FI88508B - Method for production of disaccharide derivatives - Google Patents

Description

·, 88508

The present invention relates to a novel disaccharide derivative and a salt thereof having a very good antitumor activity and low toxicity, and which is useful as an antitumor agent.

Natural lipid A has a mitogenic effect, i.e., it stimulates lymphocytes to cause stem cell deformation, and said mitogenic effect accelerates the proliferation of lymphocytes, and thus improves resistance; natural lipid A influences tumor necrosis by directing it, as well as other similar effects, and thus natural lipid A is promising as a therapeutic and prophylactic agent in the treatment of many diseases due to a weakened immune system, such as various infectious diseases or as an antitumor agent.

Known derivatives of natural lipids A include those described in JP Patent Application (OPI) Nos. 48497/84, 53295/86 20 and 227586/86 (as used herein, the term "OPI" means "unexamined published JP patent application"). These include 2-deoxy-6-O- (2-deoxy-2H-3R) -3-dodecanoyloxytetradecanoylamino] -4-O-phosphono-3-O- [(R) -4-tetradecanoyloxytetradecanoyl]? - (3-D-glucopyranosyl) -3-25 O - [(R) -3-hydroxytetradecanoyl] -2-]. (R) -3-hydroxytetradecanoylamino-7-O-phosphono-N-D-glucopyranose, which; disclosed in JP Patent Application (OPI) No. 53295/86 (hereinafter referred to as Compound A) are known to have physiological properties similar to or better than natural lipid A, as described. in Eur. J. Biochem., Vol. 148, 1-5 (1985). However, compound A is of little practical significance because it is as toxic as natural! lipid A: kin. In addition to compound A, the compounds described above are also unsatisfactory in practice due to their toxicity 2 88508 or antitumor activity. For this reason, there has been a great need to develop compounds that have useful physiological properties and are less toxic.

The inventors have conducted extensive studies to develop a compound having useful physiological effects and low toxicity, resulting in the present invention.

This invention relates to a compound represented by formula (I): 6 'HO-CH-,

5A

n ° Xf v ir2 y ~ oR u) (HOjjPO ^ rj2 '®5 ° 3 J 2 NHR3 NHR1 z1r6 where R is a phosphono group, ZR ^ or CH '20 ^ \ z2R6 where Z, Z * and Z * are each an alkylene group having 1 to 6 carbon atoms and R® is a carboxyl group or a phosphonooxy group, R1, R2, R3 and R4 are each -COR7, -COZ3R8, QQ, QQ, II7 I 11 3 g 7 -CO (CH2 ) nlCH-N-COR, -CO (CH2) nlCH-N-COZJR, -CO (CH2) n2OCOR ', -CO (CH2) n2OCOZ3R8, -CO (CH2) n2COR7, -CO (CH2) n2COZ3R8, Qi Q1 11 -CO (CH2) n2CO (CH2) n3NCOR7 or -CO (CP2) n2CO (CH2) n3NCOZ3R8, 7 in which R is an alkyl group having 1 to 30 carbon atoms and which may be substituted by one or more hydroxyl groups.

O

With 35 groups, Z is an alkylene group having 1 to 9 carbon atoms, 3,88,888

Q

R is a cycloalkyl group having 3 to 12 carbon atoms which may be substituted by one or more hydroxyl groups, Q is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, -CONH2, -COOH or -CH2OH, Q, j is a hydrogen atom, or An alkyl group having 1 to 20 carbon atoms, n1 is 0 or an integer from 1 to 10, and n2 and n3 are each an integer from 1 to 20; and is a hydrogen atom, a phosphono group or -CO (CH 2) m COOH, wherein m is 0 or an integer from 1 to 6; Provided that the combination in which R is a phosphono group, 5.12 3.4 7 R is a hydrogen atom, R, R, R and R are each -COR are not included, as well as a salt of the compound.

The compound of formula (I) and its salt have very good antitumor activity and low toxicity, and are useful as antitumor agents.

As used herein, the term "alkylene group" means a methylene group, a polymethylene group, or a methylene or polymethylene group substituted with an alkyl group having 1 to 6 carbon atoms. Specific examples of alkylene groups include methylene, ethylene, propylene, trimethylene, ethylethylene, tetramethylene, 2-methyltetramethylene, 2,3-dimethyltetramethylene, 2-ethyl: · 3-methylpentamethylene and octamethylene group. .

In formula (I), the alkene group corresponding to Z, Z, Z or Z preferably contains 1 to 4 carbon atoms.

As used herein, the term "alkyl group" means a straight or branched chain alkyl group, and includes, for example, methyl, ethyl, propyl, t-butyl-30-, hexyl, nonyl, decyl, 3-ethylundecyl, 2- ethyl-4-methyltridecyl, tetradecyl, nonadecyl, -: tetraecosyl, 2-ethyl-5-propyltetraecosyl and 7: octaicosyl. The alkyl groups corresponding to R preferably contain from 5 to 20 carbon atoms.

4,8508 The term "cycloalkyl" as used herein includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodeyl and cyclododesyl groups, and preferably those having 5 to 8 carbon atoms.

In formula (I), n1 is preferably 0 or an integer from 1 to 5 and n2 and n3 are each preferably integers from 1 to 6.

The compounds of formula (I) include the α and β isomers due to the OR substituent, and said isomers and mixtures thereof are within the scope of the present invention. Furthermore, the compounds of formula (I) comprise optical isomers due to their many substituents, and such optical isomers and mixtures thereof are also within the scope of the present invention.

The salt of a compound of formula (I) comprises salts formed between a phosphono group or its carboxyl group and organic amines, e.g. triethylamine, pyridine, N-methylamine, N-methylglucamine, etc., or between inorganic amines, e.g. ammonia, sodium, potassium, calcium, magnesium, etc.

Of the compounds of formula (I), preferred are those wherein R is ZR8 or CH. R1, R2 R3 XSSnZ2R6 q qx and R4 are each -COR7, -COZ3R8, -CO (CH2) nlCH-N-COR7, 0 Qx | J o n 3 8 -CO (CH2) n1CH-N-COZ R, -CO (CH2) n2COR or -CO (CH2) n2COZ R.

Even more preferred are those wherein R is ZOPO (OH), 1 2 3 4 7 and R, R, R and R are each -COR or Q Q, I 7 -CO (CH2) n1 CH-N-COR '.

5 88508

The compounds of the present invention can be prepared by a variety of reaction routes. One method example is illustrated below.

-...

<r120) 2PO I R 0 lii

10 NHR31 NHR

(II) 9 wherein R is a hydrogen atom or a hydroxyl protecting group (it is a protecting group for a hydroxyl group) which can be removed by catalytic reduction or the like; O .Z1COOR14

R 10 is -p (OR 13) 2 / ZCOOR 14, ZOPO (OR 13) 2 <-CH

χ! 3 'SSSSNnZ2COOR14 ^ Z OPO (OR) 2 2 ^ 11 21 31 or -CH? R, E "and RJI are WVv'Z2OPO (OR13) 0 q2 q, · ... · | 2 μl each -COR71, -COZ3R81, -CO (CH2) nlCH-NCOR71 <25 Q, Q, | 2 li

I 1 O QΛ 71 * 5 OI

-C0 (CH2) n1CH-NCOZ KÖA, -CO (CH2) n2OCOR, -CO (CH2) n2OCOZ R, -CO (CH2) n2COR71, -CO (CH2) n2COZ3R81, 0.Q,. . 30 I1 71 I1 3 81 ·· · .: -CO (CH2) n2CO (CH2) n3NCOR / J- or -COfCH2 ^ COiCH ^ ^ NCOZ ^ R; R 3 is a hydrogen atom, -CO (CHO) COOR 3 or PO (OR 3) 0, where 12 13 2 m 2 R and R are each phosphono-protecting groups which can be removed by catalytic reduction; R is an alkyl group having 1 to 30 carbon atoms which may be substituted by one or more hydroxyl groups protected by a hydroxyl protecting group; R is a cycloalkyl group having 3 to 12 carbon atoms which may be substituted by one or more hydroxyl protecting groups protected by a hydroxyl protecting group; Q? is hydrogen

mi, an alkyl group having 1 to 6 carbon atoms, -CONH 2, -COOR

9116 ^ or -CH, -O-R, wherein R is a carboxyl protecting group which

^ 1 C

can be removed by catalytic reduction; R is a phosphono protecting group which can be removed catalytically by reduction; and R is a hydroxyl protecting group which can be removed by catalytic reduction; and Z, Z, Z, 3 Z, Q 1, n 1, n 2, n 3 and m are as defined above.

Carboxyl protecting groups which can be removed by catalytic reduction include a benzyl group and the like which may be substituted by a halogen atom, a nitro group, a lower alkoxy group, etc. A phosphono protecting group which can be removed by catalytic reduction includes a phenyl group, a benzyl group, and the like. a halogen atom, a nitro group, a lower alkoxy group, etc. The hydroxyl protecting group includes groups which can be removed by catalytic reduction such as a benzyl group and the like, and may be substituted by a halogen atom, a nitro group, a lower alkoxy group, etc., a trichloroethoxycarbonyl group, a trichloroethoxycarbonyl group.

According to the process described above, the compound of formula (II) is catalytically reduced in an inert solvent such as tetrahydrofuran, methanol, ethanol, acetic acid, water, a mixture of these solutions, etc., under a hydrogen gas atmosphere, a catalyst such as black palladium, palladium on carbon, etc. to remove the protecting groups. If desired, the product can be purified by silica gel chromatography or similar methods. The reduction can usually be carried out at a temperature of from room temperature (0-30 ° C) to 60 ° C for 1-12 hours. The amount of solvent and catalyst to be used is not strictly limited.

7,8508 When a compound of formula (JI) is used, if R, R or R contains a hydroxyl protecting group, such a protecting group is preferably a group which can be removed by catalytic reduction.

A salt of a compound of formula (I) may be obtained by adding the required amount of base to the compound, then sedimenting, freeze-drying, or the like.

The methods for preparing the starting material of formula (II) may be appropriately selected, depending on the substituents R 1 and R 2, as illustrated in the figures below.

8 88508 r1? 0 ~) _o ho oK? R41) ^ OCOCH3 ^ Vor'3 CR12o> 2 "(Hn H ° ~ Tu NHCOOCH2CCÄ.3 nhr11 (IV) (III) _17_ RO | q-- / ok41 ') / '/ C ^ Y ^ -or18 ► (V)

° W 1M_Y

(R120) 2P0 I H ° ^ n NHCOOCH2CCJl3 nhr / (v) 7 \ ““ ~ μ r-μ, Λτ_. Γμ.

sfc / (CT * 1 '„if £ / (r12o) -PO 1 31 H0 I 11 (R120) 2PO 31h0f u

2 NHR NHR z NHR 1 NHR

(HA) (IIB) 9 88508 (V) 'f ,, ν>; f £ / (R120) 2PO R nhr11 NHCOOCH2CC £ 3 / (V) (C) / 1 (D)

"· (^ Ο-, ρο f R20o I H

2 nHR31 nhr · 1 · 1 O (IIC) '92 ::: R 0-1 0-1 J-O j J-O 0 vj 0k ° «4 y y« 21 v ^ op (0ri3) 2 /. (R120) 2PO2 (31R20 <^ ^ I 11: · .: 2 NHRJJ · NHR 1 (IID) 10 88508 wherein R18 is an allyl group, ZCOOR14, ZOPO (OR13) 2, ^ / ^ zlCOOR14 ^ / Z1OPOR13

CH or CH

R17 is a hydroxyl protecting group; R41 is -COR71, -COZ3R81, Q-Q, Qj Qi 1 I 71 II 3 81 —CO (CH-), CH-NCOR, -CO (CHn), CH-NCOZ ° R, 2 nl 2 nl 10 -CO (CH2) n2OCOR71, -CO (CH2) n2OCOZ3R8L, -CO (CH2) ^ 2 COR71, fi -CO (CH) _COZ3R81, -CO (CH) _CO (CH_), NCOR71 or 2 Π2 2 n2 2 n3 Ϊ1 15 - CO (CH2) n2 CO (CH2) n3 NCOZ3R81; R19 is ZCOOR14, ^ xZ1C00R14 ^ / z1opo (or13) 2

ZOPO (OR13), CH or CH

2 \ V

R20 is -CO (CH2) COOR16 or PO (OR15) 2; R92 is a hydroxyl protecting group which can be removed by catalytic reduction; and R 11, R 21, R 31, R 12, R 13, R 14, R 16, „71,„ 81, 12 3 Z, Z, Z, Z, n 1, Q 2,, n 2, n 3 and m are as defined above.

More specifically, the compound of formula (IV) is dissolved in an inert solvent (e.g., methylene chloride, acetic acid, etc., either alone or in combination with those listed above) containing hydrogen bromide gas, and these are reacted at a temperature of 0 ° C to room temperature, 30 over a period of several tens of minutes to 24 hours, and thus the acetyl group is substituted at the 1-position of the sugar moiety by a bromine tower. The resulting bromo-substituted compound is dissolved in a dried solvent, preferably methylene chloride, chloroform, etc., and then condensed with a compound of formula (III) 35, either in the presence of one or more of the following 11,850,508 compounds; mercury (II) cyanide, mercury bromide, silver carbonate, silver oxide, silver perchlorate, mercury (II) nitrate, etc., and in the presence of a dehydrating agent, e.g., anhydrous calcium sulfate, etc., at a temperature from room temperature to reflux temperature, which is from several hours to 2 days to obtain a compound of formula (V).

The resulting compound was then reacted with a compound of formula XR wherein X is a halogen atom in an organic solvent, e.g. methylene chloride, chloroform, acetonitrile, tetrahydrofuran, etc., an organic base, e.g. pyridine, 4-dimethylaminopyridine, in the presence of triethylamine, etc., or with a compound of formula HO-R and a catalyst such as dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine to give a compound of formula (V).

The compounds of formulas (HA) to (IID), i.e. the starting compounds of formula (II), can then be prepared from the compounds of formulas (V) and (V) thus obtained via reaction schemes (A) to (D). Flow chart (A): “·. 18 19

· ... ’A compound of formula (V) wherein R or R

is dissolved or suspended in acetic acid and to this is added zinc powder to carry out the reaction, and thus 17 the amino protecting group is removed at the 2 'position and R. The resulting deprotected compound is condensed with a compound of formula R-OH according to a method commonly used in peptide syntheses. . 30 (ΙΙΛ).

Deprotection is usually performed at room temperature and takes several tens of minutes to 24 hours. The condensation reaction can be carried out by the carbodiimide method, Eintopf method, active /. 35 by its ester method and the like.

12 88508

In the deprotection reactions described above, the trichloroethoxycarbonyl group or the trichloro-t-butoxy-17-carbonyl group is preferably as R, i.e., the hydroxyl-41 protecting group. When R has a hydroxyl protecting group in its molecule, the same groups are preferred as the hydroxyl protecting group.

Flow chart (B): 18

The compound of formula (V) wherein R is an allyl group is treated in the same manner as in the reaction procedure.

10 in Scheme (A) to remove R and then the group R

for attachment to an amino group at the 2 'position. After the hydroxyl group at the 6 'position is protected with a protecting group that can be removed by catalytic reduction, the compound is reacted with an iridium complex, e.g., 1.5-15 cyclooctadiene bis (methyldiphenylphosphine) iridium hexafluorophosphate, etc., then hydrolyzed. to remove the allyl group. The resulting compound II is then reacted with ClP (OR) 2 to give a compound of formula (IIB).

Protection of the hydroxyl group at the 6 'position can be carried out, for example, by reacting the compound with benzyloxymethyl chloride in an organic solvent, e.g. anhydrous chloroform, anhydrous methylene chloride, etc., in the presence of an organic base, e.g. pyridine, diisopropylethylamine, etc. temperature, for 1-2 days. Protection can also be performed using benzyl trichloroacetimidate in the presence of trifluoromethanesulfonic acid at a temperature of about 0 ° C.

The removal of the allyl group is usually carried out by reacting the compound with the iridium complex described above in an organic solvent, e.g. methylene chloride, chloroform, tetrahydrofuran 35, etc., at a temperature of about 50 ° C for a period of 13 88508 10 minutes to 3 hours, and then adding water to the reaction mixture to perform hydrolysis at room temperature, and the hydrolysis takes about 5 to 30 minutes.

The depleted allyl group and 5 O

II

the reaction between C1P (OR13) 2 is generally carried out in an anhydrous aprotic solvent, e.g. anhydrous tetrahydrofuran, in the presence of butyllithium, at a temperature of -70 ° C to 50 ° C, and the reaction takes several tens of minutes.

Flow chart (C):

The compound of formula (IIC) can be prepared by reacting a compound of formula (V) in the same manner as in Reaction Scheme (A).

15 Flow chart (D):

The compound of formula (IID) can be prepared by reacting a compound of formula (V) in the same manner as in Reaction Scheme (B).

The compound of formula (IV) used as a starting material in the process described above can be prepared according to known methods or according to the method disclosed in JP Patent Application (OPI) No. 53295/86. The compound of formula (III), the second starting material in the process, may be prepared according to the following procedure (a) or (b), depending on the nature of the substituent R.

14 88508

Flow chart (a) CH-COO 1 CH-jCOO —-η HO, 3 J — 0 ° C0CH3 j — O 1— 0

Fey / q fefeoH

CH, COO - (CH3C ° <5 - (HO - {3 NHCOCH3 nhy nhy (Via) j (VIb) (Vic) CH2COO-1 CH COO f (VII)

NHY

/ \ CH3COO-1 HO-1 / eocoA ^ ow / oh \ ~ OW6 CH3COO N [(VIII) HO N [(XII) NHR11 NHY1

* I

*> v> », /> V

J ^ OH V ^ OW1 ^^^ OH ow6 H0 I l-i (ix). N \, (XIII) NHR · 1 ·· 1 · NHY1

V

15 88508 (IX) (XIII) I t / ° "l—"

Jhr11 ΝΗϊ1 (X) (XIV) l I \ I 11 (XVb) NHR HO-1 (XI) 7 (OR ^ 1 W Ow 'HO ^ - ((XVa) / NHY1 / · ... · I / I \ / *: H0 I HO-1 or22 m ^ 1 ^ 0W? Ho (ho N (::: 11 11

NHR x NHR

(Ilia) (Ilia ') 16 88508 wherein X is a halogen atom; Y is a lower acyl group, a trichloroethoxycarbonyl group or a trichloro-t-butoxy-2,2-carbonyl group; W is ZOW, ZCOOW, J 2 OVI2 vZ1COOW3 5 dH or CH; w1 is ZOW4, ZCOOR13, ^ Nnnz2ow2 VNvs'Z2coow3 ^ / Z ^ -OW4 ^ / Z1COOR13 CH or CH; R 22 is ZOPO (OR 13) 2, X X 2 z 2ow 4 N 2 sz 2 chloro 13 z 1 chlor 14 H 2, z 1 opo (or 13) 2 ZCOOR 14, CH or CH; W6 is 15 NsSsz2coor14 NVvs'Z2opo (or13) 2

^ / Z1OH

ZOH or CH; W7 is ZOPO (OR13) 2 or

^ sZ2OH

20 ^ / z1opo (or13) 2 CH; Y1 is a trichloroethoxycarbonyl group, Z2OPO (OR13) 2 2 25 or a trichloro-t-butoxycarbonyl group; W is an acetyl group, a benzoyl group, a benzyl group or a p-chlorobenzyl group; W3 is an alkyl group having 1 to 6 carbon atoms or a carboxyl protecting group which can be removed by catalytic reduction; W is a hydrogen atom, a benzyl group or a p-30 chlorobenzyl group; and R, R 1, R, R, Z, Z and TT are as defined above.

A compound of formula (VII) may be prepared by reacting a compound of formula (Via) with a compound of formula WOH in the presence of a Lewis acid or by condensing a compound of formula (VIb) with a compound of formula 17 88508 WOH mercury (II) cyanide, silver in the presence of carbonate, mercury bromide, silver perchlorate or mercuric nitrate or a mixture thereof. A compound of formula (VII) wherein W is a ZO acetyl group can be obtained by reacting a compound of formula (Vie) with a compound of formula HOZOH in the presence of hydrochloric acid, p-toluenesulfonic acid, etc., followed by acetylation.

A compound of formula (VII) wherein Y is a lower acyl group is treated with Meerwein's reagent, or a compound of formula (VII) wherein Y is a trichloroethoxycarbonyl or trichloro-t-butoxycarbonyl group is treated with zinc powder in the presence of hydrochloric acid, acetic acid, etc. thereby removing the protecting group of the amino group 15 in the 2-position. The resulting compound is then condensed with a compound of formula 11 R OH according to the acid chloride method, the carbodiimide method, the Eintopf method or the active ester method to produce a compound of formula (VIII).

A compound of formula (VIII) wherein W is ZCOO-Z1 COO-a 1 ky y 1 i

alkyl or CH

Z 2 COO-alkyl is hydroxylated with sodium hydroxide and the like to remove acyl and alkyl groups, and the resulting compound is reacted with a compound of formula XR in the presence of an organic amine, e.g. triethylamine, to give a compound of formula (IX) . A compound of formula (VIII) wherein W has another meaning is hydrolyzed with aqueous ammonia and the like to give a compound of formula (IX).

The hydroxyl groups in the 4- and 6-positions of the compound of formula (IX) are protected using isopropylidene. 35 to give a compound of formula (X).

1. 38508

A compound of formula (X) wherein W 1 is a Z-O-benzyl or ZO-p-chlorobenzyl group is condensed with a compound of formula R-OH and the resulting compound is catalytically reduced to a compound of ZOH.

The resulting compound is reacted with a compound of formula X-PO (OR) 2 in the presence of an organic amine, e.g. triethylamine, 4-dimethylaminopyridine, pyridine and the like, to produce a compound of formula (XI).

A compound of formula (X) having ZCOOR14 or .Z1C00R14 / 21 / is condensed with a compound of formula R -OH.

CH

* SVSv'Z2coor14 with 15, to prepare a compound of formula (XI).

A compound of formula (IIIa) may be obtained by hydrolysing a compound of formula (XI) thus prepared in aqueous acetic acid, e.g. 50-90% (by weight) in aqueous acetic acid, or by treating the compound with methanol, ethanol, water or a mixture thereof. with p-toluenesulfonic acid.

A compound of formula (IIIa) wherein R is Z / z1opo (or13) 2 ZOPO (OR ^ 3) or CH is a compound of formula (IIIa) 2 <m formula (IIIa), can be prepared as follows.

A compound of formula (VII) wherein W is Z0-30 x weapon style

acetyl, ZO-benzoyl, or CH

^ 2Vacetyl '' '' '^ o-benzoyl

3a Y

35 is trichloroethoxycarbonyl or trichloro-t-butoxycarbonyl, treated with aqueous ammonia to give a compound of formula (XII) which is then protected with isopropylidene to give a compound of formula (XIII). The resulting compound is condensed with an XPO (OR> 2) compound of formula (XIV) to produce a compound of formula (XIV) .Isopropylidene is removed from the resulting compound in the same manner as described above for the preparation of a compound of formula (XVa). The resulting compound is then condensed with a compound of formula (IIIa) to give a compound of formula (IIIa) A compound of formula (XVb) may be prepared by removing Y from a compound of formula (XIV) as described above. and then condensing the resulting compound with a compound of formula R OH 15. Isopropylidene is then removed from the compound as described above to produce a compound of formula (IIIa ').

11 21

A compound of formula (IIIa ') wherein R and R are the same can be obtained by removing Y1 from a compound of formula (XIII) and condensing the resulting compound with a fatty acid and then removing isopropylidene.

Flow chart (b); 25,, / ° 7-o (and / ° ~ u (ch3) 2ch / \ _ (ch3) 2ch / - ^ • W \ A? R21> o-aiiyyii 30 NHY1 NHY1. (XVI) (XVII) / ° —I κο — 1 (ch3> 2ch / - \ r ~ ° \ X OR21 O-allyl- * A OR21 W O-allyl 20 8 8 508 NHR · * ·· 1 · NHR ^ (xviii) (mb) 10 wherein Y1, R21 and R11 are as defined above.

A compound of formula (XIV) is condensed with a compound of formula 2 "R R OH to produce a compound of formula (XVII). After Y1 is removed as described above, the compound is condensed with a compound of formula 11 R OH, a compound of formula (XVIII) Isopropylidene is then removed from the compound of formula (XVIII) as described above to give the compound of formula (IIIb).

The compounds of the present invention have antitumor activity similar to or even more potent than that of Compound A, and their toxicity is significantly lower compared to Compound A. The compounds of the present invention are then superior as antitumor agents.

The present invention will be illustrated in more detail by way of Comparative Examples, Examples and Experimental Examples, but it is to be understood that these are not intended to limit the invention. In these examples, all amounts expressed as a percentage are by weight unless otherwise indicated.

Comparative Example 1 1) Preparation of 2-acetoxyethyl-3,4,6-tri-O-acetyl-2-deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -o <-D-glucopyranoside to 5.00 g 2-Deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -D-glucose was added 5.0 ml of ethylene glycol 21 88508 and 0.5 ml of dioxane-containing hydrogen chloride gas, and the mixture was stirred for 4 hours and heated to 90 ° C. .

After cooling with ice water, 75 ml of pyridine and then 30.6 g of acetic anhydride were added to the reaction mixture, followed by stirring. After stirring for 20 minutes, the reaction mixture was warmed to room temperature and stirring was continued for another 16 hours. The reaction mixture was poured into 350 ml of ice water and stirred. The precipitated solid was collected by filtration and washed with water.

The resulting solid was dissolved in chloroform, washed successively with 1N hydrochloric acid and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from ethanol to give 4.96 g of the title compound as a colorless prism. Melting point: 138-140 ° C.

CaDp5: + 74jOe (c = 1,2, chloroform) 2) Preparation of 2-acetoxyethyl-3,4,6-tri-O-acetyl-2-deoxy-2-tetradecanoylamino-N, N-D-glucopyranosine 20 60 ml 4.96 g of the compound obtained in 1) were dissolved in acetic acid, and 7 g of zinc powder was added thereto in small portions at room temperature and with stirring. Stirring was continued for 1 hour, and all insoluble matter was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure, toluene was added to the residue, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in dioxane, and dioxane-containing hydrogen chloride gas was added to the solution. The solvent was removed by distillation under reduced pressure, and the residue was dried.

The resulting oily product was dissolved in 70 ml of anhydrous methylene chloride, and 2.88 ml of N-methylmorpholine: and 3.24 g of tetradecanoyl chloride were added to the solution simultaneously under ice-bath cooling, followed by stirring for one hour. To the reaction mixture was added 10 ml of 22,850,508 methanol. After stirring for 10 minutes at room temperature, the reaction mixture was diluted with chloroform, washed successively with 1N hydrochloric acid and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using a mixture of benzene and ethyl acetate in a ratio of 9/1 (v / v) and then 1/1 (v / v) as the eluent to give 4.77 g of the title compound as a colorless oily product.

3) Preparation of 2-hydroxyethyl-2-deoxy-2-tetradecanoyl-amino-N, N-D-glucopyranoside 80 Absolute methanol was dissolved in 4.77 g of the compound obtained in 2) above, and a methanol-15 solution containing 9 mmol of sodium methylate , was added to the solution in an ice bath under cooling, and then stirred at room temperature for 30 minutes. Tetrahydrofuran was added here to dissolve the precipitate, the solution was neutralized with a strongly acidic ion exchange resin-20a, Dowex-50 (H + type), and the resin was filtered off. The solvent was removed from the filtrate by distillation under reduced pressure. The residue was washed with diethyl ether, then filtered to give 3.02 g of the title compound as a white solid. Recrystallization from ethanol-water gave a purified product with a melting point of 158-160 ° C.

[?

(by volume) J

4) Preparation of 2-hydroxyethyl-2-deoxy-4,6-Q-isopropylidene-30 2-tetradecanoylamino-o'-D-glucopyranoside In 20 ml of dimethylformamide was dissolved 0.87 g of the compound obtained in 3) above, and , 62 g of 2-2-dimethoxypropane and 38 mg of p-toluenesulfonic acid monohydrate were added to the solution at room temperature, followed by stirring for 1.5 hours. After the reaction mixture was neutralized with 5% aqueous sodium hydrogencarbonate solution, the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using a 19/1 (v / v) mixture of chloroform and acetone as the eluent, and then a 19/1 (v / v) mixture of chloroform and methanol to give 0. .78 g of the title compound as a colorless viscous oily product.

5) Preparation of 2- (diphenylphosphonooxy) ethyl-2-deoxy-4,6-O-isopropylidene-4-tetradecanoylamino-oC-glucopyranoside In 15 ml of anhydrous methylene chloride was dissolved 0.77 g of the compound obtained in 4) above, and 0.48 g of diphenyl phosphochloridate, 0.19 ml of pyridine and 0.30 g of dimethylaminopyridine in an ice bath under cooling. After stirring for one hour, the temperature of the reaction mixture was returned to room temperature and stirring was continued for another hour. 0.17 g of diphenylphosphochloridate was added to the reaction mixture, followed by stirring for 30 minutes. To the reaction mixture was added 3 ml of methanol. After stirring for some time, the solvent was removed by distillation at 25 rpm under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of 19/1 (v / v) chloroform and acetone as the eluent to give the title compound as a colorless visc; as a constituent oil.

6) Preparation of 2- (diphenylphosphonooxy) ethyl-2-deoxy-3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino-1 H, -D-gluco-V *: pyranoside: 5 anhydrous methylene chloride was dissolved: 0.51 g of the compound obtained in 5) above and 0.22 g of N- .....: 35 dodecanoylglycine, 44 mg of dimethylaminopyridine and 24 88508 and 0.18 g of dicyclohexylcarbidimide were added to the solution under cooling in an ice bath. The mixture was stirred for 30 minutes in an ice bath and then at room temperature for two hours. The insoluble matter was removed by filtration, and the filtrate was washed successively with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and 20 ml of 90% aqueous acetic acid solution was added to the residue, followed by stirring for 10 to 30 minutes while heating at 90 ° C. The solvent was distilled off, and toluene was added to the residue, after which the solvent was removed by distillation. The addition of toluene and distillation were repeated once more. The residue was purified by silica gel column chromatography using a mixture of 19: 1 (v / v) chloroform and acetone as the eluent and then a mixture of 19: 1 (v / v) chloroform and methanol to give 0.51 g of the title compound as a colorless oily product.

Δ [α] D: + 46f 2 ° (c = 1.1, chloroform) δ NMR (CDCl 3), δ (ppm): 0.88 (6H, t), 1.26 (s), 2.07 (2H , t), 2.27 (2H, t), 4.84 (1H, d), 5.18 (1H, m), 7.2-7.4 (10H, m) Comparative Example 2 25 1) 2- Preparation of hydroxyethyl 2-deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -oc-β-glucopyranoside in 6 ml of a 28% aqueous ammonia solution and 120 ml of methanol was suspended in 5.05 g of Comparative Example 1- 1) The prepared compound and suspension were stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure to give 3.50 g of the title compound as a caramel-like substance.

NMR (CDCl 3 -CD 3 OD, ca. 1: 1), δ (ppm): 4.78 (2H, s), 4.90 (1H, d) δ 88508 2) 2-hydroxyethyl-2-deoxy-4.6 Preparation of -O-isopropyl-diene-2- (2,2,2-trichloroethoxycarbonylamino) -oc-D-glucopyranoside

The compound obtained in 1) above (3.58 g) was treated in the same manner as in Comparative Example 1-4). To the resulting fraction was added n-hexane, and the resulting precipitate was collected by filtration to give 2.78 g of the title compound as a white powder.

Melting point 190-192 ° C.

3) Preparation of 2- (diphenylphosphonoxy) ethyl-2-deoxy-4,6-O-isopropylidene-2- (2,2,2-trichloroethoxycarbonylamino) -OC-D-glucopyranoside

The compound obtained in 2) above (1.12 g) was treated in the same manner as in Comparative Example 1-5), and diethyl ether and n-hexane were added to the resulting fraction. The resulting precipitate was collected by filtration to give 1.23 g of the title compound.

Melting point 121-124 ° C.

[et] 25: + 46.4 * (c = 1.0, chloroform) D '20 4) 2- (diphenylphosphonooxy) ethyl-2-deoxy-4,6-O-isopropylidene-3-O-tetradecanoyl-2- ( Preparation of 2,2,2-trichloroethoxycarbonylamino) -QC-D-glucopyranoside In 10 ml of anhydrous methylene chloride was dissolved 0.50 g of the compound obtained in 3) above, and 0.30 ml of pyridine, 0.22 g of tetradecanoyl chloride and 20 ml of ml of dimethylaminopyridine was added to the solution, followed by stirring for 2 hours. To the reaction mixture was added 2 ml of methanol. After stirring at room temperature for some. ; time, the reaction mixture was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography using 2% acetone-containing chloroform and then 5% acetone-containing chloroform as the eluent to give 0.49 g of the title compound as a colorless oily substance, m.p. + 36 * 1 * (c = 1.0, chloroform) 26 8 B 508 5) 2- (diphenylphosphonooxy) ethyl-2-deoxy-2- (N-dodecanoylglycylamino) -4,6-Q-isopropylidene-3-Q Preparation of -tetradecanoyl-α-D-glucopyranoside In 12 ml of acetic acid was dissolved 0.47 g of the compound obtained in 4) above) and 0.5 g of zinc powder was suspended with the above, followed by stirring at room temperature for about 1.5 hours. All insoluble matter was removed by filtration, the filtrate was washed with chloroform, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in chloroform, washed successively with 5% aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the remaining oily substance was dissolved in 8 ml of anhydrous methylene chloride. To the solution was added 0.21 g of N-dode-canoylglycine. To the mixture were added 0.17 g of dicyclocarbodiimide and 32 g of dimethylaminopyridine in an ice bath. After 20 minutes, the temperature of the mixture was returned to room temperature and the mixture was allowed to react for 15 hours while stirring at the same time. All insoluble matter was removed by filtration, and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was purified by silica gel column chromatography using chloroform containing 2-10% acetone as an eluent. The desired fractions were treated with n-hexane to give 0.48 g of the title compound as a white powder. Melting point 79-80 ° C.

+ 28.1® (c = 1,1, chloroform) 6) Preparation of 2- (diphenylphosphonooxy) ethyl-2-deoxy-2- (N-30 dodecanoylglycylamino) -3-O-tetradecanoyl-α-D-glucopyranoside 0.45 g of the compound obtained in 5) above was dissolved in 20 ml of a 90% aqueous acetic acid solution, and the solution was stirred for 30 minutes while heating at 35 ° C. The solvent was removed by distillation under reduced pressure of 88,8508, and toluene was added to the residue, followed by distillation under reduced pressure. The addition of toluene and distillation were repeated once more, and the finally obtained residue was purified by silica gel column chromatography using chloroform containing 5-10% acetone and then a mixture of 19: 1 (v / v) chloroform and methanol as the eluent to give 0.39 g. the title compound as a white waxy solid.

10 [α] 25. +36; le (c = 11?, Chloroform) NMR (CDCl 3), δ (ppm); 90 (6H, t), 1.28 (s), 2.13 (2H, m), 2/36 (2H, t), 4.90 (1H, d), 7.2-7.5 (10H, m) Comparative Example 3 1) 2- (Diphenylphosphonooxy) ethyl-2-deoxy-3-O- (N-dodecanoylglycyl) -4,6-O-isopropylidene-2- (2,2,2-trichloroethoxycarbonylamino) Preparation of -o <? - D-glucopyranoside In 20 ml of anhydrous methylene chloride was dissolved the compound obtained in Comparative Example 2-3), and 0.83 g of N-dodecanoylglycine, 0.17 g of dimethylaminopyridine and 0.67 g of dicyclohexylcarbodiimide were added thereto. while cooling in a bath. After 30 minutes, the mixture was allowed to warm to room temperature and stirred for one hour at this temperature. All insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. , Y; The residue was purified by silica gel column chromatography using a mixture of 10: 1 (v / v) chloroform and acetone as the eluent to give 2.80 g. . the title compound as a colorless oily substance.

[α] D 20: + 32.2 * (c = 0.8, chloroform) 28 88508 2) 2- (diphenylphosphonoxy) ethyl-2-deoxy-3-O- (N-dodecanoylglycyl) -2- / 6- Preparation of (octanoylamino) hexanoylamino Q7-O-D-glucopyranoside In 10 ml of acetic acid was dissolved 0.71 g of the compound obtained in 1 above), and 0.5 g of zinc powder was added thereto at room temperature with stirring. After stirring for 2 hours, the insoluble matter was removed by filtration, the filtrate was washed with chloroform, and the solvent was distilled off. The residue was dissolved in chloroform-10, washed successively with 5% aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give an oily product.

0.26 g of 6- (octanoylamino) caproic acid was dissolved in 7 ml of anhydrous tetrahydrofuran and 0.16 g of 1-hydroxybenzotriazole and 0.21 g of dicyclohexylcarbodiimide were added to the solution under ice-bath cooling. The temperature of the liquid was gradually returned to room temperature, and the mixture was stirred for three hours. The precipitated insoluble matter was removed by filtration. The filtrate was combined with the oily product prepared above in an ice bath under cooling, after which the reaction mixture was allowed to warm to room temperature where it was stirred for 4 hours. The solvent was distilled off, and 20 ml of 90% aqueous acetic acid solution was added to the residue. The mixture was stirred for 20 minutes with simultaneous heating at 90 ° C. The solvent was distilled off, and the residue was purified by silica gel column chromatography using successive mixtures of 10: 1 (v / v) chloroform and acetone, 20: 1 (v / v) chloroform and methanol, and 10: 1 (v / v) chloroform and methanol as successive eluents. There was thus obtained 0.56 g of the title compound as a colorless waxy substance. [α] D 25: + 31 ^ .2 * (c = 1.1, chloroform) 35 NMR (CDCl 3), δ (ppm): 0.88 (6H, t), 2.0-2.4 (6H , m), 4.85 (1H, d), 7.2-7.4 (10H, m) 29 88508

Comparative Example 4 Preparation of 2- (diphenylphosphonoxy) ethyl-2-deoxy-3-O- (N-dodecanoyl-N-methylglycyl) -2- [1N-dodecanoyl-N-methylglycyl) amino] -N-D-glucopyranoside 5 10 ml 1.00 g of the compound obtained in Comparative Example 2-3) was dissolved in acetic acid, and 0.5 g of zinc powder was added thereto at room temperature while stirring. Stirring was continued for another 2.5 hours, and insoluble matter was removed by filtration. The batch of 10 was washed with chloroform and the solvent was removed by distillation under reduced pressure. The residue was dissolved in chloroform, washed successively with 5% aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the remaining oily substance and 1.21 g of N-dodecanoyl-N-methylglycine were dissolved in 10 ml of anhydrous methylene chloride. To the solution were added 90 mg of dimethylaminopyridine and 0.92 g of dicyclohexylcarbodiimide in an ice bath under cooling. After warming to room temperature, the mixture was stirred for 3 hours. The precipitated insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residual oily substance was purified by silica gel column chromatography using successively mixtures of 9: 1 (v / v) chloroform and acetone and 19: 1 (v / v) chloroform and methanol as eluent to give an oily substance.

The resulting oily substance was dissolved in 40 ml of a 90% aqueous acetic acid solution, followed by stirring for 30 minutes and simultaneously heating at 90 ° C. · Solvent. ; The residue was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of chloroform and methanol (50: 1 by volume) and then 20: 1 by volume (35% by volume) as the eluent to give 0.87 g of the title compound. as an oily product.

Δ 88508 [α] D 25: + 34.9 * (c = 1.0, chloroform) NMR (CDCl 3), δ (ppm): 0; 89 (6H, t), 1.28 (s), 2.36 ( 4H, m), 2.84 and 3.00 (total 3H, each), 3, .13 and 3.15 (total 3H, kkins), 4.45 (2H, m), 4.87 (1H, d), 7.2-7.4 (10 H, m)

Comparative Example 5 1) Preparation of 2- (diphenylphosphonooxy) ethyl-2-deoxy-3-O-10 tetradecanoyl-2- (2,2,2-trichloroethoxycarbonylamino) -c *, - D-glucopyranoside In 15 ml of anhydrous methylene chloride was dissolved 0 , 50 g of the compound obtained in Comparative Example 2-3) and 0.22 g of tetradecanoic acid, and 0.12 g of dimethylamino-15 pyridine and 0.20 g of dicyclohexylcarbodiimide were added to the solution under ice-bath cooling. The mixture was warmed to room temperature and stirred for 2 hours. The precipitated insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residual oily substance was purified by silica gel column chromatography using a mixture of 10: 1 (v / v) chloroform and acetone as the eluent to give an oily substance. The resulting oily substance was dissolved in any 90% aqueous acetic acid solution, after which the mixture was stirred for 25 hours while heating at 90 ° C. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using mixtures of 10: 1 (v / v) chloroform and acetone and then 10: 1 (v / v) chloroform and methanol as the eluent to give 0.61 g of an oily product.

[α] 25 · + 43.0 * (c = 1,2, chloroform) 31 88508 2) 2- (diphenylphosphonooxy) ethyl-2-deoxy-2-Z- (N-dodecanoyl-D-isoglutaminyl) aminci-3-3-0 Preparation of tetradecanoyl-α-D-glucopyranoside

The compound obtained in 1) above (0.47 g) was treated with zinc powder in acetic acid solution, and then this was reacted with N-dodecanoyl-D-iso-glutamine in the same manner as in Comparative Example 3-2) to give 0.36 g. g of the title compound as a white waxy substance.

[Α] 25 D = + 38.7 * (c = 0.1, chloroform) NMR (CDCl 3), δ (ppm): 0.88 (6H, t), 1.26 (s), 2, 1-2.5 (6H, m), 4.96 (1H, d), 5.18 (1H, d), 7.2-7.5 (10H, m) 15 Comparative Example 6 1) 1,3- Preparation of (diethoxycarbonyl) isopropyl-2-deoxy-3,4,6-trl-O-acetyl-2- (2,2,2-trichloroethoxycarbonylamino) -pC-D-glucopyranoside to 8.00 g to 1.3 4,6-Tetra-O-acetyl-2-deoxy-2-20 (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose was added to a cooled acetic acid solution containing 25% hydrogen bromide at room temperature, followed by stirring for one hour. The reaction mixture was diluted with chloroform, washed successively with 5% aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. 8 g of anhydrous calcium sulfate, suspension containing 30 g of 4.12 g of silver perchlorate in 40 ml of anhydrous. . benzene and 6.24 g of diethyl 3-hydroxyglutarate in an ice bath under cooling. The mixture was allowed to react at room temperature for 3 hours, after which the mixture was neutralized with: 5% aqueous sodium hydrogen carbonate solution. Insoluble matter was removed by filtration, and the filtrate was washed with water 32 88508 and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography using a mixture of 30: 1 (v / v) chloroform and acetone as the eluent to give the title compound as an oily substance.

[α] D 25: + 42.8® (c * = Oy7, chloroform) 2) 1,3- (diethoxycarbonyl) isopropyl-2-deoxy-2-tetradecanoylamino-3,4,6-trl-O-acetyl- Preparation of Qf-D-glucopyranoside The compound obtained in 1) above (4.00 g) was treated with zinc powder in acetic acid solution, and then the mixture was reacted with tetradecanoic acid in the same manner as in Comparative Example 3-2) to give 3.78 g. the title compound as an oily substance.

15 ° C: + 46 DEG-9 DEG (c = 0 DEG-16, chloroform) 3) Preparation of 1,3- (dibenzyloxycarbonyl) isopropyl-2-deoxy-2-tetradecanoylamino - <* - D-glucopyranoside in 30 ml of dioxane 1.80 g of the compound obtained in 2 above) was dissolved, and 10 ml of water was added thereto. After the solution was cooled to 5 ° C, 15 ml of 1N aqueous potassium hydroxide solution was added thereto. After stirring for 6 hours, 1N hydrochloric acid was added thereto to adjust the pH to 7.5. The reaction mixture was concentrated to dryness under reduced pressure. The residue was suspended in 100 ml of dimethylformamide and 1 ml of benzyl bromide was added thereto. After the mixture was stirred at 40 ° C for 3 hours, most of the dimethylformamide was removed by distillation under reduced pressure. The residue was extracted with benzene, and the benzene layer was washed successively with 5% aqueous citric acid solution, saturated aqueous sodium chloride solution, 5% aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of chloroform, methanol and acetone (50: 1: 15 by volume) as the eluent to give 0.65 g of the title compound as a white waxy solid.

[A] 25. + 13; 2e (c = 0.51, chloroform) δ 4) Preparation of 1,3- (dibenzyloxycarbonyl) isopropyl-2-deoxy-4,6-Q-isopropylidene-2-tetradecanoylamino-α-D-glycopyranoside in 10 ml of acetone 0.64 g of the compound obtained in 3) above was dissolved and treated in the same manner as in Comparative Example 1 to 4) to give 0.54 g of the title compound as an oily substance.

[α] D 25 + 3.3 * (c = 0.7, chloroform) 5) 1,3- (dibenzyloxycarbonyl) isopropyl-2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-O- D- 15 Preparation of glucopyranoside

In the same manner as in Comparative Example 1 to 6), 0.48 g of the compound obtained in the above was reacted with tetradecanoic acid, and the reaction product was heated in 90% aqueous acetic acid to give 0.53 g of the title compound as a white waxy solid.

Ca] p5s + 32f8® (c = 0.9, methanol) NMR (CDCl3), δ (ppm) s 0.88 (6H, t), 1.26 (s), 4.94 (1H), δ, Δ 20 (4H, s), 7.40 (10H, s): · 25 1 '

Comparative Example 7 Preparation of 1,3- (dibenzyloxycarbonyl) isopropyl-2-deoxy-3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino-o ('- D-glucopyranoside 30 In the same manner as in Comparative Example 1-6), 0.60 g of the compound obtained in Comparative Example 6-4) was reacted with N-dodecanoylglycine, and the reaction product was treated with a 90% aqueous acetic acid solution to give 0.63 g of the title compound as a waxy solid.

34 88508

CaD 6: + 36.9® (c c * 1.3, chloroform) NMR (CDCl 3), δ (ppm) s 0r89 (6H, t), 1.26 (s), 2.1-2.3 ( 4H, m), 2.5-2.9 (4H / m), 4.50 (1H, m), δ 4.97 (1H, d), 5.07 (1H, m), 5.18 ( 4H), 7.40 (10H, s)

Comparative Example 8 1) Preparation of 2-acetoxyethyl-3,4,6-tri-O-acetyl-2-deoxy-2- [6- (octanoylamino) hexanoylamino] -N-D-glucopyranoside

In the same manner as in Comparative Example 2-5), 3.00 g of the compound obtained in Comparative Example 1-1) was treated with zinc powder in acetic acid solution, and the reaction product was reacted with 6- (octanoylamino) caproic acid to give 2.84 g of the title compound. compound as a waxy solid.

[A] 25. + 55.4 ° (c = 1,1, chloroform) 2) Preparation of 2-hydroxyethyl-2-deoxy-2-Z1- (octanoyl-20-amino) hexanoylamino [7-oc-D-glucopyranoside

In the same manner as in Comparative Example 1-3), 2.82 g of the compound obtained in 1) above was reacted to give 1.66 g of the title compound as a white powder.

Melting point 156-157 ° C.

Ca] +: + 78.8® (c = 0.9, ethanol) 3) 2-hydroxyethyl-2-deoxy-4,10-isopropylidene (R) - (octanoylamino) hexanophylamino-Q8-D- Preparation of glucopyranoside In the same manner as in Comparative Example 1-4), 1.60 g of the compound obtained in 2) above was reacted to give 1.48 g of the title compound as an oily substance.

[α] 25: + 35.2® (c = 1.0, chloroform) 35 88508 4) 2- (Diphenylphosphonooxy) ethyl-2-deoxy-4,6-isopropylidene-2- [6- (octanoylamino) hexanoylamino? -o ("Preparation of D-glucopyranoside

In the same manner as in Comparative Example 1 to 6), 1.26 g of the compound obtained in 3) above was reacted to give 1.35 g of the title compound as an oily substance.

CaDp ^ * + 26.7 * (c = 1,2, chloroform) 5) 2- (diphenylphosphonooxy) ethyl-2-deoxy-3-10-dodecanoyl-2- (4- (octanoylamino) hexanoylamino7-oC-D- Preparation of glucopyranoside

In the same manner as in Comparative Example 1 to 6), 0.65 g of the compound obtained in 4) above was reacted with dodecanoic acid, and the reaction product was heated in 90% aqueous acetic acid to give 0.73 g of the title compound as an oily substance.

Λ max + 37.3 * (c = 1.1, chloroform) NMR (CDCl 3), δ (ppm): 0.89 (6H, m), 2.10 (4H, m), 2.33 (2H , 20 m), 3.20 (2H, m), 4.30 (1H, m), 4.46 (2H, m), 4.85 (1H, d), 5.10 (1H, m) Comparative Example 9 1) 2-acetoxyethyl-3,4,6-tri-O-acetyl-2-Z1 [R] -. ·. Preparation of 3-benzyloxytetradecanoylamino-2-deoxy-α-D-gluco- * · 25 pyranoside

In the same manner as in Comparative Example 2-5), 3.00 g of the compound obtained in Comparative Example 1-1) was treated. was treated with zinc powder in acetic acid solution, and the reaction product was treated with 1.95 g of (R) -3-benzyl-oxytetradecanoic acid to give 3.70 g of the title compound as an oily substance.

; ·: NMR (CDCl 3), δ (ppm) s 0.87 (3H, t, J = 6Hz), 2.00 (3H, s), 2.02 (3H, s), 2.04 (3H, s) ), 2.08 (3H, 35 s), 2.18 (2H, m), 4.54 (2H, ABq, J = 12Hz), 4.76 (1H, d, J = 4Hz), 7.36 V; (5H, s) 36 88508 2) Preparation of 2-hydroxyethyl-2- [(R) -3-benzyloxytetadecanoylamino] -2-deoxy-α-D-glucopyranoside

In the same manner as in Comparative Example 1-3), 3.68 g of the compound prepared in 1) above was reacted to give 2.49 g of the title compound as a pale brown powder. Recrystallized from water-ethanol. Melting point 125-127 ° C.

[A] 25. + 73.3 · (c = 0.9, methanol) 3) 2-hydroxyethyl-2-7 "(R) -3-benzyloxytetradecanoylamino] -2-deoxy-4,5-isopropylidene-α-D- preparation of glucopyranoside

In the same manner as in Comparative Example 1 to 4), 0.98 g of the title compound was obtained as a colorless oily substance from 1.20 g of the compound prepared in 2) above.

[Α] ^! + 31.4e (c = 0.9, chloroform) 4) 2- (diphenylphosphonooxy) ethyl-2-Z- (R) -3-benzyloxytetradecanoylamino] -2-deoxy-4,6-O-isopropylidene-1G- Preparation of D-glucopyranoside In the same manner as in Comparative Example 1-5), 0.98 g of the title compound was obtained as a colorless oily substance from 0.83 g of the compound prepared in 3) above.

NMR (CDCl 3), δ (ppm): 0.88 (3H, t, J = 7Hz), 1.46 (3H, s), 1.53 (3H, s), 2.47 (2H, d, J = 6Hz), 4.2 (3H, m), 4.53 (2H, ABq, J = 12Hz), 4.64 (1H, d, J = 4Hz), 7.2-7.4 (15H, m) 5) 2- (Diphenylphosphonooxy) ethyl-3-O (R) -benzyloxytetradecanoyl) -2- (7R) -3-benzyloxytetradecanoylamino] -2-deoxy-t * -D-glucopyranoside manufacturing

In the same manner as in Comparative Example 1 to 6), 0.96 g of the compound obtained in 4) above was reacted with 0.59 g of (R) -3-benzyloxytetradecanoic acid, and the reaction product was heated in a 90% acetic acid-35 solution, and thus 1.23 g of the title compound were obtained as a colorless oily substance.

378 8508 [α] D: + 31.4 * (c = 1.2, chloroform) NMR (CDCl 3), δ (ppm): 0.88 (6H, t, J = 7Hz), 2.34 (2H , d, J = 6Hz), 2.6 (2H, m), 4.51 (2Hf ABq, 5 J = 12Hz), 4.56 (2H, s), 4.71 (1H, d, J = 4Hz) ), 5.13 (1H, m), 7.2-7.4 (20H, m) Comparative Example 10 2- (Diphenylphosphonooxy) ethyl-3-OZ- (R) -3-benzyl-10-oxytetradecanoyl] -2-deoxy Preparation of -2-tetradecanoylamino-α-D-glucopyranoside

In the same manner as in Comparative Example 1 to 6), the compound obtained in Comparative Example 1 to 5) was reacted with (R) -3-benzyloxytetradecanoic acid, and the reaction product was heated in 90% acetic acid solution to give the title compound as an oily substance.

NMR (CDCl 3), δ (ρρπι) δ 0.89 (6H, t), 2.06 (2H, t), 2.1-2.8 (2H, m), 4.85 (1H, d), 5.14 (1 H, t), δ 7.1-7.3 (15 H, m)

Comparative Example 11 Preparation of 2- (diphenylphosphonooxy) ethyl-2 - [(R) -3-benzyloxytetradecanoylamino] -2-deoxy-3-O-tetradecanoyl-o [· -D-glucopyranoside In the same manner as in Comparative Example 1-6), the compound prepared in Comparative Example 9-4) was reacted with tetradecanoic acid, and the reaction product was heated in 90% aqueous acetic acid to give the title compound as a colorless oily substance.

NMR (CDCl 3, δ (ppm) s 0.88 (6H, t), 2.3-2.4 (4H, m), 4.52 (2H, d), 4.72 (1H, d) , 5.10 (1H, λ / m), 7.2-7.5 (15H, m) 38 88508

Comparative Examples 12-52

The following compounds of formula (lila) were prepared as described in Comparative Examples 1-11.

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Example 1 1) 2- (Diphenylphosphonooxy) ethyl-2-deoxy-6-O-Z2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O- (2,2,2- trichloroethoxycarbonyl) -2- (2,2,2-trichloro-5-ethoxycarbonylamino) -N-D-glucopyranosyl] -3-O- (N-dodecanoylglycyl) -2-Z-1N-dodecanoyl-N-methylglycyl) amino Preparation of -c * -D-glucopyranoside To 2 ml of anhydrous methylene chloride was dissolved 370 mg of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-3-O- (N-10 dodecanoylglycyl) -6-O- (2 , 2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose, and 6 ml of a cooled acetic acid solution containing 25% hydrogen bromide were added to the solution at room temperature, followed by stirring for 1 hour. The reaction mixture was diluted with chloroform, washed successively with ice water, 5% aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue and 344 mg of 2- (diphenyl-20-phosphonooxy) ethyl-2-deoxy-3-O- (N-dodecanoylglycyl) -2- [(N-dodecanoyl-N-methylglycyl) amino] -7-c-D-glucopyranoside was dissolved in 5 ml of anhydrous methylene chloride. To the solution were added 0.5 g of activated calcium sulfate and 182 mg of mercury (II) cyanide, and the mixture was heated to 50-60 ° C and stirred for three hours. The insoluble matter was removed by filtration through Celite, and the filtrate was washed successively with 5% aqueous potassium iodide solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography using mixtures of 10: 1 (v / v) chloroform and acetone, then 50: 1 (v / v) chloroform and methanol as the eluent to give 599 mg of the title compound as an oily substance.

35 [α] 25. + 20.0 ° (c = 1.0, chloroform) si 88508 2) 2- (diphenylphosphonooxy) ethyl-2-deoxy-6-O- (2-deoxy-4-O-diphenylphosphono-3-O- (N -dodecanovylglycyl) -2-Z- (N-dodecanoyl-N-methylglycyl) amino] -N-D-gluco-pyranoxy) -3-O- (N-dodecanoylglycyl) -2-Z1 [N-dodecanoyl-5-N- preparation of methylglycyl) aminoQ7-α-D-glucopyranoside In 8 ml of acetic acid was dissolved 587 mg of the compound prepared in 1) above, and 0.6 g of zinc powder was suspended in the solution, followed by stirring at room temperature for 2 hours. The insoluble matter was removed by filtration, and the filtrate was washed with chloroform. The solvent was removed by distillation under reduced pressure, and toluene was added to the residue, followed by distillation to remove the solvent. The addition of toluene and distillation were repeated three times in total, and the residue was dissolved in chloroform. The chloroform layer was washed successively with 1N hydrochloric acid, 5% aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to give 20 oily products.

122 mg of N-dodecanoyl-N-methylglycine was dissolved in 3 ml of anhydrous tetrahydrofuran, and to this solution were added 77 mg of 1-hydroxybenzotriazole and 103 mg of dicyclohexylcarbodiimide, followed by stirring. : 25 in an ice bath. After 30 minutes, the solution temperature was returned to room temperature and stirring was continued for a further 3 hours. The precipitated crystals were removed by filtration.

The oily substance prepared above was dissolved in 5 l! To 30 ml of anhydrous methylene chloride and the filtrate were added thereto in an ice bath under cooling. The reaction temperature was returned to room temperature, and the mixture was stirred at this temperature for 1.5 hours. The reaction mixture was diluted with chloroform, washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, and then distilled to remove solvent 52 88508. The residue was purified by silica gel column chromatography using mixtures of 10: 1 (v / v) chloroform and acetone, then 50: 1 (v / v) chloroform and methanol, and finally 20: 1 (v / v) chloroform and methanol as eluent to give 445 mg of the title compound. compound as an oily substance.

[α] D 25: + 19 ° C (c = 1f, chloroform) 3) 2-phosphonooxyethyl-2-deoxy-6-O- (2-deoxy-3-O-10- (N-dodecanoylglycyl) -2- / ~ (N-dodecanoyl-N-methyl-glycyl) amino] -4-O-phosphono- [3-D-glucopyranosyl) -3-O- (N-dodecanoylglycyl) -2- (N-dodecanoyl-N- preparation of methyl-glycyl) amino-cc * -D-glucopyranoside

To a mixture of 50 ml of tetrahydrofuran and 2.5 ml of water was dissolved 424 mg of the compound prepared in 2) above, and 0.2 g of platinum dioxide was added thereto, followed by stirring in the presence of hydrogen gas for 2 hours. The catalyst was removed by filtration, and the filtrate cake was washed with an 8: 3: 1 (v / v) mixture (lower layer 20) of chloroform, methanol, and water. The filtrate and washings were combined and the solvent was removed by distillation under reduced pressure. The residue was purified by thin layer chromatography using a mixture of 6: 4: 0.7 (v / v) chloroform, methanol and water as a developing solvent and then treated with a strongly acidic ion exchange resin, Dowex 50 (H + type) manufactured by Dow Chemical Co., Ltd. .). The solvent was removed by distillation under reduced pressure, and the residue was suspended in dioxane. Freeze-drying gave 30 204 mg of the title compound as a white powder.

Melting point 165-170 ° C (gradually discolored and turned gelatinous).

[A] 25. +4? 6 [c = * 0.7, chloroform: methanol = 3: 1 (by volume # IR vKBr cm-1: 3400, 2930, 2850, 1750, 1675, 1650 35 max NMR (CDCl3-CD3OD), δ ( ppm) s 0.90 (12H, t), 1.30 (s), 2.29 (4H, m), 2.44 (4H, t), 53 88508 2.94 and 3-11 (total 6H, 5 s each), 4.84 (1H, d), 5.18 (1H, m), 5.34 (1H, m)

A portion of the resulting product was dissolved in a mixture of 3: 1 (v / v) chloroform and methanol 10, and the pH of the solution was adjusted to 9 with triethylamine, followed by concentration under reduced pressure. The residue was dissolved in 0.1% aqueous triethylamine and then filtered through a millet pore filter. The filtrate was freeze-dried to give the triethylamine salt of the title compound as a white powder.

Example 2 1) 2- (Diphenylphosphonooxy) ethyl-2-deoxy-6-Q- Z- (2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O- ( 2,2,2-Trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) - [5-D-glucopyranosyl] -2- [6- (octanoylamino) hexanoylamino] -3-O-tetradecanoyl-of-D -Production of glucopyranoside

In a similar manner to Example 1-1), 445 mg of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-3-O- (N-dode-25-canoylglycyl) -6-O- (2,2,2 -trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D-glycopyranose and 385 mg of 2- (diphenylphosphonooxy) ethyl-2-deoxy-2- [6- (octanoylamino) hexanoylamino] -3-0-tetradecanoyl- ®CD-glucopyranoside was reacted to give '650 S of the title compound as an oily substance.

Ca] ^ 5: + 22.2 ° (c = 1.0, chloroform) 54 88508 2) 2- (diphenylphosphonooxy) ethyl-2-deoxy-6-O-Z2-deoxy-4-O-diphenylphosphono-3- Preparation of O- (N-dodecanoylglycyl) -2-tetradecanoylamino-β-D-glucopyranosyl-2- [6- (octan-5-ylamino) hexanoylamino] -3-O-tetradecanoyl-α-D-glucopyranoside was dissolved in 10 ml of acetic acid. 620 mg of the compound prepared in 1) above and 1.5 g of zinc powder were suspended therein, followed by stirring at room temperature for 3 hours. All insoluble matter was removed by filtration, and the solvent was removed by distillation under reduced pressure, and the residue was dissolved in chloroform. The solution was washed successively with 1N hydrochloric acid, water, 5% aqueous sodium hydrogencarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was removed by concentrating the mixture under reduced pressure, and the residue was dissolved in 10 ml of anhydrous tetrahydrofuran. To the solution were added 98 mg of tetradecanoic acid, 58 mg of 1-hydroxybenzotriazole and 90 mg of dicyclohexylcarbodi-20imide under ice-bath cooling, and the liquid was gradually allowed to rise to room temperature, followed by stirring overnight. The precipitated insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residual solid was purified by silica gel column chromatography using mixtures of 10: 1 (v / v) chloroform and acetone and then 30: 1 (v / v) chloroform and methanol as eluent and then triturated with acetonitrile to give 428 mg of the title compound. 30 teas as a white powder.

Melting point 105-107 ° C.

[A] 25. + 24.7 * (c = 1r0, chloroform) 55 88 508 3) 2-Phosphonooxyethyl-2-deoxy-6-O2-deoxy-4-O-phosphono-3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino Preparation of N-D-glucopyranosyl-2- [2- (octanoylamino) hexanoylamino] -3-O-tetradecanoyl-o-D-glucopyranoside

In the same manner as in Examples 1-3), 350 mg of the compound prepared in 2) above was reacted to give 162 mg of the title compound as a white powder.

Melting point 169-172 ° C (stained and turned jelly-like).

[α] D 25: + 19.5 ° [c = 0.6, chloroform: methanol = 3: 1 (v / v) - 1 · IR Vmax Cm * 3405 '2925, 2855, 1740, 1645, 1560, 1460 NMR ( CDCl 3), δ (ppm) s 0r90 (12H, t) 1.30 (s), 2.1-2.4 (10H, m), 3.19 (2H, t), 5.1.7 (1H, t), 5, 38 (1 H, t)

The resulting compound was treated in the same manner as in Example 1-3) to give the triethylamine salt of the title compound as a white powder.

Example 3 1) 2- (Diphenylphosphonooxy) ethyl-2-deoxy-6-O-A2-deoxy-4-O-diphenylphosphono-3-O- (4-oxotetradecanoyl-6-O- (2,2,2- Preparation of trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -N-D-glucopyranosyl-3-O- (4-oxo-tetradecanoyl-2-tetradecanoylamino-O-D-glucopyranoside)

In the same manner as in Example 1-1), 435 mg of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-3-O- (4-oxotetradecanoyl) -6-O- (2.2 , 2-trichloroethoxycarbonyl) -2-: (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose • and 380 mg of 2- (diphenylphosphonooxy) ethyl-2-deoxy-3-O- (4-oxotetradecanoyl) -2 -tetradecanoylamino-α-D-glyco-35 pyranoside was reacted to give 516 mg of the title compound as an oily substance.

: Y: + 14r7e (c = 0.03, chloroform) 56 88508 2) 2- (diphenylphosphonooxy) ethyl-2-deoxy-6-O- [2-deoxy-4-O-diphenylphosphono-3-O- (4 Preparation of -oxotetradecanoyl) -2-tetradecanoylamino- [1-D-glucopyranosyl] -3-O- (4-oxo-tetradecanoyl) -2-tetradecanoylamino-Q'D-alcopyranoside In 5 ml of acetic acid was dissolved 510 mg above in 1), and 0.5 g of zinc powder was suspended in the solution, followed by stirring at room temperature for 1.5 hours. Insoluble matter was removed by filtration, and the filtrate was distilled under reduced pressure. The resulting residue was diluted with chloroform, washed successively with 1N hydrochloric acid, 5% aqueous sodium hydrogencarbonate solution and water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The resulting oily substance was dissolved in 2 ml of anhydrous methylene chloride, and 88 mg of tetradecanoyl chloride and 2 ml of N-methylmorpholine were added to the solution under ice-bath cooling. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with chloroform, washed successively with 1N hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of 20: 1 (v / v) chloroform and methanol as the eluent to give 229 mg of the title compound as an oily substance.

[α] 25: +17.3 '(c = 0.2, chloroform)

D

3) 2-Phosphonooxyethyl-2-deoxy-6-O- [L2-deoxy-4-O-phosphono-3-O- (4-oxotetradecanoyl) -2-tetradecanoylamino] -3,3-D-glucopyranosyl] -3-0 Preparation of (4-oxotetradecanoyl) -2-tetradecanoylamino-oC-D-glucopyranoside

In the same manner as in Example 1-3), 225 mg of the compound prepared in 2) above was reacted and treated in the same manner to give 91 mg of the title compound as a white powder.

Melting point 166-170 ° C (colored and jelly-like) 57 88508

KBr - I

IR Vmax Cm! 3406, 2926, 2854, 1710, 1662, 1557, 1470 NMR (CDCl 3 -CD 3 OD), δ (ppm); 0.88 (12H, t), 1.26 (s), 2.22 (4H, m), 2.54 (4H, t), δ 2.64 (4H, m), 2r76 (4H, m), 5.16 (1H) , t), 5.30 (1 H, t)

The resulting compound was treated in the same manner as in Example 1-3) to give its triethylamine-10 salt as a white powder.

Example 4 1) Benzyloxycarbonylmethyl-2-deoxy-6-O-Z2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O- (2,2,2-trichloroethoxycarbonyl) - Preparation of 2- (2,2,2-trichloroethoxycarbonylamino) -N-β-glucopyranosyl-147-3-O-tetradecanoyl-1-2-tetradecanoyl-amino-XD-glucopyranoside

In the same manner as in Example 1-1), 303 mg of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoyl-20-glycyl) -6-O- (2,2,2 -trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose and 217 mg of benzyloxycarbonylmethyl-2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-D-glucopyranoside were thus reacted 408 mg of the title compound as an oil.

Ca] + + 25.8 ° (c = 1.0, chloroform) 2) Benzyloxycarbonylmethyl-2-deoxy-6-O-Z2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) li) Preparation of -2-tetradecanoylamino-β-D-glucopyranosyl-3-O-tetradecanoyl-2-tetradecanoylamino-cis-D-glucopyranoside

In the same manner as in Example 1-2), 389 mg of the compound prepared in 1) above was reacted with tetradecanoic acid to give 293 mg of the title compound as an oily substance.

[α] D 25: + 28.4 ° (c = 1,1, chloroform) 58 88508 3) Carboxymethyl-2-deoxy-6-O-Z2-deoxy-3-O- (N-dodecanoylglycyl) -4-O-phosphono Preparation of 2-tetradecanoylamino-β-D-glucopyranosyl-3-O-tetradecanoyl-2-tetradecanoylamino-β-D-glucopyranoside To a mixture of 40 ml of tetrahydrofuran and 1 ml of water was dissolved 278 mg of the above. in 2) and 0.3 g of 5% palladium on carbon were added thereto, followed by stirring in the presence of hydrogen gas for one hour. 150 mg of platinum dioxide-10 dia were then added and stirring in the presence of hydrogen gas was continued for another 2.5 hours. The catalyst was filtered off and the filtrate was distilled to remove the solvent. The residue was purified by thin layer chromatography using, as a developing solvent, the lower layer, a mixture of 8: 3: 1 (v / v) chloroform, methanol and water, and then the residue was treated with a strongly acidic ion exchange resin.

Dowex (H + type). The active fraction was distilled to remove the solvent and the residue was suspended in dioxane. The suspension was lyophilized to give 68 mg of the title compound as a white powder.

Melting point 150-155 ° C (colored and jelly-like).

IR ν max cm -1: 3400, 2925, 2855, 1745, 1650, 1470 NMR (CDCl 3), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1-2.4 (8H, 25 m), 4.82 (2H, m), 5.22 (1H, t), 5.37 (1H, t)

Example 5 1) Allyl-2-deoxy-6-Q - [2-deoxy-4-O-diphenyl-phosphono-3-O- (N-dodecanoylglycyl) -6-O- (2,2,2-trichloro) Preparation of -30-ethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -Ne-D-glucopyranosyl-3-O-tetradecanoyl-2-tetradecanoyl-amino-α-D-glucopyranoside

In the same manner as in Example 1-1), 2.00 g of 1-O-acetyl-2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoyl-35-glycyl) -6-O- (2.2 , 2-trichloroethoxycarbonyl) -2- (2,2,2- 59,8508 trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -D-glucopyranose and 1.23 g of allyl-2-deoxy-3- O-tetradecanoyl-2-tetradecanoylamino-D-glucopyranoside was reacted to give 2.65 g of the title compound 5 as a caramel-like substance.

+27-2 ° (c = 1,4, chloroform) 2) Allyl-2-deoxy-6-O-Z2-deoxy-4-O-diphenyl-phosphono-3-O- (N-dodecanoylglycyl) -2- Preparation of tetradecanoylamino-β-D-glucopyranosyl-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranoside

In the same manner as in Example 1-2), 2.65 g of the compound prepared in 1) above was reacted with tetradecanoic acid to give 2.25 g of the title compound as a caramel-like substance.

[Α] D 25: +21.8 “(c = 0.9, chloroform) 3) Allyl-6-O- [S-O-benzyloxymethyl-2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl] ) Preparation of -2-tetra-decanoylamino-β-D-glucopyranosyl] -2-deoxy-3-O-tetra-decanoyl-2-tetradecanoylamino-α-D-glucopyranoside 20 was dissolved in 25 ml of anhydrous methylene chloride at 870 mg above. 2) The prepared compound and 0.82 ml of benzyloxymethyl chloride and 1.00 ml of diisopropylethylamine were added thereto, followed by stirring at room temperature overnight. An additional 0.16 ml of benzyloxymethyl chloride and 0.20 ml of diisopropylethylamine were added to the mixture, and the mixture was stirred for a further 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, 5% aqueous sodium hydrogencarbonate solution and water.

The organic layer was dried over anhydrous magnesium sulfate. . account. The solvent was removed by distillation under reduced pressure, and acetone was added to the residue. The precipitated white powder was collected by filtration. The powder was dissolved in chloroform, purified by silica gel column chromatography using mixtures of 10: 1 60 by volume of chloroform and ethyl acetate as eluent, then 5: 1 (by volume) chloroform and ethyl acetate and finally 20: 1 (by volume) chloroform. and triturated in acetonitrile to give 5,505 mg of the title compound as a white powder.

Melting point 154-157 ° C.

Ca] p5: +32; 4e (c = 1r2, chloroform) 4) 6-O-benzyloxymethyl-2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -2-tetradecanoyl-10 Preparation of amino-β-D-glucopyranosyl-2-deoxy-3-O-tetradecanoyl-2-tetradecanoylamino-D-glucopyranose In 15 ml of anhydrous tetrahydrofuran was dissolved 480 mg of the compound prepared in 3) above. After the air surrounding the reaction was removed and replaced with nitrogen-15 gas, 10 ml of 1,5-cyclooctadiene-bis (methyldiphenylphosphine) iridium hexafluorophosphate was added to the solution. The air surrounding the system was again removed and replaced with hydrogen gas. After the red color of the iridium complex had disappeared, the surrounding gas was again replaced with nitrogen and the mixture was stirred at 50 ° C for 2.5 hours.

After allowing the reaction mixture to cool, 5 ml of water and then 180 mg of iodine were added thereto, followed by stirring at room temperature for 20 minutes. A 5% aqueous sodium thiosulfate solution was added to the reaction mixture until the color of the iodine had disappeared. The reaction mixture was extracted with chloroform, and the organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using mixtures of 10: 1 (v / v) chloroform and acetone and then 50: 1 (v / v) chloroform and methanol as eluent, and the residue was triturated with 320 mg of acetonitrile. powder.

35 Melting point 155-156 ° C.

[α] D 25: + 17.1 ° (c = 0f7, chloroform) 6i 38508 5) 2-deoxy-6-O- [2-deoxy-3-O- (N-decdanoylglycyl) -4-O-phosphono] Preparation of -2-tetradecanoylamino- [3-D-glucopyranosyl] -1-O-phosphono-3-O-tetradecanoyl-2-tetradecanoylamino-α-D-glucopyranose 5 Dissolve 170 mg in anhydrous tetrahydrofuran in 15 ml above. 4) the prepared compound. After the ambient air was replaced with nitrogen, a hexane solution containing 0.16 mmol of n-butyl lithium was added to the reaction mixture with cooling to about -70 ° C. After 5 minutes, a benzene solution containing 1.16 mmol of dibenzyl phosphorochloridate was added thereto, followed by stirring at -50 ° C for 30 minutes. To the reaction mixture were added 100 mg of black palladium and 85 mg of 5% palladium on carbon, followed by stirring in a stream of hydrogen gas overnight.

The catalyst was filtered off and the filtrate was distilled under reduced pressure. The resulting residue was dissolved in 150 ml of tetrahydrofuran, and 0.27 g of platinum dioxide was added to the solution. The mixture was stirred for 4 hours under a stream of hydrogen gas, after which the catalyst was filtered off on a filter pad. The filtrate was distilled under reduced pressure to remove the solvent, and the residue was purified by thin layer chromatography using a 6: 4: 1 (v / v) mixture of developing solvent, chloroform, methanol and water, and then the residue was treated with strongly acidic ion exchange resin, Dowex 50 (H +). To the resulting fraction, 40 μl of triethylamine was added, followed by distillation under reduced pressure. The residue was suspended in dioxane, and the suspension was lyophilized to give 38 mg of the triethylamine salt of the title compound as a white powder.

Melting point 148-150 ° C (colored and gel-like) 25 [α] D: + 10.1® [c = 0f6, chloroform: methanol = 3: 1 (v / v) _7 62 88508 IR om_1i 3400, 2925, 2855, 2680 , 2500, 1745, 1645, 1550, 1470, 1385, 1040 NMR (CDCl 3 -CD 3 OD), δ (ppm) s 0.90 (12H, t), 1.28 (s), δ 2.1-2, Δ (8H, m), 3.1-3.3. (12H, br)

Example 6 1) 2- (Diphenylphosphonooxy) ethyl-2-deoxy-6- / 2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -6-O- (2,2,2- trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) - [3-D-glucopyranosyl] -4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -2 - ['(N- Preparation of dodecanoyl-N-methylglycyl) amino-O-C-D-glucopyranoside 500 mg of anhydrous methylene chloride was dissolved in 500 mg of the compound prepared in Example 1-1), and 0.04 ml of pyridine and 139 mg of diphenylphosphorochloridate and 64 mg of 4-dimethylaminopyridine were added herein. , at room temperature, followed by stirring overnight. The reaction mixture was diluted with methylene chloride, washed successively with 10% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation at 25 rpm under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of 40: 1 (v / v) chloroform and methanol as the eluent to give 368 mg of the title compound as an oily substance.

30 [α] 25: + 21.9® (c = Of8, chloroform) 2) 2- (diphenylphosphonooxy) ethyl-2-deoxy-6-O- (2-deoxy-4-O-diphenylphosphono) -3-O- ( N-dodecanoylglycyl) -2- (N-dodecanoyl-N-methylglycyl) amino] -3- (3-D-glucopyranosyl) -4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -2- 35 L (N Preparation of -dodecanoyl-N-methylglycyl) amino-N-D-glucopyranoside

In the same manner as in Example 1-2), 350 g of the compound obtained in 1) above 1) was treated with zinc powder in acetic acid solution and then reacted with N-dodecanoyl-N-methylglycine to give 244 mg of the title compound as an oily substance.

Δ [α] 2 D: + 3.5 * (c = 0.6, chloroform) 3) 2-phosphonooxyethyl-2-deoxy-6-O- (2-deoxy-3-O- (N-dodecanoylglycyl-2-z- ( N-dodecanoyl-N-methylglycyl) amino-4- (O-O-phosphono-glucopyranosyl) -3-O- (N-dodecanoylglycyl) -2-Z1N-dodecanoyl-N-methylglycyl) amino.7-4 Preparation of -10-phosphono- [α] D-glucopyranoside

In the same manner as in Example 1-3), 238 mg of the compound prepared in 2) above was subjected to catalytic reduction to give 101 mg of the title compound as a white powder.

Melting point 184-189 ° C (colored and jelly-like) 25 [α] D: -4.3 ° [c = 0f6> chloroform]; methanol = 3: 1 (by volume ^ IR 'ίϋΐ cm-1: 3280, 2900, 1740, 1660, 1640 max NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t, J = 7fHz), 20 lf28 (brsj, 1.62 (8H, br), 2.24-2.31 (4H, m), 2.40-2.42 (4H, m), 2.91-2.96, 3.09, 3.12 (total 6H, each s), 4.84 (1H, d) , 5.19 (1H, 25t), 5.31 (1H, t)

Example 7 1) 2- (Diphenylphosphonooxy) ethyl-3-O- (1R) -3-benzyloxytetradecanoyl] -2- [(R) -3-benzyloxytetra-30-decanoylamino] -2-deoxy-6-O- (2 deoxy-4-0-difenyylifosfo-no-6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trikloo-rietoksikarbonyyliamino) -3-0- / R) -3- ( Preparation of 2,2,2-trichloroethoxycarbonyloxy) tetradecanoyl-3- (3-D-glucopyranosyl) -oc-D-glycopyranoside In the same manner as in Example 1-1), 409 mg of 1-O-acetyl-2-deoxy-4- O-Diphenylphosphono-6-O- (2,2,2-trichloro-64 8 8 5 0 8 ethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) -3-0- / 7 (R) -3- (2,2,2-Trichloroethoxycarbonyloxy) tetradecanoyl-7-D-glucopyranose was reacted with hydrogen bromide to give an oily substance, and the resulting oily substance was reacted with 370 mg of 2- (diphenylphosphonooxy) ethyl-3- O - [(R) -3-benzyloxytetradecanoyl] -2 - [(R) -3-benzyloxytetradecanoylamino] -2-deoxy- [XD-glucopyranose, in the presence of mercury (II) cyanide 577 mg of the title compound were obtained as a pale yellow, viscous oily substance.

+ 20.2® (c = 0.2, chloroform) 2) 2- (diphenylphosphonooxy) ethyl-3-O- (7R) -3-benzyloxytetradecanoyl147-2- (1R) -3-benzyloxytetradecanoylamino] -2-deoxy -6-O- (2-Deoxy-4-O-diphenylphospho-15-n-3-O - [(R) -3-hydroxytetradecanoyl] -2- [f (R) -3-hydroxytetradecanoylamino] -N- “Preparation of D-9 (pyranosyl) -α-D-glucopyranoside

In the same manner as in Example 1-2), 555 mg of the compound prepared in 1) above was treated with zinc-20 powder in acetic acid solution, and the reaction product was reacted with 93 mg of (R) -3-hydroxytetradecanoic acid to give 312 mg of the title compound. compound as a colorless oily substance.

25 [α] β s + 6,3® (c = 0; 7, chloroform) 25 3) 2-phosphonooxyethyl-2-deoxy-6-O- (2-deoxy-3-O- / (R) -3 -hydroxytetradecanoyl-2 - [((R) -3-hydroxytetradecanoylamino] -4-O-phosphono-β-D-glucopyranosyl) -3-O - ((R) -3-hydroxytetradecanoyl) -2- (1R) Preparation of 3-hydroxytetradecanoylamino-2-D-glucopyranoside In the same manner as in Example 4-3), 294 mg of the compound prepared in 2) above was catalytically reduced in the presence of 5% palladium on carbon to give the title compound. The compound was treated with 0.1% aqueous triethylamine to give 76 mg of the triethylamine salt of the title compound as a white powder. A portion of the product was treated with a strongly acidic ion exchange resin to give the title compound in free form as a white powder.

The following information is for the free compound.

65 88508 25 [«Dj; : -1.8 · [c-0.5, chloroform: methanol = 3: 1 (by volume) 5 Melting point 155-158 ° C (colored and gel-like) IR cm "1: 3440, 2930, 2860, 1740, 1660 max NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 2.3-2.5 (8H, m), 5.2 (2H, m) 10 Example 8 1) 2- (diphenylphosphonooxy) ethyl-4-O- [3- (benzyloxycarbonyl) propionyl] -2-deoxy-6-O-Z2-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -6- O- (2,2,2-Trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonyl-15-amino) -ft-D-glucopyranosyl] -SO- (N-dodecanoylglycyl) -2-tetradecanoylamino - <* - D- Preparation of glucopyranoside To 6 ml of anhydrous methylene chloride was dissolved 483 mg of 2- (diphenylphosphonooxy) ethyl-2-deoxy-6-O- [2- (deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -20 6 -O- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonylamino) - [5-D-glucopyranosyl] -3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino - «> CD-glucopyranoside and 408 mg of monobenzyl succinate and 16 mg of dimethyl liaminopyridine was added to the solution. To this solution was added 107 mg of dicyclohexylcarbodiimide in an ice bath under cooling. The liquid was allowed to return to room temperature and the mixture was stirred for one hour. The insoluble matter was removed by filtration, and the filtrate was washed with 1N hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and residual; The residue was purified by silica gel column chromatography using 10% acetone in chloroform and then 3% methanol in chloroform as the eluent to give 113 mg of the title compound as an oily substance.

35 [α] D 5: + 35.6 * (c, 1,1, chloroform) 66 8 8 508 2) 2- (diphenylphosphonoxy) ethyl-4-O-Z3- (benzyloxycarbonyl) propionyl-2- deoxy-6-O-Z12-deoxy-4-O-diphenylphosphono-3-O- (N-dodecanoylglycyl) -2-tetradecanoylamino-β-D-glucopyranosyl-7-O- (N-dodecanoyl-glycyl) Preparation of -2-tetradecanoylamino-c * -D-glucopyranoside

In the same manner as in Example 1-2), 327 mg of the compound prepared in 1) above was treated with zinc powder in acetic acid solution, and the product was reacted with tetradecanoic acid to give 226 mg of the title compound as an oily substance.

[° O]: + 29.6 * (c = 1,2, chloroform) 3) 2-phosphonooxyethyl-4-O- (3-carboxypropionyl) -2-deoxy-6-O-Z2-deoxy-3-O Preparation of - (N-dodecanoylglycyl) -4-O-phosphono-2-tetradecanoylamino-β-D-glucopyranosyl-7-O- (N-dodecanoylglycyl) -2-tetradecanoylamino-γ-D-glucopyranoside

In the same manner as in Example 4-3), 204 mg of the compound prepared in 2) above was reacted to give 97 mg of the title compound as a white powder.

Melting point 150-155 ° C (colored and gelatinous) [α] 25 D = + 24.4 * Qb = 0.5, chloroform: methanol = 3: 1 (by volume), λ K r 1 IR vmax cm s 3300, 2925, 2855 , 1755, 1660, 1555 NMR (CDCl 3 -Cp3OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.2-2.3 (8H, m), 2r6- 2.7 (4H, m), 4.18 (2H, m), 4.27 (2H, m), 4.61 (1H, 30d) * 4.82 (1H, d), 5.06 ( 1H, t), 5.24 (1H, t), 5.30 (1H, t)

Examples 9-81

The following compounds of formula (Ia) were prepared as described in Examples 1-8.

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The physical properties of the compounds of Examples 9-81 are as follows.

Example No. Physical Properties 9 Melting Point: 140-150 ° C (colored and jelly-like) [<*] ^ 5: + 13.3 * (c = 0.6, chloroform: methanol = 3: 1 (by volume) _ KBr IR Vmax cm: 3400, 2930, 2855, 1750, 1660, 1560 NMR (CDCl 3 - CD 3 OD), δ (ppm): 0.90 (12H, t), 1.32 (s), 2.1-2.3 (8H, m), 5.10 (1H, t), 5.38 (1H, t) Melting point: 174-180 ° c (colored and gelatinous) 25 [ct] D 5 + 11.8® (c = 0.7, chloroform: methanol = 1: 1 (by volume) KBr i IR Vmax cm -1: 3425, 2930, 2854, 1745, 1675, 1470 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.28 ( s), 2.27 (2H, t), 2.4-2.8 (12H, m), 2.93 (2H, m) 4.81 (1H, m), 5.14 (1H, t), δ , 32 (1H, m) 11 Melting point: 159-167 ° c (colored and gelatinous) · 25 [cx] D: + 10.2 ° (c = 0.6, chloroform: methanol = 1: 1 (by volume) VDr .. 1 IR cm: 3330, 2925, 2855, 1745, 1655, 1560

ITlaX

1470, 1025 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.20 (6H, m), 2.46 (2H, t), 2.6 -2.8 (4H, m), 3.25 (2H, m), 3.63 (1H, m), 3.71 (1H, m), 3.90 (8H, m), 4.18 (4H, m), 4.76 (1H, d), 5.13 (1H, t), 5.24 (5H, t) 78 88508

Example No. Physical Properties 12 Melting Point: 165-171 ° C (colored and jelly-like) [α] 2 ^. + 9.0 * (c = 0.6, chloroform: methanol = 1: 1 (by volume) KBi * 1 IR Vmax cm-1 3320 '2925, 2855, 1710, 1645, 1555 1470 NMR (CDCl3 ~ CD3OD), δ ( ppm): 0.89 (12H, t), 1.27 (s), 2.17 (6H, m), 2.47 (4H, m), 2.60 (4H, m), 2.73 (4H, m), 4.25 (1H, q), 4.75 (1H, d), 5.12 (1H, t), 5.25 (1H, t) 13 Melting point: 169-173 ° C (colored and jelly-like) [ α] 20 D: + 16.4 ° (c = 0r7, chloroform: methanol = 3: 1 (v / v)) KBr 1 IR νmax Cmax: 3425, 2925, 2855, 1735, 1645, 1555 NMR (CDCl3-CD3OD), Δ (ppm): 0.90 (12H, t), 2.2-2.4 (10H, m), 3.18 (2H, t), 5.16 (1H, t), 5.36 (1H, t) 14 Melting point: 161-165 ° C (colored and jelly-like) [α] 25: + 9r2 * (c = 0T6, chloroform: methanol = 3: 1 (by volume) IR vKBr cm-1: 3405, 2930, 2855, 1760, 1660, 1550 Δ3Χ NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 2.2-2.5 (8H, m), 2.96 and 3.04 (total 6H, eacn s), 5.18 ( 1H, t), 5.34 (1 H, t)

Example No. Physical Properties 79 88508 15 Melting point: 144-147 ° C (colored and jelly-like) 25 [α] β: -2.4® (c = 0.8, chloroform: methanol = 3: 1 (by volume)) KB ^ 1 IR νmax cm: 3405 '2925' 2855 '1745' 1655, 1555 NMR (CDCl3-CD3OD), δ (ppm): 0.90 (12H, t), 2.1-2.5 (8H, m), 2.82 and 3.02 and 3.04 (total 6H, each s), 4.88 (1H, d), 5.16 (1H, t), 5.29 (1H, t) Melting point: 150-154 ° C ( colored and gelatinous) 25 [cijp: + 16.8® (c = 0.6, chloroform: methanol = 3: 1 (by volume)) IR cnT1 ·. 3450, 2930, 2860, 1745, 1675,

IucLX

1470 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.88 (12H, t), 1.26 (br), 2.3-2.8 (18H, m), 2.96 and 3.10 and 3.18 (total 6H, each s), 5.16 (1H, m), 5.34 (1H, m) 17 Melting point: 190-193 ° C (colored and jelly-like) •; C ° G p: -5.4® (c = 0.7, chloroform: methanol = 3: 1 (by volume)) VD 1 -1 cm cm -1: 3305, 2925, 2855, 1750, 1650 ... max 1 H NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 2.1-2.4 (8H, m), 5.16 (1H, t), 5.38 (1H, t) ) 80 88508

Example No. Physical Properties 18 Melting Point: 175-177 ° C (colored and jelly-like) 25 [α] D: -2.2® (c = 0.8, chloroform: methanol = 3: 1 (by volume)) KB 3Γ 1 IR νmax cm-1 3310 '2925' 2855 '1745 »1660, 1555 NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t), 2.1-2.4 (8H, m), 5.18 (1H , t), 5.32 (1H, t) 19 Melting point: 145-150 ° C (colored and gel-like) 2 [α] 25 D: + 1.7® (c = 0.6, chloroform: methanol = 3: 1 (by volume)) KBr 1 IR vmax Cm ': 330 ° * 2925, 2855, 1755, 1685, 1645 1555 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.29 (4H, t), 2.48 (4H, t), 4.73 (1H, d), 4.84 (1H, d), 5.19 (1H, t), 5.32 (1H, t) Melting point: 165-168 ° C (colored and gel-like) + 10.2® (c = 0.5, chloroform: methanol = 3: 1 (by volume)) KBr-i IR Vmax Cm: 3310 '2930, 2865, 1735 1645, 1555 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t-br), 1.30 (s), 2.20 (12H, t), 2 f 36 (4H, m), 3.19 (8H, t), 4.68 (1H, d), 4.79 (1H, d), 5.16 (1H, t), 5T24 1H, t)

Example No. Physical Properties 81 88508 21 Melting point: 178-183 ° C (colored and jelly-like) [α] D: + 16.8® (c = 0.5, chloroform: methanol = 3: 1 (by volume)) IR vmax cm x: 3315, 2925, 2855, 1735, 1660, 1570 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 2.20 (8H, m), 5.18 (1H, t ,, 2.56 (4H, m), 5.30 (1H, t) 22 Melting point: 151-160 ° C (colored and gelatinous) 25 [α] β: + 2.4® (c = 0.3, chloroform: methanol = 3: 1 (by volume)) IR νmax cm-1 3350 '2925, 2855, 1750, 1647, 1555 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.88 (12H, t), 1.26 (s ), 2.2-2.7 (16H, m), 5.1 «(1H, t), 5.30 (1H, t) 23 Melting point: 160-164 ° C (colored and jelly-like) 25 [° DD s + 14.5® (c = 0.7, chloroform: methanol = 3: 1 (v / v)) IR ν max cm -1: 3330, 2930, 2860, 1755, 1660, 1565 max NMR (CDCl 3 -CD 3 OD), δ (ppm) : 0.90 (12H, t), 1.32 (s), 2.1-2.3 (8H, m), '5.10 (1H, t), 5.38 (1H, t) 24 Melting point : 168-174 ° E (colored and gelatinous) [α] D 25 = 6.6 ° (c = 0.3, chloroform: meta noli = 3: 1 • (by volume)) KBr 1 IR Vmax cm: 3315, 2930, 2860, 1760, 1660, 1555 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.88 (12H, t), 1, 26 (s), 2.1-2.8 (20H, m), 5.20 (1H, t), 5.34 (1H, t) ε2 88508

Example No. Physical properties 25 Melting point: 160-170 ° C (stained and gradually turned jelly-like) 25 C <3d: + 21.7 * (c = 0.6, chloroform: ethanol = 3: 1 (by volume))

KBr _ I

νmax cm -1 3450, 2930, 2860, 1760, 1675, 1470 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.32 (s), 2.43 (8H, m) , 2t96 and 3.08 and 3? 16 (total 12H, each m, s, s), 4.87 (2H, m), 5.20 (1H, m), 5.47 (1H, m) 26 Melting point : 166-170 ° C (colored and gel-like) 25 [α] D + + = 6.6 * (c = 1.0, chloroform: methanol = 3: 1 (v / v)) ^ I * 1 IR Vmax Cra 5 3330 '2925, 2855, 1745, 1660, 1560 NMR (CDCl 3 -CD 3 OD), δ (ρριη): 0.88 (12H, t), 1.26 (s), 2.1-2.4 (8H, m), 3.5-3.8 (4H, m) , 3.94 (6H, m), 4.20 (4H, m), 4.79 (1H, d), 5.19 (1H, t), 5.25 (1H, t) 27 Melting point: 160- 162 ° C (colored and gelatinous) [α] D: + 12.9 ° (c = 0.7, chloroform: methanol = 3: 1 (by volume)) IR Vmax cm-8 3320, 2925, 2855, 1730, 1655 1565 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 2.18 (8H, m), 2j36 (4H, m), 3.20 (4H, m), 4, 78 (1 H, d); 5.2 (2 H, m)

Example No. Physical Properties 83 88508 2® Melting Point: 162-165 ° C (colored and gelatinous) 25 [α] D: +10.7 "(c = 0.6, chloroform: methanol: water = 8: 3: 1 (by volume) lower layer KBr IR IR νmax cm δ 3315, 2925, 2860, 1760, 1645, 1555 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 2.1-2.4 (12H, m) , 3.1-3.3 (4H, t), 5.20 (1H, t), 5.37 (1H, t) 29 Melting point: 160-164 ° C (colored and jelly-like)

CaD ^ · *: + 14.1 ° (c = 0.7, chloroform: methanol = 3: 1 (v / v)) KHir IR vnax c®_1: 3410, 2925, 2855. 1750, 1645, 1560 NMR (CDCl 3 -CD 3 OD) Δ (ppm): 0.90 (12H, t), 2.1-2.4 (8H, m), 5.18 (1H, t), 5.38 (1H, t) Melting point: 16 5-1 '68 ° C (colored and gelatinous) [ot] 25. + 8.6 * (c = 0.7, chloroform: methanol: water = 6: 4: 1 (v / v)) KBr, IR νmax cm: 3315, 3100, 2925, 2855, 1745, 1660, - 1565 NMR (CDCl3-CD3OD ), Δ (ppm): 0.90 (12H, t), 2.2-2.5 ° (12H, m), 4 (.81 (1H, d), 5.19 (1H, t), 5.35 (1H, t)

Example 84 88 508 No. Physical properties 31 Melting point: 177-185 ° C (stained and gradually turned gelatinous) 25 0 *] β: + 3.7® (c = 0.6, chloroform-methanol: water = 6: 4: 1 ( by volume)) ..KBr IR max cm δ 3315 '2930' 2855 '1750? 1660, 1560 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0., 88 (12H, t), 1.26 (s), 2.1-2.5 (10H, m), 5r18 (1H, t), 5.34 <1H, t) 2 c 32: + 2.4® (chloroform: methanol: water: triethylamine = 8: 3: 0.5: 0.01 (v / v)) NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.28 (s), 2.1-2.4 (8H, m ), 5.16 (1H, t), 5.32 (1R, t) 33 Melting point: 170-175 ° C (colored and gelatinous) [α: + 5.2 * (c = 0.6, chloroform: methanol = 3 : 1 (by volume)) KBr-1 IRVmax cm-8 3300 '2925, 2855, 1750, 1680, 1565 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.30 (s ), 2.2-2.5 (8H, m), 5f 2 O (1H, m), 5.37 (1H, m) 34 Melting point: 182-185 ° C (colored and jelly-like)

Ca * + H; 5® (¢ = 0 ^ 7, chloroform: methanol = 3: 1 (v / v) KBr IRVmax cm -1: 3315, 2925, 2855, 1735, 1645, 1560 NMR (CDCl 3 -CD300), δ ( ppm): 0.90 (12H, t), 2.1-2.4 (12H, m), 3.1-3.3 (4H, m), 5.1-5.4 (2H, m)

Example No. Physical Properties 85 88508 35 Melting point: 177-185 ° C (colored and jelly-like) [a] 25. + 13 ° (c = 0.5, chloroform: methanol = 3: 1 (by volume)) IR cm-1: 3330, 2930, 2860, 1755, 1660, 1565

IltclX

NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.91 (12H, t), 1.32 (s), 2.1-2r3 (8H, m), 5.10 (1H, t), δ, 38 (1H, t) 36 Melting point: 168-172 ° C (colored and jelly-like) [α] D 5. + 14.6 * (c = 1.0, chloroform: methanol = 3: 1 (v / v)) KBr IR νmax cm: 3320, 2930, 2860, 1755, 1660, 1565 NMR (CDCl3-CP30D), δ (ppm ): 0.91 (12H, t), 1.32 (brj, 2.12-2.32 (8H, m), 5.18 (1H, m), 5.36 (1H, m)) 37 Melting point: 175-180 ° C (colored and gel-like) Ca] p ^ s + 9r9e (c = 0.7, chloroform: methanol = 3: 1 (by volume)) •!: KBr _i IR vmax cm s 3300, 2930, 2860, 1750, 1675, 1580 1560 NMR (CDCl 3 -CD 3 OD), δ v'ppm): 0.89 (12H, t), 1.30 (s), 2.2-2.5 (8H, m), 2, 95 and 3.12 (total 9H, each m), 4.85 (1H, d), 5.18 (1H, t), 5.35 (1H, m) .. i-rWci 86 885 ° 8 No. Physical properties 38 Melting point: 170-175 ° C (colored and gel-like [α] D: + 14.9 * (c = 0.6, chloroform: methanol = 3: 1 (by volume)) KBr 1 IR Vmax cm: 3450 '3300, 2930 , 2860, 1755, 1675, 1575 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.91 (12H, t), 1.32 (s), 2.29 (2H, m), 2.43 ( 6H, m), 2.94 and 3.12 (total 9H, each m), 4.83 (1H, m), 5.18 (1H, m), 5.44 (1H, m) 39 Melting point: 166-174 ° C (colored and jelly δ [α] ρ: + 9.2® (c = 0.6, chloroform: methanol = 3: 1 (by volume)) IR Vmax cm-1 3310, 2930, 2860, 1760, 1660, 1565 NMR ( CDCl 3 -CD 3 OD), Mppm): 0.88 (12H, t), 1.26 (s), 2.1-2.4 (20H, m), 2.94 (3H, s), 3.04 (3H, s), 5.18 (1H, t), 5.36 (1H, t) 40 Melting point: 170-186 ° C (stained and gradually became gelatinous) [α] D 20: + 7? 8® (c = 1,1, chloroform: methanol = 3: 1 (by volume)) KBr - 1 IR Vmax cm δ 3310, 2930, 2860, 1750, 1660, 1565 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.88 ( 12H, t), 1.26 (s), 2.20 (8H, t), 2.43 (4H, t), 2.94 (1H, m), 3.11 (6H, s), 3.19 ( 4H, m), 4.81 (1H, m), 5.19 (1H, t), 5.38 (1H, t) 87 88508

Example nrQ Physical Properties 41 Melting point: 184-186 ° C (colored and gelatinous) + 6.0 * (c = 0r5, chloroform: methanol = 3: 1 by volume)) KB * · «.1 IR vmax cm 5 3460, 1758, 1662 NMR (CDCl 3 - CD 3 OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 2.1-2.5 (8H, m), 2.94, 3.12 (6H, s), 4.80 (1H, m), 5.18 (1H, m), 5.38 (1H, m) 42 Melting point: 155-165 ° C (stained and gradually gelled) [α] 35 : + 8.2 ° (c = 0r7, chloroform: methanol: water = 6: 4: 1 (v / v)) KBr 1 IR vmax cm -1 3320, 2930, 2850, 1760, 1645, 1565 NMR (CDCl 3 -CD 3 OD), Δ (ppm) and 0.90 (12H, t), 1.30 (s), 2.2 (12H, m), 3; 18 (4H, t-br), 5.19 (1H, t), 36 (1H, t) 43 Melting point: 165-168 ° C (colored and gel-like) CQ] p: + 23.6® (c = 0.6, chloroform: methanol = 3: 1 (v / v)) KBr _i ··. IR νmax cm δ 345 ° »2925 '2855 * 1735' 1675, 1635 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.30 (s)» 2.3-2.5 (8H, m), 2.92 and 2.94 and 3.07 and 3.09 (total 6H, s), 4.74 (1H, m), 4.87 (1H, d),. Δ, 14 (1H, t), 5.38 (1H, t) and 88508

Example No. Physical Properties 44 Melting Point: 177-179 ° C (colored and jelly-like)

Λmax: + 11.7 * (c = 0.7, chloroform: methanol = 3: 1 (v / v)) IR νmax cm-1 3310, 2860, 1734, 1659, 1560 NMR (CDCl3-CD3OD), δ (ppm ): 0.90 (12H, t), 2.1-2.4 (12H, m), 3.10 (4H, t), 5.1-5.3 (2H, m) 45 Melting point: 145-150 ° C (colored and gelatinous) + 7.6 "(c = 0.8, chloroform: methanol = 3: 1 (by volume) VOr IR cm: 3300, 1760, 1665, 1555 Π) αΛ NMR (CDCl 3 -CD30D), δ (ppm) : 0.90 (12H, t), 1.30 (s), 2.30 (8H, m), 4.84 (1H, d), 5.19 (1H, t), 5.33 (1H, t) 46 Melting point: 148-153 ° C (colored and jelly-like)

Λ max δ: +18.4 ° (c = 0.9, chloroform: methanol = 3: 1 (v / v)) IR νmax cm: 3300, 1745, 1645, 1555 NMR (CDCl3-CD3OD), δ (ppm) : 0.90 (12H, t), 1.30 (s), 2.30 (8H, m), 4.86 (1H, d), 5.16 (1H, t), 5.34 (1H, t).

es 88508

Example No. Physical Properties 47 Melting point: 155-158 ° C (colored and jelly-like) [α] 25: + 11.6® (c = 1.0, chloroform: methanol = 3: 1 (v / v)) IR vKBr cm -1: 3320 , 1745, 1645, 1555 max NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.30 (s), 2.1-2.4 (12H, m), 3.18 (4H, br), 4.67 (1H, d), 5.2 (2H, m) 48 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 1.9 -2.1 (4H, m), 2.2-2.4 (8H, m), 5.16 (1H, t), 5.30 (1H, t) 49 [cQ25: + 4.3® (c = 0.8, chloroform: methanol = 3: 1

D

(by volume)) NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.88 (12H, t), 1.26 (s), 1.9-2.2 (4H, m), 2.2-2.4 (8H, m), 4.80 (1H, d), 5.14 (1H, t), 5.30 (1H, t). + 14rl® (c = 0.7, chloroform: methanol: water = 8: 3: 0.5 (v / v)) NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.88 (6H, t), 1.26 (s) , 1.4-1.8 (m), 2.08 (4H, m), 2.34 (4H, m), 4.63 (1H, d), 4.78 (1H, d), 5, 20 (2 H, m). . 51 [α] 25: + 16.6® {c = 1.0, 8: 3: 0.5 /. NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.88 (6H, t), 1.26 (s), 1.4-1.8 (m), 2.20 (4H, m), 2.36 ( 4H, m), 4.86 (1H, d), 5.14 (1H, t), 5.30 (1H, t)

Example nrQ Physical properties «o 8 8508 52 Melting point: 148-153 ° C (colored and jelly-like) 2 5

Ca] D: + 10.0 ° (c = 0.7, chloroform: methanol = 3: 1 (v / v)) KBr 1K vnax cm: 3320, 2925, 2855, 1745, 1645, 1565 NMR (CDCl 3 -CD 3 OD), δ ( ppm): 0.90 (12H, t), 1.30 (s), 2.2-2 r 3 (8H, m), 4.70 (1H, d), 4.81 (1H, d), 5.16 ( 1H, t), 5.31 (1H, t) 53 Melting point: 135-138 ° C (colored and gelatinous) [α] 25: + 13 / 3e {c = 0.1, chloroform: methanol = 3: 1 ( by volume)) KBr IR IRmax cm -1 3405, 2925, 2855, 1720, 1660, 1555 NMR (CDCl 3 -CD 3 OD), δ δ (ppm): 0.88 (12H, t), 1.26 (br), 2 , 3-2r8 (24H, m), 5.16 (1H, m), 5.30 (1H, m) 54 Melting point: 168-173 ° C (colored and gelatinous) [α] 25: + 9 ^ 4 ° (c = 0.5, chloroform: methanol: water = 6: 4: 1 (by volume)) KBx * · i IR Vmax cm! 3350 '2930' 1745 '1660 * 1570 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1-2t3 (10H, m), 3.18 (2H, t), 4.78 (2H, m), 5.18 (1H, t), 5.35 (1H, t)

Example No. Physical Properties 91 88508 55 Melting point: 182-188 ° C (colored and gel-like) [d] D: + 11.8 ° (c = 0.7, chloroform-methanol = 1: 1 (by volume)) VD *. η IR ν cm -1: 3310, 2926, 2854, 1749, 1677, 1563 λα NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.28 (s), 2.28 (4H, m ), 2, .4-2.8 (8H, m), 3.09, 3.13 (total 6H, 'each s), 3.6-4.3 (m), 4r82 (1H, d), 5.12 ( 1H, t), 5.34 (1H, t) 56 Melting point: 160-165 ° C (colored and jelly-like)

Ca] p5: + 16.8 ° (c = 0.5, chloroform: methanol = 3-: 1 (by volume)) KEz * λ IR vmax cm-3: 3330, 2925, 2855, 1735, 1645, 1550 NMR (CDCl3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.1-2.4 (10H, m), 3.16 (12H, t), 4.27 (1H, q) / 4.76 (1H, d), 4.79 (1H, d), 5.12 (1H, dd), 5.33 (1H, t) 57 Melting point: 158-162 ° C (colored and jelly) 2 [ α] β: + 13.0® (c = 0.4, chloroform: methanol = 3: 1 (by volume)). KBr 1 IR Vmax Cm ~: 3328, 2926, 2854, 1749, 1659, 1563. NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.27 (s) »1-5-1.6 (8H, m), 2.1-2.3 (8H, m), 5.14 (1H, t, t), 5.32 (1H, t) 92 88508

Example Physical properties No. · _ 58 Melting point: 168-172 ° C (colored and jelly-like) 25 [α] β: + 14.2 ° (c = 0.6, chloroform: methanol = 3: 1 (by volume)) etc. IR νmax cm: 3320, 2925, 2855, 1750, 1660, 1565 NMR (CDCl3-CD3OD), δ (ppm): 0.81 (12H, t), 1T18 (s), 1.5-1.6 (8H, m ), 2.0-2.2 (8H, m), 5.05 (1H, t), 5.23 (1H, t). 59 Melting point: 184-187 ° C (colored and gel-like) [α] 20 D. + 15.4 ° (c = 0.6, chloroform: methanol = 1: 1 (by volume)) IR VKBr cm -1: 3430, 2930, 2855, 1755, 1660, 1565, max 1470, 1385 60 Melting point: 178- 182 ° C (colored and jelly-like)

Ea3 ^: + 9.5 ° (c = 0.6, chloroform: methanol = 1: 1 (by volume)) IR Vmax cm-1! 3405 '2930f 2855, 1760, 1660, 1555, 1470, 1205/1025 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 1.61 (m), δ , 12-2.36 (10H, m), 2r91, 3.03 (total 3H, each s), 4.77 (1H, d), 5.14 (1H, t), 5.32 (1H, t) )

Example No. Physical Properties 93 38508 61 Melting point 192-198 ° C (colored and gelatinous) [α] D = + 7.8® (c = 0.5, chloroform-methanol = 1: 1 (v / v)) KBr XR cm · 3355 » 2930/2855/1745/1660/1565/1470, 1385, 1210 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.28 (s), 1.60 (ra), 2 .12-2.38 (10H, m), 3.16 (2H, t), 3.53 (2H, m), 3.62 (1H, m), 3.72 (1H, m), 3.90 (8H, m), 4.16 (6H, m), 4.23 (1H, q), 4.59 (1H, d), 5.15 (1H, t), 5.21 (1H, t) 62 Melting point: 194-195 ° C (colored and gelatinous) + 7.2® (c = 0.8, chloroform sourethanol = 1: 1 (v / v)) KBr, IR νmax cm-1: 3320, 2930, 2855, 1745, 1660, 1555, 1025 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.27 (s) * 1 ^ 60 (m), 2.03-2.35 (12H, m), 3.16 (5H , m), 3.50 (2H, m), 3.54 (1H, m), 3.72 (1H, m), 3.88 (2H, m), 4.15 (5H, m), 4 , 27 (1H, q), 4.77 (1H, d), 5.15 (1H, t), 5.23 (1H, t)

Example No. Physical Properties 94 88508 63 Melting point: 177-182 ° C (colored and jelly-like) 2 [a] D · + ll? 6e (c = 0.5, chloroform: methanol = 3: 1 (by volume)) KBr IR Vmax cm-3 3330, 2925, 2855, 1755, 1650, 1555, 1470 NMR (CDCl 3 -CD 2 OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2, 13-2 , 27 (10H, m), 3Γ16 (2H, t), 4.74-4.77 (2H, t), 5.15 (1H, t), 5.32 (1H, t) 64 Melting point: 173- 177 ° C (colored and jelly-like) [α] 25; + 9f5e (c = 0.5, chloroform: methanol: water = 6: 4: 1 (v / v)) KBr _i IR vmax cm-3330, 2925 ·, 2855, 1755, 166 (, 1565 NMR (CDCl3-CD3OD), δ ( ppm): 0.89 (12H, t), 1.27 (s), 2.1-2.3 (10H, m), 3.17 (2H, m), 4.29 (1H, q) , 4.75 (1H, d), 4.77 (1H, d), 5.14 (1H, dd), 5.33 (1H, dd) 65 NMR (CDCl 3 -CD 3 OD), δ (ppm): δ , 90 (12H, t), 1.26 (s), 2.1-2.5 (8H, m), 4.83 (1H, d), 5.1-5-4 (2H, m) 66 Melting point: 148-151 ° C (colored and gel-like) NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.26 (s), 2.10-2.50 (8H, m) Δ 4.82 (1H, d), 5.1-5.3 (2H, m)

Example No. Physical Properties 95 88508 67 Melting point: 166.5-168.5 ° C (stained and gradually turned gelatinous) NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.26 (s), 2.16 (2H, t), 2.32 (4H, m), 2.50 (2H, d), 4.82 (1H, d), 5.16, 1H, t), 5.32 ( 1H, t) 68 Melting point: 155-158®C (colored and jelly-like)

Ca325. + 1.5 ° (c = 0.5, chloroform: methanol = 3: 1 (by volume)) KBr _ i IR vmax cm! 3400, 2930, 2860, 1740, 1660 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 2.3-2.5 (8H, m), 5.2 (2H, m ) 69 Melting point: 153.5-155.0®C (browned and gradually turned gelatinous) [α: + 13.3® (c = 0.6, chloroform: methanol = 9: 1 (by volume)) KBr 1 IR νmax cm δ 3445, 2530, 1740, 1660, 1560 NMR (CDCl 3 -CD 3 OD), δ (ppm) δ 0r90 (12H), 2.10-2.26 (4H, m), 2.26-2, .46 (4H, m) 70 Melting point: 156-158.5 ° C (turned brown and gradually turned gelatinous)

Cu: + 16.5® (c = 0.9, chloroform: methanol = 9: 1: (by volume)) KBr _i IRvmax cm! 3450, 2930, 1735, 1660, 1560 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.30 (s), 2.10-2.45 (8H, m), 5.20 (m)

Example No. Physical Properties 96 33508 71 Melting point: 148-152 ° C (browned and gradually turned gelatinous) [α] 25. + 14.5 ° (c = 0.9, chloroform: methanol = 9: 1 (v / v)) KBr IR IR max cm: 3450, 2930, 1745, 1650, 1560 NMR (CDCl 3 -CD 3 OD), δ (ppm): δ, 90 (12H, t), 1.30 (s), 2.10-2.50 (8H, m), 5.10-5; 35 (2H, m) 72 Melting point: 156-158.5 ° C ( turned brown and gradually turned jelly-like) [a] 25. + 14.1 ° (c = 0.9, chloroform: methanol = 9: 1 (v / v)) KBr, IR νmax cm-@ 3350, 2930; 1730, 1660, 1560 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1-2.5 (8H, m), 5.1- 5.3 (2H, m) 73 Melting point: 184-188 ° C (brown and gradually gelatinous) [α] 25; + 8.3 ° (c = 0.7, chloroform) ν max δ IR νmax cm: 3455, 2925, 1745, 1665, 1555 NMR (CDCl3-CD3OD), δ (ppm): 0.89 (12H, t) , 2.1-2.5 (8H, m), 5.1-5.4 (2H, m). ... 97 83508

Example No. Physical Properties 74 Melting Point: 169-171 ° C (colored and gelatinous) C <32d5: + 6.2 ° (c = 1.22, chloroform: methanol = 3: 1 (v / v)) NMR (CDCl3-CD3OD) δ (ppm): 0f90 (12H, t), 1.26 (s), 2.1-2.6 (8H, m), 4.80 (1H, d), 5.16 (1H, t), δ .34 (1H, t) 75 Melting point: 140-145 ° C (colored and gel-like [α: +10.3 "(c = 0.6, chloroform: methanol = 3: 1 (by volume) KBx * IR vmax cm") 1: 3330, 2925, 2855, 1755, 1645, 1550 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t), 1.30 (s), 2.1-2.3 (8H, m ), 2.6-3.0 (4H, m), 4.89 (1H, d), 4.99 (1H, d), 5.09 (1H, t), 5.45 (1H, t) 76 Melting point: 142 -147 ° C Colored and gelatinous) [α] 25. + N? 7e (c = 0.7, chloroform: methanol = 3: 1 (v / v)) NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H , t), 1.30 (s) * 2.1-2.4 (8H, m), 5.10 (1H, t), 5.30 (1H, t) 77 Melting point: 145-148 ° C (colored and gelatinous) [α] D 25: +14.2 ° (c = 0.5, chloroform: methanol = 3: 1 (v / v)) _ KBr IR Vmax cm: 3450, 2925, 285 Δ, 1740, 1640 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.90 (12H, t, J = 6 Hz), 2.1-2.4 (8H, m), 4.80 (1H, d, J = 4 Hz), 5.24 (2H, ·. *: m) 98

Example No. Physical Properties 38508 78 Melting point: 149-153 ° C (colored and gelatinous) [α] D 5: +20.6 ° (c = 0.31, chloroform: methanol = 1: 1 (by volume)) KBr _i IR vmax cm -1 3406, 2926, 2854, 1746, 1662, 1557 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.23 (4H, m), 2.46 (6H, m), 2.59 (3H, m), 2.68 (3H, m), 4.89 (1H, d), 5.16 (1H, t), 5.25 (1H, t), ). 5.38 (1H, t) 79 Melting point: 170-175 ° C (colored and jelly) [ot] 35. + 12.6® (c = 0.5, chloroform: methanol: water = 6: 4: 1 (v / v)) KBr-i IRVmax cm -1 3320, 2925_, 2855, 1755, 1660, 1560 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.1-2.3 (8H, m), 3.18 (4H, m), 4.72 (1H, d), 5.23 (1H, t), 5.33 (1H, dd) 80 Melting point: 172-175 ° C (colored and gelatinous) 25 [α] β; + 12.6® (c = 0.5, chloroform: methanol: water = 6: 4: 1 (v / v)) IR vmax cm-1! 3320, 2920, 2850, 1755, 1655, 1550 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 1.27 (s), 2.1-2.3 (10H, m), 3.16 (2H, m), 4.28 (1H, q), 4.35 (1H, q), 4.69 (1H, d), 4.80 (1H, d), 5.21 (1H, t) ), 5, 32 (1H, t) 39 88508

Example No. Physical Properties 81 Melting Point: 170-175®C (colored and gelatinous) δ [οϋ ^ ί + 20.2® (c = 0.5, chloroform: methanol = 3: 1 (by volume)) VBv · ^ IR Vmax cm: 3330, 2930, 2855, 1755, 1655, 1555, 1470 10 NMR (CDCl 3 -CD 3 OD), δ (ppm): 0.89 (12H, t), 2.15-2.3 (10H, m), 2, 6-2.7 (4H, m), 3.17 (2H, m), 4.58 (1H, d), 4.83 (1H, d), 5.07 (1H, t), 5.23 (1H, t), 5.30 (1H, t)

Experimental Example 5

Fibrosarcoma cells (Meth A) (2 x 10) induced in methylBlanthrene in BALB / c mice were implanted intradermally per group into the flank of seven BALB / c20 mice. The triethylamine salt of each compound of the present invention was dissolved or suspended in a 0.1% (v / v) aqueous solution of triethylamine to prepare a solution or suspension having a concentration of 500 pg / ml. The solution or suspension was administered to mice at a dose level of 100 pg / mouse via the tail vein at 7, 12.

·: · And on the 21st day of planting.

The antitumor effect (%) on fibrosarcoma growth was determined by dividing the average tumor weight of the experimental group on day 21 by the average tumor weight of the control group and multiplying the quotient by 100.

For comparison, the same assessment was made using Compound A as a reference compound. The results obtained are shown in Table 1.

100 88508

table 1

Compound Antitumor effect (%) 1 19 2 13 5 3 5 9 9 19 51 26 11 33 24 10 44 7 47 8 53 27 54 6

Compound A 15 15 Comparison 100

It can be seen from Table 1 that the compounds of the present invention have an antitumor effect similar to or more potent than that of Compound A.

20 Experimental Example 2

The triethylamine salt of each compound of the present invention, as shown in Table 2 below, was dissolved or suspended in a 5% (w / v) aqueous glucose solution containing 0.1 (v / v) triethylamine, a solution or suspension having a concentration of 100 μg / ml. ml, to prepare.

Table 2

Compound Dose- Number of dead rabbits / example level Number of experimental animals 30 kittens_ (pg / kg) _ 1 50 0/3 9 50 0/3 26 50 0/3 33 50 0/3 35 47 50 0/3

Compound A 5 4/4 101 88508

It can be seen from Table 2 that the toxicity of the compounds of the present invention is less than 1/10 compared to Compound A, which is evidence of very good safety.

Although the invention has been described in detail and with reference to certain embodiments thereof, it will be apparent to those skilled in the art that many different changes and modifications may be made to the invention without departing from the spirit or scope of the invention.

Claims (4)

102 8 8 508 A process for the preparation of novel therapeutically useful disaccharide derivatives of the formula I 6 'H0-CH2 6 5Ί o ψ 0 (I) 10 o 0 »Y Kf / I N-A' r5o, | 2 (HO) 2 ^ * 0 3. 3 I wherein R is a phosphono group, ZR6 or CH, z2r6 wherein Z, Z1 and Z2 are each an alkylene group having 1 to 6 carbon atoms, and R6 is a carboxyl group or a phosphonoxy group ; R1, R2, R3 and R4 are each -COR7, -COZ3R8, 20? ? P? -CO (CH2) n1CH-N-COR7, -CO (CH2) nlCH-N-COZ3R8, -CO (CH2) n2OCOR7, -CO (CH2) n2OCOZ3R8, -CO (CH2) n2COR7, 25 -CO (CH2) n2COZ3R8 , Qi Qi II -CO (CH2) n2CO (CH2) n3NCOR7 or -CO (CH2) n2CO (CH2) n3NCOZ3R8, wherein R7 is an alkyl group having 1 to 30 carbon atoms and which may be substituted by one or more hydroxyl groups, Z3 is an alkylene group having 1 to 9 carbon atoms, R 8 is a cycloalkyl group having 3 to 12 carbon atoms and which may be substituted by one or more 103 88508 hydroxyl groups, Q is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms , -CONH 2, -COOH or -CH 2 OH, Q 1 is a hydrogen atom or an alkyl group having 1 to 20 carbon atoms, n 1 is 0 or an integer from 1 to 20, and n 2 and n 3 are each an integer from 1 to 20; and R 5 is a hydrogen atom, a phosphono group or -CO (CH 2) m COOH, wherein m is 0 or an integer from 1 to 6; provided that the combination wherein R is a phosphono group, R 5 is a hydrogen atom and R 1, R 2, R 3 and R 4 are each -COR 7 is not included, and for the preparation of their salts, characterized in that the compound of formula II 15 ° [ν / N * 2iy ° r10 (ii) <* 12o> JoM * 51 ° M u Process according to Claim 1, characterized in that R is Z 2 6 ZR 6 or CH 2; R 1, R 2, R 3, Q Q 1 and R 4 are each -COR 7, -CO 2 R 8, -CO (CH 2) n CH-N-CO 7, Q Q! -CO (CH2) n1CH-N-COZ3R8, -CO (CH2) n2COR7 or -CO (CH2) n2COZ3R8. 35 105 88508 2 UHR31 NHR wherein R9 is a hydrogen atom or a hydroxyl protecting group (that is, a protecting group for a hydroxyl group) which can be removed by catalytic reduction or the like; O Z 2 OOR 14 R 10 is -P-OR 13) 2, ZCOOR 14, ZOPO (OR 13) 2, -CiT 25 Z 2 C 20 R 14 Z xOPO (OR 13) 2 or -CH; Rn, R21 and R31 are each 'VssNvz2opo (or13) 2 92 Ql Ql -COR71, -COZ3R01, -CO (CH2) n1CH-NCOR71, -CO (CH2) nlCH-NCOZ3R01, -CO (CH2) n2OCOR71, -CO (CH2) n2OCOZ3R81, -CO (CH2) n2COR71, Q, 35 -CO (CH2) n2COZ3R01, -CO (CH2) n2CO (CH2) n3NCOR71 or 104 88 508 -CO (CH2) n2CO (CH2) n3NCOZ3R81; R 51 is a hydrogen atom, -CO (CH 2) m COOR 16 or -PO (OR 15) 2, and R 12 and R 13 are each phosphono-protecting groups which can be removed by catalytic reduction; R14 is a carboxyl protecting group which can be removed by catalytic reduction; R71 is an alkyl group having 1 to 30 carbon atoms which may be substituted by one or more hydroxyl-protected hydroxyl-protecting groups; R81 is a cycloalkyl group having 3 to 12 carbon atoms which may be substituted by one or more hydroxyl-protected hydroxyl-protecting groups; Q 2 is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, -CONH 2, -COOR 16 or -CH 2 -O-R 91, wherein R 16 is a carboxyl protecting group which can be removed by catalytic reduction; R15 is a phosphono protecting group which can be removed by catalytic reduction; and R91 is a hydroxyl protecting group which can be removed by catalytic reduction; and Z, Z1, Z2, Z3, Q1f n1, n2, n3 and m are as defined above, catalytically reduced under a hydrogen gas atmosphere, in the presence of a catalyst, in an inert solvent. Process according to Claim 2, characterized in that R is ZOPO (OH) 2; and R1, R2, R3 Q Qx 4. I 5 and R 4 are each -COR 7 or -CO (CH 2) n 11 CH-N-COR 7. 106 8 8 5 0 8