JPS59167598A - C-20- and c-23-modified macrolide derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to macrolide antibiotics, and more particularly to novel c-20 and (-]-23 modified derivatives of tyrosine and tyrosine-like macrolides. are doing.

Improvements in antibiotics are continually desired. In addition to antibiotics useful in treating human diseases, improved antibiotics are also needed in the field of veterinary disease treatment. Enhancement of potency,
Broadening the spectrum of bacterial growth inhibition, enhancing in vivo efficacy and improving pharmaceutical properties (e.g. greater oral absorption, higher blood or tissue concentrations, longer half-life in the body and A more advantageous rate of excretion or pathway N and rate of metabolism are the targets of improved antibiotics.

Tyrosine is a well-known therapeutic agent in the field of livestock disease treatment. (For example, Tetralledron Lett
ers/97θ, page 2339 and US Patent No. 3,/7. f, 3'l-/). Modifications of tyrosine and tyrosine-like macrolides have been carried out to obtain derivatives with improved properties. Although a large number of derivatives have been created, the improvement in activity has so far not been achieved to the desired degree.

More specifically, the present invention is based on the formula (1) % formula %) [wherein R is hydrogen, iodo, bromo, chloro, fluoro, cyan, -0R(', -0Ar, -8R'
, 7 Jido.

-NR'JeN-phthalimide or r, Ie is (i) hydrogen or -OB', (ii) chloro, fluoro, bromo, iodo, -0Ar, -0-tetrahydrofuranyl, -〇-tetrahydropyranyl, -8
Jt5. Azide.

-NB, ′■ (7 or N-phthalimide or 1e
and W has the formula -N (CJ=
[,,) A monocyclic amino group represented by n (ii) A monocyclic saturated or unsaturated nitrogen-containing heterocycle bonded through a nitrogen atom, the heterocycle being selected from (1) nitrogen, oxygen, and sulfur; 7 ring atoms, including up to 3 further heteroatoms.

(,2) has up to three substituents selected from methyl, ethyl and phenyl, or (ii
i) 12,3. goetetrahydroquinolin-/-yl, decahydroquinolin-/-yl, f2,3. '1-
Te1~ Lahydroisoquinoline-suyl, decahydroisoquinolin-λ-yl, indolin-/-yl, isoindoline-suyl, decahydrocyclohebuta[b]pyrrol-/-yl, decahydrocyclohebuta[b] c] pyrrolosuyl, decahydrocyclobent [c] azepine-
suil, tecahydrosic mouth vent [d, ]] azepin-3-yl flood, 3. J-tetrahydro-/J:1-
2-penzacepin-hydroyl, 2,3. Bicyclic or bicyclic selected from H-tetrahydro-/I-■-3-penzazepin-3-yl, azabicyclohebutanyl, azabicyclooctanyl, azabicyclononanyl, azabicyclodecanyl or azatricyclodecanyl ] f is hydrogen, optionally substituted C, % C,-alkanoyl or optionally substituted benzoyl, phenylacetyl or phenylpropionyl; ■ h is hydrogen, hydroxy, optionally substituted 07-C3 alkanoyloxy or optionally substituted benzoyloxy, phenylacetoxy or phenylpropionyloxy or (111 (mycalosyloxy), where IL'' is hydrogen, optionally substituted C, % C, - Alkyl, cyclohexyl.

optionally substituted benzyl, phenethyl or phenoxyethyl; Ar is (i) phenyl, derivatized phenyl or naphthyl; (ii) pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl;
Indolyl, isoquinolinyl.

Quinolinyl, quinasolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, benzotriazolyl.

an optionally substituted heteroaryl group selected from benzoxazolyl, benzimidazolyl, carbanolyl or acridinyl; or (iii) an optionally substituted ? , ;
, , C, to C5 alkanoyl, optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl, methanesulfonyl, trifluoro.

Methanesulfonyl, ＼＼＼＼＼＼ﾆﾆ＼＼＼＼Also, ＼＼＼＼＼＼ﾔ＼＼＼＼＼＼＼ Also ＼＼＼＼＼＼＼＼＼＼＼＼＼＼ﾟ＼＼＼ Also ＼＼＼＼＼＼＼＼＼＼＼＼＼＼＼＼＼＼＼Optionally substituted phenylsulfonyl ■ t3 is optionally substituted C2-Cp furkyl, cyclohexyl, optionally substituted phenyl, benzyl or phenethyl, or imidazolyl, pyrazolyl, pyridinyl,
Pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl.

Tetrazolyl, oxasilyl, isoxazolyl.

Oxadiazolyl, thiazolyl, isothiazolyl.

an optionally substituted heteroaryl group selected from thiadiazolyl, chenyl and furanyl, R6 being hydrogen, optionally substituted C,C,-alkyl, phenyl,
benzyl, phenethyl or C6-licycloalkyl; li7 is a 6 group or an optionally substituted C2
~C,-alkanoyl, optionally substituted benzoyl,
Phenylacetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl or alkoxycarbonyl, W is hydrogen, methyl, ethyl, ■
-propyl or isopropyl, or the two groups taken together -N(R')2 constitute a cyclic amine group selected from pyrrolidinyl, piperidinyl, hexahydroazepinyl or octahydroazosinyl. To,
Form a polymethylene portion. However, (1) R or xf
is hydrogen, W is never hydrogen or -01-I, and (2) R or R' is -Nl (R' or 1t3 must be hydrogen, hydroxy or mycarosyloxy, and Ar is (iii) in the definition
(3) If W is hydrogen, hole 8 must be hydrogen, hydroxy or mycarosyloxy, ("+) If R' is hydrogen or hydroxy, ■ is NR' is not R7.]
20 and C-23 modified macrolide derivatives and salts of these compounds, particularly acid addition salts.

The compounds of the invention are useful as antibiotics and/or intermediates to antibiotics.

7 or 7 bonded through a nitrogen atom and containing up to 3 further heteroatoms selected from nitrogen, oxygen and sulfur
Monocyclic saturated or unsaturated nitrogen-containing heterocycles having 1 ring atoms include pyrrolyl, pyrazolyl, imidazolyl, 1
2. 'l-oxadiazinyl, /, 3. 'l-thiadiazinyl, 12. 'I--)-riazolyl, /■(-tetrazolyl, azepinyl, morpholino, thiomorpholino, piperazinyl.

Includes groups such as thiazolidinyl, oxazolidinyl and tetrahydro-gouthiazin-hiro-yl. Such rings carry up to three substituents selected from methyl, ethyl and phenyl.

It may be present on any suitable carbon and/or nitrogen ring atoms.

As used herein, [07-9-alkanoino bJ means an acyl moiety derived from a carboxylic acid containing / to 5 carbon atoms, in which the alkyl group is
Branched or circular. If optionally substituted, the alkyl group can have / to 3 halo substituents. The halo substituent is CI.

selected from the group consisting of Br and 1'. Acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, n-butyryl.

Isobutyryl, n-valeryl and isovaleryl are examples of such groups. [C2-C5-alkanoyloxy] refers to the corresponding acyloxy moiety.

"optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl", "optionally substituted benzoyl, phenylacetyl or phenylpropionyl", "optionally substituted benzoyloxy, phenylacetoxy or phenyl""propionyloxy","optionally substituted phenyl, benzyl or phenethyl", "optionally substituted benzyl, phenethyl or phenoxyethyl" and "optionally substituted phenylsulfonyl"
It means that the phenyl moiety is optionally substituted by / to 5 halo or methyl groups or / to 2 methoxy, nitro or hydroxyl groups.

"Derivatized phenyl" means / to 3 halo, methoxy or 07~C,IL alkyl substituents or/to 2 nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, C7~ C
2o-methyleneamino, azide.

Hydroxy, hydroxymethyl, aminomethyl.

(methylamino)methyl, (ethylamino)methyl, (
dimethylamine)methyl, (diethylamino)methyl,
(CkelC10-methyleneamino)methyl.

Polmyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, carboxamide.

N-methylcarboxyamide, N,N-dimethylcarboxyamide, cyan, phenyl, phenyl group having a phenoxy or benzyl substituent, C2~lyalkyl, halo, methoxy, ethoxy, hydroxy( or its tautomer) or a suitable substituent such as a phenyl group.

"07-C3-alkyl" as used herein.

JC, ~C,1,C2~lyalkyl "C,% O,-
"Alkyl" means a straight or branched chain alkyl group containing the specified number of carbon atoms. Such groups include methyl, ethyl, isopropyl, n-butyl, t-butyl,
Includes 11-hexyl and its analogs. "Optionally substituted" C, -C7-alkyl or 07-C6-alkyl means an alkyl group containing one or more fluoro or chloro substituents.

"1'-C, ~C,-cycloalkyl" refers to a cycloalkyl group containing from 3 to 3 carbon atoms.

Examples of such groups are cyclopropyl, cyclohexyl,
It is cyclooctyl.

"Alkoxycarbonyl" means L-butoxycarbonyl, methoxycarbonyl, 1-hexycarbonyl, 21.
2,2-trichloroethoxycarbonyl.

Represents a group selected from phenoxycarbonyl and benzyloxycarbonyl.

"C7-C10-methyleneamino" refers to a cyclic amine substituent of the formula -N(CH)n, where TI is an integer from 1 to 70. Pyrrolidinyl, piperidinyl and octahydroazosinyl are examples of such groups.

(The following is a blank space) The present invention provides a macrolide represented by formula (I), (a) Q
is formyl, and Q' is R/ (however, B/ is not hydroxy). The starting material macrolide represented by formula (n) is reduced to produce the formula (1) in which R is H-roxy.
be considered a macrolide.

(b) Formula (II) where Q is formyl and Q' is R'
) reacting a starting material macrolide of formula (9) with an amine of formula HNRR or HR in the presence of a reducing agent to give a macrolide of formula (I) in which R is NRR or R; (C) Q is -OH YuOH.

A starting macrolide of formula (It) in which Q' is R' is reacted with diethyl azodicarboxylate or dimethyl azodicarboxylate 1- + triphenylphosphine and (i) an azido transfer reagent to form a compound in which R is (ii) react with phthalimide to obtain a macrolide of formula (1) in which R is phthalimide; (iii)
) Ar is Ar in (i) or (ii) in the definition of Ar above
to form a macrolide of formula (1) in which R is OAr by reacting with a phenol of the formula ArOH which is a group,
(iv) Reaction with a halogenated or polyhalogenated alkyl to give a macrolide of formula (I) in which R is C1, Br or 1, or (V) reaction with a mercaptan of the formula H8R' to form a macrolide in which R is SR. or (vi) Ar is reacted with a carboxylic acid or sulfonic acid represented by the formula ArOH, where Ar is the Ar group in (iii) in the definition of Ar, to obtain RiJS OAr. (d) A starting macrolide of formula (II) in which Q is -CH, 20H and Q/ is R' is combined with triphenylphosphine and a halogen source. (e) reacting to give a macrolide of formula (1) in which R is Cβ, Br or ■;
Formula (II) where Q is -0H20H and Q/ is R'
The starting material macrolide represented by is reacted with an acylating agent derived from a carboxylic acid or sulfonic acid represented by the formula ArOH, where Ar is an Ar group in (iii) in the definition of Ar above, so that R is OAr. (f) Q is a macrolide of formula CI), where L is a leaving group;
H, 2L.

The starting macrolide of formula (II) in which Q' is R' or a leaving group is combined with (i) an alkali metal azide or halide or a tetraalkylammonium azide in which alkyl is methyl, ethyl, propyl or methyl; (11) React with a mercaptide ion of formula R'S- to form a macrolide of formula (1) where R is azide, p, cβ, Br or fluoride, or react with a mercaptide ion of formula R'S- to form a macrolide where R is R8- or (iii) react with an amine of formula NR"R" or HR' to form a macrolide of formula (1') in which R is NR'R' or R9.
(v') A macrolide of the formula (1') in which R is -ON by reacting with a cyanide ion source, or (v') A macrolide of the formula HO in which R'' is other than hydrogen.
By reacting R with an alcohol and a silver ion source, R is OR
″, (g) Q
Hydrolyzing a macrolide of formula (II) in which is CH, R and Q' is (Jll) to obtain a macrolide of formula (I) in which R' is H-roxy, (11') Removal of the hydroxy protecting group from a macrolide of the formula (formerly) in which Q is -CH,2R and Q/ is a protected hydroxy; (i) Q is -
Reacting the starting material macrowide of formula (II) with OH, R and Q' being hydroxy with diethyl azodicarboxylate or dimethyl asocycarboxylate, triphenylphosphine and (i) the azido l-transfer reagent. (ii) React with phthalimide to produce macrolide l' of formula (1) where R' is phthalimide; (iii) Ar is reacted with phenol of ArOH in which Ar is an Ar group in (i) or (11) in the definition of Ar above to form a macrolide of formula (1) in which R' is 10Ar, or (iv) halokenization Or R' is Cβ by reacting with a polyhalokenated alkyl.

Macrolyte 1~ of the formula (I) which is Br or R is reacted with a mercaptan of the formula (■) H8R, so that R is SR.
' is the macroride of formula (1).

(vi) Ar is reacted with a carboxylic acid or sulfonic acid of the formula ArOH, which is the Ar group in (1) in the definition of Ar, to form a macrolide of the formula (I), which is R' or OAr; (j) A macrolide represented by the formula ([) in which Q is -Ci (UR and Q' is hydroxy) is prepared from Ar or a carboxylic acid or sulfonic acid represented by ArOH which is an Ar group in (iii) in the definition of Ar above. A macrolide of formula (1) in which R' is OAr or a macrolide of formula (II) in which 10Q is R and Q' is hydroxy. By reacting with triphenylbosphine and a halogenation reagent, R′ becomes C
β, Br ; i or king; (1) Macrolide of formula (II) where Q is -C)I, R and Q' is a leaving group; (i) with an alkali metal azide or halide or a tetraalkylammonium azide or fluoride in which alkyl is methyl, ethyl, propyl or butyl to form an acyl, F, Cβ.

a macrophyte of formula (1) which is Er or I;
(ii) to react with a merkabutyl ion of formula R'S- to produce a macrolyte of formula (1) in which R' is R'S-, or (iii) to prepare a macrolyte of formula I (NR'R' or HR9 (m) Q is -CH
, N3 and Q' is R', or Q is R and Q' is acid.・Reduces R to 10H, NH.

or R' is amino; (n) a macrolide of the formula (II) where Q is -CI(,2NI(R') or R' is NI(R'); ) is acylated to form a macrolide in which R is -OH, 2NHR.
or R' is -NR'R7, (0) esterifying the macrolide of formula (1), (p) macrolide of formula (1,) (q) hydrolyzing the macrolide of formula (I') in which R3 is mycarosyloxy in an acid solution at pHg or below F to obtain macrolide 1 of formula (1) in which R3 is hydroxy; -, (r) deoxygenating the macrolyte I of formula (I) in which R3 is hydroxy to produce macrolyte I· of formula (1') in which R3 is hydrogen, (s'
) The macrolide of formula (II) in which Q is CH, I and Q/ is R' is reacted with a reducing agent to obtain the formula (II) in which R is hydrogen.
1"), or (t) Q is -CH
2-sulfonate, and the macrolide of the formula (■) in which Q/ is R' is reacted with a rayodide ion source to produce the macrolide of the formula (1) in which R is iodo. They also offer it.

In general, macrolides of formula 1 ('I) are modified at the C-20 position of a macrolide having a desired group at the C-23 position, or by modification at the C-20 position of a macrolide having a desired group at the C-20 position. It is produced by modifying the 23rd position or simultaneously modifying both the 20th and 23rd positions. In addition, the 9-macrolide of formula (I) can be modified at the 20 and 23 positions using known methods to produce 1
Other macrolizations of formula (1)!・Can be created.

The following are well-known macrolides useful in preparing the macrolides of the present invention: Demidinosyltyrosine (
DMT), 20-dihydro-23-demidinosyltyrosine (dihydro-DMT).

23-te(mycinosyloxy)tyrosine (DMOT)
.

20-dihydro-23-te(misinosyloxy)tyrosine (dihydro-DM, OT), 3-0-ε caminosyltyronolide (OMT), 20-dihydro-3-
0-ε caminosyl tyronolite (dihydro-OMT)
, 23-thioxy-o-O-mycaminosyltyronolyl F
(DOMT), :lQ-Jihee I. Lo, 23-
Deoxy-3-〇-E-caminosyltyrosine (dihydro-DOMT), 20-dihydro-I-theta-thioxy-23-demidinosyltyrosine (DH-DO-DM)
T ) and 20-shihydroyu θ-deoxy-3-0
-i caminosyl tyronolite (DH-Do-OMT).

DM'T, dihydro-DMT, DMOT, dihydro-DMOT, DOMT and Schich I. Low DOMT are:
Richard H, Baltz, Gene M
, Wi Id and Eugene T, 5eno, 79g, 2. It is an antibiotic listed in the American Sukyo 3213 Otsu/and KU 3 Yu X3 Otsuno published on March 23, 2013. D H-D O-D-M T and DH-D
o-OMT: Richard H, Baaltz,
HcrborL person Kirst, Gene I ball Will
d and Eugcnc T, 5eno J, 1
American patent lA30'lJ issued in 72/9g7
! ;Described in Part B. OMT and dihydro-OMT were described by Marvin Gorrrian and Rol) crt
D9Marin, U.S. Pat. ! ;3.

The structure of the antibiotic used as a starting material is represented by // from the formula.

(Left below) Q----QIQ2. 2DMT: -CHo -OH Mycarosil 3DMT; -C) IUOH-OH//4LOMT
: -CHO -OHHjdihydro- oMT: -cHOH-OHH! Otsu DMOT: -cuo H Mikarosil 7
Dihtro DMOT: -CHOHH// fDOMT: -CHO HH9dihydro- DOM, T + -CHOHHHλ/OD H- DO-DMT: -CH-OHε carosyl//DH- DO=OMT: -aH-OHI (from the following description Obviously other known macrolides are also useful starting materials.

Method for modifying the C-, 2O position The desired group at the C-20 position can be modified by using a known starting material that already has the desired group or by modifying the c-, 2O position of an available starting material. Obtained by modifying . If other modifications are required, the C-20 position may be modified before or after the modification is performed on the starting material ζ.

Known macrolides of formula (II) in which Q is -CH,OH include dihydro-DMT (3), dihydro-DOMT (9').

The macrolide represented by formula (1) or (■) in which R is hydroxy or Q is CH, 201-I is 8
Prepared by reducing a macrolide of formula (Il'l) in which Q is formyl to give the corresponding 20-dihydro compound. Chemical reduction can be achieved by treatment with sodium.

Formula (1) in which R is OH or Q is CH, 20H
) or (II) can be converted to other macrolides of formula (I) by modifying the c-2θ hydroxyl group using any of nine different known synthetic methods. Some methods are described below.

Known macrolides of formula (II) where Q is methyl are DH-DO-DMT (#7) and DH-DO-
Includes OMT (//).

Macrolides of formula (I) or (II) in which R is hydrogen or Q is methyl, wherein Q is -CH,2
A macrolide of formula (■), which is I, is dissolved in a hydride (e.g. sodium borohydride), or l-luene or It may be prepared by reaction with a reducing agent such as an organostin hydride (eg tri-butyltin hydride) or a metal (eg zinc powder) in a non-reactive organic solvent such as nitromethane.

R is CA, Br or engineering, or Q is -CH,
The macrolide represented by formula (1) or (Il'l), which is CA, -OH,2Br or -CH,I, is
Macrolide of formula (■) where Q is -CH, 20H,
It is prepared by reaction with tidriphenylphosphine and/) a lokenization reagent in a non-reactive organic solvent such as dichloromethane. A suitable lokenizing agent is
Includes alkyl halides and polyalkyl halides such as carbon tetrachloride.

R is CA, Br or Engineering or QiJS-C
H2Cl, -CH,! B r or -CH2I
A macrolide of the formula (I) or (II), which is Q -bs -CH,0I-I,
) with triphenylphosphine, ethyl azocycarboxylate 1- or diethyl azodicarboxylate and /SS rosin or polyhalokenated alkyl.

For the reaction of cy(alkyl)azodicarboxylate with triphenylphosphine and its various applications, see
O, Mitsunobu, 5yntbesis
Volume 7, (1).

7~. It is described on page 21 (/9f/year). This reaction generally involves dehydration between the alcohol ROH and the acid component HX to yield the product RX.

R is F, CA, Br or ■ or Q is -C
Macrylite of the formula (1'l or (Il), which is H,F, -CH,2CB, -CH,2Br or -CH2I, is a macrolide of the formula (II) where Q is -CH0) in tetrahydrofuran. It is also prepared by reaction with an alkali metal or tetra(alkyl)ammonium halide in a non-reactive organic solvent such as.

The formula (where R is azide or Q is -CHYN)
The macrolide represented by I) or (II) is Q or -
Macrowide of formula (II), which is CH0, is prepared by reacting with an alkali metal or tetra(alkyl)ammonium azide in a non-reactive organic solvent.

Formula (where R is azide or Q is -CH, N3)
I) or (■) is a macrolide in which Q is -C
A macrolide of formula (■), which is It is also produced by reacting with a transfer reagent.

The formula (where R is cyano or Q is -CH,ON)
Macrolides indicated by I) or (■) are QkaCH
A macrolide of formula (lI) in which L is a halokenide or sulfonic acid ester group is reacted with a cyanide salt in a non-reactive organic solvent such as dimethyl sulfoxide.

The expression (,
1') or (■), Q is C
It is prepared by reacting a macrolide of formula (H'), H,2L, with an alcohol of formula HOR'', where R'' is other than hydrogen, in the presence of a source of silver ions.

Macrolides of formula (■) or (II) in which R is OAr or Q is CI(,20Ar) are Q
is -CH20H
is produced by reacting (]) or (ii) A in the above definition of Ar with a phenol of the formula ArOH, which is a group.

R is OAr or Q is OHyuOAr and Ar
Macrolides of formula (I) or (II') in which is optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl are macrolides of formula (■) in which Q is -CH,OH
is prepared by reacting a macrolide of formula A r OH with an acylating agent derived from a carboxylic acid of formula A r OH, where Ar is as defined above. Typical acylating agents are anhydrides. , acid halides (usually in combination with bases or other acid scavengers), and active esters. Suitable organic solvents include pyridine and triethylamine. Mixtures of dehydrating agents such as hexylcarbodiimide may also be used.

R is OAr or Q is CH20A r and A
Formula (1) or (
The macrolide represented by
It is also prepared by reacting with a di(alkyl)azodicarboxylate and a carboxylic acid of the formula ArOH.

A macrolide of formula (1) or (■) in which R is OAr or Q is CHr OA r and Ar is meclesulfonyl, trifluoromethanesulfonylmodi or optionally substituted phenylsulfonyl, wherein Q is -OH, OR is the macro wide of formula (1'), which is 1 formula A
Activated derivatives of sulfonic acids of r 0I-I.

For example, they are produced by reacting with anhydrides or acid halides. When using an acid halide, the reaction is carried out in the presence of a base 9, usually pyridine.

R is OAr or Q is (formula CI where JFIaOAr and Ar is defined in the previous section)':! , or (II) is a di(alkyl)
The azodicarboxylate/triphenylphosphine approach, i.e. by reacting a macrolide of the formula (previously is also manufactured.

The formula (where R is SR or Q is -CH, SR')
1) or (H'), Q is C
IH, 2L (previously prepared by reacting a macrolide of formula R8- with a mercaptide ion of formula R8-. L can be a halide, or a sulfonic acid or sulfonic acid ester group).

A formula in which R is SR or Q is -OHUSR'f (
The macrolide represented by I) or (It') is
alkyl) azocycarboxylene 1- / ) liphenylphosphine method, i.e., the formula (■
) triphenylphosphine macrolide.

Cy(alkyl)azodicarboxylate and formula H8R
It can also be produced by reacting with a mercaptan.

R is NRRT or Q is -CH,2NR"R"7
c A certain macrolide represented by formula (I) or (II).

Q is 10) 1. The macrolide of formula (■) is NI(R').

Formula (I
) or (■) Mac1 collide is Q is -CH,20
H (formerly macrowide) is prepared by reacting with triphenylphosphine, di(alkyl) azosicalphoxylate and phthalimide.

Compounds of formula (I) or (II) wherein R'' or L is methanesulfonyl, trifluorostanesulfonyl or optionally substituted phenylsulfonyl.

Like the compounds of formula (1') or formula (■) in which R or L is iodo or furomo, they are useful intermediates for preparing further compounds of the invention by SN/ or SN2 substitution reactions. Suitable reaction conditions for replacing a leaving group with a nucleophilic group in either the SN/ or SN2 mechanism are well illustrated in the art of nucleophilic substitution reactions.

The compound of formula (1) or (II) in which R is -NHR7 and R7 is an acyl group is a 20-azido derivative (R-N).

). This yu-θ-azido derivative is first converted into a 20-amino derivative (R,, -NII(,,2)-
＼, but aqueous tetrahydrofuran (THF
The use of triphenylphosphine in ) is an example of a suitable reducing agent for this purpose. The 20-amino derivative is then selectively acylated at the amino group using standard Qu acylation techniques to yield a derivative in which R is an acyl group.

R is -N(R'), or R2, or Q is C
Macrolides of formula (■) or (II') which are H,2N(R),2 or GH,R are DMT, OMT, D
It is produced by reductive amination of the C-20 altehyde group of MOT and DOMT using one of the following methods.

Method: A derivative having a leaving group (iodo, triflate, etc.) at the C-20 position was prepared as described above.

The reaction is carried out with a suitable amine in a suitable solvent such as acetonitrile until the desired 20-position modified derivative is formed by replacing the leaving group at the C-X0 position with a nucleophilic amine.

Method-2 This method (in this case, the aldehyde group of compound 2. V, g, or direct reaction. Sodium cyanoborohydride is an example of a suitable reducing agent, and anhydrous methanol is a useful solvent for this reaction. Although this reaction is carried out under a stream of nitrogen, this is not necessary. For less reactive amines, stronger conditions to form intermediate iminium complexes between the macrolide and the amine.

For example, heating, use of desiccants or water removal agents, or heating under conditions of azeotropic removal of water in solvents such as benzene or toluene, etc., may be required.

Methods for modifying the C''23 position Desired groups at the C-, 2, and 3 positions can likewise be modified using available starting materials that all have the desired groups at the C-23 position, or It can be obtained by manually modifying the C-23 position of a starting material.

Known macrolides of formula (II) where Q' is hydroxy are DMT (2'), dihydro-DMT=I)
O-DMT (#7) and DH-DO-OMT (//)
includes.

Formula (I) or (H
) is produced by acid hydrolysis of macrolide of formula (■) where Q/ is. The hydrolysis is described in U.S. Patent No. 3. As described in Getsubisho 3, DHL is carried out between 3 and 23-.

Macrolides of the formula (1) - or (■) in which R/ + or Q' is hydroxy may be treated with Using the methods described above, 1m macrolide of formula (1) is modified. Thus, a DEAD reaction is required to perform many C-23 position modifications. Other techniques for modification at the C-,23 position are described by A. Tanaka et al., J. Antibioics Vol. 33, (Issue 7).
/73~//Otsu pages (19g2).

Another possible method for modifying the C-23 position is a two-step process in which the 23-hydroxy group is first converted to a leaving group;
and then replacing the leaving group with a suitable nucleophilic group.

First, the 23-hydroxy group is converted into a suitable leaving group as is well known to those skilled in the art.

Triflate anions are preferred leaving groups. However, in the case of highly reactive nucleophilic groups, other leaving groups such as mesylate, tosylate, iodine or bromine anions may also be suitable.

The C-23-position-〇-1 to reflation-1~ is a combination of the 23-OH intermediate with an activated derivative of trifluoromethanesulfonic acid, such as its anhydride, and preferably with a It is preferably prepared by reaction in the presence of a sterically hindered pyridine derivative such as S-colicin at temperatures ranging from 0°C to room temperature. 0-23
Hydroacyl groups other than the positions are protected by acetyl groups, which can be removed by metathurisis, for example by refluxing in methanol. Using this method, 23
-0-trifle 1~ can be prepared without concomitant reaction with other hydroxyl groups present. A similar reaction is used to directly make the corresponding mesylate or 1.

When triflate is used as a leaving group.

There is no need to isolate the intermediate triflate derivative, and substitution with a suitable nucleophilic group can be carried out as it is. When less reactive leaving groups are used, the intermediate is sufficiently stable that it can be isolated prior to the substitution reaction, if necessary.

The second step in preparing the C-23 modified derivative is to replace the appropriate nucleophilic group under appropriate conditions well illustrated in the art of substitution reactions.

When it is desired to prepare a compound of formula (II) where Q' is SR', the most convenient nucleophile is a compound of formula H8R'. For the production of azides, the nucleophile is preferably an alkali metal acid such as lithium azide. Pyridinium compounds are preferably prepared by reaction with pyridine base. When Q' is NR'R7 or HR9, the nucleophile is the amine of formula I (NR'R7 or HR).

Nucleophilic substitution reactions are performed using inert organic solvents such as chlorinated hydrocarbons similar to dichloromethane.

It is preferably carried out at temperatures ranging from -gooC to 100°C.

Typically performed at room temperature.

The C-23 derivative in which R' is -NI (R7) is prepared via the 23-and derivative (R-N3). The azide group is first reduced to the 23-amino derivative using a specific reducing agent. Aqueous organic solvents such as ethereal solvents such as tetrahydrofuran (THF) are useful for this purpose. It is effectively carried out in a temperature range of 10θ0C.

The 23-amino derivatives are then selectively acylated using standard acylation techniques to give those derivatives where R7 is an acyl group. As is well known to those skilled in the art, acylation is accomplished at temperatures ranging from -20 to 70<0>C.

It must be noted that when compounds of formula 3 or 2 are used as starting materials, there are two primary hydroxyl groups that react in the same way. However, the primary hydroxy group at C-20 is usually displaced faster than the hydroxy group at C-23.

Many of the methods described above involve the use of 20-monosubstituted derivatives and 20.
gives a mixture of 23-disubstituted derivatives.

Such mixtures can be easily separated by known techniques such as chromatography using silica gel as an adsorbent. Formation of C-2o-monosubstituted derivatives is best accomplished by not carrying the two reactions to completion, e.g., by using less than two molar equivalents of reactants. On the contrary, C
If a -20, C-23-disubstituted derivative is desired, one reaction should be run to completion and two molar equivalents or excess of reactants are used.

Compounds in which substituent R' is different from substituent R are prepared by modifying the hydroxy group at C-23 before reducing the aldehyde at C-20.

When producing a compound of formula (1) where R is hydrogen.

Compounds io and 44 are used as starting materials and modified with the hydroxy group at C-23 as described previously.

An alternative method of preparing compounds with different substituents at the C-20 and C-23 positions is to modify the C-20 position of macrolides that do not have a free C-23 hydroxyl group. .

An example of this method involves preparing C-20-modified derivatives of tesmicosin, tyrosine, macrosin, lactenosin, temethylmacrosin, and demethyllactenosine and then using techniques known in the art (e.g., U.S. Pat. 3μ39J33) in neutral sugars. By this method, the 20th place in OMT -
Modified derivatives were selectively prepared and 5
Modifications can then be made at the C-23 position.

Prior to aldehyde reduction, OMT and DMT C-,
When a protecting group is used for the hydroxyl group at position 23, C-
Selective modification at position 20 is possible.

Removal of the protecting group after appropriate modification at the C-20 position results in C-
A C-20 modified derivative with a hydroxyl group at position 23 is produced, which may then be modified as outlined previously. Examples of useful protecting groups are ester moieties such as acetyl and trichloroacetyl and groups such as tetrahydropyranyl and tetrahydrofuranyl. Tetrahydropyranyl and Te1-rahydrofuranyl protecting groups are 2
For example, it is described by Ta, naka et al.

Modified derivatives of OMT, DOMT and DH-Do-OMT are DMT, 'DMOT and DH-Do-1)M, respectively, prepared by previously described methods.
It is also produced by acid hydrolysis of mycarose from the corresponding modified derivative of T.

OMT and DOM from DMT and DMOT respectively
Techniques for acid hydrolysis of mycarose to produce T are found in US Pat. Acid hydrolysis of DH-Do-DMT to DH-, DO-OMT is described in US Patent No. 3041J3 O.

More specifically, the mycarose sugar is p) (less than l1).

Hitting method is θj to 2.0 range, 0 to Otsu 0°
Temperature Range 2 of C 2 is conveniently hydrolytically cleaved at about room temperature. The hydrolysis is accomplished with aqueous strong mineral acids such as hydrochloric acid or sulfuric acid or strong organic acids such as p-toluenesulfonic acid.

The method for producing t'-deoxydesmicosin is described in J. of An.
tibio also 1cs 34 volumes, /3.8'/ ~g'A
Page Cl9f/year). The process is (1)
Desmicosin.

Ar+I;1biot, &Chanol,h,/
Treatment with acidic ethanol gives the corresponding diethylacecour according to the procedure described in vol. 320-27 (7767). (2) J, Org, Chem,
diethyl acetal according to the method described in Vol. 4141, p. 2oso-j2 (1979).

2. Acylation with acetic anhydride in acetonyl-IJ without external base. '%'-di-O-acetyl derivative is obtained.

(3) J, Org, Ch cm, vol. 112, 3y
72 to 'ytit pages (/V711), 2. '4''-di-O-acetyl a conductor was reacted with 2,3-dihydrofuran in the presence of hyricinium valatoluenesulfonate in dichloromethane to 3.'l
- Obtain a his(O-tetrahydrofuranyl) derivative. (
−+) Step −The product of step (3) was mixed with methanol (50°C2
- overnight) to remove the 2' and %'-o-acetyl groups. (j) Step - The product of (ri) in pyridine/3
A 4'-o-benzenesulfonyl derivative is obtained by reacting with a molar equivalent of penzenesulfonyl chloride at 1 g θ0C for j hours.

(B) Immediately, the g'-0-benzenesulfonyl derivative is reacted with an equivalent of thorium iodide in methyl ethyl ketone at 0°C for 5 minutes to obtain a'-iodo derivative. (7) ll'- in the presence of 2.2'-azobis-isobutyronitrile in benzene for 2 h at fOoC.
The iodine derivative is reductively deiodized using 1s(n-butyl)tin, and the product of step (7) is converted into θ/M dilute hydrochloric acid-acetonyl-C2,3:/, volume ratio. ) middle, 2
3; Consists of hydrolysis at °C for 30 minutes, thus deprotecting the diethylacetahel and tetrahydrofuranyl groups to yield j'-thioxidesmycosine.

The g'-deoxy derivatives of the present invention, i.e., the compounds of the formula (D) in which R3 is hydrogen, are prepared by using t'-thioxy-OMT, t'-deoxy-DOMT or g'-deoxy derivatives as a starting material.
-thioxy-DH-DO-OMT.

It is easily manufactured by techniques similar to those detailed above. These starting materials were published in J. Antibiotics
3tl-vol. /3Lf/~73g pages Cl91/year). Alternatively, deoxygenation at 111' is achieved following modification at the C-, 20 and/or C-23 positions in OMT, DOMT or DH-DO-OMT.

The compound of formula (1) which is an ester derivative has the respective C-20 and/or C-23 modified derivatives as 2. ￥
and/or 23 (if present)-hydroxy groups by esterification by treatment with an acylating agent using standard methods exemplified in the art. The preparation of 2'-o-ester derivatives of C-su theta and/or C-23 modified derivatives is described in U.S. Pat.
This is done by a technique similar to that described in 362.

2. of these modified derivatives. Esterification of the ``l' and 7- or 23-hydroxy groups is possible in the previously discussed application No. 33Q3g/, υj of 33 and 3
This is achieved by acylating the hydroxyl group using a method similar to that outlined in 30.29'1.

Alternatively, compounds of formula (1) that are esters.

Compounds 2~// are prepared starting from the appropriate esters made as described above.

Furthermore, the ester compound of formula (1) is hydrolyzed to give the corresponding compound of formula (1), thus during the reaction to modify the C-20 and 7- or C-23 positions, the ester compound is It should be noted that the group can be utilized as a protecting group.

The C-20 modified derivatives of the invention form salts, particularly acid addition salts. These acid addition salts are also useful as antibiotics and form part of this invention. From another point of view, such salts are useful as intermediates, for example for separating and purifying derivatives. In addition, salts have increased solubility in water.

Examples of suitable salts include those formed by standard reactions with both organic and inorganic acids.

Examples of these acids are sulfuric acid, hydrochloric acid, phosphoric acid, and acetic acid.

'Succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, palmitic acid, cholic acid, bamoic acid
cacicl), mucic acid, D-glutamic acid, d-camphoric acid.

Glutaric acid, glycolic acid, phthalic acid, tartaric acid.

Formic acid, lauric acid, stearic acid, salicylic acid.

methanesulfonic acid, pencenesulfonic acid, sorbic acid,
Picric acid, benzoic acid, cinnamic acid and similar acids.

Pharmaceutically acceptable acid addition salts are particularly preferred salts of the present invention.

Illustrative compounds of formula (1) of the invention are shown in Table -■.

(Left below) Derivatives of the compounds of the present invention are useful for pathogenic bacteria, particularly Durham-positive bacteria and Mycoplasma (Mycoplasrr+a).
Inhibits the growth of seeds. Some of the derivatives are active against certain Durham-negative bacteria, such as Pasteurella (Pa51.eurella) species. To illustrate, the minimum inhibitory concentrations (MIC's) at which a compound inhibits bacteria are shown in the table.
and ■ are shown. The MIC's in Table] were determined by the agar dilution standard assay method. The MIC's in Table 1 were obtained by conventional liquid dilution microtitration tests.

(Left below) a, MIC b0 at mcg/, d Compound number C0 according to Table ■ Isolated from cattle d, isolated from birds e, resistant strain r, mIc is 30 rncg, Atr 1 or more g or more bundled Certain derivatives of the present invention exhibit antibacterial activity in vivo against laboratory-induced infections in experimental animals. Mice experimentally infected with Streptococcus pyogenes C2θ3 were dosed twice with the test compound, and the observed activity was defined as the ED, o value [effective dose expressed in Icg/Icg to protect 30% of the test animals]. Amount: Eggplant rrcn Wick et al.

J, BacLeriol, g/vol., 233-X3. S
(see page 7967)]. The ED, o values for the exemplified compounds are shown in Table-■.

(Left below) Table - ■ ED, o value 1/of the exemplified compound of formula (j)
>30 >10022
〉3θ〉/θ02g ＞io
〉3θ23 ＞10
>3033'>, 23-
＞/θ03g ＞23
7f33 ＞/2.3 ＞
/θ03 Otsu >io >3゜37
>10 >1003g
〉/θ 〉10θ7
〉10〉Evening 0a,~/kq twice; After infection/
Compound No. from Table-1 Certain of the compounds of formula (1) of the present invention are also active in vivo against infections induced by Clam-negative bacteria. Table -■ summarizes the results of evaluation tests of the exemplified compounds against Pasteurella infection in -day-old chicks. After the compound is given subcutaneously at 0/ml of a 10-'' dilution.

Administered parenterally. In these tests.

Unless otherwise specified, all unmedicated infected chicks should be infected with Pasteurella at PL91 for more than 2j hours.
He died. In the tests summarized in Table -■.

The compound was administered to chicks after infection with Pasteurella multocida.
30 mg/day by subcutaneous injection
/C9 was administered.

Table V l) Test compound Number of deaths/number of treatments/9//θ 22 9/10 2 /θ/10 33 f//θ 37 10//θ 3d 10//θ a, subcutaneous administration; 30~ / 9 twice 1 Table - Compound number from ■ Compounds that show in vivo activity against Durham positive bacteria are compounds of formula (1) where R is N(R), formula (+) It is a compound of Yet another group of compounds that exhibit in vivo activity against Durham-positive bacteria and activity against Mycoplasma species are compounds of formula (1), where R is R.

The present invention also relates to methods of inhibiting infections caused by Durum-positive bacteria and Mycoplasma species. In carrying out the method of the invention, an effective amount of a designated compound of formula (1) is administered parenterally to an infected or susceptible warm-blooded animal. The dosage effective to control the infection will vary depending on the severity of the infection and the age, weight and condition of the animal. However, when administered parenterally, the total dosage required to protect an animal from infection will generally range from about / to about /θθmg/kq, preferably /
to 30 ml/'kQ.

A suitable medication regimen can be developed.

In another aspect, the present invention relates to compositions useful for combating infections caused by Durham-positive bacteria and Mycoplasma species. These compositions consist of the specified compound of formula (1) together with suitable excipients. The compositions can be formulated for parenteral administration according to methods recognized in the pharmaceutical arts.

Effective injectable compositions containing these compounds are in the form of suspensions or solutions. When formulating an appropriate drug,
It will be appreciated that generally the solubility of acid addition salts in water is greater than the solubility of the free base. Similarly, bases are more soluble in dilute acids or acidic solutions than in neutral or basic solutions.

When in the form of solutions, the compounds are dissolved in physiologically acceptable excipients. A suitable solvent for such excipients,
Contains preservatives and buffers such as benzyl alcohol if necessary. Useful solvents include, for example, water and aqueous alcohols, aqueous glycols and aqueous carbonates such as diethyl carbonate. Such aqueous solutions generally contain no more than 30% by volume of organic solvent.

Injectable suspension compositions require a liquid suspension medium as an excipient with or without adjuvants.

The suspending medium is, for example, aqueous polyvinylvinylvinylene CIIJ, aqueous carboxymethyl cellulose, or an inert oil such as vegetable or highly refined mineral oil.

Appropriate physiologically acceptable adjuvants are necessary to keep the two compounds suspended in the suspension composition. The adjuvant is selected among thickeners such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin and alginates. There are many surfactants that are also useful as suspending agents.

Lecithin, alkylphenol polyethylene oxide adducts, naphthalene sulfonate esters, alkylbenzene sulfonate esters, and polyoxyethylene sorbitan esters are useful suspending agents.

A number of substances that influence the hydrophilicity, density and surface tension of liquid temperature-sensitive media are useful in making suspensions for injection in different cases. For example, silicone antifoaming agent,
Sorbitol and sugars are useful suspending agents.

Examples are provided below to fully illustrate the operation of the invention.

(Leaving space below) Reference example-/ Su, Gooji O-a old chill-, 20-jihi 1guro OM
T flood θ-dihydro”T (3,/9,.5:2mm
ol) was dissolved in acetone Cl00ml), and acetic anhydride (2.0ml, 21.2mmol) was added for 5 minutes. After stirring at room temperature for 9 hours, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (3g0ml) to stop the reaction.

The product was extracted with dichloromethane <230πf twice). The dichloromethane extracts were combined, dried (sodium sulfate) and filtered, and the filtrate was evaporated under reduced pressure. The residue was dried in vacuo overnight to yield 3.11-1 (96%
) (7) 2. 'l-' -C 0-7 Seti J
l/-20-dihydro-OMT was obtained.

Reference example - 23-iodo-2θ, 23-dideoxyse θ-dihydro-〇MT 20-dideoxy-20-dihydro-OMT (2,0!
, 3. gmmol), tetrabutylammonium iodide (31 g Q,/0 gmmol), and s'-D lysine (13 gm1./θ3 mmol) were dissolved in dichloromethane (gmmol), and the solution was heated to -7♂°C under an argon atmosphere. The mixture was cooled to . and triflic anhydride (07πl) was added dropwise. After keeping at -7f'C for 5 minutes, remove the cooling bath9. The solution was stirred at room temperature for 30 minutes. According to thin layer chromatography ('TLC) analysis, unreacted raw materials were still present, so the solution was diluted again at -7,
Cooled to r'C to form triflic anhydride (003π
f) was added. The cooling bath was removed again and the 9 reactions were stirred at room temperature for 30 minutes. The solution was washed with saturated aqueous sodium bicarbonate solution, dried (sodium sulfate), filtered,
The P solution was evaporated to dryness and the crude product was flash chromatographed on silica gel with dichloromethane (/7i) and 3% methanol-dichloromethane solution M (
/A) linear gradient (1inear gra
dien) was purified by elution with a mixed solvent. Both fractions containing the desired product were determined by TLC analysis and combined and the solvent was removed under reduced pressure to yield 2 g of 23-iodo-2.
C23-dideoxy-20-dihydro-OMT was obtained.

Example-7 217'-di0-acetyl-20-〇-phenylacetyl-20-dihydro-〇 M, T and Su, ≠-di〇-acetyl-,20,23-diO-phenylacetyl-20- Dihydro-〇MT S, I1. -di-O-acetyl-20-dihydro-OM
Dissolve T (3,01i', 444'mmol) in a mixture of dichloromethane (50πl) and pyridine C2ml).

The solution was cooled to -7f'C and, with vigorous stirring, phenylacetyl chloride <07.23ml1°53
mmol) was added dropwise. -7,roc/5
After holding for 1 minute, the cooling bath was removed and the solution was stirred at room temperature for 1 hour. The solution was then poured into a saturated aqueous sodium bicarbonate solution (100πf) and the product was dissolved in dichloromethane (30πf).
Extracted with πl (twice). Combine the dichloromethane extracts and dry (sodium sulfate).

The solvent was removed from the P solution by filtration. Residue (l1g) Wowaters Prap! ;00 chromatography and purified by elution with a linear gradient mixed solvent of 1-toluene (gA) and ethyl acetate (41+).

Both fractions containing the target product were determined by TLC analysis, and the two fractions were combined and the solvent was removed under reduced pressure to yield 23 g.
, g-O-acetyl-flood θ-〇-phenylacetyl-,20-dihydro-OMT and 0g-U, l
1-diO-acetyl-20,23-diO-phenylacetyl-20-dihydro-OMT was obtained.

Example - Suyu θ-〇-phenylacetyl-θ-Shihi I. Law MT Yu, Gooji O-acetyl-,20-0-phenylacetyl-20-dihydro-OMT (72 g, / mmo
] ) in methanol (gaml) and water (20 tnl
) and the solution was heated under reflux for half an hour.

After returning to room temperature, the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane <30 ml), dried (sodium sulfate) and filtered. Remove solvent from tear fluid, 092'
l of 20-〇-phenylacetyl-20-dihydro-O
I got MT.

Example 3 Uθ, 23-diO-phenylacetyl-20-dihydro-OMT 2:ll-'-cyO
-Acetyl-Flood θ4.23-S-O-Phenylacetyl-20-Nhydro〇M, TC03g is hydrolyzed to θG'l-! 20,. 23-diO-phenylacetyl-20-dihydro-OMT was obtained.

Example - Gus θ-N-methylamino-,20-thioxy-20-dihydro-OMT OMT (/:, 2g) and methylamine hydrochloride (/33g
) was dissolved in dry methanol <ll-0ml) and stirred at room temperature for an hour, then sodium cyanoborohydride (3
0θm da) was added. Stir the solution for 3 hours5. The mixture was poured into a saturated aqueous solution of hydrogen carbonate (200ml). The product was extracted with dichloromethane (2 x 2θOml) and the extracts were combined, dried (sulfuric acid-sulfur) and filtered. The solvent was removed from P solution and the residue (09g)
Dissolved in dichloromethane and silica gel (Brace Otsu 0)
chromatographed with dichloromethane-methanol-concentrated ammonia water (90:10:0 evening, /
IJ) and cyclonotane-methanol-concentrated aqueous ammonia (73:, 2 evenings: θta, /l) was purified by elution with a gradient mixed solvent. Both fractions containing the desired product were found by TLC analysis.

They were combined and the solvent removed under reduced pressure to give the o/ay title compound.

Example-j 20-N-pensylamino-,20-deoxy-flood θ-
Dihydro-OMT Example - OMT (,2,,2
g) and pencilamine ('1./me) were treated with sodium carbonate (70 g) in methanol (0 ml). After the extraction process, the crude product.

Dichloromethane (gβ) and dichloromethane-methanol-concentrated aqueous ammonia (90:10:03.'
A11) is eluted with a linear gradient consisting of 0
2/g of the title compound was obtained.

Example - O-N-dimethylamino-yu θ-thioxy-20-dihydro-〇MT OMT (/27) and dimethylamine hydrochloride (ll,!;l) were prepared using a method similar to Example-V. was treated with sodium cyanoborohydride (03 g) in methanol (≠Ome). Extraction process and examples
After purification by Benako Silica Kel Chroma 1-Graphie described by Shio, 037 g of the title compound was obtained.

Example-7 20-N-pennolamino-20-theoxyse θ-dihydro-DMOT Using a method similar to Example-G, DMOT (/j
) and benzylamine ('AOml) in methanol (
(Otsu θml) Width, 1 piece of Sutorium Cyanohorohi I”
(/g). After extraction process.

The crude product was subjected to flash chromatography on silica gel using dichloromethane (/β) and dichloromethane-methanol (
Purification was carried out by elution with a linear gradient consisting of 3:/, /β) to give 0.21 g of the title compound.

Example-g θ-N-phenethylamino-,20-deoxy-20
-Dihydro-DMT D'MT (/θjg) and phenethylamine (Y, Zynl) were dissolved in dry methanol CIA, 20 ml).

The solution was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (January: <3.39') was added, the solution was stirred for λ and a half, and then poured into a saturated aqueous sodium bicarbonate solution (/l).
The product was extracted with dichloromethane (separated with SθOme). The extracts were combined, dried (Na, SO, ), filtered, and the solvent removed. The residue was dissolved in a small amount of dichloromethane, flash chromatographed on silica gel, and dichloromethane-methano-concentrated aqueous ammonia (/
23:/:θ/ to 100:10:/, /β) was purified by elution with a gradient of 1 and then a solvent of the latter composition/l. Both fractions containing the desired product were found by TLc analysis, collected, and the solvent removed to yield the title compound shown below.

Example-9 ,2O-N-phenethylaminoyl θ-teoxy-10-dihydro-〇MT 20-N-phenethylamino-20-deoxy-su θ-
Dihydro-DMT (13fj)/N sulfuric acid (Otsu0m
1) and stirred at room temperature for 7 hours. Slowly pour the solution into a saturated aqueous sodium bicarbonate solution (300 ml).
and the product was dichloromethane <300 ml (3 times).
Extracted with. Combine the extract.

Drying (Na x 8%), filtration, and solvent removal of the P solution under reduced pressure afforded the title compound Ogf'j.

Example-70 20,23-di-N-phthalimide-20,23-didioxy-,20-dihydro-DMT20-dihydro-
DMT (/g9F, 2.0 mnol).

Triphenylnisphine (2,/f, f mmo
l) and phthalimide (1/f!j, θmmo
l ) in tetrahydrofuran (30 m
l) and add diethyl azodicarboxylate (
/liq, f mmol) was added dropwise and the mixture was incubated at room temperature for 3 hours.
Stirred for 0 minutes. Methanol (approx./tnl) was added to destroy excess reagents, and after stirring for 70 min, the solution was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and 0/M acetic acid (10 θ m/, each), and 2-3 ttti of petroleum ether were added to break the emulsion that formed. The aqueous layer was separated, made alkaline with solid sodium bicarbonate, and extracted with dichloromethane. The organic extract was dried (Na,
2SOI1. ) 17 was filtered and the solvent was removed. The residue was dissolved in a few ffs of dichloromethane and subjected to flash chromatography on silica gel, first in dichloromethane (3 ffs).
00rnl), then dichloromethane (/l'),! Separation was carried out by elution with a 9% methanol-dichloromethane solution (/β) gradient. Both fractions containing the desired product were determined by TLC analysis, and the solvent was removed from them to obtain the title compound of θ/7fl.

Examples - // Flood θ, 23-di-N-phthalide ε-do-20, 23-dideoxy-20-dihydro-〇MT, 20, . 23-
C N-7 Talimito 2o9.23-dideoxy~
, 20-dihydro=DMT (10 mg) was dissolved in /N sulfuric acid (10 tnl) and dioxane (3 ml) and stirred at room temperature for 7 hours. One reaction was then neutralized with solid sodium bicarbonate and extracted twice with dichloromethane. The extracts were combined, dried (Narsot, t), filtered, and the P solution was evaporated to dryness under reduced pressure.

It was then dried in vacuo to give the title compound.

Example-72 20-N-7thalimide 2o-thioxy-2゜-dihydro-DMOT, 20-NhydroDMOT (,,?, O'IQ,
5 mmol).

Triphenylphosphine (2,6,2fl,/O
mmol) and phthalimide (/G7Q, /
ommol) was dissolved in tetrahydrofuran (410 ml) under a nitrogen stream, diethyl azodicarboxylate (13 ftne/Ommo 1 ) was added dropwise to this solution, and the mixture was stirred at room temperature for 7 hours. Methanol (,23m
The excess reagent was stopped at 1) and the solution was evaporated under reduced pressure. Dissolve the residue in a small amount of dichloromethane,
It was purified by flash chromatography on silica gel, eluting with dichloromethane (/β), followed by a linear gradient of dichloromethane (/j) and 5% methanol-dichloromethane solution (,,/β). Both fractions containing the desired product were found by TLC analysis, collected and evaporated to dryness.2. The title compound of g g fl was obtained.

Example-73 20-N-7taJl/Ii F-,20-thioxy-20=dihydro-DMT 20-dihydro-D
MT (2,9 W), T') Phenylphosph I.
(2,θg) and phthalimide (//zag) were dissolved in tetrahydrofuran (33ml) and treated with diethyl diazocarboxylate (l≠l1f).

TLC analysis of the reaction mixture after 30 minutes revealed unreacted 2o-dihydro-DMT in addition to -substituted and disubstituted derivatives.
Since there was a considerable amount of phthalimide (2967#
), triphenylphosphine (1,23π) and diethyl diazocarboxylate (θ33πf) were added. After stirring for another 30 minutes at room temperature, the reaction was quenched with methanol and worked up as described in Example-72. and silica gel chromatography to obtain 2./g, 20.3-
0799 (D20
-N-phthalai5-20-deoxy-flooded θ-dihydro-DMT was obtained.

Example-/g, 2O-N-phthalimil"-20-teoxyyl θ
-dihydro-DOMT 20-N-phthalimido-2o-thioxy-2θ-sil
)jo-DMOT(/Q9) to /N sulfuric acid(fOme
) and stirred at room temperature for 7 hours. The solution was slowly poured into a saturated aqueous sodium bicarbonate solution (!;00 ml) and extracted with dichloromethane C (3 times with 300 ml). The extracts were combined, dried (Na2SO,/,), filtered, and the P solution was evaporated under reduced pressure to yield the title compound θSOzo.

Example-/2O-N-phthalimido-20-deoxy-,20-
Dihydro-〇MT 20~N-phthalimide-,20-deoxy-20-dihydro-DMT (333mV) WIN sulfuric acid <30ml
) for 7 hours. Work-up was carried out as described in Example-/V to give the title compound /lomy.

Example~/Otsu20,. 23-di-O-phenyl-,2,0-dihydro 0MT 2O-dihydro-〇 MT (/ fl , l 7
mmol).

Triphenylphosphine (13fl, 3.'/m
mol ) and phenol (θ'l-79,3,/
mmol) was dissolved in tetrahydrofuran C30me') under a nitrogen stream.

(7) Solution M was cooled in a water bath, and diethyl azodicarboxylate (Of?9, 3./mmol') was added over 2 minutes.

The water bath was removed and the solution was stirred at room temperature for 7 hours.

After adding methanol (/θml) and stirring for 5 minutes.

The solution was evaporated under reduced pressure. The residual oil was treated with toluene and the white insoluble material was filtered off. The P solution was evaporated and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated and dried (Na
Yu5o11. ), filter and remove solvent.

The residue was chromatographed on silica gel using a methanol-dichloromethane solution, 0%
(geθθml), 2% (230tnl).

3% (230d), 'A% (300ml) and Otsu%, and %
, 230 ml of 70% and /2% solutions each. It was eluted and separated and purified. Both parts containing the desired product are T T
, C analysis, collect them, remove the solvent, /1. L gua 4, 20. It is U3-G〇-Phenyl-20-dihydro-oMT14J.

Example-77 ,20-dihydro-23-〇-phenylpropionyl-OMT 23-〇-phenylpropionyl-〇MT (/: 9g,
2. Isopropanol-water CI:
/.

Sodium borohydride (0023fl, O'03 mmol) was added to the solution and stirred for 30 minutes. The pH of the reaction was adjusted to I using 7N sulfuric acid.
)I(/θ) was adjusted to 70, the solution was concentrated under reduced pressure to form an aqueous solution, and a saturated aqueous sodium bicarbonate solution was added.

The product was extracted with dichloromethane and dried (Na, 2SO
,,).

After filtering, remove the solvent from the F solution under reduced pressure to obtain 1739c92%.
) obtained as a white foam? ,.

Example-/,! 20-dihydro-23-octahytroazosine/-
yl-23-deoxy-〇MT 23-octahydroazocin-/-yl-OMT (90
θ da, i 3 mm θl) is converted into isopro/tanol-water (
/a, /, 13ml) using sodium borohydride Cl2ml1.033mm0I) Example-7
Reduction was carried out as described in Section 7 to yield 111 g (90%) of the θ-shihi 1-lo derivative g.

Example-79 20-0-phenyl-20-dihydro-23-〇-phenylpropionyl-OMT Uθ-dihydro-23-〇-phenylpropionyl-O
MT (17 g, 2.3 mmo+), ) rifhenylphosphine CI2'j, IA mmol 1) and phenol (θtx3y, lA mmol) were dissolved in tetrahydrofuran (lA, 3 ml) under a nitrogen stream, and the solution was The mixture was cooled in a water bath and diethyl azodicarboxylate (θ and y, 1A mmol) was added dropwise. After 5 minutes, the water bath was removed and the solution was stirred at room temperature for 2 hours. TLC analysis of the reactants revealed the presence of unreacted raw materials, so
Half the original amount (2.3 mmo ) of each of triphenylphorphine, phenol and diethyl azodicarboxylate was added. After stirring for another 30 minutes.

Add methanol (10 ml) to destroy excess reagent,
The solution was evaporated under reduced pressure. The residual oil was treated with toluene and the insoluble material was removed by filtration. The solvent was removed from Part F under reduced pressure and the residue was flash chromatographed on silica gel.

The following methanol-dichloromethane solution, θ% (ge0θat), 2% < 230ml), 'A% (yu 50y
nl), 6%C73,0ml) and %C,2,30
m1).

It was separated and purified by stepwise elution. Both fractions containing the desired product were determined by TLC analysis, combined, and the solvent was removed under reduced pressure to obtain 20-Q-7 EniJl/
-,2θ-dihydro-23-〇-phenylpropionyl〇MT was obtained.

Example-20 Uθ-〇-phenyl-2θ-dihydro-23-octahydroazocin-/-yl-0,MT20-dihydro-2
3-octahydroasosin=/-yl-〇 M, T (
f 00MQ, l 2mmol'), )su7-
c=#phosphine (9'l-Omfl, 3. otsumm
o I) and phenol (3'AθN, 3.oI)
ol) in tetrahydrofuran (2θ), and the solution was dissolved in diethyl azodicarboxylate (Otsu 30 IIQ).
, 3. (mmol) and stirred for 7 hours.
Post-processing was performed as described in Example-79. The crude product was flash chromatographed on silica gel using a methanol-dichloronotane mixed solution, θ%
(≠θ0ml), 2% (230ml'), 3% (5
It was purified by stepwise elution with 2 Sθtnl of solutions of 00 ml), It%, Otsu%, g%, 72% and /Otsu%, respectively.

Both fractions containing the desired product were found by TLC analysis, combined and the solvent removed to yield the 90 my title compound.

Example-27 2,1A23-tri〇-acetyl-20-deoxy-
,20-dihydro-OMT 20-deoxy-20-dihydro-OMT (3 g) was dissolved in pyridine (70 ml), and acetic anhydride (
IA ml, ) was added, and the mixture was stirred at room temperature overnight. The solvent was removed from the solution under reduced pressure and the residue was dissolved in dichloromethane and cyclohexane and evaporated again to remove most of the pyridine. Dissolve the residue in dichloromethane and wash with saturated sodium bicarbonate.

It was dried (Na, so, ), filtered for 7 days, and the solution F was evaporated to dryness.

The residue was redissolved and reevaporated to remove pyridine as before, and finally suspended in hexane and filtered. The solid residue (43 g) was purified using Waters Prep 3θ0
chromatographed on silica gel.

Toluene (/l) and toluene-ethyl acetate (4:3,/
β) Separation and purification was carried out by elution with a glue gradient.

Both fractions containing the desired product were searched for by TLC analysis, combined and the solvent removed to give 3,729 3-tri-O-acetyl-O-thioxy-20-dihydro-
〇MT fL':.

Example-, 22 23-O-phenylacetyl-2o-thioxy-20-
dihydro~0MT 2O-thioxy-flooded θ-dihydro-OMT (;19
, 3. g mmol) in dichloromethane ('1
Phenylacetyl chloride (Oyrrl) was dissolved in pyridine (033 ml), the solution was cooled to -7°C and phenylacetyl chloride (
θj3πl.

lA/mmol) was added. The cooling bath was removed, the reaction solution was returned to room temperature, and the mixture was further stirred for 3 minutes at room temperature. The presence of the raw material was found from TLC analysis of the reaction solution.

The solution was cooled to 7°C and phenylacetyl chloride (
033m1) was added. Repeat the same operation.

At the final time, 001 ml of phenylacetyl chloride was used. The final reaction mixture was washed with saturated aqueous bicarbonate; thorium solution, dried (NaSO, ), filtered, and evaporated to dryness. The residue was purified by flash chromatography on silica gel, eluting with a linear gradient of dichloromethane (#) and 20% methanol-dichloromethane (/l). Both fractions containing the desired product were identified by TLC analysis and were combined and the two solvents removed to yield the title compound.

Example-23 23-phenylthiose θ1.23-diteoxy-20
-dihydro-〇MT 20-thioxy-20-dihydro-〇MT (3θ!!”
+3. /jrnmol') in dichloromethane ('AOtnl) and 8-colicin (/3tme), cooled the solution to -7g''C, and added Thiophenol (123ml)
) at -727'°C and the mixture was stirred at the same temperature for 1/2 hour. The reaction was allowed to warm to room temperature over a period of 2.5 hours with stirring.

Then, it was washed with a saturated aqueous sodium bicarbonate solution and dried (N
a 2S O<t ) and filtered. After removing the solvent and washing the residue with hexane, it was flash chromatographed on silica gel and treated with dichloromethane (/A) for 20 minutes.
It was separated and purified by elution with a linear gradient of % methanol-dichloromethane (/It).

Both fractions containing the desired product were found by TLC analysis, combined, and the solvent removed to yield 7007 nl of the title compound.

Example-2t 23-octahydroazocin-/-yl-20°23-
ditheoxy-20-dihydro-〇MT23-iodo2
0.2.3-diteoxy-20-dihydro-〇MT (
Otsu97η) and heptamethyleneimine (0θjml)
was dissolved in acetonitrile (2 ml), and the solution was heated under reflux for 2 hours under a stream of alcon, then returned to room temperature and poured into a saturated thulium bicarbonate solution (/θml). The product was extracted with dichloromethane and the extract was dried (N
aasoIt).

The solution was filtered to remove the solvent from the P solution. The residue was purified with dichloromethane by prevariative TLC (20 x 20 cm, silica gel plate with a thickness of ππ, E, manufactured by Merck).
Separation and purification was carried out by developing with methanol-concentrated ammonia water (90:/θ:2). The band on the silica gel plate is detected using ultraviolet light and peeled off from the plate.

The solvent was removed by drying in vacuo. The mixture was then eluted with dichloromethane-methanol (/:/, 30ml) for jj minutes. The mixture was filtered and the P solution was evaporated to dryness to obtain the compound entitled Otsu S■.

(Left space below) Example 2 23- (gu-hydroxypiperidino)'-20.23
-dideoxy-20-dihydro-(JMT23-iodo-20,23-dideoxyse θ-dihydro-OMT(
1/f', /ot+nmol) and 17-hydrooxypyheridine C03,2g, 3. ．． 2 mmol
) was dissolved in acetonitrile (20 m/'), and the solution was heated and reduced for 2 hours under an argon stream. t-Hydroxypiperidine (3007
'l! 7) was added, and the mixture was further refluxed for 3 hours. The solution was allowed to warm to room temperature and the solvent was removed under reduced pressure.

The residue was dissolved in dichloromethane, washed with a saturated aqueous sodium bicarbonate bath and dried (Na, 2So, ).

-It's been a long time. The furnace liquor was stripped of the solvent and the residue was flash chromatographed on silica gel with dichloromethane (/
It was purified by elution with a linear gradient of 72% methanol-dichloromethane (/β) and 72% methanol-dichloromethane (/β). Both fractions containing the desired product were found by TLO analysis, combined and the solvent removed to obtain the title compound in a colander.

Example 26 23-0-<2.3-dimethoxyphenyl)-20-deoxy-20-dihydro-(MT 20-deoxy-20-dihydro-0■Tc3.0 da,
release/3 mmol),) liphenylphosphine (2,',7/I,/03 mmol) and u,3-dimethoxyphenol (1,!;9 f
/ , / 03 mmol) in 730π1. ), and diethyl azodicarboxylate (/7tnl, /0
3 mmol) was added thereto, and the mixture was stirred at room temperature for 0 minutes. Methanol C'2d) was added to destroy excess reagent and the solution was evaporated to dryness under reduced pressure. The residue was taken up in toluene and insoluble material was filtered off. The P solution was washed with a saturated aqueous sodium bicarbonate solution and dried (Na x S
0.4(), and the P solution was evaporated to dryness. The residue was chromatographed on silica gel (Waters Prep).
Purification was carried out by loading with dichloromethane <271> and then eluting with a linear gradient of dichloromethane (2β) and 10% methanol-dichloromethane (,2X). Finally, the column was eluted with 70% methanol-dichloromethane (2A). Both fractions containing the target product were found by TLC analysis, combined, and the solvent was removed.
．． 0! The title compound (Tag %) was obtained.

Example-27 23-0-(3-pyridyl)-20r. 23-dideoxy-20-dihydro-OMT, 20-deoxy-20-dihydro-OM, T (3,
0fl15 / 3 mmol), ) liphenylphosphine (27 da, /θ3 mrno I) and 3-hydroxypyridine (979■, /θ3mmo
1) in an argon stream with TeI-rahydrofuran<30π
Dissolve in t).

Diethyl azodicarboxylate (17ml, / 03
+nmn1). After work-up and chromatography as described in Example No. 2, 643 g
The title compound was obtained.

Example-2 and 23-〇-(m-dimethylaminophenyl)-2゜-deoxy-20-dihydro-〇MT 20-deoxy-20-dihydro-OMT (3'0f
l, , 5:/3 mmol), ) liphenylphosphine (279,/03 mmol) and rn
-dimethylaminophenol (/Kuda, /θ3mmol
) in tetrahydrofuran (j0πl) under argon atmosphere
and diethyl azodicarboxylate (i
7 ml, 103 mmol) was added thereto, and the mixture was stirred at room temperature for 7 hours. At this point, the raw material had not been consumed, so triphenylphosphine</3! ;it'), m-dimethylaminophenol (0709) and diethyl azodicarboxylate (Of,!;ml) were added and the solution was stirred for an additional 30 minutes. The reaction was quenched by the addition of methanol (approximately 3 ml) and the solution was evaporated under reduced pressure.

The residue was post-treated as described in Example-2B.

Silica gel chromatograph (Waters Inc. P rep)
The residue was purified by elution with a linear gradient of dichloromethane (,21, then dichloromethane (Liβ) and/or 5'% methanol to dichloromethane CI!-1). Both fractions containing the target compound were found by TLC analysis, combined, and evaporated to dryness to yield the title compound//2.
iy was obtained as a purple-purple glassy solid.

Example-29 20-diphenylamino-20-deoxy-20-dihydro-avTOM',T (3,oy, 3 dishes 01) was dissolved in dimethylformamide (/θml), and the solution was dissolved in toluene (100tnl'). ) was diluted with Diphenylamine (7 g, /θmmol) and p-toluenesulfonic acid hydrate (730 mg, ) were added, and the solution was heated to reflux.

After that, the temperature was returned to room temperature, and the solvent was removed under reduced pressure. The residue was added to a solution of sodium cyanoborohydride (>123 g) in dry methanol (7!; ml) and the solution was stirred at room temperature for 2 hours'. - The solution was removed under reduced pressure and
The residue was partitioned between ethyl acetate <73 ml) and water C73 ml). The organic layer was separated and extracted with 05M pH H3 phosphate buffer (7'3 ml) and 03M pH H3 phosphate buffer (2 x 73 ml).

The combined latter extracts were back-extracted with ethyl acetate (C73πl), and the ethyl acetate solutions were combined and dried (Na2SO4).
L, 'I filtered. The furnace liquid was evaporated to dryness, the residue was dissolved in a small amount of dichloromethane, and after filtration, a silica gel chroma 1~graph (Waters Inc. Prep 300
) and 7 dichloromethane (4 tll) and methanol-Biao aqueous ammonia-dichloromethane C3:03:9'A
3. 1) Glue Near Gradient 9 and then purified by elution with the latter mixed solvent (3β). Both fractions containing the desired product were determined by TLC analysis and evaporated to dryness to give the title compound //3.

Example-30 20-Dfi-] Katana-20-[3-Azabicyclo(3,
22)-nonan-3-yl] -〇M'l'OMT (
3,θfl, 3.0 mmol) was dissolved in anhydrous methanol (/3 ml). 3-Asabicyclo [
322] - Nonane CI2 E1. /θmmol) was dissolved in anhydrous methanol (13ml) and filtered to remove white impurities. The furnace solution was added to a solution of (MT) in the presence of molecular sieves (3A).

The mixture was stirred at room temperature for 70 minutes overnight. Sodium cyanoborohydride (θ 3 g, /θ dish n01) was added. - The reaction was stirred at room temperature for 77 hours. The reaction mixture was filtered and the filtrate was removed under vacuum to remove the foam from ethyl acetate (/3θ7
111), washed with 30 ml of water and separated. The main part of the product was extracted from the ethyl acetate solution by
MN an 2 PO% buffer (750ml 1.pH
65). The phosphate buffer solution was concentrated under vacuum to remove any remaining ethyl acetate. Adjust the pH of the buffer solution to approx.
/, a white precipitate is formed.

This is filtered, collected and dried to give a yield of 31%)
of θ-DI-I-DO-su θ-[3-azabicyclo<
3.2.2) Nonan-3-yl] OMT was obtained.

[Titrated pKa values near 7 and 9.3. Electrolytic desorption mass spectrum parent ion (needle/ ) -7θ7].

Example 37 OMT (3,Q1
i', 3 mmol), morpholine (θza7 f
fl+<l/Qrnrnol) sodium cyanoborohydride (03/f/, 3 mmol) and anhydrous methanol (30π2) were reacted in the presence of molecular sieves (3A). Since no precipitate was formed when the pH of the buffer was adjusted to //, the product was extracted from the buffer with dichloromethane and
2O-DH-Do-20-morpholino- with yield jθ%)
(MT was obtained as a white foam.
)-6 Otsu9].

Example-32, 2Q-TMμDo-(4-phenylpiperidine-
/-il)-α OMT (397g, /Q mmol), 'A-
Phenylpiperidine (3.22g, 20mmol)
, sodium cyanoborohydride (723; f,
, 2 (7 mmol) and methanol (Oπl),
Nine reactions were carried out using the method in Example-/. However, for extraction, use pHIA buffer, and extract 3.7 fl of the title compound by electrolytic desorption method mass spectrum parent ion (Hariko/).
-7g3].

Example-33, IQ-DI-1-D O-23-deoxy-20
,23-di(octahydroazocin-/-yl)-(a)IT-θ,23-di-E-to-(MI'CI 21
, /, 3 volumes n01) in acetonitrile (20ml)
Dissolve in.

In this solution, hepcumethyleneimine <y, 7 g, /, 9
ytti + /3 mmo I) was added and the reaction mixture was stirred for 1/2 hour while heating to reflux. After removing volatile substances, the resulting red part was converted to (JyuC+2(15θt
The solution was washed with saturated NafiCOs solution, dried over Na25O, filtered and the solvent removed under vacuum.

The residue was converted into 9Me OIJ/cii2cl2(/:
9) was subjected to flash chromatography on silica gel Otsu θ packed in MeOH/G [(20
J2 mixed solvent.

/:9(3θ0π/'), / Nige (300 method 1)
, 3 near (23θml), 2', 3C230ml>, /
:/ (S0θml), 7:3 (300
m1) was eluted stepwise. Putting both of the desired parts together, 22/It! j<yield/9%) of 10-DHmDo
-,23-deoxy-se θ,23-di(octahydroazocin-/-yl)-〇M-T was obtained as a white foam. [Titration pKa value: B, 9. &03. and 7. Electrolytic desorption mass spectrum parent ion (MI-10/)-790].

Example 3 The following compounds were produced by the method described in the previous example.

2O-Di(-DO-λθ-(octahydroazocine-
/-yl)DMT 20-DB-Do-20(piperidin-/-yl) D
MOT, IQ -DH-DO-20-(heehe') Shin-/
-1' 71z) LX) 20-DLI-Do-20 (ll-hiFO4shihiheIJ
jin-/-il) DOMT, IQ-DI-1-DO-20-(tekahitoro 7 seshin-/-il) OM'l'' 20-]) fi-DO'-, 20-(octaL do o7zoshin-/-il ) DOMT lθ-D H-D O-su theta-(azacyclotridecane-/-yl) OMT 2()-DH-DO-20-(hexahydroazepin-/-yl) DMT 20'-DH-Do- 20-(/: 2,3.'l
-'y) Rahi F Leisoquinolin-2-yl) 0M
T2O-DH-DO,,2o-(: 12,3.'it-
Tetrahydroquinolin-/-yl) OMT Suθ-Di-II-DO-20” (azacycloundecane-/-yl) CMT 20-DM-DO-,2θ-
/-yl)0■T 20-I)H-DO-20-(pyrrolidin-/-yl)
DMT 20-DI(-DO-20(O'ytahit o-ll1
-yzonin-/-yl) OMT λθ-Dfl-Do-20-(octahydroazocine-
/-yl) DMOT Su θ-Dt-x-DO-,2o-(octahydroazocin-/-yl) D(MT,:l 0-Dli-Do-koθ-(boot22biperidin-/-yl) ) DMT 20-DB-DO-20-(4l-)xnirhihe')
Shin\-/-yl)-gudeoxy-avT20-DH
-Do 20 (y'kahi Fo7zeshin-7cool) -Gudeoxy-〇M't'20- DI (-Do
-20-(hexahydroazepin-/-yl)-guadeoxy-0MT2O-1)H-DO-20-(/:
2, 3. 'l-te)rahitolysoquinoline-suyl)
I) OM'J'20- DI-I-J) O-λθ-(
Deca upper 1 button cyclobento [c] azepine-/-il)
(MT2θ-DJ, 1-DO-)θ-(7-azabicyclohexane.

, 2/]hebutan-/-yl) OMT Example-57 Injectable formulation A) Add the base of formula (1) to propylene glycol.

Water and benzyl alcohol are added until the solution is propylene glycol jθ% (by volume ff), benzyl alcohol g% (
) and the base of formula (1) at 200 mQ/ml.

B) The solution is prepared as described in section A.

However, if the solution contains the base of formula (1). yny/ml
Contain.

C) The solution is prepared as described in section A.

However, if the solution contains the base of formula (1) at 330 In! ! /
ml.

1)) Prepare the solution as described in Section A.

However, if the solution contains the tartrate of formula (1) at a concentration of 300 η/m
1.

E) To prepare a suspension, finely ground the compound of formula (1) is added to carboxymethyl cellulose and mixed thoroughly, and the suspension is prepared by adding 200 ytr, q of the base of formula (1) per ml of suspension.
It is manufactured by adjusting it so that it contains.

A variety of feeds are used including liquid feeds and pelleted feeds.

Methods of formulating drugs into animal feed are well known. A preferred method is to create a concentrated drug premix, which in turn is used to produce drug-containing feed. A typical premix contains about θ0 grams per pound of drug. The premix may be a liquid or solid formulation.

The final feed formulation for poultry chickens will depend on the amount of drug administered. The most common methods of mixing and pelletizing will be used.

Many substances that influence the hydrophilicity, density, and surface tension of liquid suspending media can individually assist in preparing injectable suspensions; for example, silicone foaming agents. , sorbitol can be a useful suspending agent.

(Margin below) ■470890 0 shot clearer Joan E. Toth For Indiana, USA West Lafuie est wood street Apartment number 5121 991-

Claims (1)

[Claims] [In the formula, R is hydrogen, iodo, bromo, ri-rolo, fluoro, cyano, -OR'', -0Ar, -8R'',
Azide. -N'IL': N-phthalimide or 7, R' is (i) hydrogen or 10H (ii) chloro, fluoro, bromo, iodo, -OAr,
-0-tetrahydrofuranyl. -〇-Tetrahydropyranyl, -814'', 1 package of aji-
NR' R7 or N-phthalimide or Iσ! (i) optionally substituted on one or more carbon atoms by a carboethoxy or phenyl group;
a monocyclic saturated or unsaturated nitrogen-containing heterocycle bonded through a nitrogen atom; , the heterocycle has seven ring atoms from (1) up to three further heteroatoms selected from nitrogen, oxygen, and sulfur; (,2) from methyl, ethyl, and phenyl; with up to three selected substituents, or (ii
i) Otsu 2, 3. gutetrahydroquinolin-/-yl, decahydroquinolin-/-yl, /, 2,3. 'I
--Tetrahydroisoquinolin-2-yl, decahydroisoquinolin-2-yl, indolin-/-yl, isoindolin-niyl, decahydrocyclohebuta [b]
pyrrol-/-yl, decahydrocyclohebuta[c]pyrrol-nyyl, decahydrocyclobent[c]azepin-2-yl, decahydrocyclobent[d]azepin-yl
3-il. Yu, 3. ', ', 3-tetrahydro-/■-2-
Penzazepine-2-yl, 2,3. 'A, 3-Te1~
Rahydro/■■-3-penzazepin-3-yl, azabicyclohebutanyl, azabicyclooctanyl, azabicyamino group, R, 2 is hydrogen, optionally substituted 07-C-alkanoyl or optionally substituted benzyl, phenylacetyl or phenylpropionyl, and RJ is hydrogen, hydroxy, or optionally substituted C
, % C,-alkanoyloxy or optionally substituted benzoyloxy, phenylacetoxy or phenylpropionyloxy or (mycarosyloxy), W is hydrogen, optionally substituted C2-C-alkyl, cyclohexyl. Optionally substituted benzyl, phenethyl or phenoxyethyl, Ar is (i) phenyl, derivatized phenyl or naphthyl (11) pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoquinolinyl. Quinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, benzotriazolyl. an optionally substituted heteroaryl group selected from benzoxazolyl, benzimidazolyl, carbazolyl or acridinyl, phenoxyacetyl or phenylthioacetyl, methanesulfonyl, trifluoromethanesulfonyl or optionally substituted phenyl sulbonyl; 几 is an optionally substituted 07-Cke=alkyl, cyclohexyl, an optionally substituted phenyl, benzyl or phenethyl, or imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl. l-riazolyl, tetrazolyl, oxasilyl, isoxazolyl, oxadiazolyl, thiazolyl. an optionally substituted heteroaryl group selected from isothiazolyl, thiadiazolyl, chenyl and furanyl, where R' is hydrogen, optionally substituted C2-C4-alkyl, phenyl, benzyl, phenethyl or C3-
C,-cycloalkyl, Je is ]t' group or optionally substituted 07-C5-alkanoyl, optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl or alkoxycarbonyl; So, is ① hydrogen, methyl, ethyl, n-propyl, or isopropyl? The two JV-4s together form a polymethylene moiety such that -N(R')2 constitutes a cyclic amino group selected from pyrrolidinyl, piperidinyl, hexahydroazepinyl or octahydroazocinyl. . however,(
1) R' is not hydrogen or 10I-I when R or JV is hydrogen; (2) R or Jt
' is -NHIL' or 1("or") is hydrogen, then ll must be hydrogen and R' must be hydrogen, hydroxy or mycarosyloxy, and Ar is of type (iii) in the definition. W is not a substituent of and (3) W is hydrogen if ]<hydrogen. Must be hydroxy or mycarosyloxy;
(ll-) When R' is hydrogen or hydroxy the pore is not NR'R7. ] or a physiologically acceptable salt thereof. 2) A macrolide represented by formula (1) according to claim 1, wherein R is Je. 3) ]-t dihydrogen, iodo, bromo, chloro, fluoro, cyano, -OR", -〇Ar, -8
IL', 7 Jido. -NR' 7 or N-phthalimide, the macrolide represented by formula (I) according to claim 1. 1l-) R hydrogen, hydroxy, phenoxy, N-
Phthalimide, phenylacetoxy, 3-azabicyclo(3,2,2,)nonan-3-yl, morpholino. A macrolide of formula (I) as claimed in claim 1, which is boot-22 biperidin-/-yl or octahydroazocin-/-yl. 3) t' Hydrogen, hydroxy, phenoxy, acetoxy, phenylacetoxy, N-phthalimide. Claim 1 which is phenylpropionyloxy, phenylthio, octahydroazocin-/-yl, I/l-hydroxypiperidino, 2,3-dimethoxyphenoxy, 3-hyheridyloxy or m-dimethylaminophenoxy. A macrolide represented by the formula (1). B) Formula (IC,, [where It is hydrogen, iodo, bromo, chloro, fluoro, cyano, -QR'', -0Ar, -8R, azide. -NR'R7, N-phthalimide) R2,
(i) Hydrogen or 10J ((ii) Chloro, fluoro, bromo, iodo, aA, r, -0-tetrahydrofuranyl, -0-tetrahydropyranyl, -
51 (, ', azido. -N, 1.t'li7 or N-phthalimide or Je, W Yes) optionally substituted on one or more carbon atoms by a carboethoxy or phenyl group, Expression -N where +1 is an integer from 7 to 73
(CH2) A monocyclic amino group represented by n (11) A monocyclic saturated or unsaturated nitrogen-containing heterocycle bonded through a nitrogen atom, and the heterocycle is (1) nitrogen. (2) having up to 3 substituents selected from methyl, ethyl and phenyl; Do you have it? or (iii) 12,3.4'-tetrahydroquinolin-/-yl, decahydroquinolin-/-yl, 1
．． 2゜3, ri-tetrahydroisoquinolin-,2-yl, decahydroisoquinolin-2-yl, indoline-/
-yl, isoindolin-2-yl, decahydrocyclohebuta[b,]]pyrrol-/-yldecahydrocyclohebuta[C]pyrrolosuyl, decahydrocyclobento[C]azepin-2-yl. decahydrocyclobent[d]azepin-3-yl, 2
,3. 2.3.1A3-tetrahydro-/I-f-3-penzazepin-3-yl, azabicyclohebutanyl, azabicyclooctanyl, azabicyclo A bicyclic or bicyclic secondary amino group selected from nonanyl, azabicyclononanyl or azatricyclodecanyl, 1g is hydrogen, optionally substituted C2
-alkanoyl or optionally substituted benzoyl, phenylacetyl or phenylpropionyl; RJ is hydrogen; hydroxy, optionally substituted 07-C, alkanoyloxy or optionally substituted benzoyloxy, phenylacetoxy or phenylpropionyloxy or (mycarosyloxy), R'' is hydrogen, optionally substituted C/ ~C9-Alkyl, cyclohexyl. Optionally substituted benzyl, phenethyl or fumidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoquinolinyl, quinolinyl. Quinazolinyl, cinnolinyl, quinoxalinyl. Phthalazinyl, benzotriazolyl, benzoxazolyl, benzimidazolyl, carbazolyl or an optionally substituted heteroaryl group selected from acridinyl; or (iii) an optionally substituted heteroaryl group selected from acridinyl; ,
methanesulfonyl, trifluoromethanesulfonyl or optionally substituted phenylsulfonyl, R'
is optionally substituted 07-C9-alkyl, cyclohexyl, optionally substituted phenylbenzyl or phenethyl, or imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, oxasyl, isoxazolyl, oxadiazolyl, thiazolyl , isothiazolyl, thiadiazolyl, chenyl and furanyl, where is hydrogen, optionally substituted 07-C-alkyl, phenyl, benzyl, phenethyl or C8-C , -cycloalkyl or optionally substituted C, -C, -C runoyl. Optionally substituted benzoyl, phenylacetyl. phenylpropionyl, phenoxyacetyl or phenylthioacetyl or alkoxycarbonyl, R' is hydrogen, methyl, ethyl, n-propyl or isopropyl, or two 1t~ taken together -N(R') unit is pyrrolidinyl. The polymethylene moiety is formed to constitute a cyclic amine group selected from piperidinyl, hexahydroazepinyl or octahydroazocinyl. However, (1) when R or t is hydrogen, l(' is not hydrogen or -Of-i, and (2) and R' is -N1-11t' or xf or 1
If f is hydrogen, then R2 must be hydrogen.
' must be hydrogen, hydroxy or mycarosyloxy. Ar is not a substituent of type (iii),
(3) When R2 is hydrogen, ■ must be hydrogen nitride, hydroxy, or mycarosyloxy, and (lI-)
When R' is hydrogen or hydroxy, ■ is N and 6 liters 7
isn't it. ] When producing macrolides or physiologically acceptable salts thereof, (a)
Q is formyl and Q/ is it' ((danshi, 几'
is not hydroxy), the starting macrolide of formula (II) is reduced to a macrolide of formula (I), where is not hydroxy. (b) Formula (II) where Q is formyl and Q/ is R'
), the starting material macrolide represented by the formula IINR'
The amine represented by IL' or HR9 is reacted in the presence of a reducing agent to obtain the formula (N]l'R' or Je)
(c) Q is one CI−
1, +(]■. The starting material macrolide represented by formula (U) where Q' is React with reagent and R
is an azide, the macrolide of formula (I) or (
i i) react with phthalimide to give a macrolide of formula (I) in which R is phthalimide, or (iii)
Ar is A in (i) or (11) in the definition of Ar above
(iv) react with a phenol of the formula A r OH, which is an r group, to form a macrolide of formula (1) whose pores are OA r, or (iv) react with a halogenated or polyhalogenated alkyl to form a macrolide in which Ii is ct. , Br or I, or (■) formula HS It'
or (vi) to form a macrolide of formula (1) in which SJ(5) is obtained by reacting with a mercaptan represented by
Ar is the above A. Ar in (iii) in the definition of r
(d) Q is one CH201 (and Q' is Jt' Reacting a starting macrolide of formula (II) with triphenylphosphine and a halogen source to give a macrolide of formula (1) in which R is CI, Br or ■; The starting material macrolide represented by the formula (It) is cr■OH and Q/ is R', and Ar is in the above definition of Ar (iii
) is reacted with an acylating agent derived from a carboxylic acid or sulfonic acid represented by the formula Arα1, which is an Ar group of OA, to form a macrolide of the formula (I);
(QQ is 10H2L, where L is a leaving group, + Q'
The starting material macrolide of the formula (1) in which is 几' or a leaving group is (i) an alkali metal azide or a halide or alkyl is methyl. By reacting with a tetraalkylammonium azide or fluoride that is ethyl, propyl or butyl■
is azide; F, CI, 13r or (JI)
), but (ii) it is reacted with a mercaptide ion of formula 1i S to produce a macrolide of formula (1) which is It month t5S-, or (iii) it is reacted with a mercaptide ion of formula 1i S to produce a macrolide of formula (1) of formula NR'.
It' or reacted with amine of HK9 and NIL'
Gaya! The macrolide of formula (1) is
(iv) with a cyanide ion source to give a macrolide of formula (I) where it is -ON, or (■) with an alcohol and silver ion source of formula 1-101t'' where It'' is other than hydrogen. The formula (1
), (g) Q is CI-I.
Hydrolyze the macrolide represented by the formula (H) in which Q' is (hereinafter referred to as the margin) in 2 liters to produce the macrolide of the formula (1) in which t' is hydroxy; (h) Q is -C1,121L and + Q' is a protected hydroxy; (i) Q is -C1-I R and Q/ is hydroxy; Formula (It)
The starting material macrolide represented by formula (1) is reacted with diethyl azodicarboxylate or dimethyl azodicarboxylate, triphenylphosphine and (i) an azide transfer reagent to form a compound of the formula (1) in which 1t' is azide.
), or (ii) it is reacted with phthalimide to produce the macrolide of formula (1) in which R′ is phthalimide, or (iii) Ar is the above-mentioned Ar
Ar which is the Ar group in (i) or (ii) in the definition of
(iv) Reaction with a halogenated or polyhalogenated alkyl to give a macrolide of formula (I) in which E is -OA, r, or (iv) a reaction with a halogenated or polyhalogenated alkyl to give a
I. Either the macrolide of formula (1) is Br or I, or the macrolide of formula (1) is reacted with the mercaptan of formula (■) I's R'. , (vi) When Ar is reacted with a carboxylic acid or sulfonic acid of the formula Ar0Li which is the Ar group in (i) in the definition of Ar above to obtain a macrolide of the formula (1) where R' is OA r, (J ) A macrolide represented by the formula (n) in which Q is -C1-I and Q' is hydroxy;
Formula (1) in which R′ is OAr by reacting with an acylating agent derived from a carboxylic acid or a sulfonic acid represented by OH
(k) Q is R and Q
A macrolide represented by formula (II) in which / is hydroxy is reacted with triphenylphosphine and a halogenating reagent to obtain formula (1) in which ■' is CI, Br or I.
(1) Q is 10H, R is Q
A macrolide of formula (TI) in which ' is a leaving group is reacted with (i) an alkali metal azide or halide or a tetraalkylammonium azide or fluoride in which alkyl is methyl, ethyl, propyl or butyl, so that W is Azid, F. (ii) to form a macrolide of formula (D) in which I('S-) is reacted with a mercaptide ion of pore-forming 5S-; (iii) reacting with a synthetic N1t'R' or a raw amine to form a macrolide of formula (1) in which R' is lff1'R' or 1σ; (m) Q is −
CH2N, and Q' is It', or Q is 几 and Q
A macrolide of the formula (n) in which ' is azide is reduced to 10H2Nl1 (U or R'
is a macrolide of formula Q) where is an amine, (
n) Q is -CH, 2M11 (' or ' is N
The macrolide of formula (II) which is HK' is acylated to form a macrolide in which -CM, NHR7 or IJ)
-NR' R7 is a macrolide of formula (1); (0) esterifying the macrolide of formula (1); (P) converting the macrolide of formula (1) into a salt form; (q) hydrolyzing the macrolide of formula (I) in which R' is mycalosyloxy in an acid solution at less than pi-11- to give the macrolide of formula (1) in which Jt8 is hydroxy; r) Formula (1) where R' is hydroxy
deoxidizing the macrolide to obtain the macrolide of formula (1) in which W is hydrogen, (s) Q is OH, I, and
Reacting a macrolide of formula (II) in which Q/ is 几′ with a reducing agent to give a compound of formula (I) in which Q is hydrogen, or (t) Q is -0-ding-2- sulfone-1・The macrolide of the formula (II) where Q/Rikizuki7' is reacted with an iodine ion source to form the formula (1) where 1L is iodine.
A manufacturing process characterized in that it is a macrolide. 7) A feed premix containing a macrolide of formula (I) or a physiologically acceptable salt thereof as defined in any one of claims 1 to 5 as an active ingredient. and) one or more physiologically acceptable carriers or excipients; A pharmaceutical formulation for treating livestock diseases containing the indicated Macl1-1 light or a physiologically acceptable salt thereof. 9) The chemotherapeutic effect of the macrolide represented by formula (1) or a physiologically acceptable salt thereof according to any one of claims 1 to 5 on warm-blooded animals. A method for the treatment or control of bacterial infections in warm-blooded animals comprising administering a dose of