o.6.v；L.94.o.11.i；L.94.o.11.v；L.94.o.14.i；L.94.o.14.v；L.94.o.15.i；L.94.o.15.v； L.94.o.18.i；L.94.o.18.v；L.94.o.25.i；L.94.o.25.v；O.93.a.4.i；O.93.a.4.v；O.93.a.6.i； O.93.a.6.v；O.93.a.11.i；O.93.a.11.v；O.93.a.14.i；O.93.a.14.v；O.93.a.15.i； O.93.a.15.v；O.93.a.18.i；O.93.a.18.v；O.93.a.25.i；O.93.a.25.v；O.93.e.4.i；O.93.e.4.v； O.93.e.6.i；O.93.e.6.v；O.93.e.11.i；O.93.e.11.v；O.93.e.14.i；O.93.e.14.v；O.93.e.15.i；O.93.e.15.v；O.93.e.18.i；O.93.e.18.v；O.93.e.25.i；O.93.e.25.v；O.93.g.4.i；O.93.g.4.v； O.93.g.6.i；O.93.g.6.v；O.93.g.11.i；O.93.g.11.v；O.93.g.14.i；O.93.g.14.v；O.93.g.15.i； O.93.g.15.v；O.93.g.18.i；O.93.g.18.v；O.93.g.25.i；O.93.g.25.v；O.93.l.4.i；O.93.l.4.v； O.93.l.6.i；O.93.l.6.v；O.93.l.11.i；O.93.l.11.v；O.93.l.14.i；O.93.l.14.v；O.93.l.15.i； O.93.l.15.v；O.93.l.18.i；O.93.l.18.v；O.93.l.25.i；O.93.l.25.v；O.93.m.4.i；O.93.m.4.v； O.93.m.6.i；O.93.m.6.v；O.93.m.11.i；O.93.m.11.v；O.93.m.14.i；O.93.m.14.v； O.93.m.15.i；O.93.m.15.v；O.93.m.18.i；O.93.m.18.v；O.93.m.25.i；O.93.m.25.v； O.93.o.4.i；O.93.o.4.v；O.93.o.6.i；O.93.o.6.v；O.93.o.11.i；O.93.o.11.v；O.93.o.14.i； O.93.o.14.v；O.93.o.15.i；O.93.o.15.v；O.93.o.18.i；O.93.o.18.v；O.93.o.25.i； O.93.o.25.v；O.94.a.4.i；O.94.a.4.v；O.94.a.6.i；O.94.a.6.v；O.94.a.11.i；O.94.a.11.v； O.94.a.14.i；O.94.a.14.v；O.94.a.15.i；O.94.a.15.v；O.94.a.18.i；O.94.a.18.v； O.94.a.25.i；O.94.a.25.v；O.94.e.4.i；O.94.e.4.v；O.94.e.6.i；O.94.e.6.v；O.94.e.11.i； O.94.e.11.v；O.94.e.14.i；O.94.e.14.v；O.94.e.15.i；O.94.e.15.v；O.94.e.18.i； O.94.e.18.v；O.94.e.25.i；O.94.e.25.v；O.94.g.4.i；O.94.g.4.v；O.94.g.6.i；O.94.g.6.v； O.94.g.11.i；O.94.g.11.v；O.94.g.14.i；O.94.g.14.v；O.94.g.15.i；O.94.g.15.v； O.94.g.18.i；O.94.g.18.v；O.94.g.25.i；O.94.g.25.v；O.94.l.4.i；O.94.l.4.v；O.94.l.6.i； O.94.l.6.v；O.94.l.11.i；O.94.l.11.v；O.94.l.14.i；O.94.l.14.v；O.94.l.15.i；O.94.l.15.v； O.94.l.18.i；O.94.l.18.v；O.94l.25.i；O.94.l.25.v；O.94.m.4.i；O.94.m.4.v；O.94.m.6.i； O.94.m.6.v；O.94.m.11.i；O.94.m.11.v；O.94.m.14.i；O.94.m.14.v；O.94.m.15.i； O.94.m.15.v；O.94.m.18.i；O.94.m.18.v；O.94.m.25.i；O.94.m.25.v；O.94.o.4.i； O.94.o.4.v；O.94.o.6.i；O.94.o.6.v；O.94.o.11.i；O.94.o.11.v；O.94.o.14.i；O.94.o.14.v； O.94.o.15.i；O.94.o.15.v；O.94.o.18.i；O.94.o.18.v；O.94.o.25.i；O.94.o.25.v； P.93.a.4.i；P.93.a.4.v；P.93.a.6.i；P.93.a.6.v；P.93.a.11.i；P.93.a.11.v；P.93.a.14.i； P.93.a.14.v；P.93.a.15.i；P.93.a.15.v；P.93.a.18.i；P.93.a.18.v；P.93.a.25.i；P.93.a.25.v； P.93.e.4.i；P.93.e.4.v；P.93.e.6.i；P.93.e.6.v；P.93.e.11.i；P.93.e.11.v；P.93.e.14.i； P.93.e.14.v；P.93.e.15.i；P.93.e.15.v；P.93.e.18.i；P.93.e.18.v；P.93.e.25.i；P.93.e.25.v； P.93.g.4.i；P.93.g.4.v；P.93.g.6.i；P.93.g.6.v；P.93.g.11.i；P.93.g.11.v；P.93.g.14.i； P.93.g.14.v；P.93.g.15.i；P.93.g.15.v；P.93.g.18.i；P.93.g.18.v；P.93.g.25.i；P.93.g.25.v； P.93.l.4.i；P.93.l.4.v；P.93.l.6.i；P.93.l.6.v；P.93.l.11.i；P.93.l.11.v；P.93.l.14.i； P.93.l.14.v；P.93.l.15.i；P.93.l.15.v；P.93.l.18.i；P.93.l.18.v；P.93.l.25.i；P.93.l.25.v； P.93.m.4.i；P.93.m.4.v；P.93.m.6.i；P.93.m.6.v；P.93.m.11.i；P.93.m.11.v； P.93.m.14.i；P.93.m.14.v；P.93.m.15.i；P.93.m.15.v；P.93.m.18.i；P.93.m.18.v； P.93.m.25.i；P.93.m.25.v；P.93.o.4.i；P.93.o.4.v；P.93.o.6.i；P.93.o.6.v；P.93.o.11.i； P.93.o.11.v；P.93.o.14.i；P.93.o.14.v；P.93.o.15.i；P.93.o.15.v；P.93.o.18.i；P.93.o.18.v； P.93.o.25.i；P.93.o.25.v；P.94.a.4.i；P.94.a.4.v；P.94.a.6.i；P.94.a.6.v；P.94.a.11.i； P.94.a.11.v；P.94.a.14.i；P.94.a.14.v；P.94.a.15.i；P.94.a.15.v；P.94.a.18.i；P.94.a.18.v； P.94.a.25.i；P.94.a.25.v；P.94.e.4.i；P.94.e.4.v；P.94.e.6.i；P.94.e.6.v；P.94.e.11.i； P.94.e.11.v；P.94.e.14.i；P.94.e.14.v；P.94.e.15.i；P.94.e.15.v；P.94.e.18.i；P.94.e.18.v； P.94.e.25.i；P.94.e.25.v；P.94.g.4.i；P.94.g.4.v；P.94.g.6.i；P.94.g.6.v；P.94.g.11.i； P.94.g.11.v；P.94.g.14.i；P.94.g.14.v；P.94.g.15.i；P.94.g.15.v；P.94.g.18.i；P.94.g.18.v； P.94.g.25.i；P.94.g.25.v；P.94.l.4.i；P.94.l.4.v；P.94.l.6.i；P.94.l.6.v；P.941.11.i； P.94.l.11.v；P.94.l.14.i；P.94.l.14.v；P.94.l.15.i；P.94.l.15.v；P.94.l.18.i；P.94.l.18.v； P.94.l.25.i；P.94.l.25.v；P.94.m.4.i；P.94.m.4.v；P.94.m.6.i；P.94.m.6.v；P.94.m.11.i； P.94.m.11.v；P.94.m.14.i；P.94.m.14.v；P.94.m.15.i；P.94.m.15.v；P.94.m.18.i； P.94.m.18.v；P.94.m.25.i；P.94.m.25.v；P.94.o.4.i；P.94.o.4.v；P.94.o.6.i；P.94.o.6.v； P.94o.11.i；P.94.o.11.v；P.94.o.14.i；P.94.o.14.v；P.94.o.15.i；P.94.o.15.v；P.94.o.18.i； P.94.o.18.v；P.94.o.25.i；P.94.o.25.v；A.2.a.4.o；A.2.a.4.bh；A.2.a.4.bi；A.2.a.4.bj；A.2.a.4.bk；A.2.a.11.o；A.2.a.11.bh；A.2.a.11.bi；A.2.a.11.bj；A.2.a.11.bk；A.2.a.15.i； A.2.a.15.o；A.2.a.15.bh；A.2.a.15.bi；A.2.a.15.bj；A.2.a.15.bk；A.2.a.37.i；A.2.a.37.o； A.2.a.37.bh；A.2.a.37.bi；A.2.a.37.bj；A.2.a.37.bk；A.2.a.38.i；A.2.a.38.o；A.2.a.38.bh； A.2.a.38.bi；A.2.a.38.bj；A.2.a.38.bk；A.2.a.39.i；A.2.a.39.o；A.2.a.39.bh；A.2.a.39.bi； A.2.a.39.bj；A.2.a.39.bk；A.2.a.40.i；A.2.a.40.o；A.2.a.40.bh；A.2.a.40.bi；A.2.a.40.bj； A.2.a.40.bk；A.2.a.41.i；A.2.a.41.o；A.2.a.41.bh；A.2.a.41.bi；A.2.a.41.bj；A.2.a.41.bk； A.2.a.42.i；A.2.a.42.o；A.2.a.42.bh；A.2.a.42.bi；A.2.a.42.bj；A.2.a.42.bk；A.2.a.43.i； A.2.a.43.o；A.2.a.43.bh；A.2.a.43.bi；A.2.a.43.bj；A.2.a.43.bk； A.3.a.4.o；A.3.a.4.bh；A.3.a.4.bi；A.3.a.4.bj；A.3.a.4.bk；A.3.a.11.o；A.3.a.11.bh； A.3.a.11.bi；A.3.a.11.bj；A.3.a.11.bk；A.3.a.15.i；A.3.a.15.o；A.3.a.15.bh；A.3.a.15.bi； A.3.a.15.bj；A.3.a.15.bk；A.3.a.37.i；A.3.a.37.o；A.3.a.37.bh；A.3.a.37.bi；A.3.a.37.bj； A.3.a.37.bk；A.3.a.38.i；A.3.a.38.o；A.3.a.38.bh；A.3.a.38.bi；A.3.a.38.bj；A.3.a.38.bk； A.3.a.39.i；A.3.a.39.o；A.3.a.39.bh；A.3.a.39.bi；A.3.a.39.bj；A.3.a.39.bk；A.3.a.40.i； A.3.a.40.o；A.3.a.40.bh；A.3.a.40.bi；A.3.a.40.bj；A.3.a.40.bk；A.3.a.41.i；A.3.a.41.o； A.3.a.41.bh；A.3.a.41.bi；A.3.a.41.bj；A.3.a.41.bk；A.3.a.42.i；A.3.a.42.o；A.3.a.42.bh； A.3.a.42.bi；A.3.a.42.bj；A.3.a.42.bk；A.3.a.43.i；A.3.a.43.o；A.3.a.43.bh；A.3.a.43.bi； A.3.a.43.bj；A.3.a.43.bk；A.4.a.4.o；A.4.a.4.bh；A.4.a.4.bi；A.4.a.4.bj；A.4.a.4.bk； A.4.a.11.o；A.4.a.11.bh；A.4.a.11.bi；A.4.a.11.bj；A.4.a.11.bk；A.4.a.15.i；A.4.a.15.o； A.4.a.15.bh；A.4.a.15.bi；A.4.a.15.bj；A.4.a.15.bk；A.4.a.37.i；A.4.a.37.o；A.4.a.37.bh； A.4.a.37.bi；A.4.a.37.bj；A.4.a.37.bk；A.4.a.38.i；A.4.a.38.o；A.4.a.38.bh；A.4.a.38.bi； A.4.a.38.bj；A.4.a.38.bk；A.4.a.39.i；A.4.a.39.o；A.4.a.39.bh；A.4.a.39.bi；A.4.a.39.bj； A.4.a.39.bk；A.4.a.40.i；A.4.a.40.o；A.4.a.40.bh；A.4.a.40.bi；A.4.a.40.bj；A.4.a.40.bk； A.4.a.41.i；A.4.a.41.o；A.4.a.41.bh；A.4.a.41.bi；A.4.a.41.bj；A.4.a.41.bk；A.4.a.42.i； A.4.a.42.o；A.4.a.42.bh；A.4.a.42.bi；A.4.a.42.bj；A.4.a.42.bk；A.4.a.43.i；A.4.a.43.o； A.4.a.43.bh；A.4.a.43.bi；A.4.a.43.bj；A.4.a.43.bk；A.7.a.4.o；A.7.a.4.bh；A.7.a.4.bi； A.7.a.4.bj；A.7.a.4.bk；A.7.a.11.o；A.7.a.11.bh；A.7.a.11.bi；A.7.a.11.bj；A.7.a.11.bk； A.7.a.15.i；A.7.a.15.o；A.7.a.15.bh；A.7.a.15.bi；A.7.a.15.bj；A.7.a.15.bk；A.7.a.37.i； A.7.a.37.o；A.7.a.37.bh；A.7.a.37.bi；A.7.a.37.bj；A.7.a.37.bk；A.7.a.38.i；A.7.a.38.o； A.7.a.38.bh；A.7.a.38.bi；A.7.a.38.bj；A.7.a.38.bk；A.7.a.39.i；A.7.a.39.o；A.7.a.39.bh； A.7.a.39.bi；A.7.a.39.bj；A.7.a.39.bk；A.7.a.40.i；A.7.a.40.o；A.7.a.40.bh；A.7.a.40.bi； A.7.a.40.bj；A.7.a.40.bk；A.7.a.41.i；A.7.a.41.o；A.7.a.41.bh；A.7.a.41.bi；A.7.a.41.bj； A.7.a.41.bk；A.7.a.42.i；A.7.a.42.o；A.7.a.42.bh；A.7.a.42.bi；A.7.a.42.bj；A.7.a.42.bk； A.7.a.43.i；A.7.a.43.o；A.7.a.43.bh；A.7.a.43.bi；A.7.a.43.bj；A.7.a.43.bk； A.17.a.4.i；A.17.a.4.o；A.17.a.4.bh；A.17.a.4.bi；A.17.a.4.bj；A.17.a.4.bk；A.17.a.11.i； A.17.a.11.o；A.17.a.11.bh；A.17.a.11.bi；A.17.a.11.bj；A.17.a.11.bk；A.17.a.15.i； A.17.a.15.o；A.17.a.15.bh；A.17.a.15.bi；A.17.a.15.bj；A.17.a.15.bk；A.17.a.37.i； A.17.a.37.o；A.17.a.37.bh；A.17.a.37.bi；A.17.a.37.bj；A.17.a.37.bk；A.17.a.38.i； A.17.a.38.o；A.17.a.38.bh；A.17.a.38.bi；A.17.a.38.bj；A.17.a.38.bk；A.17.a.39.i； A.17.a.39.o；A.17.a.39.bh；A.17.a.39.bi；A.17.a.39.bj；A.17.a.39.bk；A.17.a.40.i； A.17.a.40.o；A.17.a.40.bh；A.17.a.40.bi；A.17.a.40.bj；A.17.a.40.bk；A.17.a.41.i； A.17.a.41.o；A.17.a.41.bh；A.17.a.41.bi；A.17.a.41.bj；A.17.a.41.bk；A.17.a.42.i； A.17.a.42.o；A.17.a.42.bh；A.17.a.42.bi；A.17.a.42.bj；A.17.a.42.bk；A.17.a.43.i； A.17.a.43.o；A.17.a.43.bh；A.17.a.43.bi；A.17.a.43.bj；A.17.a.43.bk；A.18.a.4.i； A.18.a.4.o；A.18.a.4.bh；A.18.a.4.bi；A.18.a.4.bj；A.18.a.4.bk；A.18.a.11.i； A.18.a.11.o；A.18.a.11.bh；A.18.a.11.bi；A.18.a.11.bj；A.18.a.11.bk；A.18.a.15.i； A.18.a.15.o；A.18.a.15.bh；A.18.a.15.bi；A.18.a.15.bj；A.18.a.15.bk；A.18.a.37.i； A.18.a.37.o；A.18.a.37.bh；A.18.a.37.bi；A.18.a.37.bj；A.18.a.37.bk；A.18.a.38.i；A.18.a.38.o；A.18.a.38.bh；A.18.a.38.bi；A.18.a.38.bj；A.18.a.38.bk；A.18.a.39.i； A.18.a.39.o；A.18.a.39.bh；A.18.a.39.bi；A.18.a.39.bj；A.18.a.39.bk；A.18.a.40.i； A.18.a.40.o；A.18.a.40.bh；A.18.a.40.bi；A.18.a.40.bj；A.18.a.40.bk；A.18.a.41.i； A.18.a.41.o；A.18.a.41.bh；A.18.a.41.bi；A.18.a.41.bj；A.18.a.41.bk；A.18.a.42.i； A.18.a.42.o；A.18.a.42.bh；A.18.a.42.bi；A.18.a.42.bj；A.18.a.42.bk；A.18.a.43.i； A.18.a.43.o；A.18.a.43.bh；A.18.a.43.bi；A.18.a.43.bj；A.18.a.43.bk；A.19.a.4.i； A.19.a.4.o；A.19.a.4.bh；A.19.a.4.bi；A.19.a.4.bj；A.19.a.4.bk；A.19.a.11.i； A.19.a.11.o；A.19.a.11.bh；A.19.a.11.bi；A.19.a.11.bj；A.19.a.11.bk；A.19.a.15.i； A.19.a.15.o；A.19.a.15.bh；A.19.a.15.bi；A.19.a.15.bj；A.19.a.15.bk；A.19.a.37.i； A.19.a.37.o；A.19.a.37.bh；A.19.a.37.bi；A.19.a.37.bj；A.19.a.37.bk；A.19.a.38.i； A.19.a.38.o；A.19.a.38.bh；A.19.a.38.bi；A.19.a.38.bj；A.19.a.38.bk；A.19.a.39.i； A.19.a.39.o；A.19.a.39.bh；A.19.a.39.bi；A.19.a.39.bj；A.19.a.39.bk；A.19.a.40.i； A.19.a.40.o；A.19.a.40.bh；A.19.a.40.bi；A.19.a.40.bj；A.19.a.40.bk；A.19.a.41.i； A.19.a.41.o；A.19.a.41.bh；A.19.a.41.bi；A.19.a.41.bj；A.19.a.41.bk；A.19.a.42.i； A.19.a.42.o；A.19.a.42.bh；A.19.a.42.bi；A.19.a.42.bj；A.19.a.42.bk；A.19.a.43.i； A.19.a.43.o；A.19.a.43.bh；A.19.a.43.bi；A.19.a.43.bj；A.19.a.43.bk；A.97.a.4.i； A.97.a.4.o；A.97.a.4.bh；A.97.a.4.bi；A.97.a.4.bj；A.97.a.4.bk；A.97.a.11.i； A.97.a.11.o；A.97.a.11.bh；A.97.a.11.bi；A.97.a.11.bj；A.97.a.11.bk；A.97.a.15.i； A.97.a.15.o；A.97.a.15.bh；A.97.a.15.bi；A.97.a.15.bj；A.97.a.15.bk；A.97.a.37.i； A.97.a.37.o；A.97.a.37.bh；A.97.a.37.bi；A.97.a.37.bj；A.97.a.37.bk；A.97.a.38.i； A.97.a.38.o；A.97.a.38.bh；A.97.a.38.bi；A.97.a.38.bj；A.97.a.38.bk；A.97.a.39.i； A.97.a.39.o；A.97.a.39.bh；A.97.a.39.bi；A.97.a.39.bj；A.97.a.39.bk；A.97.a.40.i； A.97.a.40.o；A.97.a.40.bh；A.97.a.40.bi；A.97.a.40.bj；A.97.a.40.bk；A.97.a.41.i； A.97.a.41.o；A.97.a.41.bh；A.97.a.41.bi；A.97.a.41.bj；A.97.a.41.bk；A.97.a.42.i； A.97.a.42.o；A.97.a.42.bh；A.97.a.42.bi；A.97.a.42.bj；A.97.a.42.bk；A.97.a.43.i； A.97.a.43.o；A.97.a.43.bh；A.97.a.43.bi；A.97.a.43.bj；A.97.a.43.bk；A.98.a.4.i； A.98.a.4.o；A.98.a.4.bh；A.98.a.4.bi；A.98.a.4.bj；A.98.a.4.bk；A.98.a.11.i； A.98.a.11.o；A.98.a.11.bh；A.98.a.11.bi；A.98.a.11.bj；A.98.a.11.bk；A.98.a.15.i； A.98.a.15.o；A.98.a.15.bh；A.98.a.15.bi；A.98.a.15.bj；A.98.a.15.bk；A.98.a.37.i； A.98.a.37.o；A.98.a.37.bh；A.98.a.37.bi；A.98.a.37.bj；A.98.a.37.bk；A.98.a.38.i； A.98.a.38.o；A.98.a.38.bh；A.98.a.38.bi；A.98.a.38.bj；A.98.a.38.bk；A.98.a.39.i； A.98.a.39.o；A.98.a.39.bh；A.98.a.39.bi；A.98.a.39.bj；A.98.a.39.bk；A.98.a.40.i； A.98.a.40.o；A.98.a.40.bh；A.98.a.40.bi；A.98.a.40.bj；A.98.a.40.bk；A.98.a.41.i； A.98.a.41.o；A.98.a.41.bh；A.98.a.41.bi；A.98.a.41.bj；A.98.a.41.bk；A.98.a.42.i； A.98.a.42.o；A.98.a.42.bh；A.98.a.42.bi；A.98.a.42.bj；A.98.a.42.bk；A.98.a.43.i； A.98.a.43.o；A.98.a.43.bh；A.98.a.43.bi；A.98.a.43.bj；A.98.a.43.bk；A.2.a.4.i； A.3.a.4.i；A.4.a.4.i；A.5.a.4.i；A.6.a.4.i；A.7.a.4.i；A.9.a.4.i；A.10.a.4.i；A.15.a.4.i； A.100.a.4.i；A.101.a.4.i；A.102.a.4.i；A.103.a.4.i；A.104.a.4.i；A.105.a.4.i；A.106.a.4.i； A.107.a.4.i；A.108.a.4.i；A.109.a.4.i；A.110.a.4.i；A.111.a.4.i；A.112.a.4.i；A.113.a.4.i； A.114.a.4.i；A.115.a.4.i；A.116.a.4.i；A.117.a.4.i；A.118.a.4.i；A.119.a.4.i；A.120.a.4.i； A.121.a.4.i；A.122.a.4.i；A.123.a.4.i；A.124.a.4.i；A.125.a.4.i；A.126.a.4.i；A.127.a.4.i； A.128.a.4.i；A.129.a.4.i；A.130.a.4.i；A.131.a.4.i；A.132.a.4.i；A.133.a.4.i；A.134.a.4.i； A.135.a.4.i；A.136.a.4.i；A.137.a.4.i；A.138.a.4.i；A.139.a.4.i；A.140.a.4.i；A.141.a.4.i； A.142.a.4.i；A.143.a.4.i；A.144.a.4.i；A.145.a.4.i；A.146.a.4.i；A.147.a.4.i；A.148.a.4.i； A.149.a.4.i；A.150.a.4.i；A.151.a.4.i；A.152.a.4.i；A.153.a.4.i；A.154.a.4.i；A.155.a.4.i； A.156.a.4.i；A.157.a.4.i；A.158.a.4.i；A.159.a.4.i；A.160.a.4.i；A.161.a.4.i；A.162.a.4.i； A.163.a.4.i；A.164.a.4.i；A.165.a.4.i；A.166.a.4.i；A.167.a.4.i；A.168.a.4.i；A.169.a.4.i；A.170.a.4.i；A.171.a.4.i；A.172.a.4.i；A.173.a.4.i；A.174.a.4.i；A.175.a.4.i；A.176.a.4.i； A.177.a.4.i；A.178.a.4.i；A.179.a.4.i；A.180.a.4.i；A.181.a.4.i；A.182.a.4.i；A.183.a.4.i； A.184.a.4.i；A.185.a.4.i；A.186.a.4.i；A.187.a.4.i；A.188.a.4.i；A.189.a.4.i；A.190.a.4.i； 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A.569.a.4.i；A.570.a.4.i；A.571.a.4.i；A.572.a.4.i；A.573.a.4.i；A.574.a.4.i；A.575.a.4.i； A.576.a.4.i；A.577.a.4.i；A.578.a.4.i；A.579.a.4.i；A.580.a.4.i；A.581.a.4.i；A.582.a.4.i； A.583.a.4.i；A.584.a.4.i；A.585.a.4.i；A.586.a.4.i；A.587.a.4.i；A.588.a.4.i；A.589.a.4.i； A.590.a.4.i；A.591.a.4.i；A.592.a.4.i；A.593.a.4.i；A.594.a.4.i；A.595.a.4.i；A.596.a.4.i； A.597.a.4.i；A.598.a.4.i；A.599.a.4.i；A.600.a.4.i；A.601.a.4.i；A.602.a.4.i；A.603.a.4.i； A.604.a.4.i；A.605.a.4.i；A.606.a.4.i；A.607.a.4.i；A.608.a.4.i；A.609.a.4.i；A.610.a.4.i； A.611.a.4.i；A.612.a.4.i；A.613.a.4.i；A.614.a.4.i；A.615.a.4.i；A.616.a.4.i；A.617.a.4.i； A.618.a.4.i；A.619.a.4.i；A.620.a.4.i；A.621.a.4.i；A.622.a.4.i；A.623.a.4.i；A.624.a.4.i； A.625.a.4.i；A.626.a.4.i；A.627.a.4.i；A.628.a.4.i；A.629.a.4.i；A.630.a.4.i；A.631.a.4.i； A.632.a.4.i；A.633.a.4.i；A.634.a.4.i；A.635.a.4.i；A.636.a.4.i；A.637.a.4.i；A.638.a.4.i； A.639.a.4.i；A.640.a.4.i；A.641.a.4.i；A.642.a.4.i；A.643.a.4.i；A.644.a.4.i；A.645.a.4.i； A.646.a.4.i；A.647.a.4.i；A.648.a.4.i；A.649.a.4.i；A.650.a.4.i；A.651.a.4.i；A.652.a.4.i； A.653.a.4.i；A.654.a.4.i；A.655.a.4.i；A.656.a.4.i；A.657.a.4.i；A.658.a.4.i；A.659.a.4.i； A.660.a.4.i；A.2.a.11.i；A.3.a.11.i；A.4.a.11.i；A.5.a.11.i；A.6.a.11.i；A.7.a.11.i； A.9.a.11.i；A.10.a.11.i；A.15.a.11.i；A.100.a.11.i；A.101.a.11.i；A.102.a.11.i； A.103.a.11.i；A.104.a.11.i；A.105.a.11.i；A.106.a.11.i；A.107.a.11.i；A.108.a.11.i； A.109.a.11.i；A.110.a.11.i；A.111.a.11.i；A.112.a.11.i；A.113.a.11.i；A.114.a.11.i； A.115.a.11.i；A.116.a.11.i；A.117.a.11.i；A.118.a.11.i；A.119.a.11.i；A.120.a.11.i； A.121.a.11.i；A.122.a.11.i；A.123.a.11.i；A.124.a.11.i；A.125.a.11.i；A.126.a.11.i； A.127.a.11.i；A.128.a.11.i；A.129.a.11.i；A.130.a.11.i；A.131.a.11.i；A.132.a.11.i； A.133.a.11.i；A.134.a.11.i；A.135.a.11.i；A.136.a.11.i；A.137.a.11.i；A.138.a.11.i； A.139.a.11.i；A.140.a.11.i；A.141.a.11.i；A.142.a.11.i；A.143.a.11.i；A.144.a.11.i； A.145.a.11.i；A.146.a.11.i；A.147.a.11.i；A.148.a.11.i；A.149.a.11.i；A.150.a.11.i； A.151.a.11.i；A.152.a.11.i；A.153.a.11.i；A.154.a.11.i；A.155.a.11.i；A.156.a.11.i； A.157.a.11.i；A.158.a.11.i；A.159.a.11.i；A.160.a.11.i；A.161.a.11.i；A.162.a.11.i； A.163.a.11.i；A.164.a.11.i；A.165.a.11.i；A.166.a.11.i；A.167.a.11.i；A.168.a.11.i； A.169.a.11.i；A.170.a.11.i；A.171.a.11.i；A.172.a.11.i；A.173.a.11.i；A.174.a.11.i； A.175.a.11.i；A.176.a.11.i；A.177.a.11.i；A.178.a.11.i；A.179.a.11.i；A.180.a.11.i； A.181.a.11.i；A.182.a.11.i；A.183.a.11.i；A.184.a.11.i；A.185.a.11.i；A.186.a.11.i； A.187.a.11.i；A.188.a.11.i；A.189.a.11.i；A.190.a.11.i；A.191.a.11.i；A.192.a.11.i； A.193.a.11.i；A.194.a.11.i；A.195.a.11.i；A.196.a.11.i；A.197.a.11.i；A.198.a.11.i； A.199.a.11.i；A.200.a.11.i；A.201.a.11.i；A.202.a.11.i；A.203.a.11.i；A.204.a.11.i； A.205.a.11.i；A.206.a.11.i；A.207.a.11.i；A.208.a.11.i；A.209.a.11.i；A.210.a.11.i； A.211.a.11.i；A.212.a.11.i；A.213.a.11.i；A.214.a.11.i；A.215.a.11.i；A.216.a.11.i； A.217.a.11.i；A.218.a.11.i；A.219.a.11.i；A.220.a.11.i；A.221.a.11.i；A.222.a.11.i； A.223.a.11.i；A.224.a.11.i；A.225.a.11.i；A.226.a.11.i；A.227.a.11.i；A.228.a.11.i； A.229.a.11.i；A.230.a.11.i；A.231.a.11.i；A.232.a.11.i；A.233.a.11.i；A.234.a.11.i；A.235.a.11.i；A.236.a.11.i；A.237.a.11.i；A.238.a.11.i；A.239.a.11.i；A.240.a.11.i； A.241.a.11.i；A.242.a.11.i；A.243.a.11.i；A.244.a.11.i；A.245.a.11.i；A.246.a.11.i； A.247.a.11.i；A.248.a.11.i；A.249.a.11.i；A.250.a.11.i；A.251.a.11.i；A.252.a.11.i； A.253.a.11.i；A.254.a.11.i；A.255.a.11.i；A.256.a.11.i；A.257.a.11.i；A.258.a.11.i； A.259.a.11.i；A.260.a.11.i；A.261.a.11.i；A.262.a.11.i；A.263.a.11.i；A.264.a.11.i； A.265.a.11.i；A.266.a.11.i；A.267.a.11.i；A.268.a.11.i；A.269.a.11.i；A.270.a.11.i； A.271.a.11.i；A.272.a.11.i；A.273.a.11.i；A.274.a.11.i；A.275.a.11.i；A.276.a.11.i； A.277.a.11.i；A.278.a.11.i；A.279.a.11.i；A.280.a.11.i；A.281.a.11.i；A.282.a.11.i； A.283.a.11.i；A.284.a.11.i；A.285.a.11.i；A.286.a.11.i；A.287.a.11.i；A.288.a.11.i； A.289.a.11.i；A.290.a.11.i；A.291.a.11.i；A.292.a.11.i；A.293.a.11.i；A.294.a.11.i； A.295.a.11.i；A.296.a.11.i；A.297.a.11.i；A.298.a.11.i；A.299.a.11.i；A.300.a.11.i； A.301.a.11.i；A.302.a.11.i；A.303.a.11.i；A.304.a.11.i；A.305.a.11.i；A.306.a.11.i； A.307.a.11.i；A.308.a.11.i；A.309.a.11.i；A.310.a.11.i；A.311.a.11.i；A.312.a.11.i； A.313.a.11.i；A.314.a.11.i；A.315.a.11.i；A.316.a.11.i；A.317.a.11.i；A.318.a.11.i； A.319.a.11.i；A.320.a.11.i；A.321.a.11.i；A.323.a.11.i；A.324.a.11.i；A.325.a.11.i； A.326.a.11.i；A.327.a.11.i；A.328.a.11.i；A.329.a.11.i；A.330.a.11.i；A.331.a.11.i； A.332.a.11.i；A.333.a.11.i；A.334.a.11.i；A.335.a.11.i；A.336.a.11.i；A.337.a.11.i； A.338.a.11.i；A.339.a.11.i；A.340.a.11.i；A.341.a.11.i；A.342.a.11.i；A.343.a.11.i； A.344.a.11.i；A.345.a.11.i；A.346.a.11.i；A.347.a.11.i；A.348.a.11.i；A.349.a.11.i； A.350.a.11.i；A.351.a.11.i；A.352.a.11.i；A.353.a.11.i；A.354.a.11.i；A.355.a.11.i； A.356.a.11.i；A.357.a.11.i；A.358.a.11.i；A.359.a.11.i；A.360.a.11.i；A.361.a.11.i； A.362.a.11.i；A.363.a.11.i；A.364.a.11.i；A.365.a.11.i；A.366.a.11.i；A.367.a.11.i； A.368.a.11.i；A.369.a.11.i；A.370.a.11.i；A.371.a.11.i；A.372.a.11.i；A.373.a.11.i； A.374.a.11.i；A.375.a.11.i；A.376.a.11.i；A.377.a.11.i；A.378.a.11.i；A.379.a.11.i； A.380.a.11.i；A.381.a.11.i；A.382.a.11.i；A.383.a.11.i；A.384.a.11.i；A.385.a.11.i； A.386.a.11.i；A.387.a.11.i；A.388.a.11.i；A.389.a.11.i；A.390.a.11.i；A.391.a.11.i； A.392.a.11.i；A.393.a.11.i；A.394.a.11.i；A.395.a.11.i；A.396.a.11.i；A.397.a.11.i； A.398.a.11.i；A.399.a.11.i；A.400.a.11.i；A.401.a.11.i；A.402.a.11.i；A.403.a.11.i； A.404.a.11.i；A.405.a.11.i；A.406.a.11.i；A.407.a.11.i；A.408.a.11.i；A.409.a.11.i； A.410.a.11.i；A.411.a.11.i；A.412.a.11.i；A.413.a.11.i；A.414.a.11.i；A.415.a.11.i； A.416.a.11.1；A.417.a.11.i；A.418.a.11.i；A.419.a.11.i；A.420.a.11.i；A.421.a.11.i； A.422.a.11.i；A.423.a.11.i；A.424.a.11.i；A.425.a.11.i；A.426.a.11.i；A.427.a.11.i； A.428.a.11.i；A.429.a.11.i；A.430.a.11.i；A.431.a.11.i；A.432.a.11.i；A.433.a.11.i； A.434.a.11.i；A.435.a.11.i；A.436.a.11.i；A.437.a.11.i；A.438.a.11.i；A.439.a.11.i； A.440.a.11.i；A.441.a.11.i；A.442.a.11.i；A.443.a.11.i；A.444.a.11.i；A.445.a.11.i； A.446.a.11.i；A.447.a.11.i；A.448.a.11.i；A.449.a.11.i；A.450.a.11.i；A.451.a.11.i； A.452.a.11.i；A.453.a.11.i；A.454.a.11.i；A.455.a.11.i；A.456.a.11.i；A.457.a.11.i； A.458.a.11.i；A.459.a.11.i；A.460.a.11.i；A.461.a.11.i；A.462.a.11.i；A.463.a.11.i； A.464.a.11.i；A.465.a.11.i；A.466.a.11.i；A.467.a.11.i；A.468.a.11.i；A.469.a.11.i； A.470.a.11.i；A.471.a.11.i；A.472.a.11.i；A.473.a.11.i；A.474.a.11.i；A.475.a.11.i； A.476.a.11.i；A.477.a.11.i；A.478.a.11.i；A.479.a.11.i；A.480.a.11.i；A.481.a.11.i； A.482.a.11.i；A.483.a.11.i；A.484.a.11.i；A.485.a.11.i；A.486.a.11.i；A.487.a.11.i； A.488.a.11.i；A.489.a.11.i；A.490.a.11.i；A.491.a.11.i；A.492.a.11.i；A.493.a.11.i； A.494.a.11.i；A.495.a.11.i；A.496.a.11.i；A.497.a.11.i；A.498.a.11.i；A.499.a.11.i； A.500.a.11.i；A.501.a.11.i；A.502.a.11.i；A.503.a.11.i；A.504.a.11.i；A.505.a.11.i； A.506.a.11.i；A.507.a.11.i；A.508.a.11.i；A.509.a.11.i；A.510.a.11.i；A.511.a.11.i； A.512.a.11.i；A.512.a.11.i；A.513.a.11.i；A.514.a.11.i；A.515.a.11.i；A.516.a.11.i；A.517.a.11.i；A.518.a.11.i；A.519.a.11.i；A.520.a.11.i；A.521.a.11.i；A.522.a.11.i； A.523.a.11.i；A.524.a.11.i；A.525.a.11.i；A.526.a.11.i；A.527.a.11.i；A.528.a.11.i； A.529.a.11.i；A.530.a.11.i；A.531.a.11.i；A.532.a.11.i；A.533.a.11.i；A.534.a.11.i； A.535.a.11.i；A.536.a.11.i；A.537.a.11.i；A.538.a.11.i；A.539.a.11.i；A.540.a.11.i； A.541.a.11.i；A.542.a.11.i；A.543.a.11.i；A.544.a.11.i；A.545.a.11.i；A.546.a.11.i； A.547.a.11.i；A.548.a.11.i；A.549.a.11.i；A.550.a.11.i；A.551.a.11.i；A.552.a.11.i； A.553.a.11.i；A.554.a.11.i；A.555.a.11.i；A.556.a.11.i；A.557.a.11.i；A.558.a.11.i； A.559.a.11.i；A.560.a.11.i；A.561.a.11.i；A.562.a.11.i；A.563.a.11.i；A.564.a.11.i； A.565.a.11.i；A.566.a.11.i；A.567.a.11.i；A.568.a.11.i；A.569.a.11.i；A.570.a.11.i； A.571.a.11.i；A.572.a.11.i；A.573.a.11.i；A.574.a.11.i；A.575.a.11.i；A.576.a.11.i； A.577.a.11.i；A.578.a.11.i；A.579.a.11.i；A.580.a.11.i；A.581.a.11.i；A.582.a.11.i； A.583.a.11.i；A.584.a.11.i；A.585.a.11.i；A.586.a.11.i；A.587.a.11.i；A.588.a.11.i； A.589.a.11.i；A.590.a.11.i；A.591.a.11.i；A.592.a.11.i；A.593.a.11.i；A.594.a.11.i； A.595.a.11.i；A.596.a.11.i；A.597.a.11.i；A.598.a.11.i；A.599.a.11.i；A.600.a.11.i； A.601.a.11.i；A.602.a.11.i；A.603.a.11.i；A.604.a.11.i；A.605.a.11.i；A.606.a.11.i； A.607.a.11.i；A.608.a.11.i；A.609.a.11.i；A.610.a.11.i；A.611.a.11.i；A.612.a.11.i； A.613.a.11.i；A.614.a.11.i；A.615.a.11.i；A.616.a.11.i；A.617.a.11.i；A.618.a.11.i； A.619.a.11.i；A.620.a.11.i；A.621.a.11.i；A.622.a.11.i；A.623.a.11.i；A.624.a.11.i； A.625.a.11.i；A.626.a.11.i；A.627.a.11.i；A.628.a.11.i；A.629.a.11.i；A.630.a.11.i； A.631.a.11.i；A.632.a.11.i；A.633.a.11.i；A.634.a.11.i；A.635.a.11.i；A.636.a.11.i； A.637.a.11.i；A.638.a.11.i；A.639.a.11.i；A.640.a.11.i；A.641.a.11.i；A.642.a.11.i； A.643.a.11.i；A.644.a.11.i；A.645.a.11.i；A.646.a.11.i；A.647.a.11.i；A.648.a.11.i； A.649.a.11.i；A.650.a.11.i；A.651.a.11.i；A.652.a.11.i；A.653.a.11.i；A.654.a.11.i； A.655.a.11.i；A.656.a.11.i；A.657.a.11.i；A.658.a.11.i；A.659.a.11.i；A.660.a.11.i； A.2.b.4.i；A.3.b.4.i；A.4.b.4.i；A.5.b.4.i；A.6.b.4.i；A.7.b.4.i；A.9.b.4.i；A.10.b.4.i； A.15.b.4.i；A.100.b.4.i；A.101.b.4.i；A.102.b.4.i；A.103.b.4.i；A.104.b.4.i；A.105.b.4.i； A.106.b.4.i；A.107.b.4.i；A.108.b.4.i；A.109.b.4.i；A.110.b.4.i；A.111.b.4.i；A.112.b.4.i； A.113.b.4.i；A.114.b.4.i；A.115.b.4.i；A.116.b.4.i；A.117.b.4.i；A.118.b.4.i；A.119.b.4.i； A.120.b.4.i；A.121.b.4.i；A.122.b.4.i；A.123.b.4.i；A.124.b.4.i；A.125.b.4.i；A.126.b.4.i； A.127.b.4.i；A.128.b.4.i；A.129.b.4.i；A.130.b.4.i；A.131.b.4.i；A.132.b.4.i；A.133.b.4.i； A.134.b.4.i；A.135.b.4.i；A.136.b.4.i；A.137.b.4.i；A.138.b.4.i；A.139.b.4.i；A.140.b.4.i； A.141.b.4.i；A.142.b.4.i；A.143.b.4.i；A.144.b.4.i；A.145.b.4.i；A.146.b.4.i；A.147.b.4.i； A.148.b.4.i；A.149.b.4.i；A.150.b.4.i；A.151.b.4.i；A.152.b.4.i；A.153.b.4.i；A.154.b.4.i； A.155.b.4.i；A.156.b.4.i；A.157.b.4.i；A.158.b.4.i；A.159.b.4.i；A.160.b.4.i；A.161.b.4.i； A.162.b.4.i；A.163.b.4.i；A.164.b.4.i；A.165.b.4.i；A.166.b.4.i；A.167.b.4.i；A.168.b.4.i； A.169.b.4.i；A.170.b.4.i；A.171.b.4.i；A.172.b.4.i；A.173.b.4.i；A.174.b.4.i；A.175.b.4.i； A.176.b.4.i；A.177.b.4.i；A.178.b.4.i；A.179.b.4.i；A.180.b.4.i；A.181.b.4.i；A.182.b.4.i； A.183.b.4.i；A.184.b.4.i；A.185.b.4.i；A.186.b.4.i；A.187.b.4.i；A.188.b.4.i；A.189.b.4.i； A.190.b.4.i；A.191.b.4.i；A.192.b.4.i；A.193.b.4.i；A.194.b.4.i；A.195.b.4.i；A.196.b.4.i； A.197.b.4.i；A.198.b.4.i；A.199.b.4.i；A.200.b.4.i；A.201.b.4.i；A.202.b.4.i；A.203.b.4.i； A.204.b.4.i；A.205.b.4.i；A.206.b.4.i；A.207.b.4.i；A.208.b.4.i；A.209.b.4.i；A.210.b.4.i； A.211.b.4.i；A.212.b.4.i；A.213.b.4.i；A.214.b.4.i；A.215.b.4.i；A.216.b.4.i；A.217.b.4.i； A.218.b.4.i；A.219.b.4.i；A.220.b.4.i；A.221.b.4.i；A.222.b.4.i；A.223.b.4.i；A.224.b.4.i； A.225.b.4.i；A.226.b.4.i；A.227.b.4.i；A.228.b.4.i；A.229.b.4.i；A.230.b.4.i；A.231.b.4.i； A.232.b.4.i；A.233.b.4.i；A.234.b.4.i；A.235.b.4.i；A.236.b.4.i；A.237.b.4.i；A.238.b.4.i； A.239.b.4.i；A.240.b.4.i；A.241.b.4.i；A.242.b.4.i；A.243.b.4.i；A.244.b.4.i；A.245.b.4.i； A.246.b.4.i；A.247.b.4.i；A.248.b.4.i；A.249.b.4.i；A.250.b.4.i；A.251.b.4.i；A.252.b.4.i；A.253.b.4.i；A.254.b.4.i；A.255.b.4.i；A.256.b.4.i；A.257.b.4.i；A.258.b.4.i；A.259.b.4.i； A.260.b.4.i；A.261.b.4.i；A.262.b.4.i；A.263.b.4.i；A.264.b.4.i；A.265.b.4.i；A.266.b.4.i； A.267.b.4.i；A.268.b.4.i；A.269.b.4.i；A.270.b.4.i；A.271.b.4.i；A.272.b.4.i；A.273.b.4.i； A.274.b.4.i；A.275.b.4.i；A.276.b.4.i；A.277.b.4.i；A.278.b.4.i；A.279.b.4.i；A.280.b.4.i； A.281.b.4.i；A.282.b.4.i；A.283.b.4.i；A.284.b.4.i；A.285.b.4.i；A.286.b.4.i；A.287.b.4.i； A.288.b.4.i；A.289.b.4.i；A.290.b.4.i；A.291.b.4.i；A.292.b.4.i；A.293.b.4.i；A.294.b.4.i； A.295.b.4.i；A.296.b.4.i；A.297.b.4.i；A.298.b.4.i；A.299.b.4.i；A.300.b.4.i；A.301.b.4.i； A.302.b.4.i；A.303.b.4.i；A.304.b.4.i；A.305.b.4.i；A.306.b.4.i；A.307.b.4.i；A.308.b.4.i； A.309.b.4.i；A.310.b.4.i；A.311.b.4.i；A.312.b.4.i；A.313.b.4.i；A.314.b.4.i；A.315.b.4.i； A.316.b.4.i；A.317.b.4.i；A.318.b.4.i；A.319.b.4.i；A.320.b.4.i；A.321.b.4.i；A.323.b.4.i； A.324.b.4.i；A.325.b.4.i；A.326.b.4.i；A.327.b.4.i；A.328.b.4.i；A.329.b.4.i；A.330.b.4.i； A.331.b.4.i；A.332.b.4.i；A.333.b.4.i；A.334.b.4.i；A.335.b.4.i；A.336.b.4.i；A.337.b.4.i； A.338.b.4.i；A.339.b.4.i；A.340.b.4.i；A.341.b.4.i；A.342.b.4.i；A.343.b.4.i；A.344.b.4.i； A.345.b.4.i；A.346.b.4.i；A.347.b.4.i；A.348.b.4.i；A.349.b.4.i；A.350.b.4.i；A.351.b.4.i； A.352.b.4.i；A.353.b.4.i；A.354.b.4.i；A.355.b.4.i；A.356.b.4.i；A.357.b.4.i；A.358.b.4.i； A.359.b.4.i；A.360.b.4.i；A.361.b.4.i；A.362.b.4.i；A.363.b.4.i；A.364.b.4.i；A.365.b.4.i； A.366.b.4.i；A.367.b.4.i；A.368.b.4.i；A.369.b.4.i；A.370.b.4.i；A.371.b.4.i；A.372.b.4.i； A.373.b.4.i；A.374.b.4.i；A.375.b.4.i；A.376.b.4.i；A.377.b.4.i；A.378.b.4.i；A.379.b.4.i； A.380.b.4.i；A.381.b.4.i；A.382.b.4.i；A.383.b.4.i；A.384.b.4.i；A.385.b.4.i；A.386.b.4.i； A.387.b.4.i；A.388.b.4.i；A.389.b.4.i；A.390.b.4.i；A.391.b.4.i；A.392.b.4.i；A.393.b.4.i； A.394.b.4.i；A.395.b.4.i；A.396.b.4.i；A.397.b.4.i；A.398.b.4.i；A.399.b.4.i；A.400.b.4.i； A.401.b.4.i；A.402.b.4.i；A.403.b.4.i；A.404.b.4.i；A.405.b.4.i；A.406.b.4.i；A.407.b.4.i； A.408.b.4.i；A.409.b.4.i；A.410.b.4.i；A.411.b.4.i；A.412.b.4.i；A.413.b.4.i；A.414.b.4.i； A.415.b.4.i；A.416.b.4.i；A.417.b.4.i；A.418.b.4.i；A.419.b.4.i；A.420.b.4.i；A.421.b.4.i； A.422.b.4.i；A.423.b.4.i；A.424.b.4.i；A.425.b.4.i；A.426.b.4.i；A.427.b.4.i；A.428.b.4.i； A.429.b.4.i；A.430.b.4.i；A.431.b.4.i；A.432.b.4.i；A.433.b.4.i；A.434.b.4.i；A.435.b.4.i； A.436.b.4.i；A.437.b.4.i；A.438.b.4.i；A.439.b.4.i；A.440.b.4.i；A.441.b.4.i；A.442.b.4.i； A.443.b.4.i；A.444.b.4.i；A.445.b.4.i；A.446.b.4.i；A.447.b.4.i；A.448.b.4.i；A.449.b.4.i； A.450.b.4.i；A.451.b.4.i；A.452.b.4.i；A.453.b.4.i；A.454.b.4.i；A.455.b.4.i；A.456.b.4.i； A.457.b.4.i；A.458.b.4.i；A.459.b.4.i；A.460.b.4.i；A.461.b.4.i；A.462.b.4.i；A.463.b.4.i； A.464.b.4.i；A.465.b.4.i；A.466.b.4.i；A.467.b.4.i；A.468.b.4.i；A.469.b.4.i；A.470.b.4.i； A.471.b.4.i；A.472.b.4.i；A.473.b.4.i；A.474.b.4.i；A.475.b.4.i；A.476.b.4.i；A.477.b.4.i； A.478.b.4.i；A.479.b.4.i；A.480.b.4.i；A.481.b.4.i；A.482.b.4.i；A.483.b.4.i；A.484.b.4.i； A.485.b.4.i；A.486.b.4.i；A.487.b.4.i；A.488.b.4.i；A.489.b.4.i；A.490.b.4.i；A.491.b.4.i； A.492.b.4.i；A.493.b.4.i；A.494.b.4.i；A.495.b.4.i；A.496.b.4.i；A.497.b.4.i；A.498.b.4.i； A.499.b.4.i；A.500.b.4.i；A.501.b.4.i；A.502.b.4.i；A.503.b.4.i；A.504.b.4.i；A.505.b.4.i； A.506.b.4.i；A.507.b.4.i；A.508.b.4.i；A.509.b.4.i；A.510.b.4.i；A.511.b.4.i；A.512.b.4.i； A.512.b.4.i；A.513.b.4.i；A.514.b.4.i；A.515.b.4.i；A.516.b.4.i；A.517.b.4.i；A.518.b.4.i； A.519.b.4.i；A.520.b.4.i；A.521.b.4.i；A.522.b.4.i；A.523.b.4.i；A.524.b.4.i；A.525.b.4.i； A.526.b.4.i；A.527.b.4.i；A.528.b.4.i；A.529.b.4.i；A.530.b.4.i；A.531.b.4.i；A.532.b.4.i； A.533.b.4.i；A.534.b.4.i；A.535.b.4.i；A.536.b.4.i；A.537.b.4.i；A.538.b.4.i；A.539.b.4.i； A.540.b.4.i；A.541.b.4.i；A.542.b.4.i；A.543.b.4.i；A.544.b.4.i；A.545.b.4.i；A.546.b.4.i； A.547.b.4.i；A.548.b.4.i；A.549.b.4.i；A.550.b.4.i；A.551.b.4.i；A.552.b.4.i；A.553.b.4.i； A.554.b.4.i；A.555.b.4.i；A.556.b.4.i；A.557.b.4.i；A.558.b.4.i；A.559.b.4.i；A.560.b.4.i； A.561.b.4.i；A.562.b.4.i；A.563.b.4.i；A.564.b.4.i；A.565.b.4.i；A.566.b.4.i；A.567.b.4.i； A.568.b.4.i；A.569.b.4.i；A.570.b.4.i；A.571.b.4.i；A.572.b.4.i；A.573.b.4.i；A.574.b.4.i； A.575.b.4.i；A.576.b.4.i；A.577.b.4.i；A.578.b.4.i；A.579.b.4.i；A.580.b.4.i；A.581.b.4.i；A.582.b.4.i；A.583.b.4.i；A.584.b.4.i；A.585.b.4.i；A.586.b.4.i；A.587.b.4.i；A.588.b.4.i； A.589.b.4.i；A.590.b.4.i；A.591.b.4.i；A.592.b.4.i；A.593.b.4.i；A.594.b.4.i；A.595.b.4.i； A.596.b.4.i；A.597.b.4.i；A.598.b.4.i；A.599.b.4.i；A.600.b.4.i；A.601.b.4.i；A.602.b.4.i； A.603.b.4.i；A.604.b.4.i；A.605.b.4.i；A.606.b.4.i；A.607.b.4.i；A.608.b.4.i；A.609.b.4.i； A.610.b.4.i；A.611.b.4.i；A.612.b.4.i；A.613.b.4.i；A.614.b.4.i；A.615.b.4.i；A.616.b.4.i； A.617.b.4.i；A.618.b.4.i；A.619.b.4.i；A.620.b.4.i；A.621.b.4.i；A.622.b.4.i；A.623.b.4.i； A.624.b.4.i；A.625.b.4.i；A.626.b.4.i；A.627.b.4.i；A.628.b.4.i；A.629.b.4.i；A.630.b.4.i； A.631.b.4.i；A.632.b.4.i；A.633.b.4.i；A.634.b.4.i；A.635.b.4.i；A.636.b.4.i；A.637.b.4.i； A.638.b.4.i；A.639.b.4.i；A.640.b.4.i；A.641.b.4.i；A.642.b.4.i；A.643.b.4.i；A.644.b.4.i； A.645.b.4.i；A.646.b.4.i；A.647.b.4.i；A.648.b.4.i；A.649.b.4.i；A.650.b.4.i；A.651.b.4.i； A.652.b.4.i；A.653.b.4.i；A.654.b.4.i；A.655.b.4.i；A.656.b.4.i；A.657.b.4.i；A.658.b.4.i； A.659.b.4.i；A.660.b.4.i；A.2.b.11.i；A.3.b.11.i；A.4.b.11.i；A.5.b.11.i；A.6.b.11.i； A.7.b.11.i；A.9.b.11.i；A.10.b.11.i；A.15.b.11.i；A.100.b.11.i；A.101.b.11.i； A.102.b.11.i；A.103.b.11.i；A.104.b.11.i；A.105.b.11.i；A.106.b.11.i；A.107.b.11.i； A.108.b.11.i；A.109.b.11.i；A.110.b.11.i；A.111.b.11.i；A.112.b.11.i；A.113.b.11.i； A.114.b.11.i；A.115.b.11.i；A.116.b.11.i；A.117.b.11.i；A.118.b.11.i；A.119.b.11.i； A.120.b.11.i；A.121.b.11.i；A.122.b.11.i；A.123.b.11.i；A.124.b.11.i；A.125.b.11.i； A.126.b.11.i；A.127.b.11.i；A.128.b.11.i；A.129.b.11.i；A.130.b.11.i；A.131.b.11.i； 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A.204.b.11.i；A.205.b.11.i；A.206.b.11.i；A.207.b.11.i；A.208.b.11.i；A.209.b.11.i； A.210.b.11.i；A.211.b.11.i；A.212.b.11.i；A.213.b.11.i；A.214.b.11.i；A.215.b.11.i； A.216.b.11.i；A.217.b.11.i；A.218.b.11.i；A.219.b.11.i；A.220.b.11.i；A.221.b.11.i； A.222.b.11.i；A.223.b.11.i；A.224.b.11.i；A.225.b.11.i；A.226.b.11.i；A.227.b.11.i； A.228.b.11.i；A.229.b.11.i；A.230.b.11.i；A.231.b.11.i；A.232.b.11.i；A.233.b.11.i； A.234.b.11.i；A.235.b.11.i；A.236.b.11.i；A.237.b.11.i；A.238.b.11.i；A.239.b.11.i； A.240.b.11.i；A.241.b.11.i；A.242.b.11.i；A.243.b.11.i；A.244.b.11.i；A.245.b.11.i； A.246.b.11.i；A.247.b.11.i；A.248.b.11.i；A.249.b.11.i；A.250.b.11.i；A.251.b.11.i； A.252.b.11.i；A.253.b.11.i；A.254.b.11.i；A.255.b.11.i；A.256.b.11.i；A.257.b.11.i； A.258.b.11.i；A.259.b.11.i；A.260.b.11.i；A.261.b.11.i；A.262.b.11.i；A.263.b.11.i； A.264.b.11.i；A.265.b.11.i；A.266.b.11.i；A.267.b.11.i；A.268.b.11.i；A.269.b.11.i； A.270.b.11.i；A.271.b.11.i；A.272.b.11.i；A.273.b.11.i；A.274.b.11.i；A.275.b.11.i； A.276.b.11.i；A.277.b.11.i；A.278.b.11.i；A.279.b.11.i；A.280.b.11.i；A.281.b.11.i； A.282.b.11.i；A.283.b.11.i；A.284.b.11.i；A.285.b.11.i；A.286.b.11.i；A.287.b.11.i； A.288.b.11.i；A.289.b.11.i；A.290.b.11.i；A.291.b.11.i；A.292.b.11.i；A.293.b.11.i； A.294.b.11.i；A.295.b.11.i；A.296.b.11.i；A.297.b.11.i；A.298.b.11.i；A.299.b.11.i； A.300.b.11.i；A.301.b.11.i；A.302.b.11.i；A.303.b.11.i；A.304.b.11.i；A.305.b.11.i；A.306.b.11.i；A.307.b.11.i；A.308.b.11.i；A.309.b.11.i；A.310.b.11.i；A.311.b.11.i； A.312.b.11.i；A.313.b.11.i；A.314.b.11.i；A.315.b.11.i；A.316.b.11.i；A.317.b.11.i； A.318.b.11.i；A.319.b.11.i；A.320.b.11.i；A.321.b.11.i；A.323.b.11.i；A.324.b.11.i； A.325.b.11.i；A.326.b.11.i；A.327.b.11.i；A.328.b.11.i；A.329.b.11.i；A.330.b.11.i； A.331.b.11.i；A.332.b.11.i；A.333.b.11.i；A.334.b.11.i；A.335.b.11.i；A.336.b.11.i； A.337.b.11.i；A.338.b.11.i；A.339.b.11.i；A.340.b.11.i；A.341.b.11.i；A.342.b.11.i； A.343.b.11.i；A.344.b.11.i；A.345.b.11.i；A.346.b.11.i；A.347.b.11.i；A.348.b.11.i； A.349.b.11.i；A.350.b.11.i；A.351.b.11.i；A.352.b.11.i；A.353.b.11.i；A.354.b.11.i； A.355.b.11.i；A.356.b.11.i；A.357.b.11.i；A.358.b.11.i；A.359.b.11.i；A.360.b.11.i； A.361.b.11.i；A.362.b.11.i；A.363.b.11.i；A.364.b.11.i；A.365.b.11.i；A.366.b.11.i； A.367.b.11.i；A.368.b.11.i；A.369.b.11.i；A.370.b.11.i；A.371.b.11.i；A.372.b.11.i； A.373.b.11.i；A.374.b.11.i；A.375.b.11.i；A.376.b.11.i；A.377.b.11.i；A.378.b.11.i； A.379.b.11.i；A.380.b.11.i；A.381.b.11.i；A.382.b.11.i；A.383.b.11.i；A.384.b.11.i； A.385.b.11.i；A.386.b.11.i；A.387.b.11.i；A.388.b.11.i；A.389.b.11.i；A.390.b.11.i； A.391.b.11.i；A.392.b.11.i；A.393.b.11.i；A.394.b.11.i；A.395.b.11.i；A.396.b.11.i； A.397.b.11.i；A.398.b.11.i；A.399.b.11.i；A.400.b.11.i；A.401.b.11.i；A.402.b.11.i； A.403.b.11.i；A.404.b.11.i；A.405.b.11.i；A.406.b.11.i；A.407.b.11.i；A.408.b.11.i； A.409.b.11.i；A.410.b.11.i；A.411.b.11.i；A.412.b.11.i；A.413.b.11.i；A.414.b.11.i； A.415.b.11.i；A.416.b.11.i；A.417.b.11.i；A.418.b.11.i；A.419.b.11.i；A.420.b.11.i； A.421.b.11.i；A.422.b.11.i；A.423.b.11.i；A.424.b.11.i；A.425.b.11.i；A.426.b.11.i； A.427.b.11.i；A.428.b.11.i；A.429.b.11.i；A.430.b.11.i；A.431.b.11.i；A.432.b.11.i； A.433.b.11.i；A.434.b.11.i；A.435.b.11.i；A.436.b.11.i；A.437.b.11.i；A.438.b.11.i； A.439.b.11.i；A.440.b.11.i；A.441.b.11.i；A.442.b.11.i；A.443.b.11.i；A.444.b.11.i； A.445.b.11.i；A.446.b.11.i；A.447.b.11.i；A.448.b.11.i；A.449.b.11.i；A.450.b.11.i； A.451.b.11.i；A.452.b.11.i；A.453.b.11.i；A.454.b.11.i；A.455.b.11.i；A.456.b.11.i； A.457.b.11.i；A.458.b.11.i；A.459.b.11.i；A.460.b.11.i；A.461.b.11.i；A.462.b.11.i； A.463.b.11.i；A.464.b.11.i；A.465.b.11.i；A.466.b.11.i；A.467.b.11.i；A.468.b.11.i； A.469.b.11.i；A.470.b.11.i；A.471.b.11.i；A.472.b.11.i；A.473.b.11.i；A.474.b.11.i； A.475.b.11.i；A.476.b.11.i；A.477.b.11.i；A.478.b.11.i；A.479.b.11.i；A.480.b.11.i； A.481.b.11.i；A.482.b.11.i；A.483.b.11.i；A.484.b.11.i；A.485.b.11.i；A.486.b.11.i； A.487.b.11.i；A.488.b.11.i；A.489.b.11.i；A.490.b.11.i；A.491.b.11.i；A.492.b.11.i； A.493.b.11.i；A.494.b.11.i；A.495.b.11.i；A.496.b.11.i；A.497.b.11.i；A.498.b.11.i； A.499.b.11.i；A.500.b.11.i；A.501.b.11.i；A.502.b.11.i；A.503.b.11.i；A.504.b.11.i； A.505.b.11.i；A.506.b.11.i；A.507.b.11.i；A.508.b.11.i；A.509.b.11.i；A.510.b.11.i； A.511.b.11.i；A.512.b.11.i；A.512.b.11.i；A.513.b.11.i；A.514.b.11.i；A.515.b.11.i； A.516.b.11.i；A.517.b.11.i；A.518.b.11.i；A.519.b.11.i；A.520.b.11.i；A.521.b.11.i； A.522.b.11.i；A.523.b.11.i；A.524.b.11.i；A.525.b.11.i；A.526.b.11.i；A.527.b.11.i； A.528.b.11.i；A.529.b.11.i；A.530.b.11.i；A.531.b.11.i；A.532.b.11.i；A.533.b.11.i； A.534.b.11.i；A.535.b.11.i；A.536.b.11.i；A.537.b.11.i；A.538.b.11.i；A.539.b.11.i； A.540.b.11.i；A.541.b.11.i；A.542.b.11.i；A.543.b.11.i；A.544.b.11.i；A.545.b.11.i； A.546.b.11.i；A.547.b.11.i；A.548.b.11.i；A.549.b.11.i；A.550.b.11.i；A.551.b.11.i； A.552.b.11.i；A.553.b.11.i；A.554.b.11.i；A.555.b.11.i；A.556.b.11.i；A.557.b.11.i； A.558.b.11.i；A.559.b.11.i；A.560.b.11.i；A.561.b.11.i；A.562.b.11.i；A.563.b.11.i； 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A.442.y.4.i；A.443.y.4.i；A.444.y.4.i；A.445.y.4.i；A.446.y.4.i；A.447.y.4.i；A.448.y.4.i； A.449.y.4.i；A.450.y.4.i；A.451.y.4.i；A.452.y.4.i；A.453.y.4.i；A.454.y.4.i；A.455.y.4.i； A.456.y.4.i；A.457.y.4.i；A.458.y.4.i；A.459.y.4.i；A.460.y.4.i；A.461.y.4.i；A.462.y.4.i； A.463.y.4.i；A.464.y.4.i；A.465.y.4.i；A.466.y.4.i；A.467.y.4.i；A.468.y.4.i；A.469.y.4.i； A.470.y.4.i；A.471.y.4.i；A.472.y.4.i；A.473.y.4.i；A.474.y.4.i；A.475.y.4.i；A.476.y.4.i； A.477.y.4.i；A.478.y.4.i；A.479.y.4.i；A.480.y.4.i；A.481.y.4.i；A.482.y.4.i；A.483.y.4.i； A.484.y.4.i；A.485.y.4.i；A.486.y.4.i；A.487.y.4.i；A.488.y.4.i；A.489.y.4.i；A.490.y.4.i； A.491.y.4.i；A.492.y.4.i；A.493.y.4.i；A.494.y.4.i；A.495.y.4.i；A.496.y.4.i；A.497.y.4.i； A.498.y.4.i；A.499.y.4.i；A.500.y.4.i；A.501.y.4.i；A.502.y.4.i；A.503.y.4.i；A.504.y.4.i； A.505.y.4.i；A.506.y.4.i；A.507.y.4.i；A.508.y.4.i；A.509.y.4.i；A.510.y.4.i；A.511.y.4.i； A.512.y.4.i；A.512.y.4.i；A.513.y.4.i；A.514.y.4.i；A.515.y.4.i；A.516.y.4.i；A.517.y.4.i； 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A.595.y.4.i；A.596.y.4.i；A.597.y.4.i；A.598.y.4.i；A.599.y.4.i；A.600.y.4.i；A.601.y.4.i； A.602.y.4.i；A.603.y.4.i；A.604.y.4.i；A.605.y.4.i；A.606.y.4.i；A.607.y.4.i；A.608.y.4.i； A.609.y.4.i；A.610.y.4.i；A.611.y.4.i；A.612.y.4.i；A.613.y.4.i；A.614.y.4.i；A.615.y.4.i； A.616.y.4.i；A.617.y.4.i；A.618.y.4.i；A.619.y.4.i；A.620.y.4.i；A.621.y.4.i；A.622.y.4.i； A.623.y.4.i；A.624.y.4.i；A.625.y.4.i；A.626.y.4.i；A.627.y.4.i；A.628.y.4.i；A.629.y.4.i； A.630.y.4.i；A.631.y.4.i；A.632.y.4.i；A.633.y.4.i；A.634.y.4.i；A.635.y.4.i；A.636.y.4.i； A.637.y.4.i；A.638.y.4.i；A.639.y.4.i；A.640.y.4.i；A.641.y.4.i；A.642.y.4.i；A.643.y.4.i； A.644.y.4.i；A.645.y.4.i；A.646.y.4.i；A.647.y.4.i；A.648.y.4.i；A.649.y.4.i；A.650.y.4.i； A.651.y.4.i；A.652.y.4.i；A.653.y.4.i；A.654.y.4.i；A.655.y.4.i；A.656.y.4.i；A.657.y.4.i； A.658.y.4.i；A.659.y.4.i；A.660.y.4.i；A.2.y.11.i；A.3.y.11.i；A.4.y.11.i；A.5.y.11.i； A.6.y.11.i；A.7.y.11.i；A.9.y.11.i；A.10.y.11.i；A.15.y.11.i；A.100.y.11.i；A.101.y.11.i； A.102.y.11.i；A.103.y.11.i；A.104.y.11.i；A.105.y.11.i；A.106.y.11.i；A.107.y.11.i； A.108.y.11.i；A.109.y.11.i；A.110.y.11.i；A.111.y.11.i；A.112.y.11.i；A.113.y.11.i； A.114.y.11.i；A.115.y.11.i；A.116.y.11.i；A.117.y.11.i；A.118.y.11.i；A.119.y.11.i； A.120.y.11.i；A.121.y.11.i；A.122.y.11.i；A.123.y.11.i；A.124.y.11.i；A.125.y.11.i； A.126.y.11.i；A.127.y.11.i；A.128.y.11.i；A.129.y.11.i；A.130.y.11.i；A.131.y.11.i； A.132.y.11.i；A.133.y.11.i；A.134.y.11.i；A.135.y.11.i；A.136.y.11.i；A.137.y.11.i； A.138.y.11.i；A.139.y.11.i；A.140.y.11.i；A.141.y.11.i；A.142.y.11.i；A.143.y.11.i； A.144.y.11.i；A.145.y.11.i；A.146.y.11.i；A.147.y.11.i；A.148.y.11.i；A.149.y.11.i； A.150.y.11.i；A.151.y.11.i；A.152.y.11.i；A.153.y.11.i；A.154.y.11.i；A.155.y.11.i； A.156.y.11.i；A.157.y.11.i；A.158.y.11.i；A.159.y.11.i；A.160.y.11.i；A.161.y.11.i； A.162.y.11.i；A.163.y.11.i；A.164.y.11.i；A.165.y.11.i；A.166.y.11.i；A.167.y.11.i；A.168.y.11.i；A.169.y.11.i；A.170.y.11.i；A.171.y.11.i；A.172.y.11.i；A.173.y.11.i； A.174.y.11.i；A.175.y.11.i；A.176.y.11.i；A.177.y.11.i；A.178.y.11.i；A.179.y.11.i； A.180.y.11.i；A.181.y.11.i；A.182.y.11.i；A.183.y.11.i；A.184.y.11.i；A.185.y.11.i； A.186.y.11.i；A.187.y.11.i；A.188.y.11.i；A.189.y.11.i；A.190.y.11.i；A.191.y.11.i； A.192.y.11.i；A.193.y.11.i；A.194.y.11.i；A.195.y.11.i；A.196.y.11.i；A.197.y.11.i； A.198.y.11.i；A.199.y.11.i；A.200.y.11.i；A.201.y.11.i；A.202.y.11.i；A.203.y.11.i； A.204.y.11.i；A.205.y.11.i；A.206.y.11.i；A.207.y.11.i；A.208.y.11.i；A.209.y.11.i； A.210.y.11.i；A.211.y.11.i；A.212.y.11.i；A.213.y.11.i；A.214.y.11.i；A.215.y.11.i； A.216.y.11.i；A.217.y.11.i；A.218.y.11.i；A.219.y.11.i；A.220.y.11.i；A.221.y.11.i； A.222.y.11.i；A.223.y.11.i；A.224.y.11.i；A.225.y.11.i；A.226.y.11.i；A.227.y.11.i； A.228.y.11.i；A.229.y.11.i；A.230.y.11.i；A.231.y.11.i；A.232.y.11.i；A.233.y.11.i； A.234.y.11.i；A.235.y.11.i；A.236.y.11.i；A.237.y.11.i；A.238.y.11.i；A.239.y.11.i； A.240.y.11.i；A.241.y.11.i；A.242.y.11.i；A.243.y.11.i；A.244.y.11.i；A.245.y.11.i； A.246.y.11.i；A.247.y.11.i；A.248.y.11.i；A.249.y.11.i；A.250.y.11.i；A.251.y.11.i； A.252.y.11.i；A.253.y.11.i；A.254.y.11.i；A.255.y.11.i；A.256.y.11.i；A.257.y.11.i； A.258.y.11.i；A.259.y.11.i；A.260.y.11.i；A.261.y.11.i；A.262.y.11.i；A.263.y.11.i； A.264.y.11.i；A.265.y.11.i；A.266.y.11.i；A.267.y.11.i；A.268.y.11.i；A.269.y.11.i； A.270.y.11.i；A.271.y.11.i；A.272.y.11.i；A.273.y.11.i；A.274.y.11.i；A.275.y.11.i； A.276.y.11.i；A.277.y.11.i；A.278.y.11.i；A.279.y.11.i；A.280.y.11.i；A.281.y.11.i； A.282.y.11.i；A.283.y.11.i；A.284.y.11.i；A.285.y.11.i；A.286.y.11.i；A.287.y.11.i； A.288.y.11.i；A.289.y.11.i；A.290.y.11.i；A.291.y.11.i；A.292.y.11.i；A.293.y.11.i； A.294.y.11.i；A.295.y.11.i；A.296.y.11.i；A.297.y.11.i；A.298.y.11.i；A.299.y.11.i； A.300.y.11.i；A.301.y.11.i；A.302.y.11.i；A.303.y.11.i；A.304.y.11.i；A.305.y.11.i； A.306.y.11.i；A.307.y.11.i；A.308.y.11.i；A.309.y.11.i；A.310.y.11.i；A.311.y.11.i； A.312.y.11.i；A.313.y.11.i；A.314.y.11.i；A.315.y.11.i；A.316.y.11.i；A.317.y.11.i； A.318.y.11.i；A.319.y.11.i；A.320.y.11.i；A.321.y.11.i；A.323.y.11.i；A.324.y.11.i； A.325.y.11.i；A.326.y.11.i；A.327.y.11.i；A.328.y.11.i；A.329.y.11.i；A.330.y.11.i； A.331.y.11.i；A.332.y.11.i；A.333.y.11.i；A.334.y.11.i；A.335.y.11.i；A.336.y.11.i； A.337.y.11.i；A.338.y.11.i；A.339.y.11.i；A.340.y.11.i；A.341.y.11.i；A.342.y.11.i； A.343.y.11.i；A.344.y.11.i；A.345.y.11.i；A.346.y.11.i；A.347.y.11.i；A.348.y.11.i； A.349.y.11.i；A.350.y.11.i；A.351.y.11.i；A.352.y.11.i；A.353.y.11.i；A.354.y.11.i； A.355.y.11.i；A.356.y.11.i；A.357.y.11.i；A.358.y.11.i；A.359.y.11.i；A.360.y.11.i； A.361.y.11.i；A.362.y.11.i；A.363.y.11.i；A.364.y.11.i；A.365.y.11.i；A.366.y.11.i； A.367.y.11.i；A.368.y.11.i；A.369.y.11.i；A.370.y.11.i；A.371.y.11.i；A.372.y.11.i； A.373.y.11.i；A.374.y.11.i；A.375.y.11.i；A.376.y.11.i；A.377.y.11.i；A.378.y.11.i； A.379.y.11.i；A.380.y.11.i；A.381.y.11.i；A.382.y.11.i；A.383.y.11.i；A.384.y.11.i； A.385.y.11.i；A.386.y.11.i；A.387.y.11.i；A.388.y.11.i；A.389.y.11.i；A.390.y.11.i； A.391.y.11.i；A.392.y.11.i；A.393.y.11.i；A.394.y.11.i；A.395.y.11.i；A.396.y.11.i； A.397.y.11.i；A.398.y.11.i；A.399.y.11.i；A.400.y.11.i；A.401.y.11.i；A.402.y.11.i； A.403.y.11.i；A.404.y.11.i；A.405.y.11.i；A.406.y.11.i；A.407.y.11.i；A.408.y.11.i； A.409.y.11.i；A.410.y.11.i；A.411.y.11.i；A.412.y.11.i；A.413.y.11.i；A.414.y.11.i； A.415.y.11.i；A.416.y.11.i；A.417.y.11.i；A.418.y.11.i；A.419.y.11.i；A.420.y.11.i； A.421.y.11.i；A.422.y.11.i；A.423.y.11.i；A.424.y.11.i；A.425.y.11.i；A.426.y.11.i； A.427.y.11.i；A.428.y.11.i；A.429.y.11.i；A.430.y.11.i；A.431.y.11.i；A.432.y.11.i； A.433.y.11.i；A.434.y.11.i；A.435.y.11.i；A.436.y.11.i；A.437.y.11.i；A.438.y.11.i； A.439.y.11.i；A.440.y.11.i；A.441.y.11.i；A.442.y.11.i；A.443.y.11.i；A.444.y.11.i； A.445.y.11.i；A.446.y.11.i；A.447.y.11.i；A.448.y.11.i；A.449.y.11.i；A.450.y.11.i；A.451.y.11.i；A.452.y.11.i；A.453.y.11.i；A.454.y.11.i；A.455.y.11.i；A.456.y.11.i； A.457.y.11.i；A.458.y.11.i；A.459.y.11.i；A.460.y.11.i；A.461.y.11.i；A.462.y.11.i； 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A.588.z.11.i；A.589.z.11.i；A.590.z.11.i；A.591.z.11.i；A.592.z.11.i；A.593.z.11.i； A.594.z.11.i；A.595.z.11.i；A.596.z.11.i；A.597.z.11.i；A.598.z.11.i；A.599.z.11.i； A.600.z.11.i；A.601.z.11.i；A.602.z.11.i；A.603.z.11.i；A.604.z.11.i；A.605.z.11.i； A.606.z.11.i；A.607.z.11.i；A.608.z.11.i；A.609.z.11.i；A.610.z.11.i；A.611.z.11.i； A.612.z.11.i；A.613.z.11.i；A.614.z.11.i；A.615.z.11.i；A.616.z.11.i；A.617.z.11.i； A.618.z.11.i；A.619.z.11.i；A.620.z.11.i；A.621.z.11.i；A.622.z.11.i；A.623.z.11.i； A.624.z.11.i；A.625.z.11.i；A.626.z.11.i；A.627.z.11.i；A.628.z.11.i；A.629.z.11.i； A.630.z.11.i；A.631.z.11.i；A.632.z.11.i；A.633.z.11.i；A.634.z.11.i；A.635.z.11.i； A.636.z.11.i；A.637.z.11.i；A.638.z.11.i；A.639.z.11.i；A.640.z.11.i；A.641.z.11.i； A.642.z.11.i；A.643.z.11.i；A.644.z.11.i；A.645.z.11.i；A.646.z.11.i；A.647.z.11.i； A.648.z.11.i；A.649.z.11.i；A.650.z.11.i；A.651.z.11.i；A.652.z.11.i；A.653.z.11.i； A.654.z.11.i；A.655.z.11.i；A.656.z.11.i；A.657.z.11.i；A.658.z.11.i；A.659.z.11.i； A.660.z.11.i；A.2.A.4.i；A.3.A.4.i；A.4.A.4.i；A.5.A.4.i；A.6.A.4.i；A.7.A.4.i； A.9.A.4.i；A.10.A.4.i；A.15.A.4.i；A.100.A.4.i；A.101.A.4.i；A.102.A.4.i； A.103.A.4.i；A.104.A.4.i；A.105.A.4.i；A.106.A.4.i；A.107.A.4.i；A.108.A.4.i； A.109.A.4.i；A.110.A.4.i；A.111.A.4.i；A.112.A.4.i；A.113.A.4.i；A.114.A.4.i； A.115.A.4.i；A.116.A.4.i；A.117.A.4.i；A.118.A.4.i；A.119.A.4.i；A.120.A.4.i； A.121.A.4.i；A.122.A.4.i；A.123.A.4.i；A.124.A.4.i；A.125.A.4.i；A.126.A.4.i； A.127.A.4.i；A.128.A.4.i；A.129.A.4.i；A.130.A.4.i；A.131.A.4.i；A.132.A.4.i； A.133.A.4.i；A.134.A.4.i；A.135.A.4.i；A.136.A.4.i；A.137.A.4.i；A.138.A.4.i； A.139.A.4.i；A.140.A.4.i；A.141.A.4.i；A.142.A.4.i；A.143.A.4.i；A.144.A.4.i； A.145.A.4.i；A.146.A.4.i；A.147.A.4.i；A.148.A.4.i；A.149.A.4.i；A.150.A.4.i； A.151.A.4.i；A.152.A.4.i；A.153.A.4.i；A.154.A.4.i；A.155.A.4.i；A.156.A.4.i； A.157.A.4.i；A.158.A.4.i；A.159.A.4.i；A.160.A.4.i；A.161.A.4.i；A.162.A.4.i； A.163.A.4.i；A.164.A.4.i；A.165.A.4.i；A.166.A.4.i；A.167.A.4.i；A.168.A.4.i； A.169.A.4.i；A.170.A.4.i；A.171.A.4.i；A.172.A.4.i；A.173.A.4.i；A.174.A.4.i； A.175.A.4.i；A.176.A.4.i；A.177.A.4.i；A.178.A.4.i；A.179.A.4.i；A.180.A.4.i； A.181.A.4.i；A.182.A.4.i；A.183.A.4.i；A.184.A.4.i；A.185.A.4.i；A.186.A.4.i； A.187.A.4.i；A.188.A.4.i；A.189.A.4.i；A.190.A.4.i；A.191.A.4.i；A.192.A.4.i； A.193.A.4.i；A.194.A.4.i；A.195.A.4.i；A.196.A.4.i；A.197.A.4.i；A.198.A.4.i； A.199.A.4.i；A.200.A.4.i；A.201.A.4.i；A.202.A.4.i；A.203.A.4.i；A.204.A.4.i； A.205.A.4.i；A.206.A.4.i；A.207.A.4.i；A.208.A.4.i；A.209.A.4.i；A.210.A.4.i； A.211.A.4.i；A.212.A.4.i；A.213.A.4.i；A.214.A.4.i；A.215.A.4.i；A.216.A.4.i； A.217.A.4.i；A.218.A.4.i；A 219.A.4.i；A.220.A.4.i；A.221.A.4.i；A.222.A.4.i； A.223.A.4.i；A.224.A.4.i；A.225.A.4.i；A.226.A.4.i；A.227.A.4.i；A.228.A.4.i； A.229.A.4.i；A.230.A.4.i；A.231.A.4.i；A.232.A.4.i；A.233.A.4.i；A.234.A.4.i；A.235.A.4.i；A.236.A.4.i；A.237.A.4.i；A.238.A.4.i；A.239.A.4.i；A.240.A.4.i； A.241.A.4.i；A.242.A.4.i；A.243.A.4.i；A.244.A.4.i；A.245.A.4.i；A.246.A.4.i； A.247.A.4.i；A.248.A.4.i；A.249.A.4.i；A.250.A.4.i；A.251.A.4.i；A.252.A.4.i； A.253.A.4.i；A.254.A.4.i；A.255.A.4.i；A.256.A.4.i；A.257.A.4.i；A.258.A.4.i； A.259.A.4.i；A.260.A.4.i；A.261.A.4.i；A.262.A.4.i；A.263.A.4.i；A.264.A.4.i； A.265.A.4.i；A.266.A.4.i；A.267.A.4.i；A.268.A.4.i；A.269.A.4.i；A.270.A.4.i； A.271.A.4.i；A.272.A.4.i；A.273.A.4.i；A.274.A.4.i；A.275.A.4.i；A.276.A.4.i； A.277.A.4.i；A.278.A.4.i；A.279.A.4.i；A.280.A.4.i；A.281.A.4.i；A.282.A.4.i； A.283.A.4.i；A.284.A.4.i；A.285.A.4.i；A.286.A.4.i；A.287.A.4.i；A.288.A.4.i； A.289.A.4.i；A.290.A.4.i；A.291.A.4.i；A.292.A.4.i；A.293.A.4.i；A.294.A.4.i； A.295.A.4.i；A.296.A.4.i；A.297.A.4.i；A.298.A.4.i；A.299.A.4.i；A.300.A.4.i； A.301.A.4.i；A.302.A.4.i；A.303.A.4.i；A.304.A.4.i；A.305.A.4.i；A.306.A.4.i； A.307.A.4.i；A.308.A.4.i；A.309.A.4.i；A.310.A.4.i；A.311.A.4.i；A.312.A.4.i； A.313.A.4.i；A.314.A.4.i；A.315.A.4.i；A.316.A.4.i；A.317.A.4.i；A.318.A.4.i； A.319.A.4.i；A.320.A.4.i；A.321.A.4.i；A.323.A.4.i；A.324.A.4.i；A.325.A.4.i； A.326.A.4.i；A.327.A.4.i；A.328.A.4.i；A.329.A.4.i；A.330.A.4.i；A.331.A.4.i； A.332.A.4.i；A.333.A.4.i；A.334.A.4.i；A.335.A.4.i；A.336.A.4.i；A.337.A.4.i； A.338.A.4.i；A.339.A.4.i；A.340.A.4.i；A.341.A.4.i；A.342.A.4.i；A.343.A.4.i； A.344.A.4.i；A.345.A.4.i；A.346.A.4.i；A.347.A.4.i；A.348.A.4.i；A.349.A.4.i； A.350.A.4.i；A.351.A.4.i；A.352.A.4.i；A.353.A.4.i；A.354.A.4.i；A.355.A.4.i； A.356.A.4.i；A.357.A.4.i；A.358.A.4.i；A.359.A.4.i；A.360.A.4.i；A.361.A.4.i； A.362.A.4.i；A.363.A.4.i；A.364.A.4.i；A.365.A.4.i；A.366.A.4.i；A.367.A.4.i； A.368.A.4.i；A.369.A.4.i；A.370.A.4.i；A.371.A.4.i；A.372.A.4.i；A.373.A.4.i； A.374.A.4.i；A.375.A.4.i；A.376.A.4.i；A.377.A.4.i；A.378.A.4.i；A.379.A.4.i； A.380.A.4.i；A.381.A.4.i；A.382.A.4.i；A.383.A.4.i；A.384.A.4.i；A.385.A.4.i； A.386.A.4.i；A.387.A.4.i；A.388.A.4.i；A.389.A.4.i；A.390.A.4.i；A.391.A.4.i； A.392.A.4.i；A.393.A.4.i；A.394.A.4.i；A.395.A.4.i；A.396.A.4.i；A.397.A.4.i； A.398.A.4.i；A.399.A.4.i；A.400.A.4.i；A.401.A.4.i；A.402.A.4.i；A.403.A.4.i； 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A.507.A.11.i；A.508.A.11.i；A.509.A.11.i；A.510.A.11.i；A.511.A.11.i；A.512.A.11.i；A.512.A.11.i；A.513.A.11.i；A.514.A.11.i；A.515.A.11.i；A.516.A.11.i；A.517.A.11.i； A.518.A.11.i；A.519.A.11.i；A.520.A.11.i；A.521.A.11.i；A.522.A.11.i；A.523.A.11.i； A.524.A.11.i；A.525.A.11.i；A.526.A.11.i；A.527.A.11.i；A.528.A.11.i；A.529.A.11.i； A.530.A.11.i；A.531.A.11.i；A.532.A.11.i；A.533.A.11.i；A.534.A.11.i；A.535.A.11.i； A.536.A.11.i；A.537.A.11.i；A.538.A.11.i；A.539.A.11.i；A.540.A.11.i；A.541.A.11.i； A.542.A.11.i；A.543.A.11.i；A.544.A.11.i；A.545.A.11.i；A.546.A.11.i；A.547.A.11.i； A.548.A.11.i；A.549.A.11.i；A.550.A.11.i；A.551.A.11.i；A.552.A.11.i；A.553.A.11.i； A.554.A.11.i；A.555.A.11.i；A.556.A.11.i；A.557.A.11.i；A.558.A.11.i；A.559.A.11.i； A.560.A.11.i；A.561.A.11.i；A.562.A.11.i；A.563.A.11.i；A.564.A.11.i；A.565.A.11.i； A.566.A.11.i；A.567.A.11.i；A.568.A.11.i；A.569.A.11.i；A.570.A.11.i；A.571.A.11.i； A.572.A.11.i；A.573.A.11.i；A.574.A.11.i；A.575.A.11.i；A.576.A.11.i；A.577.A.11.i； A.578.A.11.i；A.579.A.11.i；A.580.A.11.i；A.581.A.11.i；A.582.A.11.i；A.583.A.11.i； A.584.A.11.i；A.585.A.11.i；A.586.A.11.i；A.587.A.11.i；A.588.A.11.i；A.589.A.11.i； A.590.A.11.i；A.591.A.11.i；A.592.A.11.i；A.593.A.11.i；A.594.A.11.i；A.595.A.11.i； A.596.A.11.i；A.597.A.11.i；A.598.A.11.i；A.599.A.11.i；A.600.A.11.i；A.601.A.11.i； A.602.A.11.i；A.603.A.11.i；A.604.A.11.i；A.605.A.11.i；A.606.A.11.i；A.607.A.11.i； A.608.A.11.i；A.609.A.11.i；A.610.A.11.i；A.611.A.11.i；A.612.A.11.i；A.613.A.11.i； A.614.A.11.i；A.615.A.11.i；A.616.A.11.i；A.617.A.11.i；A.618.A.11.i；A.619.A.11.i； A.620.A.11.i；A.621.A.11.i；A.622.A.11.i；A.623.A.11.i；A.624.A.11.i；A.625.A.11.i； A.626.A.11.i；A.627.A.11.i；A.628.A.11.i；A.629.A.11.i；A.630.A.11.i；A.631.A.11.i； A.632.A.11.i；A.633.A.11.i；A.634.A.11.i；A.635.A.11.i；A.636.A.11.i；A.637.A.11.i； A.638.A.11.i；A.639.A.11.i；A.640.A.11.i；A.641.A.11.i；A.642.A.11.i；A.643.A.11.i； A.644.A.11.i；A.645.A.11.i；A.646.A.11.i；A.647.A.11.i；A.648.A.11.i；A.649.A.11.i； A.650.A.11.i；A.651.A.11.i；A.652.A.11.i；A.653.A.11.i；A.654.A.11.i；A.655.A.11.i； A.656.A.11.i；A.657.A.11.i；A.658.A.11.i；A.659.A.11.i；A.660.A.11.i；A.2.B.4.i； A.3.B.4.i；A.4.B.4.i；A.5.B.4.i；A.6.B.4.i；A.7.B.4.i；A.9.B.4.i；A.10.B.4.i；A.15.B.4.i； A.100.B.4.i；A.101.B.4.i；A.102.B.4.i；A.103.B.4.i；A.104.B.4.i；A.105.B.4.i； A.106.B.4.i；A.107.B.4.i；A.108.B.4.i；A.109.B.4.i；A.110.B.4.i；A.111.B.4.i； A.112.B.4.i；A.113.B.4.i；A.114.B.4.i；A.115.B.4.i；A.116.B.4.i；A.117.B.4.i； A.118.B.4.i；A.119.B.4.i；A.120.B.4.i；A.121.B.4.i；A.122.B.4.i；A.123.B.4.i； A.124.B.4.i；A.125.B.4.i；A.126.B.4.i；A.127.B.4.i；A.128.B.4.i；A.129.B.4.i； A.130.B.4.i；A.131.B.4.i；A.132.B.4.i；A.133.B.4.i；A.134.B.4.i；A.135.B.4.i； A.136.B.4.i；A.137.B.4.i；A.138.B.4.i；A.139.B.4.i；A.140.B.4.i；A.141.B.4.i； A.142.B.4.i；A.143.B.4.i；A.144.B.4.i；A.145.B.4.i；A.146.B.4.i；A.147.B.4.i； A.148.B.4.i；A.149.B.4.i；A.150.B.4.i；A.151.B.4.i；A.152.B.4.i；A.153.B.4.i； A.154.B.4.i；A.155.B.4.i；A.156.B.4.i；A.157.B.4.i；A.158.B.4.i；A.159.B.4.i； A.160.B.4.i；A.161.B.4.i；A.162.B.4.i；A.163.B.4.i；A.164.B.4.i；A.165.B.4.i； A.166.B.4.i；A.167.B.4.i；A.168.B.4.i；A.169.B.4.i；A.170.B.4.i；A.171.B.4.i； A.172.B.4.i；A.173.B.4.i；A.174.B.4.i；A.175.B.4.i；A.176.B.4.i；A.177.B.4.i； A.178.B.4.i；A.179.B.4.i；A.180.B.4.i；A.181.B.4.i；A.182.B.4.i；A.183.B.4.i； A.184.B.4.i；A.185.B.4.i；A.186.B.4.i；A.187.B.4.i；A.188.B.4.i；A.189.B.4.i； A.190.B.4.i；A.191.B.4.i；A.192.B.4.i；A.193.B.4.i；A.194.B.4.i；A.195.B.4.i； A.196.B.4.i；A.197.B.4.i；A.198.B.4.i；A.199.B.4.i；A.200.B.4.i；A.201.B.4.i； A.202.B.4.i；A.203.B.4.i；A.204.B.4.i；A.205.B.4.i；A.206.B.4.i；A.207.B.4.i； A.208.B.4.i；A.209.B.4.i；A.210.B.4.i；A.211.B.4.i；A.212.B.4.i；A.213.B.4.i； A.214.B.4.i；A.215.B.4.i；A.216.B.4.i；A.217.B.4.i；A.218.B.4.i；A.219.B.4.i； A.220.B.4.i；A.221.B.4.i；A.222.B.4.i；A.223.B.4.i；A.224.B.4.i；A.225.B.4.i；A.226.B.4.i；A.227.B.4.i；A.228.B.4.i；A.229.B.4.i；A.230.B.4.i；A.231.B.4.i； A.232.B.4.i；A.233.B.4.i；A.234.B.4.i；A.235.B.4.i；A.236.B.4.i；A.237.B.4.i； A.238.B.4.i；A.239.B.4.i；A.240.B.4.i；A.241.B.4.i；A.242.B.4.i；A.243.B.4.i； A.244.B.4.i；A.245.B.4.i；A.246.B.4.i；A.247.B.4.i；A.248.B.4.i；A.249.B.4.i； A.250.B.4.i；A.251.B.4.i；A.252.B.4.i；A.253.B.4.i；A.254.B.4.i；A.255.B.4.i； A.256.B.4.i；A.257.B.4.i；A.258.B.4.i；A.259.B.4.i；A.260.B.4.i；A.261.B.4.i； A.262.B.4.i；A.263.B.4.i；A.264.B.4.i；A.265.B.4.i；A.266.B.4.i；A.267.B.4.i； A.268.B.4.i；A.269.B.4.i；A.270.B.4.i；A.271.B.4.i；A.272.B.4.i；A.273.B.4.i； A.274.B.4.i；A.275.B.4.i；A.276.B.4.i；A.277.B.4.i；A.278.B.4.i；A.279.B.4.i； A.280.B.4.i；A.281.B.4.i；A.282.B.4.i；A.283.B.4.i；A.284.B.4.i；A.285.B.4.i； A.286.B.4.i；A.287.B.4.i；A.288.B.4.i；A.289.B.4.i；A.290.B.4.i；A.291.B.4.i； A.292.B.4.i；A.293.B.4.i；A.294.B.4.i；A.295.B.4.i；A.296.B.4.i；A.297.B.4.i； A.298.B.4.i；A.299.B.4.i；A.300.B.4.i；A.301.B.4.i；A.302.B.4.i；A.303.B.4.i； A.304.B.4.i；A.305.B.4.i；A.306.B.4.i；A.307.B.4.i；A.308.B.4.i；A.309.B.4.i； A.310.B.4.i；A.311.B.4.i；A.312.B.4.i；A.313.B.4.i；A.314.B.4.i；A.315.B.4.i； A.316.B.4.i；A.317.B.4.i；A.318.B.4.i；A.319.B.4.i；A.320.B.4.i；A.321.B.4.i； A.323.B.4.i；A.324.B.4.i；A.325.B.4.i；A.326.B.4.i；A.327.B.4.i；A.328.B.4.i； A.329.B.4.i；A.330.B.4.i；A.331.B.4.i；A.332.B.4.i；A.333.B.4.i；A.334.B.4.i； A.335.B.4.i；A.336.B.4.i；A.337.B.4.i；A.338.B.4.i；A.339.B.4.i；A.340.B.4.i； A.341.B.4.i；A.342.B.4.i；A.343.B.4.i；A.344.B.4.i；A.345.B.4.i；A.346.B.4.i； A.347.B.4.i；A.348.B.4.i；A.349.B.4.i；A.350.B.4.i；A.351.B.4.i；A.352.B.4.i； A.353.B.4.i；A.354.B.4.i；A.355.B.4.i；A.356.B.4.i；A.357.B.4.i；A.358.B.4.i； A.359.B.4.i；A.360.B.4.i；A.361.B.4.i；A.362.B.4.i；A.363.B.4.i；A.364.B.4.i； A.365.B.4.i；A.366.B.4.i；A.367.B.4.i；A.368.B.4.i；A.369.B.4.i；A.370.B.4.i； A.371.B.4.i；A.372.B.4.i；A.373.B.4.i；A.374.B.4.i；A.375.B.4.i；A.376.B.4.i； A.377.B.4.i；A.378.B.4.i；A.379.B.4.i；A.380.B.4.i；A.381.B.4.i；A.382.B.4.i； A.383.B.4.i；A.384.B.4.i；A.385.B.4.i；A.386.B.4.i；A.387.B.4.i；A.388.B.4.i； A.389.B.4.i；A.390.B.4.i；A.391.B.4.i；A.392.B.4.i；A.393.B.4.i；A.394.B.4.i； A.395.B.4.i；A.396.B.4.i；A.397.B.4.i；A.398.B.4.i；A.399.B.4.i；A.400.B.4.i； A.401.B.4.i；A.402.B.4.i；A.403.B.4.i；A.404.B.4.i；A.405.B.4.i；A.406.B.4.i； A.407.B.4.i；A.408.B.4.i；A.409.B.4.i；A.410.B.4.i；A.411.B.4.i；A.412.B.4.i； A.413.B.4.i；A.414.B.4.i；A.415.B.4.i；A.416.B.4.i；A.417.B.4.i；A.418.B.4.i； A.419.B.4.i；A.420.B.4.i；A.421.B.4.i；A.422.B.4.i；A.423.B.4.i；A.424.B.4.i； A.425.B.4.i；A.426.B.4.i；A.427.B.4.i；A.428.B.4.i；A.429.B.4.i；A.430.B.4.i； A.431.B.4.i；A.432.B.4.i；A.433.B.4.i；A.434.B.4.i；A.435.B.4.i；A.436.B.4.i； A.437.B.4.i；A.438.B.4.i；A.439.B.4.i；A.440.B.4.i；A.441.B.4.i；A.442.B.4.i； A.443.B.4.i；A.444.B.4.i；A.445.B.4.i；A.446.B.4.i；A.447.B.4.i；A.448.B.4.i； A.449.B.4.i；A.450.B.4.i；A.451.B.4.i；A.452.B.4.i；A.453.B.4.i；A.454.B.4.i； A.455.B.4.i；A.456.B.4.i；A.457.B.4.i；A.458.B.4.i；A.459.B.4.i；A.460.B.4.i； A.461.B.4.i；A.462.B.4.i；A.463.B.4.i；A.464.B.4.i；A.465.B.4.i；A.466.B.4.i； A.467.B.4.i；A.468.B.4.i；A.469.B.4.i；A.470.B.4.i；A.471.B.4.i；A.472.B.4.i； 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A.628.B.4.i；A.629.B.4.i；A.630.B.4.i；A.631.B.4.i；A.632.B.4.i；A.633.B.4.i； A.634.B.4.i；A.635.B.4.i；A.636.B.4.i；A.637.B.4.i；A.638.B.4.i；A.639.B.4.i； A.640.B.4.i；A.641.B.4.i；A.642.B.4.i；A.643.B.4.i；A.644.B.4.i；A.645.B.4.i； A.646.B.4.i；A.647.B.4.i；A.648.B.4.i；A.649.B.4.i；A.650.B.4.i；A.651.B.4.i； A.652.B.4.i；A.653.B.4.i；A.654.B.4.i；A.655.B.4.i；A.656.B.4.i；A.657.B.4.i； A.658.B.4.i；A.659.B.4.i；A.660.B.4.i；A.2.B.11.i；A.3.B.11.i；A.4.B.11.i；A.5.B.11.i； A.6.B.11.i；A.7.B.11.i；A.9.B.11.i；A.10.B.11.i；A.15.B.11.i；A.100.B.11.i； A.101.B.11.i；A.102.B.11.i；A.103.B.11.i；A.104.B.11.i；A.105.B.11.i；A.106.B.11.i； A.107.B.11.i；A.108.B.11.i；A.109.B.11.i；A.110.B.11.i；A.111.B.11.i；A.112.B.11.i； A.113.B.11.i；A.114.B.11.i；A.115.B.11.i；A.116.B.11.i；A.117.B.11.i；A.118.B.11.i； A.119.B.11.i；A.120.B.11.i；A.121.B.11.i；A.122.B.11.i；A.123.B.11.i；A.124.B.11.i； A.125.B.11.i；A.126.B.11.i；A.127.B.11.i；A.128.B.11.i；A.129.B.11.i；A.130.B.11.i； A.131.B.11.i；A.132.B.11.i；A.133.B.11.i；A.134.B.11.i；A.135.B.11.i；A.136.B.11.i； A.137.B.11.i；A.138.B.11.i；A.139.B.11.i；A.140.B.11.i；A.141.B.11.i；A.142.B.11.i； A.143.B.11.i；A.144.B.11.i；A.145.B.11.i；A.146.B.11.i；A.147.B.11.i；A.148.B.11.i； A.149.B.11.i；A.150.B.11.i；A.151.B.11.i；A.152.B.11.i；A.153.B.11.i；A.154.B.11.i； A.155.B.11.i；A.156.B.11.i；A.157.B.11.i；A.158.B.11.i；A.159.B.11.i；A.160.B.11.i； A.161.B.11.i；A.162.B.11.i；A.163.B.11.i；A.164.B.11.i；A.165.B.11.i；A.166.B.11.i； A.167.B.11.i；A.168.B.11.i；A.169.B.11.i；A.170.B.11.i；A.171.B.11.i；A.172.B.11.i； A.173.B.11.i；A.174.B.11.i；A.175.B.11.i；A.176.B.11.i；A.177.B.11.i；A.178.B.11.i； A.179.B.11.i；A.180.B.11.i；A.181.B.11.i；A.182.B.11.i；A.183.B.11.i；A.184.B.11.i； A.185.B.11.i；A.186.B.11.i；A.187.B.11.i；A.188.B.11.i；A.189.B.11.i；A.190.B.11.i； A.191.B.11.i；A.192.B.11.i；A.193.B.11.i；A.194.B.11.i；A.195.B.11.i；A.196.B.11.i； A.197.B.11.i；A.198.B.11.i；A.199.B.11.i；A.200.B.11.i；A.201.B.11.i；A.202.B.11.i； A.203.B.11.i；A.204.B.11.i；A.205.B.11.i；A.206.B.11.i；A.207.B.11.i；A.208.B.11.i； A.209.B.11.i；A.210.B.11.i；A.211.B.11.i；A.212.B.11.i；A.213.B.11.i；A.214.B.11.i； A.215.B.11.i；A.216.B.11.i；A.217.B.11.i；A.218.B.11.i；A.219.B.11.i；A.220.B.11.i；A.221.B.11.i；A.222.B.11.i；A.223.B.11.i；A.224.B.11.i；A.225.B.11.i；A.226.B.11.i； A.227.B.11.i；A.228.B.11.i；A.229.B.11.i；A.230.B.11.i；A.231.B.11.i；A.232.B.11.i； A.233.B.11.i；A.234.B.11.i；A.235.B.11.i；A.236.B.11.i；A.237.B.11.i；A.238.B.11.i； A.239.B.11.i；A.240.B.11.i；A.241.B.11.i；A.242.B.11.i；A.243.B.11.i；A.244.B.11.i； A.245.B.11.i；A.246.B.11.i；A.247.B.11.i；A.248.B.11.i；A.249.B.11.i；A.250.B.11.i； A.251.B.11.i；A.252.B.11.i；A.253.B.11.i；A.254.B.11.i；A.255.B.11.i；A.256.B.11.i； A.257.B.11.i；A.258.B.11.i；A.259.B.11.i；A.260.B.11.i；A.261.B.11.i；A.262.B.11.i； A.263.B.11.i；A.264.B.11.i；A.265.B.11.i；A.266.B.11.i；A.267.B.11.i；A.268.B.11.i； A.269.B.11.i；A.270.B.11.i；A.271.B.11.i；A.272.B.11.i；A.273.B.11.i；A.274.B.11.i； A.275.B.11.i；A.276.B.11.i；A.277.B.11.i；A.278.B.11.i；A.279.B.11.i；A.280.B.11.i； A.281.B.11.i；A.282.B.11.i；A.283.B.11.i；A.284.B.11.i；A.285.B.11.i；A.286.B.11.i； A.287.B.11.i；A.288.B.11.i；A.289.B.11.i；A.290.B.11.i；A.291.B.11.i；A.292.B.11.i； A.293.B.11.i；A.294.B.11.i；A.295.B.11.i；A.296.B.11.i；A.297.B.11.i；A.298.B.11.i； A.299.B.11.i；A.300.B.11.i；A.301.B.11.i；A.302.B.11.i；A.303.B.11.i；A.304.B.11.i； A.305.B.11.i；A.306.B.11.i；A.307.B.11.i；A.308.B.11.i；A.309.B.11.i；A.310.B.11.i； A.311.B.11.i；A.312.B.11.i；A.313.B.11.i；A.314.B.11.i；A.315.B.11.i；A.316.B.11.i； A.317.B.11.i；A.318.B.11.i；A.319.B.11.i；A.320.B.11.i；A.321.B.11.i；A.323.B.11.i； A.324.B.11.i；A.325.B.11.i；A.326.B.11.i；A.327.B.11.i；A.328.B.11.i；A.329.B.11.i； A.330.B.11.i；A.331.B.11.i；A.332.B.11.i；A.333.B.11.i；A.334.B.11.i；A.335.B.11.i； A.336.B.11.i；A.337.B.11.i；A.338.B.11.i；A.339.B.11.i；A.340.B.11.i；A.341.B.11.i； A.342.B.11.i；A.343.B.11.i；A.344.B.11.i；A.345.B.11.i；A.346.B.11.i；A.347.B.11.i； A.348.B.11.i；A.349.B.11.i；A.350.B.11.i；A.351.B.11.i；A.352.B.11.i；A.353.B.11.i； A.354.B.11.i；A.355.B.11.i；A.356.B.11.i；A.357.B.11.i；A.358.B.11.i；A.359.B.11.i； A.360.B.11.i；A.361.B.11.i；A.362.B.11.i；A.363.B.11.i；A.364.B.11.i；A.365.B.11.i； A.366.B.11.i；A.367.B.11.i；A.368.B.11.i；A.369.B.11.i；A.370.B.11.i；A.371.B.11.i； A.372.B.11.i；A.373.B.11.i；A.374.B.11.i；A.375.B.11.i；A.376.B.11.i；A.377.B.11.i； A.378.B.11.i；A.379.B.11.i；A.380.B.11.i；A.381.B.11.i；A.382.B.11.i；A.383.B.11.i； A.384.B.11.i；A.385.B.11.i；A.386.B.11.i；A.387.B.11.i；A.388.B.11.i；A.389.B.11.i； A.390.B.11.i；A.391.B.11.i；A.392.B.11.i；A.393.B.11.i；A.394.B.11.i；A.395.B.11.i； A.396.B.11.i；A.397.B.11.i；A.398.B.11.i；A.399.B.11.i；A.400.B.11.i；A.401.B.11.i； A.402.B.11.i；A.403.B.11.i；A.404.B.11.i；A.405.B.11.i；A.406.B.11.i；A.407.B.11.i； A.408.B.11.i；A.409.B.11.i；A.410.B.11.i；A.411.B.11.i；A.412.B.11.i；A.413.B.11.i； A.414.B.11.i；A.415.B.11.i；A.416.B.11.i；A.417.B.11.i；A.418.B.11.i；A.419.B.11.i； A.420.B.11.i；A.421.B.11.i；A.422.B.11.i；A.423.B.11.i；A.424.B.11.i；A.425.B.11.i； A.426.B.11.i；A.427.B.11.i；A.428.B.11.i；A.429.B.11.i；A.430.B.11.i；A.431.B.11.i； A.432.B.11.i；A.433.B.11.i；A.434.B.11.i；A.435.B.11.i；A.436.B.11.i；A.437.B.11.i； A.438.B.11.i；A.439.B.11.i；A.440.B.11.i；A.441.B.11.i；A.442.B.11.i；A.443.B.11.i； A.444.B.11.i；A.445.B.11.i；A.446.B.11.i；A.447.B.11.i；A.448.B.11.i；A.449.B.11.i； A.450.B.11.i；A.451.B.11.i；A.452.B.11.i；A.453.B.11.i；A.454.B.11.i；A.455.B.11.i； A.456.B.11.i；A.457.B.11.i；A.458.B.11.i；A.459.B.11.i；A.460.B.11.i；A.461.B.11.i； A.462.B.11.i；A.463.B.11.i；A.464.B.11.i；A.465.B.11.i；A.466.B.11.i；A.467.B.11.i； A.468.B.11.i；A.469.B.11.i；A.470.B.11.i；A.471.B.11.i；A.472.B.11.i；A.473.B.11.i； A.474.B.11.i；A.475.B.11.i；A.476.B.11.i；A.477.B.11.i；A.478.B.11.i；A.479.B.11.i； A.480.B.11.i；A.481.B.11.i；A.482.B.11.i；A.483.B.11.i；A.484.B.11.i；A.485.B.11.i； A.486.B.11.i；A.487.B.11.i；A.488.B.11.i；A.489.B.11.i；A.490.B.11.i；A.491.B.11.i； A.492.B.11.i；A.493.B.11.i；A.494.B.11.i；A.495.B.11.i；A.496.B.11.i；A.497.B.11.i； A.498.B.11.i；A.499.B.11.i；A 500.B.11.i；A.501.B.11.i；A.502.B.11.i；A.503.B.11.i；A.504.B.11.i；A.505.B.11.i；A.506.B.11.i；A.507.B.11.i；A.508.B.11.i；A.509.B.11.i； A.510.B.11.i；A.511.B.11.i；A.512.B.11.i；A.512.B.11.i；A.513.B.11.i；A.514.B.11.i； A.515.B.11.i；A.516.B.11.i；A.517.B.11.i；A.518.B.11.i；A.519.B.11.i；A.520.B.11.i； A.521.B.11.i；A.522.B.11.i；A.523.B.11.i；A.524.B.11.i；A.525.B.11.i；A.526.B.11.i； A.527.B.11.i；A.528.B.11.i；A.529.B.11.i；A.530.B.11.i；A.531.B.11.i；A.532.B.11.i； A.533.B.11.i；A.534.B.11.i；A.535.B.11.i；A.536.B.11.i；A.537.B.11.i；A.538.B.11.i； A.539.B.11.i；A.540.B.11.i；A.541.B.11.i；A.542.B.11.i；A.543.B.11.i；A.544.B.11.i； A.545.B.11.i；A.546.B.11.i；A.547.B.11.i；A.548.B.11.i；A.549.B.11.i；A.550.B.11.i； A.551.B.11.i；A.552.B.11.i；A.553.B.11.i；A.554.B.11.i；A.555.B.11.i；A.556.B.11.i； A.557.B.11.i；A.558.B.11.i；A.559.B.11.i；A.560.B.11.i；A.561.B.11.i；A.562.B.11.i； A.563.B.11.i；A.564.B.11.i；A.565.B.11.i；A.566.B.11.i；A.567.B.11.i；A.568.B.11.i； A.569.B.11.i；A.570.B.11.i；A.571.B.11.i；A.572.B.11.i；A.573.B.11.i；A.574.B.11.i； A.575.B.11.i；A.576.B.11.i；A.577.B.11.i；A.578.B.11.i；A.579.B.11.i；A.580.B.11.i； A.581.B.11.i；A.582.B.11.i；A.583.B.11.i；A.584.B.11.i；A.585.B.11.i；A.586.B.11.i； A.587.B.11.i；A.588.B.11.i；A.589.B.11.i；A.590.B.11.i；A.591.B.11.i；A.592.B.11.i； A.593.B.11.i；A.594.B.11.i；A.595.B.11.i；A.596.B.11.i；A.597.B.11.i；A.598.B.11.i； A.599.B.11.i；A.600.B.11.i；A.601.B.11.i；A.602.B.11.i；A.603.B.11.i；A.604.B.11.i； A.605.B.11.i；A.606.B.11.i；A.607.B.11.i；A.608.B.11.i；A.609.B.11.i；A.610.B.11.i； A.611.B.11.i；A.612.B.11.i；A.613.B.11.i；A.614.B.11.i；A.615.B.11.i；A.616.B.11.i； A.617.B.11.i；A.618.B.11.i；A.619.B.11.i；A.620.B.11.i；A.621.B.11.i；A.622.B.11.i； A.623.B.11.i；A.624.B.11.i；A.625.B.11.i；A.626.B.11.i；A.627.B.11.i；A.628.B.11.i； A.629.B.11.i；A.630.B.11.i；A.631.B.11.i；A.632.B.11.i；A.633.B.11.i；A.634.B.11.i； A.635.B.11.i；A.636.B.11.i；A.637.B.11.i；A.638.B.11.i；A.639.B.11.i；A.640.B.11.i； A.641.B.11.i；A.642.B.11.i；A.643.B.11.i；A.644.B.11.i；A.645.B.11.i；A.646.B.11.i； A.647.B.11.i；A.648.B.11.i；A.649.B.11.i；A.650.B.11.i；A.651.B.11.i；A.652.B.11.i； A.653.B.11.i；A.654.B.11.i；A.655.B.11.i；A.656.B.11.i；A.657.B.11.i；A.658.B.11.i； A.659.B.11.i；A.660.B.11.i；A.2.C.4.i；A.3.C.4.i；A.4.C.4.i；A.5.C.4.i；A.6.C.4.i； A.7.C.4.i；A.9.C.4.i；A.10.C.4.i；A.15.C.4.i；A.100.C.4.i；A.101.C.4.i；A.102.C.4.i； A.103.C.4.i；A.104.C.4.i；A.105.C.4.i；A.106.C.4.i；A.107.C.4.i；A.108.C.4.i； A.109.C.4.i；A.110.C.4.i；A.111.C.4.i；A.112.C.4.i；A.113.C.4.i；A.114.C.4.i； A.115.C.4.i；A.116.C.4.i；A.117.C.4.i；A.118.C.4.i；A.119.C.4.i；A.120.C.4.i； A.121.C.4.i；A.122.C.4.i；A.123.C.4.i；A.124.C.4.i；A.125.C.4.i；A.126.C.4.i； A.127.C.4.i；A.128.C.4.i；A.129.C.4.i；A.130.C.4.i；A.131.C.4.i；A.132.C.4.i； A.133.C.4.i；A.134.C.4.i；A.135.C.4.i；A.136.C.4.i；A.137.C.4.i；A.138.C.4.i； A.139.C.4.i；A.140.C.4.i；A.141.C.4.i；A.142.C.4.i；A.143.C.4.i；A.144.C.4.i； A.145.C.4.i；A.146.C.4.i；A.147.C.4.i；A.148.C.4.i；A.149.C.4.i；A.150.C.4.i； A.151.C.4.i；A.152.C.4.i；A.153.C.4.i；A.154.C.4.i；A.155.C.4.i；A.156.C.4.i； A.157.C.4.i；A.158.C.4.i；A.159.C.4.i；A.160.C.4.i；A.161.C.4.i；A.162.C.4.i； A.163.C.4.i；A.164.C.4.i；A.165.C.4.i；A.166.C.4.i；A.167.C.4.i；A.168.C.4.i； A.169.C.4.i；A.170.C.4.i；A.171.C.4.i；A.172.C.4.i；A.173.C.4.i；A.174.C.4.i； A.175.C.4.i；A.176.C.4.i；A.177.C.4.i；A.178.C.4.i；A.179.C.4.i；A.180.C.4.i； A.181.C.4.i；A.182.C.4.i；A.183.C.4.i；A.184.C.4.i；A.185.C.4.i；A.186.C.4.i； A.187.C.4.i；A.188.C.4.i；A.189.C.4.i；A.190.C.4.i；A.191.C.4.i；A.192.C.4.i； A.193.C.4.i；A.194.C.4.i；A.195.C.4.i；A.196.C.4.i；A.197.C.4.i；A.198.C.4.i； A.199.C.4.i；A.200.C.4.i；A.201.C.4.i；A.202.C.4.i；A.203.C.4.i；A.204.C.4.i； A.205.C.4.i；A.206.C.4.i；A.207.C.4.i；A.208.C.4.i；A.209.C.4.i；A.210.C.4.i； A.211.C.4.i；A.212.C.4.i；A.213.C.4.i；A.214.C.4.i；A.215.C.4.i；A.216.C.4.i；A.217.C.4.i；A.218.C.4.i；A.219.C.4.i；A.220.C.4.i；A.221.C.4.i；A.222.C.4.i； A.223.C.4.i；A.224.C.4.i；A.225.C.4.i；A.226.C.4.i；A.227.C.4.i；A.228.C.4.i； A.229.C.4.i；A.230.C.4.i；A.231.C.4.i；A.232.C.4.i；A.233.C.4.i；A.234.C.4.i； A.235.C.4.i；A.236.C.4.i；A.237.C.4.i；A.238.C.4.i；A.239.C.4.i；A.240.C.4.i； A.241.C.4.i；A.242.C.4.i；A.243.C.4.i；A.244.C.4.i；A.245.C.4.i；A.246.C.4.i； A.247.C.4.i；A.248.C.4.i；A.249.C.4.i；A.250.C.4.i；A.251.C.4.i；A.252.C.4.i； A.253.C.4.i；A.254.C.4.i；A.255.C.4.i；A.256.C.4.i；A.257.C.4.i；A.258.C.4.i； A.259.C.4.i；A.260.C.4.i；A.261.C.4.i；A.262.C.4.i；A.263.C.4.i；A.264.C.4.i； A.265.C.4.i；A.266.C.4.i；A.267.C.4.i；A.268.C.4.i；A.269.C.4.i；A.270.C.4.i； A.271.C.4.i；A.272.C.4.i；A.273.C.4.i；A.274.C.4.i；A.275.C.4.i；A.276.C.4.i； A.277.C.4.i；A.278.C.4.i；A.279.C.4.i；A.280.C.4.i；A.281.C.4.i；A.282.C.4.i； A.283.C.4.i；A.284.C.4.i；A.285.C.4.i；A.286.C.4.i；A.287.C.4.i；A.288.C.4.i； A.289.C.4.i；A.290.C.4.i；A.291.C.4.i；A.292.C.4.i；A.293.C.4.i；A.294.C.4.i； A.295.C.4.i；A.296.C.4.i；A.297.C.4.i；A.298.C.4.i；A.299.C.4.i；A.300.C.4.i； A.301.C.4.i；A.302.C.4.i；A.303.C.4.i；A.304.C.4.i；A.305.C.4.i；A.306.C.4.i； A.307.C.4.i；A.308.C.4.i；A.309.C.4.i；A.310.C.4.i；A.311.C.4.i；A.312.C.4.i； A.313.C.4.i；A.314.C.4.i；A.315.C.4.i；A.316.C.4.i；A.317.C.4.i；A.318.C.4.i； A.319.C.4.i；A.320.C.4.i；A.321.C.4.i；A.323.C.4.i；A.324.C.4.i；A.325.C.4.i； A.326.C.4.i；A.327.C.4.i；A.328.C.4.i；A.329.C.4.i；A.330.C.4.i；A.331.C.4.i； A.332.C.4.i；A.333.C.4.i；A.334.C.4.i；A.335.C.4.i；A.336.C.4.i；A.337.C.4.i； A.338.C.4.i；A.339.C.4.i；A.340.C.4.i；A.341.C.4.i；A.342.C.4.i；A.343.C.4.i； A.344.C.4.i；A.345.C.4.i；A.346.C.4.i；A.347.C.4.i；A.348.C.4.i；A.349.C.4.i； A.350.C.4.i；A.351.C.4.i；A.352.C.4.i；A.353.C.4.i；A.354.C.4.i；A.355.C.4.i； A.356.C.4.i；A.357.C.4.i；A.358.C.4.i；A.359.C.4.i；A.360.C.4.i；A.361.C.4.i； A.362.C.4.i；A.363.C.4.i；A.364.C.4.i；A.365.C.4.i；A.366.C.4.i；A.367.C.4.i； A.368.C.4.i；A.369.C.4.i；A.370.C.4.i；A.371.C.4.i；A.372.C.4.i；A.373.C.4.i； A.374.C.4.i；A.375.C.4.i；A.376.C.4.i；A.377.C.4.i；A.378.C.4.i；A.379.C.4.i； A.380.C.4.i；A.381.C.4.i；A.382.C.4.i；A.383.C.4.i；A.384.C.4.i；A.385.C.4.i； A.386.C.4.i；A.387.C.4.i；A.388.C.4.i；A.389.C.4.i；A.390.C.4.i；A.391.C.4.i； A.392.C.4.i；A.393.C.4.i；A.394.C.4.i；A.395.C.4.i；A.396.C.4.i；A.397.C.4.i； A.398.C.4.i；A.399.C.4.i；A.400.C.4.i；A.401.C.4.i；A.402.C.4.i；A.403.C.4.i； A.404.C.4.i；A.405.C.4.i；A.406.C.4.i；A.407.C.4.i；A.408.C.4.i；A.409.C.4.i； A.410.C.4.i；A.411.C.4.i；A.412.C.4.i；A.413.C.4.i；A.414.C.4.i；A.415.C.4.i； A.416.C.4.i；A.417.C.4.i；A.418.C.4.i；A.419.C.4.i；A.420.C.4.i；A.421.C.4.i； A.422.C.4.i；A.423.C.4.i；A.424.C.4.i；A.425.C.4.i；A.426.C.4.i；A.427.C.4.i； A.428.C.4.i；A.429.C.4.i；A.430.C.4.i；A.431.C.4.i；A.432.C.4.i；A.433.C.4.i； A.434.C.4.i；A.435.C.4.i；A.436.C.4.i；A.437.C.4.i；A.438.C.4.i；A.439.C.4.i； A.440.C.4.i；A.441.C.4.i；A.442.C.4.i；A.443.C.4.i；A.444.C.4.i；A.445.C.4.i； A.446.C.4.i；A.447.C.4.i；A.448.C.4.i；A.449.C.4.i；A.450.C.4.i；A.451.C.4.i； A.452.C.4.i；A.453.C.4.i；A.454.C.4.i；A.455.C.4.i；A.456.C.4.i；A.457.C.4.i； A.458.C.4.i；A.459.C.4.i；A.460.C.4.i；A.461.C.4.i；A.462.C.4.i；A.463.C.4.i； A.464.C.4.i；A.465.C.4.i；A.466.C.4.i；A.467.C.4.i；A.468.C.4.i；A.469.C.4.i； A.470.C.4.i；A.471.C.4.i；A.472.C.4.i；A.473.C.4.i；A.474.C.4.i；A.475.C.4.i； A.476.C.4.i；A.477.C.4.i；A.478.C.4.i；A.479.C.4.i；A.480.C.4.i；A.481.C.4.i； A.482.C.4.i；A.483.C.4.i；A.484.C.4.i；A.485.C.4.i；A.486.C.4.i；A.487.C.4.i； A.488.C.4.i；A.489.C.4.i；A.490.C.4.i；A.491.C.4.i；A.492.C.4.i；A.493.C.4.i； A.494.C.4.i；A.495.C.4.i；A.496.C.4.i；A.497.C.4.i；A.498.C.4.i；A.499.C.4.i；A.500.C.4.i；A.501.C.4.i；A.502.C.4.i；A.503.C.4.i；A.504.C.4.i；A.505.C.4.i； A.506.C.4.i；A.507.C.4.i；A.508.C.4.i；A.509.C.4.i；A.510.C.4.i；A.511.C.4.i； A.512.C.4.i；A.512.C.4.i；A.513.C.4.i；A.514.C.4.i；A.515.C.4.i；A.516.C.4.i； A.517.C.4.i；A.518.C.4.i；A.519.C.4.i；A.520.C.4.i；A.521.C.4.i；A.522.C.4.i； A.523.C.4.i；A.524.C.4.i；A.525.C.4.i；A.526.C.4.i；A.527.C.4.i；A.528.C.4.i； A.529.C.4.i；A.530.C.4.i；A.531.C.4.i；A.532.C.4.i；A.533.C.4.i；A.534.C.4.i； A.535.C.4.i；A.536.C.4.i；A.537.C.4.i；A.538.C.4.i；A.539.C.4.i；A.540.C.4.i； A.541.C.4.i；A.542.C.4.i；A.543.C.4.i；A.544.C.4.i；A.545.C.4.i；A.546.C.4.i； A.547.C.4.i；A.548.C.4.i；A.549.C.4.i；A.550.C.4.i；A.551.C.4.i；A.552.C.4.i； A.553.C.4.i；A.554.C.4.i；A.555.C.4.i；A.556.C.4.i；A.557.C.4.i；A.558.C.4.i； A.559.C.4.i；A.560.C.4.i；A.561.C.4.i；A.562.C.4.i；A.563.C.4.i；A.564.C.4.i； A.565.C.4.i；A.566.C.4.i；A.567.C.4.i；A.568.C.4.i；A.569.C.4.i；A.570.C.4.i； A.571.C.4.i；A.572.C.4.i；A.573.C.4.i；A.574.C.4.i；A.575.C.4.i；A.576.C.4.i； A.577.C.4.i；A.578.C.4.i；A.579.C.4.i；A.580.C.4.i；A.581.C.4.i；A.582.C.4.i； A.583.C.4.i；A.584.C.4.i；A.585.C.4.i；A.586.C.4.i；A.587.C.4.i；A.588.C.4.i； A.589.C.4.i；A.590.C.4.i；A.591.C.4.i；A.592.C.4.i；A.593.C.4.i；A.594.C.4.i； A.595.C.4.i；A.596.C.4.i；A.597.C.4.i；A.598.C.4.i；A.599.C.4.i；A.600.C.4.i； A.601.C.4.i；A.602.C.4.i；A.603.C.4.i；A.604.C.4.i；A.605.C.4.i；A.606.C.4.i； A.607.C.4.i；A.608.C.4.i；A.609.C.4.i；A.610.C.4.i；A.611.C.4.i；A.612.C.4.i； A.613.C.4.i；A.614.C.4.i；A.615.C.4.i；A.616.C.4.i；A.617.C.4.i；A.618.C.4.i； A.619.C.4.i；A.620.C.4.i；A.621.C.4.i；A.622.C.4.i；A.623.C.4.i；A.624.C.4.i； A.625.C.4.i；A.626.C.4.i；A.627.C.4.i；A.628.C.4.i；A.629.C.4.i；A.630.C.4.i； A.631.C.4.i；A.632.C.4.i；A.633.C.4.i；A.634.C.4.i；A.635.C.4.i；A.636.C.4.i； A.637.C.4.i；A.638.C.4.i；A.639.C.4.i；A.640.C.4.i；A.641.C.4.i；A.642.C.4.i； A.643.C.4.i；A.644.C.4.i；A.645.C.4.i；A.646.C.4.i；A.647.C.4.i；A.648.C.4.i； A.649.C.4.i；A.650.C.4.i；A.651.C.4.i；A.652.C.4.i；A.653.C.4.i；A.654.C.4.i； A.655.C.4.i；A.656.C.4.i；A.657.C.4.i；A.658.C.4.i；A.659.C.4.i；A.660.C.4.i； A.2.C.11.i；A3.C.11.i；A.4.C.11.i；A.5.C.11.i；A.6.C.11.i；A.7.C.11.i；A.9.C.11.i； A.10.C.11.i；A.15.C.11.i；A.100.C.11.i；A.101.C.11.i；A.102.C.11.i；A.103.C.11.i； A.104.C.11.i；A.105.C.11.i；A.106.C.11.i；A.107.C.11.i；A.108.C.11.i；A.109.C.11.i； A.110.C.11.i；A.111.C.11.i；A.112.C.11.i；A.113.C.11.i；A.114.C.11.i；A.115.C.11.i； A.116.C.11.i；A.117.C.11.i；A.118.C.11.i；A.119.C.11.i；A.120.C.11.i；A.121.C.11.i； A.122.C.11.i；A.123.C.11.i；A.124.C.11.i；A.125.C.11.i；A.126.C.11.i；A.127.C.11.i； A.128.C.11.i；A.129.C.11.i；A.130.C.11.i；A.131.C.11.i；A.132.C.11.i；A.133.C.11.i； A.134.C.11.i；A.135.C.11.i；A.136.C.11.i；A.137.C.11.i；A.138.C.11.i；A.139.C.11.i； A.140.C.11.i；A.141.C.11.i；A.142.C.11.i；A.143.C.11.i；A.144.C.11.i；A.145.C.11.i； A.146.C.11.i；A.147.C.11.i；A.148.C.11.i；A.149.C.11.i；A.150.C.11.i；A.151.C.11.i； A.152.C.11.i；A.153.C.11.i；A.154.C.11.i；A.155.C.11.i；A.156.C.11.i；A.157.C.11.i； A.158.C.11.i；A.159.C.11.i；A.160.C.11.i；A.161.C.11.i；A.162.C.11.i；A.163.C.11.i； A.164.C.11.i；A.165.C.11.i；A.166.C.11.i；A.167.C.11.i；A.168.C.11.i；A.169.C.11.i； A.170.C.11.i；A.171.C.11.i；A.172.C.11.i；A.173.C.11.i；A.174.C.11.i；A.175.C.11.i； A.176.C.11.i；A.177.C.11.i；A.178.C.11.i；A.179.C.11.i；A.180.C.11.i；A.181.C.11.i； A.182.C.11.i；A.183.C.11.i；A.184.C.11.i；A.185.C.11.i；A.186.C.11.i；A.187.C.11.i； A.188.C.11.i；A.189.C.11.i；A.190.C.11.i；A.191.C.11.i；A.192.C.11.i；A.193.C.11.i； A.194.C.11.i；A.195.C.11.i；A.196.C.11.i；A.197.C.11.i；A.198.C.11.i；A.199.C.11.i； A.200.C.11.i；A.201.C.11.i；A.202.C.11.i；A.203.C.11.i；A.204.C.11.i；A.205.C.11.i； A.206.C.11.i；A.207.C.11.i；A.208.C.11.i；A.209.C.11.i；A.210.C.11.i；A.211.C.11.i；A.212.C.11.i；A.213.C.11.i；A.214.C.11.i；A.215.C.11.i；A.216.C.11.i；A.217.C.11.i； A.218.C.11.i；A.219.C.11.i；A.220.C.11.i；A.221.C.11.i；A.222.C.11.i；A.223.C.11.i； A.224.C.11.i；A.225.C.11.i；A.226.C.11.i；A.227.C.11.i；A.228.C.11.i；A.229.C.11.i； A.230.C.11.i；A.231.C.11.i；A.232.C.11.i；A.233.C.11.i；A.234.C.11.i；A.235.C.11.i； A.236.C.11.i；A.237.C.11.i；A.238.C.11.i；A.239.C.11.i；A.240.C.11.i；A.241.C.11.i； A.242.C.11.i；A.243.C.11.i；A.244.C.11.i；A.245.C.11.i；A.246.C.11.i；A.247.C.11.i； A.248.C.11.i；A.249.C.11.i；A.250.C.11.i；A.251.C.11.i；A.252.C.11.i；A.253.C.11.i； A.254.C.11.i；A.255.C.11.i；A.256.C.11.i；A.257.C.11.i；A.258.C.11.i；A.259.C.11.i； A.260.C.11.i；A.261.C.11.i；A.262.C.11.i；A.263.C.11.i；A.264.C.11.i；A.265.C.11.i； A.266.C.11.i；A.267.C.11.i；A.268.C.11.i；A.269.C.11.i；A.270.C.11.i；A.271.C.11.i； A.272.C.11.i；A.273.C.11.i；A.274.C.11.i；A.275.C.11.i；A.276.C.11.i；A.277.C.11.i； A.278.C.11.i；A.279.C.11.i；A.280.C.11.i；A.281.C.11.i；A.282.C.11.i；A.283.C.11.i； A.284.C.11.i；A.285.C.11.i；A.286.C.11.i；A.287.C.11.i；A.288.C.11.i；A.289.C.11.i； A.290.C.11.i；A.291.C.11.i；A.292.C.11.i；A.293.C.11.i；A.294.C.11.i；A.295.C.11.i； A.296.C.11.i；A.297.C.11.i；A.298.C.11.i；A.299.C.11.i；A.300.C.11.i；A.301.C.11.i； A.302.C.11.i；A.303.C.11.i；A.304.C.11.i；A.305.C.11.i；A.306.C.11.i；A.307.C.11.i； A.308.C.11.i；A.309.C.11.i；A.310.C.11.i；A.311.C.11.i；A.312.C.11.i；A.313.C.11.i； A.314.C.11.i；A.315.C.11.i；A.316.C.11.i；A.317.C.11.i；A.318.C.11.i；A.319.C.11.i； A.320.C.11.i；A.321.C.11.i；A.323.C.11.i；A.324.C.11.i；A.325.C.11.i；A.326.C.11.i； A.327.C.11.i；A.328.C.11.i；A.329.C.11.i；A.330.C.11.i；A.331.C.11.i；A.332.C.11.i； A.333.C.11.i；A.334.C.11.i；A.335.C.11.i；A.336.C.11.i；A.337.C.11.i；A.338.C.11.i； A.339.C.11.i；A.340.C.11.i；A.341.C.11.i；A.342.C.11.i；A.343.C.11.i；A.344.C.11.i； A.345.C.11.i；A.346.C.11.i；A.347.C.11.i；A.348.C.11.i；A.349.C.11.i；A.350.C.11.i； 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A.423.C.11.i；A.424.C.11.i；A.425.C.11.i；A.426.C.11.i；A.427.C.11.i；A.428.C.11.i； A.429.C.11.i；A.430.C.11.i；A.431.C.11.i；A.432.C.11.i；A.433.C.11.i；A.434.C.11.i； A.435.C.11.i；A.436.C.11.i；A.437.C.11.i；A.438.C.11.i；A.439.C.11.i；A.440.C.11.i； A.441.C.11.i；A.442.C.11.i；A.443.C.11.i；A.444.C.11.i；A.445.C.11.i；A.446.C.11.i； A.447.C.11.i；A.448.C.11.i；A.449.C.11.i；A.450.C.11.i；A.451.C.11.i；A.452.C.11.i； A.453.C.11.i；A.454.C.11.i；A.455.C.11.i；A.456.C.11.i；A.457.C.11.i；A.458.C.11.i； A.459.C.11.i；A.460.C.11.i；A.461.C.11.i；A.462.C.11.i；A.463.C.11.i；A.464.C.11.i； A.465.C.11.i；A.466.C.11.i；A.467.C.11.i；A.468.C.11.i；A.469.C.11.i；A.470.C.11.i； A.471.C.11.i；A.472.C.11.i；A.473.C.11.i；A.474.C.11.i；A.475.C.11.i；A.476.C.11.i； A.477.C.11.i；A.478.C.11.i；A.479.C.11.i；A.480.C.11.i；A.481.C.11.i；A.482.C.11.i； A.483.C.11.i；A.484.C.11.i；A.485.C.11.i；A.486.C.11.i；A.487.C.11.i；A.488.C.11.i； 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A.560.C.11.i；A.561.C.11.i；A.562.C.11.i；A.563.C.11.i；A.564.C.11.i；A.565.C.11.i； A.566.C.11.i；A.567.C.11.i；A.568.C.11.i；A.569.C.11.i；A.570.C.11.i；A.571.C.11.i； A.572.C.11.i；A.573.C.11.i；A.574.C.11.i；A.575.C.11.i；A.576.C.11.i；A.577.C.11.i； A.578.C.11.i；A.579.C.11.i；A.580.C.11.i；A.581.C.11.i；A.582.C.11.i；A.583.C.11.i； A.584.C.11.i；A.585.C.11.i；A.586.C.11.i；A.587.C.11.i；A.588.C.11.i；A.589.C.11.i； A.590.C.11.i；A.591.C.11.i；A.592.C.11.i；A.593.C.11.i；A.594.C.11.i；A.595.C.11.i； A.596.C.11.i；A.597.C.11.i；A.598.C.11.i；A.599.C.11.i；A.600.C.11.i；A.601.C.11.i； A.602.C.11.i；A.603.C.11.i；A.604.C.11.i；A.605.C.11.i；A.606.C.11.i；A.607.C.11.i； A.608.C.11.i；A.609.C.11.i；A.610.C.11.i；A.611.C.11.i；A.612.C.11.i；A.613.C.11.i； A.614.C.11.i；A.615.C.11.i；A.616.C.11.i；A.617.C.11.i；A.618.C.11.i；A.619.C.11.i； A.620.C.11.i；A.621.C.11.i；A.622.C.11.i；A.623.C.11.i；A.624.C.11.i；A.625.C.11.i； A.626.C.11.i；A.627.C.11.i；A.628.C.11.i；A.629.C.11.i；A.630.C.11.i；A.631.C.11.i； 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A.255.E.11.i；A.256.E.11.i；A.257.E.11.i；A.258.E.11.i；A.259.E.11.i；A.260.E.11.i； A.261.E.11.i；A.262.E.11.i；A.263.E.11.i；A.264.E.11.i；A.265.E.11.i；A.266.E.11.i； A.267.E.11.i；A.268.E.11.i；A.269.E.11.i；A.270.E.11.i；A.271.E.11.i；A.272.E.11.i； A.273.E.11.i；A.274.E.11.i；A.275.E.11.i；A.276.E.11.i；A.277.E.11.i；A.278.E.11.i； A.279.E.11.i；A.280.E.11.i；A.281.E.11.i；A.282.E.11.i；A.283.E.11.i；A.284.E.11.i； A.285.E.11.i；A.286.E.11.i；A.287.E.11.i；A.288.E.11.i；A.289.E.11.i；A.290.E.11.i； A.291.E.11.i；A.292.E.11.i；A.293.E.11.i；A.294.E.11.i；A.295.E.11.i；A.296.E.11.i； A.297.E.11.i；A.298.E.11.i；A.299.E.11.i；A.300.E.11.i；A.301.E.11.i；A.302.E.11.i； A.303.E.11.i；A.304.E.11.i；A.305.E.11.i；A.306.E.11.i；A.307.E.11.i；A.308.E.11.i； A.309.E.11.i；A.310.E.11.i；A.311.E.11.i；A.312.E.11.i；A.313.E.11.i；A.314.E.11.i； A.315.E.11.i；A.316.E.11.i；A.317.E.11.i；A.318.E.11.i；A.319.E.11.i；A.320.E.11.i； A.321.E.11.i；A.323.E.11.i；A.324.E.11.i；A.325.E.11.i；A.326.E.11.i；A.327.E.11.i； 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A.615.E.11.i；A.616.E.11.i；A.617.E.11.i；A.618.E.11.i；A.619.E.11.i；A.620.E.11.i； A.621.E.11.i；A.622.E.11.i；A.623.E.11.i；A.624.E.11.i；A.625.E.11.i；A.626.E.11.i； A.627.E.11.i；A.628.E.11.i；A.629.E.11.i；A.630.E.11.i；A.631.E.11.i；A.632.E.11.i； A.633.E.11.i；A.634.E.11.i；A.635.E.11.i；A.636.E.11.i；A.637.E.11.i；A.638.E.11.i； A.639.E.11.i；A.640.E.11.i；A.641.E.11.i；A.642.E.11.i；A.643.E.11.i；A.644.E.11.i； A.645.E.11.i；A.646.E.11.i；A.647.E.11.i；A.648.E.11.i；A.649.E.11.i；A.650.E.11.i； A.651.E.11.i；A.652.E.11.i；A.653.E.11.i；A.654.E.11.i；A.655.E.11.i；A.656.E.11.i； A.657.E.11.i；A.658.E.11.i；A.659.E.11.i；A.660.E.11.i；A.2.F.4.i；A.3.F.4.i；A.4.F.4.i； A.5.F.4.i；A.6.F.4.i；A.7.F.4.i；A.9.F.4.i；A.10.F.4.i；A.15.F.4.i；A.100.F.4.i； A.101.F.4.i；A.102.F.4.i；A.103.F.4.i；A.104.F.4.i；A.105.F.4.i；A.106.F.4.i； A.107.F.4.i；A.108.F.4.i；A.109.F.4.i；A.110.F.4.i；A.111.F.4.i；A.112.F.4.i； A.113.F.4.i；A.114.F.4.i；A.115.F.4.i；A.116.F.4.i；A.117.F.4.i；A.118.F.4.i； 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A.587.F.4.i；A.588.F.4.i；A.589.F.4.i；A.590.F.4.i；A.591.F.4.i；A.592.F.4.i； A.593.F.4.i；A.594.F.4.i；A.595.F.4.i；A.596.F.4.i；A.597.F.4.i；A.598.F.4.i； A.599.F.4.i；A.600.F.4.i；A.601.F.4.i；A.602.F.4.i；A.603.F.4.i；A.604.F.4.i； A.605.F.4.i；A.606.F.4.i；A.607.F.4.i；A.608.F.4.i；A.609.F.4.i；A.610.F.4.i； A.611.F.4.i；A.612.F.4.i；A.613.F.4.i；A.614.F.4.i；A.615.F.4.i；A.616.F.4.i； A.617.F.4.i；A.618.F.4.i；A.619.F.4.i；A.620.F.4.i；A.621.F.4.i；A.622.F.4.i； A.623.F.4.i；A.624.F.4.i；A.625.F.4.i；A.626.F.4.i；A.627.F.4.i；A.628.F.4.i； A.629.F.4.i；A.630.F.4.i；A.631.F.4.i；A.632.F.4.i；A.633.F.4.i；A.634.F.4.i； A.635.F.4.i；A.636.F.4.i；A.637.F.4.i；A.638.F.4.i；A.639.F.4.i；A.640.F.4.i； A.641.F.4.i；A.642.F.4.i；A.643.F.4.i；A.644.F.4.i；A.645.F.4.i；A.646.F.4.i； A.647.F.4.i；A.648.F.4.i；A.649.F.4.i；A.650.F.4.i；A.651.F.4.i；A.652.F.4.i； A.653.F.4.i；A.654.F.4.i；A.655.F.4.i；A.656.F.4.i；A.657.F.4.i；A.658.F.4.i； A.659.F.4.i；A.660.F.4.i；A.2.F.11.i；A.3.F.11.i；A.4.F.11.i；A.5.F.11.i；A.6.F.11.i； A.7.F.11.i；A.9.F.11.i；A.10.F.11.i；A.15.F.11.i；A.100.F.11.i；A.101.F.11.i； A.102.F.11.i；A.103.F.11.i；A.104.F.11.i；A.105.F.11.i；A.106.F.11.i；A.107.F.11.i； A.108.F.11.i；A.109.F.11.i；A.110.F.11.i；A.111.F.11.i；A.112.F.11.i；A.113.F.11.i； A.114.F.11.i；A.115.F.11.i；A.116.F.11.i；A.117.F.11.i；A.118.F.11.i；A.119.F.11.i； A.120.F.11.i；A.121.F.11.i；A.122.F.11.i；A.123.F.11.i；A.124.F.11.i；A.125.F.11.i； A.126.F.11.i；A.127.F.11.i；A.128.F.11.i；A.129.F.11.i；A.130.F.11.i；A.131.F.11.i； A.132.F.11.i；A.133.F.11.i；A.134.F.11.i；A.135.F.11.i；A.136.F.11.i；A.137.F.11.i； A.138.F.11.i；A.139.F.11.i；A.140.F.11.i；A.141.F.11.i；A.142.F.11.i；A.143.F.11.i； A.144.F.11.i；A.145.F.11.i；A.146.F.11.i；A.147.F.11.i；A.148.F.11.i；A.149.F.11.i； A.150.F.11.i；A.151.F.11.i；A.152.F.11.i；A.153.F.11.i；A.154.F.11.i；A.155.F.11.i； A.156.F.11.i；A.157.F.11.i；A.158.F.11.i；A.159.F.11.i；A.160.F.11.i；A.161.F.11.i； A.162.F.11.i；A.163.F.11.i；A.164.F.11.i；A.165.F.11.i；A.166.F.11.i；A.167.F.11.i； A.168.F.11.i；A.169.F.11.i；A.170.F.11.i；A.171.F.11.i；A.172.F.11.i；A.173.F.11.i； A.174.F.11.i；A.175.F.11.i；A.176.F.11.i；A.177.F.11.i；A.178.F.11.i；A.179.F.11.i； A.180.F.11.i；A.181.F.11.i；A.182.F.11.i；A.183.F.11.i；A.184.F.11.i；A.185.F.11.i；A.186.F.11.i；A.187.F.11.i；A.188.F.11.i；A.189.F.11.i；A.190.F.11.i；A.191.F.11.i； A.192.F.11.i；A.193.F.11.i；A.194.F.11.i；A.195.F.11.i；A.196.F.11.i；A.197.F.11.i； A.198.F.11.i；A.199.F.11.i；A.200.F.11.i；A.201.F.11.i；A.202.F.11.i；A.203.F.11.i； A.204.F.11.i；A.205.F.11.i；A.206.F.11.i；A.207.F.11.i；A.208.F.11.i；A.209.F.11.i； A.210.F.11.i；A.211.F.11.i；A.212.F.11.i；A.213.F.11.i；A.214.F.11.i；A.215.F.11.i； A.216.F.11.i；A.217.F.11.i；A.218.F.11.i；A.219.F.11.i；A.220.F.11.i；A.221.F.11.i； A.222.F.11.i；A.223.F.11.i；A.224.F.11.i；A.225.F.11.i；A.226.F.11.i；A.227.F.11.i； A.228.F.11.i；A.229.F.11.i；A.230.F.11.i；A.231.F.11.i；A.232.F.11.i；A.233.F.11.i； A.234.F.11.i；A.235.F.11.i；A.236.F.11.i；A.237.F.11.i；A.238.F.11.i；A.239.F.11.i； A.240.F.11.i；A.241.F.11.i；A.242.F.11.i；A.243.F.11.i；A.244.F.11.i；A.245.F.11.i； A.246.F.11.i；A.247.F.11.i；A.248.F.11.i；A.249.F.11.i；A.250.F.11.i；A.251.F.11.i； A.252.F.11.i；A.253.F.11.i；A.254.F.11.i；A.255.F.11.i；A.256.F.11.i；A.257.F.11.i； A.258.F.11.i；A.259.F.11.i；A.260.F.11.i；A.261.F.11.i；A.262.F.11.i；A.263.F.11.i； A.264.F.11.i；A.265.F.11.i；A.266.F.11.i；A.267.F.11.i；A.268.F.11.i；A.269.F.11.i； A.270.F.11.i；A.271.F.11.i；A.272.F.11.i；A.273.F.11.i；A.274.F.11.i；A.275.F.11.i； A.276.F.11.i；A.277.F.11.i；A.278.F.11.i；A.279.F.11.i；A.280.F.11.i；A.281.F.11.i； A.282.F.11.i；A.283.F.11.i；A.284.F.11.i；A.285.F.11.i；A.286.F.11.i；A.287.F.11.i； A.288.F.11.i；A.289.F.11.i；A.290.F.11.i；A.291.F.11.i；A.292.F.11.i；A.293.F.11.i； A.294.F.11.i；A.295.F.11.i；A.296.F.11.i；A.297.F.11.i；A.298.F.11.i；A.299.F.11.i； A.300.F.11.i；A.301.F.11.i；A.302.F.11.i；A.303.F.11.i；A.304.F.11.i；A.305.F.11.i； A.306.F.11.i；A.307.F.11.i；A.308.F.11.i；A.309.F.11.i；A.310.F.11.i；A.311.F.11.i； A.312.F.11.i；A.313.F.11.i；A.314.F.11.i；A.315.F.11.i；A.316.F.11.i；A.317.F.11.i； A.318.F.11.i；A.319.F.11.i；A.320.F.11.i；A.321.F.11.i；A.323.F.11.i；A.324.F.11.i； A.325.F.11.i；A.326.F.11.i；A.327.F.11.i；A.328.F.11.i；A.329.F.11.i；A.330.F.11.i； A.331.F.11.i；A.332.F.11.i；A.333.F.11.i；A.334.F.11.i；A.335.F.11.i；A.336.F.11.i； A.337.F.11.i；A.338.F.11.i；A.339.F.11.i；A.340.F.11.i；A.341.F.11.i；A.342.F.11.i； A.343.F.11.i；A.344.F.11.i；A.345.F.11.i；A.346.F.11.i；A.347.F.11.i；A.348.F.11.i； A.349.F.11.i；A.350.F.11.i；A.351.F.11.i；A.352.F.11.i；A.353.F.11.i；A.354.F.11.i； A.355.F.11.i；A.356.F.11.i；A.357.F.11.i；A.358.F.11.i；A.359.F.11.i；A.360.F.11.i； A.361.F.11.i；A.362.F.11.i；A.363.F.11.i；A.364.F.11.i；A.365.F.11.i；A.366.F.11.i； A.367.F.11.i；A.368.F.11.i；A.369.F.11.i；A.370.F.11.i；A.371.F.11.i；A.372.F.11.i； A.373.F.11.i；A.374.F.11.i；A.375.F.11.i；A.376.F.11.i；A.377.F.11.i；A.378.F.11.i； A.379.F.11.i；A.380.F.11.i；A.381.F.11.i；A.382.F.11.i；A.383.F.11.i；A.384.F.11.i； A.385.F.11.i；A.386.F.11.i；A.387.F.11.i；A.388.F.11.i；A.389.F.11.i；A.390.F.11.i； A.391.F.11.i；A.392.F.11.i；A.393.F.11.i；A.394.F.11.i；A.395.F.11.i；A.396.F.11.i； A.397.F.11.i；A.398.F.11.i；A.399.F.11.i；A.400.F.11.i；A.401.F.11.i；A.402.F.11.i； A.403.F.11.i；A.404.F.11.i；A.405.F.11.i；A.406.F.11.i；A.407.F.11.i；A.408.F.11.i； A.409.F.11.i；A.410.F.11.i；A.411.F.11.i；A.412.F.11.i；A.413.F.11.i；A.414.F.11.i； A.415.F.11.i；A.416.F.11.i；A.417.F.11.i；A.418.F.11.i；A.419.F.11.i；A.420.F.11.i； A.421.F.11.i；A.422.F.11.i；A.423.F.11.i；A.424.F.11.i；A.425.F.11.i；A.426.F.11.i； A.427.F.11.i；A.428.F.11.i；A.429.F.11.i；A.430.F.11.i；A.431.F.11.i；A.432.F.11.i； A.433.F.11.i；A.434.F.11.i；A.435.F.11.i；A.436.F.11.i；A.437.F.11.i；A.438.F.11.i； A.439.F.11.i；A.440.F.11.i；A.441.F.11.i；A.442.F.11.i；A.443.F.11.i；A.444.F.11.i； A.445.F.11.i；A.446.F.11.i；A.447.F.11.i；A.448.F.11.i；A.449.F.11.i；A.450.F.11.i； A.451.F.11.i；A.452.F.11.i；A.453.F.11.i；A.454.F.11.i；A.455.F.11.i；A.456.F.11.i； A.457.F.11.i；A.458.F.11.i；A.459.F.11.i；A.460.F.11.i；A.461.F.11.i；A.462.F.11.i； A.463.F.11.i；A.464.F.11.i；A.465.F.11.i；A.466.F.11.i；A.467.F.11.i；A.468.F.11.i；A.469.F.11.i；A.470.F.11.i；A.471.F.11.i；A.472.F.11.i；A.473.F.11.i；A.474.F.11.i； A.475.F.11.i；A.476.F.11.i；A.477.F.11.i；A.478.F.11.i；A.479.F.11.i；A.480.F.11.i； A.481.F.11.i；A.482.F.11.i；A.483.F.11.i；A.484.F.11.i；A.485.F.11.i；A.486.F.11.i； A.487.F.11.i；A.488.F.11.i；A.489.F.11.i；A.490.F.11.i；A.491.F.11.i；A.492.F.11.i； A.493.F.11.i；A.494.F.11.i；A.495.F.11.i；A.496.F.11.i；A.497.F.11.i；A.498.F.11.i； A.499.F.11.i；A.500.F.11.i；A.501.F.11.i；A.502.F.11.i；A.503.F.11.i；A.504.F.11.i； A.505.F.11.i；A.506.F.11.i；A.507.F.11.i；A.508.F.11.i；A.509.F.11.i；A.510.F.11.i； A.511.F.11.i；A.512.F.11.i；A.512.F.11.i；A.513.F.11.i；A.514.F.11.i；A.515.F.11.i； A.516.F.11.i；A.517.F.11.i；A.518.F.11.i；A.519.F.11.i；A.520.F.11.i；A.521.F.11.i； A.522.F.11.i；A.523.F.11.i；A.524.F.11.i；A.525.F.11.i；A.526.F.11.i；A.527.F.11.i； A.528.F.11.i；A.529.F.11.i；A.530.F.11.i；A.531.F.11.i；A.532.F.11.i；A.533.F.11.i； A.534.F.11.i；A.535.F.11.i；A.536.F.11.i；A.537.F.11.i；A.538.F.11.i；A.539.F.11.i； A.540.F.11.i；A.541.F.11.i；A.542.F.11.i；A.543.F.11.i；A.544.F.11.i；A.545.F.11.i； A.546.F.11.i；A.547.F.11.i；A.548.F.11.i；A.549.F.11.i；A.550.F.11.i；A.551.F.11.i； A.552.F.11.i；A.553.F.11.i；A.554.F.11.i；A.555.F.11.i；A.556.F.11.i；A.557.F.11.i； A.558.F.11.i；A.559.F.11.i；A.560.F.11.i；A.561.F.11.i；A.562.F.11.i；A.563.F.11.i； A.564.F.11.i；A.565.F.11.i；A.566.F.11.i；A.567.F.11.i；A.568.F.11.i；A.569.F.11.i； A.570.F.11.i；A.571.F.11.i；A.572.F.11.i；A.573.F.11.i；A.574.F.11.i；A.575.F.11.i； A.576.F.11.i；A.577.F.11.i；A.578.F.11.i；A.579.F.11.i；A.580.F.11.i；A.581.F.11.i； A.582.F.11.i；A.583.F.11.i；A.584.F.11.i；A.585.F.11.i；A.586.F.11.i；A.587.F.11.i； A.588.F.11.i；A.589.F.11.i；A.590.F.11.i；A.591.F.11.i；A.592.F.11.i；A.593.F.11.i； A.594.F.11.i；A.595.F.11.i；A.596.F.11.i；A.597.F.11.i；A.598.F.11.i；A.599.F.11.i； A.600.F.11.i；A.601.F.11.i；A.602.F.11.i；A.603.F.11.i；A.604.F.11.i；A.605.F.11.i； A.606.F.11.i；A.607.F.11.i；A.608.F.11.i；A.609.F.11.i；A.610.F.11.i；A.611.F.11.i； A.612.F.11.i；A.613.F.11.i；A.614.F.11.i；A.615.F.11.i；A.616.F.11.i；A.617.F.11.i； A.618.F.11.i；A.619.F.11.i；A.620.F.11.i；A.621.F.11.i；A.622.F.11.i；A.623.F.11.i； A.624.F.11.i；A.625.F.11.i；A.626.F.11.i；A.627.F.11.i；A.628.F.11.i；A.629.F.11.i； A.630.F.11.i；A.631.F.11.i；A.632.F.11.i；A.633.F.11.i；A.634.F.11.i；A.635.F.11.i； A.636.F.11.i；A.637.F.11.i；A.638.F.11.i；A.639.F.11.i；A.640.F.11.i；A.641.F.11.i； A.642.F.11.i；A.643.F.11.i；A.644.F.11.i；A.645.F.11.i；A.646.F.11.i；A.647.F.11.i； A.648.F.11.i；A.649.F.11.i；A.650.F.11.i；A.651.F.11.i；A.652.F.11.i；A.653.F.11.i； A.654.F.11.i；A.655.F.11.i；A.656.F.11.i；A.657.F.11.i；A.658.F.11.i；A.659.F.11.i； A.660.F.11.i；A.2.a.44.i；A.3.a.44.i；A.4.a.44.i；A.5.a.44.i；A.9.a.44.i；A.100.a.44.i； A.101.a.44.i；A.102.a.44.i；A.103.a.44.i；A.104.a.44.i；A.105.a.44.i；A.106.a.44.i； A.107.a.44.i；A.108.a.44.i；A.109.a.44.i；A.110.a.44.i；A.111.a.44.i；A.112.a.44.i； A.113.a.44.i；A.114.a.44.i；A.115.a.44.i；A.116.a.44.i；A.117.a.44.i；A.118.a.44.i； A.119.a.44.i；A.120.a.44.i；A.121.a.44.i；A.122.a.44.i；A.123.a.44.i；A.124.a.44.i； A.125.a.44.i；A.126.a.44.i；A.127.a.44.i；A.128.a.44.i；A.129.a.44.i；A.130.a.44.i； A.131.a.44.i；A.132.a.44.i；A.133.a.44.i；A.134.a.44.i；A.135.a.44.i；A.136.a.44.i； A.137.a.44.i；A.138.a.44.i；A.139.a.44.i；A.140.a.44.i；A.141.a.44.i；A.142.a.44.i； A.143.a.44.i；A.144.a.44.i；A.145.a.44.i；A.146.a.44.i；A.147.a.44.i；A.148.a.44.i； A.149.a.44.i；A.150.a.44.i；A.151.a.44.i；A.152.a.44.i；A.153.a.44.i；A.154.a.44.i； A.155.a.44.i；A.156.a.44.i；A.157.a.44.i；A.158.a.44.i；A.159.a.44.i；A.160.a.44.i； A.161.a.44.i；A.162.a.44.i；A.163.a.44.i；A.164.a.44.i；A.165.a.44.i；A.166.a.44.i； A.167.a.44.i；A.168.a.44.i；A.169.a.44.i；A.170.a.44.i；A.171.a.44.i；A.172.a.44.i； A.173.a.44.i；A.174.a.44.i；A.175.a.44.i；A.176.a.44.i；A.177.a.44.i；A.178.a.44.i； A.179.a.44.i；A.180.a.44.i；A.181.a.44.i；A.182.a.44.i；A.183.a.44.i；A.184.a.44.i；A.185.a.44.i；A.186.a.44.i；A.187.a.44.i；A.188.a.44.i；A.189.a.44.i；A.190.a.44.i； A.191.a.44.i；A.192.a.44.i；A.193.a.44.i；A.194.a.44.i；A.195.a.44.i；A.196.a.44.i； A.197.a.44.i；A.198.a.44.i；A.199.a.44.i；A.200.a.44.i；A.201.a.44.i；A.202.a.44.i； A.203.a.44.i；A.204.a.44.i；A.205.a.44.i；A.206.a.44.i；A.207.a.44.i；A.208.a.44.i； A.209.a.44.i；A.210.a.44.i；A.211.a.44.i；A.212.a.44.i；A.213.a.44.i；A.214.a.44.i； A.215.a.44.i；A.216.a.44.i；A.217.a.44.i；A.218.a.44.i；A.219.a.44.i；A.220.a.44.i； A.221.a.44.i；A.222.a.44.i；A.223.a.44.i；A.224.a.44.i；A.225.a.44.i；A.226.a.44.i； A.227.a.44.i；A.228.a.44.i；A.229.a.44.i；A.230.a.44.i；A.231.a.44.i；A.232.a.44.i； A.233.a.44.i；A.234.a.44.i；A.235.a.44.i；A.236.a.44.i；A.237.a.44.i；A.238.a.44.i； A.239.a.44.i；A.240.a.44.i；A.241.a.44.i；A.242.a.44.i；A.243.a.44.i；A.244.a.44.i； A.245.a.44.i；A.246.a.44.i；A.247.a.44.i；A.248.a.44.i；A.249.a.44.i；A.250.a.44.i； A.251.a.44.i；A.252.a.44.i；A.253.a.44.i；A.254.a.44.i；A.255.a.44.i；A.256.a.44.i； A.257.a.44.i；A.258.a.44.i；A.259.a.44.i；A.260.a.44.i；A.261.a.44.i；A.262.a.44.i； A.263.a.44.i；A.264.a.44.i；A.265.a.44.i；A.266.a.44.i；A.267.a.44.i；A.268.a.44.i； A.269.a.44.i；A.270.a.44.i；A.271.a.44.i；A.272.a.44.i；A.273.a.44.i；A.274.a.44.i； A.275.a.44.i；A.276.a.44.i；A.277.a.44.i；A.278.a.44.i；A.279.a.44.i；A.280.a.44.i； A.281.a.44.i；A.282.a.44.i；A.283.a.44.i；A.284.a.44.i；A.285.a.44.i；A.286.a.44.i； A.287.a.44.i；A.288.a.44.i；A 289.a.44.i；A.290.a.44.i；A.291.a.44.i；A.292.a.44.i； A.293.a.44.i；A.294.a.44.i；A.295.a.44.i；A.296.a.44.i；A.297.a.44.i；A.298.a.44.i； A.299.a.44.i；A.300.a.44.i；A.301.a.44.i；A.302.a.44.i；A.303.a.44.i；A.304.a.44.i； A.305.a.44.i；A.306.a.44.i；A.307.a.44.i；A.308.a.44.i；A.309.a.44.i；A.310.a.44.i； A.311.a.44.i；A.312.a.44.i；A.313.a.44.i；A.314.a.44.i；A.315.a.44.i；A.316.a.44.i； A.317.a.44.i；A.318.a.44.i；A.319.a.44.i；A.320.a.44.i；A.321.a.44.i；A.322.a.44.i； A.323.a.44.i；A.324.a.44.i；A.325.a.44.i；A.326.a.44.i；A.327.a.44.i；A.328.a.44.i； A.329.a.44.i；A.330.a.44.i；A.331.a.44.i；A.332.a.44.i；A.333.a.44.i；A.334.a.44.i； A.335.a.44.i；A.336.a.44.i；A.337.a.44.i；A.338.a.44.i；A.339.a.44.i；A.340.a.44.i； A.341.a.44.i；A.342.a.44.i；A.343.a.44.i；A.344.a.44.i；A.345.a.44.i；A.346.a.44.i； A.347.a.44.i；A.348.a.44.i；A.349.a.44.i；A.350.a.44.i；A.351.a.44.i；A.352.a.44.i； A.353.a.44.i；A.354.a.44.i；A.355.a.44.i；A.356.a.44.i；A.357.a.44.i；A.358.a.44.i； B.2.a.44.i；B.3.a.44.i；B.4.a.44.i；B.5.a.44.i；B.9.a.44.i；B.100.a.44.i；B.101.a.44.i； B.102.a.44.i；B.103.a.44.i；B.104.a.44.i；B.105.a.44.i；B.106.a.44.i；B.107.a.44.i； B.108.a.44.i；B.109.a.44.i；B.110.a.44.i；B.111.a.44.i；B.112.a.44.i；B.113.a.44.i； B.114.a.44.i；B.115.a.44.i；B.116.a.44.i；B.117.a.44.i；B.118.a.44.i；B.119.a.44.i； B.120.a.44.i；B.121.a.44.i；B.122.a.44.i；B.123.a.44.i；B.124.a.44.i；B.125.a.44.i； B.126.a.44.i；B.127.a.44.i；B.128.a.44.i；B.129.a.44.i；B.130.a.44.i；B.131.a.44.i； B.132.a.44.i；B.133.a.44.i；B.134.a.44.i；B.135.a.44.i；B.136.a.44.i；B.137.a.44.i； B.138.a.44.i；B.139.a.44.i；B.140.a.44.i；B.141.a.44.i；B.142.a.44.i；B.143.a.44.i； B.144.a.44.i；B.145.a.44.i；B.146.a.44.i；B.147.a.44.i；B.148.a.44.i；B.149.a.44.i； B.150.a.44.i；B.151.a.44.i；B.152.a.44.i；B.153.a.44.i；B.154.a.44.i；B.155.a.44.i； B.156.a.44.i；B.157.a.44.i；B.158.a.44.i；B.159.a.44.i；B.160.a.44.i；B.161.a.44.i； B.162.a.44.i；B.163.a.44.i；B.164.a.44.i；B.165.a.44.i；B.166.a.44.i；B.167.a.44.i； B.168.a.44.i；B.169.a.44.i；B.170.a.44.i；B.171.a.44.i；B.172.a.44.i；B.173.a.44.i； B.174.a.44.i；B.175.a.44.i；B.176.a.44.i；B.177.a.44.i；B.178.a.44.i；B.179.a.44.i； B.180.a.44.i；B.181.a.44.i；B.182.a.44.i；B.183.a.44.i；B.184.a.44.i；B.185.a.44.i； B.186.a.44.i；B.187.a.44.i；B.188.a.44.i；B.189.a.44.i；B.190.a.44.i；B.191.a.44.i； B.192.a.44.i；B.193.a.44.i；B.194.a.44.i；B.195.a.44.i；B.196.a.44.i；B.197.a.44.i； B.198.a.44.i；B.199.a.44.i；B.200.a.44.i；B.201.a.44.i；B.202.a.44.i；B.203.a.44.i；B.204.a.44.i；B.205.a.44.i；B.206.a.44.i；B.207.a.44.i；B.208.a.44.i；B.209.a.44.i； B.210.a.44.i；B.211.a.44.i；B.212.a.44.i；B.213.a.44.i；B.214.a.44.i；B.215.a.44.i； B.216.a.44.i；B.217.a.44.i；B.218.a.44.i；B.219.a.44.i；B.220.a.44.i；B.221.a.44.i； B.222.a.44.i；B.223.a.44.i；B.224.a.44.i；B.225.a.44.i；B.226.a.44.i；B.227.a.44.i； B.228.a.44.i；B.229.a.44.i；B.230.a.44.i；B.231.a.44.i；B.232.a.44.i；B.233.a.44.i； B.234.a.44.i；B.235.a.44.i；B.236.a.44.i；B.237.a.44.i；B.238.a.44.i；B.239.a.44.i； B.240.a.44.i；B.241.a.44.i；B.242.a.44.i；B.243.a.44.i；B.244.a.44.i；B.245.a.44.i； B.246.a.44.i；B.247.a.44.i；B.248.a.44.i；B.249.a.44.i；B.250.a.44.i；B.251.a.44.i； B.252.a.44.i；B.253.a.44.i；B.254.a.44.i；B.255.a.44.i；B.256.a.44.i；B.257.a.44.i； B.258.a.44.i；B.259.a.44.i；B.260.a.44.i；B.261.a.44.i；B.262.a.44.i；B.263.a.44.i； B.264.a.44.i；B.265.a.44.i；B.266.a.44.i；B.267.a.44.i；B.268.a.44.i；B.269.a.44.i； B.270.a.44.i；B.271.a.44.i；B.272.a.44.i；B.273.a.44.i；B.274.a.44.i；B.275.a.44.i； B.276.a.44.i；B.277.a.44.i；B.278.a.44.i；B.279.a.44.i；B.280.a.44.i；B.281.a.44.i； B.282.a.44.i；B.283.a.44.i；B.284.a.44.i；B.285.a.44.i；B.286.a.44.i；B.287.a.44.i； B.288.a.44.i；B.289.a.44.i；B.290.a.44.i；B.291.a.44.i；B.292.a.44.i；B.293.a.44.i； B.294.a.44.i；B.295.a.44.i；B.296.a.44.i；B.297.a.44.i；B.298.a.44.i；B.299.a.44.i； B.300.a.44.i；B.301.a.44.i；B.302.a.44.i；B.303.a.44.i；B.304.a.44.i；B.305.a.44.i； B.306.a.44.i；B.307.a.44.i；B.308.a.44.i；B.309.a.44.i；B.310.a.44.i；B.311.a.44.i； B.312.a.44.i；B.313.a.44.i；B.314.a.44.i；B.315.a.44.i；B.316.a.44.i；B.317.a.44.i； B.318.a.44.i；B.319.a.44.i；B.320.a.44.i；B.321.a.44.i；B.322.a.44.i；B.323.a.44.i； B.324.a.44.i；B.325.a.44.i；B.326.a.44.i；B.327.a.44.i；B.328.a.44.i；B.329.a.44.i； B.330.a.44.i；B.331.a.44.i；B.332.a.44.i；B.333.a.44.i；B.334.a.44.i；B.335.a.44.i； B.336.a.44.i；B.337.a.44.i；B.338.a.44.i；B.339.a.44.i；B.340.a.44.i；B.341.a.44.i； B.342.a.44.i；B.343.a.44.i；B.344.a.44.i；B.345.a.44.i；B.346.a.44.i；B.347.a.44.i； B.348.a.44.i；B.349.a.44.i；B.350.a.44.i；B.351.a.44.i；B.352.a.44.i；B.353.a.44.i； B.354.a.44.i；B.355.a.44.i；B.356.a.44.i；B.357.a.44.i；B.358.a.44.i；E.2.a.44.i；E.3.a.44.i； E.4.a.44.i；E.5.a.44.i；E.9.a.44.i；E.100.a.44.i；E.101.a.44.i；E.102.a.44.i；E.103.a.44.i； E.104.a.44.i；E.105.a.44.i；E.106.a.44.i；E.107.a.44.i；E.108.a.44.i；E.109.a.44.i； E.110.a.44.i；E.111.a.44.i；E.112.a.44.i；E.113.a.44.i；E.114.a.44.i；E.115.a.44.i； E.116.a.44.i；E.117.a.44.i；E.118.a.44.i；E.119.a.44.i；E.120.a.44.i；E.121.a.44.i； E.122.a.44.i；E.123.a.44.i；E.124.a.44.i；E.125.a.44.i；E.126.a.44.i；E.127.a.44.i； E.128.a.44.i；E.129.a.44.i；E.130.a.44.i；E.131.a.44.i；E.132.a.44.i；E.133.a.44.i； E.134.a.44.i；E.135.a.44.i；E.136.a.44.i；E.137.a.44.i；E.138.a.44.i；E.139.a.44.i； E.140.a.44.i；E.141.a.44.i；E.142.a.44.i；E.143.a.44.i；E.144.a.44.i；E.145.a.44.i； E.146.a.44.i；E.147.a.44.i；E.148.a.44.i；E.149.a.44.i；E.150.a.44.i；E.151.a.44.i； E.152.a.44.i；E.153.a.44.i；E.154.a.44.i；E.155.a.44.i；E.156.a.44.i；E.157.a.44.i； E.158.a.44.i；E.159.a.44.i；E.160.a.44.i；E.161.a.44.i；E.162.a.44.i；E.163.a.44.i； E.164.a.44.i；E.165.a.44.i；E.166.a.44.i；E.167.a.44.i；E.168.a.44.i；E.169.a.44.i； E.170.a.44.i；E.171.a.44.i；E.172.a.44.i；E.173.a.44.i；E.174.a.44.i；E.175.a.44.i； E.176.a.44.i；E.177.a.44.i；E.178.a.44.i；E.179.a.44.i；E.180.a.44.i；E.181.a.44.i； E.182.a.44.i；E.183.a.44.i；E.184.a.44.i；E.185.a.44.i；E.186.a.44.i；E.187.a.44.i； E.188.a.44.i；E.189.a.44.i；E.190.a.44.i；E.191.a.44.i；E.192.a.44.i；E.193.a.44.i； E.194.a.44.i；E.195.a.44.i；E.196.a.44.i；E.197.a.44.i；E.198.a.44.i；E.199.a.44.i； E.200.a.44.i；E.201.a.44.i；E.202.a.44.i；E.203.a.44.i；E.204.a.44.i；E.205.a.44.i； E.206.a.44.i；E.207.a.44.i；E.208.a.44.i；E.209.a.44.i；E.210.a.44.i；E.211.a.44.i； E.212.a.44.i；E.213.a.44.i；E.214.a.44.i；E.215.a.44.i；E.216.a.44.i；E.217.a.44.i； E.218.a.44.i；E.219.a.44.i；E.220.a.44.i；E.221.a.44.i；E.222.a.44.i；E.223.a.44.i；E.224.a.44.i；E.225.a.44.i；E.226.a.44.i；E.227.a.44.i；E.228.a.44.i；E.229.a.44.i； E.230.a.44.i；E.231.a.44.i；E.232.a.44.i；E.233.a.44.i；E.234.a.44.i；E.235.a.44.i； E.236.a.44.i；E.237.a.44.i；E.238.a.44.i；E.239.a.44.i；E.240.a.44.i；E.241.a.44.i； E.242.a.44.i；E.243.a.44.i；E.244.a.44.i；E.245.a.44.i；E.246.a.44.i；E.247.a.44.i； E.248.a.44.i；E.249.a.44.i；E.250.a.44.i；E.251.a.44.i；E.252.a.44.i；E.253.a.44.i； E.254.a.44.i；E.255.a.44.i；E.256.a.44.i；E.257.a.44.i；E.258.a.44.i；E.259.a.44.i； E.260.a.44.i；E.261.a.44.i；E.262.a.44.i；E.263.a.44.i；E.264.a.44.i；E.265.a.44.i； E.266.a.44.i；E.267.a.44.i；E.268.a.44.i；E.269.a.44.i；E.270.a.44.i；E.271.a.44.i； E.272.a.44.i；E.273.a.44.i；E.274.a.44.i；E.275.a.44.i；E.276.a.44.i；E.277.a.44.i； E.278.a.44.i；E.279.a.44.i；E.280.a.44.i；E.281.a.44.i；E.282.a.44.i；E.283.a.44.i； E.284.a.44.i；E.285.a.44.i；E.286.a.44.i；E.287.a.44.i；E.288.a.44.i；E.289.a.44.i； E.290.a.44.i；E.291.a.44.i；E.292.a.44.i；E.293.a.44.i；E.294.a.44.i；E.295.a.44.i； E.296.a.44.i；E.297.a.44.i；E.298.a.44.i；E.299.a.44.i；E.300.a.44.i；E.301.a.44.i； E.302.a.44.i；E.303.a.44.i；E.304.a.44.i；E.305.a.44.i；E.306.a.44.i；E.307.a.44.i； E.308.a.44.i；E.309.a.44.i；E.310.a.44.i；E.311.a.44.i；E.312.a.44.i；E.313.a.44.i； E.314.a.44.i；E.315.a.44.i；E.316.a.44.i；E.317.a.44.i；E.318.a.44.i；E.319.a.44.i； E.320.a.44.i；E.321.a.44.i；E.322.a.44.i；E.323.a.44.i；E.324.a.44.i；E.325.a.44.i； E.326.a.44.i；E.327.a.44.i；E.328.a.44.i；E.329.a.44.i；E.330.a.44.i；E.331.a.44.i； E.332.a.44.i；E.333.a.44.i；E.334.a.44.i；E.335.a.44.i；E.336.a.44.i；E.337.a.44.i； E.338.a.44.i；E.339.a.44.i；E.340.a.44.i；E.341.a.44.i；E.342.a.44.i；E.343.a.44.i； E.344.a.44.i；E.345.a.44.i；E.346.a.44.i；E.347.a.44.i；E.348.a.44.i；E.349.a.44.i； E.350.a.44.i；E.351.a.44.i；E.352.a.44.i；E.353.a.44.i；E.354.a.44.i；E.355.a.44.i； E.356.a.44.i；E.357.a.44.i；E.358.a.44.i；B.2.a.4.i；B.3.a.4.i；B.4.a.4.i；B.5.a.4.i；B.9.a.4.i； B.100.a.4.i；B.101.a.4.i；B.102.a.4.i；B.103.a.4.i；B.104.a.4.i；B.105.a.4.i；B.106.a.4.i； B.107.a.4.i；B.108.a.4.i；B.109.a.4.i；B.110.a.4.i；B.111.a.4.i；B.112.a.4.i；B.113.a.4.i； B.114.a.4.i；B.115.a.4.i；B.116.a.4.i；B.117.a.4.i；B.118.a.4.i；B.119.a.4.i；B.120.a.4.i； B.121.a.4.i；B.122.a.4.i；B.123.a.4.i；B.124.a.4.i；B.125.a.4.i；B.126.a.4.i；B.127.a.4.i； B.128.a.4.i；B.129.a.4.i；B.130.a.4.i；B.131.a.4.i；B.132.a.4.i；B.133.a.4.i；B.134.a.4.i； B.135.a.4.i；B.136.a.4.i；B.137.a.4.i；B.138.a.4.i；B.139.a.4.i；B.140.a.4.i；B.141.a.4.i； B.142.a.4.i；B.143.a.4.i；B.144.a.4.i；B.145.a.4.i；B.146.a.4.i；B.147.a.4.i；B.148.a.4.i； B.149.a.4.i；B.150.a.4.i；B.151.a.4.i；B.152.a.4.i；B.153.a.4.i；B.154.a.4.i；B.155.a.4.i； B.156.a.4.i；B.157.a.4.i；B.158.a.4.i；B.159.a.4.i；B.160.a.4.i；B.161.a.4.i；B.162.a.4.i； B.163.a.4.i；B.164.a.4.i；B.165.a.4.i；B.166.a.4.i；B.167.a.4.i；B.168.a.4.i；B.169.a.4.i； B.170.a.4.i；B.171.a.4.i；B.172.a.4.i；B.173.a.4.i；B.174.a.4.i；B.175.a.4.i；B.176.a.4.i； B.177.a.4.i；B.178.a.4.i；B.179.a.4.i；B.180.a.4.i；B.181.a.4.i；B.182.a.4.i；B.183.a.4.i； B.184.a.4.i；B.185.a.4.i；B.186.a.4.i；B.187.a.4.i；B.188.a.4.i；B.189.a.4.i；B.190.a.4.i； B.191.a.4.i；B.192.a.4.i；B.193.a.4.i；B.194.a.4.i；B.195.a.4.i；B.196.a.4.i；B.197.a.4.i； B.198.a.4.i；B.199.a.4.i；B.200.a.4.i；B.201.a.4.i；B.202.a.4.i；B.203.a.4.i；B.204.a.4.i； B.205.a.4.i；B.206.a.4.i；B.207.a.4.i；B.208.a.4.i；B.209.a.4.i；B.210.a.4.i；B.211.a.4.i； B.212.a.4.i；B.213.a.4.i；B.214.a.4.i；B.215.a.4.i；B.216.a.4.i；B.217.a.4.i；B.218.a.4.i； B.219.a.4.i；B.220.a.4.i；B.221.a.4.i；B.222.a.4.i；B.223.a.4.i；B.224.a.4.i；B.225.a.4.i； B.226.a.4.i；B.227.a.4.i；B.228.a.4.i；B.229.a.4.i；B.230.a.4.i；B.231.a.4.i；B.232.a.4.i； B.233.a.4.i；B.234.a.4.i；B.235.a.4.i；B.236.a.4.i；B.237.a.4.i；B.238.a.4.i；B.239.a.4.i； B.240.a.4.i；B.241.a.4.i；B.242.a.4.i；B.243.a.4.i；B.244.a.4.i；B.245.a.4.i；B.246.a.4.i； B.247.a.4.i；B.248.a.4.i；B.249.a.4.i；B.250.a.4.i；B.251.a.4.i；B.252.a.4.i；B.253.a.4.i； B.254.a.4.i；B.255.a.4.i；B.256.a.4.i；B.257.a.4.i；B.258.a.4.i；B.259.a.4.i；B.260.a.4.i； B.261.a.4.i；B.262.a.4.i；B.263.a.4.i；B.264.a.4.i；B.265.a.4.i；B.266.a.4.i；B.267.a.4.i；B.268.a.4.i；B.269.a.4.i；B.270.a.4.i；B.271.a.4.i；B.272.a.4.i；B.273.a.4.i；B.274.a.4.i； B.275.a.4.i；B.276.a.4.i；B.277.a.4.i；B.278.a.4.i；B.279.a.4.i；B.280.a.4.i；B.281.a.4.i； B.282.a.4.i；B.283.a.4.i；B.284.a.4.i；B.285.a.4.i；B.286.a.4.i；B.287.a.4.i；B.288.a.4.i； B.289.a.4.i；B.290.a.4.i；B.291.a.4.i；B.292.a.4.i；B.293.a.4.i；B.294.a.4.i；B.295.a.4.i； B.296.a.4.i；B.297.a.4.i；B.298.a.4.i；B.299.a.4.i；B.300.a.4.i；B.301.a.4.i；B.302.a.4.i； B.303.a.4.i；B.304.a.4.i；B.305.a.4.i；B.306.a.4.i；B.307.a.4.i；B.308.a.4.i；B.309.a.4.i； B.310.a.4.i；B.311.a.4.i；B.312.a.4.i；B.313.a.4.i；B.314.a.4.i；B.315.a.4.i；B.316.a.4.i； B.317.a.4.i；B.318.a.4.i；B.319.a.4.i；B.320.a.4.i；B.321.a.4.i；B.322.a.4.i；B.323.a.4.i； B.324.a.4.i；B.325.a.4.i；B.326.a.4.i；B.327.a.4.i；B.328.a.4.i；B.329.a.4.i；B.330.a.4.i； B.331.a.4.i；B.332.a.4.i；B.333.a.4.i；B.334.a.4.i；B.335.a.4.i；B.336.a.4.i；B.337.a.4.i； B.338.a.4.i；B.339.a.4.i；B.340.a.4.i；B.341.a.4.i；B.342.a.4.i；B.343.a.4.i；B.344.a.4.i； B.345.a.4.i；B.346.a.4.i；B.347.a.4.i；B.348.a.4.i；B.349.a.4.i；B.350.a.4.i；B.351.a.4.i； B.352.a.4.i；B.353.a.4.i；B.354.a.4.i；B.355.a.4.i；B.356.a.4.i；B.357.a.4.i；B.358.a.4.i； E.2.a.4.i；E.3.a.4.i；E.4.a.4.i；E.5.a.4.i；E.9.a.4.i；E.100.a.4.i；E.101.a.4.i；E.102.a.4.i； E.103.a.4.i；E.104.a.4.i；E.105.a.4.i；E.106.a.4.i；E.107.a.4.i；E.108.a.4.i；E.109.a.4.i； E.110.a.4.i；E.111.a.4.i；E.112.a.4.i；E.113.a.4.i；E.114.a.4.i；E.115.a.4.i；E.116.a.4.i； E.117.a.4.i；E.118.a.4.i；E.119.a.4.i；E.120.a.4.i；E.121.a.4.i；E.122.a.4.i；E.123.a.4.i； E.124.a.4.i；E.125.a.4.i；E.126.a.4.i；E.127.a.4.i；E.128.a.4.i；E.129.a.4.i；E.130.a.4.i； E.131.a.4.i；E.132.a.4.i；E.133.a.4.i；E.134.a.4.i；E.135.a.4.i；E.136.a.4.i；E.137.a.4.i； E.138.a.4.i；E.139.a.4.i；E.140.a.4.i；E.141.a.4.i；E.142.a.4.i；E.143.a.4.i；E.144.a.4.i； E.145.a.4.i；E.146.a.4.i；E.147.a.4.i；E.148.a.4.i；E.149.a.4.i；E.150.a.4.i；E.151.a.4.i； E.152.a.4.i；E.153.a.4.i；E.154.a.4.i；E.155.a.4.i；E.156.a.4.i；E.157.a.4.i；E.158.a.4.i； E.159.a.4.i；E.160.a.4.i；E.161.a.4.i；E.162.a.4.i；E.163.a.4.i；E.164.a.4.i；E.165.a.4.i； E.166.a.4.i；E.167.a.4.i；E.168.a.4.i；E.169.a.4.i；E.170.a.4.i；E.171.a.4.i；E.172.a.4.i； E.173.a.4.i；E.174.a.4.i；E.175.a.4.i；E.176.a.4.i；E.177.a.4.i；E.178.a.4.i；E.179.a.4.i； E.180.a.4.i；E.181.a.4.i；E.182.a.4.i；E.183.a.4.i；E.184.a.4.i；E.185.a.4.i；E.186.a.4.i； E.187.a.4.i；E.188.a.4.i；E.189.a.4.i；E.190.a.4.i；E.191.a.4.i；E.192.a.4.i；E.193.a.4.i； E.194.a.4.i；E.195.a.4.i；E.196.a.4.i；E.197.a.4.i；E.198.a.4.i；E.199.a.4.i；E.200.a.4.i； E.201.a.4.i；E.202.a.4.i；E.203.a.4.i；E.204.a.4.i；E.205.a.4.i；E.206.a.4.i；E.207.a.4.i； E.208.a.4.i；E.209.a.4.i；E.210.a.4.i；E.211.a.4.i；E.212.a.4.i；E.213.a.4.i；E.214.a.4.i； E.215.a.4.i；E.216.a.4.i；E.217.a.4.i；E.218.a.4.i；E.219.a.4.i；E.220.a.4.i；E.221.a.4.i； E.222.a.4.i；E.223.a.4.i；E.224.a.4.i；E.225.a.4.i；E.226.a.4.i；E.227.a.4.i；E.228.a.4.i； E.229.a.4.i；E.230.a.4.i；E.231.a.4.i；E.232.a.4.i；E.233.a.4.i；E.234.a.4.i；E.235.a.4.i； E.236.a.4.i；E.237.a.4.i；E.238.a.4.i；E.239.a.4.i；E.240.a.4.i；E.241.a.4.i；E.242.a.4.i； E.243.a.4.i；E.244.a.4.i；E.245.a.4.i；E.246.a.4.i；E.247.a.4.i；E.248.a.4.i；E.249.a.4.i； E.250.a.4.i；E.251.a.4.i；E.252.a.4.i；E.253.a.4.i；E.254.a.4.i；E.255.a.4.i；E.256.a.4.i； E.257.a.4.i；E.258.a.4.i；E.259.a.4.i；E.260.a.4.i；E.261.a.4.i；E.262.a.4.i；E.263.a.4.i； E.264.a.4.i；E.265.a.4.i；E.266.a.4.i；E.267.a.4.i；E.268.a.4.i；E.269.a.4.i；E.270.a.4.i； E.271.a.4.i；E.272.a.4.i；E.273.a.4.i；E.274.a.4.i；E.275.a.4.i；E.276.a.4.i；E.277.a.4.i； E.278.a.4.i；E.279.a.4.i；E.280.a.4.i；E.281.a.4.i；E.282.a.4.i；E.283.a.4.i；E.284.a.4.i； E.285.a.4.i；E.286.a.4.i；E.287.a.4.i；E.288.a.4.i；E.289.a.4.i；E.290.a.4.i；E.291.a.4.i； E.292.a.4.i；E.293.a.4.i；E.294.a.4.i；E.295.a.4.i；E.296.a.4.i；E.297.a.4.i；E.298.a.4.i； E.299.a.4.i；E.300.a.4.i；E.301.a.4.i；E.302.a.4.i；E.303.a.4.i；E.304.a.4.i；E.305.a.4.i； E.306.a.4.i；E.307.a.4.i；E.308.a.4.i；E.309.a.4.i；E.310.a.4.i；E.311.a.4.i；E.312.a.4.i； E.313.a.4.i；E.314.a.4.i；E.315.a.4.i；E.316.a.4.i；E.317.a.4.i；E.318.a.4.i；E.319.a.4.i； E.320.a.4.i；E.321.a.4.i；E.322.a.4.i；E.323.a.4.i；E.324.a.4.i；E.325.a.4.i；E.326.a.4.i； E.327.a.4.i；E.328.a.4.i；E.329.a.4.i；E.330.a.4.i；E.331.a.4.i；E.332.a.4.i；E.333.a.4.i；E.334.a.4.i；E.335.a.4.i；E.336.a.4.i；E.337.a.4.i；E.338.a.4.i；E.339.a.4.i；E.340.a.4.i； E.341.a.4.i；E.342.a.4.i；E.343.a.4.i；E.344.a.4.i；E.345.a.4.i；E.346.a.4.i；E.347.a.4.i； E.348.a.4.i；E.349.a.4.i；E.350.a.4.i；E.351.a.4.i；E.352.a.4.i；E.353.a.4.i；E.354.a.4.i； E.355.a.4.i；E.356.a.4.i；E.357.a.4.i；E.358.a.4.i；B.2.a.11.i；B.3.a.11.i；B.4.a.11.i； B.5.a.11.i；B.9.a.11.i；B.100.a.11.i；B.101.a.11.i；B.102.a.11.i；B.103.a.11.i； B.104.a.11.i；B.105.a.11.i；B.106.a.11.i；B.107.a.11.i；B.108.a.11.i；B.109.a.11.i； B.110.a.11.i；B.111.a.11.i；B.112.a.11.i；B.113.a.11.i；B.114.a.11.i；B.115.a.11.i； B.116.a.11.i；B.117.a.11.i；B.118.a.11.i；B.119.a.11.i；B.120.a.11.i；B.121.a.11.i； B.122.a.11.i；B.123.a.11.i；B.124.a.11.i；B.125.a.11.i；B.126.a.11.i；B.127.a.11.i； B.128.a.11.i；B.129.a.11.i；B.130.a.11.i；B.131.a.11.i；B.132.a.11.i；B.133.a.11.i； B.134.a.11.i；B.135.a.11.i；B.136.a.11.i；B.137.a.11.i；B.138.a.11.i；B.139.a.11.i； B.140.a.11.i；B.141.a.11.i；B.142.a.11.i；B.143.a.11.i；B.144.a.11.i；B.145.a.11.i； B.146.a.11.i；B.147.a.11.i；B.148.a.11.i；B.149.a.11.i；B.150.a.11.i；B.151.a.11.i； B.152.a.11.i；B.153.a.11.i；B.154.a.11.i；B.155.a.11.i；B.156.a.11.i；B.157.a.11.i； B.158.a.11.i；B.159.a.11.i；B.160.a.11.i；B.161.a.11.i；B.162.a.11.i；B.163.a.11.i； B.164.a.11.i；B.165.a.11.i；B.166.a.11.i；B.167.a.11.i；B.168.a.11.i；B.169.a.11.i； B.170.a.11.i；B.171.a.11.i；B.172.a.11.i；B.173.a.11.i；B.174.a.11.i；B.175.a.11.i； B.176.a.11.i；B.177.a.11.i；B.178.a.11.i；B.179.a.11.i；B.180.a.11.i；B.181.a.11.i； B.182.a.11.i；B.183.a.11.i；B.184.a.11.i；B.185.a.11.i；B.186.a.11.i；B.187.a.11.i； B.188.a.11.i；B.189.a.11.i；B.190.a.11.i；B.191.a.11.i；B.192.a.11.i；B.193.a.11.i； B.194.a.11.i；B.195.a.11.i；B.196.a.11.i；B.197.a.11.i；B.198.a.11.i；B.199.a.11.i； B.200.a.11.i；B.201.a.11.i；B.202.a.11.i；B.203.a.11.i；B.204.a.11.i；B.205.a.11.i； B.206.a.11.i；B.207.a.11.i；B.208.a.11.i；B.209.a.11.i；B.210.a.11.i；B.211.a.11.i； B.212.a.11.i；B.213.a.11.i；B.214.a.11.i；B.215.a.11.i；B.216.a.11.i；B.217.a.11.i； B.218.a.11.i；B.219.a.11.i；B.220.a.11.i；B.221.a.11.i；B.222.a.11.i；B.223.a.11.i； B.224.a.11.i；B.225.a.11.i；B.226.a.11.i；B.227.a.11.i；B.228.a.11.i；B.229.a.11.i； B.230.a.11.i；B.231.a.11.i；B.232.a.11.i；B.233.a.11.i；B.234.a.11.i；B.235.a.11.i； B.236.a.11.i；B.237.a.11.i；B.238.a.11.i；B.239.a.11.i；B.240.a.11.i；B.241.a.11.i； B.242.a.11.i；B.243.a.11.i；B.244.a.11.i；B.245.a.11.i；B.246.a.11.i；B.247.a.11.i； B.248.a.11.i；B.249.a.11.i；B.250.a.11.i；B.251.a.11.i；B.252.a.11.i；B.253.a.11.i； B.254.a.11.i；B.255.a.11.i；B.256.a.11.i；B.257.a.11.i；B.258.a.11.i；B.259.a.11.i； B.260.a.11.i；B.261.a.11.i；B.262.a.11.i；B.263.a.11.i；B.264.a.11.i；B.265.a.11.i； B.266.a.11.i；B.267.a.11.i；B.268.a.11.i；B.269.a.11.i；B.270.a.11.i；B.271.a.11.i； B.272.a.11.i；B.273.a.11.i；B.274.a.11.i；B.275.a.11.i；B.276.a.11.i；B.277.a.11.i； B.278.a.11.i；B.279.a.11.i；B.280.a.11.i；B.281.a.11.i；B.282.a.11.i；B.283.a.11.i； B.284.a.11.i；B.285.a.11.i；B.286.a.11.i；B.287.a.11.i；B.288.a.11.i；B.289.a.11.i； B.290.a.11.i；B.291.a.11.i；B.292.a.11.i；B.293.a.11.i；B.294.a.11.i；B.295.a.11.i； B.296.a.11.i；B.297.a.11.i；B.298.a.11.i；B.299.a.11.i；B.300.a.11.i；B.301.a.11.i； B.302.a.11.i；B.303.a.11.i；B.304.a.11.i；B.305.a.11.i；B.306.a.11.i；B.307.a.11.i； B.308.a.11.i；B.309.a.11.i；B.310.a.11.i；B.311.a.11.i；B.312.a.11.i；B.313.a.11.i； B.314.a.11.i；B.315.a.11.i；B.316.a.11.i；B.317.a.11.i；B.318.a.11.i；B.319.a.11.i； B.320.a.11.i；B.321.a.11.i；B.322.a.11.i；B.323.a.11.i；B.324.a.11.i；B.325.a.11.i； B.326.a.11.i；B.327.a.11.i；B.328.a.11.i；B.329.a.11.i；B.330.a.11.i；B.331.a.11.i； B.332.a.11.i；B.333.a.11.i；B.334.a.11.i；B.335.a.11.i；B.336.a.11.i；B.337.a.11.i； B.338.a.11.i；B.339.a.11.i；B.340.a.11.i；B.341.a.11.i；B.342.a.11.i；B.343.a.11.i； B.344.a.11.i；B.345.a.11.i；B.346.a.11.i；B.347.a.11.i；B.348.a.11.i；B.349.a.11.i； B.350.a.11.i；B.351.a.11.i；B.352.a.11.i；B.353.a.11.i；B.354.a.11.i；B.355.a.11.i；B.356.a.11.i；B.357.a.11.i；B.358.a.11.i；E.2.a.11.i；E.3.a.11.i；E.4.a.11.i；E.5.a.11.i； E.9.a.11.i；E.100.a.11.i；E.101.a.11.i；E.102.a.11.i；E.103.a.11.i；E.104.a.11.i； E.105.a.11.i；E.106.a.11.i；E.107.a.11.i；E.108.a.11.i；E.109.a.11.i；E.110.a.11.i； E.111.a.11.i；E.112.a.11.i；E.113.a.11.i；E.114.a.11.i；E.115.a.11.i；E.116.a.11.i； E.117.a.11.i；E.118.a.11.i；E.119.a.11.i；E.120.a.11.i；E.121.a.11.i；E.122.a.11.i； E.123.a.11.i；E.124.a.11.i；E.125.a.11.i；E.126.a.11.i；E.127.a.11.i；E.128.a.11.i； E.129.a.11.i；E.130.a.11.i；E.131.a.11.i；E.132.a.11.i；E.133.a.11.i；E.134.a.11.i； E.135.a.11.i；E.136.a.11.i；E.137.a.11.i；E.138.a.11.i；E.139.a.11.i；E.140.a.11.i； E.141.a.11.i；E.142.a.11.i；E.143.a.11.i；E.144.a.11.i；E.145.a.11.i；E.146.a.11.i； E.147.a.11.i；E.148.a.11.i；E.149.a.11.i；E.150.a.11.i；E.151.a.11.i；E.152.a.11.i； E.153.a.11.i；E.154.a.11.i；E.155.a.11.i；E.156.a.11.i；E.157.a.11.i；E.158.a.11.i； E.159.a.11.i；E.160.a.11.i；E.161.a.11.i；E.162.a.11.i；E.163.a.11.i；E.164.a.11.i； E.165.a.11.i；E.166.a.11.i；E.167.a.11.i；E.168.a.11.i；E.169.a.11.i；E.170.a.11.i； E.171.a.11.i；E.172.a.11.i；E.173.a.11.i；E.174.a.11.i；E.175.a.11.i；E.176.a.11.i； E.177.a.11.i；E.178.a.11.i；E.179.a.11.i；E.180.a.11.i；E.181.a.11.i；E.182.a.11.i； E.183.a.11.i；E.184.a.11.i；E.185.a.11.i；E.186.a.11.i；E.187.a.11.i；E.188.a.11.i； E.189.a.11.i；E.190.a.11.i；E.191.a.11.i；E.192.a.11.i；E.193.a.11.i；E.194.a.11.i； E.195.a.11.i；E.196.a.11.i；E.197.a.11.i；E.198.a.11.i；E.199.a.11.i；E.200.a.11.i； E.201.a.11.i；E.202.a.11.i；E.203.a.11.i；E.204.a.11.i；E.205.a.11.i；E.206.a.11.i； E.207.a.11.i；E.208.a.11.i；E.209.a.11.i；E.210.a.11.i；E.211.a.11.i；E.212.a.11.i； E.213.a.11.i；E.214.a.11.i；E.215.a.11.i；E.216.a.11.i；E.217.a.11.i；E.218.a.11.i； E.219.a.11.i；E.220.a.11.i；E.221.a.11.i；E.222.a.11.i；E.223.a.11.i；E.224.a.11.i； E.225.a.11.i；E.226.a.11.i；E.227.a.11.i；E.228.a.11.i；E.229.a.11.i；E.230.a.11.i； E.231.a.11.i；E.232.a.11.i；E.233.a.11.i；E.234.a.11.i；E.235.a.11.i；E.236.a.11.i； E.237.a.11.i；E.238.a.11.i；E.239.a.11.i；E.240.a.11.i；E.241.a.11.i；E.242.a.11.i； E.243.a.11.i；E.244.a.11.i；E.245.a.11.i；E.246.a.11.i；E.247.a.11.i；E.248.a.11.i； E.249.a.11.i；E.250.a.11.i；E.251.a.11.i；E.252.a.11.i；E.253.a.11.i；E.254.a.11.i； E.255.a.11.i；E.256.a.11.i；E.257.a.11.i；E.258.a.11.i；E.259.a.11.i；E.260.a.11.i； E.261.a.11.i；E.262.a.11.i；E.263.a.11.i；E.264.a.11.i；E.265.a.11.i；E.266.a.11.i； E.267.a.11.i；E.268.a.11.i；E.269.a.11.i；E.270.a.11.i；E.271.a.11.i；E.272.a.11.i； E.273.a.11.i；E.274.a.11.i；E.275.a.11.i；E.276.a.11.i；E.277.a.11.i；E.278.a.11.i； E.279.a.11.i；E.280.a.11.i；E.281.a.11.i；E.282.a.11.i；E.283.a.11.i；E.284.a.11.i； E.285.a.11.i；E.286.a.11.i；E.287.a.11.i；E.288.a.11.i；E.289.a.11.i；E.290.a.11.i； E.291.a.11.i；E.292.a.11.i；E.293.a.11.i；E.294.a.11.i；E.295.a.11.i；E.296.a.11.i； E.297.a.11.i；E.298.a.11.i；E.299.a.11.i；E.300.a.11.i；E.301.a.11.i；E.302.a.11.i； E.303.a.11.i；E.304.a.11.i；E.305.a.11.i；E.306.a.11.i；E.307.a.11.i；E.308.a.11.i； E.309.a.11.i；E.310.a.11.i；E.311.a.11.i；E.312.a.11.i；E.313.a.11.i；E.314.a.11.i； E.315.a.11.i；E.316.a.11.i；E.317.a.11.i；E.318.a.11.i；E.319.a.11.i；E.320.a.11.i； E.321.a.11.i；E.322.a.11.i；E.323.a.11.i；E.324.a.11.i；E.325.a.11.i；E.326.a.11.i； E.327.a.11.i；E.328.a.11.i；E.329.a.11.i；E.330.a.11.i；E.331.a.11.i；E.332.a.11.i； E.333.a.11.i；E.334.a.11.i；E.335.a.11.i；E.336.a.11.i；E.337.a.11.i；E.338.a.11.i； E.339.a.11.i；E.340.a.11.i；E.341.a.11.i；E.342.a.11.i；E.343.a.11.i；E.344.a.11.i； E.345.a.11.i；E.346.a.11.i；E.347.a.11.i；E.348.a.11.i；E.349.a.11.i；E.350.a.11.i； E.351.a.11.i；E.352.a.11.i；E.353.a.11.i；E.354.a.11.i；E.355.a.11.i；E.356.a.11.i； E.357.a.11.i；E.358.a.11.i；A.661.a.4.i；A.662.a.4.i；A.663.a.4.i；A.664.a.4.i； A.665.a.4.i；B.661.a.4.i；B.662.a.4.i；B.663.a.4.i；B.664.a.4.i；B.665.a.4.i；C.661.a.4.i； C.662.a.4.i；C.663.a.4.i；C.664.a.4.i；C.665.a.4.i；A.661.a.11.i；A.662.a.11.i；A.663.a.11.i；A.664.a.11.i；A.665.a.11.i；B.661.a.11.i；B.662.a.11.i；B.663.a.11.i； B.664.a.11.i；B.665.a.11.i；C.661.a.11.i；C.662.a.11.i；C.663.a.11.i；C.664.a.11.i； C.665.a.11.i；A.661.a.44.i；A.662.a.44.i；A.663.a.44.i；A.664.a.44.i；A.665.a.44.i； B.661.a.44.i；B.662.a.44.i；B.663.a.44.i；B.664.a.44.i；B.665.a.44.i；C.661.a.44.i； C.662.a.44.i；C.663.a.44.i；C.664.a.44.i；C.665.a.44.i；A.666.a.4.i；A.666.a.11.i； A.666.a.44.i；A.666.b.4.i；A.666.b.11.i；A.666.b.44.i；A.666.x.4.i；A.666.x.11.i； A.666.x.44.i；A.666.y.4.i；A.666.y.11.i；A.666.y.44.i；A.666.z.4.i；A.666.z.11.i； A.666.z.44.i；A.666.A.4.i；A.666.A.11.i；A.666.A.44.i；A.666.B.4.i；A.666.B.11.i； A.666.B.44.i；A.666.C.4.i；A.666.C.11.i；A.666.C.44.i；A.666.D.4.i；A.666.D.11.i； A.666.D.44.i；A.666.E.4.i；A.666.E.11.i；A.666.E.44.i；A.666.F.4.i；A.666.F.11.i； A.666.F.44.i；B.666.a.4.i；B.666.a.11.i；B.666.a.44.i；B.666.b.4.i；B.666.b.11.i； B.666.b.44.i；B.666.x.4.i；B.666.x.11.i；B.666.x.44.i；B.666.y.4.i；B.666.y.11.i； B.666.y.44.i；B.666.z.4.i；B.666.z.11.i；B.666.z.44.i；B.666.B.4.i；B.666.B.11.i； B.666.B.44.i；B.666.B.4.i；B.666.B.11.i；B.666.B.44.i；B.666.C.4.i；B.666.C.11.i； B.666.C.44.i；B.666.D.4.i；B.666.D.11.i；B.666.D.44.i；B.666.E.4.i；B.666.E.11.i； B.666.E.44.i；B.666.F.4.i；B.666.F.11.i；B.666.F.44.i；E.666.a.4.i；E.666.a.11.i； E.666.a.44.i；E.666.b.4.i；E.666.b.11.i；E.666.b.44.i；E.666.x.4.i；E.666.x.11.i； E.666.x.44.i；E.666.y.4.i；E.666.y.11.i；E.666.y.44.i；E.666.z.4.i；E.666.z.11.i； E.666.z.44.i；E.666.E.4.i；E.666.E.11.i；E.666.E.44.i；E.666.B.4.i；E.666.B.11.i； E.666.B.44.i；E.666.C.4.i；E.666.C.11.i；E.666.C.44.i；E.666.D.4.i；E.666.D.11.i； E.666.D.44.i；E.666.E.4.i；E.666.E.11.i；E.666.E.44.i；E.666.F.4.i；E.666.F.11.i； E.666.F.44.i； A.2.a.46.i；A.3.a.46.i；A.4.a.46.i；A.5.a.46.i；A.7.a.46.i；A.9.a.46.i；A.100.a.46.i； A.101.a.46.i；A.102.a.46.i；A.103.a.46.i；A.104.a.46.i；A.105.a.46.i；A.106.a.46.i； A.107.a.46.i；A.108.a.46.i；A.109.a.46.i；A.110.a.46.i；A.111.a.46.i；A.112.a.46.i； A.113.a.46.i；A.114.a.46.i；A.115.a.46.i；A.116.a.46.i；A.117.a.46.i；A.118.a.46.i； A.119.a.46.i；A.120.a.46.i；A.121.a.46.i；A.122.a.46.i；A.123.a.46.i；A.124.a.46.i； A.125.a.46.i；A.126.a.46.i；A.127.a.46.i；A.128.a.46.i；A.129.a.46.i；A.130.a.46.i； A.131.a.46.i；A.132.a.46.i；A.133.a.46.i；A.134.a.46.i；A.135.a.46.i；A.136.a.46.i； A.137.a.46.i；A.138.a.46.i；A.139.a.46.i；A.140.a.46.i；A.141.a.46.i；A.2.a.47.i； A.3.a.47.i；A.4.a.47.i；A.5.a.47.i；A.7.a.47.i；A.9.a.47.i；A.100.a.47.i；A.101.a.47.i； A.102.a.47.i；A.103.a.47.i；A.104.a.47.i；A.105.a.47.i；A.106.a.47.i；A.107.a.47.i； A.108.a.47.i；A.109.a.47.i；A.110.a.47.i；A.111.a.47.i；A.112.a.47.i；A.113.a.47.i； A.114.a.47.i；A.115.a.47.i；A.116.a.47.i；A.117.a.47.i；A.118.a.47.i；A.119.a.47.i； A.120.a.47.i；A.121.a.47.i；A.122.a.47.i；A.123.a.47.i；A.124.a.47.i；A.125.a.47.i； A.126.a.47.i；A.127.a.47.i；A.128.a.47.i；A.129.a.47.i；A.130.a.47.i；A.131.a.47.i； A.132.a.47.i；A.133.a.47.i；A.134.a.47.i；A.135.a.47.i；A.136.a.47.i；A.137.a.47.i； A.138.a.47.i；A.139.a.47.i；A.140.a.47.i；A.141.a.47.i；A.2.a.48.i；A.3.a.48.i； A.4.a.48.i；A.5.a.48.i；A.7.a.48.i；A.9.a.48.i；A.100.a.48.i；A.101.a.48.i；A.102.a.48.i； A.103.a.48.i；A.104.a.48.i；A.105.a.48.i；A.106.a.48.i；A.107.a.48.i；A.108.a.48.i； A.109.a.48.i；A.110.a.48.i；A.111.a.48.i；A.112.a.48.i；A.113.a.48.i；A.114.a.48.i； A.115.a.48.i；A.116.a.48.i；A.117.a.48.i；A.118.a.48.i；A.119.a.48.i；A.120.a.48.i； A.121.a.48.i；A.122.a.48.i；A.123.a.48.i；A.124.a.48.i；A.125.a.48.i；A.126.a.48.i； A.127.a.48.i；A.128.a.48.i；A.129.a.48.i；A.130.a.48.i；A.131.a.48.i；A.132.a.48.i； A.133.a.48.i；A.134.a.48.i；A.135.a.48.i；A.136.a.48.i；A.137.a.48.i；A.138.a.48.i； A.139.a.48.i；A.140.a.48.i；A.141.a.48.i；A.2.a.49.i；A.3.a.49.i；A.4.a.49.i；A.5.a.49.i； A.7.a.49.i；A.9.a.49.i；A.100.a.49.i；A.101.a.49.i；A.102.a.49.i；A.103.a.49.i；A.104.a.49.i；A.105.a.49.i；A.106.a.49.i；A.107.a.49.i；A.108.a.49.i；A.109.a.49.i； A.110.a.49.i；A.111.a.49.i；A.112.a.49.i；A.113.a.49.i；A.114.a.49.i；A.115.a.49.i； A.116.a.49.i；A.117.a.49.i；A.118.a.49.i；A.119.a.49.i；A.120.a.49.i；A.121.a.49.i； A.122.a.49.i；A.123.a.49.i；A.124.a.49.i；A.125.a.49.i；A.126.a.49.i；A.127.a.49.i； A.128.a.49.i；A.129.a.49.i；A.130.a.49.i；A.131.a.49.i；A.132.a.49.i；A.133.a.49.i； A.134.a.49.i；A.135.a.49.i；A.136.a.49.i；A.137.a.49.i；A.138.a.49.i；A.139.a.49.i； A.140.a.49.i；A.141.a.49.i；A.2.a.50.i；A.3.a.50.i；A.4.a.50.i；A.5.a.50.i；A.7.a.50.i； A.9.a.50.i；A.100.a.50.i；A.101.a.50.i；A.102.a.50.i；A.103.a.50.i；A.104.a.50.i； A.105.a.50.i；A.106.a.50.i；A.107.a.50.i；A.108.a.50.i；A.109.a.50.i；A.110.a.50.i； A.111.a.50.i；A.112.a.50.i；A.113.a.50.i；A.114.a.50.i；A.115.a.50.i；A.116.a.50.i； A.117.a.50.i；A.118.a.50.i；A.119.a.50.i；A.120.a.50.i；A.121.a.50.i；A.122.a.50.i； A.123.a.50.i；A.124.a.50.i；A.125.a.50.i；A.126.a.50.i；A.127.a.50.i；A.128.a.50.i； A.129.a.50.i；A.130.a.50.i；A.131.a.50.i；A.132.a.50.i；A.133.a.50.i；A.134.a.50.i； A.135.a.50.i；A.136.a.50.i；A.137.a.50.i；A.138.a.50.i；A.139.a.50.i；A.140.a.50.i； A.141.a.50.i；A.2.a.51.i；A.3.a.51.i；A.4.a.51.i；A.5.a.51.i；A.7.a.51.i；A.9.a.51.i； A.100.a.51.i；A.101.a.51.i；A.102.a.51.i；A.103.a.51.i；A.104.a.51.i；A.105.a.51.i； A.106.a.51.i；A.107.a.51.i；A.108.a.51.i；A.109.a.51.i；A.110.a.51.i；A.111.a.51.i； A.112.a.51.i；A.113.a.51.i；A.114.a.51.i；A.115.a.51.i；A.116.a.51.i；A.117.a.51.i； A.118.a.51.i；A.119.a.51.i；A.120.a.51.i；A.121.a.51.i；A.122.a.51.i；A.123.a.51.i； A.124.a.51.i；A.125.a.51.i；A.126.a.51.i；A.127.a.51.i；A.128.a.51.i；A.129.a.51.i； A.130.a.51.i；A.131.a.51.i；A.132.a.51.i；A.133.a.51.i；A.134.a.51.i；A.135.a.51.i； A.136.a.51.i；A.137.a.51.i；A.138.a.51.i；A.139.a.51.i；A.140.a.51.i；A.141.a.51.i； A.2.b.46.i；A.3.b.46.i；A.4.b.46.i；A.5.b.46.i；A.7.b.46.i；A.9.b.46.i；A.100.b.46.i； A.101.b.46.i；A.102.b.46.i；A.103.b.46.i；A.104.b.46.i；A.105.b.46.i；A.106.b.46.i； A.107.b.46.i；A.108.b.46.i；A.109.b.46.i；A.110.b.46.i；A.111.b.46.i；A.112.b.46.i； A.113.b.46.i；A.114.b.46.i；A.115.b.46.i；A.116.b.46.i；A.117.b.46.i；A.118.b.46.i； A.119.b.46.i；A.120.b.46.i；A.121.b.46.i；A.122.b.46.i；A.123.b.46.i；A.124.b.46.i； A.125.b.46.i；A.126.b.46.i；A.127.b.46.i；A.128.b.46.i；A.129.b.46.i；A.130.b.46.i； A.131.b.46.i；A.132.b.46.i；A.133.b.46.i；A.134.b.46.i；A.135.b.46.i；A.136.b.46.i； A.137.b.46.i；A.138.b.46.i；A.139.b.46.i；A.140.b.46.i；A.141.b.46.i；A.2.b.47.i； A.3.b.47.i；A.4.b.47.i；A.5.b.47.i；A.7.b.47.i；A.9.b.47.i；A.100.b.47.i；A.101.b.47.i； A.102.b.47.i；A.103.b.47.i；A.104.b.47.i；A.105.b.47.i；A.106.b.47.i；A.107.b.47.i； A.108.b.47.i；A.109.b.47.i；A.110.b.47.i；A.111.b.47.i；A.112.b.47.i；A.113.b.47.i； A.114.b.47.i；A.115.b.47.i；A.116.b.47.i；A.117.b.47.i；A.118.b.47.i；A.119.b.47.i； A.120.b.47.i；A.121.b.47.i；A.122.b.47.i；A.123.b.47.i；A.124.b.47.i；A.125.b.47.i； A.126.b.47.i；A.127.b.47.i；A.128.b.47.i；A.129.b.47.i；A.130.b.47.i；A.131.b.47.i； A.132.b.47.i；A.133.b.47.i；A.134.b.47.i；A.135.b.47.i；A.136.b.47.i；A.137.b.47.i； A.138.b.47.i；A.139.b.47.i；A.140.b.47.i；A.141.b.47.i；A.2.b.48.i；A.3.b.48.i； A.4.b.48.i；A.5.b.48.i；A.7.b.48.i；A.9.b.48.i；A.100.b.48.i；A.101.b.48.i；A.102.b.48.i； A.103.b.48.i；A.104.b.48.i；A.105.b.48.i；A.106.b.48.i；A.107.b.48.i；A.108.b.48.i； A.109.b.48.i；A.110.b.48.i；A.111.b.48.i；A.112.b.48.i；A.113.b.48.i；A.114.b.48.i； A.115.b.48.i；A.116.b.48.i；A.117.b.48.i；A.118.b.48.i；A.119.b.48.i；A.120.b.48.i； A.121.b.48.i；A.122.b.48.i；A.123.b.48.i；A.124.b.48.i；A.125.b.48.i；A.126.b.48.i； A.127.b.48.i；A.128.b.48.i；A.129.b.48.i；A.130.b.48.i；A.131.b.48.i；A.132.b.48.i； A.133.b.48.i；A.134.b.48.i；A.135.b.48.i；A.136.b.48.i；A.137.b.48.i；A.138.b.48.i； A.139.b.48.i；A.140.b.48.i；A.141.b.48.i；A.2.b.49.i；A.3.b.49.i；A.4.b.49.i；A.5.b.49.i； A.7.b.49.i；A.9.b.49.i；A.100.b.49.i；A.101.b.49.i；A.102.b.49.i；A.103.b.49.i；A.104.b.49.i；A.105.b.49.i；A.106.b.49.i；A.107.b.49.i；A.108.b.49.i；A.109.b.49.i； A.110.b.49.i；A.111.b.49.i；A.112.b.49.i；A.113.b.49.i；A.114.b.49.i；A.115.b.49.i； A.116.b.49.i；A.117.b.49.i；A.118.b.49.i；A.119.b.49.i；A.120.b.49.i；A.121.b.49.i； A.122.b.49.i；A.123.b.49.i；A.124.b.49.i；A.125.b.49.i；A.126.b.49.i；A.127.b.49.i； A.128.b.49.i；A.129.b.49.i；A.130.b.49.i；A.131.b.49.i；A.132.b.49.i；A.133.b.49.i； A.134.b.49.i；A.135.b.49.i；A.136.b.49.i；A.137.b.49.i；A.138.b.49.i；A.139.b.49.i； A.140.b.49.i；A.141.b.49.i；A.2.b.50.i；A.3.b.50.i；A.4.b.50.i；A.5.b.50.i；A.7.b.50.i； A.9.b.50.i；A.100.b.50.i；A.101.b.50.i；A.102.b.50.i；A.103.b.50.i；A.104.b.50.i； A.105.b.50.i；A.106.b.50.i；A.107.b.50.i；A.108.b.50.i；A.109.b.50.i；A.110.b.50.i； A.111.b.50.i；A.112.b.50.i；A.113.b.50.i；A.114.b.50.i；A.115.b.50.i；A.116.b.50.i； A.117.b.50.i；A.118.b.50.i；A.119.b.50.i；A.120.b.50.i；A.121.b.50.i；A.122.b.50.i； A.123.b.50.i；A.124.b.50.i；A.125.b.50.i；A.126.b.50.i；A.127.b.50.i；A.128.b.50.i； A.129.b.50.i；A.130.b.50.i；A.131.b.50.i；A.132.b.50.i；A.133.b.50.i；A.134.b.50.i； A.135.b.50.i；A.136.b.50.i；A.137.b.50.i；A.138.b.50.i；A.139.b.50.i；A.140.b.50.i； A.141.b.50.i；A.2.b.51.i；A.3.b.51.i；A.4.b.51.i；A.5.b.51.i；A.7.b.51.i；A.9.b.51.i； A.100.b.51.i；A.101.b.51.i；A.102.b.51.i；A.103.b.51.i；A.104.b.51.i；A.105.b.51.i； A.106.b.51.i；A.107.b.51.i；A.108.b.51.i；A.109.b.51.i；A.110.b.51.i；A.111.b.51.i； A.112.b.51.i；A.113.b.51.i；A.114.b.51.i；A.115.b.51.i；A.116.b.51.i；A.117.b.51.i； A.118.b.51.i；A.119.b.51.i；A.120.b.51.i；A.121.b.51.i；A.122.b.51.i；A.123.b.51.i； A.124.b.51.i；A.125.b.51.i；A.126.b.51.i；A.127.b.51.i；A.128.b.51.i；A.129.b.51.i； A.130.b.51.i；A.131.b.51.i；A.132.b.51.i；A.133.b.51.i；A.134.b.51.i；A.135.b.51.i； A.136.b.51.i；A.137.b.51.i；A.138.b.51.i；A.139.b.51.i；A.140.b.51.i；A.141.b.51.i； A.2.x.46.i；A.3.x.46.i；A.4.x.46.i；A.5.x.46.i；A.7.x.46.i；A.9.x.46.i；A.100.x.46.i； A.101.x.46.i；A.102.x.46.i；A.103.x.46.i；A.104.x.46.i；A.105.x.46.i；A.106.x.46.i； A.107.x.46.i；A.108.x.46.i；A.109.x.46.i；A.110.x.46.i；A.111.x.46.i；A.112.x.46.i； A.113.x.46.i；A.114.x.46.i；A.115.x.46.i；A.116.x.46.i；A.117.x.46.i；A.118.x.46.i； A.119.x.46.i；A.120.x.46.i；A.121.x.46.i；A.122.x.46.i；A.123.x.46.i；A.124.x.46.i； A.125.x.46.i；A.126.x.46.i；A.127.x.46.i；A.128.x.46.i；A.129.x.46.i；A.130.x.46.i； A.131.x.46.i；A.132.x.46.i；A.133.x.46.i；A.134.x.46.i；A.135.x.46.i；A.136.x.46.i； A.137.x.46.i；A.138.x.46.i；A.139.x.46.i；A.140.x.46.i；A.141.x.46.i；A.2.x.47.i； A.3.x.47.i；A.4.x.47.i；A.5.x.47.i；A.7.x.47.i；A.9.x.47.i；A.100.x.47.i；A.101.x.47.i； A.102.x.47.i；A.103.x.47.i；A.104.x.47.i；A.105.x.47.i；A.106.x.47.i；A.107.x.47.i； A.108.x.47.i；A.109.x.47.i；A.110.x.47.i；A.111.x.47.i；A.112.x.47.i；A.113.x.47.i； A.114.x.47.i；A.115.x.47.i；A.116.x.47.i；A.117.x.47.i；A.118.x.47.i；A.119.x.47.i； A.120.x.47.i；A.121.x.47.i；A.122.x.47.i；A.123.x.47.i；A.124.x.47.i；A.125.x.47.i； A.126.x.47.i；A.127.x.47.i；A.128.x.47.i；A.129.x.47.i；A.130.x.47.i；A.131.x.47.i； A.132.x.47.i；A.133.x.47.i；A.134.x.47.i；A.135.x.47.i；A.136.x.47.i；A.137.x.47.i； A.138.x.47.i；A.139.x.47.i；A.140.x.47.i；A.141.x.47.i；A.2.x.48.i；A.3.x.48.i； A.4.x.48.i；A.5.x.48.i；A.7.x.48.i；A.9.x.48.i；A.100.x.48.i；A.101.x.48.i；A.102.x.48.i； A.103.x.48.i；A.104.x.48.i；A.105.x.48.i；A.106.x.48.i；A.107.x.48.i；A.108.x.48.i； A.109.x.48.i；A.110.x.48.i；A.111.x.48.i；A.112.x.48.i；A.113.x.48.i；A.114.x.48.i； A.115.x.48.i；A.116.x.48.i；A.117.x.48.i；A.118.x.48.i；A.119.x.48.i；A.120.x.48.i； A.121.x.48.i；A.122.x.48.i；A.123.x.48.i；A.124.x.48.i；A.125.x.48.i；A.126.x.48.i； A.127.x.48.i；A.128.x.48.i；A.129.x.48.i；A.130.x.48.i；A.131.x.48.i；A.132.x.48.i； A.133.x.48.i；A.134.x.48.i；A.135.x.48.i；A.136.x.48.i；A.137.x.48.i；A.138.x.48.i； A.139.x.48.i；A.140.x.48.i；A.141.x.48.i；A.2.x.49.i；A.3.x.49.i；A.4.x.49.i；A.5.x.49.i； A.7.x.49.i；A.9.x.49.i；A.100.x.49.i；A.101.x.49.i；A.102.x.49.i；A.103.x.49.i；A.104.x.49.i；A.105.x.49.i；A.106.x.49.i；A.107.x.49.i；A.108.x.49.i；A.109.x.49.i； A.110.x.49.i；A.111.x.49.i；A.112.x.49.i；A.113.x.49.i；A.114.x.49.i；A.115.x.49.i； A.116.x.49.i；A.117.x.49.i；A.118.x.49.i；A.119.x.49.i；A.120.x.49.i；A.121.x.49.i； A.122.x.49.i；A.123.x.49.i；A.124.x.49.i；A.125.x.49.i；A.126.x.49.i；A.127.x.49.i； A.128.x.49.i；A.129.x.49.i；A.130.x.49.i；A.131.x.49.i；A.132.x.49.i；A.133.x.49.i； A.134.x.49.i；A.135.x.49.i；A.136.x.49.i；A.137.x.49.i；A.138.x.49.i；A.139.x.49.i； A.140.x.49.i；A.141.x.49.i；A.2.x.50.i；A.3.x.50.i；A.4.x.50.i；A.5.x.50.i；A.7.x.50.i； A.9.x.50.i；A.100.x.50.i；A.101.x.50.i；A.102.x.50.i；A.103.x.50.i；A.104.x.50.i； A.105.x.50.i；A.106.x.50.i；A.107.x.50.i；A.108.x.50.i；A.109.x.50.i；A.110.x.50.i； A.111.x.50.i；A.112.x.50.i；A.113.x.50.i；A.114.x.50.i；A.115.x.50.i；A.116.x.50.i； A.117.x.50.i；A.118.x.50.i；A.119.x.50.i；A.120.x.50.i；A.121.x.50.i；A.122.x.50.i； A.123.x.50.i；A.124.x.50.i；A.125.x.50.i；A.126.x.50.i；A.127.x.50.i；A.128.x.50.i； A.129.x.50.i；A.130.x.50.i；A.131.x.50.i；A.132.x.50.i；A.133.x.50.i；A.134.x.50.i； A.135.x.50.i；A.136.x.50.i；A.137.x.50.i；A.138.x.50.i；A.139.x.50.i；A.140.x.50.i； A.141.x.50.i；A.2.x.51.i；A.3.x.51.i；A.4.x.51.i；A.5.x.51.i；A.7.x.51.i；A.9.x.51.i； A.100.x.51.i；A.101.x.51.i；A.102.x.51.i；A.103.x.51.i；A.104.x.51.i；A.105.x.51.i； A.106.x.51.i；A.107.x.51.i；A.108.x.51.i；A.109.x.51.i；A.110.x.51.i；A.111.x.51.i； A.112.x.51.i；A.113.x.51.i；A.114.x.51.i；A.115.x.51.i；A.116.x.51.i；A.117.x.51.i； A.118.x.51.i；A.119.x.51.i；A.120.x.51.i；A.121.x.51.i；A.122.x.51.i；A.123.x.51.i； A.124.x.51.i；A.125.x.51.i；A.126.x.51.i；A.127.x.51.i；A.128.x.51.i；A.129.x.51.i； A.130.x.51.i；A.131.x.51.i；A.132.x.51.i；A.133.x.51.i；A.134.x.51.i；A.135.x.51.i； A.136.x.51.i；A.137.x.51.i；A.138.x.51.i；A.139.x.51.i；A.140.x.51.i；A.141.x.51.i； A.2.y.46.i；A.3.y.46.i；A.4.y.46.i；A.5.y.46.i；A.7.y.46.i；A.9.y.46.i；A.100.y.46.i； A.101.y.46.i；A.102.y.46.i；A.103.y.46.i；A.104.y.46.i；A.105.y.46.i；A.106.y.46.i； A.107.y.46.i；A.108.y.46.i；A.109.y.46.i；A.110.y.46.i；A.111.y.46.i；A.112.y.46.i； A.113.y.46.i；A.114.y.46.i；A.115.y.46.i；A.116.y.46.i；A.117.y.46.i；A.118.y.46.i； A.119.y.46.i；A.120.y.46.i；A.121.y.46.i；A.122.y.46.i；A.123.y.46.i；A.124.y.46.i； A.125.y.46.i；A.126.y.46.i；A.127.y.46.i；A.128.y.46.i；A.129.y.46.i；A.130.y.46.i； A.131.y.46.i；A.132.y.46.i；A.133.y.46.i；A.134.y.46.i；A.135.y.46.i；A.136.y.46.i； A.137.y.46.i；A.138.y.46.i；A.139.y.46.i；A.140.y.46.i；A.141.y.46.i；A.2.y.47.i； A.3.y.47.i；A.4.y.47.i；A.5.y.47.i；A.7.y.47.i；A.9.y.47.i；A.100.y.47.i；A.101.y.47.i； A.102.y.47.i；A.103.y.47.i；A.104.y.47.i；A.105.y.47.i；A.106.y.47.i；A.107.y.47.i； A.108.y.47.i；A.109.y.47.i；A.110.y.47.i；A.111.y.47.i；A.112.y.47.i；A.113.y.47.i； A.114.y.47.i；A.115.y.47.i；A.116.y.47.i；A.117.y.47.i；A.118.y.47.i；A.119.y.47.i； A.120.y.47.i；A.121.y.47.i；A.122.y.47.i；A.123.y.47.i；A.124.y.47.i；A.125.y.47.i； A.126.y.47.i；A.127.y.47.i；A.128.y.47.i；A.129.y.47.i；A.130.y.47.i；A.131.y.47.i； A.132.y.47.i；A.133.y.47.i；A.134.y.47.i；A.135.y.47.i；A.136.y.47.i；A.137.y.47.i； A.138.y.47.i；A.139.y.47.i；A.140.y.47.i；A.141.y.47.i；A.2.y.48.i；A.3.y.48.i； A.4.y.48.i；A.5.y.48.i；A.7.y.48.i；A.9.y.48.i；A.100.y.48.i；A.101.y.48.i；A.102.y.48.i； A.103.y.48.i；A.104.y.48.i；A.105.y.48.i；A.106.y.48.i；A.107.y.48.i；A.108.y.48.i； A.109.y.48.i；A.110.y.48.i；A.111.y.48.i；A.112.y.48.i；A.113.y.48.i；A.114.y.48.i； A.115.y.48.i；A.116.y.48.i；A.117.y.48.i；A.118.y.48.i；A.119.y.48.i；A.120.y.48.i； A.121.y.48.i；A.122.y.48.i；A.123.y.48.i；A.124.y.48.i；A.125.y.48.i；A.126.y.48.i； A.127.y.48.i；A.128.y.48.i；A.129.y.48.i；A.130.y.48.i；A.131.y.48.i；A.132.y.48.i； A.133.y.48.i；A.134.y.48.i；A.135.y.48.i；A.136.y.48.i；A.137.y.48.i；A.138.y.48.i； A.139.y.48.i；A.140.y.48.i；A.141.y.48.i；A.2.y.49.i；A.3.y.49.i；A.4.y.49.i；A.5.y.49.i； A.7.y.49.i；A.9.y.49.i；A.100.y.49.i；A.101.y.49.i；A.102.y.49.i；A.103.y.49.i；A.104.y.49.i；A.105.y.49.i；A.106.y.49.i；A.107.y.49.i；A.108.y.49.i；A.109.y.49.i； A.110.y.49.i；A.111.y.49.i；A.112.y.49.i；A.113.y.49.i；A.114.y.49.i；A.115.y.49.i； A.116.y.49.i；A.117.y.49.i；A.118.y.49.i；A.119.y.49.i；A.120.y.49.i；A.121.y.49.i； A.122.y.49.i；A.123.y.49.i；A.124.y.49.i；A.125.y.49.i；A.126.y.49.i；A.127.y.49.i； A.128.y.49.i；A.129.y.49.i；A.130.y.49.i；A.131.y.49.i；A.132.y.49.i；A.133.y.49.i； A.134.y.49.i；A.135.y.49.i；A.136.y.49.i；A.137.y.49.i；A.138.y.49.i；A.139.y.49.i； A.140.y.49.i；A.141.y.49.i；A.2.y.50.i；A.3.y.50.i；A.4.y.50.i；A.5.y.50.i；A.7.y.50.i； A.9.y.50.i；A.100.y.50.i；A.101.y.50.i；A.102.y.50.i；A.103.y.50.i；A.104.y.50.i； A.105.y.50.i；A.106.y.50.i；A.107.y.50.i；A.108.y.50.i；A.109.y.50.i；A.110.y.50.i； A.111.y.50.i；A.112.y.50.i；A.113.y.50.i；A.114.y.50.i；A.115.y.50.i；A.116.y.50.i； A.117.y.50.i；A.118.y.50.i；A.119.y.50.i；A.120.y.50.i；A.121.y.50.i；A.122.y.50.i； A.123.y.50.i；A.124.y.50.i；A.125.y.50.i；A.126.y.50.i；A.127.y.50.i；A.128.y.50.i； A.129.y.50.i；A.130.y.50.i；A.131.y.50.i；A.132.y.50.i；A.133.y.50.i；A.134.y.50.i； A.135.y.50.i；A.136.y.50.i；A.137.y.50.i；A.138.y.50.i；A.139.y.50.i；A.140.y.50.i； A.141.y.50.i；A.2.y.51.i；A.3.y.51.i；A.4.y.51.i；A.5.y.51.i；A.7.y.51.i；A.9.y.51.i； A.100.y.51.i；A.101.y.51.i；A.102.y.51.i；A.103.y.51.i；A.104.y.51.i；A.105.y.51.i； A.106.y.51.i；A.107.y.51.i；A.108.y.51.i；A.109.y.51.i；A.110.y.51.i；A.111.y.51.i； A.112.y.51.i；A.113.y.51.i；A.114.y.51.i；A.115.y.51.i；A.116.y.51.i；A.117.y.51.i； A.118.y.51.i；A.119.y.51.i；A.120.y.51.i；A.121.y.51.i；A.122.y.51.i；A.123.y.51.i； A.124.y.51.i；A.125.y.51.i；A.126.y.51.i；A.127.y.51.i；A.128.y.51.i；A.129.y.51.i； A.130.y.51.i；A.131.y.51.i；A.132.y.51.i；A.133.y.51.i；A.134.y.51.i；A.135.y.51.i； A.136.y.51.i；A.137.y.51.i；A.138.y.51.i；A.139.y.51.i；A.140.y.51.i；A.141.y.51.i； A.2.z.46.i；A.3.z.46.i；A.4.z.46.i；A.5.z.46.i；A.7.z.46.i；A.9.z.46.i；A.100.z.46.i； A.101.z.46.i；A.102.z.46.i；A.103.z.46.i；A.104.z.46.i；A.105.z.46.i；A.106.z.46.i； A.107.z.46.i；A.108.z.46.i；A.109.z.46.i；A.110.z.46.i；A.111.z.46.i；A.112.z.46.i； A.113.z.46.i；A.114.z.46.i；A.115.z.46.i；A.116.z.46.i；A.117.z.46.i；A.118.z.46.i； A.119.z.46.i；A.120.z.46.i；A.121.z.46.i；A.122.z.46.i；A.123.z.46.i；A.124.z.46.i； A.125.z.46.i；A.126.z.46.i；A.127.z.46.i；A.128.z.46.i；A.129.z.46.i；A.130.z.46.i； A.131.z.46.i；A.132.z.46.i；A.133.z.46.i；A.134.z.46.i；A.135.z.46.i；A.136.z.46.i； A.137.z.46.i；A.138.z.46.i；A.139.z.46.i；A.140.z.46.i；A.141.z.46.i；A.2.z.47.i； A.3.z.47.i；A.4.z.47.i；A.5.z.47.i；A.7.z.47.i；A.9.z.47.i；A.100.z.47.i；A.101.z.47.i； A.102.z.47.i；A.103.z.47.i；A.104.z.47.i；A.105.z.47.i；A.106.z.47.i；A.107.z.47.i； A.108.z.47.i；A.109.z.47.i；A.110.z.47.i；A.111.z.47.i；A.112.z.47.i；A.113.z.47.i； A.114.z.47.i；A.115.z.47.i；A.116.z.47.i；A.117.z.47.i；A.118.z.47.i；A.119.z.47.i； A.120.z.47.i；A.121.z.47.i；A.122.z.47.i；A.123.z.47.i；A.124.z.47.i；A.125.z.47.i； A.126.z.47.i；A.127.z.47.i；A.128.z.47.i；A.129.z.47.i；A.130.z.47.i；A.131.z.47.i； A.132.z.47.i；A.133.z.47.i；A.134.z.47.i；A.135.z.47.i；A.136.z.47.i；A.137.z.47.i； A.138.z.47.i；A.139.z.47.i；A.140.z.47.i；A.141.z.47.i；A.2.z.48.i；A.3.z.48.i； A.4.z.48.i；A.5.z.48.i；A.7.z.48.i；A.9.z.48.i；A.100.z.48.i；A.101.z.48.i；A.102.z.48.i； A.103.z.48.i；A.104.z.48.i；A.105.z.48.i；A.106.z.48.i；A.107.z.48.i；A.108.z.48.i； A.109.z.48.i；A.110.z.48.i；A.111.z.48.i；A.112.z.48.i；A.113.z.48.i；A.114.z.48.i； A.115.z.48.i；A.116.z.48.i；A.117.z.48.i；A.118.z.48.i；A.119.z.48.i；A.120.z.48.i； A.121.z.48.i；A.122.z.48.i；A.123.z.48.i；A.124.z.48.i；A.125.z.48.i；A.126.z.48.i； A.127.z.48.i；A.128.z.48.i；A.129.z.48.i；A.130.z.48.i；A.131.z.48.i；A.132.z.48.i； A.133.z.48.i；A.134.z.48.i；A.135.z.48.i；A.136.z.48.i；A.137.z.48.i；A.138.z.48.i； A.139z.48.i；A.140.z.48.i；A.141.z.48.i；A.2.z.49.i；A.3.z.49.i；A.4.z.49.i；A.5.z.49.i； A.7.z.49.i；A.9.z.49.i；A.100.z.49.i；A.101.z.49.i；A.102.z.49.i；A.103.z.49.i；A.104.z.49.i；A.105.z.49.i；A.106.z.49.i；A.107.z.49.i；A.108.z.49.i；A.109.z.49.i； A.110.z.49.i；A.111.z.49.i；A.112.z.49.i；A.113.z.49.i；A.114.z.49.i；A.115.z.49.i； A.116.z.49.i；A.117.z.49.i；A.118.z.49.i；A.119.z.49.i；A.120.z.49.i；A.121.z.49.i； A.122.z.49.i；A.123.z.49.i；A.124.z.49.i；A.125.z.49.i；A.126.z.49.i；A.127.z.49.i； A.128.z.49.i；A.129.z.49.i；A.130.z.49.i；A.131.z.49.i；A.132.z.49.i；A.133.z.49.i； A.134.z.49.i；A.135.z.49.i；A.136.z.49.i；A.137.z.49.i；A.138.z.49.i；A.139.z.49.i； A.140.z.49.i；A.141.z.49.i；A.2.z.50.i；A.3.z.50.i；A.4.z.50.i；A.5.z.50.i；A.7.z.50.i； A.9.z.50.i；A.100.z.50.i；A.101.z.50.i；A.102.z.50.i；A.103.z.50.i；A.104.z.50.i； A.105.z.50.i；A.106.z.50.i；A.107.z.50.i；A.108.z.50.i；A.109.z.50.i；A.110.z.50.i； A.111.z.50.i；A.112.z.50.i；A.113.z.50.i；A.114.z.50.i；A.115.z.50.i；A.116.z.50.i； A.117.z.50.i；A.118.z.50.i；A.119.z.50.i；A.120.z.50.i；A.121.z.50.i；A.122.z.50.i； A.123.z.50.i；A.124.z.50.i；A.125.z.50.i；A.126.z.50.i；A.127.z.50.i；A.128.z.50.i； A.129.z.50.i；A.130.z.50.i；A.131.z.50.i；A.132.z.50.i；A.133.z.50.i；A.134.z.50.i； A.135.z.50.i；A.136.z.50.i；A.137.z.50.i；A.138.z.50.i；A.139.z.50.i；A.140.z.50.i； A.141.z.50.i；A.2.z.51.i；A.3.z.51.i；A.4.z.51.i；A.5.z.51.i；A.7.z.51.i；A.9.z.51.i； A.100.z.51.i；A.101.z.51.i；A.102.z.51.i；A.103.z.51.i；A.104.z.51.i；A.105.z.51.i； A.106.z.51.i；A.107.z.51.i；A.108.z.51.i；A.109.z.51.i；A.110.z.51.i；A.111.z.51.i； A.112.z.51.i；A.113.z.51.i；A.114.z.51.i；A.115.z.51.i；A.116.z.51.i；A.117.z.51.i； A.118.z.51.i；A.119.z.51.i；A.120.z.51.i；A.121.z.51.i；A.122.z.51.i；A.123.z.51.i； A.124.z.51.i；A.125.z.51.i；A.126.z.51.i；A.127.z.51.i；A.128.z.51.i；A.129.z.51.i； A.130.z.51.i；A.131.z.51.i；A.132.z.51.i；A.133.z.51.i；A.134.z.51.i；A.135.z.51.i； A.136.z.51.i；A.137.z.51.i；A.138.z.51.i；A.139.z.51.i；A.140.z.51.i；A.141.z.51.i； A.2.A.46.i；A.3.A.46.i；A.4.A.46.i；A.5.A.46.i；A.7.A.46.i；A.9.A.46.i；A.100.A.46.i； 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A.138.C.51.i；A.139.C.51.i；A.140.C.51.i；A.141.C.51.i；A.2.D.46.i；A.3.D.46.i； A.4.D.46.i；A.5.D.46.i；A.7.D.46.i；A.9.D.46.i；A.100.D.46.i；A.101.D.46.i； A.102.D.46.i；A.103.D.46.i；A.104.D.46.i；A.105.D.46.i；A.106.D.46.i；A.107.D.46.i； A.108.D.46.i；A.109.D.46.i；A.110.D.46.i；A.111.D.46.i；A.112.D.46.i；A.113.D.46.i； A.114.D.46.i；A.115.D.46.i；A.116.D.46.i；A.117.D.46.i；A.118.D.46.i；A.119.D.46.i； A.120.D.46.i；A.121.D.46.i；A.122.D.46.i；A.123.D.46.i；A.124.D.46.i；A.125.D.46.i； A.126.D.46.i；A.127.D.46.i；A.128.D.46.i；A.129.D.46.i；A.130.D.46.i；A.131.D.46.i； A.132.D.46.i；A.133.D.46.i；A.134.D.46.i；A.135.D.46.i；A.136.D.46.i；A.137.D.46.i； A.138.D.46.i；A.139.D.46.i；A.140.D.46.i；A.141.D.46.i；A.2.D.47.i；A.3.D.47.i； A.4.D.47.i；A.5.D.47.i；A.7.D.47.i；A.9.D.47.i；A.100.D.47.i；A.101.D.47.i； A.102.D.47.i；A.103.D.47.i；A.104.D.47.i；A.105.D.47.i；A.106.D.47.i；A.107.D.47.i； A.108.D.47.i；A.109.D.47.i；A.110.D.47.i；A.111.D.47.i；A.112.D.47.i；A.113.D.47.i； 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A.138.D.51.i；A.139.D.51.i；A.140.D.51.i；A.141.D.51.i；A.2.E.46.i；A.3.E.46.i； A.4.E.46.i；A.5.E.46.i；A.7.E.46.i；A.9.E.46.i；A.100.E.46.i；A.101.E.46.i；A.102.E.46.i； A.103.E.46.i；A.104.E.46.i；A.105.E.46.i；A.106.E.46.i；A.107.E.46.i；A.108.E.46.i； A.109.E.46.i；A.110.E.46.i；A.111.E.46.i；A.112.E.46.i；A.113.E.46.i；A.114.E.46.i； A.115.E.46.i；A.116.E.46.i；A.117.E.46.i；A.118.E.46.i；A.119.E.46.i；A.120.E.46.i； A.121.E.46.i；A.122.E.46.i；A.123.E.46.i；A.124.E.46.i；A.125.E.46.i；A.126.E.46.i； A.127.E.46.i；A.128.E.46.i；A.129.E.46.i；A.130.E.46.i；A.131.E.46.i；A.132.E.46.i； A.133.E.46.i；A.134.E.46.i；A.135.E.46.i；A.136.E.46.i；A.137.E.46.i；A.138.E.46.i； A.139.E.46.i；A.140.E.46.i；A.141.E.46.i；A.2.E.47.i；A.3.E.47.i；A.4.E.47.i；A.5.E47.i； A.7.E.47.i；A.9.E.47.i；A.100.E.47.i；A.101.E.47.i；A.102.E.47.i；A.103.E.47.i； A.104.E.47.i；A.105.E.47.i；A.106.E.47.i；A.107.E.47.i；A.108.E.47.i；A.109.E.47.i； A.110.E.47.i；A.111.E.47.i；A.112.E.47.i；A.113.E.47.i；A.114.E.47.i；A.115.E.47.i； A.116.E.47.i；A.117.E.47.i；A.118.E.47.i；A.119.E.47.i；A.120.E.47.i；A.121.E.47.i； A.122.E.47.i；A.123.E.47.i；A.124.E.47.i；A.125.E.47.i；A.126.E.47.i；A.127.E.47.i； A.128.E.47.i；A.129.E.47.i；A.130.E.47.i；A.131.E.47.i；A.132.E.47.i；A.133.E.47.i； A.134.E.47.i；A.135.E.47.i；A 136.E.47.i；A.137.E.47.i；A.138.E.47.i；A.139.E.47.i； A.140.E.47.i；A.141.E.47.i；A.2.E.48.i；A.3.E.48.i；A.4.E.48.i；A.5.E.48.i；A.7.E.48.i； A.9.E.48.i；A.100.E.48.i；A.101.E.48.i；A.102.E.48.i；A.103.E.48.i；A.104.E.48.i； A.105.E.48.i；A.106.E.48.i；A.107.E.48.i；A.108.E.48.i；A.109.E.48.i；A.110.E.48.i； A.111.E.48.i；A.112.E.48.i；A.113.E.48.i；A.114.E.48.i；A.115.E.48.i；A.116.E.48.i； A.117.E.48.i；A.118.E.48.i；A.119.E.48.i；A.120.E.48.i；A.121.E.48.i；A.122.E.48.i； A.123.E.48.i；A.124.E.48.i；A.125.E.48.i；A.126.E.48.i；A.127.E.48.i；A.128.E.48.i；A.129.E.48.i；A.130.E.48.i；A.131.E.48.i；A.132.E.48.i；A.133.E.48.i；A.134.E.48.i； A.135.E.48.i；A.136.E.48.i；A.137.E.48.i；A.138.E.48.i；A.139.E.48.i；A.140.E.48.i； A.141.E.48.i；A.2.E.49.i；A.3.E.49.i；A.4.E.49.i；A.5.E.49.i；A.7.E.49.i；A.9.E.49.i； A.100.E.49.i；A.101.E.49.i；A.102.E.49.i；A.103.E.49.i；A.104.E.49.i；A.105.E.49.i； A.106.E.49.i；A.107.E.49.i；A.108.E.49.i；A.109.E.49.i；A.110.E.49.i；A.111.E.49.i； A.112.E.49.i；A.113.E.49.i；A.114.E.49.i；A.115.E.49.i；A.116.E.49.i；A.117.E.49.i； A.118.E.49.i；A.119.E.49.i；A.120.E.49.i；A.121.E.49.i；A.122.E.49.i；A.123.E.49.i； A.124.E.49.i；A.125.E.49.i；A.126.E.49.i；A.127.E.49.i；A.128.E.49.i；A.129.E.49.i； A.130.E.49.i；A.131.E.49.i；A.132.E.49.i；A.133.E.49.i；A.134.E.49.i；A.135.E.49.i； A.136.E.49.i；A.137.E.49.i；A.138.E.49.i；A.139.E.49.i；A.140.E.49.i；A.141.E.49.i； A.2.E.50.i；A.3.E.50.i；A.4.E.50.i；A.5.E.50.i；A.7.E.50.i；A.9.E.50.i；A.100.E.50.i； A.101.E.50.i；A.102.E.50.i；A.103.E.50.i；A.104.E.50.i；A.105.E.50.i；A.106.E.50.i； A.107.E.50.i；A.108.E.50.i；A.109.E.50.i；A.110.E.50.i；A.111.E.50.i；A.112.E.50.i； A.113.E.50.i；A.114.E.50.i；A.115.E.50.i；A.116.E.50.i；A.117.E.50.i；A.118.E.50.i； A.119.E.50.i；A.120.E.50.i；A.121.E.50.i；A.122.E.50.i；A.123.E.50.i；A.124.E.50.i； A.125.E.50.i；A.126.E.50.i；A.127.E.50.i；A.128.E.50.i；A.129.E.50.i；A.130.E.50.i； A.131.E.50.i；A.132.E.50.i；A.133.E.50.i；A.134.E.50.i；A.135.E.50.i；A.136.E.50.i； A.137.E.50.i；A.138.E.50.i；A.139.E.50.i；A.140.E.50.i；A.141.E.50.i；A.2.E.51.i； A.3.E.51.i；A.4.E.51.i；A.5.E.51.i；A.7.E.51.i；A.9.E.51.i；A.100.E.51.i；A.101.E.51.i； A.102.E.51.i；A.103.E.51.i；A.104.E.51.i；A.105.E.51.i；A.106.E.51.i；A.107.E.51.i； A.108.E.51.i；A.109.E.51.i；A.110.E.51.i；A.111.E.51.i；A.112.E.51.i；A.113.E.51.i； A.114.E.51.i；A.115.E.51.i；A.116.E.51.i；A.117.E.51.i；A.118.E.51.i；A.119.E.51.i； A.120.E.51.i；A.121.E.51.i；A.122.E.51.i；A.123.E.51.i；A.124.E.51.i；A.125.E.51.i； A.126.E.51.i；A.127.E.51.i；A.128.E.51.i；A.129.E.51.i；A.130.E.51.i；A.131.E.51.i； A.132.E.51.i；A.133.E.51.i；A.134.E.51.i；A.135.E.51.i；A.136.E.51.i；A.137.E.51.i； A.138.E.51.i；A.139.E51.i；A.140.E.51.i；A.141.E.51.i；A.2.F.46.i；A.3.F.46.i； A.4.F.46.i；A.5.F.46.i；A.7.F.46.i；A.9.F.46.i；A.100.F.46.i；A.101.F.46.i；A.102.F.46.i； A.103.F.46.i；A.104.F.46.i；A.105.F.46.i；A.106.F.46.i；A.107.F.46.i；A.108.F.46.i； A.109.F.46.i；A.110.F.46.i；A.111.F.46.i；A.112.F.46.i；A.113.F.46.i；A.114.F.46.i； A.115.F.46.i；A.116.F.46.i；A.117.F.46.i；A.118.F.46.i；A.119.F.46.i；A.120.F.46.i； A.121.F.46.i；A.122.F.46.i；A.123.F.46.i；A.124.F.46.i；A.125.F.46.i；A.126.F.46.i； A.127.F.46.i；A.128.F.46.i；A.129.F.46.i；A.130.F.46.i；A.131.F.46.i；A.132.F.46.i； A.133.F.46.i；A.134.F.46.i；A.135.F.46.i；A.136.F.46.i；A.137.F.46.i；A.138.F.46.i； A.139.F.46.i；A.140.F.46.i；A.141.F.46.i；A.2.F.47.i；A.3.F.47.i；A.4.F.47.i；A.5.F.47.i； A.7.F.47.i；A.9.F.47.i；A.100.F.47.i；A.101.F.47.i；A.102.F.47.i；A.103.F.47.i； A.104.F.47.i；A.105.F.47.i；A.106.F.47.i；A.107.F.47.i；A.108.F.47.i；A.109.F.47.i； A.110.F.47.i；A.111.F.47.i；A.112.F.47.i；A.113.F.47.i；A.114.F.47.i；A.115.F.47.i； A.116.F.47.i；A.117.F.47.i；A.118.F.47.i；A.119.F.47.i；A.120.F.47.i；A.121.F.47.i； A.122.F.47.i；A.123.F.47.i；A.124.F.47.i；A.125.F.47.i；A.126.F.47.i；A.127.F.47.i； A.128.F.47.i；A.129.F.47.i；A.130.F.47.i；A.131.F.47.i；A.132.F.47.i；A.133.F.47.i； A.134.F.47.i；A.135.F.47.i；A.136.F.47.i；A.137.F.47.i；A.138.F.47.i；A.139.F.47.i； A.140.F.47.i；A.141.F.47.i；A.2.F.48.i；A.3.F.48.i；A.4.F.48.i；A.5.F.48.i；A.7.F.48.i； A.9.F.48.i；A.100.F.48.i；A.101.F.48.i；A.102.F.48.i；A.103.F.48.i；A.104.F.48.i； A.105.F.48.i；A.106.F.48.i；A.107.F.48.i；A.108.F.48.i；A.109.F.48.i；A.110.F.48.i； A.111.F.48.i；A.112.F.48.i；A.113.F.48.i；A.114.F.48.i；A.115.F.48.i；A.116.F.48.i； A.117.F.48.i；A.118.F.48.i；A.119.F.48.i；A.120.F.48.i；A.121.F.48.i；A.122.F.48.i； A.123.F.48.i；A.124.F.48.i；A.125.F.48.i；A.126.F.48.i；A.127.F.48.i；A.128.F.48.i；A.129.F.48.i；A.130.F.48.i；A.131.F.48.i；A.132.F.48.i；A.133.F.48.i；A.134.F.48.i； A.135.F.48.i；A.136.F.48.i；A.137.F.48.i；A.138.F.48.i；A.139.F.48.i；A.140.F.48.i； A.141.F.48.i；A.2.F.49.i；A.3.F.49.i；A.4.F.49.i；A.5.F.49.i；A.7.F.49.i；A.9.F.49.i； A.100.F.49.i；A.101.F.49.i；A.102.F.49.i；A.103.F.49.i；A.104.F.49.i；A.105.F.49.i； A.106.F.49.i；A.107.F.49.i；A.108.F.49.i；A.109.F.49.i；A.110.F.49.i；A.111.F.49.i； A.112.F.49.i；A.113.F.49.i；A.114.F.49.i；A.115.F.49.i；A.116.F.49.i；A.117.F.49.i； A.118.F.49.i；A.119.F.49.i；A.120.F.49.i；A.121.F.49.i；A.122.F.49.i；A.123.F.49.i； A.124.F.49.i；A.125.F.49.i；A.126.F.49.i；A.127.F.49.i；A.128.F.49.i；A.129.F.49.i； A.130.F.49.i；A.131.F.49.i；A.132.F.49.i；A.133.F.49.i；A.134.F.49.i；A.135.F.49.i； A.136.F.49.i；A.137.F.49.i；A.138.F.49.i；A.139.F.49.i；A.140.F.49.i；A.141.F.49.i； A.2.F.50.i；A.3.F.50.i；A.4.F.50.i；A.5.F.50.i；A.7.F.50.i；A.9.F.50.i；A.100.F.50.i； A.101.F.50.i；A.102.F.50.i；A.103.F.50.i；A.104.F.50.i；A.105.F.50.i；A.106.F.50.i； A.107.F.50.i；A.108.F.50.i；A.109.F.50.i；A.110.F.50.i；A.111.F.50.i；A.112.F.50.i； A.113.F.50.i；A.114.F.50.i；A.115.F.50.i；A.116.F.50.i；A.117.F.50.i；A.118.F.50.i； A.119.F.50.i；A.120.F.50.i；A.121.F.50.i；A.122.F.50.i；A.123.F.50.i；A.124.F.50.i； A.125.F.50.i；A.126.F.50.i；A.127.F.50.i；A.128.F.50.i；A.129.F.50.i；A.130.F.50.i； A.131.F.50.i；A.132.F.50.i；A.133.F.50.i；A.134.F.50.i；A.135.F.50.i；A.136.F.50.i； A.137.F.50.i；A.138.F.50.i；A.139.F.50.i；A.140.F.50.i；A.141.F.50.i；A.2.F.51.i； A.3.F.51.i；A.4.F.51.i；A.5.F.51.i；A.7.F.51.i；A.9.F.51.i；A.100.F.51.i；A.101.F.51.i； A.102.F.51.i；A.103.F.51.i；A.104.F.51.i；A.105.F.51.i；A.106.F.51.i；A.107.F.51.i； A.108.F.51.i；A.109.F.51.i；A.110.F.51.i；A.111.F.51.i；A.112.F.51.i；A.113.F.51.i； A.114.F.51.i；A.115.F.51.i；A.116.F.51.i；A.117.F.51.i；A.118.F.51.i；A.119.F.51.i； A.120.F.51.i；A.121.F.51.i；A.122.F.51.i；A.123.F.51.i；A.124.F.51.i；A.125.F.51.i； A.126.F.51.i；A.127.F.51.i；A.128.F.51.i；A.129.F.51.i；A.130.F.51.i；A.131.F.51.i； A.132.F.51.i；A.133.F.51.i；A.134.F.51.i；A.135.F.51.i；A.136.F.51.i；A.137.F.51.i； A.138.F.51.i；A.139.F.51.i；A.140.F.51.i；A.141.F.51.i；
Salt and hydrate
The present composition at random contains the salt of this paper compound, particularly medical acceptable non-toxic salt, and it for example contains, Na +, Li +, K +, Ca ++With Mg ++This type of salt also can comprise that those derive from and mix suitable positively charged ion (as alkalimetal ion, alkaline-earth metal ions or ammonium ion and amino ion of season) and partly (be typically W with acid anion 1Carboxylic acid) salt.Then be preferably monovalent salt if be contemplated to water-soluble salt.
Typically, make metal-salt with the reaction of metal hydroxides and The compounds of this invention.The example of the metal-salt made from this method is for containing Li +, Na +With K +Salt.Add from the easy solution of molten salt that suitable metallic compound is precipitable to go out more insoluble metal-salt.
In addition, also can (be preferably G by adding the acid to alkaline center 1Amine) or to acidic-group (as E 1) and form salt, for example, some organic acid and mineral acid (as, HCl, HBr, H 2SO 4) or organic sulfonic acid.At last, should be understood that The compounds of this invention that this paper composition comprises can be not dissociate, or be zwitterionic form, or in the example of hydrate, be mixed with stoichiometric water.
Also comprise within the scope of the present invention be parent compound and one or more amino acid whose salt.Any above-mentioned amino acid all is suitable for, and particularly as the naturally occurring amino acid of protein composition, but this amino acid is preferably the amino acid that has the side chain that contains alkalescence or acidic-group, as, Methionin, arginine or L-glutamic acid, or have the amino acid of neutral group, as, glycine, Serine, Threonine, L-Ala, Isoleucine or leucine.
The inhibition method of neuraminidase
The present invention relates on the other hand and suppresses the active method of neuraminidase, and it comprises the step of handling the sample that may contain neuraminidase with The compounds of this invention.
The present composition is as the inhibitor of neuraminidase, the intermediate of this type of inhibitor or have following purposes.This inhibitor is bonded on the neuraminidase surface or the position in the hole (this position has the structure that neuraminidase only just has).Composition and combining of neuraminidase have reversibility in various degree.Those in fact the compound of irreversible fixation be the desirable material that is used for the inventive method.In case behind the mark, this in fact the composition of irreversible fixation can be used as the probe that detects neuraminidase.Therefore, the present invention relates to detect the method for the neuraminidase in the sample that may contain neuraminidase, it comprises the steps: with containing bond may contain neuraminidase to the compositions-treated of the The compounds of this invention of marker (label) sample; Observe sample to the active effect of marker.Suitable marker is known for the diagnosis circle, comprises stable free radical, fluorophore, radio isotope, enzyme, chemiluminescent groups and chromophoric group.This paper compound gives mark with functional group (as hydroxyl or amino) with ordinary method.
In the present invention, the sample that may contain neuraminidase comprises natural or artificial material, as live body; Tissue or cell culture; Biological material is as biomass sample (blood, serum, urine, celiolymph, tear, phlegm, saliva, tissue sample etc.); Laboratory sample; Food, water or air sample; The biological products sample is as cell extraction thing, particularly reconstitution cell (it can synthesize expection glycoprotein) etc.Typically, possible sample is to contain the organism that can produce neuraminidase, pathogenicity bo organism normally, for example, virus.Sample can be contained in the medium of any moisture and organic solvent/water mixture.Sample comprises organism alive, as the mankind or manmade materials, as cell culture.
Treatment step of the present invention comprises the present composition is added in the sample, or the precursor of said composition is added in the sample.This adds step and comprises any above-mentioned application process.
If need, use active available any method (comprise directly with indirect neuraminidase detection method) observation of the neuraminidase behind the composition.Quantitatively, qualitative and semiquantitative neuraminidase activity detection is all available.Typically, use in the above-mentioned sieve method any, but also available any other method, for example, to the observation method of live body physiological property.
The organism that contains neuraminidase comprises bacterium (vibrio cholerae, clostridium perfringens, streptococcus pneumoniae and Arthrobacter sialophilus) and virus (particularly orthomyxovirus or Paramyxo virus, as influenza virus A and B, parainfluenza virus, mumps virus, ewcastle disease virus, the poultry plague virus is with sendai virus).The active restraining effect of neuraminidase that takes place in these organisms or find is all in the object of the invention.The virusology of influenza virus is of " Fundamental Virology " (Raven Press, New York, 1986) the 24th chapter.The compounds of this invention can be used for treating or preventing this type of infection of animal or human's class, and aforementioned examples of animals has duck, rodent or pig.
Yet when screening can suppress the compound of influenza virus, should keep the enzyme analytical results firmly in mind might not be consistent with the cell culture analytical results, as people such as Chandler, The same, table 1 shown in.So should be with spot regression analysis (plaque reduction assay) as main screening method.
The screening of neuraminidase inhibitor
Be used for assessing the inhibition activity of the technology screening present composition of enzymic activity so that routine is any to neuraminidase.In this article, typically the screening composition is used for the vitro inhibition neuraminidase earlier, has the active composition of inhibition and screens its activity in vivo again.External Ki (inhibition constant) is lower than about 5 * 10 -6M better is lower than about 1 * 10 -7M better is lower than about 5 * 10 -8M, composition preferable to using in the body.
Useful in-vitro screening is described in detail, so this paper repeats no more.
Itzstein, people such as M.von; " Nature ", 363 (6428): 418-423 (1933), particularly the 420th page of the 2nd hurdle the 3rd full section to the 421st page of the 2nd hurdle the 1st section have illustrated people such as Potier M.; " Analyt.Biochem. ", a kind of suitable analyzed in vitro among the 94:287-296 (1979), this is analyzed and is Chong, people such as A.K.J.; " Biochem.Biophys.Acta ", 1077:65-71 (1991) improves, in addition, Colman, P.M. wait people's WO 92/06691 (Int.App.No.PCT/AU90/00501, open day on April 30th, 1992) to walk to the 35th page of the 16th another kind of useful in-vitro screening method of row explanation for the 34th page the 13rd.
Sieve method is also described in detail in the body, with reference to Itzstein, and people such as M.von; As indicated above, particularly the 421st page of the 2nd hurdle the 1st full section is to the 423rd page of the 2nd hurdle the 1st section, and Colman, people such as P.M.; As indicated above, the 36th page of 1-38 is capable, and it has illustrated suitable in-vitro screening method.
Pharmaceutical preparation and route of administration
The compounds of this invention is allocated with conventional carrier and vehicle, and this carrier and vehicle are selected by general practice.Tablet will comprise vehicle, glidant, filler, tackiness agent etc.Aqueous compositions is made sterile form, and if when desiring with non-orally using, normally isoosmotic.All prescriptions at random contain vehicle, as " Handbook of Pharmaceutical Excipients " (1986) described those.Vehicle comprises xitix and other antioxidants, as the sequestrant of ED-TA and so on, and carbohydrate, as dextrin, hydroxy alkyl cellulose, hydroxyalkyl methylcellulose gum, stearic acid etc.The pH of these prescriptions is about 3 to 11, but is generally about 7 to 10.
One or more compound of the present invention (being called activeconstituents herein) comes administration with the approach that is suitable for symptom to be treated.Suitable route comprises per os, per rectum, intranasal, local (comprising cheek and hypogloeeis), transvaginal and parenteral (comprise subcutaneous, intramuscular, intravenously, intracutaneous, the interior and epidural of sheath) etc.Look the person's that is subjected to the medicine situation and different preferable approach are arranged.The advantage of The compounds of this invention is its oral biological usability, thus can oral administration, and needn't be via approach in the lung or in the nose.Unexpectedly, WO 91/16320, and the influenza of WO 92/06691 and United States Patent (USP) 5360817 emits compound, and successfully per os or intraperitoneal come administration.Embodiment 161 sees below.
Although can use activeconstituents separately, better be to use with pharmaceutical preparation.Preparation of the present invention, for animals or human comprises at least a activeconstituents as defined above, and one or more can accept carrier and other treatment composition arbitrarily.This carrier must be " acceptable ", can be compatible with other compositions of preparation and to being subjected to the medicine person is harmless.
Preparation comprises those that are fit to aforementioned route of administration, is to be unit dosage preferably, and any known method of its available pharmaceutical industry is made.Usually, can (Mack Publishing Co., Easton PA) learn these technology and preparation by Remington ' s Pharmaceuti-cal Sciences.These methods comprise the step that merges activeconstituents and carrier (constituting one or more ancillary component).Usually by mixed active composition evenly and fully and liquid vehicle or solid carrier fine powder or the two, then, if needs prepare preparation with this product moulding.
The present invention is suitable for oral preparation and makes the dispersive unit, as capsule, and cachet or tablet (it respectively contains the activeconstituents of predetermined amount); Powder or particle; Solution or suspension (in liquid, aqueous or on-aqueous liquid); Oil-in-water liq emulsion or water-in-oil-type liquid emulsion.Activeconstituents can be bolus, electuary or paste.
Tablet and is mixed with one or more ancillary components arbitrarily by compacting or molded forming.Compressed tablets is made by following: in suitable machine, compacting be free-flowing form activeconstituents (as, powder or particle), and be mixed with tackiness agent, lubricant, inert diluent, sanitas, tensio-active agent or dispersion agent arbitrarily.Molded tablet then is in suitable machine, and the mixture of the activeconstituents that humidifies with powdered and through inert liquid diluent gives molded forming.These tablets are dressing or indentation at random, and at random is modulated into and can slowly releases or control the activeconstituents of emitting wherein.
Be used for eye or other outside organizations (as, mouth or skin) infection the time, better use with topical ointment or creme, it for example contains 0.075 to 20%W/W activeconstituents, and (active principle that comprises is 0.1% to 20%, and be the cumulative amount of 0.1%W/W, as 0.6%W/W, 0.7%W/W etc.), be preferably 0.2 to 15%W/W, be preferably 0.5 to 10%W/W.When being modulated into ointment, this activeconstituents can and be used with paraffin or the miscible ointment base of water.In addition, this activeconstituents also can be modulated into creme with oil-in-water cream base.
If need, the water of cream base can comprise, for example, and 30%W/W polyhydroxy-alcohol at least, the alcohol that promptly has two or more hydroxyls, for example, propylene glycol, butane-1, the 3-glycol, N.F,USP MANNITOL, Sorbitol Powder, glycerine and polyoxyethylene glycol (comprising PEG 400) and composition thereof.Local prescription better contain can the enhanced activity composition via the compound of the absorption or the infiltration of skin or other affected area.This type of example of wearing the skin penetration enhancers comprises dimethyl sulfoxide (DMSO) and related analogs.
The oil phase of emulsion of the present invention can be grouped into known one-tenth by known way.Although this mutually can only comprise emulsifying agent, better be the mixture that comprises at least a emulsifying agent and fat or oil (or fat and oily the two).Preferred hydrophilic emulsifying agent and lipophilic emulsifier (as stablizer) are also used.Also preferred package oil scraper and fat the two.The emulsifying agent that contains or do not contain stablizer is formed so-called emulsifying wax, and wax is formed so-called emulsification ointment base with oil and fat, and it forms the oily disperse phase of creme.
Be applicable to that emulsifying agent and emulsion stabilizer that the present invention fills a prescription comprise Tween _69, Span _80, cetostearyl alcohol, benzylalcohol, tetradecyl alcohol, Zerol and Sodium Lauryl Sulphate BP/USP.
Oil that this prescription is suitable for or fat are looked required cosmetic character and are selected.Creme is preferably non-greasy, the product that does not dye and can wash off, and have d spiss and can from pipe or in other containers, not leak out.Can use straight or branched, monobasic or binary alkyl ester, as two dissidents, two acid esters, different hexadecyl stearate, coconut fatty acid propylene glycol diesters, isopropyl myristic acid ester, Tegosoft DO, isopropyl cetylate, butyl stearate, the mixture of 2-ethylhexyl cetylate or branched ester (as Crodamol CAP), back three is preferable ester.Look required character, it can separately or merge use.Also available in addition high-melting fat is as white soft wax and/or whiteruss or other mineral oil.
The prescription that suitable part is used in eye also comprises eye drop, and wherein activeconstituents is dissolved in or is suspended in the suitable carrier, particularly in its water-containing solvent.The concentration of activeconstituents is preferably 0.5 to 20%w/w, and more preferably 0.5 to 10%, be preferably about 1.5%.
The prescription that suitable part is used in the mouth comprises: lozenge, and it comprises the activeconstituents that is contained in the flavoured base, this matrix is generally sucrose, gum arabic and tragacanth gum; Pastille, it comprises and is contained in inert base such as gelatin and glycerine, or the activeconstituents in sucrose and the gum arabic; And mouth-washes, it comprises the activeconstituents that is contained in the suitable liquid vehicle.
Rectum can be suppository form with prescription, is suitable for matrix with its blended and comprises for example theobroma oil or salicylate.
In the lung or nose (comprise particle diameter in 0.1 to 500 micrometer range, and be cumulative combination, for example for for example 0.1 to 500 micron with the particle diameter that has of filling a prescription, 0.5,1,30 micron, 35 microns etc.), it sucks fast via nasal passage or reaches alveolar sac via the mouth suction.Suitable prescription comprises the moisture or oily solution of activeconstituents.Be fit to make according to a conventional method, and can together use with other treatment agent (as the compound that is used for the treatment of before following or prevents influenza A or B to infect) with the prescription of aerosol or dry powder administration.
The prescription that is used for vagina administration can be made hysterophore, cotton wool, and creme, gel, paste, foam or spray composition form, it also contains the appropriate carriers that is known in the art except containing activeconstituents.
The prescription that is used for administered parenterally comprises moisture and non-water aseptic parenteral solution, and it can contain antioxidant, buffer substance, antibacterial substance and can make this prescription and be subjected to the medicine person's blood is isoosmotic solute; Moisture and non-water sterile suspensions, it can contain suspension agent and thickening material.
These prescriptions are presented in unitary dose or the multi-dose container, for example, and the ampoule of sealing and bottle, and can under lyophilisation condition, store, and only need add sterile liquid carrier more before use, and for example, water for injection.Jury injection liquid and suspension are by aseptic aforementioned powder, and particle or tablet are made.Preferable unitary dose prescription is for containing suitably those of activeconstituents of part amount of per daily dose or day time dose unit (as indicated above) or its.
Should be understood that the composition except above particularly pointing out, prescription of the present invention can comprise other reagent that are usually used in this prescription, and they need consider the type of described prescription, and for example, formula of oral just can contain seasonings.
The present invention also provides veterinary composition, and it comprises at least a above-mentioned activeconstituents and carrier for animals.
Carrier for animals is the material of the usefulness in order to use said composition, can be solid, liquid or gaseous matter, and for inertia or animal doctor circle can accept, and can be compatible with this activeconstituents.These veterinary compositions can per os, and the approach that parenteral or other are wanted comes administration.
The compounds of this invention can be used for providing and contains one or more The compounds of this invention as activeconstituents sustained release medicine ingredients (controlled release ingredients), the wherein release Be Controlled of activeconstituents and adjusting and needn't frequent drug administration, or improve the pharmacokinetics or the toxicity character of this activeconstituents.
The effective dose of activeconstituents is decided on following factor at least: the essence of desire treatment symptom, toxicity, this compound are used for still therapeutic activity influenza infection of prevention (than low dosage), application process, and the medicine ingredients, it can be studied according to the routine dose correction by the doctor and make.But projected dose is about 0.0001 to 100mg/kg body weight/day, is preferably about 0.01 to 10mg/kg body weight/day, and more preferably about 0.01 to 5mg/kg body weight/day is preferably about 0.05 to 0.5mg/kg body weight/day.For example, the adult of the about 70kg of a body weight is when with the suction medication, and the dosage of every day is 1mg to 1000mg, is preferably 5mg to 500mg, and can take by single or multiple dosage.
Activeconstituents of the present invention also can and be used with other activeconstituentss.This combination is according to desire treatment symptom, the pharmacological properties of the active and combination of the intersection between composition and determining.For example, when the virus infection that is used for the treatment of respiratory system, particularly during influenza infection, the present composition can with antiviral agent (as, amantadine (amantidine), Rimantadine and ribavirin), mucolytic agent, expectorant, bronchodilator, antibiotic, antipyretic or pain killer merge use.Usually, antibiotic, antipyretic and pain killer and The compounds of this invention are together used.
The meta-bolites of The compounds of this invention
The interior metabolism product of this paper compound also within the scope of the present invention, as long as this type of product is novel and non-apparent to prior art.This type of product can be by for example oxidation of administered compound, reduction, and hydrolysis, amidation, esterifications etc. obtain, and mainly are because enzyme is urged process.Therefore the present invention includes the novel and non-obvious compound of making by following method: make The compounds of this invention contact for some time and can produce its meta-bolites with mammal.Typically, by preparation earlier through radio-labeling (as, C 14Or H 3) The compounds of this invention, can detect dosage (as, usually greater than about 0.5mg/kg) compound through parenteral administration to animal (as, rat, mouse, cavy, monkey) or the people, after the time that metabolism is enough to take place, (typically be about 30 seconds to 30 hours),, isolate its converted product in blood or the other biological sample from urine.These products are because be labeled, so be easy to separate (isolating but other then utilize the antibody of epitope residual in the conjugated metabolite).The structure of meta-bolites in a usual manner, for example MS or NMR assay determination go out.Usually, the analysis of meta-bolites is carried out with conventional medicine metabolism research mode well known in the art.This converted product only otherwise its elsewhere is found in vivo, suppresses active even itself have neuraminidase, also can be used for the diagnositc analysis of The compounds of this invention treatment.
Other of The compounds of this invention are done the way
The compounds of this invention, or its biologically active substance that produces via hydrolysis in the body or metabolism can be used as immunogen or is used for and protein conjugation, promptly as the composition of immunogenic composition and prepare and to be bonded to this protein specifically, the antibody of this compound or its meta-bolites, aforementioned meta-bolites still keep the epitope (antibodies position) of immunogenicity identification.Intermediate when so this immunogenic composition can be used as this antibody (being used for the diagnosis of this compound or its novel meta-bolites, method or analyses such as quality control) preparation.This compound can be used for creating antagonism antibody of other non-immunogenic polypeptide, at this moment, these compounds are useed the haptens position as, stimulate the immune response with the cross reaction of the conjugated protein of non-modified.
Hydrolysate comprises above-mentioned acidity and basic group hydrolyzed product through protection preferably.As mentioned above, contain the acid or alkaline acid amides (, being fixed in the hemocyanin of keyhole) of immunogenic polypeptide usually as immunogen as, albumin.Above-mentioned meta-bolites can keep significance degree and immunity The compounds of this invention and intersect active.So antibody of the present invention can be bonded to the The compounds of this invention without protection, and can not be bonded to compound through protection; In addition, when meta-bolites was arranged, this antibody can be bonded to compound and/or the meta-bolites through protection, and can not be bonded to the The compounds of this invention through protection, or can be specifically with one of them or the three is whole combines.The expection of this antibody will be substantially not can with the crude substance cross reaction.The cross reactivity of essence refers to the reactivity under the specific analyte particular analysis condition of (it is enough to the interferometric analysis result).
Immunogen of the present invention comprises the The compounds of this invention that epitope is provided, and it is combined with immunogenic substance.In this article, this forms the immunogenic conjugate (when suitable) or the mixture of non-covalent binding substance in conjunction with the expression covalent attachment, or its combination.Immunogenic substance comprises auxiliary substance, and as the Freund auxiliary substance, immunogenic protein is as virus, bacterium, yeast, Plants and Animals polypeptide, particularly be fixed in the hemocyanin of keyhole, serum albumin, bovine thyroglobulin or Trypsin inhibitor SBTI and immunogenicity polysaccharide.Typically, the compound with required epitope structure by (being generally two functional groups) linking agent covalency conjugation of multiple functional radical to immunogenic polypeptide or polysaccharide.The immunogenic method of preparation haptens itself is common, be used for before any haptens conjugation to the method on the immunogenic polypeptide etc. also is applicable to this, consider the functional group's (it can be used for crosslinked) on parent or the hydrolysate and produce possibility the special antibody of described epitope (opposite) with immunogenic substance.
Typically, this polypeptide conjugation is to the position of The compounds of this invention away from epitope to be identified.
This conjugate is made with ordinary method.For example, available linking agent such as N-hydroxy-succinamide, succinyl oxide or alkyl-N=C=N-alkyl prepares conjugate of the present invention.This conjugate comprises The compounds of this invention, and it is with a key or C 1-C 100(better, C 1-C 25, better, C 1-C 10) connect base and be connected on the immunogenic substance.With methods such as chromatograms this conjugate is gone out from initiator and separation of by-products, sterile filtration then, bottling is stored.
The compounds of this invention comes crosslinked by any one or more following groups, for example, and U 1Hydroxyl, E 1Carboxyl, U 1, E 1, G 1Or T 1Carbon atom (replace H); G 1Amido.This compounds also comprises the acid amides of polypeptide, and wherein this polypeptide serves as above-mentioned R 6cOr R 6bGroup.
Typically, make animal be immunity to this immunogenic conjugate or derivative and the antiserum(antisera) of making in a usual manner or monosystem (monoclonal) antibody.
The compounds of this invention can be used for keeping the structural integrity of glycoprotein in the reconstitution cell culture, that is, it is added in the fermented product that glycoprotein generates and suppresses the catalytic fracture of the proteic neuraminidase of this desired sugars.This point in heterologous host cell, carry out protein be re-combined into particularly useful because this cell can partly be degraded the proteinic carbohydrate that synthesizes.
The compounds of this invention is polyfunctional.It can be used as a class special monomer of polymkeric substance when synthetic.And unrestricted, the polymkeric substance that The compounds of this invention is made comprises polymeric amide and polyester as an example.
The compounds of this invention is as making the monomer of the polymkeric substance with unique side functional group, and it can be used for homopolymer, or as with the non-scope of the invention in the comonomer of monomer copolymerization.The purposes of homopolymer that The compounds of this invention becomes has: in molecular sieve (polymeric amide), and fabric, fiber, film, when preparation such as forming composition is as cationite (polyester or polymeric amide), wherein acid functional group E 1By U 1In hydroxy esterification, so side chain basic group G 1Just can combine with acid functional groups, for example, the acid functional groups in the polypeptide of desiring to be purified.Polymeric amide is by E 1With G 1Crosslinked and form, and U 1Go up neighbouring part with ring and can free (look selected U as wetting ability or hydrophobic group 1And decide).The method itself of being made polymkeric substance by The compounds of this invention is known.
The compounds of this invention also can be used as the multifunctional tensio-active agent of a class uniqueness.Particularly work as U 1Do not contain the wetting ability substituting group, and during for for example alkyl or alkoxyl group, this compound has the character of difunctionality tensio-active agent.They itself have useful interfacial activity, and surface-coated is emulsion modified, rheological modification and surface wettability character.
When having ad hoc structure and having polarity and nonpolar part simultaneously, chemical combination of the present invention can be used as the consisting of phase-transferring agent of a class uniqueness.And unrestricted, The compounds of this invention can be used in phase-transfer catalysis and the liquid/liquid ion extractuin (LIX) as an example.
The compounds of this invention is in group U 1, E 1, G 1With T 1In can comprise unsymmetrical carbon arbitrarily, this moment, it can be the unique chiral adjuvant of a class that is used for the synthetic of other optically active substances or resolves.For example, the racemic mixture of carboxylic acid can resolve to its enantiomorph with laxative remedy: 1) with The compounds of this invention (U wherein 1Be asymmetric hydroxyl alkane or aminoalkyl) form the mixture of non-mapping ester or acid amides; 2) separate this diastereomer; 3) this ester structure of hydrolysis.Racemic alcohol is then used E 1Acidic group form ester and separate.In addition, this method also is used for resolving The compounds of this invention itself, if use this optical activity acid or alcohol to replace the racemize initiator.
The compounds of this invention can be used for the immobilized enzyme of process control at preparation affinity absorption base, or during immunological assay reagents, with connecting base or spacer.Compound herein comprises a plurality of functional groups, as the position of crosslinked expection material.For example, traditionally with affinity reagent, as hormone, peptide, antibody, bonds such as medicine are to insoluble matrix.Become insoluble reagent then to be used for from preparation with currently known methods, absorb in diagnosis sample or other the impure mixtures this affinity reagent in conjunction with the companion.Similarly, immobilized enzyme then is used for carrying out catalyzed conversion, and can reclaim enzyme simply.When the preparation diagnostic reagent, difunctional's compound is commonly used to analyte is linked to each other with detectable group.
Many functional groups can be used for crosslinked in the The compounds of this invention.E for example 1Carboxylic acid or phosphonate group can form ester or acid amides respectively with alcohol or the amine of desiring cross-linking reagent.The position that is fit to is through OH, NHR 1, SH, azido-(can become amino in crosslinked pre reduction), CN, NO if need 2, amino, guanidine radicals, the G that halogen etc. replace 1The position.When reacting,, reactive group can be given due care for preventing difunctional's compound of the present invention polymerization with linking agent.Usually the compound of this paper is bonded to first in conjunction with hydroxyl or amino on the companion via carboxylic acid or phosphonic acids, and then with T 1Or G 1Combine companion's covalent attachment with other and use.For example, first in conjunction with the carboxylic esterification of companion's (as, steroid hormone) with The compounds of this invention, and this conjugate is with G then 1Hydroxyl is cross-linked to the Sepaharose (agarose trade(brand)name) through cyanogen bromide-activated, so can get the immobilization steroid.Other chemical conjugates are known.Reference, Maggio for example, " Enzyme-Immunoas-say " (CRC, 1988,71-135 page or leaf) and the bibliography of being quoted from herein.
As mentioned above, the present invention treats useful compound (W wherein 1Or G 1Hydroxyl, carboxyl or amino protected) can make oral or slow release formulation.In these purposes, protection is based on being removed (for example, hydrolysis or oxidation), to generate free carboxy, amino or hydroxyl in the body.The ester or the acid amides that are suitable for this purposes are decided according to the substrate specificity of esterase and/or carboxypeptidase, and the expection in the cell that the precursor hydrolytic action is carried out of this enzyme can be found.If specificity the unknown of this enzyme then can be screened many The compounds of this invention, until the substrate specificity that finds expection.This can be learnt by the outward appearance or the antiviral activity of free cpds.Usually select the acid amides or the ester of The compounds of this invention with following two principles: (i) in last enteron aisle, be not hydrolyzed or slowly hydrolysis (ii) enteron aisle and cell permeability and (iii) hydrolysis in cytoplasm and/or systemic circulation.Preferred cell, for example pulmonary branches tunica mucosa tracheae during screening is analyzed with particular organization's (being subject to influenza infection).Analytical method known in the art can be used to measure biological available rate in the body, comprises enteric cavity stability, cell permeability, liver homogenate stability and plasma stability analysis.But even ester, acid amides or other derivatives through protection do not get transformed into free carboxy in vivo, amino or hydroxyl, and it still is useful chemical intermediate.
Make the exemplary method of The compounds of this invention
The invention still further relates to the method for making the present composition.Said composition is made by arbitrary Appropriate technology of organic synthesis.Many this kind technology are known in this area, manyly then are specified in: " Compendium of Organic Synthetic Methods " (John Wiley ﹠amp; Sons, New York), Vol.1, Ian T.Harrison and Shuyen Harri-son, 1971; Vol 2, Ina T.Harrison and Shuyen Harrison, 1974; Vol.3, Louis S.Hegedus and Leroy Wade, 1977; Vol.4, LeroyG.Wade, jr., 1980; Vol.5, Leroy G.Wade, Jr., 1984; AndVol.6 Michael B.Smith; And March., J., " Advanced OrganicChemistry, Third Edition ", (John Wiley ﹠amp; Sons, New York, 1985), " Comprehensive Organic.Synthesis.Selectivity, Strategy﹠amp; Efficiency in Modern Organic Chemistry.In 9 Volumes ", BarryM.Trost, Editor-in-Chief (Pergamon Press, New York, printing in 1993).
The exemplary method of the preparation present composition is as hereinafter contained, and it is used to illustrate the essence of these preparation methods, but not is used for restriction.
Usually, reaction conditions such as temperature, the reaction times, solvent, treatment steps etc. are well known in the art for pending specific reaction.The bibliography of citation comprises (comprising the wherein data of citation) detailed description of these conditions.Typically, temperature is-100 ℃ to 200 ℃, and solvent is non-proton or protonic solvent, and the reaction times is 10 seconds to 10 days.Handle and mainly form: interrupt any unreacted reagent, then be allocated in water/organic layer system (extraction), separate the layer that contains product by the following step.
Oxidation and reduction reaction are typically carried out under the temperature near room temperature (about 20 ℃), yet when using metal hydride reduction, usually temperature are reduced to 0 ℃ to-100 ℃, and reduction mostly is non-proton property with solvent, and oxidation be can be protic or non-proton property.Adjust the reaction times to reach the expection transformation efficiency.
Condensation reaction is carried out under near the temperature of room temperature usually, yet for non-equilibrium, the condensation of kinetic control, the temperature of common available reduction (0 ℃ to-100 ℃).Solvent can be protic (common in balanced reaction) or non-proton property (common in the kinetic control reaction).
The synthetic technology of standard, removing byproduct of reaction and use anhydrous response condition (as, inert gas environment) as azeotropic be that this area is common, just and work as where applicable and can use it.
Shown in the following reaction scheme 1 of a kind of exemplary method of preparation The compounds of this invention.It is described in detail in following " experiment " part.
Reaction scheme 1
Figure C20051008765901931
The improvement of reaction scheme 1 changes to form other particular instantiation in reaction scheme 2-4.
Reaction scheme 2
Figure C20051008765901941
Reaction scheme 2
Press Utimoto and its colleague, " Tetrahedron Lett. ", the step of 31:6379 (1990) with aziridine 5 with Yb (CN) 3Catalysis addition TMSCN and change into amino-nitrile 9.
Nitrile 9 changes into corresponding amidine 10 use standards three step procedure and finishes: i) H 2S, ii) CH 3I, iii) NH 4OAc.At " J.Med.Chem. ", can find among the 36:1811 (1993) that a typical case transforms.
Nitrile 9 is with " Modern Synthetic Reactions " second edition, H.O.House, and Benjamin/Cummings Publishing Co., 1972 described arbitrary methods availalbes are reduced into amino methyl compound 11.
Amino methyl compound 11 is through N, and N '-two-Boc-1H-pyrazoles-1-carboxylic carbonamidine changes into the guanidine compound 12 of two-Boc protection by the described method processing of " Tetrahedron lett. " 36:299 (1995).
Reaction scheme 3
Figure C20051008765901951
Reaction scheme 3
Aziridine 5 usefulness alpha-cyano tert.-butyl acetate open loops and draw 13.This type aziridine ring-opening reaction can be with reference to " Tetrahedron Lett. ", 23:5021 (1 982).Optionally with tert-butyl ester partial hydrolysis, then decarboxylation draws nitrile 14 under acidic conditions.
Being reduced into aminoethyl derivative 15 to 14 finishes in the mode identical with 9 to 11 conversion.Then amine 15 is used N, N '-two-Boc-1H-pyrazoles-1-carboxylic carbonamidine is by " Tetrahedron Lett. ", and the described method of 36:299 (1995) changes into guanidine derivative 16.
Nitrile 14 changes into corresponding amidine 17 with the step identical with above-mentioned 9 to 10 conversion.
Reaction scheme 4
Reaction scheme 4
With 1 protection (PG=protecting group) of epoxy group(ing) alcohol, for example use MOMCl.Typical condition can be with reference to " Protective Groups in Organic Synthesis " second edition, T.W.Greene and P.G.M.Wuts, John Wiley ﹠amp; Sons, New York, NY, 1991.
19 of epoxide are pressed Sharpless and its colleague " J.Org.Chem. ", the step NaN of 50:1557 (1985) 3/ NH 4The Cl open loop becomes amino alcohol 20.
Being reduced into N-ethanoyl aziridine 21 to 20 finishes with following three step reaction: 1) MsCl/ triethylamine; 2) H 2/ Pd; 3) AcCl/ pyridine.This type of conversion can be with reference to " Angew.Chem.Int.Ed.Engl. ", 35:599 (1994).
Aziridine 21 is used NaN in 65 ℃ in DMF 3/ NH 4Cl is by " J.Chem.Soc.Perkin Trans I ", and 801 (1976) described open loops change into azido-acid amides 22.
With " Protective Groups in Organic Synthesis " second edition, T.W.Greene and P.G.M.Wuts, John Wiley ﹠amp; Sons, New York, NY, 1991 described methods are removed 22 MOM protecting group.Gained alcohol directly changes into aziridine 24 with TsCl in pyridine.This type of conversion can be with reference to " Angew.Chem.Int.Ed.En-gl. ", 33:599 (1994).
Allow aziridine 24 and ROH then, RNH 2, (metal-R) reaction draws corresponding open loop derivative 25,26,27 and 27.1 respectively for RSH or organo-metallic.This type of aziridine open loop can be with reference to " Tetrahedron Lett. ", 23:5021 (1982) and " Angew.Chem.Int.Ed.Engl. ", 33:599 (1994).
Reaction scheme 5
The another kind of compound of the present invention is made by the method for reaction scheme 5a and 5b.With people such as Shing, T.K.M. " Tetrahedron ", 47 (26): 4571 (1991) method changes into 28 with quinic acid.At TEA/CH 2Cl 2In with MsCl carry out methylsulfonylization draw 29,29 in DMF with NaN 3Reaction draws 30.30 at CH 2Cl 2In draw 31,31 at TEA/CH with TFA reaction 2Cl 2In draw 32 with the MsCl methylsulfonylization.Draw 33 with triphenyl phosphine reaction in water, it uses 1 in regular turn) CH in pyridine 3C (O) Cl; 2) NaN in DMF 3And 3) NaH in THF handles and changes into 35.Draw chemical compound lot as 36 with various nucleophilic reagent alkylations 35 known in the art.The method that will change into other concrete examples of the present invention as 36 compound is as indicated above.
Reaction scheme 5a
Figure C20051008765901971
Figure C20051008765901981
Reaction scheme 5b
Figure C20051008765901982
Reaction scheme 6
Figure C20051008765901992
Reaction scheme 6
The method of another kind of compound of the present invention such as reaction scheme 6 makes.The protection alcohol 22 (PG=methoxymethyl ether) as " Protective Groups in Organic Synthesis " second edition, T.W.Greene and P.G.M.Wuts, John Wiley ﹠amp; Sons, NewYork, NY, the protection of going down of 1991 described standard conditions.Alcohol 51 changes into acetic ester 52 with diacetyl oxide and pyridine under standard conditions.Acetic ester 52 usefulness TMSOTf or BF 3OEt 2Processing draws _ azoles quinoline 53.This type of conversion can be respectively with reference to " Liebigs Ann.Chem. " 129 (1991) and " Carbohydrate Research ", 181 (1993).Also can allow alcohol 51 as described below changing into _ azoles quinoline 53 in addition: change into corresponding methanesulfonates or p-toluenesulfonic esters 23 earlier, then under standard conditions, be cyclized into _ the azoles quinoline, as " J.Org.Chem. ", 50:1126 (1985) and " J.Chem.Soc. ", 1385 (1970) is described.Oxazoline 53 and ROH, RR ' NH or RSH (wherein R and R ' and above-mentioned W 6Definition conform to) reaction draws corresponding open loop derivative 54,55 and 56 respectively.This type of conversion can be with reference to " J.Org.Chem. ", 49:4889 (1 984) and " Chem.Rev. ", 71:483 (1971).
Other exemplary methods that reaction scheme 7-35 prepares The compounds of this invention show reaction scheme 7-35 as follows.In the detailed description of these methods " experiment " part hereinafter.
Reaction scheme 7a
Figure C20051008765902001
Reaction scheme 7b
Figure C20051008765902011
Reaction scheme 7c
Figure C20051008765902021
Reaction scheme 8
Figure C20051008765902031
Reaction scheme 9
Reaction scheme 10
Figure C20051008765902041
Reaction scheme 11
Figure C20051008765902042
Reaction scheme 12
Figure C20051008765902051
Reaction scheme 13
Figure C20051008765902052
Reaction scheme 14
Figure C20051008765902061
Reaction scheme 15a
Figure C20051008765902071
Reaction scheme 15b
Reaction scheme 16
Figure C20051008765902081
Reaction scheme 17
Figure C20051008765902091
Reaction scheme 18
Figure C20051008765902101
Reaction scheme 19
Figure C20051008765902102
Reaction scheme 20
Figure C20051008765902111
Reaction scheme 21
Figure C20051008765902112
Reaction scheme 22
Figure C20051008765902121
Reaction scheme 23
Figure C20051008765902122
Reaction scheme 24
Figure C20051008765902131
Reaction scheme 25
Figure C20051008765902132
Reaction scheme 26
Figure C20051008765902141
Reaction scheme 27
Reaction scheme 28
Figure C20051008765902151
Reaction scheme 29
Figure C20051008765902152
Reaction scheme 30
Figure C20051008765902161
Reaction scheme 31
Figure C20051008765902162
Reaction scheme 32
Reaction scheme 33
Figure C20051008765902181
Reaction scheme 34
Figure C20051008765902191
Reaction scheme 35
Figure C20051008765902192
Reaction scheme 36
Figure C20051008765902201
Reaction scheme 37
Figure C20051008765902211
Reaction scheme 38
Figure C20051008765902221
Reaction scheme 39
Reaction scheme 40
Reaction scheme 40.1
Figure C20051008765902241
The other particular instantiation of the preparation and the use present composition is in reaction scheme 36-40.1.One aspect of the present invention relates to the method A that comprises reaction scheme 36-40.1, B, C, D, E, F, G, H, I, J, K.L, M.N, O, P, Q, R, S, T, U, the method for preparing The compounds of this invention of V or W (making up separately or mutually).The concrete example of table 27 illustration method A-W exemplary method.Each concrete example is for using the single method of element method A-W (alone or in combination).In the table 27 each method concrete example with branch "; " separate.If concrete example be single letter then corresponding to one of method A-W, if more than a letter, then corresponding to each method and order shown in complying with carry out.
The present invention relates to the method (shown in A in the reaction scheme 36) of using shikimic acid to prepare compound 270 on the other hand, use compound 270 to prepare the method (shown in B in the reaction scheme 36) of compound 271, use compound 271 to prepare the method (shown in C in the reaction scheme 36) of compound 272, use compound 272 to prepare the method (shown in D in the reaction scheme 36) of compound 273, use quinic acid to prepare the method (shown in E in the reaction scheme 37) of compound 274, use compound 274 to prepare the method (shown in F in the reaction scheme 37) of compound 275, use compound 275 to prepare the method (shown in G in the reaction scheme 37) of compound 276, use compound 276 to prepare the method (shown in H in the reaction scheme 37) of compound 272, use compound 273 to prepare the method (shown in I in the reaction scheme 38) of compound 277, use compound 277 to prepare the method (shown in J in the reaction scheme 38) of compound 278, use compound 278 to prepare the method (shown in K in the reaction scheme 38) of compound 279, use compound 279 to prepare the method (shown in L in the reaction scheme 38) of compound 280, use compound 280 to prepare the method (shown in M in the reaction scheme 38) of compound 281, use compound 281 to prepare the method (shown in N in the reaction scheme 39) of compound 282, use compound 282 to prepare the method (shown in O in the reaction scheme 39) of compound 283, use compound 283 to prepare the method (shown in P in the reaction scheme 39) of compound 284, use compound 283 to prepare the method (shown in Q in the reaction scheme 40) of compound 285, use compound 285 to prepare the method (shown in R in the reaction scheme 40) of compound 286, use compound 287 to prepare the method (shown in S in the reaction scheme 40.1) of compound 288, use compound 288 to prepare the method (shown in T in the reaction scheme 40.1) of compound 289, use compound 289 to prepare the method (shown in U in the reaction scheme 40.1) of compound 290, use compound 290 to prepare the method (shown in V in the reaction scheme 40.1) of compound 291, use compound 291 to prepare the method ((shown in W in the reaction scheme 40.1) of compound 292.
The general content of these exemplary methods is as hereinafter with as described in the embodiment.Each product in the following method is at random separated before being used for next method, segregation and/or purifying.
" processing " speech abutment is mixed, and reaction makes it reaction, makes it to contact and the general processed term that changes into one or more chemical bodies in addition of one or more chemical bodies of representing in other this areas.So " handle compound 1 " and following synonym: " making compound 1 and compound 2 reactions " with compound 2, " compound 1 contacts with compound 2 ", " compound 1 and compound 2 reactions " and other organic syntheses are general represent compound 1 usefulness compound 2 " processing " or with the words and expressions of compound 2 " reaction ".
" processing " expression organifying is learned the reasonable and general fashion of thing reaction.Except as otherwise noted, refer to normal concentration (0.01M to 10M is preferably 0.1M to 1M), temperature (100 ℃ to 250 ℃ are preferably-78 ℃ to 150 ℃, more preferably-78 ℃ to 100 ℃, be preferably 0 ℃ to 100 ℃), reaction vessel (is preferably glass, plastics, metal), solvent, pressure, atmosphere is (during to oxygen and the insensitive reaction of water, being preferably air, then is nitrogen or argon to the reaction of oxygen and water sensitive) etc.Understanding to the known similar reaction in organic synthesis field can be used to select " processing " used condition and device in the given method.Especially, the personnel that generally are familiar with organic synthesis technology select expection can successfully carry out the condition and the device of the chemical reaction of described method based on knowledge known in the art.
Method A, reaction scheme 36
Prepare compound 270 with following method with shikimic acid.
The cis of shikimic acid-4,5-functionalized with glycols base can make them different with carboxylic acid group on the carbon 1 by selective protection this two.Typically, protect this cis-4 with cyclic ketal, 5-functionalized with glycols base is protected this carboxylic acid group with ester.
R 50Be 1 of easy acid decomposition, 2-glycerol protection base, those that illustrate in the works of Yin Shu Greene typically are cyclic ketal or acetal as mentioned, more preferably the ketal of pimelinketone or acetone.R 51Be the stable carboxylic acid protecting group of acid, those that illustrate in the works of Gereene as hereinafter citation typically are line style, branch or ring-type C 1-C 12Alkyl, alkenyl or alkynyl, group 2-7 as shown in table 2,9-10,15 or 100-660, more preferably line style or the C of branch 1-C 8Alkyl, group 2-5 as shown in table 2,9 or 100-358, be preferably line style or the C of branch 1-C 6Alkyl, group 2-5 as shown in table 2,9 or 100-141, however R better 51Be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, or the tertiary butyl.
Make the shikimic acid reaction and make its carboxylic acid by radicals R 51Protection, cis-4, the 5-glycol is by radicals R 50Protection.Typically; shikimic acid uses alcohol (as methyl alcohol; ethanol, n-propyl alcohol or Virahol) with acid catalyst (as mineral acid or sulfonic acid, as methylsulfonic acid; Phenylsulfonic acid or toluenesulphonic acids) handle; then protect with the dialkyl group ketal or the acetal of ketone or aldehyde, as 2,2-Propanal dimethyl acetal or 1; 1-dimethoxy hexanaphthene, and in the presence of corresponding ketone or aldehyde (as acetone or pimelinketone), carry out.At random, before handling with dialkyl group ketal or ketal, the product that alcohol and acid catalyst are handled separates, segregation and/or purifying.In addition, shikimic acid CH 2N 2Handle.
Typically, this method comprises that shikimic acid handles with alkanol or sulfonic acid, then uses together with-dialkoxy alkane or together with-dialkoxy cycloalkanes and handles with generation compound 270 with alkane ketone or naphthenone.More typically, this method comprises with alkanol and sulfonic acid processing shikimic acid; Evaporate excessive alkanol and get resistates; To handle this resistates to generate compound 270 together with-dialkoxy alkane or together with-dialkoxy cycloalkanes and alkane ketone or naphthenone.More typically comprise with methyl alcohol and tosic acid and handle shikimic acid; The evaporation excessive methanol draws resistates, and with 2, this resistates of 2-Propanal dimethyl acetal and acetone treatment is to generate compound 270.
Demonstration concrete example of this method such as embodiment 35.
Method B, reaction scheme 36
Prepare compounds 271 with following method with compound 270.
Make the hydroxyl activation of position 3, typically,, more typically, the displacement of position 4 alcohol is formed the reaction activation of oxirane ring the replacement(metathesis)reaction activation.
R 52Be alcohol activation base, typically, replacement(metathesis)reaction activation base more typically, forms epoxy reactive activation base by position 4 alcohol displacements.This type of group comprises those that this area typical case is used, as sulphonate, and methanesulfonates more preferably, benzene sulfonate, or tosylate.In a concrete example, R 52Merge with O (promptly-OR 52) be the leaving group that this area is used always.
Typically, this method comprises with carboxylic acid halides processing compound 270 to generate compound 271.More typically, this method is included in the suitable solvent and handles compound 270 and form compound 271 with sulfonic acid halide.More typically, this method is included in the suitable solvent, amine for example, and randomly exist down at cosolvent (for example, haloalkane), handle compound 270 and form compound 271 with sulfonic acid halide.Best, this method is included in triethylamine/methylene dichloride and handles compound 270 and form compound 271 with methylsulfonyl chloride.
The demonstration particular instantiation of this method is as embodiment 56 hereinafter.
Method C, reaction scheme 36
Compound 271 is used for preparing compound 272 with following method.
But remove the acid decomposing protection base (R of the hydroxyl of position 4 and 5 50).Typically, remove R 50Shi Jiben does not remove lixiviating can decompose carboxylic acid protecting group (for example, R 51) or hydroxyl activation base (for example, R 52).More typically, R 50Under acidic conditions, rupture.
Typically, this method comprises with protonic solvent handles compound 271, more typically, carries out in the presence of above-mentioned acid catalyst.Best, this method comprises with above-mentioned alkanol and acid catalyst handles compound 271.Best, this method comprises with methyl alcohol and tosic acid to be handled compound 271 and makes compound 272.
The demonstration concrete example of this method is shown in hereinafter embodiment 57.
Method D, reaction scheme 36
Compound 272 is used for preparing compound 273 with following method.
Hydroxyl on the combined thing of activation hydroxyl on compound 272 positions 3 272 positions 4 displacement and become epoxide 273.Typically, this replacement(metathesis)reaction is preferably the amine alkali as DBU or DBN and so on suitable base catalysis.
Typically, this method comprises with alkaline catalysts (at random in the presence of suitable solvent) processing compound 272.More typically, in polarity, in the aprotonic solvent (as ether or THF) with amine alkaline purification compound 272.More typically, this method is included among the THF and handles compound 272 and make compound 273 with DBU.
The demonstration concrete example of this method is shown in hereinafter embodiment 58.
Method E, reaction scheme 37
Quinic acid is used for making compound 274 with following method.
The cis of quinic acid-4,5-functionalized with glycols base are different with the carboxylic acid on the carbon 1 by selective protection.Typically, this cis-4,5-functionalized with glycols base is protected with cyclic ketal, and the carboxylic-acid functional base then forms lactone with the hydroxyl protection on the position 3.
R 50As mentioned above.
Typically, this method comprises using together with-dialkoxy alkane or together with-dialkoxy cycloalkanes (as mentioned above) handles quinic acid with alkane ketone or naphthenone (as mentioned above), at random in the presence of acid catalyst (as mentioned above), carry out, thus formation compound 274.More typically, this method comprises to be used together with-dialkoxy alkane or together with-dialkoxy cycloalkanes, alkane ketone or naphthenone, and acid catalyst is handled quinic acid and is formed compound 274.More typically, this method comprises with 2, the 2-Propanal dimethyl acetal, and acetone and tosic acid are handled quinic acid and are formed compound 274.
The demonstration concrete example of this method is shown in hereinafter embodiment 101.
Method F, reaction scheme 37
Compound 274 is used for preparing compound 275 with following method.
The lactone open loop is become compound 275.Typically, the lactone open loop is formed on position 1 for 3 being free hydroxyl group through the carboxylic acid of protection with in the position.More typically, under alkaline condition, make the lactone open loop form position 1 and be R 51The carboxylic acid of protection, 3 of positions are free hydroxyl group.
R 51As mentioned above.
Typically, in suitable protonic solvent with suitable alkaline purification compound 274.More typically, compound 274 is handled with metal alkoxide alkali (as sodium, potassium, lithium alkoxide) in alkanol (as above-mentioned).More typically, compound 274 is handled and formation compound 275 with NaOMe in MeOH.
The demonstration concrete example of this method is shown in hereinafter embodiment 102.
Method G, reaction scheme 37
Compound 275 is used to prepare compound 276 with following method.
Make the hydroxyl activation of position 3, typically,, more typically, the displacement of position 4 alcohol is formed the reaction activation of oxirane ring the replacement(metathesis)reaction activation.
R 52Be alcohol activation base, typically, the activation base of replacement(metathesis)reaction, more typically, by the activation base of position 4 alcohol displacement formation oxirane ring reactions.This type of group comprises those that this area typical case is used, as sulphonate, and methanesulfonates more preferably, benzene sulfonate, or tosylate.In a concrete example, R 52Merge with O (that is ,-OR 52) be the leaving group that this area is used always.
Typically, this method comprises with carboxylic acid halides processing compound 275 to generate compound 276.More typically, this method is included in the suitable solvent and handles compound 275 and form compound 276 with sulfonic acid halide.More typically, this method is included in the suitable solvent, amine for example, and choose wantonly at cosolvent (for example, haloalkane) and exist down, handle compound 275 and form compound 276 with sulfonic acid halide.Best, this method is included in pyridine/methylene dichloride and handles compound 275 and form compound 276 with Tosyl chloride.
The demonstration concrete example of this method is shown in hereinafter embodiment 103.
Method H, reaction scheme 37
Compound 276 is used for preparing compound 272 with following method.
The hydroxyl of cancellation position 1 is removed cis-4, the protecting group of 5-glycol.1 and 6 in the position of the hydroxyls of cancellation position 1 form ethylene linkage, and remove cis-4, regeneration this cis-4 behind the 5-glycerol protection base, 5-glycol.
Typically, this method comprises uses suitable dewatering agent, as mineral acid (HCl, H 2SO 4) or SO 2Cl 2Handle compound 276.More typically, compound 276 is used SO 2Cl 2Handle, then handle, and in the presence of acid catalyst, carry out arbitrarily with alkanol.More typically, compound 276 is used CH in suitable polar aprotic solvent (as, amine) 2Cl 2Handle and formation alkene; Handle this alkene and form compound 272 with alkanol (as above-mentioned) and acid catalyst (as above-mentioned).More typically, compound 276 is at pyridine/SO 2Cl 2In, under the temperature of-100 ℃ to 0 ℃ (are preferably-100 ℃ to-10 ℃, are preferably-78 ℃), use SO 2Cl 2Handle and formation alkene; Handle this alkene to form compound 272 with methyl alcohol and tosic acid.
The demonstration concrete example of this method is shown in hereinafter embodiment 104.
Method I, reaction scheme 38
Compound 273 is used for preparing compound 277 with following method.
The hydroxyl of position 5 is protected.Typically, this protecting group is that acid can be decomposed hydroxyl protecting group.More typically, this protecting group can not be transferred to adjacent hydroxyl.
R 53Can decompose hydroxyl protecting group for acid, quote from as mentioned the works of Greene described those.More typically, R 53Be the acid ether that can rupture, preferably R 53Be methoxymethyl (MOM, CH 3-O-CH 2-).
Typically, this method comprises with hydroxyl protecting group reagent (as described in Greene) processing compound 273.More typically, this method comprise compound 273 in suitable solvent (as, polar aprotic solvent) with the haloalkane that is substituted or is unsubstituted or alkene (as methoxyl methyl chlorine (MOM muriate, CH 3-O-CH 2Cl) handle.More typically, this method is included in and makes compound 273 MOM chloride treatment in the amine solvent.More typically, this method is included in and makes compound 273 MOM chloride treatment in the diisopropylethylamine.
The demonstration concrete example of this method is shown in hereinafter embodiment 59.
Method J, reaction scheme 38
Compound 277 is used for preparing compound 278 with following method.
The epoxy ring-opening of position 3 and 4 is formed trinitride.More typically, make the epoxy ring-opening of position 3 and 4 form 3-azido--4-oxy-compound 278.
Typically, this method is included in the suitable solvent and handles compound 277 with azide salt.More typically, this method comprise make compound 277 in polar aprotic solvent (as alkanol or water) with the processing of sodiumazide and irenine (as ammonium halide).Now typically, this method comprises and makes compound 277 be processed into compound 278 with sodiumazide and ammonium chloride in water/methanol solution.
The demonstration concrete example of this method is shown in hereinafter embodiment 60.
Method K, reaction scheme 38
Compound 278 is used for preparing compound 279 with following method.
The hydroxyl of compound 278 in 4 positions replaced by the 3-azido-form aziridine cpd 279.
Typically, this method comprises with hydroxyl activation base (as above-mentioned), organic phosphine and alkaline purification compound 278.More typically, this method comprises with sulfonic acid halide (as mentioned above) handles compound 278 to form the activation oxy-compound, handle this activation oxy-compound with formation _ salt with trialkyl phosphine or triaryl phosphine (as, triphenyl phosphine) again, again with alkali (as amine) handle should _ salt forming compound 279.More typically, this method comprises with methylsulfonyl chloride handles compound 278 to form the activation oxy-compound, handles this activation oxy-compound formation _ salt with triphenyl phosphine again, is somebody's turn to do _ salt forming compound 279 with triethylamine and water treatment.
The demonstration concrete example of this method is shown in hereinafter embodiment 61 and 62.
Method L, reaction scheme 38
Compound 279 is used for preparing compound 280 with following method.
Aziridine cpd 279 usefulness trinitride open loops become nitrine amine 280.
Typically, this method is included in the suitable solvent and handles compound 279 with azide salt.More typically, this method comprise make compound 279 in the polar aprotic solvent (as ether, amine, acid amides) with sodiumazide and irenine (as ammonium halide) processing.More typically, this method is included in the DMF solution and handles compound 279 and make compound 280 with sodiumazide and ammonium chloride.
The demonstration concrete example of this method is shown in hereinafter embodiment 63.
Method M, reaction scheme 38
Compound 280 is used for preparing compound 281 with following method.
The protection hydroxyl of 5 positions is formed aziridine 281 by the displacement of the amine of position 4.Typically, aziridine 281 can be decomposed group by acid and replace, and is more preferably by aziridine activation base to replace.
R 54Can decompose group for acid, typically be acid can decompose amine protecting group (as the works of above-mentioned Greene described those).More typically, R 54For aziridine activation base, more preferably can activate the group that aziridine carries out the acid catalysis open loop.Typically, radicals R 54Comprise, as an example and unrestricted, line style or ramose C 1-C 12, 1-oxo-alkane-1-base, wherein moieties is C 1-C 11Line style or branch's alkyl (as, CH 3(CH 2) zC (O)-, z is 0 to 10 integer, that is, and ethanoyl (CH 3C (O)-) etc.), the methyl that is substituted (as, trityl (Ph 3C-), or be abbreviated as Tr), or carbamate is as BOC or Cbz or sulphonate (as, alkyl sulfonate esters (for example sulfonic acid methyl ester)).More typically, R 54Group comprises trityl and C 1-C 81-oxo-alkane-1-base more preferably has 1,2,3,4,5 or 6 carbon atoms, be preferably and have 2 or 3 carbon atoms.
Typically, this method comprises that spending protective material handles compound 280 to remove radicals R 53, R 54Generation reagent (as described in Greene, R 54-halogenide, for example Acetyl Chloride 98Min. or Tr-Cl, or R 54-O-R 54, as diacetyl oxide) and hydroxyl activation base (as method B, reaction scheme 36 described those).More typically, this method comprises with polar aprotic solvent handles compound 280, at random carries out when above-mentioned acid catalyst exists, to form first intermediate; In polar aprotic solvent (for example, amine), handle this first intermediate and form second intermediate with Tr-Cl; Be used in the polar aprotic solvent (as, amine) with sulfonic acid halide (as, methylsulfonyl chloride or Tosyl chloride) handle this second intermediate to make compound 281.More typically, this method comprises with methyl alcohol and HCl to be handled compound 280 and forms first intermediate, handles this first intermediate with Tr-Cl and triethylamine, forms second intermediate, handles this second intermediate with methylsulfonyl chloride and triethylamine, makes compound 281.
The demonstration concrete example of this method is shown in hereinafter embodiment 64.
Method N, reaction scheme 39
Compound 281 is used for preparing compound 282 with following method.
After aziridine 281 open loops, become amine R 55Group replaces and formation compound 282.Typically, aziridine 281 open loop by the acid catalysis ring-opening reaction, become amine then by acidylate.
R 55Be above-mentioned W 3Typically, R 55For-C (O) R 5More typically, R 55For-C (O) R 1, better R 55For-C (O) CH 3
R 56Be above-mentioned U 1Typically, R 56Be W 6-O-, W 6-S-, or W 6-N (H)-.More typically, R 56Be R 5-O-, R 5-S-or R 5-N (H)-, better, R 56Be R 5-O-, preferably R 56Be R 1-O-.
Typically, this method comprise make compound 281 usefulness acid catalysts with suc as formula W 6-X 1The compound treatment of-H (X wherein 1As above definition) forms the amine intermediate; It uses formula W 3-X 1-W 3, W 3-X 10Compound treatment (X wherein 10Be leaving group) formation compound 282.Acid catalyst is preferably this area Lewis acid commonly used, for example BF 3Et 2O, TiCl 3, TMSOTf, SmI 2(THF) 2, LiClO 4, Mg (ClO 4) 2, Ln (OTf) 3(Ln=Yb wherein, Gd, Nd), Ti (Oi-Pr) 4, AlCl 3, AlBr 3, BeCl 2, CdCl 2, ZnCl 2, BF 3, BCl 3, BBr 3, GaCl 3, GaBr 3, TiCl 4, TiBr 4, ZrCl 4, SnCl 4, SnBr 4, Sb-Cl 5, SbCl 3, BiCl 3, FeCl 3, UCl 4, ScCl 3, YCl 3, LaCl 3, CeCl 3, PrCl 3, Nd-Cl 3, SmCl 3, EuCl 3, GdCl 3, TbCl 3, LuCl 3, DyCl 3, HoCl 3, ErCl 3, Tm-Cl 3, YbCl 3, ZnI 2, Al (OPr i) 3, Al (acac) 3, ZnBr 2, or SnCl 4Typically, X 1For-O-,-S-, or-N (H)-.X 10Typically be halogen, for example, Cl, Br or I.More typically, this method comprises and uses R 5-OH, R 5-SH or R 5-NH 2Compound and BF 3Et 2O handles compound 281 and forms intermediate, handles this intermediate with the alkane acid anhydrides again and forms compound 282.More typically, this method comprises and uses R 5-OH compound and BF 3Et 2O handles compound 281 and forms intermediate, handles this intermediate and forms compound 282 with the diacetyl oxide that is substituted or is unsubstituted.R 5The example of-OH compound comprises 2-7 in the table 2,9-10,15 and 660 (Q wherein 1For-OH) described those, those (comprising its CAS accession number) that other example is as shown in table 25 below and those (the comprising its CAS accession number and Aldrich chemical company production code member) shown in the following table 26.More typical R 5The example of-OH compound is 2-5 in the table 2,9 with 100-141 (Q wherein 1For-OH) described those.
Method N, in another concrete example of reaction scheme 39, R 55Be H.
Typically, this method comprises with acid catalyst and R 56-X 1-H compound (X wherein 1As above definition) handles compound 281 and form the amine intermediate, to form compound 282.Acid catalyst and X 1As above definition.More typically, this method comprises and uses R 5-OH, R 5-SH or R 5-NH 2Compound and BF 3Et 2O handles compound 281 and forms compound 282.More typically, this method comprises and uses R 5-OH compound and BF 3Et 2O handles compound 281 and forms compound 282.R 5The example of-OH compound as mentioned above.
The demonstration concrete example of this method is shown in hereinafter embodiment 65,86,92 and 95.
Method O, reaction scheme 39 compounds 282 are used for preparing compound 283 with following method.
Trinitride 282 is reduced into aminocompound 283.
Typically, this method comprises with reductive agent processing compound 282 and forms compound 283.More typically, this method comprise with hydrogen and catalyzer (as Pt/C, or Lindlar catalyzer) or reductive agent (as, above-mentioned trialkyl phosphine or triaryl phosphine) handle compound 282.More typically, this method is included among water/THF and handles compound 282 and form compound 283 with triphenyl phosphine.
The demonstration concrete example of this method is shown in hereinafter embodiment 87,93 and 96.
Method P, reaction scheme 39
Compound 283 is used for preparing compound 284 with following method.
Remove the carboxylic acid protecting group.
Typically, this method comprises with alkaline purification compound 283.More typically, this method is included in the suitable solvent (as aprotic polar solvent) and handles compound 283 with metal hydroxides.More typically, this method is included among the THF and handles compound 283 and make compound 284 with potassium hydroxide aqueous solution.
The demonstration concrete example of this method is shown in hereinafter embodiment 88,94 and 97.
Method O, reaction scheme 40
Compound 283 is used for preparing compound 285 with following method.
Amine is converted to the guanidine through protection.
R 57For the general guanidine protecting group in this area, as BOC or Me.
Typically, this method comprises with guanidine radicals reagent (as commonly used those in this area) and handles compound 283.The example of guanidine radicals reagent comprises two-BOC thiosemicarbazido imino-methylsulfonic acid (people such as Kim; " Tet.Lett. " 29 (26): 3183-3186 (1988) and 1-amidino groups pyrazoles (people such as Bernatowicz; " Tet.Lett. " 34 (21): 3389-3392 (1993)).More typically, this method comprises with two-BOC thiocarbamide acid treatment compound 283.More typically, this method is with acid of two-BOC thiocarbamide and HgCl 2Handle compound 283 and form compound 285.
The demonstration concrete example of this method is shown in hereinafter embodiment 67.
Method R, reaction scheme 40
Compound 285 is used for preparing compound 286 with following method.
Remove carboxylic acid protecting group and guanidine protecting group.
Typically, this method comprises with alkaline purification compound 285, then uses acid treatment as mentioned above.More typically, this method comprises that handling compound 285 with metal hydroxides alkali (as above-mentioned) forms intermediate, forms compound 286 with acid treatment again.More typically, this compound comprises that handling compound 285 with potassium hydroxide aqueous solution and THF forms intermediate, handles this intermediate with TFA again and forms compound 286.
Method S, reaction scheme 40.1
Compound 287 is used for preparing compound 288 with following method.
Compound 287 and 288 E 1, J 1With J 2As mentioned above.Typically, E 1For-CO 2R 51(as mentioned above), J 1Be H, F or methyl, more preferably H.Typically, J 1Be H or line style or the C of branch 1-C 6Alkyl, H more preferably, methyl, ethyl, n-propyl or sec.-propyl, more preferably H.
R 60With R 61Form in the compound 288 through R for reacting 63The group of the aziridine ring that (as giving a definition) replaces.Typically, R 60With R 61In one of be uncle or secondary amine, or can change into the uncle or the group of secondary amine.R 60With R 61This type of group comprise, as an example and unrestricted-NH 2,-N (H) (R 6b) ,-N (R 6b) 2,-NH (R 1) ,-N (R 1) (R 6b) with-N 3R 60With R 61Another be preferably the group that can be formed aziridine by uncle or secondary amine displacement, comprise, as an example and unrestricted ,-OH ,-OR 6a, Br, Cl and I.Typically, R 60With R 61Be transconfiguration.More typically, R 60Be uncle or secondary amine, maybe can change into the group of uncle or secondary amine, R 61For being replaced the group that forms aziridine by uncle or secondary amine, better, R 60Be β-azido-or β-NH 2, R 61Be α-OH, α-O-methylsulfonyl, or α-O-p-toluenesulfonyl.
R 61Method U hereinafter, explanation in the reaction scheme 40.1.
This method comprises that handling compound 287 forms compound 288.It typically makes R by handling compound 287 60Displacement R 61And finish.More typically, compound 287 processed activation R 61, make it by R 60Displacement.More typically, handle compound 287 and make R 61The activation and by R 60Displacement, and R 60Then be activated into replaceable R 61If R 60With R 61The two all is activated, and then can carry out simultaneously or activate in regular turn.If carry out in regular turn, can any order finish, typically, R 61Activation at R 60Activation before.
Typically, make R 61To R 60Displacement activation be performed as follows, handle compound 287 with hydroxyl activating reagent (as methylsulfonyl chloride or toluene sulfonyl chloride).Make R 60To displacement R 61Activation is typically finished by following: handle compound 287 and form uncle or secondary amine, again with this amine of alkaline purification.As an example and unrestricted, become the reductive agent and the alkaline purification compound 287 of amine with reducible trinitride.
In this method one concrete example, compound 287 is used R 61Activating reagent and R 60Activating reagent is treated as compound 288.In another concrete example, compound 287 is used R 61Activating reagent and R 60Activating reagent is treated as compound 288 in suitable solvent.In another concrete example, compound 287 is used R 61Activating reagent, R 60Activating reagent and alkaline purification become compound 288.In another concrete example, compound 287 is used R in suitable solvent 61Activating reagent, R 60Activating reagent and alkaline purification become compound 288.In another concrete example, compound 287 (R wherein 60Be trinitride) use R 61Activating reagent and trinitride reduce agent treated and make compound 288.In another concrete example, compound 287 (R wherein 60Be trinitride) in suitable solvent, use R 61Activating reagent and trinitride reduce agent treated and make compound 288.In another concrete example, compound 287 (R wherein 60Be trinitride) use R 61Also original reagent and the alkaline purification and make compound 288 of activating reagent, trinitride.In another concrete example, compound 287 (R wherein 60Be trinitride) in suitable solvent, use R 61Also original reagent and the alkaline purification and make compound 288 of activating reagent and trinitride.In another concrete example, compound 28 7 (R wherein 60Be trinitride, R 61Be hydroxyl) use the hydroxyl activating reagent, trinitride reduction agent treated becomes compound 288.In another concrete example, compound 287 (R wherein 60Be trinitride, R 61Be hydroxyl) in suitable solvent, use the hydroxyl activating reagent, trinitride reduction agent treated becomes compound 288.In another concrete example, compound 287 (R wherein 60Be trinitride, R 61Be hydroxyl) use the hydroxyl activating reagent, trinitride also original reagent and alkaline purification becomes compound 288.In another concrete example, compound 287 (R wherein 60Be trinitride, R 61Be hydroxyl) in suitable solvent with hydroxy activating reagent, trinitride reductive agent and alkaline purification become compound 288.
The demonstration concrete example of this method is method K as mentioned, shown in the reaction scheme 38.
Method T, reaction scheme 40.1
Compound 288 is used for making compound 289 with following method.
R 64Typically be H, R 6bMaybe can change into H or R 6bGroup.More typically, R 64Be H.R 65Typically be G 1Maybe can change into G 1Group, R preferably 65For-N 3,-CN or-(CR 1R 2) M1W 2, best R 65For-N 3,-NH 2,-N (H) (R 6b) ,-N (R 6b) 2,-CH 2N 3Or-CH 2CN.
Typically, compound 288 is processed into amine 289.More typically, compound 288 usefulness nucleophilic reagents (are preferably nitrogen nucleophile, as R 65, R 65Cationic salts, or R 65Protonated congener, as an example and unrestricted, for example, NH 3, azide salt (NaN 3, KN 3Deng), HCN, cyanide salt (as, NaCN, KCN etc.) or salt (for example, (CH of cyano group alkyl 2CN) -, as NaCH 2CN, KCH 2CN etc.)) handle.More typically, compound 288 usefulness azide salts are handled.Can use arbitrarily again alkali (be preferably irenine, for example, ammonium halide) and solvent (be preferably polar aprotic solvent (as, ether, amine or acid amides).
In a concrete example, compound 288 usefulness nucleophilic reagents are handled.In another concrete example, compound 288 is made compound 289 with the nucleophilic reagent processing in suitable solvent.In another concrete example, compound 288 usefulness nucleophilic reagents become compound 289 with alkaline purification.In another concrete example, compound 288 becomes compound 289 with nucleophilic reagent with alkaline purification in suitable solvent.In another concrete example, compound 288 usefulness nitrogen nucleophiles are processed into compound 289.In another concrete example, compound 288 is processed into compound 289 with nitrogen nucleophile in suitable solvent.In another concrete example, compound 288 usefulness nitrogen nucleophiles become compound 289 with alkaline purification.In another concrete example, compound 288 becomes compound 289 with nitrogen nucleophile with alkaline purification in suitable solvent.In another concrete example, compound 288 usefulness azide salts are processed into compound 289.In another concrete example, compound 288 is processed into compound 289 with azide salt in suitable solvent.In another concrete example, compound 288 usefulness azide salts become compound 289 with alkaline purification.In another concrete example, compound 288 becomes compound 289 with azide salt with alkaline purification in suitable solvent.
The demonstration particular instantiation of this method is in method L above, reaction scheme 38.
Method U, reaction scheme 40.1
Compound 289 is used for making compound 290 with following method.
R 62For being formed in the compound 290 through R with the amine reaction 66The group of the aziridine ring that (as giving a definition) replaces.Typically, R 62For being replaced the group that forms aziridine by uncle or secondary amine.This type of group comprises, as an example and unrestricted, and-OR 53,-OH ,-OR 6a, Br, Cl and I.Typically, R 62Be transconfiguration with the nitrogen of position 4.Better, R 62For-OR 53
R 64Be H or R 6bBut, typically be acid decomposing protection base, as R 54
R 66Be H, R 6bOr R 54
This method comprises that handling compound 289 forms compound 290.Typically, this makes its R by handling compound 289 62Undertaken by the displacement of the amine of position 4.More typically, handling compound 289 makes the amine activation of position 4 and replaces R 62Better, handle compound 289 and replace R with the amine of activated positions 4 62, and R 62Be activated and replaced by the amine of position 4.If R 62All be activated with the amine of position 4, then can simultaneously or activate in regular turn.If activate in regular turn, can any order carry out, better R 62Activation before the activation of position 4 amine.
Make R 62The displacement of 4 amine in position activation is performed as follows usually, handles compound 289 with hydroxy activating reagent (as method B, reaction scheme 36 described those).At random make R 62Before activation, go protection.Make on position 4 amine to displacement R 62Activation is performed as follows usually, handles compound 289 and forms uncle or secondary amine, handles this amine with acid catalyst (as method N, reaction scheme 39 described those) again.
Typically, work as R 62For-OR 53, and R 66During for Rx, this method comprises spending protects agent treated compound 289 to remove R 53, R 54Produce reagent such as the described those (R of Greene 54-halogenide, for example Acetyl Chloride 98Min. or Tr-Cl, or R 54-O-R 54, as diacetyl oxide) and hydroxyl activating group (as method B, reaction scheme 36 described those).More typically, this method comprises with polar aprotic solvent handles compound 289, carries out when above-mentioned acid catalyst exists arbitrarily, to form first intermediate; In polar aprotic solvent (for example, amine), handle this first intermediate and form second intermediate with Tr-Cl; Again in polar aprotic solvent (as, amine) with sulfonic acid halide (as, methylsulfonyl chloride or toluoyl sulphur chlorine) handle this second intermediate to make compound 290.More typically, this method comprises with methyl alcohol and HCl to be handled compound 289 and forms first intermediate, and it is handled with Tr-Cl and triethylamine and forms second intermediate, and it is handled with methylsulfonyl chloride and triethylamine and makes compound 290.
In a concrete example, compound 289 usefulness an acidic catalysts are processed into compound 290.In another concrete example, compound 289 is processed into compound 290 with an acidic catalyst in suitable solvent.In another concrete example, compound 289 usefulness hydroxyl activating reagents and acid catalyst are processed into compound 290.In another concrete example, compound 289 is processed into compound 290 with hydroxyl activating reagent and acid catalyst in suitable solvent.In another concrete example, compound 289 usefulness hydroxyls remove to protect reagent, and hydroxyl activating reagent and acid catalyst are processed into compound 290.In another concrete example, compound 289 removes to protect reagent with hydroxyl in suitable solvent, and hydroxyl activating reagent and acid catalyst are processed into compound 290.
The particular instantiation of this method is in top method M, reaction scheme 38.
Method V, reaction scheme 40.1
Compound 290 is used for preparing compound 291 with following method.
Aziridine 290 is processed into compound 291.Typically, aziridine 290 open loop by the acid catalysis ring-opening reaction, and become amine then by acidylate.
R 68Be H independently, R 6b, R 1Or R 55(as above-mentioned).Typically, R 55For-C (O) R 5R typically 68Be H or R 6b, another then is W 3
R 67Be U 1(as above-mentioned).Typically, R 67Be W 6-O-, W 6-S-, or W 6-N (H)-, better R 67Be R 5-O-, R 5-S-or R 5-N (H)-.
Typically, this method comprises with acid catalyst and W 6-X 1-H compound (X wherein 1As above definition) handles compound 290 and form the amine intermediate; Again with W 3-X 1-W 3Or W 3-X 10Compound (X wherein 10Be leavings group) handle this amine intermediate and form compound 291.W 6-X 1The processing of-H compound and acid catalyst can with W 3-X 1-W 3Or W 3-X 10The processing of compound simultaneously or carried out before it.Acid catalyst typically is method N, a kind of during reaction scheme 39 is described.More typically, this method comprises and uses R 5-OH, R 5-SH, or R 5-NH 2Compound and acid catalyst are handled compound 290; Handle intermediate with the alkane acid anhydrides again and form compound 291.
One concrete example comprises uses W 6-X 1-H compound and acid catalyst are handled compound 290 to form compound 291.Another concrete example is for using W in suitable solvent 6-X 1-H compound and acid catalyst are handled compound 290 and are made compound 291.Another concrete example is for using W 6-X 1-H compound, acid catalyst and W 3-X 1-W 3Or W 3-X 10Compound treatment chemical combination 290 is made compound 291.Another concrete example is for using W in suitable solvent 6-X 1-H compound, acid catalyst and W 3-X 1-W 3Or W 3-W 10Compound treatment compound 290 is made compound 291.
Concrete example of this method such as top method N, reaction scheme 39.
Method W, reaction scheme 40.1
Compound 291 is used to prepare compound 292 with following method.
Compound 291 is processed into compound 292.R typically 65Be converted into G 1U 1Be R 67A concrete example, T 1For-N (R 68) 2A concrete example.Method V as mentioned, reaction scheme 40.1 preparations.
In a concrete example, R 65Gone protection, alkylation, guanidine radicalsization, oxidation or be reduced into G 1Can any order or side by side carry out any kind of above-mentioned processing.As an example and unrestricted, work as R 65During for azido-, present method concrete example comprises method O, OQ, OQR and OP.Typically, alkylating reagent is that this area is commonly used, include, as an example and unrestricted, alkyl halide (as, methyl-iodide, monobromomethane, iodoethane, monobromoethane, n-propyl iodide, positive propyl bromo, isopropyl iodide, isopropyl bromide) and alkene oxide (as oxyethane or propylene oxide).In alkylation step, can use described alkaline catalysts arbitrarily herein.
One concrete example comprises makes compound 291 (R wherein 65Be azido-) be processed into compound 292 with reductive agent.Another concrete example comprises makes compound 291 (R wherein 65Be azido-) in suitable solvent, be processed into compound 292 with reductive agent.Another concrete example comprises makes compound 291 (R wherein 65Be amino) be processed into compound 292 with alkylating reagent.Another concrete example comprises makes compound 291 (R wherein 65Be amino) in suitable solvent, be processed into compound 292 with alkylating reagent.Another concrete example comprises makes compound 291 (R wherein 65Be azido-) be processed into compound 292 with reductive agent and alkylating reagent.Another concrete example comprises makes compound 291 (R wherein 65Be azido-) in suitable solvent, be processed into compound 292 with reductive agent and alkylating reagent.Another concrete example comprises makes compound 291 (R wherein 65Be amino) be processed into compound 292 with alkylating reagent and alkaline catalysts.Another concrete example comprises makes compound 291 (R wherein 65Be amino) in suitable solvent, be processed into compound 292 with alkylating reagent and alkaline catalysts.Another concrete example comprises makes compound 291 (R wherein 65Be azido-) use reductive agent, alkylating reagent and alkaline catalysts are processed into compound 292.Another concrete example comprises makes compound 291 (R wherein 65Be azido-) in suitable solvent with reductive agent, alkylating reagent and alkaline catalysts are processed into compound 292.
The demonstration concrete example of present method provides with the method O of top scheme 39.The demonstration concrete example of this method is as embodiment 68 and 69 hereinafter.
Table 25-formula R 5The example compound of-OH (CAS No.)
The C4 fluorinated alcohols
(R *, R *)-(±)-3-fluoro-2-butanols (139755-61-6)
1-fluoro-2-butanols (124536-12-5)
(R)-3-fluoro-1-butanols (120406-57-7)
3-fluoro-1-butanols (19808-95-8)
4-fluoro-2-butanols (18804-31-4)
(R *, S *)-3-fluoro-2-butanols (6228-94-0)
(R *, R *)-3-fluoro-2-butanols (6133-82-0)
2-fluoro-1-butanols (4459-24-9)
2-fluoro-2-methyl isophthalic acid-propyl alcohol (3109-99-7)
3-fluoro-2-butanols (1813-13-4)
4-fluoro-1-butanols (372-93-0)
1-fluoro-2-methyl-2-propyl alcohol (353-80-0)
The C5 fluorinated alcohols
2-fluoro-1-amylalcohol (123650-81-7)
(R)-2-fluoro-3-methyl isophthalic acid-butanols (113943-11-6)
(S)-2-fluoro-3-methyl isophthalic acid-butanols (113942-98-6)
4-fluoro-3-methyl isophthalic acid-butanols (104715-25-5)
1-fluoro-3-amylalcohol (30390-84-2)
4-fluoro-2-amylalcohol (19808-94-7)
5-fluoro-2-amylalcohol (18804-35-8)
3-fluoro-2-methyl-2-butanols (7284-96-0)
2-fluoro-2-methyl-1-butene alcohol (4456-02-4)
3-fluoro-3-methyl-2-butanols (1998-77-2)
5-fluoro-1-amylalcohol (592-80-3)
The C6 fluorinated alcohols
(R-(R *, S *))-2-fluoro-3-methyl-1-pentene alcohol (168749-88-0)
1-fluoro-2,3-dimethyl-2-butanols (161082-90-2)
2-fluoro-2,3-dimethyl-1-butanols (161082-89-9)
(R)-2-fluoro-4-methyl-1-pentene alcohol (157988-30-2)
(S-(R *, R *))-2-fluoro-3-methyl-1-pentene alcohol (151717-18-9)
(R *, S *)-2-fluoro-3-methyl-1-pentene alcohol (151657-14-6)
(S)-and 2-fluoro-3,3-dimethyl-1-butanols (141022-94-8)
(M)-2-fluoro-2-methyl-1-pentene alcohol (137505-57-8)
(S)-2-fluoro-1-hexanol (127608-47-3)
3-fluoro-3-methyl-1-pentene alcohol (112754-22-0)
3-fluoro-2-methyl-2-amylalcohol (69429-54-5)
2-fluoro-2-methyl-3-amylalcohol (69429-53-4)
1-fluoro-3-hexanol (30390-85-3)
5-fluoro-2-methyl-2-amylalcohol (21871-78-3)
5-fluoro-3-hexanol (19808-92-5)
4-fluoro-3-methyl-2-amylalcohol (19808-90-3)
4-fluoro-4-methyl-2-amylalcohol (19031-69-7)
1-fluoro-3,3-dimethyl-2-butanols (4604-66-4)
2-fluoro-2-methyl-1-pentene alcohol (4456-03-5)
2-fluoro-4-methyl-1-pentene alcohol (4455-95-2)
2-fluoro-1-hexanol (1786-48-7)
3-fluoro-2,3-dimethyl-2-butanols (661-63-2)
6-fluoro-1-hexanol (373-32-0)
The C7 fluorinated alcohols
5-fluoro-5-methyl isophthalic acid-hexanol (168268-63-1)
(R)-1-fluoro-2-methyl-2-hexanol (153683-63-7)
(S)-3-fluoro-1-enanthol (141716-56-5)
(S)-2-fluoro-2-methyl isophthalic acid-hexanol (132354-09-7)
(R)-3-fluoro-1-enanthol (120406-54-4)
(S)-2-fluoro-1-enanthol (110500-31-7)
1-fluoro-3-enanthol (30390-86-4)
7-fluoro-2-enanthol (18804-38-1)
2-ethyl-2-(methyl fluoride)-1-butanols (14800-35-2)
2-(methyl fluoride)-2-methyl-1-pentene alcohol (1 3674-80-1)
2-fluoro-5-methyl isophthalic acid-hexanol (4455-97-4)
2-fluoro-1-enanthol (1786-49-8)
7-fluoro-1-enanthol (408-16-2)
The C8 fluorinated alcohols
(M)-2-fluoro-2-methyl isophthalic acid-enanthol (137505-55-6)
6-fluoro-6-methyl isophthalic acid-enanthol (135124-57-1)
1-fluoro-sec-n-octyl alcohol (127296-11-1)
(R)-2-fluoro-1-octanol (118205-91-7)
(±)-2-fluoro-2-methyl isophthalic acid-enanthol (117169-40-1)
(S)-2-fluoro-1-octanol (110500-32-8)
(S)-1-fluoro-sec-n-octyl alcohol (110270-44-5)
(R)-1-fluoro-sec-n-octyl alcohol (110270-42-3)
(±)-1-fluoro-sec-n-octyl alcohol (110229-70-4)
2-fluoro-4-methyl-3-enanthol (87777-41-1)
2-fluoro-6-methyl isophthalic acid-enanthol (4455-99-6)
2-fluoro-1-octanol (4455-93-0)
8-fluoro-1-octanol (408-27-5)
The C9 fluorinated alcohols
6-fluoro-2,6-dimethyl-2-enanthol (160981-64-6)
(S)-3-fluoro-1 nonyl alcohol (160706-24-1)
(R-(R *, R *))-3-fluoro-2-nonyl alcohol (137909-46-7)
(R-(R *, S *))-3-fluoro-2-nonyl alcohol (137909-45-6)
3-fluoro-2-nonyl alcohol (137639-20-4)
(S-(R *, R *))-3-fluoro-2-nonyl alcohol (137639-19-1)
(S-(R *, S *))-3-fluoro-2-nonyl alcohol (137639-18-0)
(±)-3-fluoro-1 nonyl alcohol (134056-76-1)
2-fluoro-1 nonyl alcohol (123650-79-3)
2-fluoro-2-methyl isophthalic acid-octanol (120400-89-7)
(R)-2-fluoro-1 nonyl alcohol (118243-18-8)
(S)-1-fluoro-2-nonyl alcohol (111423-41-7)
(S)-2-fluoro-1 nonyl alcohol (110500-33-9)
1-fluoro-3-nonyl alcohol (30390-87-5)
2-fluoro-2,6-dimethyl-3-enanthol (684-74-2)
9-fluoro-1 nonyl alcohol (463-24-1)
The C10 fluorinated alcohols
4-fluoro-1-decanol (167686-45-5)
(P)-10-fluoro-3-decyl alcohol (145438-91-1)
(R-(R *, R *))-3-fluoro-5-methyl isophthalic acid-nonyl alcohol (144088-79-9)
(P)-10-fluoro-2-decyl alcohol (139750-57-5) 1-fluoro-2-decyl alcohol (130876-22-1)
(S)-2-fluoro-1-decanol (127608-48-4)
(R)-1-fluoro-2-decyl alcohol (119105-16-7)
(S)-1-fluoro-2-decyl alcohol (119105-15-6)
2-fluoro-1-decanol (110500-35-1)
1-fluoro-5-decyl alcohol (106533-31-7)
4-fluoro-2,2,5,5-tetramethyl--3-hexanol (24212-87-1)
10-fluoro-1-decanol (334-64-5)
The C11 fluorinated alcohols
10-fluoro-2-methyl isophthalic acid-decyl alcohol (139750-53-1)
2-fluoro-1-hendecanol (110500-34-0)
8-fluoro-5,8-dimethyl-5-nonyl alcohol (110318-90-6)
11-fluoro-2-hendecanol (101803-63-8)
11-fluoro-1-hendecanol (463-36-5)
The C12 fluorinated alcohols
11-fluoro-2-methyl isophthalic acid-hendecanol (139750-52-0)
1-fluoro-dodecanol (132547-33-2)
(R *, S *)-7-fluoro-6-dodecanol (130888-52-7)
(R *, R *)-7-fluoro-6-dodecanol (130876-18-5)
(S)-2-fluoro-1-+ dialkanol (127608-49-5)
12-fluoro-2-amyl group-enanthol (120400-91-1)
(R *, S *)-(±)-7-fluoro-6-dodecanol (119174-39-9)
(R *, R *)-(±)-7-fluoro-6-dodecanol (119174-38-8)
2-fluoro-1-dodecanol (110500-36-2)
11-fluoro-2-methyl-2-dodecanol (101803-67-2)
1-fluoro-1-dodecanol (100278-87-3)
12-fluoro-1-dodecanol (353-31-1)
The C4 nitroalcohol
(R)-4-nitro-2-butanols (129520-34-9)
(S)-4-nitro-2-butanols (120293-74-5)
The 4-nitro-1-butanols radical ion (1-) (83051-13-2)
(R *, S *)-3-nitro-2-butanols (82978-02-7)
(R *, R *)-3-nitro-2-butanols (82978-01-6)
4-nitro-1-butanols (75694-90-5)
(±)-4-nitro-2-butanols (72959-86-5)
4-nitro-2-butanols (55265-82-2),
1-acid-nitro-2-butanols (22916-75-2)
3-acid-nitro-2-butanols (22916-74-1)
2-methyl-3-nitro-1-propyl alcohol (21527-52-6)
3-nitro-2-butanols (6270-16-2)
2-methyl isophthalic acid-nitro-2-propyl alcohol (5447-98-3)
2-acid-nitro-1-butanols (4167-97-9)
1-nitro-2-butanols (3156-74-9)
2-nitro-1-butanols (609-31-4)
2-methyl-2-nitro-1-propyl alcohol (76-39-1)
The C5 nitroalcohol
(R)-3-methyl-3-nitro-2-butanols (154278-27-0)
3-methyl isophthalic acid-nitro-1-butanols (153977-20-9)
(±)-1-nitro-3-amylalcohol (144179-64-6)
(S)-1-nitro-3-amylalcohol (144139-35-5)
(R)-1-nitro-3-amylalcohol (144139-34-4)
(R)-3-methyl isophthalic acid-nitro-2-butanols (141434-98-2)
(±)-3-methyl isophthalic acid-nitro-2-butanols (141377-55-1)
(R *, R *)-3-nitro-2-amylalcohol (138751-72-1)
(R *, S *)-3-nitro-2-amylalcohol (138751-71-0)
(R *, R *)-2-nitro-3-amylalcohol (138668-26-5)
(R *, S *)-2-nitro-3-amylalcohol (138668-19-6)
3-nitro-1-amylalcohol (135462-98-5)
(R)-5-nitro-2-amylalcohol (129520-35-0)
(S)-5-nitro-2-amylalcohol (120293-75-6)
4-nitro-1-amylalcohol (116435-64-4)
(±)-3-methyl-3-nitro-2-butanols (114613-30-8)
(S)-3-methyl-3-nitro-2-butanols (109849-50-5)
3-methyl-4-nitro-2-butanols (96597-30-7)
(±)-5-nitro-2-amylalcohol (78174-81-9)
2-methyl-2-nitro-1-butanols (77392-55-3)
3-methyl-2-nitro-1-butanols (77392-54-2)
3-methyl-4-nitro-1-butanols (75694-89-2)
2-methyl-4-nitro-2-butanols (72183-50-7)
3-methyl-3-nitro-1-butanols (65102-50-3)
5-nitro-2-amylalcohol (54045-33-9)
2-methyl-3-acid-nitro-2-butanols (22916-79-6)
2-methyl isophthalic acid-acid-nitro-2-butanols (22916-78-5)
2-methyl-3-nitro-2-butanols (22916-77-4)
2-methyl isophthalic acid-nitro-2-butanols (22916-76-3)
5-nitro-1-amylalcohol (21823-27-8)
2-methyl-3-nitro-1-butanols (21527-53-7)
2-nitro-3-amylalcohol (20575-40-0)
3-methyl-3-nitro-2-butanols (20575-38-6)
3-nitro-2-amylalcohol (5447-99-4)
2-nitro-1-amylalcohol (2899-90-3)
3-methyl isophthalic acid-nitro-2-butanols (2224-38-6)
1-nitro-2-amylalcohol (2224-37-5)
The C6 nitroalcohol
(-)-4-methyl isophthalic acid-nitro-2-amylalcohol (158072-33-4)
3-(nitre methyl)-3-amylalcohol (156544-56-8)
(R *, R *)-3-methyl-2-nitro-3-amylalcohol (148319-17-9)
(R *, S *)-3-methyl-2-nitro-3-amylalcohol (148319-16-8)
6-nitro-2-hexanol (146353-95-9)
(±)-6-nitro-3-hexanol (144179-63-5)
(S)-6-nitro-3-hexanol (144139-33-3)
(R)-6-nitro-3-hexanol (144139-32-2)
3-nitro-2-hexanol (127143-52-6)
5-nitro-2-hexanol (110364-37-9)
4-methyl isophthalic acid-nitro-2-amylalcohol (102014-44-8)
(R *, S *)-2-methyl-4-nitro-3-amylalcohol (82945-29-7)
(R *, R *)-2-methyl-4-nitro-3-amylalcohol (82945-20-8)
2-methyl-5-nitro-2-amylalcohol (79928-61-3)
2,3-dimethyl-1-nitro-2-butanols (68454-59-1)
2-methyl-3-nitro-2-amylalcohol (59906-62-6)
3,3-dimethyl-1-nitro-2-butanols (58054-88-9)
2,3-dimethyl-3-nitro-2-butanols (51483-61-5)
2-methyl isophthalic acid-nitro-2-amylalcohol (49746-26-1)
3,3-dimethyl-2-nitro-1-butanols (37477-66-0)
6-nitro-1-hexanol (31968-54-4)
2-methyl-3-nitro-1-amylalcohol (21527-55-9)
2,3-dimethyl-3-nitro-1-butanols (21527-54-8)
2-methyl-4-nitro-3-amylalcohol (20570-70-1)
2-methyl-2-nitro-3-amylalcohol (20570-67-6)
2-nitro-3-hexanol (5448-00-0)
4-nitro-3-hexanol (5342-71-2)
4-methyl-4-nitro-1-amylalcohol (5215-92-9)
1-nitro-2-hexanol (2224-40-0)
The C7 nitroalcohol
1-nitro-4-enanthol (167696-66-4)
(R)-1-nitro-4-enanthol (146608-19-7)
7-nitro-1-enanthol (133088-94-5)
(R *, S *)-3-nitro-2-enanthol (127143-73-1)
(R *, R *)-3-nitro-2-enanthol (127143-72-0)
(R *, S *)-2-nitro-3-enanthol (127143-71-9)
(R *, R *)-2-nitro-3-enanthol (127143-70-8)
(R *, S *)-2-methyl-5-nitro-3-hexanol (103077-95-8)
(R *, R *)-2-methyl-5-nitro-3-hexanol (103077-87-8)
3-ethyl-4-nitro-1-amylalcohol (92454-38-1)
3-ethyl-2-nitro-3-amylalcohol (77922-54-4)
2-nitro-3-amylalcohol (61097-77-6)
2-methyl isophthalic acid-nitro-3-hexanol (35469-17-1)
2-methyl-4-nitro-3-hexanol (20570-71-2)
2-methyl-2-nitro-3-hexanol (20570-69-8)
5-methyl-5-nitro-2-hexanol (7251-87-8)
1-nitro-2-enanthol (6302-74-5)
3-nitro-4-enanthol (5462-04-4)
4-nitro-3-enanthol (5342-70-1)
The C8 nitroalcohol
(±)-1-nitro-3-octanol (141956-93-6)
1-nitro-4-octanol (167642-45-7)
(S)-1-nitro-4-octanol (167642-18-4)
6-methyl-6-nitro-2-enanthol (142991-77-3)
(R *, S *)-2-nitro-3-octanol (135764-74-8)
(R *, R *)-2-nitro-3-octanol (135764-73-7)
5-nitro-4-octanol (132272-46-9)
(R *, R *)-3-nitro-4-octanol (130711-79-4)
(R *, S *)-3-nitro-4-octanol (130711-78-3)
4-ethyl-2-nitro-3-hexanol (126939-74-0)
2-nitro-3-octanol (126939-73-9)
1-nitro-3-octanol (126495-48-5)
(R *, R *)-(±)-3-nitro-4-octanol (118869-22-0)
(R *, S *)-(±)-3-nitro-4-octanol (118869-21-9)
3-nitro-sec-n-octyl alcohol (127143-53-7)
(R *, S *)-2-methyl-5-nitro-3-enanthol (103078-03-1)
(R *, R *)-2-methyl-5-nitro-3-enanthol (103077-90-3)
8-nitro-1-octanol (101972-90-1)
(±)-2-nitro-1-octanol (96039-95-1)
3,4-dimethyl-1-nitro-2-hexanol (64592-02-5)
3-(nitre methyl)-4-enanthol (35469-20-6)
2,5-dimethyl-1-nitro-3-hexanol (35469-19-3)
2-methyl isophthalic acid-nitro-3-enanthol (35469-18-2)
2,4,, 4-trimethylammonium-1-nitro-2-amylalcohol (35223-67-7)
2,5-dimethyl-4-nitro-3-hexanol (22482-65-1)
2-nitro-1-octanol (2882-67-9)
1-nitro-sec-n-octyl alcohol (2224-39-7)
The C9 nitroalcohol
4-nitro-3-nonyl alcohol (160487-89-8)
(R *, R *)-3-ethyl-2-nitro-3-enanthol (148319-18-0)
2,6-dimethyl-6-nitro-2-enanthol (117030-50-9)
(R *, S *)-2-nitro-4-nonyl alcohol (103077-93-6)
(R *, R *)-2-nitro-4-nonyl alcohol (103077-85-6)
2-nitro-3-nonyl alcohol (99706-65-7)
9-nitro-1 nonyl alcohol (81541-84-6)
2-methyl isophthalic acid-nitro-3-octanol (53711-06-1)
4-nitro-5-nonyl alcohol (34566-13-7)
2-methyl-3-(nitre methyl)-3-enanthol (5582-88-7)
1-nitro-2-nonyl alcohol (4013-87-0)
The C10 nitroalcohol
2-nitro-4-decyl alcohol (141956-94-7)
(R *, S *)-3-nitro-4-decyl alcohol (135764-76-0)
(R *, R *)-3-nitro-4-decyl alcohol (135764-75-9)
5,5-dimethyl-4-(2-nitre ethyl)-1-hexanol (133088-96-7)
(R *, R *)-(±)-3-nitro-4-decyl alcohol (118869-20-8)
(R *, S *)-(±)-3-nitro-4-decyl alcohol (118869-19-5)
5-nitro-2-decyl alcohol (112882-29-8)
3-nitro-4-decyl alcohol (93297-82-6)
4,6,6-trimethylammonium-1-nitro-2-enanthol (85996-72-1)
2-methyl-2-nitro-3-nonyl alcohol (80379-17-5)
1-nitro-2-decyl alcohol (65299-35-6)
2,2,4,4-tetramethyl--3-(nitre methyl)-3-amylalcohol (58293-26-8)
The C11 nitroalcohol
11-nitro-5-hendecanol (167696-69-7)
(R *, R *)-2-nitro-3-hendecanol (144434-56-0)
(R *, S *)-2-nitro-3-hendecanol (144434-55-9)
2-nitro-3-hendecanol (143464-92-0)
2,2-dimethyl-4-nitro-3-nonyl alcohol (126939-76-2)
4,8-dimethyl-2-nitro-1 nonyl alcohol (118304-30-6)
11-nitro-1-hendecanol (81541-83-5)
The C12 nitroalcohol
2-methyl-2-nitro-3-hendecanol (126939-75-1)
2-nitro-1-dodecanol (62322-32-1)
1-nitro-2-dodecanol (62322-31-0)
2-nitro-3-dodecanol (82981-40-6)
12-nitro-1-+ dialkanol (81541-78-8)
Table 26-formula R 5The example compound of OH (CAS No./Aldrich No.)
3-bromo-1-propyl alcohol 627,189 167169
1,3-two chloro-2-propyl alcohol 96,231 184489
3-chloro-2,2-dimethyl-1-propyl alcohol 13,401,564 189316
2,2-two (chloromethyl)-1-propyl alcohol 5,355,544 207691
1,3-two fluoro-2-propyl alcohol 453,134 176923
2-(methylthio group) ethanol 5,271,385 226424
2-(dibutylamino) ethanol 102,818 168491
2-(diisopropylaminoethyl) ethanol 96,800 168726
3-methyl-3-butene-1-alcohol 763,326 129402
2-methyl-3-butene-2-alcohol 115,184 136816
3-methyl-2-butene-1-alcohol 556,821 162353
4-hexen-1-ol 928,927 237604
5-hexen-1-ol 821,410 230324
Suitable-2-hexen-1-ol 928,949 224707
Instead-blatter alcohol 928,972 224715
Instead-2-hexen-1-ol 928,950 132667
(+/-)-6-methyl-5-heptene-2-alcohol 4,630,062 195871
Dihydro myrcenol 18,479,588 196428
Instead, anti--2,4-hexadiene-1-alcohol 17,102,646 183059
2,4-dimethyl-2,6-heptadiene-1-alcohol 80,192,569 238767
Geraniol 106,241 163333
3-butine-1-alcohol 927,742 130850
3-pentyne-1-alcohol 10,229,104 208698
Isethionic acid, sodium salt 1,562,001 220078
(4-(2-hydroxyethyl)-1-piperazinyl 16,052,065 163740
Propanesulfonic acid)
HEPES, sodium salt 75,277,393 233889
1-methyl cyclopropane methyl alcohol 2,746,147 236594
2-methyl cyclopropane methyl alcohol 6,077,721 233811
(+/-)-alantol 18,383,590 194654
Tetramethylene methyl alcohol 4,415,821 187917
3-cyclopentyl-1-propyl alcohol 767,055 187275
1-ethynyl cyclopentanol 17,356,193 130869
3 methyl cyclohexanol 591,231 139734
3,3,5,5-tetramethyl-ring hexanol 2,650,400 190624
4-cyclohexyl-1-butanols 4,441,570 197408
Tetrahydrogeraniol 619,012 218421
(1S, 2R, 5S)-(+)-menthol 15,356,704 224464
(1S, 2S, 5R)-(+)-neomenthol 2,216,526 235180
(1S, 2R, 5S)-(+)-isomenthol 23,283,978 242195
(+/-)-3-tetrahydrobenzene-1-menthol 72,581,329 162167
(+)-P-_-1-alkene-9-alcohol 13,835,308 183741
(S)-(-)-perillalcohol 536,594 218391
Terpinene-4-alcohol 562,743 218383
α-terpinol 98,555 218375
(+/-)-anti--P-_-6-alkene-32,226,643 247774
2, the 8-glycol
Suberane methyl alcohol 4,448,753 138657
Tetrahydrofurfuryl alcohol 97,994 185396
(S)-(+)-2-pyrrolidine carbinol 23,356,969 186511
1-methyl-2-tetramethyleneimine ethanol 67,004,642 139513
1-ethyl-4-hydroxy piperidine 3,518,830 224634
3-hydroxyl piperidine hydrochloric acid salt 64,051,792 174416
(+/-)-2-piperidine carbinols 3,433,372 155225
3-piperidine carbinols 4,606,659 155233
1-methyl-2-piperidine carbinols 20,845,345 155241
1-methyl-3-piperidine carbinols 7,583,531 146145
2-piperidines ethanol 1,484,840 131520
4-hydroxy piperidine 5,382,161 128775
4-methyl isophthalic acid-piperazine propyl alcohol 5,317,339 238716
Outward-norborneol 497,370 179590
In-norborneol 497,369 186457
5-norbornylene-2-methyl alcohol 95,125 248533
(+/-)-3-methyl-2-norbornane methyl alcohol 6,968,758 130575
(1S)-Nei-(-)-borneol 464,459 139114
(1R)-Nei-(+)-fenchol 2,217,029 196444
9-ethyl two ring (3.3.1) ninth of the ten Heavenly Stems-9-alcohol 21,951,333 193895
(+/-)-isopinocampheol 51,152,115 183229
(S)-along verbenol 18,881,044 247065
(1R, 2R, 3R, 5S)-(-)-isopinocampheol 25,465,650 221902
(1R)-(-)-myrthenol 515,004 188417
1-adamantanol 768,956 130346
3,5-dimethyl-1-adamantanol 707,379 231290
2-adamantanol 700,572 153826
1-diamantane methyl alcohol 770,718 184209
1-diamantane ethanol 6,240,115 188115
3-furfuralcohol 4,412,913 196398
Furfuryl alcohol 98,000 185930
2-(3-thienyl) ethanol 13,781,674 228796
4-methyl-5-imidazolemethanol hydrochloride 38,585,625 227420
Metronidazole 443,481 226742
4-(methylol) imidazole hydrochloride 32,673,419 219908
4-methyl-5-thiazole ethanol 137,008 190675
2-(2-hydroxyethyl) pyridine 103,742 128643
2-hydroxyl-6-picoline 3,279,763 128740
4-pyridyl methyl alcohol 586,958 151629
3-pyridyl methyl alcohol N-oxide compound 6,968,725 184446
1-benzyl-4-hydroxy piperidine 4,727,724 152986
1-(4-chloro-phenyl-)-1-pentamethylene methyl alcohol 80,866,791 188697
(4S, 5S)-(-)-2-methyl-5-phenyl-
2-_ azoles quinoline-4-methyl alcohol 53,732,415 187666
6-(4-chloro-phenyl-)-4,5-dihydro-2-
(2-hydroxyl butyl)-3 (2H)-pyridazinones 38,958,826 243728
N-(2-hydroxyethyl) phthalimide 3,891,074 138339
2-naphthyl ethyl alcohol 1,485,070 188107
1-naphthyl ethyl alcohol 773,999 183458
2-isopropyl-phenol 88,697 129526
4-chloro-α, alpha-alpha-dimethyl styroyl alcohol 5,468,973 130559
4-fluoro-α-Jia Jibenjiachun 403,418 132705
3-phenyl-1-propyl alcohol 122,974 140856
3-(4-methoxyphenyl)-1-propyl alcohol 5,406,188 142328
4-fluorobenzene ethanol 7,589,277 154172
4-anisole ethanol 702,238 154180
Instead-2-methyl-3-phenyl-2-propylene-1-alcohol 1,504,558 155888
2-Ben Anjiyichun 122,985 156876
3-fluorophenyl methanol 456,473 162507
2-fluorophenyl methanol 446,515 162515
2-methyl isophthalic acid-phenyl-2-propyl alcohol 100,867 170275
α-(chloromethyl)-2,4 dichloro benzene methyl alcohol 13,692,143 178403
2-phenyl-1-propyl alcohol 1,123,859 179817
4-chlorophenethylol 1,875,883 183423
4-bromobenzene ethanol 4,654,391 183431
4-nitre phenylethyl alcohol 100,276 183466
2-nitre phenylethyl alcohol 15,121,843 183474
β-ethylbenzene ethanol 2,035,941 183482
4-phenyl-1-butanols 3,360,416 184756
2-anisole ethanol 7,417,187 187925
3-anisole ethanol 5,020,417 187933
3-phenyl-1-butanols 2,722,363 187976
2-methylbenzene ethanol 19,819,988 188123
3-methylbenzene ethanol 1,875,894 188131
4-methylbenzene ethanol 699,025 188158
5-phenyl-1-amylalcohol 10,521,912 188220
4-(4-methoxyphenyl)-1-butanols 22,135,508 188239
4-(4-nitrophenyl)-1-butanols 79,524,202 188751
3,3-phenylbenzene-1-propyl alcohol 20,017,678 188972
1-phenyl-2-propyl alcohol 14,898,874 189235
(+/-)-α-ethylbenzene ethanol 701,702 190136
1,1-phenylbenzene-2-propyl alcohol 29,338,496 190756
3-chlorophenethylol 5,182,445 193518
2-chlorophenethylol 19,819,955 193844
(+/-)-1-phenyl-2-amylalcohol 705,737 195286
2,2-phenylbenzene ethanol 1,883,325 196568
4-oxyethyl group-3-anisole ethanol 77,891,293 197599
3,4-dimethoxy-benzene ethanol 7,417,212 197653
3-(3, the 4-dimethoxy phenyl)-1-propyl alcohol 3,929,473 197688
2-(4-bromine phenoxy group) ethanol 34,743,889 198765
2-fluorobenzene ethanol 50,919,067 228788
3-(trifluoromethyl) phenylethyl alcohol 455,016 230359
2-(thiophenyl) ethanol 699,127 232777
1-(2-methoxyphenyl)-2-propyl alcohol 15,541,261 233773
The method concrete example example A of table 27-method A-R; B; C; D; I; J; K; L; M; N; O; P; Q; R; E; F; G; H; AB; BC; CD; DI; IL; JK; KL; LM; MN; NO; OP; OQ; QR; EF; FG; GH; HI; ABC; BCD; CDI; DIJ; IJK; JKL; KLM; LMN; MNO; NOP; NOQ; OQR; EFG; FGH; GHI; HIJ ABDC; BCDI; CDIJ; DIJK; IJKL; JKLM; KLMN; LMNO; MNOP; MNOQ; NOQR; EFHG; FGHI; GHIJ; HIJK; ABCDI; BCDIJ; CDIJK; DIJKL; IJKLM; JKLMN; KLMNO; LMNOP; LMNOQ; MNOQR; EFGHI; FGHIJ; GHIJK; HIJKL; ABCDIJ; BCDIJK; CDIJKL; DIJKLM; IJKLMN; JKLMNO; KLMNOP; KLMNOQ; LMNOQR; EFGHIJ; FGHIJK; GHIJKL; HIJKLM; ABCDIJK; BCDIJKL; CDIJKLM; DIJKLMN; IJKLMNO; JKLMNOP; JKLMNOQ; KLMNOQR; EFGHIJK; FGHIJKL; GHIJKLM; HIJKLMN; ABCDIJKL; BCDIJKLM; CDIJKLMN; DIJKLMNO; IJKLMNOP; IJKLMNOQ; JKLMNOQR; EFGHIJKL; FGHIJKLM; GHIJKLMN; HIJKLMNO; ABCDIJKLM; BCDIJKLMN; CDIJKLMNO; DIJKLMNOP; DIJKLMNOQ; IJKLMNOQR; EFGHIJKLM; FGHIJKLMN; GHIJKLMNO; HIJKLMNOP; HIJKLMNOQ; ABCDIJKLMN; BCDIJKLMNO; CDIJKLMNOP; CDIJKLMNOQ; DIJKLMNOQR; EFGHIJKLMN; FGHIJKLMNO; GHIJKLMNOP; GHIJKLMNOQ; HIJKLMNOQR; ABCDIJKLMNO; BCDIJKLMNOP; BCDIJKLMNOQ; CDIJKLMNOQR; EFGHIJKLMNO; FGHIJKLMNOP; FGHIJKLMNOQ; GHIJKLMNOQR; ABCDIJKLMNOP; ABCDIJKLMNOQ; BCDIJKLMNOQR; EFGHIJKLMNOP; EFGHIJKLMNOQ; FGHIJKLMNOQR; ABCDIJKLMNOQR; EFGHIJKLMNOQR; S; T; U; V; W; ST; TU; UV; VW; STU; TUV; UVW; STUV; TUVW; STUVW.
Reaction scheme 41
Figure C20051008765902571
Reaction scheme 41
Handle amine 300 (intermediate of embodiment 52, can be arbitrarily before using purifying) with the Boc acid anhydrides and draw the amine 301 of single Boc protection in addition.This conversion can be with reference to Greene, T.W. " Protective Groups in Organic Synthesis " 2nd Ed. (John Wiley ﹠amp; Sons, New York, 1991) the 327-328 page or leaf.
Methyl esters 301 usefulness DIBAL become corresponding uncle's vinyl carbinol 302 at low-temperature reduction.This transforms as Garner, P. and Park, and J.M., " J.Org.Chem. ", 52-2361 (1987) is described.
Primary alconol 302 is handled and protected paired methoxybenzyl ether derivant 303 with 4-methoxybenzyl chlorine under alkaline condition.This transforms as Horita, people such as K., " Tetrahedron ", 42:3021 (1986) is described.
303 MOM and Boc protecting group are by using TFA/CH 2Cl 2Handle and remove, make amino alcohol 304.This one transforms as Greene T.W. " Protective Groups inOrganic Synthesis ", 2nd.Ed. (John Wiley ﹠amp; Sons, New York, 1991) described.
304 aziridine 305 that change into corresponding trityl as protecting group are finished with two step programs of following still reaction: 1) TrCl/TEA, 2) MsCl/TEA.This conversion as above-mentioned.Then as the following derivative 307 that aziridine 305 is changed into corresponding Boc protection: remove trityl and obtain 306 with HCl/ acetone earlier; this conversion is as Hanson; R.W. with Law; H.D. " J.Chem.Soc. " 7285 (1965) is described; handle aziridine 306 and change into corresponding Boc derivative 307 with the Boc acid anhydrides again, this one transforms as Fitre-mann people such as J.; " Tetrahedron Lett. ", 35:1201 (1994) is described.
Allyl group aziridine 307 with carbon nucleophile (carrying) via high price organic copper hydrochlorate at BF 3Et 2O exists down in optionally open loop and draw open loop affixture 308 on allylic positions under the low temperature.This open loop such as Hudlicky, people such as T. " Synlett. " 1125 (1995) are described.
With two step programs: 1) TFA/CH 2Cl 22) Ac 2The O/ pyridine changes into N-acetyl derivative 309 with the amine 308 of Boc protection.This conversion can be with reference to Greene, T.W., " Protective Groups in Organic Synthesis ", 2nd.Ed. (JohnWiley ﹠amp; Sons, New York, 1991) 327-328 page or leaf and 351-352 page or leaf.
Make benzylic ether 309 go protection in room temperature with DDQ, obtain uncle's allyl alcohol 310.This transforms as Horita, and people such as K. " Tetrahedron " 42:3021 (1986) is described.
Alcohol 310 reacts oxidized and changes into methyl esters 311 with a still, uses MnO 2/ A-cOH/MeOH/NaCN carries out the Corey oxidation and finishes.This transforms as Corey, people such as E.J. " J.Am.Chem.Soc. ", and 90:5616 (1968) is described.
Azido-ester 311 goes on foot response procedures in two: 1) Ph 3P/H 2O/THF:2) KOH/THF changes into amino acid 312.This transforms as mentioned above.
Reaction scheme 42
Figure C20051008765902601
Reaction scheme 42
(Sutherland, people such as J.K. " J.Chem.Soc.Chem.Commun. " 464 (1993)) goes to protect into free alcohol with known fluoro acetic ester 320, changes into corresponding methanesulfonates 321:1 with two steps then) NaOMe; 2) MsCl/TEA.This transforms as Greene, T.W., " Protective Groups in Organic Synthesis ", second edition (John Wiley ﹠amp; Sons, New York, 1991) described.
Go protection to draw glycol 322 with 321 under acidic conditions, it is cyclized into epoxy alcohol 323 under alkaline condition.This conversion as previously mentioned.323 aziridine 324 that are converted into the N-trityl as protecting group are finished by following order: 1) MOMCl/TEA; 2) NaN 3/ NH 4Cl; 3) MsCl/TEA; 4) PPh 3/ TEA/H 2O; 5) NaN 3/ NH 4Cl; 6) HCl/MeOH; 7) i) TrCl, ii) MsCl/TEA.This order is as indicated above.
The suitable alcohol of usefulness with aziridine 324 open loops, is used Ac then under the Lewis acid condition then 2The O/ pyridine is handled and is drawn acetylate 325.This conversion is as indicated above.
Ester 325 is converted to corresponding amino acid 326, via following two step programs: 1) PPh 3/ H 2O/THF; 2) KOH/THF.This transforms as mentioned above.
No. the 5214165th, United States Patent (USP), particularly the 9th hurdle 61 walk to " the Descriptions and Examples " of the 18th hurdle 26 row, and the preparation of 6 α and 6 β fluoro shikimic acids is described.These fluoric compounds are suitable for use in the The compounds of this invention method for making of using shikimic acid as initiator.
Scheme 43 is answered by the side
Figure C20051008765902621
Reaction scheme 43
Unsaturated ester 330 (is made with standard acetylize method by acetonide alcohol; as Campbell; M.M. wait the people; " Synthesis "; 179 (1993) is described) with suitable organic copper hydrochlorate (wherein R ' is transferred to ligand on the compound for organic copper hydrochlorate since then) reaction; become intermediate to catch to draw 331, use 30%H then with PhSeCl 2O 2Processing draws alpha, beta-unsaturated esters 332.This conversion can be with reference to Hayashi, people such as Y., " J.Org.Chem. " 47:3428 (1982).
Then with two step programs: 1) NaO Me/MeOH; 2) MsCl/TEA changes into corresponding methanesulfonates 333 with acetic ester 332.This conversion is as indicated above, and can be with reference to Greene, T.W., " Protective Groups in Organic Synthesis ", second edition (John Wiley ﹠amp; Sons, New York, 1991).
Then with two step programs: 1) p-TsOH/MeOH/ Δ; 2) DBU/THF changes into epoxy group(ing) alcohol 334 with acetonide 333.This conversion is as indicated above.
Epoxide 3 34 changes into N-trityl aziridine 335:1 with following program) MOMCl/TEA; 2) NaN 3/ NH 4Cl; 3) MsCl/TEA; 4) PPh 3/ TEA/H 2O; 5) NaN 3/ NH 4Cl; 6) HCl/MeOH; 7) i) TrCl, ii) MsCl/TEA.This program is as indicated above.
The suitable alcohol of usefulness with aziridine 335 open loops, is used Ac then under the Lewis acid condition then 2The O/ pyridine is handled and is drawn acetylate 336.This transforms as mentioned above.
Azido-ester 336 is converted to corresponding amino acid 337, via following two step programs: 1) PPh 3/ H 2O/THF; 2) KOH/THF.This conversion is as indicated above.
Can reference reaction scheme 44 and 45 among the embodiment.
Reaction scheme 44
Figure C20051008765902631
Figure C20051008765902641
Reaction scheme 45
Figure C20051008765902642
The initiator that changes example is to form different E 1Group described in detail already, and this paper repeats no more.Referring to Fleet, people such as G.W.J., " J.Chem.Soc.Perkin Trans.I ", 905-908 (1984), Fleet, people such as G.W.J.; " J.Chem.Soc., Chem.Com-mun. ", 849-850 (1983), Yee, people such as Ying K.; " J.Med.Chem. ", 33:2437-2451 (1990); Olson, people such as R.E.: " Bioorganic ﹠amp; Medici-nal Chemistry Letters ", 4 (18): 2229-2234 (1994); Santella, people such as J.B.III; Bioorganic ﹠amp; Medicinal Chemistry Letters ", 4 (18): 2235-2240 (1994); Judd, people such as D.B.; " J.Med.Chem. ", 37:3108-3120 (1994) and Lombaert, people such as S.De; Bioorganic ﹠amp; Medici-nal Chemistry Letters ", 5 (2): 151-154 (1994).
The E of carboxylic acid cpd of the present invention 1Sulfur analogs is made by arbitrary standard technique, as an example and unrestricted, carboxylic acid is reduced into alcohol with standard method, with standard method alcohol is changed into halogenide or sulphonate again, become compound and NaSH to be reacted into the sulfide product.This type of reaction is stated from Patai, " The Chemistry of the Thiol Group " (John Wiley, New York, 1974), pt.2, particularly 721-735 page or leaf.
The improvement of above-mentioned each reaction scheme can obtain the various congeners of above-mentioned specific example compound.The works of the suitable organic synthesis method of above-mentioned explanation can be applied in these improvement.
In above-mentioned each reaction scheme, better reaction product is separated from each other out and/or from initiator, isolates.The expection product of each step or series of steps separates with this area common technology and/or purifying (hereinafter being referred to as separations) required uniformity coefficient extremely.Typically, this separation relates to heterogeneous extraction, from solvent or solvent mixture crystallization, and distillation, distillation or chromatographic separation.Available several different methods is carried out chromatographic separation, and for example, size is repelled or ion-exchange chromatography, height, in, the low pressure liquid chromatography, on a small scale with preparation type thin layer or thick layer chromatography, and small-scale thin layer and flash chromatography.
Another kind of partition method relates to be used agent treated mixture, this reagent to be chosen to be bonded to the expection product, unreacted starting material, byproduct of reaction etc. or make it separable.This type of reagent comprises sorbent material or absorption agent, as gac, and molecular sieve, Ion Exchange Medium etc.In addition, in the example of alkaline matter, this reagent can be acid, and in the example of acidic substance, it can be alkali, and perhaps it can be wedding agent, as antibody, and conjugated protein, selectivity chelator, as crown ether, liquid/liquid ion extractuin agent (LIX) etc.
The selection of suitable partition method is decided on the essence that participates in material.For example, whether the boiling point and the molecular weight in distillation and when distillation have the polar functional base during chromatographic separation, material stability in acidity or alkaline medium or the like during heterogeneous extraction.The one skilled in the art can use best skill and reach the expection separating resulting.
Above described all documents and patent are all incorporated this paper reference into.The paragraph or the number of pages of the special citation of above-mentioned works are then as a reference described with it clearly.The present invention describes in detail and makes the one skilled in the art can make and use the subject matter of following claims.Can know clearly, to some improvement of the method and composition of following claims still within the scope of the invention and spirit.
Embodiment
General rule
The following example reference reaction scheme.
Several is carried out in some enforcement, and in multiple was implemented, reaction conditions (as the time, temperature, concentration etc.) and productive rate were in normal experimental error scope.If come repeated experiments with remarkable improvement, then sign has remarkable Different Results person.If embodiment uses different initiators also to indicate it.In multiple embodiment, use " correspondence " congener of compound, for example " corresponding ethyl ester ", it be meant another group (in this example, being generally methyl esters) be changed shown in group.For example, " the corresponding ethyl ester of compound 1 " refers to
Figure C20051008765902661
Embodiment 1
Epoxy alcohol 1: from shikimic acid with McGowan and Berchtold, " J.Org.Chem. ", the step of 46:2381 (1981) is made.
Embodiment 2
Epoxy group(ing) allyl ethers 2: (2.37g once adds ethanol thallium (I) (1.01mL) in dry-out benzene 14.08mmol) (50mL) solution toward epoxy alcohol 1.2 hours final vacuum concentrated reaction mixtures are dissolved in resistates in the acetonitrile.Add allyl iodide (3.0mL), this mixture was stirred in dark 16 hours.Leach solid with Celite pad, wash with chloroform.Behind the vacuum concentration, carry out flash chromatography separation (hexane solution of 40%EtOAc) and draw 1.24g (42%) 2, it is light thick oil.
1H NMR(300MHz，CDCl 3)：δ
6.75(1H，m)
(6.10-5.90 1H, m ,-CH=, allyl group);
5.40-5.15 (2H, m ,=CH 2, allyl group); 4.47-4.43 (1H, m);
4.30-4.15 (2H, m ,-CH 2-, allyl group); 3.73 (3H, s);
3.55-3.50(1H，m)；
3.45-3.40(1H，m)；
3.15-3.00(1H，dm，J＝19.5Hz)；
2.50-2.35(1H，dm，J＝2.7，19.5Hz)。
Embodiment 3
Azido-alcohol 3: (1.17g, 5.57mmol), sodiumazide (1.82g) and ammonium chloride (658mg) are in MeOH/H to make epoxide 2 2O (8: 1) is middle the backflow 18 hours (35mL).Concentrated reaction mixture in vacuum is distributed in ether and the water resistates then.Organic layer salt water washing after drying.Vacuum concentration gets 3, and it is a light color oil, and 1.3g (92%) need not purifying and just can directly use.
1H NMR(300MHz，CDCl 3)：δ
6.95-6.85(1H，m)；
(6.00-5.85 1H, m ,-CH=, allyl group);
5.35-5.25 (2H, m ,=CH 2, allyl group);
4.25-4.10 (2H, m ,-CH 2-, allyl group);
4.12(1H，bt，J＝4.2Hz)；3.95-3.75(2H，m)，
3.77(3H，s)；2.85(1H，dd，J＝5.3，18.3Hz)；2.71(1H，bs)；
2.26(1H，dd，J＝7.2，18，3Hz)。
Embodiment 4
Aziridine 4: (637mg 2.52mmol) is dissolved in CH toward alcohol 3 2Cl 2(20mL) and be cooled to and add DMAP (several crystal) and triethylamine (442 μ L) in 0 ℃ the solution.Then add MsCl (287 μ L) again, make to react on 0 ℃ of stirring 2 hours.Remove volatile matter, resistates is allocated in ether and the water.Organic layer saturated bicarbonate, salt solution and water are washed and are washed after drying.Vacuum concentration draws the rough methanesulfonates of 881mg.
1H NMR(300MHz，CDCl 3)：δ
6.87-6.84(1H，s)；
6.00-5.85 (1H, m ,-CH 2=, allyl group);
5.40-5.25 (2H, m ,=CH 2, allyl group);
4.72(1H，dd，J＝3.9，8.5Hz)；
4.32(1H，bt，J＝3.9Hz)；
4.30-4.15 (2H, m ,-CH 2-, allyl group);
3.77(3H，s)；3.14(3H，s)；
2.95(1H，dd，J＝5.7，18.6Hz)；
2.38(1H，dd，J＝6.7，18.6Hz)。
This rough methanesulfonates is dissolved among the anhydrous THF (20mL), and uses Ph 3P (727mg) handles.After 3 hours, add water (15mL) and solid NaH-CO in stirring at room 3(1.35g), under room temperature, stir this mixture overnight again.Vacuum concentration reaction mixture then, resistates then is distributed in EtOAc, between saturated bicarbonate and salt solution.Isolate organic layer, use MgSO 4Dry.Behind the vacuum concentration, resistates draws aziridine 4 with the flash chromatography separation, 170mg (33%), and it is a light yellow oil.
1H NMR(300MHz，CDCl 3)：δ
6.82-6.80(1H，m)；
(6.04-5.85 1H, m ,-CH=, allyl group);
5.35-5.20 (2H, m ,=CH 2, allyl group);
4.39(1H，bd，J＝2.4Hz)；
4.20-4.05 (2H, m ,-CH 2-, allyl group);
3.73(3H，s)；
2.90-2.80(1H，bd，J＝18.9Hz)；2.65-2.40(2H，m)。
Embodiment 5
N-ethanoyl aziridine 5: (170mg 0.814mmol) is dissolved in CH with aziridine 4 2Cl 2(2ml) with pyridine (4ml) in, be cooled to 0 ℃.Add Acetyl Chloride 98Min. (87 μ l) then, stirred 1 hour in 0 ℃.Vacuum is removed volatile matter, and resistates is distributed in ethyl acetate, in saturated bicarbonate and the salt solution.Isolate organic layer, use MgSO 4Dry.Concentrate and to draw roughly 5,196mg (96%) need not purifying and just can directly use.
1H NMR(300MHz，CDCl 3)：δ
6.88-6.86(1H，m)；
(6.00-5.85 1H, m ,-CH=, allyl group);
5.40-5.20 (2H, m ,=CH 2, allyl group);
4.45-4.40(1H，m)；
4.16 (2H, d, J=6.0Hz ,-CH 2-, allyl group);
3.76(3H，s) 3.00-2.95(2H，m)；
2.65(1H，bd，J＝18.5HZ)；
2.14(3H，s)。
Embodiment 6
Azido-allyl ethers 6: with aziridine 5 (219mg, 0.873mmol), sodiumazide (426mg) and ammonium chloride (444mg) in dry DMF (7mL), under nitrogen in 65 ℃ of heated overnight.Reaction mixture is poured in saturated bicarbonate/salt solution, for several times with extracted with diethyl ether.Combined ether layer is with salt water washing after drying.Carry out flash chromatography separation (only using EtOAc) after concentrating and draw azido-amine 77mg (35%), it is dissolved in CH 2Cl 2(1mL) with pyridine (1mL) in, be cooled to 0 ℃.Add Acetyl Chloride 98Min. (38 μ L), add solid NaHCO again after 45 minutes 3, vacuum is removed volatile matter.Resistates is distributed in EtOAc and the salt solution.Organic layer MgSO 4Dry final vacuum concentrates.Flash chromatography separates (only using EtOAc) and draws 6 (99%) of 90mg.
1H NMR(500MHZ，CDCl 3)；δ
6.86(1H，bt，J＝2.2HZ)；
(5.95-5.82 1H, m, CH=, allyl group);
5.68(1H，bd，J＝7.3HZ)；
5.35-5.20 (2H, m ,=CH 2, allyl group);
4.58-4.52(1H，m)；
4.22-4.10(2H，m)；
4.04(1H，dd，J＝5.9，12.5HZ)；3.77(3H，s)；
3.54-3.52(1H，m)；
2.89(1H，dd，J＝5.9，17.6HZ)；2.32-2.22(1H，m)；
2.06(3H，s)。
Embodiment 7
Azido-glycol 7: (90mg 0.306mmol) is dissolved in the solution in acetone (3mL) and the water (258 μ L) and adds N-methylmorpholine-N-oxide compound (39mg) and O toward alkene 6 SO 4(73 μ L, 2.5%w/w t-butanol solution).Then with this reaction mixture in stirring at room 3 days.Add the solid sodium bisulfite, stir after 20 minutes, filter with Celite pad.Use the capacity washing with acetone.Behind the vacuum concentration, carry out flash chromatography and separate (10%MeOH/CH 2Cl 2) draw glycol 7,50mg (50%).
1H NMR(300MHZ，CD 3CN)：δ
6.80-6.70(1H，m)；
4.20-4.15(1H，bm)；
3.95-3.80(1H，m)；
3.80-3.25(6H，m)；
3.70(3H，s)；3.10(1H，bs)；
2.85(1H，bs)；
2.85-2.75(1H，m)；
2.30-2.15(1H，m)；
2.16(1H，bs)；1.92(3H，s)。
Embodiment 8
Amino acid glycol 8: (223 μ L 0.40M) handle glycol 7 (23mg, 0.07mmol) solution in THF (1mL) with the KOH aqueous solution under room temperature.Stir after 1.5 hours, reaction mixture is acidified to pH=4 with Amberlite IR-120 (sun) ion exchange resin.Leach resin, wash with MeOH.Draw rough carboxylic acid behind the vacuum concentration, it is dissolved in the ethanol (1.5mL).In this solution, add Lindlar catalyzer (20mg), in atmosphere of hydrogen (1atm is via balloon), stirred 20 hours.Reaction mixture filters by Celite pad, with hot ethanol and water washing.Remove ethanol under the vacuum, draw the mixture of expection amino acid 8 and initial trinitride 7 after the lyophilize of gained water layer, it is a white powder.Compound 8:
1H NMR(500MHZ，D 2O)：δ
6.5(1H，s)；
4.24-4.30(2H，m)；
4.25-4.18(1H，m)；
(3.90-3.55 5H, compound m);
2.96-2.90(1H，m)；
(2.58-2.50 1H, compound m);
2.12(3H，s)。
Embodiment 9
Compound 62: with quinic acid (60g), ring ethyl ketone (160mL) refluxed 14 hours with the Dean-Stark device with the suspension of toluenesulphonic acids (600mg) in benzene (450mL).After reaction mixture is cooled to room temperature, pour saturated NaHCO into 3Solution (150mL).Water layer CH 2Cl 2Extract 3 times.Merge organic layer, water (2 times), salt solution (1 time) washing, Na 2SO 4Dry back concentrates, and draws white solid, recrystallize from ether (75g, 95%);
1H NMR(CDCl 3)δ
4.73(dd，J＝6.1，2.5HZ，1H)；
4.47(ddd，J＝7.0，7.0，3.0HZ，1H)；
4.30(ddd，J＝5.4，2.6，1.4HZ，1H)，
2.96(s，1H)，
2.66(d，J＝11.7HZ，1H)，
2.40-2.15(m，3H)，
1.72-1.40(m，10H)。
Embodiment 10
Compound 63: (12.7g, 50mmol) once (2.7g 500mmol) adds with sodium methylate in the solution in methyl alcohol (300mL) toward lactone 62.This mixture in stirring at room 3 hours, was interrupted reaction back restir 10 minutes with acetate (3mL).Pour reaction mixture into saturated NH 4In the Cl solution (300mL), use CH 2Cl 2Extract three times.Merge organic layer, clean once MgSO with salt solution 4Dry.Draw glycol (11.5g, 80%) and initiator (1.2g, 10%) with flash column chromatography (hexane/EtOAc=1/1 to 1/2) purifying;
1H NMR(CDCl 3)δ
4.47(ddd，J＝7.4，5.8，3.5HZ，1H)，4.11(m，1H)，
3.98(m，1H)，3.81(s，3H)，
3.45(s，1H)，
2.47(d，J＝3.3HZ，1H)，
2.27(m，2H)，
2.10(dd，J＝11.8，4.3HZ，1H)，1.92-1.26(m，10H)。
Embodiment 11
Compound 64: with PCC (3.3g, 15.6mmol) once add glycol 63 (1.100g, 3.9mmol), molecular sieve (3A, 2.2g) with pyridine (1.1g) at CH 2Cl 2In the mixture (15mL).Under room temperature, stir this mixture 26 hours, use ether (30mL) dilution again.This suspension is filtered through a Celite pad, with ether washing (2 * 20mL).Combined ether layer is with using MgSO after the salt water washing (2x) 4Dry.Concentrate after flash column chromatography (hexane/EtOAc=3/1) purifying draws ketone (0.690g, 67%);
1H NMR(CDCl 3)δ
6.84(d，J＝2.8HZ，1H)，
4.69(ddd，J＝6.4，4.9，1.6HZ，1H)，
4.30(d，J＝5.0HZ，1H)，
3.86(s，3H)，
3.45(d，J＝22.3HZ，1H)，
2.86(m，1H)，
1.69-1.34(m，10H)。
Embodiment 12
Compound 28: in 0 ℃, in 30 minutes with NaBH 4(0.630g is in MeOH 2.4-mmol) (12mL) solution to add ketone 64.With this mixture in 0 ℃ of restir 1.5 hours, with the saturated NH of 15mL 4Cl solution interrupts reaction.This solution CH 2Cl 2Extract three times, merge organic extract, use MgSO 4Dry.With flash column chromatography (hexane/EtOAc=2/1) purifying draws alcohol (0.614g, 97%):
1H NMR(CDCl 3)δ
6.94(d，J＝0.5Hz，1H)，
4.64(ddd，J＝9.8，6.7，3.2Hz，1H)，
4.55(dd，J＝7.1，4.2Hz，1H)，
4.06(m，1H)，3.77(s，3H)，
3.04(dd，J＝16.5，2.1Hz，1H)，
2.73(d，J＝10.2Hz，1H)，
1.94(m，1H)，
1.65-1.29(m，10H)。
Embodiment 13
Compound 66: (2.93g 10.9mmol) is dissolved in the acetone (75mL) with toluenesulphonic acids (1.5g), stirs this mixture 15 hours under room temperature with alcohol 28.Water (30mL) interrupts reaction, uses dense NH 3-H 2O alkalizes to pH=9.Acetone is removed in decompression, and water is then used CH 2Cl 2Extract 3 times.Merge organic extract, with the salt water washing once, Na 2SO 4Dry.Draw the expection product after concentrating:
1H NMR(CDCl 3)δ
7.01(m，1H)，4.73(m，1H)，
4.42(m，1H)，3.97(m，1H)，
3.76(s，3H)，
2.71-2.27(m，2H)，
2.02(s，3H)，1.98(s，3H)。
Embodiment 14
Compound 67: in the time of 0 ℃ with pyridine (4.4mL, 54.5mmol) add to alcohol 66 (10.9mmol) CH 2Cl 2(60mL) in the solution, then add again trimethyl-acetyl chloride (2.7mL, 21.8mmol).Mixture is warmed to room temperature and stirred 14 hours, use CH again 2Cl 2Dilution through washing twice, after the salt water washing once, is used MgSO 4Dry.Flash column chromatography (draw diester (2.320g, 68%) behind the purifying of hexane/EtOAc=9/1):
1H NMR(CDCl 3)δ
6.72(m，1H)，5.04(m，1H)，
4.76(m，1H)，4.40(m，1H)，
3.77(s，3H)，
2.72-2.49(m，2H)，
1.37(s，3H)，1.35(s，3H)，
1.23(s，9H)。
Embodiment 15
Compound 68: with diester 67 (2.32g, 2.3mmol) be dissolved in acetone (1/1,100mL) in and in 55 ℃ the heating 16 hours.Remove and desolvate, add water (2 * 50mL) also evaporations.With toluene (2 * 50mL) together concentrate and draw glycol, directly use to need not to be further purified:
1H NMR(CDCl 3)δ
6.83(m，1H)，5.06(m，1H)，
4.42(m，1H)，4.09(m，1H)，
3.77(s，3H)，
2.68-2.41(m，2H)，
1.22(s，9H)。
Embodiment 16
Compound 69: in 0 ℃ with triethylamine (0.83mL, 6.0mmol) add to glycol 68 (0.410g, in THF 1.5mmol) (8mL) solution, then slowly add thionyl chloride (0.33mL, 4.5mmol).Mixture is warmed to room temperature and stirred 3 hours.Use CHCl 3Wash with water after the dilution three times, the salt water washing once, MgSO 4Dry.(hexane/EtOAc=5/1) purifying draws outer/inner mixture (0.430g, 90%) to flash column chromatography;
1H NMR(CDCl 3)δ
6.89-6.85(m，1H)，
5.48-4.84(m，3H)，
3.80，3.78(s，3H)，
2.90-2.60(m，2H)，
1.25，1.19(s，9H)。
Embodiment 17
Compound 70: (0.400g, 1.3mmol) (0.410g, 6.29mmol) mixture in DMF (10mL) stirred 20 hours with sodiumazide with sulfone 69.Use the ethyl acetate diluted reaction mixture then, use saturated NH 4Cl solution, water and salt water washing, MgSO 4Dry.Concentrate and draw trinitride (0.338g, 90%);
1H NMR(CDCl 3)δ
6.78(m，1H)，5.32(m，1H)，
4.20(m，1H)，3.89(m，1H)，
3.78(s，3H)，
3.00-2.60(m，2H)，
1.21(s，9H)。
Embodiment 18
Compound 71: (0.4mL 2.9mmol) adds to alcohol 70 (0.338g, CH 1.1mmol) with triethylamine in 0 ℃ 2Cl 2(11mL) in the solution, and then slow adding methylsulfonyl chloride (0.18mL, 2.3mmol).This mixture in 0 ℃ of stirring 30 minutes, is used CH 2Cl 2Dilution, organic layer washes secondary with water, uses the salt water washing again, MgSO 4Dry.(hexane/EtOAc=3/1) purifying gets expecting compound (0.380g, 82%) to flash column chromatography;
1H NMR(CDCl 3)δ
6.82(m，1H)，5.44(m，1H)，
4.76(dd，J＝7.3，1.4Hz，1H)，
4.48(m，1H)，3.80(s，3H)，
3.11(s，3H)，
2.82-2.61(m，2H)，
1.21(s，9H)。
Embodiment 19
Compound 72: (0.380g, 0.94mmol) (0.271g, 1.04mmol) mixture in THF (19mL) stirred 2 hours with triphenyl phosphine with trinitride 71.(0.39mL 2.82mmol) interrupts restir 14 hours to reaction water (1.9mL) with triethylamine.Removal of solvent under reduced pressure, mixture are directly used in next step.(0.68mL 8.4mmol) adds said mixture in CH with pyridine in 0 ℃ 2Cl 2In the solution (20mL), and then slow adding acyl chlorides (0.30mL, 4.2mmol).This mixture in 0 ℃ of stirring 5 minutes, is diluted with ethyl acetate.Mixture washes twice with water, and the salt water washing is once used MgSO 4Dry.Flash column chromatography (draw aziridine (0.205g, 83%) behind the purifying of hexane/EtOAc=3/1):
1H NMR(CDCl 3)δ
7.19(m，1H)，5.58(m，1H)，
3.77(s，3H)，3.14(m，2H)，
2.85(dd，J＝7.0，1.6Hz，1H)，
2.34(m，1H)，2.16(s，3H)，
1.14(s，9H)。
Embodiment 20
Compound 73: (0.200g, 0.68mmol), (0.221g, 3.4mmol) (0.146g, 2.7mmol) mixture in DMF (10mL) at room temperature stirred 14 hours sodiumazide with ammonium chloride with aziridine 72.Then, dilute this mixture, wash with water five times, use MgSO after the salt water washing once with ethyl acetate 4Dry.Flash column chromatography (hexane/E-tOAc=2/1) draw expection product and deacetylation amine (0.139g) behind the purifying.Be dissolved in this mixture in the diacetyl oxide (2mL) and stirred 2 hours.Excessive acid anhydrides is removed in decompression, draws expection product (149mg):
1H NMR(CDCl 3)δ
6.76(m，1H)，
5.53(d，J＝8.5Hz，1H)，
5.05(m，1H)，4.31(m，1H)，
4.08(m，1H)，3.79(s，3H)，
2.91(m，1H)，2.51(m，1H)，
1.99(s，3H)，1.20(s，9H)。
Embodiment 21
Compound 74: with the MeOH/H of KOH 2O solution (0.5M, 4.4mL, 2.2mmol) add to ester 73 (149mg, 0.44mmol) in, this mixture was stirred under room temperature 3 hours, be cooled to 0 ℃ then, be acidified to pH=3-4 with Amberlite (acidity).Mixture filters, and after the MeOH washing, concentrates and draws carboxylic acid, and it is white solid (73mg, 69%):
1H NMR(CD 3OD)δ
6.62(m，1H)，4.15(m，1H)，
3.95-3.72(m，2H)，2.84(dd，J＝6.7，1.4Hz，1H)，2.23(m，1H)，1.99(s，3H)。
Embodiment 22
Compound 75: with trinitride 74 (8mg) and Pd-C (Lindlar) (15mg) in ethanol (2mL)) in mixture under hydrogen, stirred 16 hours.With the mixture diatomite filtration, use hot MeOH-H 2O (1/1) washing.Concentrate and draw solid.This solid is soluble in water, and the C-8 post of a weak point of feeding washes with water, concentrates and draws white solid (6mg):
1H NMR(D 2O)δ
6.28(m，1H)，
4.06-3.85(m，3H)，
2.83(dd，J＝17.7，5.4Hz，1H)，2.35(m，1H)，2.06(s，3H)。
Embodiment 23
Compound 76: (68mg, 0.28mmol) (61mg 0.31mmol) is dissolved in the ethanol (12mL) and stirred 16 hours with diphenyl diazomethane with carboxylic acid 74.Reaction is interrupted with acetate (0.5mL), and restir 10 minutes.Removal of solvent under reduced pressure gets ester output (56mg, 50%) behind flash column chromatography (E-tOAc) purifying;
1H NMR(CD 3OD)δ
7.36-7.23(m，10H)，
6.88(s，1H)，6.76(s，1H)，
4.21(m，1H)，
3.93-3.79(m，2H)，
2.89(dd，J＝17.7，5.0Hz，1H)，2.34(m，1H)，
2.00(s，3H)。
Embodiment 24
Compound 77: (40 μ L 0.5mmol) add to alcohol 76 (20mg, CH 0.05mmol) with pyridine 2Cl 2(1mL) in the solution, then add diacetyl oxide (24 μ L, 0.25mmol).This mixture was stirred 24 hours removal of solvent under reduced pressure and reagent.Flash column chromatography (hexane/EtOAc=1/2) purifying draws diester (20mg, 91%):
1H NMR(CDCl 3)δ
7.40-7.27(m，10H)，
6.95(s，1H)，6.87(m，1H)，
5.60(m，1H)，
5.12(ddd，J＝16.4，10.2，5.9Hz，1H)，
4.28(dd，J＝20.0，9.4Hz，1H)，4.15(m，1H)，
2.93(dd，J＝17.8，5.2Hz，1H)，2.57(m，1H)，
2.09(s，3H)，2.01(s，3H)。
Embodiment 25
Compound 78: with diester 77 (20mg, 0.045mmol), phenylmethylether (50 μ L, 0.45mmol) with TFA (1mL) in CH 2Cl 2Mixture (1mL) stirred 20 minutes.Removal of solvent under reduced pressure and reagent.Flash column chromatography (EtOAc to EtOAc/AcOH=100/1) purifying draws carboxylic acid (6mg):
1H NMR(CDCl 3)δ
6.85(m，1H)，5.54(m，1H)，
5.12(m，1H)，
4.31-4.03(m，2H)，
2.89(m，1H)，
2.60-2.41(m，1H)，2.11(s，3H)，2.03(s，3H)。
Embodiment 26
Compound 79: with trinitride 78 (6mg, 0.02mmol) with Pd-C (Lindlar) (15mg) in EtOH/H 2Mixture among the O (2.2mL, 10/1) stirred 3 hours under hydrogen.Mixture filters with Celite pad, uses hot MeOH/H 2O (1/1) washing.Evaporation draws white solid, and it is soluble in water, by the C-8 post.Boil off water and draw white powder (3mg):
1H NMR(D 2O)δ
6.32(m，1H)，5.06(m，1H)，
4.06(t，J＝10.4Hz，1H)，
3.84(m，1H)，2.83(m，1H)，
2.42(m，1H)，2.06(s，3H)，
2.00(s，3H)。
Embodiment 27
Compound 80: with DCC (35mg, 0.172mmol) add to alcohol 76 (35mg, 0.086mmol), the Boc-glycine (30mg, 0.172mmol) with catalytic amount DMAP in CH 2Cl 2In the solution (1mL).This mixture was stirred 30 minutes, filter and use CHCl 3Washing.Gained CHCl 3Solution with water washing secondary.Concentrate and draw white solid.Flash column chromatography (hexane/EtOAc=1/2) purifying draws product (30mg):
1H NMR(CDCl 3)δ
7.39-7.26(m，10H)，
6.95(s，1H)，6.86(m，1H)，
5.77(m，1H)，5.27(m，1H)，
4.99(m，1H)，
4.18-4.01(m，2H)，
3.94-3.84(m，2H)，
2.96(dd，J＝7.8，5.9Hz，1H)，
2.57(m，1H)，2.02(s，3H)，
1.45(s，9H)。
Embodiment 28
Compound 81: (30mg, 0.05mmol), phenylmethylether (150 μ L) and TFA (1mL) are in CH with diester 80 2Cl 2Mixture (1mL) stirred 3 hours.Boil off solvent and reagent.This mixture is soluble in water, use CHCl 3Wash three times.Draw white solid (15mg) after the water evaporation:
1H NMR(CD 3OD)δ
6.73(m，1H)，
5.25-5.15(m，1H)，
4.35(m，1H)，4.17(m，1H)，
3.82(m，2H)，
2.93(dd，J＝17.7，5.6Hz，1H)，2.42(m，1H)，1.97(s，3H)。
Embodiment 29
Compound 82: with trinitride 81 (15mg, 0.05mmol) with Pd-C (Lindlar) (30mg) in EtOH/H 2Mixture among the O (4mL, 1/1) stirred 3 hours under hydrogen.Reaction mixture filters with Celite pad, uses hot MeOH/H 2O (1/1) washing.Concentrate and draw vitreous solid, it is dissolved in the water, by the C-8 post.Boil off and draw amino acid behind the water:
1H NMR(D 2O)δ
6.68(m，1H)，5.28(m，1H)，
4.29(m，1H)，
4.08-3.79(m，3H)，
2.85(m，1H)，2.41(m，1H)，
2.04(s，3H)。
Embodiment 30
Two-Boc guanidine radicals methyl ester 92: as Kim and Qian, " TetrahedronLett. ", the described step process of 34:7677 (1993).With mercury chloride (46mg, 0.170mmol) once add amine 91 (42mg, 0.154mmol), two-Boc thiocarbamide (43mg, 0.155mmol) with the 0 ℃ solution of triethylamine (72 μ L) in dry DMF (310 μ L) in.After 30 minutes, reaction mixture is warmed to room temperature, and restir 2.5 hours.Reaction mixture filters with Celite pad, concentrates, and draws 70mg (89%) 92 with flash column chromatography (100% ethyl acetate) purifying, and it is a colourless foam.
1H NMR(CDCl 3，300MHz)：δ
11.37(s，1H)；
8.60(d，1H，J＝7.8Hz)；
6.83(t，1H，J＝2.1Hz)；
6.63(d，1H，J＝8.4Hz)；
4.76(d，1H，J＝7.0Hz)；
4.71(d，1H，J＝7.0Hz)；
4.45-4.10 (compound m, 2H);
3.76(s，3H)；3.39(s，3H)；
2.84(dd，1H，J＝5.4，17.4Hz)；2.45-2.30(m，1H)；
1.92(s，3H)；1.49(s，18H)。
Embodiment 31
Two-Boc guanidine radicals carboxylic acid 93: toward ester 92 (70mg, 0.136mmol) in the solution (being cooled to 0 ℃) of THF (3mL) in the interpolation KOH aqueous solution (350 μ L, 0.476M).Then reaction mixture is warmed to room temperature and stirred 2 hours, use Amberlite IR-120 (just) acidic resins to be acidified to pH=4.5 again.Leach resin, with ethanol and water washing.Vacuum concentration draws 66mg (97%) carboxylic acid 93, and it is a white solid.
1H NMR(CDCl 3，300MHz)：δ
11.40(br s，1H)；
8.67(d，1H，J＝7.8Hz)；
6.89(s，1H)；
6.69(br d，1H，J＝8.4Hz)；
4.77(d，1H，J＝7.2Hz)；
4.70(d，1H，J＝7.2Hz)；
4.40-4.15(m，2H)；
3.39(s，3H)；
2.84(dd，1H，J＝4.8，17.1Hz)；
2.45-2.30(m，1H)；
1.95(s，3H)；1.49(s，9H)；
1.48(s，9H)。
Embodiment 32
Guanidine carboxylic acid tfa salt 94: (23mg is 0.046mmol) in CH toward two-Boc guanidine radicals carboxylic acid 93 2Cl 2Add pure trifluoroacetic acid (500 μ L) in the solution (1mL) (being cooled to 0 ℃).After 30 minutes reaction mixture is warmed to room temperature, restir 1.25 hours.Vacuum is removed volatile matter, resistates H 2The O co-evaporated obtains the light orange solid for several times.Use anti-phase C 18Chromatogram is with H 2O makes eluent, and this resistates of purifying merges to contain and expects the fraction of product, and lyophilize draws 15mg 93, and it is a white powder.
1H NMR(D 2O，500MHz)：δ
6.82(t，1H，J＝2.0Hz)；
4.51-4.47(m，1H)；
3.93 (dd, 1H, J=9.0,11.2Hz); 3.87-3.80 (apparent ddd, 1H);
2.88(m，1H)；
(2.48-2.45 compound m);
2.07(s，3H)。
13C NMR(D 2O)：δ
176.1；170.0；157.1；139.2；129.5；69.4；56.2；50.9；30.3；22.2。
Embodiment 33
102 synthesize: (24mg, ethanol 0.082mmol) (1mL) solution go up with hydrogen (1atm) at Lindlar catalyzer (30mg) and handled 1.5 hours azido-allyl ethers 6.Reaction mixture filters with Celite pad, washs with hot ethanol.Vacuum concentration draws light solid, and it is dissolved among the THF (1.5mL), and (246 μ L 0.50M) handle, and stir 2 hours under the room temperature, use Amberlite IR-120 (just) acidic resins to be acidified to pH=4.0 then, filter back ethanol and H to use the KOH aqueous solution 2The O washing.Vacuum concentration obtains orange solids, and it is used C 18Column chromatography (H 2The O wash-out) purifying.Merge the fraction that contains product, lyophilize draws the mixture of 2: 1 102 and complete saturated compound 103, and it is a white powder.Compound 102 1H NMR data:
1H NMR(D 2O，500MHz)：δ
7.85(s，1H)；
4.29(br d，1H，J＝9.2Hz)；
4.16(dd，1H，J＝11.6，11.6Hz)；3.78-3.72(m，2H)；
3.62 (apparent ddd, 1H);
2.95 (apparent dd, 1H);
2.58-2.52(m，1H)；
2.11(s，3H)；
1.58(q，2H，J＝7.3Hz)；
0.91(t，3H，J＝7.3Hz)。
Embodiment 34
115 synthesize: with amino acid/11 14 (10.7mg, 0.038mmol) water (1.3mL) solution be cooled to 0 ℃, be adjusted to pH=9.0 with 1.0M NaOH, once add benzyl formyl imines (formimidate) hydrochloride (26mg then, 0.153mmol), when keeping pH=8.5 to 9.0 reaction mixture was stirred 3 hours in 0-5 ℃ with 1.0MNaOH.Vacuum concentration reaction mixture then, resistates is through C 18Post water wash-out.Merge the fraction that contains product, lyophilize draws carbonamidine carboxylic acid 115 (10mg), and it is a white powder.
1H NMR (D 2O, 300MHz, isomer mixture): δ 7.83 (s, 1H);
(6.46 (s) ﹠amp; 6.43 (s); Add up to 1H); 4.83 (d, 1H, J=7.3Hz); 4.73 (d, 1H, J=7.3Hz);
4.50-4.35(m，1H)；
4.10-4.05(m，1H)；
(4.04-3.95 (m) ﹠amp; 3.80-3.65 (m), add up to 1H); 3.39 (s, 3H);
2.90-2.75(m，1H)；
2.55-2.30(m，1H)；
(2.03 (s) ﹠amp; 2.01 (s), add up to 3H).
Embodiment 35
Compound 123: with toluene sulfonyl chloride (4.3g, 22.6mmol) add to alcohol 63 (5.842g, 20.5mmol) with pyridine (40mL) solution of DMAP (200mg) in.This mixture stirred under room temperature 40 hours, and pyridine is removed in decompression.Water interrupts reaction, with E-tOAc extraction three times.Merge organic extract liquid, water and salt water washing, MgSO 4After the drying, flash column chromatography (hexane/EtOAc=2/1) purifying draws p-toluenesulfonic esters (8.04g, 89%):
1H NMR(CDCl 3)δ
7.84(d，J＝8.3Hz，2H)，
7.33(d，J＝8.1Hz，2H)
4.78(m，1H)，4.43(m，1H)，
4.06(m，1H)，3.79(s，3H)，
2.44(s，3H)，
2.43-1.92(m，4H)，
1.61-1.22(m，10H)。
Embodiment 36
Compound 124: with POCl 3(100 μ L, (440mg is in pyridine 1.0mmol) (3mL) solution 1.1mmol) to add to alcohol 123.This mixture was stirred under room temperature 12 hours, use saturated NH 4Cl solution interrupts reaction.Water extracted with diethyl ether three times, combined ether layer washes secondary with water, and 2N HCl solution washing secondary is used MgSO after the salt water washing 4Dry.Flash column chromatography (draws the mixture (350mg, 83%, 2/1) of expection product 124 and some impurity behind the purifying of hexane/EtOAc=2/1).
Embodiment 37
Compound 1: with methylsulfonyl chloride (330 μ L, 4.23mmol) add to the acetonide (877mg of-10 ℃ known methyl shikimate, 3.85mmol, " Tetrahedron Lett. ", 26:21 (1985)) in methylene dichloride (15mL) solution, then dropwise add triethylamine (640 μ L, 4.62mmol).This solution in-10 ℃ of stirrings 1 hour, then in 0 ℃ of stirring 2 hours, is added methylsulfonyl chloride (30 μ L), triethylamine (64 μ L) this moment.After 1 hour, add cold water, separate organic phase, washing after drying (MgSO 4), revaporization.Crude product separates (1/1 hexane/ethyl acetate) with silica gel chromatography and draws oily methanesulfonates 130 (1.1g, 93%).(990mg 3.2mmol) is dissolved in the tetrahydrofuran (THF) (5 μ L), handles with 1M HCl (5mL) with methanesulfonates 130.This solution was stirred under room temperature 19 hours, use dilution of 5mL water and restir 7 hours.Steam organic solvent and draw the oily resistates, use ethyl acetate extraction.Merge organic extract, salt water washing after drying (MgSO 4), evaporation then.Add CH 2Cl 2To rough resistates, filter the white solid of separating out, use CH 2Cl 2Draw glycol 131 (323mg, 38%) after the washing.With this glycol 131 (260mg, 0.98mmol) the part suspension in THF (5mL) is cooled to 0 ℃, (154 μ L, 1.03mmol), this solution stirred 3 hours in 0 ℃, was warmed to stirring at room again 5 hours to add DBU.Boil off solvent, rough resistates is distributed in ethyl acetate (40mL) and 5% citric acid (20mL).Organic phase salt water washing, water is stripped with ethyl acetate (15mL), merges organic extract, dry (MgSO 4) the back evaporation, drawing epoxide (117mg, 70%), it is a white solid, its 1H NMR spectrum is consistent with the structure 1 that makes with literature method.
Embodiment 38
Alcohol 51: with trifluoroacetic acid (8mL) add to 0 ℃ through the protection alcohol (PG=methoxyl methyl) (342mg, CH 1.15mmol) 2Cl 2(10mL) in the solution.In 0 ℃ after 5 minutes, evaporate after 1 hour in stirring this solution under the room temperature.Raw product is gone up purifying at silica gel (ethyl acetate) and is drawn oily alcohol 51 (237mg, 82%):
1H NMR(300MHz，CDCl 3)δ
2.11(s，3H)，2.45(m，1H)，
2.97(dd，1H，J＝3.8，18.8)，
3.66(m，2H)，3.78(s，3H)，
4.40(br s，1H)，
5.22(br s，1H)，
6.19(br s，1H)，
6.82(m，1H)。
Embodiment 39
Methyl ether 150: (0.20mmol) (46mg, 0.18mmol) (56 μ L in THF 0.90mmol) (0.7mL) solution, after 2.5 hours, add second part of NaH (2mg) in 0 ℃ of stirring again with methyl-iodide to alcohol 51 for 60% mineral oil dispersion liquid, 8mg to add NaH.In ℃ stirring 1 hour, stirred 4 hours under the room temperature, it is cooled to 0 ℃, add 5% citric acid (0.5mL).(4 * 2mL) extractions merge organic extract to mixture, dry (MgSO with ethyl acetate 4) the back evaporation.Rough resistates draws solid state methyl ether 150 (12mg, 25%) behind (ethyl acetate) purifying on the silica gel:
1H NMR(300MHz，CDCl 3)δ
2.07(s，3H)，
2.23-2.34(m，1H)，
2.89 (apparent ddd, 1H),
3.43(s，3H)，3.58(m，1H)，
3.78(s，3H)，4.13(m，1H)，
4.40(m，1H)，
5.73(d，1H，J＝7.6)，
6.89(m，1H)。
Embodiment 40
Amino acid/11 51: with the Ph of polymkeric substance carrying 3P (75mg, 3mmol P/g resin) adds to methyl ether 150 (12mg, THF 0.45mmol) (1mL)/H 2In O (the 100 μ L) solution.This mixture was stirred under room temperature 19 hours.Leach resin, with the THF washing for several times, merging filtrate and washings, evaporation draws the rough resistates of 8mg, and it is dissolved among the THF (0.5mL), adds 0.5M KOH (132 μ L)/water (250 μ L).This solution was stirred under room temperature 1.25 hours, with IR 120 ion exchange resin pH is adjusted to 3-4, leaches resin and together stir, after the filtration with 1M HCl, similarly use 1M HCl process resin again, in acidic cleaning liquid, do not have amine (predicting) with ninidrine.Merge the resin washings, evaporation back resistates C-18 reverse phase silica gel purifying (water wash-out), lyophilize draws amino acid/11 51 (1.8mg, 15%), and it is a white solid:
1H NMR(300MHz，D 2O)δ
2.09(S，3H)，
2.48-2.59 (apparent qt, 1H),
2.94(dd，1H，J＝5.7，17.4)，
3.61(m，1H)，
4.14-4.26(m，2H)，
6.86(br s，1H)。
Embodiment 41
Amino acid allyl ethers 153: with the PPh of polystyrene carrying 3(50mg) add to trinitride 6 (16mg, THF 0.054mmol) (0.5mL)/H 2In O (the 35 μ L) solution.This reaction mixture was stirred under room temperature 24 hours, filter, the hot methanol washing with sintered glass funnel.Vacuum concentration draws rough amino ester, and it is dissolved in THF (1.0mL), and (220 μ L 0.5M) handle with the KOH aqueous solution.After stirring 2 hours under the room temperature, add Amber-lite IR-120 (just) acidic resins, until pH value of solution=4.5.Leach resin, with ethanol and H 2The O washing.Vacuum concentration draws the light orange solid, uses anti-phase C 18Chromatogram (H 2The O wash-out) purifying.Merge to contain and expect the fraction of product, lyophilize draws the amino acid of white powder. 1H
NMR(D 2O，300MHz)：δ
6.51(br t，1H)；
(6.05-5.80 m, 1H ,-CH=, allyl group); 5.36-5.24 (m, 2H ,=CH 2, allyl group); 4.35-4.25 (m, 1H);
4.25-4.05 (m, 2H ,-CH 2-, allyl group); 4.02-3.95 (m, 1H);
3.81-3.70(m，1H)；
2.86-2.77 (apparent dd, 1H);
2.35-2.24 (compound m, 1H);
2.09(s，3H)。
Embodiment 42
Epoxide 161: MCPBA (690mg) added in 0 ℃ methylene dichloride (15mL) solution of alkene 160 (embodiment 14 is obtained for 532mg, 1.61mmol, before using rough methanesulfonates is filtered with the 30%EtOAc/ hexane through silica gel).This mixture is warmed to room temperature and stirs spend the night.Remove under the vacuum and desolvate, dilute with ethyl acetate again.Organic layer is with aqueous solution of sodium bisulfite, saturated sodium bicarbonate, salt water washing, MgSO 4Drying, vacuum concentration, resistates then draws light oily 161 (437mg, 78%) with flash column chromatography (30% hexane/ethyl acetate) purifying.
1H NMR(CDCl 3，300MHz)：
(1: 1 non-enantiomer mixture) δ (4.75 (dd, J=3.9,8.2Hz) ﹠amp; (4.71 dd, J=3.9 8.4Hz), add up to 1H);
4.37(m，1H)；
4.25-4.00(m，2H)；
3.78(s，3H)；
〔3.68(dd，J＝5.7，11.7Hz)&
(3.51 dd, J=6.6 11.7Hz), add up to 1H);
(3.17 (s) ﹠amp; 3.16 (s), add up to 3H);
(2.99 (m) ﹠amp; 2.93 (m), add up to 1H);
(2.83 (and t, J=4.1Hz) and
(2.82 t J=4.5Hz), adds up to 1H);
2.70-2.60(m，1H)；
2.45-2.30(m，1H)。
Embodiment 43
Glycol 162: (437mg is 1.23mmol) in containing 5 70%HClO with epoxide 161 4THF (20mL)/H 2Gentle reflux is 1 hour among the O (10mL).Add solid NaHCO 3, vacuum concentrated mixture.Resistates is dissolved among the EtOAc, and salt solution cleans after drying.Vacuum concentration draws rough glycol 162, and it is light oily (quantitative yield).Need not purifying and be directly used in next reaction.
Embodiment 44
Aldehyde 163: press Vo-Quang and its colleague, " Synthesis ", 68 (1988) described steps are carried out the oxidation of glycol 162.With NaIO 4(4.4mL, the 0.65M aqueous solution) adds to silica gel (4.3g) in the slurry of methylene dichloride (30mL).Add EtOAc (the 5mL)/CH of rough glycol 162 (520mg) again 2Cl 2(15mL) solution.Leach solid after 1 hour, with 20% hexane/EtOAc washing.Concentrate the oily resistates, it is dissolved in EtOAc, use MgSO 4Dry.Vacuum concentration draws light oily aldehyde 163, and it is directly used in next reaction.
1H NMR(CDCl 3，300MHz)：δ
9.69(s，1H)；6.98(m，1H)；
4.72(dd，1H，J＝3.7，9.1Hz)；
4.53(d，1H，J＝18.3Hz)；
4.45(d，1H，J＝18.3Hz)；
4.31(m，1H)；
4.26-4.18(m，1H)；
3.79(s，3H)；3.19(s，3H)；
3.05(dd，1H，J＝5.7，18.6Hz)；2.20-2.45(m，1H)。
Embodiment 45
Alcohol 164: crude aldehyde 163 is pressed Borch and its colleague, and " J.Amer.Chem.Soc. ", the described step of 93:2897 (1971) is with NaCNBH 3Handle, flash chromatography separate (40% hexane/EtOAc) draws 269mg (65%) alcohol 164:
1H NMR(CDCl 3，300MHz)：δ
6.91(m，1H)；
4.75(dd，1H，J＝3.9，8.7Hz)；
4.34(br t，1H，J＝4.1Hz)；
4.25-4.15(m，1H)；
3.85-3.70(m，4H)；
3.77(s，3H)；3.16(s，3H)；
2.95(dd，1H，J＝5.7，18.6Hz)；
2.37(dd，1H，J＝7.1，18.6Hz)；
2.26(br s，1H)。
Embodiment 46
Aziridine 165: (208mg, 0.62mmol) acetylize draw acetic ester (241mg, 100%) with alcohol 164 with habitual method (AcCl, pyridine, methylene dichloride, DMAP catalyzer).(202mg 0.54mmol) uses Ph with the crude acetic acid ester in THF (12mL) under the room temperature 3P (155mg) handled 2 hours.Add H then 2O (1.1mL) and triethylamine (224 μ L) spend the night solution stirring.Concentrated reaction mixture is distributed in resistates between ethyl acetate and saturated bicarbonate/salt solution.Dry organic layer, vacuum concentration, purification by flash chromatography (10%MeOH/EtOAc) draws white solid aziridine 165 (125mg, 90%).
1H NMR(CDCl 3，300MHz)：δ
6.80(m，1H)；4.44(br s，1H)；4.23(t，2H，J＝4.8Hz)；
3.82-3.65(m，2H)；
3.74(s，3H)；
2.85(br d，1H，J＝19.2Hz)；
2.65-2.40(m，3H)；
2.09(s，3H)；
1.25(br s，1H)。
Embodiment 47
N-Boc aziridine 166: (113mg, (125mg, 0.49mmol), triethylamine (70 μ L) is in the solution of DMAP (catalytic amount) in methylene dichloride (7mL) 0.52mmol) to add to aziridine 165 with the Boc acid anhydrides.Concentrate after 1 hour, resistates draws the light oily N-Boc of 154mg (88%) aziridine 166 with flash chromatography (40%EtOAc/ hexane) purifying.
1H NMR(CDCl 3，300MHz)：δ
6.82(m，1H)； 4.47(brm，1H)；
4.23(t，2H，J＝4.7Hz)；
3.81(t，2H，J＝4.7Hz)；
3.75(s，3H)；
3.00(brd，1H，J＝18.0Hz)；
2.90-2.85(m，2H)；
2.65-2.55(m，1H)；
2.10(s，3H)；1.44(s，9H)。
Embodiment 48
Nitrine ester 167: (154mg, 0.43mmol), sodiumazide (216mg) heated 18 hours in 100 ℃ in DMF (5mL) with ammonium chloride (223mg) with aziridine 166.After the reaction mixture cooling, be distributed in ether and the salt solution.Ether layer water and salt washing after drying (MgSO 4).Concentrate and to draw rough resistates, its under room temperature at CH 2Cl 2In handle with 40%TFA.2 hours final vacuums concentrate and draw light color oil, and it is passed through silica gel short column (using the EtOAc wash-out).(AcCl, pyridine, methylene dichloride, DMAP catalyzer) acylate in a usual manner, flash chromatography separate (5%MeOH/ chloroform) and draw nitrine ester 167, and it is a light yellow oil, 16mg (three step totally 11%).
1H NMR(CDCl 3，300MHz)：δ
6.85(m，1H)；
5.80(brd，1H，J＝7.8Hz)；
4.55(m，1H)；
4.25-4.10(m，3H)；
3.90-3.85(m，2H)；
3.78(s，3H)；3.55(m，1H)；
2.90(dd，1H，J＝5.4，17.0Hz)；2.45-2.25(m，1H)；
2.10(s，3H)；2.05(s，3H)。
Embodiment 49
Amino acid/11 68: (208 μ L, (16mg is 0.047mmol) in the solution of THF (1mL) 0.0476M) to add to 0 ℃ ester 167 with the KOH aqueous solution.Then reaction mixture is warmed to room temperature and stirred 2 hours, use Amberlite IR-120 (just) acidic resins acidified reaction mixture again to pH=4.0.Leach resin, with ethanol and H 2The O washing.Vacuum concentration draws the nitrine carboxylic acid of 14mg (100%) white solid, it is dissolved in the ethanol (2mL), according to Corey and its colleague, " Synthesis ", 590 (1975) described steps go up with hydrogen (1atm) at Lindlar catalyzer (15mg) and handled 16 hours.Reaction mixture is filtered with Celite pad, with hot ethanol and water washing.Draw the light orange solid behind the vacuum concentration, use C 18Column chromatography (H 2The O wash-out) purifying merges the fraction that contains product, and lyophilize draws 9.8mg white powder 168.
1H NMR(D 2O，500MHz)：δ
6.53(br s，1H)；
4.28(br m，1H)；
4.08 (dd, 1H, J=11.0,11.0Hz); 3.80-3.65 (compound m, 4H);
3.44(m，1H)；
2.84 (apparent dd, 1H);
2.46-2.39 (compound m, 1H);
2.08(s，3H)。
Embodiment 50
Epoxy MOM ether 19 (PG=methoxyl methyl): according to Mordini and its colleague, " J.Org.Chem. ", the described step of 59:4784 (1994) makes (74%) from epoxy group(ing) alcohol 1. 1H NMR(CDCl 3，300MHz)：δ
6.73(m，1H)；4.87(s，2H)；
4.59(t，1H，J＝2.4Hz)；
3.76(s，3H)；
3.57(m，1H)；
3.50-3.40(m，1H)；
3.48(s，3H)；
3.10(d，J＝19.5Hz)；
2.45(m，1H)。
Embodiment 51
Aziridine 170: make (overall yield 77%) from epoxide 19 (PG=methoxyl methyl) according to embodiment 3 and 4 described general steps.
1H NMR(CDCl 3，300MHz)：δ
6.85(m，1H)；4.78(s，2H)；
4.54(m，1H)；3.73(s，3H)；
3.41(s，3H)；
2.87(d，1H，J＝18.9Hz)；
2.70-2.45(m，3H)。
Embodiment 52
Nitrine ester 22 (PG=methoxyl methyl): with aziridine 170 (329mg, 1.54mmol), NaN 3(446mg) and NH 4Cl (151mg) heated 18 hours in 65 ℃ in DMF (20mL).After the reaction mixture cooling, be distributed in ether and the salt solution.The ether layer water, salt water washing after drying (MgSO 4).Vacuum concentration draws the rough nitrine amine of light oily, and it is dissolved in CH 2Cl 2(15mL), handle with AcCl (150 μ L) with pyridine (4mL).Resistates is handled back flash chromatography separation and is drawn 350mg (76%) nitrine ester 22 (PG=methoxyl methyls), light color oil.
1H NMR(CDCl 3，300MHz)：δ
6.78(s，1H)；
6.39(br d，1H，J＝7.8Hz)；
4.72(d，1H，J＝6.9Hz)；
4.66(d，1H，J＝6.9Hz)；
4.53(br d，1H，J＝8.4Hz)；
4.00-3.90(m，1H)；
3.80-3.65(m，1H)；
3.75(s，3H)；3.37(s，3H)；
2.85(dd，1H，J＝5.4，17.7Hz)；
2.35-2.20(m，1H)；
2.04(s，3H)。
Embodiment 53
Amino acid/11 14: press Corey and its colleague, " Synthesis ", 590 (1975) step, (39mg 0.131mmol) upward handled 2.5 hours in ethanol at Lindlar catalyzer (39mg) with hydrogen (1atm) with trinitride 22 (PG=methoxyl methyl).Reaction mixture filters through Celite pad, concentrates with hot ethanol washing back and draws the rough amine of light spumescence, 33mg (92%).(380 μ L 0.476M) handle, and are acidified to pH=4.0 with Amberlite IR-120 (just) acidic resins after 1 hour with the KOH aqueous solution in THF (1mL) with this amine.Leach resin then, the washing back concentrates and draws light solid, through C 18Column chromatography (H 2The O wash-out) purifying is collected the fraction that contains product, and lyophilize draws 20mg white powder 114.
1H NMR(D 2O，300MHz)：δ
6.65(s，1H)；
4.87(d，1H，J＝7.5Hz)；
4.76(d，1H，J＝7.5Hz)；
4.47(br d，1H，J＝8.7Hz)；
4.16(dd，1H，J＝11.4，11.4Hz)；
3.70-3.55(m，1H)；
3.43(s，3H)；
2.95(dd，1H，J＝5.7，17.4Hz)；
2.60-2.45(m，1H)；
2.11(s，3H)。
Embodiment 54
Amino acid/11 71: with 40%TFA/CH 2Cl 2(1mL is cooled to 0 ℃ earlier before the interpolation) add to solid amino acid 114 (4mg, 0.015mmol) in.This reaction mixture was stirred under room temperature 1.5 hours, get white foam shape thing after concentrating.With H 2O coevaporation several, lyophilize gets 5.5mg white solid 117, and it is a tfa salt.
1H NMR(D 2O，300MHz)：δ
6.85(m，1H)；4.45(m，1H)；
4.05(dd，1H，J＝11.4，11.4Hz)；
3.65-3.55(m，1H)；
3.00-2.90(m，1H)；
2.60-2.45(m，1H)；
2.09(s，3H)。
Embodiment 55
Acetonide 180: ((25g, 144mmol in methyl alcohol Aldrich) (300mL) suspension, reflux this mixture heating up 2 hours 1mol%) to add to shikimic acid for 274mg, 1.44mmol with tosic acid.Add more tosic acid (1mol%) again, evaporation after 26 hours refluxes.(28.17g) is suspended in the acetone with rough methyl esters, and (35mL 288mmol) handles, and stirs evaporation after 6 hours under the room temperature with Propanal dimethyl acetal.This raw product is dissolved in the ethyl acetate (400mL), uses saturated NaHCO 3(3 * 125mL) with saturated NaCl washing.Organic phase drying (MgSO 4), filter, evaporate crude acetone compound 180 (～29.4g), it can directly use:
1H NMR(CDCl 3)：δ
6.91(t，1H，J＝1.1)，
4.74(t，1H，J＝4.8)，
4.11(t，1H，J＝6.9)，
3.90(m，1H)；
2.79(dd，1H，J＝4.5，17.4)，
2.25(m，2H)，1.44(s，3H)，
1.40(s，3H)。
Embodiment 56
Methanesulfonates 130: with triethylamine (29.5mL, 212mmol) add to 0 ℃ acetonide 180 (29.4, CH 141mmol) 2Cl 2(250mL) in the solution, then during 10 minutes, add Fumette (13.6mL, 176mmol).Reaction mixture was stirred 1 hour in 0 ℃, adds icy water (250mL), be transferred to separating funnel after, organic phase water, 5% citric acid (300mL), saturated NaHCO 3(300mL) washing, dry (MgSO 4) evaporation of filtration back.Crude product filters (using eluent ethyl acetate) with sintered glass funnel (a bit of silica gel is housed).Evaporated filtrate draws methanesulfonates 130 (39.5g, 91%), and it is a toughening oil, and is directly used in next step:
1H NMR(CDCl 3)：δ
6.96(m，1H)，4.80(m，2H)，
4.28(dd，1H，J＝6.6，7.5)，
3.90(s，3H)，3.12(s，3H，)，
3.01(dd，1H，J＝5，17.7)，
2.56-2.46(m，1H)。
Embodiment 57
Glycol 131: ((35.85g is in methyl alcohol 117mmol) (500mL) solution, with this solution backflow evaporation after 1.5 hours 5mol%) to add to methanesulfonates 130 for 1.11g, 5.85mmol with tosic acid.After resistates is dissolved in methyl alcohol (500mL) again, refluxed 4 hours.Evaporating solvent, raw oil is developed with ether (250mL).After 0 ℃ of crystallization is spent the night, leach solid, with the cold diethyl ether washing, drying draws glycol 131 (24.76g), and it is a white solid.After the filtrate evaporation, resistates draws 1.55g again from the methanol crystallization.Altogether 26.3g (85%) glycol 131: 1H NMR (CD 3OD): δ
6.83(m，1H)，4.86(m，1H)，
4.37(t，1H，J＝4.2)，
3.87(dd，1H，J＝4.2，8.4)，
3.75(s，3H)，3.13(s，3H)，
2.98-2.90(m，1H)，
2.53-2.43(m，1H)。
Embodiment 58
Epoxy group(ing) alcohol 1: in 0 ℃ with glycol 131 (20.78g, tetrahydrofuran (THF) 78mmol) (400mL) suspension be with 1,8-diazabicylo (5.4.0) 11 carbon-7-alkene (11.7mL 78mmol) handles, in stirring at room 9 hours to finish reaction.After the evaporation rough resistates is dissolved in CH 2Cl 2(200mL), and wash with saturated NaCl (300mL).Water CH 2Cl 2Extraction (2 * 200mL).Merge organic extract liquid, dry (MgSO 4) evaporation of filtration back.Crude product obtains white solid epoxy group(ing) alcohol 1 (12g, 90%) with silica gel (ethyl acetate) purifying, its 1H NMR spectrum is consistent with reported in literature: McGowan, D.A.; Berchtold, G.A., " J.Org.Chem. ", 46:2381 (1981).
Embodiment 59
Methoxyl methyl ether 22 (PG=methoxyl methyl): with N, (12.3mL 70.5mmol) adds to epoxy group(ing) alcohol 1 (4g, CH 23.5mmol) to N '-diisopropylethylamine 2Cl 2(100mL) in the solution, then add chloromethyl methyl ether (3.6mL, 47mmol are drawn by the technical grade distillation).This solution backflow after 3.5 hours, is boiled off solvent, and resistates then is distributed in ethyl acetate (200mL) and the water (200mL).Water merges organic extract liquid with ethyl acetate (100mL) extraction, with saturated NaCl (100mL) washing, and dry (MgSO 4) after the filtration, evaporation draws the 4.9g solid residue, its purity is fit to be directly used in next step: mp 62-65 ℃ (rough); Mp 64-66 ℃ (ether/hexane);
1H NMR(CDCl 3)：δ
6.73(m，1H)，4.87(s，2H)，
4.59(m，1H)，3.75(s，3H)，
3.57(m，1H)，
3.48 (the overlapping s that m is arranged, 4H),
3.07(dd，1H，J＝1.2，19.8)，
2.47(dq，1H，J＝2.7，19.5)。
The ethyl ester congener of compound 22:
(34.0mL 0.13mmol) adds to corresponding ethyl ester (12.0g, CH 0.065mol) of the compound 1 of room temperature with diisopropylethylamine 2Cl 2(277mL) in the solution, then add the chloromethyl methyl ether (10.0mL, 0.19mol).With this reaction mixture gentle reflux 2 hours, the cooling final vacuum concentrated, and reallocation is in EtOAc and water.Separate organic layer, in regular turn with rare HCl, saturated bicarbonate, salt water washing, MgSO 4Dry final vacuum evaporation.Then carry out flash chromatography and separate that (silica gel, 50% hexane/EtOAc) draw the corresponding ethyl ester of 13.3g (90%) colourless liquid compound 22.
1H NMR(300MHz，CDCl 3)：δ
6.73-6.71(m，1H)；
4.87(s，2H)；
4.61-4.57(m，1H)；
4.21(q，2H，J＝7.2Hz)；
3.60-3.55(m，1H)；
3.50-3.45(m，1H)；
3.48(s，3H)；
3.12-3.05(m，1H)；
2.52-2.42(m，1H)；
1.29(t，3H，J＝7.2Hz)。
Embodiment 60
Alcohol 181: (7.44g, 114.5mmol) (2.69g 50.4mmol) adds to methoxyl methyl ether 22 (PG=methoxyl methyl) (4.9g, 8/1-MeOH/H 22.9mmol) with ammonium chloride with sodiumazide 2(175mL's O v/v) in the solution, refluxes mixture 15 hours.The salt that water (75mL) dilution is separated out with dissolving concentrates this solution to remove methyl alcohol.Gained contains the water of separating out the oily resistates and is diluted with water to 200mL, with ethyl acetate (3 * 100mL) extractions.Merge organic extract liquid, with saturated NaCl (100mL) washing, dry (MgSO 4) after-filtration, and evaporation.Rough thing draws alcohol 181 (5.09g, 86%) with silica gel (1/1-hexane/ethyl acetate) purifying, and it is a light yellow oil.Alcohol 181 need not repurity and can be directly used in next step and carry out follow-up preparation.
1H NMR(CDCl 3)：δ
6.86(m，1H)，4.79(s，2H)，
4.31(brt，1H，J＝4.2)，
3.90-3.75,3.77 (the overlapping s that m is arranged, 5H), 3.43 (s, 1H),
2.92(d，1H，J＝6.6)，
2.87(dd，1H，J＝5.4，18.6)，
2.21-2.30(m，1H)。
Embodiment 61
Methanesulfonates 184: (4.4mL, 31.5mmol) (2.14mL 27.7mmol) adds to 0 ℃ alcohol 181 (6.47g, CH 25.2mmol) with methylsulfonyl chloride with triethylamine in regular turn 2Cl 2(100mL) in the solution.Reaction mixture in 0 ℃ of stirring 5 minutes, was warmed to the room temperature restir 15 minutes then.After the evaporation, resistates is distributed in ethyl acetate (200mL) and the water (100mL) organic phase water (100mL), saturated NaHCO 3(100mL), saturated NaCl (100mL) washing.Water lotion with ethyl acetate extraction once, with identical NaH-CO 3This ethyl acetate of/NaCl solution washing.Merge organic extract liquid, dry (MgSO 4) evaporation of filtration back.The purity of crude product is suitable for directly being used in the next step: 1H NMR (CDCl 3) δ
6.85(m，1H)，
4.82(d，1H，J＝6.9)，
4.73(d，1H，J＝6.9)，
4.67(dd，1H，J＝3.9，9.0)，
4.53(brt，1H，J＝4.2)，
3.78(s，3H)，3.41(s，3H)，
3.15(s，3H)，
2.98(dd，1H，J＝6.0，18.6)，
2.37(m，1H)；
13C NMR(CDCl 3)δ165.6，134.3，129.6，96.5，78.4，69.6，55.8，55.7，52.1，38.2，29.1。
Embodiment 62
Aziridine 170: in 0 ℃ with Ph 3(8.2g, (8.56g in THF 25mmol) (150mL) solution, at first adds 1/3 amount in when cooling to P, removes behind the ice bath in 10-15 minute remaining Ph 31mmol) to add to methanesulfonates 184 3P adds.Ph 3P stirred 3 hours under room temperature after adding fully, had white depositions therebetween and formed.(5.2mL 37.5mmol) with water (10mL), at room temperature stirred this mixture 12 hours to add triethylamine in this suspension.Concentrate and remove THF, resistates is distributed in CH 2Cl 2(200mL) with saturated NaCl 2(200mL).Water CH 2Cl 2Extracted several times merges organic extract liquid, dry (MgSO 4), to filter, evaporation draws crude product, draws oily aziridine 170 (4.18g, 78%) with silica gel (10%MeOH/EtOAc) purifying, and it generally contains the triphenyl phosphine oxide impurity of trace:
1H NMR(CDCl 3)δ
6.81(m，1H)，4.78(s，2H)，
4.54(m，1H)，3.73(s，3H)，
3.41(s，3H)，
2.87 (apparent dd, 1H),
2.64(brs，1H)，
2.56-2.47(m，2H)，
The NH signal is not obvious;
13C NMR(CDCl 3)δ166.9，132.5，128.0，95.9，69.5，55.2，51.6，31.1，27.7，24.1。
Embodiment 63
Amine 182: (3.2g, DMF 15mmol) (30mL) solution apply vacuum number minute on rotatory evaporator (40 ℃) so that this solution degassing with aziridine 170.(4.9g, 75mmol) (1.6g 30mmol), heated this mixture 21 hours in 65-70 ℃ with ammonium chloride to add sodiumazide then.After being cooled to room temperature, with ethyl acetate (～100mL) dilution after-filtration.Evaporated filtrate is distributed in resistates among ether (100mL) and the saturated NaCl (100mL).Organic phase is used saturated NaCl (100mL) washing once again, dry (MgSO 4), filter the back evaporation.Can be again after water lotion is handled with ethyl acetate extraction and the same method crude product additionally.Crude product silica gel (5%MeOH/CH 2Cl 2) purifying draws oily amine 182 (2.95g), it contains on a small quantity the triphen phosphorous oxides impurity from previous step:
1H NMR(CDCl 3)δ
6.82(t，1H，J＝2.3)，
4.81(d，1H，J＝7.2)，
4.77(d，1H，J＝6.9)，
4.09-4.04(m，1H)，
3.76(s，3H)，
3.47 and 3.44 (the overlapping s that m is arranged, 4H),
2.94-2.86(m，2H)，
2.36-2.24(m，1H)，
13C NMR(CDCl 3)δ165.9，137.3，128.2，96.5，79.3，61.5，55.7，55.6，51.9，29.5。
Embodiment 64
N-trityl aziridine 183: (2.59g 10.2mmol) is dissolved among the 5%HCl/MeOH (30mL), and this solution was stirred under room temperature 3 hours with amine 182.Add 5%HCl/MeOH (10mL) again and stirred 1 hour, boil off solvent, obtain 2.52gHCl salt after the high vacuum, it is a brown solid.CH toward this HCl salt of 0 ℃ 2Cl 2(50mL) add in the suspension triethylamine (3.55mL, 25.5mmol), then once add the solid trityl chloride (5.55g, 12.8mmol).This mixture was stirred 1 hour in 0 ℃, be warmed to stirring at room 2 hours after many, be cooled to 0 ℃ again, (3.6mL 25.5mmol), adds methylsulfonyl chloride (0.97mL again to add triethylamine, 12.5mmol), institute's resulting mixture stirred 22 hours under room temperature in 0 ℃ of stirring 1 hour again.After the evaporation, resistates is distributed in ether (200mL) and the water (200mL).Organic phase water (200mL) washing merges water, uses ether (200mL) extraction again.Merge organic extract liquid, water (100mL) and saturated NaCl (200mL) washing, dry (MgSO 4), filter the back evaporation.Crude product is in silica gel (1/1 hexane/CH 2Cl 2) go up purifying and draw white foam shape N-trityl aziridine 183 (3.84g, 86%).
1H NMR(CDCl 3)δ
7.4-7.23(m，16H)，
4.32(m，1H)，3.81(s，3H)，
3.06(dt，1H，J＝1.8，17.1)，
2.94-2.86(m，1H)，
2.12(m，1H)，
1.85(t，1H，J＝5.0)。
Embodiment 65
Compound 190: (100mg, 0.23mmol), (42 μ L, solution 0.35mmol) is in 70 ℃ of heating 1.25 hours, evaporation then with boron trifluoride diethyl etherate for hexalin (2mL) with N-trityl aziridine 183.Resistates is dissolved in the pyridine (2mL), and (100 μ L 1.15mmol) handle with catalytic amount DMAP with diacetyl oxide.Evaporation after stirring 3 hours under the room temperature is distributed in resistates in ethyl acetate and 5% citric acid.The water ethyl acetate extraction merges organic extract liquid, uses saturated NaHCO 3With saturated NaCl washing.Organic phase drying (MgSO 4) evaporation of filtration back.Crude product draws solid chemical compound 190 (53mg, 69%) with silica gel (1/1-hexane/ethyl acetate) purifying: mp 105-107 ℃ (ethyl acetate/hexane);
1H NMR(CDCl 3)δ
6.78(m，1H)，
6.11(dd，1H，J＝7.4)，
4.61(m，1H)，
4.32-4.23(m，1H)，
3.76(s，3H)，
3.44-3.28(m，2H)，
2.85(dd，1H，J＝5.7，17.6)，
2.28-2.17(m，1H)，
2.04(s，3H)，
1.88-1.19(m，10H)。
Embodiment 66
Compound 191: (57mg, (49mg in THF solution 0.15mmol), heated these solution 10 hours in 50 ℃ then 0.22mmol) to add to compound 190 with water (270 μ L) with triphenyl phosphine.After the evaporation resistates is dissolved in the ethyl acetate dry (Na2SO 4) evaporation of filtration back.Crude product (1/1-MeOH/EtOAc) purifying on silica gel draws light yellow solid shape amine (46mg).1.039N KOH solution (217 μ L) and water (200 μ L) are added so far in the THF of amine (1.5mL) solution, under room temperature, stir 1 hour postcooling to 0 ℃, become pH6-6.5 with the acidifying of IR120 ion exchange resin.Leach resin, after methanol wash, filtrate is evaporated.Solid residue then is dissolved in the water, and (4 * 1cm), water reaches used 2.5% acetonitrile/water wash-out afterwards to make it pass through C-18 reverse phase silica gel post.Merge the product part, evaporation, resistates is dissolved in the water, and lyophilize draws white solid amino acid/11 91 (28mg): 1HNMR (D 2O) δ
6.47(brs，1H)，
4.80(brd，1H)，
4.00(dd，1H，J＝8.9，11.6)，
3.59-3.50(m，2H)，
2.87(dd，1H，J＝5.5，17.2)，
2.06(s，3H)，
1.90-1.15 (serial m, 10H);
C 15H 24N 2O 4H 2O ultimate analysis calculated value:
C，57.31；H，8.34；N，8.91。
Measured value: C, 57.38; H, 8.09; N, 8.77.
Embodiment 67
Two-Boc guanidine radicals ester 201: press Kim and Qian, " Tetrahedron Lett. ", the step of 34:7677 (1993) is handled.With HgCl 2(593mg 2.18mmol) once adds 0 ℃ amine 200 (529mg, 1.97mmol make with the method for embodiment 109), and two-Boc thiocarbamide (561mg, 2.02mmol) and Et 3In dry DMF (5.0mL) solution of N (930 μ L).This heterogeneous reaction mixture stirred 45 minutes in 0 ℃, in stirring at room 15 minutes, with the EtOAc dilution, filtered with Celite pad then again.Behind the vacuum concentration, resistates flash chromatography on silica gel separates (10% hexane/ethyl acetate) and draws the light oily 201 of 904mg (90%).
1H NMR(CDCl 3，300MHz)δ
11.39(s，1H)；
8.63(d，1H，J＝7.8Hz)；
6.89(t，1H，J＝2.4Hz)；
6.46(d，1H，J＝8.7Hz)；
4.43-4.32(m，1H)；
4.27-4.17(m，1H)；
4.13-4.06(m，1H)；
3.77(s，3H)；
3.67-3.59(m，1H)；
2.83(dd，1H，J＝5.1，17.7Hz)；
2.45-2.33(m，1H)；
1.95(s，3H)；
1.65-1.50(m，2H)；
1.45(s，18H)；
0.90(t，3H，J＝7.5Hz)。
Embodiment 68
Carboxylic acid 202: (3.45mL, (904mg is in THF 1.77mmol) (10mL) solution 1.039N) to add to methyl esters 201 with the KOH aqueous solution.This reaction mixture in stirring at room 17 hours, is cooled to 0 ℃, with Amberlite IR-120 (H +) acidic resins are acidified to pH4.0.Leach resin, water and methanol wash, vacuum concentration draws light spumescence free acid, need not purifying and is directly used in next reaction.
Embodiment 69
Guanidine carboxylic acid 203: the CH that pure trifluoroacetic acid (25mL) is added to two-Boc guanidino-acid 202 (raw product that obtains from last reaction) of 0 ℃ 2Cl 2In the solution (40mL), this reaction mixture was stirred 1 hour in 0 ℃, then in stirring at room 2 hours.Vacuum concentration draws the light orange solid, uses C 18Reverse-phase chromatography (water wash-out) purifying.Collection contains expects the fraction of product, and lyophilize draws the trifluoroacetate of 495mg (68%, 2 step) guanidine carboxylic acid 203.
1H NMR(D 2O，300MHz)：δ
6.66(s，1H)；
4.29(bd，1H，J＝9.0Hz)；
4.01(dd，1H，J＝10.8，10.8Hz)；
3.87-3.79(m，1H)；
3.76-3.67(m，1H)；
3.60-3.50(m，1H)；
2.83(dd，1H，J＝5.1，17.4Hz)；
2.47-2.36(m，1H)，
2.06(s，3H)；
1.65-1.50(m，2H)；
0.90(t，3H，J＝7.2Hz)。
C 15H 23O 6N 4F 3The ultimate analysis calculated value:
C，43.69；H，5.62；N，13.59。
Measured value: C, 43.29; H, 5.90; N, 13.78.
Embodiment 70
Carbonamidine carboxylic acid 204: water (the 500 μ L) solution of amino acid/11 02 (25mg, 0.10mmol are made by the method for embodiment 110) is adjusted pH to 8.5 with 0.1N NaOH in the time of 0-5 ℃.Once (45mg 0.26mmol) adds, and when the pH that keeps this reaction mixture is 8.5-9.0 (using 1.0N NaOH) it is stirred 3 hours in 0-5 ℃ with benzyl formyl inferior amine salt hydrochlorate.Vacuum concentration then, C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 4.0mg (13%) carbonamidine carboxylic acid 204.
1H NMR(D 2O，300MHz)：δ
7.85(s，1H)；
6.53(bd，1H，J＝7.8Hz)；
4.32-4.25(bm，1H)；
4.10-3.97(m，1H)；
3.76-3.67(m，2H)；
3.57-3.49(m，1H)；
2.86-2.81(m，1H)；
2.55-2.40(m，1H)；
2.04(s，1H)；
1.65-1.50(m，2H)；
0.90(t，3H，J＝7.4Hz)。
Embodiment 71
Amino acid 206: (481 μ L 1.039N) add in THF (1.0mL) solution of amino methyl 205 (84mg, 0.331mmol are made by embodiment 107) with the KOH aqueous solution.This reaction mixture was at room temperature stirred 2.5 hours, with Amberlite IR-120 (H +) acidic resins are acidified to pH6.5.Leach resin, water and methanol wash, vacuum concentration draws the amino acid of white solid, and it is through C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 59mg (74%) amino acid 206.
1H NMR(CD 3OD，300MHz)：δ
6.60(bd，1H，J＝1.8Hz)；
4.01-3.95(m，1H)；
3.71-3.60(m，2H)；
3.50-3.42(m，1H)；
3.05-2.85(m，2H)；
2.39-2.28(m，1H)；
1.70-1.55(m，2H)；
0.95(t，3H，J＝7.5Hz)。
Embodiment 72
Trifluoroacetamide 207: (59mg 0.246mmol) in the solution of anhydrous methanol (1.0mL), adds Et down in argon gas after outgasing toward amino acid 206 3N (35 μ L) adds trifluoro-acetate (35 μ L) again, and it is stirred 1 week and concentrated under room temperature.By 1H NMR analyzes and shows that reaction has 40% to finish.Rough reaction product is dissolved in anhydrous methanol (1.0mL) again, trifluoro-acetate (1.0mL) and Et 3Among the N (0.5mL), and in stirring at room 5 days.In vacuum concentration, be dissolved in 50%THF/H more then 2Among the O (2.0mL), with AmberliteIR-120 (H +) acidic resins are acidified to pH4, filter, and concentrate and draw rough trifluoroacetamide carboxylic acid, it need not purifying can be directly used in next reaction.
Embodiment 73
Amino acid 208: trinitride 207 (by the rough thing of last reaction gained) is at room temperature handled with the triphenyl phosphine (225mg) that is carried on the polymkeric substance with the solution of water (160 μ L) in THF (2.0mL), stir after 20 hours, leach polymkeric substance, use methanol wash.Vacuum concentration draws light solid, uses C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws the trifluoroacetamide amino acid 208 of 6.5mg (9%).
1H NMR(D 2O，300MHz)：δ
6.59(bs，1H)；
4.40-4.30(m，1H)；
4.26(t，1H，J＝10.1Hz)；
3.80-3.66(m，2H)；
3.56-3.47(m，1H)；
2.96(bdd，1H，J＝5.4，17.7Hz)；
2.58-2.45(m，1H)；
1.62-1.50(m，2H)；
0.89(t，3H，J＝7.5Hz)。
Embodiment 74
Toluidrin methyl esters 209: methylsulfonyl chloride (19 μ L) is added to 0 ℃ amine 205 (58mg, 0.23mmol are made by embodiment 107), Et 3N (97 μ L) and catalytic amount DMAP (several crystal) are at CH 2Cl 2In the solution (1.0mL).After 30 minutes reaction mixture is warmed to room temperature and restir 1 hour, vacuum concentration, resistates is gone up the flash chromatography separation in silica gel (50% hexane/ethyl acetate) and is drawn 61mg (79%) sulphonamide 209.
1H NMR(CDCl 3，300MHz)：δ
6.87(t，1H，J＝2.3Hz)；
5.08(d，1H，J＝7.5Hz)；
4.03-3.90(m，1H)；
3.78(s，3H)；
3.75-3.45(m，4H)；
3.14(s，3H)；
2.95(dd，1H，J＝5.2，17.3Hz)；
2.42-2.30(m，1H)；
1.75-1.55(m，2H)；
0.95(t，3H，J＝7.5Hz)。
Embodiment 75
Amino ester 210: (61mg 0.183mmol) at room temperature handles with the triphenyl phosphine (170mg) that is carried on the polymkeric substance with the solution of water (118 μ L) in THF (2.0mL), stirs and leaches polymkeric substance after 17.5 hours, uses methanol wash with trinitride 209.Behind the vacuum concentration, resistates carries out the flash chromatography separation with short silicagel column (100% methyl alcohol) and draws the light spumescence amino ester 210 of 45mg (80%).
1H NMR(CDCl 3，300MHz)：δ
6.85(s，1H)；
3.94(bd，1H，J＝7.8Hz)；
3.77(s，3H)；
3.74-3.60(m，2H)；
3.55-3.45(m，1H)；
3.25-3.15(m，1H)；
3.11(s，3H)；
2.94-2.85(m，1H)；
2.85(bs，2H)；
2.22-2.10(m，1H)；
1.70-1.56(m，2H)；
0.94(t，3H，J＝7.5Hz)。
Embodiment 76
Amino acid 211: (21mg, (135 μ L 1.039N) handle THF 0.069mmol) (200 μ L) solution, and reaction mixture stirred under room temperature 40 minutes, with Amberlite IR-120 (H with the KOH aqueous solution with methyl esters 210 +) acidic resins are neutralized to pH7.0, leach resin, water and methanol wash, vacuum concentration draws the amino acid of light solid state, uses C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 3.5mg (17%) amino acid 211.
1H NMR(D 2O，300MHz)：δ
6.60(d，1H，J＝1.8Hz)；
4.30-4.20(m，1H)；
3.84-3.75(m，1H)；
3.68-3.58(m，1H)；
3.60-3.40(m，2H)；
3.20(s，3H)；
2.96-2.88(m，1H)；
2.55-2.45(m，1H)；
1.72-1.59(m，2H)；
0.93(t，3H，J＝7.4Hz)。
Embodiment 77
Two-Boc guanidine radicals ester 212: press Kim and Qian, " Tetrahedron Lett. " 34:7677 (1993) step is handled.With HgCl 2(30mg, 0.11mmol) once add 0 ℃ amine 210 (31mg, 0.101mmol), 21 Boc thiocarbamides (28.5mg, 0.103mmol) and Et 3In dry DMF (the 203 μ L) solution of N (47 μ L).This heterogeneous reaction mixture stirred 30 minutes at 0 ℃, and restir is 30 minutes under room temperature, and then with the EtOAc dilution, recycle silicon algae soil pad filters.Vacuum concentration, resistates is gone up the flash chromatography separation at silica gel (40% hexane/ethyl acetate) and is drawn the light oily 212 of 49mg (89%).
1H NMR(CDCl 3，300MHz)：δ
11.47(s，1H)；
8.66(d，1H，J＝8.4Hz)；
6.87(s，1H)；6.01(bs，1H)；
4.50-4.35(m，1H)；
4.04(bd，1H，J＝8.4Hz)；
3.76(s，3H)；
3.70-3.60(m，1H)；
3.53-3.45(m，2H)；
3.02(s，3H)；
2.85(dd，1H，J＝5.3，17.3Hz)；
2.42-2.30(m，1H)；
1.66-1.55(m，2H)；
1.49(s，9H)；1.48(s，9H)；
0.93(t，3H，J＝7.3Hz)。
Embodiment 78
Carboxylic acid 213: (260 μ L, (49mg is in THF 0.090mmol) (1.0mL) solution 1.039N) to add to methyl esters 212 with the KOH aqueous solution.This reaction mixture stirred under room temperature 16 hours, was cooled to 0 ℃, with Amberlite IR-120 (H +) the acidic resins acidifying becomes pH4.0.Leach resin, water and methanol wash.Vacuum concentration draws light spumescence free acid, and it need not purifying and directly is used in the next reaction.
Embodiment 79
Guanidine carboxylic acid 214: the CH that pure trifluoroacetic acid (2.0mL) is added to two-Boc guanidino-acid 213 (deriving from the rough thing of last reaction) of 0 ℃ 2Cl 2(2.0mL) in the solution.This reaction mixture was stirred 1 hour at 0 ℃, under room temperature, stirred 1 hour again.Vacuum concentration draws the light orange solid, uses C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 10mg (25%, 2 step) guanidine carboxylic acid 214.
1H NMR(D 2O，300MHz)：δ
6.60(bs，1H)；
4.22(bd，1H，J＝9.0Hz)；
3.82-3.66(m，2H)；
3.65-3.54(m，1H)；
3.43(bt，1H，J＝9.9Hz)；
3.15(s，3H)；
2.82(dd，1H，J＝5.0，17.5Hz)；
2.48-2.30(m，1H)；
1.71-1.58(m，2H)；
0.93(t，3H，J＝7.3Hz)。
Embodiment 80
Propionic acid amide methyl esters 215: (96 μ L 1.1mmol) add to 0 ℃ the amine 205 (178mg, 0.70mmol are made by embodiment 107) and the CH of pyridine (1.5mL) with propionyl chloride 2Cl 2(2.0mL) in the solution,, it is distributed in ethyl acetate and the salt solution in 0 ℃ of concentrated reaction mixture after 30 minutes.Separate organic layer, in regular turn with saturated sodium bicarbonate, salt water washing, dry (MgSO 4) final vacuum concentrates, resistates in silica gel (40% hexane/EtOAc) go up flash chromatography separate 186mg (86%) light yellow solid shape propionic acid amide methyl esters 215.
1H NMR(CDCl 3，300MHz)：δ
6.86(t，1H，J＝2.3Hz)；
5.72(bd，1H，J＝7.8Hz)；
4.52-4.49(m，1H)；
4.25-4.15(m，1H)；
3.77(s，3H)；
3.65-3.38 (compound m, 3H);
2.87(dd，1H，J＝5.7，17.7Hz)；
2.28(q，2H，J＝7.5Hz)；
2.25-2.20(m，1H)；
1.65-1.50(m，2H)；
1.19(t，3H，J＝7.5Hz)。
0.92(t，3H，J＝7.5Hz)。
Embodiment 81
Amino methyl 216: (186mg 0.60mmol) at room temperature handles with the triphenyl phosphine (560mg) that is carried on the polymkeric substance with the solution of water (400 μ L) at THF (5.0mL), stirs after 21 hours, leaches polymkeric substance, uses methanol wash with trinitride 215.Vacuum concentration draws rough amino ester 216, and it need not purifying and can directly be used in next reaction.
Embodiment 82
Amino acid 217: (866 μ L 1.039N) handle, and this reaction mixture is in stirring at room after 3 hours, with Amberlite IR-120 (H with the KOH aqueous solution with THF (the 500 μ L) solution of methyl esters 216 (deriving from the rough thing of last reaction) +) acidic resins are neutralized to pH 7.0.Leach resin, water and methanol wash.Vacuum concentration draws light solid state amino acid, uses C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 49mg (31%, 2 step) amino acid 217.
1H NMR(D 2O，300MHz)：δ
6.54(s，1H)；
4.25(bd，1H，J＝8.7Hz)；
4.13(dd，1H，J＝9.0，11.3Hz)；
3.74-3.60(m，1H)；
3.61-3.40(m，2H)；
2.85(dd，1H，J＝5.9，17.1Hz)；
2.55-2.40(m，1H)；
2.35(q，2H，J＝7.5Hz)；
1.65-1.45(m，2H)；
1.13(t，3H，J＝7.5Hz)；
0.88(t，3H，J＝7.5Hz)。
Embodiment 83
(monomethyl) two-Boc guanidine radicals ester 218: under the room temperature, with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (38mg) and Et 3N (56 μ L) add to amine 200 (51mg, 0.19mmol) with monomethyl two-Boc thiocarbamide (36mg, in dry DMF 0.19mmol) (1.0mL) solution, room temperature after following 1.5 hours with HgCl 2(about 75mg, excessive) once adds.This heterogeneous reaction mixture was stirred 45 minutes, after the ethyl acetate dilution, filter with Celite pad.Filtrate is diluted with extra ethyl acetate again, through rare HCl, and saturated sodium bicarbonate, after the salt water washing, dry (MgSO 4), vacuum concentration.Resistates is gone up the flash chromatography separation at silica gel (10%MeOH/EtOAc) and is drawn 13mg (16%) colourless foam shape (monomethyl) two-Boc guanidine radicals ester 218.
1H NMR(CDCl 3，300MHz)：δ
6.84(s，1H)；
6.20(bd，1H，J＝5.1Hz)；
5.45(bs，1H)；
4.25-4.40(bm，1H)；
4.20-4.05(bm，2H)；
3.76(s，3H)；
3.60-3.50(m，1H)；
3.43-3.30(m，1H)；
2.90(dd，1H，J＝5.4，17.7Hz)；
2.77(d，3H，J＝4.8Hz)；
2.35-2.25(m，1H)；
1.96(s，3H)；
1.60-1.50(m，2H)；
1.47(s，9H)；
0.91(t，3H，J＝7.2Hz)。
Embodiment 84
(monomethyl) two-Boc guanidino-acid 219: with the KOH aqueous solution (60 μ L, 1.039N) add to methyl esters 218 (13mg, 0.031mmol) THF (500 μ L) solution in, this reaction mixture was stirred under room temperature 1 hour, gentle reflux is 1 hour then, after being cooled to 0 ℃, with Amberlite IR-120 (H +) acidic resins are acidified to pH6.0.Leach resin, water and methanol wash.Vacuum concentration draws free acid 219, and it need not pure can directly being used in next reaction.
Embodiment 85
(monomethyl) guanidine radicals amino acid 220: the CH that pure trifluoroacetic acid (1.0mL) is added to (monomethyl) two-Boc guanidino-acid 219 (deriving from the rough thing of last reaction) of 0 ℃ 2Cl 2(1.0mL) in the solution.This reaction mixture was stirred 1 hour at 0 ℃, under room temperature, stirred 1 hour then.Vacuum concentration draws light solid, uses C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 4.4mg (33%, 2 step) guanidine carboxylic acid 220.
1H NMR(D 2O，300MHz)：δ
6.52(bs，1H)；
4.27(bd，1H，J＝8.4Hz)；
4.01(dd，1H，J＝9.2，10.3Hz)；
3.86-3.75(m，1H)；
3.75-3.67(m，1H)；
3.60-3.49(m，1H)；
2.85(s，3H)；
2.80(dd，1H，J＝5.1，17.7Hz)；
2.47-2.37(m，1H)；
2.04(s，3H)；
1.64-1.50(m，2H)；
0.90(t，3H，J＝7.2Hz)。
Embodiment 86
(R)-methyl-propyl ester 221: under argon gas and room temperature, in the stirring with BF 3Et 2(63 μ L, (150mg is in (R)-(-) 0.341mmol)-2-butanols (1.2mL) solution 0.51mmol) to add to N-trityl aziridine 183 for O.With this light solution 70 ℃ the heating 2 hours after, vacuum concentration, get brown resistates, it is dissolved in the anhydrous pyridine (2.0mL), handle with catalytic amount DMAP (several crystal) with diacetyl oxide (225 μ L) down at 0 ℃, reaction mixture is warmed to room temperature and stirred 2 hours, vacuum concentration is distributed in ethyl acetate and the salt solution.Separate organic layer, in regular turn with rare HCl, saturated sodium bicarbonate, salt water washing, dry (MgSO 4) final vacuum concentrates.Resistates is gone up the flash chromatography separation at silica gel (50% hexane/ethyl acetate) and is drawn the light solid state of 75mg (72%) (R)-methyl-propyl ester 221.
1H NMR(CDCl 3，300MHz)：δ
6.79(t，1H，J＝2.2Hz)；
6.14(d，1H，J＝7.3Hz)；
4.55(bd，1H，J＝8.7Hz)；
4.33-4.23(m，1H)；
3.77(s，3H)
3.56-3.45(m，1H)；
3.40-3.27(m，1H)；
2.85(dd，1H，J＝5.5，17.5Hz)；
2.30-2.15(m，1H)；
2.04(s，3H)；
1.59-1.40(m，2H)；
1.10(d，3H，J＝6.0Hz)
0.91(t，3H，J＝7.4Hz)。
Embodiment 87
(R)-and methyl-propyl amino ester 222: with Ph 3(95mg, (75mg is 0.24mmol) and in THF (3.0mL) solution of water (432 μ L) 0.36mmol) once to add trinitride 221 for P.In 50 ℃ of heating 10 hours, the cooling final vacuum concentrated and draws light solid with this pale yellow solution.Draw the light solid state amino ester 222 of 66mg (97%) with silica gel (50%MeOH/EtOAc) purification by flash chromatography.
Embodiment 88
Amino acid 223: (34mg, (175 μ L 1.039N) handle THF 0.12mmol) (1.0mL) solution with the KOH aqueous solution with methyl esters 222.Reaction mixture is after stirring 3 hours under the room temperature, with Amberlite IR-120 (H +) the acidic resins acidifying becomes pH6.0, leaches resin, water and methanol wash, vacuum concentration draws light solid state amino acid, uses C 18Reverse-phase chromatography (water wash-out) purifying.Collection contains expects the fraction of product, and lyophilize draws 11.5mg (36%) amino acid 223.
1H NMR(D 2O，300MHz)：δ
6.52(bs，1H)；
4.28(bd，1H，J＝8.7Hz)；
4.04(dd，1H，J＝8.8，11.5Hz)；
3.74-3.65(m，1H)；
3.50-3.60(m，1H)；
2.90(dd，1H，J＝5.5，17.2Hz)；
2.50-2.40(m，1H)；
2.10(s，3H)；
1.60-1.45(m，2H)；
1.14(d，3H，J＝6.2Hz)；
0.91(t，3H，J＝7.4Hz)。
Embodiment 89
Two-Boc guanidine radicals ester 224: press Kim and Qian, " Tetrahedron Lett. ", 34:7677 (1993) step is handled.With HgCl 2(34mg, 0.125mmol) once add 0 ℃ amine 222 (32mg, 0.113mmol), two-Boc thiocarbamide (32mg, 0.115mmol) and Et 3In dry DMF (the 350 μ L) solution of N (53 μ L).This heterogeneous reaction mixture in 0 ℃ of stirring 45 minutes, was stirred 1 hour under room temperature again, then with the EtOAc dilution, the filtration of recycle silicon algae soil pad.Vacuum concentration, resistates is gone up the flash chromatography separation at silica gel (20% hexane/ethyl acetate) and is drawn 57mg (96%) colourless foam shape 224.
1H NMR(CDCl 3，300MHz)：δ
11.40(s，1H)；
8.65(d，1H，J＝7.8hz)；
6.82(s，1H)；
6.36(d，1H，J＝8.7Hz)；
4.46-4.34(m，1H)；
4.20-4.10(m，1H)；
4.10-3.95(m，1H)；
3.76(s，3H)；
2.79(dd，1H，J＝5.4，17.7Hz)；
2.47-2.35(m，1H)；
1.93(s，3H)；
1.60-1.45(m，2H)；
1.49(s，18H)；
1.13(d，3H，J＝6.0Hz)；
0.91(t，3H，J＝7.5Hz)。
Embodiment 90
Carboxylic acid 225: (212 μ L, (57mg is in THF 0.11mmol) (1.5mL) solution 1.039N) to add to methyl esters 224 with the KOH aqueous solution.This reaction mixture was at room temperature stirred 16 hours, be cooled to 0 ℃, with Amberlite IR-120 (H +) the acidic resins acidifying becomes pH 4.0.Leach resin, water and methanol wash.Vacuum concentration draws light spumescence free acid, and it need not purifying and can directly be used in next reaction.
Embodiment 91
Guanidine carboxylic acid 226: the CH that pure trifluoroacetic acid (4.0mL) is added to two-Boc guanidino-acid 225 (deriving from the rough thing of last reaction) of 0 ℃ 2Cl 2(4.0mL) in the solution.This reaction mixture was stirred 1 hour in 0 ℃, again in stirring at room 2 hours; Vacuum concentration obtains the light orange solid, uses C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 18.4mg (40%, 2 step) guanidine carboxylic acid 226.
1H NMR(D 2O，300MHz)：δ
6.47(s，1H)；
4.28(bd，1H，J＝8.4Hz)；
3.93-3.74(m，2H)；
3.72-3.63(m，1H)；
2.78(dd，1H，J＝4.8，17.4Hz)；
2.43-2.32(m，1H)；
1.58-1.45(m，2H)；
1.13(d，3H，J＝6.0Hz)；
0.90(t，3H，J＝7.4Hz)。
Embodiment 92
(diethyl) methyl ether ester 227: under argon gas and room temperature, in stirring with BF 3Et 2(6.27mL, (15g is in 3-amylalcohol (230mL) solution 34mmol) 51mmol) to add to N-trityl aziridine 183 for O.70-75 ℃ of heating 1.75 hours, vacuum concentration drew brown resistates with this light solution, and it is dissolved in the anhydrous pyridine (2.0mL) again, and (16mL 170mmol) handles with catalytic amount DMAP (200mg) with diacetyl oxide.Reaction mixture was stirred under room temperature 18 hours, be distributed in behind the vacuum concentration among ethyl acetate and the 1M HCl.Separate organic layer, use saturated sodium bicarbonate in regular turn, salt water washing, dry (MgSO 4) final vacuum concentrates.Resistates is gone up the flash chromatography separation in silica gel (50% hexane/ethyl acetate) and is drawn 7.66g (diethyl) methyl ether ester, draws colourless needle-like 227 (7.25g, 66%) from the ethyl acetate/hexane recrystallize.
1H NMR(CDCl 3，300MHz)：δ
6.79(t，1H，J＝2.1Hz)；
5.92(d，1H，J＝7.5Hz)；
4.58(bd，1H，J＝8.7Hz)；
4.35-4.2(m，1H)；
3.77(s，3H)；
3.36-3.25(m，2H)；
2.85(dd，1H，J＝5.7，17.4Hz)；
2.29-2.18(m，1H)；
2.04(s，3H)；
1.60-1.45(m，4H)；
0.91(t，3H，J＝3.7Hz)；
0.90(t，3H，J＝7.3Hz)。
Embodiment 93
(diethyl) methyl ether amino ester 228: with Ph 3(1.21g, (1g is 3.1mmol) and in the solution of water (5.6mL) in THF (30mL) 4.6mmol) once to add trinitride 227 for P.Then with this pale yellow solution in 50 ℃ of heating 10 hours, the cooling final vacuum concentrates.Aqueous oily resistates is distributed among EtOAc and the saturated NaCl.Organic phase drying (Mg-SO 4), filter the back evaporation.Draw the shallow white solid amino ester 228 of 830mg (90%) with the separation of silica gel (50% methanol/ethyl acetate) flash chromatography.
1H NMR(CDCl 3，300MHz)：δ
6.78(t，1H，J＝2.1Hz)；
5.68(bd，1H，J＝7.8Hz)；
4.21-4.18(m，1H)；
3.75(s，3H)；
3.54-3.45(m，1H)；
3.37-3.15(m，2H)；
2.74(dd，1H，J＝5.1，17.7Hz)；
2.20-2.07(m，1H)；
2.03(s，3H)；
1.69(bs，2H，-NH 2)；
1.57-1.44(m，4H)；
0.90(t，3H，J＝7.5Hz)；
0.89(t，3H，J＝7.5Hz)。
Embodiment 94
Amino acid 229: (830mg, (4mL 1.039N) handles THF 2.8mmol) (15mL) solution methyl esters 228 with the KOH aqueous solution.This reaction mixture was at room temperature stirred 40 minutes, become pH5.5-6.0 with the acidifying of Dowex 50WX8 acidic resins.Leach resin, water and methanol wash.Vacuum concentration draws light solid state amino acid, uses C 18(water is 5%CH to reverse-phase chromatography then 3The CN/ water elution) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 600mg (75%) amino acid 229.
1H NMR(D 2，300MHz)：δ
6.50(t，1H，J＝2.1Hz)；
4.30-4.26(m，1H)；
4.03(dd，1H，J＝9.0，11.7Hz)；
3.58-3.48(m，2H)；
2.88(dd，1H，J＝5.4，16.8Hz)；
2.53-2.41(m，1H)；
1.62-1.40(m，4H)；
0.90(t，3H，J＝7.5Hz)；
0.85(t，3H，J＝7.5Hz)。
Embodiment 95
Tert-pentyl ether-ether 230: under argon gas and room temperature, in stirring with BF 3Et 2(43 μ L, (104mg is in tertiary amyl alcohol 0.24mmol) (2.5mL) solution 0.35mmol) to add to N-trityl aziridine 183 for O.75 ℃ of heating 3 hours, vacuum concentration drew brown resistates with this light solution, and it is dissolved in the anhydrous pyridine (2.0mL), handled with catalytic amount DMAP (several crystal) with diacetyl oxide (250 μ L).Reaction mixture was at room temperature stirred 1.5 hours, behind the vacuum concentration, be distributed in ethyl acetate and the salt solution.Separate organic layer, in regular turn with rare HCl, saturated sodium bicarbonate, salt water washing, dry (MgSO 4) final vacuum concentrates.Resistates is gone up the flash chromatography separation in silica gel (50% hexane/ethyl acetate) and is drawn 27mg (35%) light orange oily tert-pentyl ether-ether 230.
1H NMR(CDCl 3，300MHz)：δ
6.72(t，1H，J＝2.1Hz)；
5.83(d，1H，J＝7.2Hz)；
4.71(bd，1H，J＝8.1Hz)；
4.45-4.35(m，1H)；
3.75(s，3H)；
3.27-3.17(m，1H)；
2.27-2.15(m，1H)；
2.84(dd，1H，J＝5.7，17.4Hz)；
2.05(s，3H)；
1.57-1.47(m，2H)；
1.19(s，3H)；1.15(s，3H)；
0.90(t，3H，J＝7.5Hz)。
Embodiment 96
Tert-amyl ether amino ester 231: with Ph 3(35mg, (27mg is 0.083mmol) and in the solution of water (160 μ L) in THF (1.5mL) 0.133mmol) once to add to trinitride 230 for P.In 50 ℃ of heating 10 hours, the cooling final vacuum concentrated and draws light solid with this light orange solution.Go up the flash chromatography separation at silica gel (50%MeOH/EtOAc) and draw the light oily amino ester 231 of 20mg (82%).
Embodiment 97
Amino acid 232: (20mg, (131 μ L 1.039N) handle THF 0.068mmol) (1.0mL) solution with the KOH aqueous solution with methyl esters 231.This reaction mixture was stirred under room temperature 2.5 hours, use Amberlite IR-120 (H again +) acidic resins are acidified to pH 5.0.Leach resin, water and methanol wash.Vacuum concentration draws light solid state amino acid, and it uses C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 8.6mg (45%) amino acid 232.
1H NMR(D 2O，300MHz)：δ
6.47(bs，1H)；
4.42(bd，1H，J＝8.1Hz)；
3.97(dd，1H，J＝8.4，11.4Hz)；
3.65-3.54(m，1H)；
2.88(dd，1H，J＝5.5，17.3Hz)；
2.51-2.39(m，1H)；
2.08(s，3H)；
1.61-1.46(m，2H)；
1.23(s，3H)；1.18(s，3H)；
0.86(t，3H，J＝7.5Hz)。
Embodiment 98
N-propyl thioether ester 233: under argon gas and room temperature, in stirring with BF 3Et 2(130 μ L, (300mg is in 1-propylmercaptan (8.0mL) solution 0.68mmol) 1.06mmol) to add to N-trityl aziridine 183 for O.This light solution in 65 ℃ of heating 45 minutes, is distributed in ethyl acetate and the salt solution after concentrating.Separate organic layer, with saturated sodium bicarbonate, salt water washing, dry (MgSO 4) final vacuum concentrates.Resistates is gone up the flash chromatography separation in silica gel (30% hexane/ethyl acetate) and is drawn the light oily n-propyl of 134mg (73%) thioether ester 233.
1H NMR(CDCl 3，300MHz)：δ
6.87(t，1H，J＝2.4Hz)。
3.77(s，3H)；
3.48-3.38(m，1H)；
3.22-3.18(m，1H)；
2.93(dd，1H，J＝5.4，17.4Hz)；
2.80(t，1H，J＝9.9Hz)。
2.51(t，2H，J＝7.2Hz)。
2.32-2.20(m，1H)；
1.96(bs，2H，-NH 2)；
1.69-1.56(m，2H)；
1.00(t，3H，J＝7.2Hz)。
Embodiment 99
N-propyl thioether azido-ester 234: (60 μ L, (134mg is in pyridine 0.50mmol) (1.5mL) solution 0.84mmol) to add to 0 ℃ amine 233 with pure Acetyl Chloride 98Min..Reaction mixture was warmed to the room temperature restir 15 minutes after stirring 1 hour.Reaction mixture is distributed in ethyl acetate and the salt solution after concentrating, in regular turn with rare HCl, and water, saturated sodium bicarbonate, salt water washing, dry (MgSO 4) final vacuum concentrates.Resistates draws 162mg (100%) light yellow solid shape n-propyl thioether azido-ester 234 with the separation of silica gel (30% hexane/ethyl acetate) flash chromatography.
1H NMR(CDCl 3，300MHz)：δ
6.90(t，1H，J＝2.7Hz)；
5.87(bd，1H，J＝7.8Hz)；
4.07-3.98(m，1H)；
3.77(s，3H)；
3.65-3.55(m，1H)；
2.95-2.85(m，1H)；
2.60-2.45(m，2H)；
2.30-2.18(m，1H)；
2.08(s，3H)；
1.65-1.53(m，2H)；
0.98(t，3H，J＝7.2Hz)。
Embodiment 100
N-propyl thioether amino ester 235: (130mg, ethyl acetate 0.416mmol) (10mL) solution is at room temperature used Lindlar catalyzer (150mg) hydrogenation (1atm) 18 hours with trinitride 234.Leach catalyzer with Celite pad then, after hot ethyl acetate and methanol wash, vacuum concentration, orange residue draws 62mg (53%) n-propyl thioether amino ester 235 through the flash chromatography separation.
1H NMR(CDCl 3，300MHz)：δ
6.88(t，1H，J＝2.7Hz)；
5.67(bd，1H，J＝8.7Hz)；
3.76(s，3H)；
3.75-3.65(m，1H)；
3.45-3.35(bm，1H)；
3.05-2.95(m，1H)；
2.87-2.78(m，1H)；
2.56-2.40(m，2H)；
2.18-2.05(m，1H)；
2.09(s，3H)；
1.65-1.50(m，2H)；
1.53(bs，2H，-NH 2)；
0.98(t，3H，J＝7.2Hz)。
Embodiment 101
Compound 240: with quinic acid (103g), 2,2-Propanal dimethyl acetal (200mL) stirred under room temperature 4 days with the suspension of toluenesulphonic acids (850mg) in acetone (700mL).Removal of solvent under reduced pressure and excess reagent.Flash column chromatography (hexane/EtOAc=2/1-1.5/1) purifying draws lactone 240 (84g, 73%): 1H NMR (CDCl 3) δ
4.72(dd，J＝2.4，6.1Hz，1H)，
4.50(m，1H)，4.31(m，1H)，
2.67(m，2H)，
2.4-2.2(m，3H)；
1.52(s，3H)，1.33(s，3H)。Refluxed 4 hours if will react, (be distributed in ethyl acetate/water) behind the water treatment purifying and make crude product go out lactone 240 (productive rate 71%) from the ethyl acetate/hexane recrystallize.
Embodiment 102
Compound 241: ((43.5g is in methyl alcohol 203mmol) (1200mL) solution 203mmol) once to add to lactone 240 for 4.37M, 46.5mL with sodium methylate.This mixture was stirred under room temperature 3 hours, interrupt reaction with acetate (11.62mL).Methyl alcohol is removed in decompression.The mixture dilute with water is with EtOAc extraction three times.Merge organic phase, wash once after drying (MgSO of salt water washing 4).Flash column chromatography (hexane/EtOAc=1/1 to 1/4) purifying draws glycol (43.4g, 87%):
1H NMR(CDCl 3)δ
4.48(m，1H)，4.13(m，1H)，
3.99(t，J＝6.4Hz，1H)；
3.82(s，3H)，3.34(s，1H)，
2.26(d，J＝3.8Hz，2H)，
2.08(m，1H)，1.91(m，1H)，
1.54(s，3H)，1.38(s，3H)。
In addition, if lactone 240 is handled with catalytic amount sodium ethylate (1mol%) in ethanol, crude product draws corresponding ethyl ester (67%) behind the ethyl acetate/hexane recrystallize.The resistates that derives from mother liquor (being made up of initiator and product) is handled once more with same reaction conditions, draws additional product behind the recrystallize.Overall yield is 83%.
Embodiment 103
Compound 242: with Tosyl chloride (27.7g, 145mmol) add to glycol 241 (29.8g, 121mmol) with pyridine (230mL) solution of 4-(N, N-two methylaminos) pyridine (500mg) in.This mixture was stirred under room temperature 3 days, and pyridine is removed in decompression.The dilute with water mixture is with EtOAc extraction three times.Merge organic phase, wash secondary with water, the salt water washing once, dry (MgSO 4) back concentrating.(hexane/EtOAc=2/1-1/1) purifying draws p-toluenesulfonic esters 242 (44.6g, 92%) to flash column chromatography.
1H NMR(CDCl 3)δ
7.84(d，J＝8.4Hz，2H)
7.33(d，J＝8.1Hz，2H)
4.76(m，1H)，4.42(m，1H)，
4.05(dd，J＝5.5，7.5Hz，1H)，
3.80(s，3H)，2.44(s，3H)，
2.35(m，1H)，2.24(m，2H)，
1.96(m，1H)，1.26(s，3H)，
1.14(s，3H)。
The corresponding ethyl ester of compound 241 in 0 ℃ at CH 2Cl 2Middle with methylsulfonyl chloride and triethylamine processing, draw mesylate derivatives (quantitative yield) after the water treatment.This methanesulfonates need not to be further purified just and can directly use.
Embodiment 104
Compound 243: toward p-toluenesulfonic esters 242 (44.6g, CH 111.5mmol) 2Cl 2(450mL) solution adds pyridine (89mL) down at-78 ℃, then slowly adds SO 2Cl 2(26.7mL, 335mmol).With this mixture in-78 ℃ stir 5 hours after, dropwise add methyl alcohol (45mL), warm mixture restir 12 hours to the room temperature.After adding ether, wash mixture with water three times, the salt water washing once, dry (MgSO 4) back concentrating, draw oily intermediate (44.8g).(1.06g, (44.8g in MeOH 111.5mmol) (500mL) solution, refluxed 4 hours 5.6mmol) to add so far intermediate with TsOH.After reaction mixture was cooled to room temperature, methyl alcohol was removed in decompression.Add fresh methyl alcohol (500mL), this mixture refluxed 4 hours again, be cooled to room temperature after, methyl alcohol is removed in decompression.Flash column chromatography (hexane/EtOAc=3/1-1/3) draw two mixture of isomers (26.8g) behind the purifying.Draw pure expection product 243 (20.5g, 54%) from EtOAc/ hexane recrystallize:
1H NMR(CDCl 3)δ
7.82(d，J＝8.3Hz，2H)
7.37(d，J＝8.3Hz，2H)
6.84(m，1H)，
4.82(dd，J＝5.8，7.4Hz，1H)，
4.50(m，1H)，
3.90(dd，J＝4.4，8.2Hz，1H)，
3.74(s，3H)，
2.79(dd，J＝5.5，18.2Hz，1H)，
2.42(dd，J＝6.6，18.2Hz，1H)。
Similarly handle the corresponding methanesulfonates-ethyl ester derivative of compound 242 as described.Remove the acetonide protecting group with acetic acid treatment in backflow ethanol, from then on crude reaction mixture can draw glycol (39% productive rate) with the direct precipitation of ether.
Embodiment 105
Compound 1: (8.75mL, (20.0g is in THF 58.5mmol) (300mL) solution 58.5mmol) to add to 0 ℃ glycol 243 with DBU.This reaction mixture is warmed to room temperature and stirred 12 hours.Removal of solvent under reduced pressure (THF).Flash column chromatography (hexane/E-tOAc=1/3) purifying draws epoxide 1 (9.72g, 100%):
1H NMR(CDCl 3)δ
6.72(m，1H)，
4.56(td，J＝2.6，10.7Hz，1H)，
3.76(s，3H)，
3.56(m，2H)，
3.0(d，J＝21Hz，1H)，
2.50(d，J＝20Hz，1H)，
2.11(d，10.9Hz，1H)。
Handle the corresponding methanesulfonates-ethyl ester derivative of compound 243 as described in the same manner, draw epoxide with quantitative yield almost.
Embodiment 106
Aziridine 244: (223mg 1.07mmol) at room temperature uses hydrogen (1atm) to handle 50 minutes with dehydrated alcohol (8.0mL) solution of Lindlar catalyzer (200mg) with allyl ethers 4.Leach catalyzer with Celite pad then, wash with hot methanol.Vacuum concentration draws the light yellow oily 244 of about 230mg, and it need not to be further purified and just can be used in next reaction.
Embodiment 107
Azido-amine 205: with rough aziridine 244 (230mg), (309mg, 4.75mmol) (105mg, 1.96mmol) solution in dry DMF (10mL) is under argon gas, in 70 ℃ of heating 16 hours with ammonium chloride for sodiumazide.The sintered glass funnel solids removed by filtration is used in the cooling back, is distributed in then in ethyl acetate and the salt solution.Separate organic layer, use MgSO 4Dry.Vacuum concentration, resistates is gone up the flash chromatography separation in silica gel (10% hexane/ethyl acetate) and is obtained 154mg (57%, 2 step) 205, and it is yellow toughening oil, and its purity is enough to directly be used in next reaction.
Embodiment 108
N-ethanoyl trinitride 245: (70 μ L, (154mg is 0.61mmol) with the CH of pyridine (1.3mL) 0.98mmol) to add to 0 ℃ amine 205 with Acetyl Chloride 98Min. 2Cl 2(4.0mL) in the solution.0 ℃ after following 1.5 hours, concentrated reaction mixture and be distributed in ethyl acetate and salt solution in.Separate organic layer, in regular turn with saturated sodium bicarbonate, MgSO is used in the salt water washing 4Dry final vacuum concentrates, and resistates is gone up the flash chromatography separation in silica gel (ethyl acetate) and obtained 167mg (93%) light yellow solid 245.
Embodiment 109
Amino ester 200: (1.7g, (1.78g in the solution of THF 6.01mmol) (40mL) and water (1.5mL), stirred reaction mixture 42.5 hours under room temperature 6.48mmol) to divide several to add to 245 with triphenyl phosphine.Vacuum is removed volatile matter, and rough solid absorption on silica gel, is gone up in silica gel (100% ethyl acetate is 100% methyl alcohol then) and draws the light solid 200 of 1.24g (77%) with purification by flash chromatography.
Embodiment 110
Amino acid/11 02: (1.37mL, (368mg in THF 1.37mmol) (4.0mL) solution, stirs reaction mixture 10 minutes in 0 ℃, and stirring at room is after 1.5 hours, with Amberlite IR-120 (H 1.0N) to add to 0 ℃ methyl esters 200 with the NaOH aqueous solution +) the acidic resins acidifying becomes pH7.0-7.5.Leach resin, water and methanol wash.Vacuum concentration draws white solid amino acid, uses C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 290mg (83%) amino acid/11 02.
Embodiment 111
Amine hydrochlorate 250: (15.6mg 0.05mmol) handles and evaporation with 0.1N HCl amine 228.Resistates is dissolved in the water, with a short C 18The reverse phase silica gel post filters.Lyophilize obtains solid state hydrochloride 250 (12mg):
1H NMR(D 2O)δ
6.86(s，1H)，
4.35(br d，J＝9.0)，
4.06(dd，1H，J＝9.0，11.6)，
3.79(s，3H)
3.65-352(m，2H)，
2.97(dd，1H，J＝5.5，17.2)，
2.58-2.47(m，1H)，
2.08(s，3H)，
1.61-1.41(m，4H)，
0.88(t，3H，J＝7.4)，
0.84(t，3H，J＝7.4)。
Embodiment 112
Two-Boc-guanidine 251: with HgCl 2(125mg, 0.46mmol) add to 0 ℃ amine 228 (126mg, 0.42mmol), N, (127mg, 0.46mmol) (123 μ L are in DMF 0.88mmol) (4mL) solution with triethylamine for N '-two-tertbutyloxycarbonyl thiocarbamide.This mixture was stirred 30 minutes at 0 ℃, stirred 1.5 hours under the room temperature.Dilute after diatomite filtration with ethyl acetate.Boil off solvent, resistates is distributed in ethyl acetate and the water.Organic phase is washed after drying (MgSO with saturated NaCl 4), boil off solvent after the filtration.This crude product is gone up purifying in silica gel (2/1, the 1/1-hexane/ethyl acetate) and is drawn solid state two-Boc-guanidine 251 (155mg, 69%).
1H NMR(CDCl 3)δ
11.40(s，1H)，
8.66(d，1H，J＝7.9)，
6.8(s，1H)，
6.22(d，1H，J＝8.9)，
4.43-4.34(m，1H)，
4.19-4.08(m，1H)，
4.03(m，1H)，3.76(s，3H)，
3.35(m，1H)，
2.79(dd，1H，J＝5.4，17.7)，
2.47-2.36(m，1H)，
1.92(s，3H)，1.50，1.49(2s，18H)，
0.89(m，6H)。
Embodiment 113
Guanidino-acid 252: (150mg adds 1.039N KOH solution (337 μ L) and water (674 μ L) in THF 0.28mmol) (3mL) solution in two-Boc guanidine 251.This mixture was stirred 3 hours, added 1.039N KOH solution (67 μ L) and restir again 2 hours.Filter reaction mixture is to remove a small amount of dark throw out.Filtrate is cooled to 0 ℃, becomes pH4.5-5.0 with the acidifying of IR-120 ion exchange resin.Leach resin, use methanol wash.Evaporated filtrate is dissolved in CH with resistates 2Cl 2(3mL) and be cooled to 0 ℃, use trifluoroacetic acid (3mL) to handle it again, stirred 10 minutes in 0 ℃, again in stirring at room 2.5 hours.Boil off solvent, resistates is dissolved in the water, and (3 * 1.5cm) carry out chromatographic separation (first water is used 5% acetonitrile/water wash-out then) with C-18 reverse phase silica gel short column.Merge the fraction that contains product, evaporation, after resistates was dissolved in the water, lyophilize drew white solid guanidino-acid 252 (97mg, 79%).
Embodiment 114
Azido-acid 260: (1.60mL, (268mg is in THF 0.83mmol) (7.0mL) solution 1.039N) to add to methyl esters 227 with the KOH aqueous solution under the room temperature.Stirred 19 hours under the room temperature, with Amberlite IR-120 (H +) acidic resins are acidified to pH4.0, leach resin, water and washing with alcohol, vacuum concentration draws the rough azido-acid 260 of light orange spumescence, and it need not to be further purified and just is used for next reaction.
Embodiment 115
Azido-ethyl ester 261: (172mg 0.83mmol) adds to carboxylic acid 260 (the rough thing from last reaction is assumed to be 0.83mmol), the CH of ethanol (150 μ L) and catalytic amount DMAP with DCC next time in room temperature 2Cl 2(6.0mL) in the solution.Have throw out to form after several minutes, restir filtered after 1 hour, used CH 2Cl 2Washing.Draw light solid behind the vacuum concentration, draw 272mg (96%, a small amount of DCU impurity is arranged) white solid 261 after separating with silica gel (50% hexane/ethyl acetate) flash chromatography.When DCC was changed into the di-isopropyl carbodiimide, 261 productive rate was 93%, but existed chromatogram purification to remove the urea impurity of existence when using DCC.
Embodiment 116
Amino-ethyl ester 262: (342mg, (272g is in THF 0.80mmol) (17mL)/water (1.6mL) solution 1.30mmol) once to add to 261 with triphenyl phosphine.Then with reaction mixture in 50 ℃ of heating 10 hours, the cooling final vacuum concentrates and to draw shallow white solid.This rough solid draws the amino ethyl ester 262 of the light solid of 242mg (96%) with silica gel (50% methanol/ethyl acetate) purification by flash chromatography.It is dissolved among the 3N HCl, and lyophilize draws corresponding water-soluble HCl salt.
1H NMR(D 2O，300MHz)：δ
6.84(s，1H)；
4.36-4.30(br m，1H)；
4.24(q，2H，J＝7.2Hz)；
4.05(dd，1H，J＝9.0，11.7Hz)；
3.63-3.50(m，2H)；
2.95(dd，1H，J＝5.7，17.1Hz)；
2.57-2.45(m，1H)；
1.60-1.39(m，4H)；
1.27(t，3H，J＝7.2Hz)；
0.89-0.80(m，6H)。
Embodiment 117
Two-Boc GE ester 263: press Kim and Qian, the step of " Tetrahedron Lett. " 34:7677 (1993) is handled.With HgCl 2(69mg, 0.25mmol) once add to 0 ℃ amine 262 (72mg, 0.23mmol), two-Boc thiocarbamide (66mg, 0.24mmol) and Et 3In dry DMF (the 600 μ L) solution of N (108 μ L).The reaction mixture that this is heterogeneous stirred 1 hour in 0 ℃, in stirring at room 15 minutes, with the EtOAc dilution, filtered with Celite pad then again.Behind the vacuum concentration, resistates is gone up the flash chromatography separation in silica gel (20% hexane/ethyl acetate) and is provided 113mg (89%) colourless foam shape 263.
1H NMR(CDCl 3，300MHz)：δ
11.41(s，1H)；
8.65(d，1H，J＝8.1Hz)；
6.83(s，1H)；
6.22(d，1H，J＝9.0Hz)；
4.46-4.34(m，1H)；
4.21(q，2H，J＝6.9Hz)；
4.22-4.10(m，1H)；
4.04-4.00(m，1H)；
3.36 (quintet, 1H, J=5.7Hz);
2.78(dd，1H，J＝5.4，17.7Hz)；2.46-2.35(m，1H)；
1.94(s，3H)；
1.60-1.40(m，4H)；
1.49(s，9H)；1.50(s，9H)；
1.30(t，3H，J＝6.9Hz)；
0.93-0.84(m，6H)。
Embodiment 118
264: two-Boc of GE ester GE ester, 263 (113mg, CH 0.20mmol) 2Cl 2After (5.0mL) solution is cooled to 0 ℃, add pure trifluoroacetic acid (5.0mL), this reaction mixture was stirred stirring at room 1.5 hours 30 minutes in 0 ℃.Vacuum concentration draws the light orange solid, uses C 18Reverse-phase chromatography (water wash-out) purifying is collected to contain and is expected the fraction of product, and lyophilize draws 63mg (66%) white solid GE ester 264.
1H NMR(D 2O，300MHz)：δ 6.82(s，1H)；
4.35-4.31(m，1H)；
4.24(q，2H，J＝7.1Hz)；
3.95-3.87(m，1H)；
3.85-3.76(m，1H)；
3.57-3.49(m，1H)；
2.87(dd，1H，J＝5.1，17.7Hz)；2.46-2.34(m，1H)；
2.20(s，3H)；
1.60-1.38(m，4H)；
1.28(t，3H，J＝7.1Hz)；
0.90-0.80(m，6H)。
Embodiment 119
Enzyme inhibition: use above-mentioned external activity sieve method, record following activity (+10-100 μ m, ++ 1-10 μ m, +++＜1.0 μ m).
Compound IC 50
102/103(2∶1) +++
8 ++
A.17.a.4.i ++
114 ++
A.1.a.4.i ++
79 +
82/75(1.2∶1) +
94 +++
A.100.a.11.i +++
A.101.a.11.i +++
A.113.a.4.i +++
Embodiment 120
As described in the embodiment 119 respectively with compd A .113.b.4.i with A.113.x.4.i in the enzyme analysis buffer, cultivate and measure active.All active＞100 μ the m of the two.Before as embodiment 119 tests, each compound places rat plasma to cultivate respectively, and activity of the two and compd A .113.a.4.i are similar.
Embodiment 121
Under the DrRobert Sidwell of the Institute for of Utah State University Antiviral Research supervision, study, with comparative compound 203 (embodiment 69), GG167 and the ribavirin influenza of (i.p. or the administration of p.o. path) in the mouse body emits the A activity.GG167 and ribavirin are the compound that known influenza emits virus.
Figure C20051008765903281
Mouse: male 13-15g do not have specificity cause of disease BALB/c mouse derive from SimonsenLaboratories (Gilroy, CA).Use quarantine in preceding 24 hours, place Wayne LabBlox and tap water environment.In case infect, (Pfizer, New York is NY) to control possible secondary bacterial infections to contain 0.006% terramycin in the tap water.
Virus: influenza virus A/NWS/33 (H1N1) derives from K.W.Cochran, and University of Michigan (Ann Arbor, MI).After allowing the fusion individual layer of nephrocyte (mdck cell) of MadinDarby dog infect, in 37 ℃ at 5%CO 2In cultivate, when virocyte pathology effect reaches 90-100%, collect cell and make virus base after 3 to 5 days.With its envelope bottle and store in-80 ℃, in the time will using.
Compound: compound 203 is dissolved in the stroke-physiological saline solution to study with GG167.
Arterial oxygen saturation (SaO 2) measure: (Ohmeda, Lonisville OH) measure SaO with Ohmeda Biox 3740 pulsed oximeters 2Use aural sound, this probe is placed animal thigh place, and select for use at a slow speed and measure.Every animal was read reading after 30 second stationary phase.With this instrument measure influenza virus to the influence of artery saturation ratio by people such as Sid-well, Antimicrob.Agents Chemother, 36:473-476 (1992) explanation.
The experimental design of oral research: 11 mouse become one group, make the virus of about 95% lethal dose of its intranasal infection, and accept the test compounds of various dosage.203 with the dosage of GG167 be 50,10,2 and 0.5mg/kg/ days.Carry out i.p treatment (twice/day) totally 5 days after virus infected in advance in 4 hours.Got at the 3rd day to the 10th day 8 infected and infected and with the control group of brine treatment with the mouse of each dosage treatment and 16, analyze its SaO 2Value writes down the death toll totally 21 days of these animals every day.3 animals and 6 control groups with brine treatment remaining in every group were killed at the 6th day, took out lung, weighed, with the given mark of the degree of lung intense violet color (plum) (0=is normal, and the 4=100% lung is influenced).Because do not find toxicity when 203 dosage is 300mg/kg/ days, and reported in literature shows that GG167 does not also have toxicity, so carry out the toxicity contrast in the research.
The experimental design of intraperitoneal administration research: 11 mouse are one group, make the virus of about 95% lethal dose of its intranasal infection, and with dosage be 250,50 or 10mg/kg/ days 203 or GG167 or dosage be 100,32 or 10mg/kg/ days ribavirin treatment.Virus infected a laggard mouthful tube feed (p.o.) treatment (twice/day) totally 5 days of passing through in advance in 4 hours.8 animals were kept somewhere 21 days in each group, write down death toll every day, measured SaO at the 3rd day to the 10th day 2Value.3 remaining in every group mice infected were killed at the 6th day, took out lung, weighed, with the given mark of the degree of lung intense violet color (0=is normal, and the 4=100% lung is influenced).15 infected mouse are only used brine treatment, keep somewhere and also as above-mentioned measure SaO in 21 days 2, get again in addition 6 infected and with the mouse of brine treatment, at the 6th day it is killed and to carry out the lung analysis.3 normal control groups were kept somewhere 21 days, with the above-mentioned SaO that carries out 2Measure, other gets 3 intact animals, kills in the 6th day, and lung is weighed and scored.
The experimental design of low dose oral research: 8 mouse are one group, the virus of about 90% lethal dose of its intranasal infection, and accept the test compounds of various dosage.The dosage of each compound be 10,1 with 0.1mg/kg/ days.Carry out p.o. (twice/day) treatment totally 5 days after virus infected in advance in 4 hours.At 3-11 days, get 8 infected and infected and with the control group of brine treatment with the mouse of each dosage treatment and 16, analyze its SaO 2Value writes down the death toll totally 21 days of these animals every day.
Statistical estimation: with χ 2Analyze the increase of proofreading and correct assessment survival number with Yates.Increase and SaO with t-check analysis mean survival time 2Difference, lung weight and Pneumovirinae titre.Lung mark difference is assessed with total number of grades analysis (ranked sum analysis).In all examples, study the poor of pharmacological agent and brine treatment control group.
I.p. the administration result of experiment is summarized in Table I and Fig. 1 and 2.In this model, two compounds all have remarkable inhibition at high dosage, and 203 is that 10mg/kg/ days treatment also has remarkable survival in dosage.Two compounds significantly suppress SaO when 50mg/kg/ days dosage 2Reduction, and GG167 is when 10mg/kg/ days dosage, or even 2mg/kg/ days, also can suppress above-mentioned reduction.The lung fractional data shows identical trend, and wherein GG167 is all effective when a plurality of dosage.Can see that in lung weight some come and go, the lung that takes out from the mouse of accepting maximum dose level GG167 has higher weight in average than the brine treatment control group.
P.o administration result of experiment is summarized in Table II, the SaO of every day 2Value then is shown in Fig. 3-5.In this model, the oral administration popularity common cold virus of three kinds of medicines infects remarkable inhibition, and can prevent death, reduces lung mark and the lung weight relevant with infection, and can suppress SaO 2Reduce.
P.o. the low dosage result of study is concluded and is done Table III and Fig. 6-8.In this experiment, infect making in 16 brine treatment animals 14 death are arranged, mean survival time is 9.6 days in this group.Three kinds of compounds all have the retarding effect of some degree to virus infection, and 262 (ethyl ester prodrugs) are the most effective at each dosage, and this can be by the survival number, and mean survival time prevents SaO 2Reduction is verified.
Table III shows the average SaO of all analysis times 2%.Value every day of each compound is illustrated among Fig. 6 to 8.Fig. 6 represents the SaO of each compound maximum concentration 2Data; SaO when the numerical value when Fig. 7 represents each compound median dose, Fig. 8 then compare each compound low dosage 2Value.
Table III and Fig. 6-8 expressions three compounds all bring out influenza A (H1N1) virus infection to experiment when oral active function, the most effective with 262.Can not determine whether 262 improvement anti-virus ability is not attended by higher animal toxicity, but because inferring its higher effectiveness is the result because of higher oral biological available rate, so high animal toxicity can not take place.
Table I .203 and GG167i.p aThe effect that delivers medicine to the mouse of influenza A (H1N1) virus infection compares
Infect treatment
Compound Dosage mg/kg/ days Survival number/sum Mean survival time b(my god) Average SaO 2 c ％ Average lung parameter d
Mark Weight (mg)
203 GG167 salt solution 50 10 2 0.5 50 10 2 0.5 - 8/8 ** 3/8 * 0/7 0/8 8/8 ** 7/8 * 1/8 0/8 0/16 ＞21.0 ** 10.8 12.6 11.1 ＞21.0 ** 15.0 12.6 12.3 11.0 87.2 ** 84.7 84.4 85.2 * 87.6 ** 87.5 ** 86.0 ** 84.5 82.9 0.7 * 2.5 2.0 2.0 0.7 * 1.7 1.3 2.3 2.0 173 *217 203 230 230 170 *213 227 220
Table II .203, GG167 and ribavirin are oral aThe back is to mouse influenza A.(H1N1) effect of virus infection relatively
Infect treatment
Compound Dosage The survival number Average survival Average SaO 2 c Average lung parameter d
Mg/kg/ days / sum Time b(my god) ％ Mark Weight (mg)
203 GG167 ribavirin salt solution 250 50 10 250 50 10 100 32 10 - 8/8 ** 8/8 ** 4/8 * 8/8 ** 8/8 ** 5/7 * 8/8 ** 6/8 * 3/8 1/16 ＞21.0 ** ＞21.0 ** 12.8 * ＞21.0 ** ＞21.0 ** 10.5 ＞21.0 ** 13.0 11.0 10.9 87.9 * 87.9 * 87.7 * 88.6 * 88.0 * 85.2 88.2 * 88.0 * 86.4 84.5 0.8 ** 1.3 * 1.3 * 0.3 ** 1.5 * 1.5 * 0.3 ** 0.8 ** 2.2 2.4 160 ** 200 240 163 ** 187 * 250 140 ** 163 ** 267 203
Table III .260,262 is oral with GG167 aCompare the effect of mouse influenza A (H1N1) virus infection the back
Compound Dosage mg/kg/ days Survival number/sum Survival % Mean survival time b(my god) Average SaO 2 c (％)
260 262 GG167 salt solution 10 1 0.1 10 1 0.1 10 1 0.1 0 6/8 ** 3/5 0/8 8/8 *** 7/8 *** 2/8 5/8 * 2/8 0/8 2/16 75 ** 38 0 100 *** 88 *** 25 63 * 25 0 13 13.5 ** 11.8 10.0 ＞21.0 ** 14.0 ** 11.1 ** 12.3 ** 11.7 ** 9.8 9.6 87.6 ** 86.8 84.3 88.1 ** 87.4 * 85.7 86.9 85.7 83.5 83.5
The footnote of Table I-III
After infecting in advance, 4 hours virus of a carried out 5 days
B the 21st day or before dead animal
The mean value that c measured in 3-10 days
D measured in the 6th day
With respect to the brine treatment control group *P＜0.05, *P＜0.01, * *P＜0.001
Unexpectedly, above be presented in this model, it is effective to reducing the influenza infection mortality of mice when practical therapeutic dose that oral or i.p. gives GG167, though people's such as this point and Ryan conclusion (Antimicrob.Agents Chemother., 38 (10): 2270-2275) [1994] difference, Ryan think " the GG167 intraperitoneal delivers medicine to the low activity in vivo in the mouse; though the good biological available rate is arranged; be because it is eliminated from blood plasma apace; so be difficult for penetrating into respiratory secretions; add and can not infiltrate and rest on cell interior ... ... similarly, oral low effectiveness may be because, except above-mentioned other factors, low oral biological available rate " (p.2274).These observe the WO 91/16320 with people such as Von Izstein, and WO 92/06691 and United States Patent (USP) 5360817 (its covering or be specifically related to GG167 research) are consistent.These patent documentations are not instructed or suggestion gives GG167 in the mode beyond in the nose.But, not only inconvenience but also not cheap of intranasal administration in some cases.If it will be very favourable having more feasible path to give GG167 and related compound thereof (as WO 91/16320, WO 92/06691 is with shown in the United States Patent (USP) 5360817).
So the method that relate to the present invention's one concrete example a kind of treatment or prevention host influenza virus infect comprises via the path of non local medication to respiratory system, give formula (X) that this host treats effective dose or antiviral activity compound (Y)
Figure C20051008765903331
Wherein
A is an oxygen in general formula (X), carbon or sulphur, and A is nitrogen or carbon in general formula (Y);
R 1Be COOH, P (O) (OH) 2, NO 2, SOOH, SO 3H, tetrazolium, CH 2CHO, CHO or CH (CHO) 2,
R 2Be H, OR 6, F, Cl, Br, CN, NHR 6, SR 6, or CH 2X, wherein X is NHR 6, halogen or OR 6And
R 6Be hydrogen; C 1-C 4Acyl group; Line style or ring-type C 1-C 6Alkyl or its congener that replaces through halogen; Allyl group; Aryl that is unsubstituted or the aryl that replaces through following groups: halogen, OH group, NO 2Group, NH 2Group or COOH group;
R 3With R 3 'Identical or inequality ground is hydrogen independently, CN, NHR 6, N 3, SR 6,=N-OR 6, OR 6, guanidine radicals,
Figure C20051008765903332
NR 6，
Figure C20051008765903333
Figure C20051008765903334
R 4Be NHR 6, SR 6, OR 6, COOR 6, NO 2, C (R 6) 3, CH 2COOR 6, CH 2NO 2Or CH 2NHR 6,
And R 5Be CH 2YR 6, CHYR 6CH 2YR 6Or CHYR 6CHYR 6CH 2YR 6, wherein Y is O, S, NH or H, and R 5Each Y partly is identical or inequality in the group,
And pharmacy acceptable salt or derivative,
Condition is in general formula (X)
(i) work as R 3Or R 3 'Be OR 6Or hydrogen, and A is when being oxygen or sulphur, this compound can not have (a) simultaneously and be the R of hydrogen 2(b) be the R of NH-acyl group 4And
(ii) when Y is hydrogen, R 6Be covalent linkage, and in formula logical (y)
(i) work as R 3Or R 3 'Be OR 6Or hydrogen, and A is when being nitrogen, this compound can not have (a) simultaneously and be the R of hydrogen 2(b) be the R of NH-acyl group 4And
(ii) when Y is hydrogen, R 6Be covalent linkage.
Formula (X) walks to the 7th page of the 1st row with (Y) compound in WO 91/16320 page 3 the 23rd, is described in more detail in WO 92/06691 and the United States Patent (USP) 5360819, in the document, (X) and (Y) is denoted as I and Ia.
Be the Da Benwen purpose, described path via " the non local respiratory tract that is administered to " is not got rid of through cheek or sublingual administration, and do not get rid of oral, sporadic oesophagus absorbs when cheek or sublingual administration, so long as should press from both sides, mouthful, it not is to be used for pulmonary administration or by similar situations such as nasal cavity suctions that hypogloeeis or oesophagus absorb.Usually, compound is with forming composition, and slurry or solution come administration.
In the present invention typical case concrete example, compound is GG167, and the host is the animal (as ferret or people) of non-muroid, and the administration path is oral, and treatment is to reduce mortality ratio with the purpose of prevention.Can arbitrarily use the formula (X) or (Y) prodrug of compound, but shown as mentioned, do not need so to do to reach oral antiviral efficacy.As the prodrug of the relevant compound of having come into the open of GG167 with it, the ester of any described The compounds of this invention in this article, acid amides or other prodrugs all can with formula (X) or (Y) analogue of compound (as, carboxyl ester or acid amides) and use.
When GG167 and its related compound with oral or during through the administration of other non-nose paths, its treatment effective dose can be by general doctor according to the medication instruction of described The compounds of this invention and determine.Topmost administration path and the host type of being thought of as.Usually, intravenously is to subcutaneous cumulative to oral dosage, if medication is used to then amplifying principle according to conventional pharmacology than large animal.The general technology that is defined as this field of therapeutic activity dosage, but this dosage and The compounds of this invention are used roughly the same usually.
Embodiment 122
Each reaction shown in the table 50 is undertaken by reaction scheme 50, and the reaction of having carried out is represented with " √ ".Unless shown in having in addition in the table 50, steps A A, AB and AC press embodiment 92,93 and 94 respectively and carry out, steps A D makes up by embodiment 112 and 113 and carries out.
Reaction scheme 50
Table 50
Figure C20051008765903361
Table 50 (continuing)
Figure C20051008765903371
Table 50 (notes)
A) the ester hydrolysis before the trinitride reduction
B) use Ph 3P at room temperature carries out the trinitride reduction
C) carry out the ester hydrolysis with the KOH aqueous solution/MeOH
D) Ph that carries with polymkeric substance 3P at room temperature carries out the trinitride reduction
E) be separated into HCl salt
F) use Ph 3The MeOH/THF/H of P 2O carries out the trinitride reduction
G) non-enantiomer mixture, main diastereomer indicates
H) use Me 3P carries out the trinitride reduction
I) in 55 ℃ of open loops of carrying out aziridine
J) isolate the C-alkylate
Figure C20051008765903381
Embodiment 123
Trifluoroacetamide 340: (41 μ L, 0.51mmol) (52 μ L 0.37mmol) add to 0 ℃ amine 228 (100mg, CH 34mmol) with trifluoroacetic anhydride (TFAA) with pyridine 2Cl 2(3.5mL) in the solution, it was stirred 45 minutes, add extra TFAA (0.5 equivalent) therebetween again.After 15 minutes, reduction vaporization, resistates are distributed among ethyl acetate and the 1MHCl.The saturated NaHCO of organic phase 3, saturated NaCl washing, dry (MgSO 4) evaporation of filtration back.Resistates is gone up chromatographic separation in silica gel (2/1-hexane/ethyl acetate) and is drawn trifluoroacetamide 340 (105mg, 78%):
1H NMR(CDCl 3)δ
8.64(d，1H，J＝7.7)，
6.81(s，1H)，
6.48(d，1H，J＝8.2)，
4.25-4.07(m，3H)，
3.75(s，3H)，3.37(m，1H)，
2.76(dd，1H，J＝4.5，18.7)，
2.54(m，1H)，1.93(s，3H)，
1.48(m，4H)，0.86(m，6H)。
Embodiment 124
N-methyl trifluoro ethanamide 341: ((90mg is in DMF 0.23mmol) (2mL) solution 0.25mmol) to add to 0 ℃ trifluoroacetamide 340 for 10mg, 60% mineral oil dispersion liquid with sodium hydride.0 ℃ adds methyl-iodide 71 μ L after 15 minutes, 1.15mmol), it is stirred 2 hours in 0 ℃, stirs 1 hour under the room temperature.Add acetate (28 μ L), with solution evaporation.Resistates is distributed in ethyl acetate and the water.Organic phase is washed with saturated NaCl, dry (MgSO 4) evaporation of filtration back.Resistates is gone up chromatographic separation in silica gel (1/1-hexane/ethyl acetate) and is drawn flint glass shape N-methyl trifluoro ethanamide 341 (81mg, 87%):
1H NMR(CDCl 3)δ
6.80(s，1H)，
6.26(d，1H，J＝9.9)，
4.67(m，1H)，4.32(m，1H)，
4.11(m，l H)，3.78(s，3H)，
3.32(m，1H)，
3.07(br s，3H)，
2.60(m，2H)，1.91(s，3H)，
1.48(m，4H)，0.87(m，6H)。
Embodiment 125
N-methylamine 342: with 1.04N KOH (48 μ L, 0.50mmol) add to N-methyl trifluoro ethanamide 341 (81mg, 0.20mmol) THF (3mL) solution in, this mixture was stirred under room temperature 14 hours, be acidified to pH with IR-120 ion exchange resin and be about 4.Leach resin, with THF washing, evaporated filtrate.Resistates is dissolved in back evaporation in the 10%TFA/ water (5mL), resistates water wash-out is passed through C-18 reverse phase silica gel post (1.5 * 2.5cm).Collect the product fraction, lyophilize draws white solid N-methylamine 342 (46mg, 56%):
1H NMR(D 2O)δ
6.80(s，1H)，
4.31(br d，1H，J＝8.8)，
4.09(dd，1H，J＝8.9，11.6)，
3.53(m，2H)，
2.98(dd，1H，J＝5.4，16.9)，
2.73(s，3H)，
2.52-2.41(m，1H)，
2.07(s，3H)，
1.61-1.39(m，4H)，
0.84(m，6H)。
Embodiment 126
Compound 346: toward epoxide 345 (13.32g, 8/1-MeOH/H 58.4mmol) 2(440mL, (19.0g, 292.0mmol) (2.69g's O 129.3mmol), refluxes this mixture 15 hours with ammonium chloride v/v) to add sodiumazide in the solution.Cooling back concentrating under reduced pressure is distributed in EtOAc and the water.Organic layer is used saturated bicarbonate in regular turn, the salt water washing.Dry (MgSO 4) final vacuum concentrates.Go up the flash chromatography separation at silica gel (30%EtOAc/ hexane) and draw 11.81g (75%) toughening oil azido-alcohol 346.
1H NMR(300MHz，CDCl 3)δ
6.90-6.86(m，1H)；
4.80(s，2H)；
4.32(bt，1H，J＝4.2Hz)；
4.22(q，2H，J＝7.2Hz)；
3.90-3.74 (overlapping m, 2H);
3.44(s，3H)；
2.90(d，1H；J＝6.9Hz)；
2.94-2.82(m，1H)；
2.35-2.21(m，1H)；
1.30(t，3H，J＝7.2Hz)。
Embodiment 127
Compound 437: through syringe toward ethyl ester 346 (420mg, 1,55mmol) drip DIBAL (5.1ml, 1.0M toluene solution) in the solution in anhydrous THF (8.0ml) (being cooled to-78 ℃).The glassy yellow reaction mixture stirred 1.25 hours at-78 ℃, slowly added MeOH (1.2ml) then and slowly hydrolysis.Decompression is removed volatile matter and resistates is distributed between EtOAc and the cold rare HCl.Separate organic layer and with the EtOAc water layer of stripping.Merge organic layer and use saturated bicarbonate, salt water washing successively, use MgSO 4Dry.Vacuum concentration, flash chromatography separates that (20% hexane/EtOAc), obtain 127mg (36%) glycol 347, it is colourless toughening oil on silica gel then.
1H NMR (300MHz, CDCl 3) δ 5.83-5.82 (m, 1H); 4.78 (s, 2H); 4.21 (bt, 1H, J=4.4Hz); 4.06 (bs, 2H); 3.85-3.65 (overlapping m, 2H); 3.43 (s, 3H); 3.18 (d, 1H, J=8.1Hz); 2.51 (dd, 1H, J=5.5,17.7Hz); 2.07-1.90 (m, 1H); 1.92 (bs, 1H).
Below claims relate to concrete example of the present invention, and should think that to cover it many
Change.

Claims (66)

1. the compound that has formula (II)
Wherein
A 2For-C (J 1) 2-;
E 1For-(CR 1R 1) M1W 1
G 1Be N 3,-CN ,-OH ,-OR 6a,-NO 2Or-(CR 1R 1) M1W 2
T 1For-NR 1W 3, heterocycle, or and U 1Or G 1Form group together with following structure
Figure C2005100876590002C2
U 1For H or-X 1W 6
J 1And J 1aBe R independently 1, Br, Cl, F, I, CN, NO 2Or N 3
J 2And J 2aBe H or R independently 1
R 1Be H or C independently 1-C 12Alkyl,
R 2Be R independently 3Or R 4, each R wherein 4Use 0-3 R independently 3Group replaces;
R 3Be F independently, Cl, Br, I ,-CN, N 3,-NO 2,-OR 6a,-OR 1,-N (R 1) 2,-N (R 1) (R 6b) ,-N (R 6b) 2,-SR 1,-SR 6a,-S (O) R 1,-S (O) 2R 1,-S (O) OR 1,-S (O) OR 6a,-S (O) 2OR 1,-S (O) 2OR 6a,-C (O) OR 1,-C (O) R 6c,-C (O) OR 6a,-OC (O) R 1,-N (R 1) (C (O) R 1) ,-N (R 6b) (C (O) R 1) ,-N (R 1) (C (O) OR 1) ,-N (R 6b) (C (O) OR 1) ,-C (O) N (R 1) 2,-C (O) N (R 6b) (R 1) ,-C (O) N (R 6b) 2,-C (NR 1) (N (R 1) 2) ,-C (N (R 6b)) (N (R 1) 2) ,-C (N (R 1)) (N (R 1) (R 6b)) ,-C (N (R 6b)) (N (R 1) (R 6b)) ,-C (N (R 1)) (N (R 6b) 2) ,-C (N (R 6b)) (N (R 6b) 2) ,-N (R 1) C (N (R 1)) (N (R 1) 2) ,-N (R 1) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) 2) ,-N (R 6b) C (N (R 1)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 1) C (N (R 1)) N (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 1) (R 6b)) ,-N (R 6b) C (N (R 1)) (N (R 6b) 2) ,-N (R 1) C (N (R 6b)) (N (R 6b) 2) ,-N (R 6b) C (N (R 6b)) (N (R 6b) 2) ,=O ,=S ,=N (R 1) or=N (R 6b);
R 4Be C independently 1-C 12Alkyl, C 2-C 12Alkenyl, or C 2-C 12Alkynyl;
R 5Be R independently 4, each R wherein 4Be 0 to 3 R 3Group replaces;
R 5aBe C independently 1-C 12Alkylidene group, C 2-C 12Alkylene group, or C 2-C 12Alkynylene, arbitrary alkylidene group, alkylene group or alkynylene are by 0 to 3 R 3Group replaces;
R 6aBe H or one-tenth ether or the group that becomes ester independently;
R 6bBe H independently, the residue of amino protecting group or carboxylated compound;
R 6cBe H or the residue that contains aminocompound independently;
W 1For containing the group of acidic hydrogen, the acidic-group of protection, or contain the R of the group of acidic hydrogen 6cAcid amides;
W 2For containing the alkaline heteroatomic group of alkaline heteroatoms or protection, or should the heteroatomic R of alkalescence 6bAcid amides;
W 3Be W 4Or W 5
W 4Be R 5Or-C (O) R 5,-C (O) W 5,-SO 2R 5Or-SO 2W 5
W 5Be carbocyclic ring or heterocycle, wherein W 5Independently by 0 to 3 R 2Group replaces;
W 6For-R 5,-W 5,-R 5aW 5,-C (O) OR 6a,-C (O) R 6c,-C (O) N (R 6b) 2,-C (NR 6b) (N (H) (R 6b)) ,-C (NR 6b) (N (R 6b) 2) ,-C (N (H) (N (R 6b) 2) ,-C (S) N (R 6b) 2, or-C (O) R 2
X 1Be a key ,-O-,-N (H)-,-N (W 6)-,-N (OH)-,-N (OW 6)-,-N (NH 2)-,-N (N (H) (W 6))-,-N (N (W 6) 2)-,-N (H) N (W 6)-,-S-,-SO-, or-SO 2-; With
Each m 1Be 0 to 2 integer independently; But condition is not comprise following compounds, wherein;
(a) A 2For-CH 2-;
(b) E 1Be COOH, P (O) (OH) 2, SOOH, SO 3H, or tetrazolium;
(c) G 1Be CN, N (H) R 20, N 3, SR 20, OR 20, guanidine radicals ,-N (H) CN
Figure C2005100876590004C1
NR 20,
Figure C2005100876590004C2
Figure C2005100876590004C3
(d) T 1For-NHR 20
(e) R 20Be H; C 1-C 4Acyl group; C 1-C 6Line style or cyclic alkyl, or the analogue of its halogen replacement; Allyl group or unsubstituted aryl, or by halogen, OH group, NO 2Group, NH 2The aryl that group or COOH group replace;
(f) J 1Be H and J 1aBe H, F, Cl, Br or CN;
(g) J 2Be H and J 2aBe H, CN or N 3
(h) U 1Be CH 2YR 20a, CHYR 20aCH 2YR 20a, or CHYR 20aCHYR 20aCH 2YR 20a
(i) R 20aBe H or C 1-C 4Acyl group;
(j) Y is O, S, H or NH;
(k) 0 to 2 YR 20aBe H, and
(l) U 1Each Y partly is identical or different in the group, and when Y is H, R 20aBe covalent linkage, and if condition is G 1Be N 3, U then 1Be not-CH 2OCH 2Ph,
And the above-mentioned pharmacologically acceptable salts of getting rid of compound;
With and salt, the enantiomorph of parsing and the diastereomer of purifying.
2. according to the compound of claim 1, further if condition is G 1Be N 3, U then 1Not the C that uses through the hydroxyl replacement of protection 1-C 3Alkyl.
3. according to the compound of claim 1, R wherein 6aBlocking group for hydroxyl or sulfydryl.
4. according to the compound of claim 1, X wherein 1Be a key and W 6Neither C 1-C 4Positive alkyl neither be used 1-3 OH, SH or NH 2The C that replaces 1-C 4Positive alkyl.
5. according to the compound of claim 1, X wherein 1Be a key and W 6Neither C 1-C 3Positive alkyl neither be used 1-3 OH, SH or NH 2The C that replaces 1-C 3Positive alkyl.
6. according to the compound of claim 1, X wherein 1Be a key and W 6Neither C 1-C 4Positive alkyl neither be used 1-3 OH, OR 6a, SH or NH 2The C that replaces 1-C 4Positive alkyl, wherein R 6aBe blocking group.
7. according to the compound of claim 1, X wherein 1Be a key and W 6Neither C 1-C 3Positive alkyl neither be used 1-3 OH, OR 6a, SH or NH 2The C that replaces 1-C 3Positive alkyl, wherein R 6aBe blocking group.
8. according to the compound of claim 1, wherein condition is further to get rid of wherein G 1Be (alk) M4NR 6bR 7bCompound;
Alk is the methylene radical that does not replace or replace;
m 4Be 0 or 1;
R 6bBe hydrogen, C 1-C 6Alkyl, aryl, aralkyl, amidine, NR 7bR 8b, or contain one or more heteroatomic unsaturated or saturated rings;
R 7bBe hydrogen, C 1-6Alkyl, or allyl group, or NR 6bR 7bForm optional 5 or 6 yuan of rings that replace, this ring is chosen wantonly and is contained one or more extra heteroatomss; With
R 8bBe hydrogen or C 1-6Alkyl.
9. compound according to Claim 8, wherein condition is further to get rid of wherein G 1Be NR 6bR 7bCompound.
10. according to the compound of claim 1, W wherein 6For using 1-3 OR 6aOr SR 6aThe C that replaces 1-C 3Alkyl, OR 6aOr SR 6aGroup is to the hydrolysis-stable in gastrointestinal fluid.
11. according to the compound of claim 1, wherein if W 6Use R 3Replace and R 3Use OR 6aReplace, then R 6aIt is not ethanoyl.
12. according to the compound of claim 1, wherein W 6For-(CH 2) M1CH ((CH 2) M3R 3) 2,-(CH 2) M1C ((CH 2) M3R 3) 3-(CH 2) M1CH ((CH 2) M3R 5aW 5) 2-(CH 2) M1CH ((CH 2) M3R 3) ((CH 2) M3R 5aW 5);-(CH 2) M1C ((CH 2) M3R 3) 2((CH 2) M3R 5aW 5), (CH 2) M1C ((CH 2) M3R 5aW 5) 3Or-(CH 2) M1C ((CH 2) M3R 3) ((CH 2) M3R 5aW 5) 2With m3 be the integer of 1-3.
13. according to the compound of claim 1, wherein X 1Be a key, W 6For-R 5,-W 5Or-R 5aW 5
14. according to the compound of claim 1, wherein X 1Be a key, W 6For-R 5
15. according to the compound of claim 14, wherein said R 5For using 0-3-OR 1The R that replaces 4
16. according to the compound of claim 14, wherein said R 5For using 0-3-NO 2Or N 3The R that group replaces 4
17. it is, wherein said-OR according to the compound of claim 15 1Exist and at least one described R 1Be C 4-C 12
18. according to the compound of claim 1, wherein U 1Be-N (R 5) 2,-N (H) (CH (R 5b) 2) ,-N (H) (CH 2CH (R 5c) 2) ,-N (OR 5) (R 5) ,-N (N (H) (R 5)) (R 5) ,-N (H) (N (R 5) 2) ,-N (R 5) (C (O) R 5) ,-C (O) N (R 5) 2,-C (S) N (R 5) 2,-OR 5d,-OCH (R 5b) 2,-OCH 2CH (R 5c) 2,-SR 5d,-SCH (R 5b) 2,-SCH 2CH (R 5c) 2,-S (O) R 5d,-S (O) CH (R 5b) 2,-S (O) CH 2CH (R 5c) 2,-S (O) 2R 5d,-S (O) 2CH (R 5b) 2,-S (O) 2CH 2CH (R 5c) 2,-C (N (R 5)) (N (H) (R 5)) ,-C (O) R 5d,-C (O) CH (R 5b) 2Or-C (O) CH 2CH (R 5c) 2With
Wherein:
Described U 1-CH 2-or-the optional usefulness-OR of CH-hydrogen partly 1,-SR 1, NO 2, N 3, F ,-CN, Cl or Br replace;
R 5bBe C independently 1-C 11Alkyl, C 2-C 11Alkenyl or C 2-C 11Alkynyl, arbitrary alkyl, alkenyl or alkynyl are by 0-3 R 3Group replaces;
R 5cBe C independently 1-C 10Alkyl, C 2-C 10Alkenyl or C 2-C 10Alkynyl, 0-3 R of arbitrary alkyl, alkenyl or alkynyl 3Group replaces;
R 5dBe branching R 5Group; With
Wherein if R 5, R 5b, R 5cOr R 5dWith 1-3 R 3Group replaces, then R 3For-OR 1,-SR 1, NO 2, N 3, F ,-CN, Cl or Br.
19. according to the compound of claim 1, wherein W 6Be side chain R 5Group.
20. according to the compound of claim 19, wherein said R 5Be branching R 4Group.
21. according to the compound of claim 1, wherein W 6Be R 5e, R wherein 5eFor using 1-3 OR 1aOr SR 1aThe C that replaces 1-C 12Just or secondary alkyl, wherein R 1aBe C 1-4Alkyl.
22. according to the compound of claim 19, condition is to work as W 6For using 1-3 R 3The R that group replaces 5And at least one R 3Group is OH, COOH, NH 2, C (O) H, C (O) NH 2, S (O) 2OH, S (O) OH, N (H) (C (O) OH), C (N (H)) NH 2, N (H) (C (NH 2) N (H)) ,=O or=during N (H), described R 5Use one OH, COOH, NH 2, C (O) H, C (O) NH 2, S (O) 2OH, S (O) OH, N (H) (C (O) OH), C (N (H)) NH 2, N (H) (C (NH 2) N (H)) ,=O or=the NH group replaces.
23. according to the compound of claim 19, wherein said R 5For using 0-3 R 3The C that group replaces 4-C 8Alkyl.
24. according to the compound of claim 19, wherein said R 5With 0-2 R 3Group replaces.
25. according to the compound of claim 24, wherein said R 5With 1-2 R 3Group replaces and at least one described R 3Group is OH, COOH, NH 2, C (O) H, C (O) NH 2, S (O) 2OH, S (O) OH, N (H) (C (O) OH), C (N (H)) NH 2, N (H) C ((NH 2) N (H)) ,=O or=NH.
26. according to the compound of claim 25, OH wherein, COOH, NH 2, C (O) H, C (O) NH 2, S (O) 2OH, S (O) OH, N (H) (C (O) OH), C (N (H)) NH 2, N (H) C ((NH 2) N (H)) ,=O or=the NH group replaces X 1The end carbon in distally.
27. according to the compound of claim 25, OH wherein, COOH, NH 2, C (O) H, C (O) NH 2, S (O) 2OH, S (O) OH, N (H) (C (O) OH), C (N (H)) NH 2, N (H) C ((NH 2) N (H)) ,=O or=it is not X that the NH group replaces 1The carbon atom of the end carbon atom in distally.
28. according to the compound of claim 1, wherein W 6For having the R of 1-7 carbon atom 4
29. according to the compound of claim 1, wherein said U 1Not with OH or the C that replaces through the OH of aralkyl, acyl group, silicon protecting group or tetrahydropyrans protection 1-C 3Alkyl.
30. according to the compound of claim 29, wherein the aralkyl protecting group is benzyl, trityl or diphenyl-methyl; Acyl group is an ethanoyl, and the silicon protecting group is a trimethyl silyl.
31. according to the compound of claim 1, wherein X 1For-O-,-N (H)-,-N (R 5)-,-N (OH)-,-N (OR 5)-,-S (O)-or-S-.
32. according to the compound of claim 1, wherein X 1For-O-.
33. according to the compound of claim 1, wherein X 1For-NH-.
34. according to the compound of claim 1, wherein X 1For-N (R 5)-.
35. according to the compound of claim 1, wherein X 1For-N (OH)-.
36. according to the compound of claim 1, wherein X 1For-N (OR 5)-.
37. according to the compound of claim 1, wherein X 1For-S-.
38. according to the compound of claim 1, wherein X 1For-SO-.
39. according to the compound of claim 1, wherein X 1For-O-or-N (H)-.
40. according to the compound of claim 1, wherein X 1For-N (OR 5)-or-N (R 5)-and described R 5R for 1-5 carbon atom 4
41. according to the compound of claim 1, wherein G 1For-NHR 1,-N (R 6b) (R 1) ,-N (R 6b) 2,-N (H) (R 5) ,-N (R 6b) (R 5) ,-N (R 5) 2-C (NH) (NH 2) ,-N (R 1) C (NR 1) (NR 1R 3) ,-NHC (NH) (NHR 3) ,-NHC (NH) (NHR 1) ,-NHC (NH) NH 2) ,-CH (CH 2NHR 1) (CH 2OH) ,-CH (CH 2NHR 1) (CH 2NHR 1) ,-CH (NHR 1)-(CR 1R 1) M2-CH (NHR 1) R 1,-CH (OH)-(CR 1R 1) M2-CH (NHR 1) R 1Or-CH (NHR 1)-(CR 1R 1) M2-CH (OH) R 1,-(CR 1R 1) M2-S-C (NH) NH 2,-N=C (NHR 1) (R 3) or-N=C (NHR 1) (R 1); And m 2Be the integer of 0-1 independently.
42. according to the compound of claim 1, wherein W 6-C (O) R 2For-C (O) R 4And X 1Be a key ,-N (H)-,-N (R 5)-,-N (OH)-or-N (OR 5)-.
43. according to the compound of claim 1, wherein W 1For-CO 2R 1
44. according to the compound of claim 1, wherein E 1Be selected from as follows: the phenethyl ester of carboxyl,
Figure C2005100876590009C1
45. according to the compound of claim 1, wherein G 1Be amino, amidino groups or guanidine radicals, or C 1-C 6Amino, amidino groups or guanidine radicals that alkyl replaces.
46. according to the compound of claim 1, wherein W 2For-NHR 1,-N (R 6b) (R 1) ,-N (R 6b) 2,-N (H) (R 5) ,-N (R 6b) (R 5) ,-N (R 5) 2,-C (NH) (NH 2) ,-N (R 1) C (NR 1) (NR 1R 3) ,-NHC (NH) (NHR 3) ,-NHC (NH) (NHR 1) ,-NHC (NH) NH 2) ,-CH (CH 2NHR 1) (CH 2OH) ,-CH (CH 2NHR 1) (CH 2NHR 1) ,-CH (NHR 1)-(CR 1R 1) M2-CH (NHR 1) R 1,-CH (OH)-(CR 1R 1) M2CH (NHR 1) R 1Or-CH (NHR 1)-(CR 1R 1) M2CH (OH) R 1,-(CR 1R 1) M2SC (NH) NH 2,-N=C (NHR 1) (R 3) or-N=C (NHR 1) (R 1); With m2 be the integer of 0-1 independently.
47. according to the compound of claim 1, wherein G 1Be selected from as follows: C 1-C 6Monoalkylamine,
Figure C2005100876590010C1
48. according to the compound of claim 1, wherein W 3For-C (O)-R 5
49. according to the compound of claim 1, group U wherein 1R 5For using 0-3 F, Br, Cl, N 3, NO 2Or the C of CN replacement 1-C 6Alkyl.
50. according to the compound of claim 1, wherein W 5Be selected from as follows:
Figure C2005100876590011C1
51. according to the composition of claim 1, wherein T 1Be selected from as follows:
Figure C2005100876590011C2
52. according to the compound of claim 1, wherein J 1Be H, C 1-C 2Alkyl or F.
53. according to the compound of claim 1, wherein J 1aBe H.
54. according to the compound of claim 1, wherein J 2aBe H or C 1-C 2Alkyl.
55. according to the compound of claim 1, wherein J 2aBe H.
56. according to the compound of claim 1, wherein W 6Be the second month in a season or the tertiary alkyl that contains 4-12 carbon atom, it is unsubstituted or through NO 2, N 3, F, Br, Cl, OR 1Or SR 1Replace.
57. according to the compound of claim 45, it replaces through nitro, azido-or F.
58. according to the compound of claim 1, wherein W 6For-(CH 2) M1CH (R 1) aW 7, W wherein 7For through 0-3 R 3The C that replaces 1-C 4Alkyl, a are 0 or 1, and when a is 0 W 7Link to each other through two keys with CH.
59. according to the compound of claim 58, wherein U 1For-O-CH 2CH (R 1) W 7
60. according to the compound of claim 58, wherein W 7For-CH 2OR 1And R 1Be C 4-C 12Alkyl.
61. according to the compound of claim 1, wherein U 1Be (CH 3CH 2) 2CHO-, (CH 3CH 2) (CH 3) CHO-, (CH 3) 2CHO-, (CH 3) 2CHCH 2O-, CH 3(CH 2) 4O-, CH 3(CH 2) 3O-, CH 3(CH 2) 2O-, (CH 3CH 2) (CH 3) 2CO-, (CH 3CH 2) (CH 3CH 2) HCO-, (CH 3CH 2CH 2) (CH 3CH 2) HCO-, (CH 3CH 2CH 2) (CH 3CH 2CH 2) HCO-, cyclohexyl-O-or cyclopentyl-O-.
62. according to the compound of claim 1, wherein:
E 1For-COOR 5,
Figure C2005100876590012C1
G 1For-N (R 5) 2,-NH (R 5) 2,
Figure C2005100876590013C1
And U 1Be the O-alkyl of 1-12 carbon atom, the O-alkenyl of 2-12 carbon atom, or the O-alkynyl of 2-12 carbon atom, and U 1By 0-3 be selected from F, Cl, Br, I ,-CN, NO 2, N 3,-OR 6a,-NR 6bR 6b,-SR 6a,-O-C (O) R 6aOr-NR 6b-C (O) R 6aGroup replace.
63. according to the compound of claim 62, wherein U 1Be selected from (CH 3CH 2) 2CHO-, (CH 3CH 2) (CH 3) CHO-, (CH 3) 2CHO-, (CH 3) 2CHCH 2O-, CH 3(CH 2) 4O-, CH 3(CH 2) 3O-, CH 3(CH 2) 2O-, (CH 3CH 2) (CH 3) 2CO-, (CH 3CH 2) (CH 3CH 2) HCO-, (CH 3CH 2CH 2) (CH 3CH 2) HCO-, (CH 3CH 2CH 2) (CH 3CH 2CH 2) HCO-, cyclohexyl-O-and cyclopentyl-O-.
64. according to the compound of claim 1, wherein E 1Be-COOH, or can be hydrolyzed in vivo-carboxyl ester or the carboxylic acid amides of COOH.
65. according to the compound of claim 1, it further comprises a kind of pharmaceutical acceptable carrier.
66., wherein further get rid of following compound, wherein G according to the compound of claim 1 1For-N (R 21) C (=N (R 21)) N (R 21) 2, R 21Be H independently, C 1-C 6Alkyl, C 3-C 8Cycloalkyl, C 1-C 6Alkoxyl group, aryl, aralkyl, aryloxy, aralkoxy, amino, hydroxyl, cyano group, nitro, COR 22, CO 2R 22, SO 2R 22, R wherein 22Be C 1-C 6Alkyl or aralkyl, or CONR 23, R wherein 23Be H or C independently 1-C 6Alkyl or aralkyl.
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