IE880539L - Disaccharide derivatives - Google Patents

Disaccharide derivatives

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Publication number
IE880539L
IE880539L IE53988A IE53988A IE880539L IE 880539 L IE880539 L IE 880539L IE 53988 A IE53988 A IE 53988A IE 53988 A IE53988 A IE 53988A IE 880539 L IE880539 L IE 880539L
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Ireland
Prior art keywords
deoxy
compound
chloroform
group
phosphono
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IE53988A
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IE61418B1 (en
Inventor
Tsunehiko Soga
Tetsuo Shiba
Tsuneo Kusama
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Daiichi Seiyaku Co
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Priority to IE53988A priority Critical patent/IE61418B1/en
Publication of IE880539L publication Critical patent/IE880539L/en
Publication of IE61418B1 publication Critical patent/IE61418B1/en

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  • Saccharide Compounds (AREA)

Description

DISACCHARIDE DERIVATIVES FIELD OF THE INVENTION This invention relates to a novel disaccharide derivative and a salt thereof which exhibit, excellent antitumor activity and low toxicity / and is useful as an antitumor agent- BACKGROUND OF THE INVENTION Natural lipid A has mitogenic activity, i.e., an activity to stimulate lymphocytes to cause blast transformation,, which accelerates increase of lymphatic cells thereby to enhance immunity, an activity to derive a tumor necrosis factor,, and the like, and is# therefore, promising as treating and prophylactic agent.' for many diseases'caused by reduction of Immune function, such as various infectious diseases, or antitumor agents.
Known derivatives oi natural lipid A include those described in Japanese Patent Application (OPI) Nos. 48497/84, 53295/86, and 227586/86 (the term u,OPI8' as used herein means "unexamined published Japanese patent application.0" )- Among them* 2-deoxy-6-0-(2-deoxy-2~C(R)~3«dodeca~ noyloxytetradecanoylamino3-4-0-phosphono-3-0-[(R)-4-tetra-decanoyloxytetradecanoyl] -8 -D-giucopyranosyl)-3-0-C (R)-3-hydroxytetradecanoyl3-2-[(R)-3-hydroxytatradecanoylamino3-l-O-phosphono-a-D-glucopyranose disclosed in Japanese Patent Application (OPI) Wo. 53295/86 (hereinafter referred to as Compound A) is known to have physiological activities equal to or even higher than natural lipid A as reported in Eur- J, Biochem.. Vol. 148, 1-5 (1985). Compound A, however, is of low practical use due to high toxicity similar to natural lipid A.
Japanese Patent Application (OPI) 227586/86 (Chemical Abstracts, Vol. 106, 67627k, 1987) discloses disaccharid lipid A analogues of the formula: HOCHj 0 ^ $ Li H0 I 2 NHR wherein C0CH2CHR3(CH?) Me; R2 = C0CH2CHR4(CH2) Me; id, n = 8-12; R3, R = H, OH; R6, R7 = alkanoyl .
These analogues were shown to have tumor-necrosis factor inducing activity in mice.
In Infection and Immunity, 225-237, 1985, S. Kotani, et al, disclose a synthetic compound,^(1-6) D-glucosamine disaccharide l,4'-bisphosphate, 15 which is acvlated at the 2'-amino and 3'hydroxy1 groups with (R)-3-dodecanovloxytetradecanoyl and (R)-3~tetradecanoyloxvtetradecanoyl groups, respectively, and has (R)-3-hydroxvtetradecanoy1 groups at 2«amino and 3~hvdroxyl groups. This compound exhibited full endotoxic activities identical to or sometimes stronger than those of a reference lipid A from an 20 Escherichia choli Re-mutant.
In Infection and Immunity, 2636-2644, 1987, L. Brade, et al, investigated the immunogenicity and antigenicity of synthetic lipid A and partial structures thereof, among them those compounds which varied in the 25 position of phosphate (1-mono-, 4'-mono-, and l,4'~bisphosphate) and in the acylation (type, number and distribution of fatty acids).
It has been keenly demanded to develop compounds exhibiting useful physiological properties with reduced toxicity.
This invention relates to a compound represented by formula (I) 618 HO-CH2 (X) (HO)2P0 3 1 2 NHR3 61418 ^ z!Rs wherein R represents ZR^ or C i 9 wherein Z, Z~e, and z each represents an alKylene group having from 1 to 6 carbon atoms,, and R® represents a car- boxyl group or a phosphonoxy group ? 1 o 3 a 7 3 8 R 4 R", R , and R" each represents -COR , -COS R , Q Q, Q Q, | | II"* « -CO( CH2 ) nlCH-N-COR' , -CO( CH2) nlCH-N-COZ3R8 , ~CO(CH2 ) ^OCOR' , »CO(CH2)r2OCX)Z3R8, -CO(CH2)n2COR/, ~CO(CH ) ^9COZ3R8, Q, Q, J1 J1 -CO(CH2)n2CO(CH2)yi3NCOR/ or -CO(Cn2 ) n ,C0 (CH2) M 3NCOZ3R8, 7 wherein R' represents an alkyl group having from 1 to 30 y carbon atoms which may be substituted with one or more 3 hydroxyl groups, % represents an alkylene group having from 8 1 to 9 carbon atoms,, R represents a cycloalkyl group having from 3 to 12 carbon atoms which may be substituted with one or more hydroxyl groups,. Q represents a hydrogen atom,, an alkyX group having from 1 to 6 carbon atoms,, -CONH^-COOH or -CH2OH,„ Q7 represents a hydrogen atom or an alkyX group having from 1 to 20 carbon atoms 4 nl represents 0 or an integer of from 1 to 10 s and n2 and n3 each represents an integer of from 1 to 20; and represents a hydrogen atom, a phosphon.o group or -CO(GH2 )m COOHwherein zn represents 0 or an integer of from 1 to S; and salts thereof.
- I The compounds .represented by formula (I) and the salts thereof exhibit, excellent, antitumor activity and low toxicity and are useful as antitumor agents. 10 DETAILED DESCRIPTION OF THE INVENTION The term "alkylene group" as used herein means a methylene groupa polvmethylene group, or a methylene or polymethylene group substituted with an alkyl group "having from 1 to 6 -sarbon atoms. Specific examples of the alkvlene 15 group are methylene, ethylene, propylene* trimethvlene, ethylethylene, tetramethylene, 2-methyltetramethylene, 2S,3~ diraethyltetr&methylene, 2 - e thy 1- 3 -me thy Ip-en. tame thy I eoe and octaraethylene groupsetc. In formula £ I) * the alkylene 3 group as represented by Z, Z , Z or % preferably contains 20 from 1 to 4 carbon atoms.
The term "alkyl group" as used herein means a straight or branched chain alkyl group and includes,, for example. methyl „ ethyl, propyl,, t~butyl hexyl t, nonyl s decyl,, 3-ethylundecyl, 2-ethyl~4-methyltridecyl(, tetradecvl, 25 nonadecyl3 tetraeicosyl, 2~efchyl-5~propyltetraeicosyl„ and octaeicosyl groups. The alkyl group as represented by R preferably contains from 5 to 20 carbon atoms.
The term "cycloalkyl group" as used herein include, for example, .cyclopropyl, cyclobutyl, cycloheptyl, cyclo-5 hexylj, cycloheptyl f cyclodecyl£, and cyclododecyl groups, and preferably those having from 5 to 8 carbon atoms.
In formula (I)» nl preferably represents 0 or an integer of from 1 to 5 e and n2 and n3 each preferably represents an integer of from 1 to 6.
The compound of formula (I) include ex- and 6-iso mers due to the substltuent OR. both of which and a mixture of Which fall within the scope of the present invention« Further,, the compounds of formula (I) embrace optical isomers and such optical isomers 15 and mixtures thereof also fall within the scope of the present invention.
The salts of the compounds of formula (I) include salts formed between the phosphono group or carboxyl group thereof and organic amines, e.g., triethylaraine, pyridine„ N-methylamine, N-methylglucamine, etc., or inorganic bases,. hydroxide e.g., ammonia, sodium, potassium, calcium, magnesium^ etc* Of the compounds of formula (l)f preferred are those wherein R represents ZR^ or CH ; R1, R^, , and R^ VSSV>nZ2R6 _ 5 _ Q Qi each represents -COR7, -COZ,3R8/ -CO(CH2)^xCH-N-COR7. Q Q, II -~CO(ch9)nlCH-N"COS3R8, -co(ch2)n2 COR7 or -CO(CH2)n2COZ3R8„ More preferred are those wherein R represents ZOPO(OH) and R~,, R24J R3,, and R4 each represents -COR7 or Q Q.
I I 7 -CO(CH0 )nl ch-n-cor' .
Further preferred compounds are those, wherein R represents 6 fi ZR wherein Z represents a methylene or an ethylene group and R represents a carboxyl group or a phosphonoxv grouD. 13 7 7 R and R each represents -COR wherein R represents an a'lkvl group having from 1 to 30 carbon atoms, 2 4 0 0 R and R each represent f VI 7 -C0(CH2)nlCH - N - COR wherein n-j represents O(zero),, Q and each represent a hydrogen atom and R'' represents an alkyl group having from 1 to 30 carbon atoms or -COR^ wherein R^ represents an alkyl group having from 1 to 30 carbon atomss and R represents a hydrogen atom- The compounds according to the present invention can be prepared through various reaction routes. One example ot the processes is illustrated below.
(I) 31 NHR (II) g wherein R represents a hydrogen atom or a hydroxyl-protec-tive group (i.e., a protective group for the hydroxyl group) which can be removed by catalytic reduction or the like; R*® represents ZCOOR14, ZOPOfOR13) , -CH - 6 ,Z1COOR14 'Z2COOR14 1 13 .1 OPO( OR )2 ~CH y R11, R?1, and R31 each repre- ^VSv'g2OPO(ORi3)2 ,71 _3„8l Q0 Q, i. i: 7i sents -COR "COS R , -CO (CH2)CH-NCOR Q« Q, (I 1 1 -CO(CH2)^3 CH-NCOZ3R81, -CO(CH2)n2OCOR71, ~CO(CH9)n2OCOZ3R81» -CO(CH2)n2COR/A, -CO(CH2)n2 COZ3R8X, Q, Q, |1 I i -CO(CH2)n2CO(CH9 )n3NCOR'1 or ~CO(CH2)n2CO(CH?)n3NCOZ3R81; 31 1 § R represents a hydrogen atom,, -CO(CEL ) COOR~ or ■j5 12 13 ?0(0IT )7, wherein R and R each represents a phosp'nono- protective group which can be removed by catalytic reduction j represents a carboxyl-protective group which - can ba removed by catalytic reduction? R represents an alkyl group having from. 1 to 30 carbon a-corns which may be substituted with one or more hydroxyl groups protected with a hydroxy1-protective group; R8* represents a cycloalkyl group having from 3 to 12 carbon atoms which may be substituted with one or snore hydroxyl groups protected with a hydroxyl-protective group;? Q2 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms,. -COMB^ ,■ -COOR"*"3 or 91 -j 6 -CH^-O-R , wherein R represents a carboxyl-protective group which can be removed by catalytic reduction; R" represents a phosphono-protective group which can be removed by catalytic reduction? and R^l represents a hydroxyl-protective group which can be removed by catalytic reduction; 12 3 and Z, Z", % , Z x Q,, nl, n2, n3, and m are as defined above- 'The carboxyl-protective group which can be removed by catalytic reduction includes a bensyl group, etc«which may be substituted with a halogen atom* a nitro group,, a lower alkoxy group,, etc« The phosphono-protective group which can be removed by catalytic reduction includes a 10 phenyl group, a benzyl group, etc..., each of which may be substituted with a halogen atom,, a nitro group,, a lover alkoxy group, etc. The hydroxyl-protective group includes those removable by catalytic reduction, such as a benzyl group* etc., which may be substituted with a halogen atom, a 15 nitro group,, a lower alkoxy group, etc., a trichloroethoxy-carbonyl groupt a trichloro-t-butoxycarbonyl group, etc- According to the above-described process „ the compound of formula (II) is catalvtically reduced in an inert solvent, e.g., tetrahydrofuran» methanolethanol, acetic 20 acid,, water, a mixture of these solvents,, etc™* in a hydrogen gas atmosphere in the presence of a catalyst? such as palladium black# palladium-on-carbon, platinum dioxide, etc., to thereby remove the protective groups. If desired,, the product may be purified by silica gel chromatography or 25 the like technique. The reduction reaction can usually be carried out. at a temperature of from room temperature (0 to 30eC) to 60°C for a period of from .1 to 12 hours. The amounts of the solvent and catalyst to be used are not particularly limited- In cases of using the compound of formula (II) wherein or R31 contains therein a hydroacyl-protec- tive group,, such a protective group is preferably the one removable by catalytic reduction.
The salt of the compound of formula (I) can be obtained by adding a necessary amount of a base to the com pound ,• followed by sedimentation, freese-drying or the like means.
The process for preparing the starting compound represented by formula (II) can be selected appropriately i 0 51 depending on the kind of the substituents R~ ' and R ~ as illustrated below.
(Ill) Y (IIA) (IIB) (V) Hr OR21 VvOR18 (R12O)2PO NHCOOCH?CC£.3 (V*) (c) I 1 K NHR (r12o) 2po ,,20 R O v OR KOR \L_y 19 1 31 NHR HHR' 11 (1ic) 13 op (or )2 (r12o)2po nhr nhr (iid) - 11 18 14 13 % wherein R represents an allyl group,, ZCOOR • , £OPO(OR ) 2.
'Z1COOR14 / IT OPOR13 / 17 CH or CH ; R represents a hydroxyl- ^SvZ2COOR14 " ^^^OPOR13 41 71 3 pi protective group? R represents -COR "% -COS R *% Q, Qn Q1 1 I 71 , , I I* 3 81 -CO (CH..) , CH-NCOR' , ~CO(CH„) CH-NCOZ R » jl nJL 2 nl n *3 *5 81 *71 ■ 5 -CO(CH2)r2 OCOR , ~CO(CH2)n2OCOS R , ~CO(CH2)n2COR , I1 - —CO(CH ) -COZ3R81«, —CO(CHn) _ CO(CH„ ) ^ NCOR71 or J 2 Xi2 2 n3 Q, I ~ ' 1 hi ho 14.
-CO(CH0^9 CO(CEL,)n3 NCOZ R ; R" represents ZCOOR"" " , ^/Z^-COOR14 ^/Z1OPO(OR13)2 ZOPO(OR13)2, CH or CH ; R20 Ns'SsZ2COOR14 VSVnsZ2opo(OR13)2 represents -COtCB^) COOR16 or PO(OR15)2? R92 represents a 10 byfirosryl-protectiva group removable by catalytic reduction; and R11, R21, R31, R12, R13, R14, R15, R16, R/X, R81, Z, Z1, 2 3 Z , Z t nl, Qj, Qj, n2, n3, and m are as defined above.
More specifically® the compound of formula (IV) is dissolved in an inert solvent ( 2.. g - ,, methylene chloride, 15 acetic acidt» etc., either alone or combinations thereof) containing hydrogen bromide gas and allowed to react at 0°C to room temperature for several tens minutes to about 24 hours to thereby substitute the acetyl group at the 1-posi- tion of the sugar moiety by a bromine atom. The resulting bromo-substituted compound is dissolved in a dried solvents preferably,, methylene chloride,, chloroform., etc®* and then condensed with- the compound of formula (III) in the presence of either one or more of 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 of from room temperature to the reflux temperature for a period of several hours to 2 days,, thereby to obtain the compound of formula (v).
The resulting compound was then reacted with a com-20 pound of formula X-R , wherein X represents a halogen atom,, in an organic solvent, e.g., methylene chloride, chloroform, acetonitrile, tetrahydrofuran, etc., in the presence of an organic base,, e.g., pyridine, 4-dimethylaminopyridine, tri-ethylamine, etc., or reacted with a compound of formula HO-R and a catalyst such as dieyclohsxylcarbodiimide in the presence of 4-diiaethyIaminopyridine to obtain the compound of formula (v°)- The compounds represented by formula (IIA) to (aid), i.e., the starting compounds of formula (II) „ can then a synthesized from the thus obtained compounds of formula (v) and (V5 ) through the following reaction routes (A) to (D) » Reaction Route (&)i A compound of formula (V) wherein R~® or is dissolved or suspended in. acetic acid, and a sine powder is added thereto to effect reaction thereby removing the amino- protectiv® group at the 2"-position and R1'. The resulting compound freed"from the protective group is then condensed 31 with the compound of formula R -OH according to a process commonly employed in peptide synthesis to prepare the compound of formula (IIA).
The removal of the protective group is usually performed at room temperature for several tens minutes to 24 hours. The condensation reaction can be effected by a carbodiimide method, the Eintopf method, an active ester method, and the liXe.
Ib. the above-described reaction for removal of protective groups, a trichloroethoxycarbonyl group or a tri- "8 7 chloro-t-butoxycarbonyl group is preferred as R , i.e., a protective group for a hydroxyl group - When R^~ has a hydroxyl-protective group in the molecule thereof, the same groups are preferred as the hydroxyl-protective group. Reaction Route (B)s 18 A compound of formula (V) wherein R is an allyl group is treated in the same manner as in Reaction Route (h) 17 31 to remove R and then to bond R to the 28 -positioned amino group. After protecting the 6'-positioned hydroxyl group with a protective group removable by catalytic reduction, the compound is reacted with an iridium complex, e»g»c, 1,5-cyclooctadienebi s (methyldiphenylphosphine) -iridium hexa- fluorophosphateetc.,,, followed by hydrolysis to remove the allyl group. The resulting compound is then reacted with 0 « 13 ClP(OR )„? to obtain the compound of formula (IIB).
Protection of the 6"-positioned hydroxy1 group can be carried outs, for example, by reacting with benzyloxymeth-yl 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.# at room temperature for 1 to 2 days. The protection may also be effected by using bensyl trxchloroacetimidate in the presence of trifluoromethanesulfonic acid at around 0*C.
Removal of the allyl group is usually carried out by • reacting with the above-described iridium complex in an organic solvent,, e.g., methylene chloride, chloroform,, tetrahvdrofuran, etc.* at about 50aC for a period of from 10 minutes to 3 hours and then adding water and iodine to the reaction mixture to effect hydrolysis at room temperature for about 5 to 30 minutes.
The reaction between the allyl-free compound and 0 II 13 9" ClP(OR ) is usually conducted in an anhydrous aprotxc solvent , e.g., anhydrous tetrahydrofuran,, in the presence of butyl lithium at a temperature of from -70°C to 50°C for several tens minutes.
Reaction Route (C) : The compound of formula- (IXC) can be prepared by subjecting a compound of formula (V°) to the same reactions of Reaction Routs (A).
Reaction Route (P)s The compound of formula (IID) can be prepared by subjecting the compound of formula (¥' ) to the same reactions of Reaction Route (B)» The compound of formula (IV) used as starting mate-10 rial in the above-illustrated process can be synthesized according to known processes or the process disclosed in Japanese patent Application (OPI) No- 53295/86.
The compound of formula (IIX)» the other starting material in the process, can be prepared by Reaction Route (a) or (b) shown below, selected according to the kind of 1 g the substituent R~ .
Reaction Route (a) ho (CH3)2C, /°~j—o OW" OH OW ho NHR 11 (IX) (xiii) NHY v Sf (IX) 1 (XIII) (CH3)2CH (ch,)_ch J 2 (xiv) MHY~ \ O. / (ch-j.ch ) 0 o 21 \ *>2 OR W OR*" HHR" 11 (xi) HO- / (CH-)0CH \> 21 V-°w (XVb) OW (XVa) NHY NHR* 1 i ho- O OR21 -OR22 HO HHR 11 NHR (rila) (Ilia') wherein X represents a halogen atom- Y represents a lower acyl group,, a trichloroethoxycarbonvl group or a. trichloro- 2 2 t~butoxycarbonyl group; W represents ZOW * ZCOOW , Z1OW2 % 1COOM3 :h ^Z^OOM3 i 4 13 or CH ; W" represents SOW , ZCOOR~ , 'Z2OW2 ,1™«„13 .zW ✓S"COOR" CH or CH •? R22 represents ZOPO(OR13)9, 'Z2OW4 VNSs'22C00R13 ^^Z1 COOR14 Z^'OPO (OR13) ? ZCOOR14, CH or CH y W° represents 9 14 9 11 *Z~COOR ^Z"OPO(OR )2 .Z^OH SOH or CH ? vP represents ZOPO(ORi3) or 220H ^OPOtOR13), CH j Y1 represents a triehloroethoxycarbonyl Z2OPO(OR13)2 2 group or a trxchloro-t-butoxycarbonyl group; W represents 10 an acetyl group,, a benzoyl group,, a bensyl group or a p-chlorotoensyl group; W represents an alkyl group having from 1 to 5 carbon atoms or a carboxyl-protecfcive group removable A. by catalytic reduce ion.; W" represents a hydrogen atom,, a 11 71 13 bensyl group or a p-chlorobenzyl group; and R "", R" , R" , 14 1 2 R , Z, Z s and Z are as defined above.
The compound of formula (VII) can'be prepared by reacting a compound of formula* (Via) with a compound of formula WOH in the presence of a Lewis acid or condensing a compound of formula (VIb) with the compound MOB in the 5 presence of mercury (IX) cyanideL, silver carbonate,, mercury bromidesilver perchlorate or mercury (II) nitrate,, or a mixture thereof,, The compound of formula (VII) wherein W is a EO-aeetyl group can be obtained by reacting a compound of formula (vie) with a compound of formula HOEOH in the 10 presence of hydrogen chloride,, p-toluenesulfonic acid, etc -, followed by acetylation.
The compound of formula (VII) wherein Y is a lower acyl group is treated with a Meerwein reagent# or the compound of formula (VII) wherein Y is a txichloroethoxvcarbon-15 yl or trichloro-t-butoxycarbonyl group is treated with a sine powder in the presence of hydrochloric acid# acetic acid# etc., to thereby remove the protective group for the 2~ positioned amino group- The resulting compound is then 11 condensed with a compound of formula R""~OH according to an 20 acid chloride method# a carbodiimide method# the Eintopf method or an active ester method to prepare the compound of formula (VIII).
The compound of formula (VIII) wherein W is 5ZC00- ,S1COO»alkyl alkyl or CH is hydrolysed with sodium hydrox- ^^S^COO-alkyl ides, etc. to" resaove the acyl and alkyl groups, and the resulting compound is reacted with a compound of formula X~ lA R xn the presence of an organic amine, e.g., triethyl-5 amine,, to prepare the compound of formula (IX). The compound of formula (VIII) wherein W has other meaning is hydrolysed with aqueous ammonia,, etc., to obtain the compound of formula (IX).
The hydroxy1 groups at the 4- and S-positions of the 10 compound of formula (IX) are protected using isopropylidene to obtain the compound of formula (X).
The compound of formula (X) wherein W™ is a z-O-bensyi or ZO-p~chlorobenzyl group is condensed with a com-pound of formula and then the resulting compound is catalytically reduced to the compound wherein W*" is ZOH-The resulting compound is reacted with a compound of formula 1 3 X~PO(OR~ )^ in the presence of an organic amine, e.g., tri-ethylamine, 4-dimethylaminopyridine, pyridine,, etc. to prepare the compound of formula (XI).
The compound of formula (X) wherein W1 is SCOOR1^ or ZXCOOR14 CH is condensed with the compound of formula >Z2C00R14 t' 21 R -OH to prepare the compound of formula (XI).
The compound of formula (Ilia) can toe obtained by hydrolyzing the thus prepared compound of formula (XI) in water-containing acetic acid,, s-g- ,■ a 50 to 90% by weight 5 aqueous solution of acetic acid,, or treating the compound with p~toluenesul£onic acid in methanol, ethanol, water or a mixture thereof- 22 The compound of formula (11 la) wherein R is .z1opo(or13)2 i 3 / SOPO(OR"" )9 or CH i.sv the compound of 212OPO (OR1312 formula (IIla") can b® prepared as follows™ The compound of formula C'VII) wherein W is EO-acet- 1 "ft 0-acefcyl Z~0-benzoyl yl, ZO-benzoyl, CH or CH , and Y ^Z^O-acetyl '^^^^^Z^O-bensoyl is a. trichloroethoxycarbonyl or trichloro-t-butoxycarbonyl group is treated with aqueous ammonia to obtain the compound 15 of formula (XII), which is then protected with isopropyli-dene to obtain the compound of formula (XIII)- The resulting compound is condensed with the compound of formula n 21 XPO(OR""") and then with the compound of formula R "OH to prepare the compound of formula (XIV)- The isopropylidene 20 is removed from the resulting compound in the same manner as described above to prepare the compound of formula (XVa).
Y1 of the compound of formula (XVa) is removed in the same manner as described above,, and" the resulting compound, is then condensed with the compound of formula R~~OH to obtain the compound of formula (Ilia")- The compound of formula (XVb) can be prepared by removing Y1 from the compound of formula (XIV) in the same manner as described above and then condensing the resulting compound with the compound of for- ■ l"3 mula R "OH, The isopropylidene is then removed therefrom in the same manner as described above to prepare the compound of formula (Ilia'). 11 01 The compound of formula (Ilia' ) wherein R and R "~ are the same can also be obtained by removing from the compound of formula (XIII) and condensing the resulting compound with a fatty acid,,, followed by removing the isopropylidene -Reaction Route (b)s NHY (XVI) (XVII) / /°~7-0 (CH ) CH / x x OR21 K 0-allyl NHR11 (XVIII) (Illb) wherein. Y'^"* R21* and. R""' exe as defined above™ The compound of formula (XVI) is condensed with the 21 compound of formula R OH to prepare the compound of formula 5 (XVII) „ After is removed in the same manner as de scribed above., the compound is condensed with the compound 11 of formula R "OH to obtain the compound of formula (2CVIII) » The isopropylidene is then removed from the compound of formula (XVIJX) in the same manner as described above to 10 obtain the compound or formula (Illb).
The compounds according to the present invention exhibit antitumor activity equal to or even higher than that - of Compound A and have remarkably lower toxicity as compared with Compound A- Therefore, the compounds of the invention 15 are superior as antitumor agents.
The invention also relates to pharmaceutical compositions comprising at least one compound of the invention,, optionally together with conventional pharmaceutically acceptable carriers and/or adjuvants.
The present invention is now illustrated in greater o detail with reference to Reference Examples, Examples., and Test Examples, but it should be understood that the present invention is not construed to be limited thereto. ±n these examples,, all the percents are by weight unless otherwise indicated» REFERENCE EXAMPLE 1 1) preparation of 2-acetoxyethvl 3 £,41?6-tri~0~acetyl~2- deoxy-2- (2 22 2™tricliloroethoxycarbonylamino) -a -D-gluco-pvranoside To 5 - 00 g of 2-deoxy-2- {2/2,2-trichloroethoxycar-bonylamino)-D-glucose was added 5-0 ml of ethylene glycol and 0-5 nil of dioxane containing hydrogen chloride gas,, and the mixture was stirred for 4 hours under heating 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 20 minutes' stirring,, the reaction mixture was warmed to room temperature,, and the stirring was continued for an additional 16 hours- The reaction mixture was poured into 350 ml of ice-water and stirred- The precipitated solid Mas collected by filtration and washed with water - The resulting solid was dissolved in chloroform, washed successively with IN hydrochloric acid and a saturated sodium chloride aqueous solution,. and dried over anhydrous sodium sulfate- The solvent was removed by distillation under reduced pressure, and the residue was recrystallised from ethanol to obtain 4.96 g of the entitled compound as a colorless prism.
Melting Point: 138 - 140°C Lalrf* • +74-0° (c=1.2„ chloroform) 2) Preparation of 2-acetoxyethyl 3t,4*6-tri-o-aeetyl-2-deo3£y~2"-tetradecanoylamino-a~D~glucopyranoside In 60 ml of acetic acid was dissolved 4.96 g of the compound obtained in 1) above, and 7 g of a sine powder was 5 added thereto in small portions at room temperature while stirring. The stirring was continued for 1 hour, and any 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 10 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 sal of anhydrous methylene chloride,, and 2-88 ml of if-rsethylmo r-pholine a.nd 3.24 g of tetradeeanoyl chloride were added to the solution under ice-cooling„ followed by stirring for 1 hour,. To the reaction mixture was added 10 ml of methanol. 20 After stirring at room temperature for 10 minutes, the reaction mixture was diluted with chloroform,, washed successively with IN hydrochloric acid and a saturated sodium chloride aqueous solution* and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,, and 25 the residue was purified by silica gel column chromatography using, as eluent, a mixture of bensene and ethyl acetate at a ratio of 9/1 (v/v) and than l/l (v/v) to obtain 4.77 g. of the entitled compound as a colorless oily product- 3) Preparation of 2-hydroxyethyl 2-deoxy-2-tetradacanoyl-ami no-ct-D-g lueopyr anos ide In 80 ml of absolute methanol was dissovled 4.77 g of the compound obtained in 2) above, and a methanol solution containing 9 ramol of sodium methyl a, te was added to the solution under ice-cooling, followed by stirring at room temperature for 30 minutes. Tetrahydrofuran was added 10 thereto to dissolve the precipitate, the solution was neutralized with a strongly acidic ion exchange resin, Dows3c-50 (rf type), and the resin was filtered off. The solvent was removed from the filtrate toy distillation under reduced pressure- The residue was washed with diethyl 15 ether, followed by filtration to give 3.02 g of the entitled compound as a white solid. Recrystallization from ethanol-water gave a purified product having a melting point of 158 to 1S0°C. •p C s +8.21" l]c=0.8tetrahydrofuran:water = 4:1 (v/v)] 4) Preparation of 2-hydroxyethyl 2~deoxy~4,6~0-isopropyl~ idene-2-tetradecanoylaxnino-<x-D-glucopyranoside In 20 ml of dimethylfomamide was dissolved 0.87 g of the compound obtained in 3) aboveand 0-52 g of 22-dimethoxypropane and 38 mg of p-toluenesulfonic acid mono-hydrate were added to the solution at room temperaturee - 27 ~ followed by stirring for 1-5 hours- After neutralising with a 51 aqueous solution of sodium hydrogencarbonate „ the solvent was removed by distillation under reduced pressure, The residue was dissolved in ethyl acetate ti washed succas-5 sively with water and a saturated sodium chloride aqueous 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 aasing,, as eluent, a 19/1 (v/v) mixture of chloroform 10 and acetone and then a 19/1 (v/v) mixture of chloroform and methanol to obtain, 0.78 g of the entitled compound as a colorless and viscous oily product.
) Preporation of 2-(dip<henylphospbonoxy)ethyl 2-deoxy-4,6-O-isopropylidene-2-tetradecanoylamino-ci-glucopyranoside la : 15 ml of anhydrous methylene chloride was dis-15 solved 0,77 g of the compound obtained in 4) above„ and to the solution were added 0 ..48 g of diphenyl phosphorochlorid-ate^ 0-19 mil of pyridine,? and 0.30 g of dimethylaminopyrid-i:o.a under ice-cooling- After stirring for 1 hour,- the temperature of the fixture was returned to room temperature,, 20 and the stirring was continued for an additional one hour. To the reaction mixture, 0.17 g of diphenyl phosphorochlo-ridate was added thereto,, followed by stirring for 30 minutes . To the reaction mixture was added 3 ml of methanol. After stirring for a while, the solvent was removed by 25 distillation under reduced pressure. The residue was puri- fied by silica gal column chromatography using a 19/l (v/v) mixture of chloroform and acetone as an eluent to obtain 0.81 g of the entitled compound as a colorless viscous oil™ 6) Preparation of 2-(diphenylphosphonoxy)ethyX 2~-<Sso^y~3-0-(N-dodecanoylglycyl)-2-tetradecanoylamino~ci-D-gluco~ pyranoside In 5 ml of anhydrous methylene chloride was dissolved 0*51 g of the compound obtained in 5) above,, and 0-22 g of N-dodecanoylglycine, 44 mg of diraethylaminopyrd-ine, and 0-18 g of dicyclohexylcarbadiimide were added to the solution under ice-cooling- The mixture was stirred for 30 minutes under ice-cooling and then at room temperature for 2 hours- The insoluble .matter was removed by filtration,, and the filtrate was washed successively with IN hydrochloric acid,, water, and a saturated sodium chloride aqueous so.Vat.ion,, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure,, and to the residue %?as added 20 ml of a 90% acetic acid aqueous solution,, followed by stirring for 30 minutes while heating at 90®C» The solvent was distilled off,, and toluene was added to the residue,, followed by distillation to remove the solvent- Addition of toluene and subsequent distillation were repeated once more- The residue was purified by silica gel column chromatography using., as eluent,, a 19si (v/v) mixture of chloroform and acetona and then a 19si (v/v) mixture of chloroform and methanol to obtain 0.51 g of 'the entitled compound as a colorless oily product™ [ofi s +46.2® {o,~I »le chloroform) -D MMR -(CDCl^) t 6(ppm) s 0,88 (6H, r.) , 1*26 (s), 2.07 (2H, t) , ; " 2-27 (2H» t) , 4-84 (1H, d) , 5.3,8 (1H, m), 7.2-7.4 J10H, m) reference example 2 1} Preparation of 2-hydrozyethyl 2-deoacy-2-(2,2i,2-tri~ cbloroethoxycarbonylamino)-a-D-glucopvranoside In S ml of a 28% aqueous ammonia and 120 ml of methanol was suspended 5-05 g of the compound prepared in Reference Example 1-1), and the suspension was stirred at room temperature for 8 hours- The reaction mixture was concentrated under reduced pressure to obtain 3-50 g of the entitled compound as a caramel-like -substance.
NMR (CDC13-CD30D, ca. 1 = 1), $(ppm)= 4-78 (2H, s) , 4.90 (1H, d) 2) Preparation of 2-hydroxyethyl~2-deoxy-4(,6-0-isopropyl-idene-2-(2 , 2,2-tr ichloroethoxycarbonylamino) -ci -D-glucopyranoside The compound (3-58 g) obtained in 1) above was treated in the same manner as in Reference Example 1-4)- To the resulting fraction was added n-hexane, and the precipitated formed was collected by filtration to yield 2.78 g of the entitled compound as a white powder.
Melting Points 190 - 192°C 3) Preparation of 2-(diphenvlphosphonoxy)ethyl 2-deoxy-4,6~ 0~isopropylidene--2-( 2 „ 2,2-trichloroethoxycarbonylamino)-ce-D-g 1 ucopyr ano s ide The compound (3.„12 g) obtained in 2) above was treated in the same manner as in Reference Example 1-5), and to the resulting fraction were added diethyl ether and n-hexane. The precipitate formed was collected by filtration to obtain 1.23 g of the entitled compound-Melting Points 121 - 124"C EcG^S. +46.4e (c—1 ^ 0 ^ chloroform) 4) Preparation of 2- (diphenylphosphonoxy)ethyl 2-deoxy~4,6- G-isopropylidene-3-o-tetradecanoyl-2- (2,, 2 ^.-x-rLchlo-zo-ethoxycarbonylamino)-a'-D~glucopyranos±de In 10 ml of anhydrous methylene chloride was dissolved 0.50 g of the compound obtained in 3) above,, and 0.30 ail of pyridine, 0»22 g of tetradecanoyl chloride, and 20 gal of dimethyl aiuinopyridine were added to the solution,, followed by stirring for 2 hours- To the reaction fixture was added 2 ml of methanol- After stirring at room temperature for a while, 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 eluent to give 0»49 g of the entiled compound as a colorless oily substance™ [a]^5 x +36-1° (c=l-0, chloroform) ) Preparation of 2- (diphenylphosphonoxv) ethyl 2-deoxy-2-(£?-dodecanoylglycyl amino j-4S-0™isopropyXidene-3 -O-tetradeeanoyl-a-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 a sine powder was suspended therein,, followed by stirring at room tempera-5 ture for about 1«5 hours- Any 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% sodium Iiydrogen carbonate aqueous soiu-.10 tione and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate- The solvent was distilled off, and the residual oily substance' was dissolved in 8 ml of anhydrous methylene chloride- To the solution was added 0-21 g of N-dodecanoylglycijje- To the mixture were 15 added 0.17 g of dicyclohexylcarbodiimide and 32 mg of dime-thylaminopyridine under ice-cooling. 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. Any insoluble matter • wars removed by filtration, 20 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 to 10% acetone as eluent- The desired fraction was treated with n-hexane to obtain 0.48 g of the entitled compound as a white powder.
Melting points 79 - 80°C [cOp5s +28.1° (c=i « 1, chloroform) 6) Preparation of 2-(diphenvlphosphonoxy)ethyl 2~deoxv-2~ (&l-dodecanoylg lycylamino) -3 ~0-tetradecanoyl~ a~D~g luco-pyranoside In 20 ml of a 90% acetic acid aqueous solution was dissolved 0-45 g of the compound prepared in 5) above,- and the solution was stirred for 30 minutes while heating at 90SC» The solvent was removed by distillation under reduced pressure, and toluene was added to the residue, followed by distillation under reduced pressure. Addition of toluene and the subsequent distillation were repeated,, and the finally obtained residue was purified by silica gel column chromatography using, as eluent, chloroform containing 5 to 10% acetone and then a 19si (v/v) mixture of chloroform and methanol to obtain 0.39 g of the entitled compound as a white waxy solid- C a3q5 = +36-I® (c-1«1 chloroform) NMR (CDC13), 5(ppm): 0.90 (6H, t), 1.28 (s)„ 2.13 (2H, m), 2.36 (2H, t) , 4.90 (IE,, d) , 7.2-7-5 (10Hi? m) REFERENCE EXAMPLE 3 1) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-3-0-cM-dodecanoylglycyl)-4 f 6-O-isopropylidene-2~(2 f 2 ^2-tri-chloroethoxycarbonylamino)-a~D*-gIucopyranoside In 20 ml of anhydrous methylene chloride was dis- solved 1.89 g of the compound obtained in Reference example 2-3), and 0-83 g of H-dodecanoylglycine* 0.17 g of dimethyl- aminopyridine, and 0.57 g of dicyclohexylcarbodiimide were added thereto tender ice-cooling- After 30 minutesthe mixture was allowed to warm to room temperature and stirred for 1 "hour at that, temperature. Any insoluble matter was removed by filtration.,, and the filtrate vas concentrated under reduced pressure- The residue was purified by silica gel column chromatography using a 10si Cv/v) mixture of chloroform and acetone as eluent to obtain 2-80 g of the entitled compound as a colorless oily substance. : +3 2 • 2e (c-0.8, chloroform) 2) Preparation of 2 -(diphenylphosphonoxy)ethyl 2-deoxy~3-0-CN-dodecanoylglycyl}-2-C6-(octanoylaaiino5hexanoylamino3-a-D-glucopyranoside In 10 ml of acetic acid was dissolved 0.71 g of the 15 compound obtained in 1) above, and 0-5 g of .a sine powder was added thereto at room temperature while 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 20 chloroform,, washed successively with a 5% sodium hydrogen-carbonate aqueous solution and a saturated sodium chloride aqueous solution,, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain an oily product.
Separately, 0.26 g of S-(octanoylamino)caproic acid was dissolved in 7 ml of anhydrous tetrahydrofuran„ and 0«16 g of 1-hydroxybenSotriasole and 0.21 g of dicycloheasyl-earbodi imide were added to the solution under ice-cooling. The liquid temperature was gradually returned to room temperature,, and the mixture was stirred for 3 hours- The precipitated insoluble matter was removed by filtration. The filtrate was combined with the above-prepared oily product under ice-cooling, followed by warming up to room temperature, at which the mixture was stirred for 4 hours-The solvent was distilled off, and to the residue was added 20 ml of a 90% acetic acid aqueous solution. The mixture was stirred for 20 minutes under heating at 90°C- The solvent was distilled off,, and the residue was purified by silica gel column chromatography using successive eluents of a 10si (v/v) mixture of chloroform and acetone,, a 20 = 1 (v/v) mixture of chloroform and methanol, and a 10si (v/v) mixture of chloroform and methanol to thereby obtain 0-56 g of the entitled compound as a colorless waxy substance. [a]^5s -1-31 »2° (c-1.1, chloroform) m-iR (CDC1 ) „ 6(ppm) s 0.88 (5H, t) 2.0-2.4 (SH„ ffl) , 3. 4.85 (1H, d), 7.2-7.4 (10H, m) REFERENCE EXAMPLE 4 Preparation of 2™(diphenylphosphonoxv)ethyl 2-deoxy-3-0-(N-dodecanoyl-N-iaethylglycyl) -2-[ (M-dodecanoyl-M~methyl-glycyl)amino]-a-D~glucopyranoside In 10 ml of acetic acid was dissolved 1-00 g of the compound obtained in Reference Et,ample 2-3),. and 0„5 g of a 5 sine powder was added t.o thereto at room temperature while stirring. The stirring was continued for an additional 2*5 hours, and the insoluble matter was removed by filtration-The filtrate was washed with chloroform* and the solvent was removed by distillation under reduced pressure. The residue 10 was dissolved in chloroform* washed successively with a 5% aqueous solution of sodium hydrogencar'taonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure* and the residual oily sub-15 stance and 1.21 g of N~dodecanovl~N-methylglycine were dissolved in 10 ml of anhydrous methylene chloride. To the solution were added 90 mg of dimthylaminopyridine and 0.92 g of dicyclohexylcarbodiimide under ice-cooling.. After warming to room temperature* the mixture was stirred for 3 20 hours- The precipitated insoluble matter was removed toy filtration* and the filtrate was concentrated under reduced pressure. The residual oily substance was purified by silica gel column chromatography successively using a 9 si (v/v) mixture of chloroform and acetone and a 19 si (v/v) mixture of. chloroform and methanol as eluent' to obtain an oily substance™ The resulting oily substance was dissolved ia 40 ml of a 90% acetic acid aqueous solution,, followed toy stirring for 30 minutes under heating at 90"C The solvent was removed by distillation under reduced pressure, and the residua was purified toy silica gel column chromatography using, as eluent, a mixture of chloroform and methanol at a ratio of 50si (v/v) a^d then 20si (v/v) to obtain 0.8? g of the entitled compound as an oily product. [a s +34- 9 ° C c—1.0, chloroform) NMR fCDCi^K 6(ppm): 0-89 (6H, t), 1.28 (s) , 2-35 (4H„ m), 2.84 and 3»00 (total 3H,- each s),, 3-13 and 3.15 (total 3H, each s), 4.45 (2H, ®), 4.87 (1H, d), 7.2-7.4 (10H, m) REFERENCE EXftMPLE 5 1) preparation of 2-( diphenylphosphonoxy)ethyl 2-deoxy-3~0~ t.etradecanoyl-2- (2,2 -trichloroethoxycarbonylamino) -a™ D-glucopyranoside In 15 ml of anhydrous methylene chloride were dissolved 0.50 g of the compound obtained in Reference Example 2-3) and 0-22 g of tetradecanoic acid, and 0-12 g of dimeth-ylarainopyridine and 0 *20 g of dicyclohexylcarbodiimide were added to the solution under ice-cooling. The mixture was warmed to room temperature and stirred for 2 hours. The precipitated insoluble matter was removed by filtration t, and the filtrate was concentrated under reduced pressure- The residual oily substance was subjected to silica gel column chromatography using a 10si (v/v) mixture of chloroform and acetone as eluent to obtain an oily substance. The resulting oily substance was dissolved in 10 ml of a 90% acetic acid aqueous solution,, followed by stirring 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,, as eluent* .a 10si (v/v) mixture of chloroform and acetone and then a 10si (v/v) mixture of chloroform and methanol to obtain 0.61 g of an oily product.
Ca3^5: +43.0® (c=l-2, chloroform) D 2) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-2~ C (Kh-dodecanoyl-D-isoglutamnyl) amino]-3-0-fcetradecanoyl- et-D-g lu copyr anos ide The compound (0.47 g) obtained in 1) above was treated with a zinc po^sder in an acetic acid solution and then reacted with N-cLodecanoyl-D-isoglutamine in the same manner as in Reference Example 3-2) to obtain 0-36 g of the entitled compound as a white waxy substance. [c]p^s +38.70 (c=0-1, chloroform) KMR (CDC1_)„ 6 (ppm) ; 0.88 (6H, t) , 1.26 (s), 2.1-2.5 J (6H, m)„ 4.96 (1H, d)f 5.18 (1H, d), 7 .2-7,5 (1OH a m) REFERENCE EXAMPLE 6 1) Preparation of 1,3-(diethoxycarbonyl)isopropyl 2-deoxy-3 g4 *6-tri-0-acetyl-2~(2,2„2-trichloroethoxycarbonvl-" amino) -a'-D-glucopyranoside To 8 . 00 g of 1 3 # 4,, 6-tetra~0~acatyX-2"deoxy-2~ (2,2 2-trichloroethoxycarbonylamino)-D-glucopyranose was 5 added a cooled acetic acid solution containing 25% hydrogen bromide at room temperature,, followed by stirring for 1 hour „ The reaction mixture was diluted with chloroform, washed successively with a 5% sodiuxn hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solu-10 tion, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 72 sal of anhydrous methyl- a ene chloride.. To the solution were added 8 g of anhydrous calcium sulfate,, a suspension of 4-12 g of silver perchlo-15 rate in 40 ml of anhydrous bensene, and 6-24 g of diethyl-3-hydroxyglutarate under ice-cooling. The mixture was allowed to react at room temperature for 3 hours, followed by neutralising with a 5% aqueous solution of sodium hydrogen-carbonate™ The insoluble matter was removed by filtratione 20 and the filtrate was washed with water and dried over anhydrous magnesium sulfate„ The solvent was distilled offe and to the residue was purified by silica gel column, chromatography using 30 si (v/v) mixture of chloroform and acetone as eluent to obtain 7.36 g of the entitled compound as an oily substance, * -r42«8° (c=0~7t» chloroform)- D 2) Preparation of 1,»3~(diethoxycarbonyl) isopropyl 2-deoxy-2~tetradecanoylamino™3,4,6-tri-O-aeetyL-a-D-gluco-pyranoside" The compound (4.00 g) obtained in 1) above was treated with a sine powder in an acetic acid solution and then reacted with tetradecanoic acid in the same manner as in Reference Example 3-2) to obtain 3.78 g of the entitled compound as an oily substance. do". +46-9° (c~0 -.16,, chloroform) 3) Preparation of 1,»3-(dibensyloxycarbonyl) isopropyl 2-deozy-2-tetradecanoylamino--a~D-giueapyr&noside Irs. 30 ml of dioxane v?as dissolved 1.80 g of the compound obtained in 2) above, and -10 ml of water was added thereto. After cooling to 15 ml of a IN potassium hydroxide aqueous solution was added to the solution. After 15 stirring for S hours» IN hydrochloric acid was added thereto to adjust to a pH of 7»5« The reaction mixture was concentrated to dryness under reduced pressure- The residue was suspended in 100 ml of dime thy! formamide,, and 1 ml of bensyl bromide was added thereto. After stirring at 40°C for 3 20 hourSi most of the dime thy Iformamide was removed by distillation under reduced pressure. The residue was extracted with bensene, and the bensene layer was washed successively with a 5% citric acid aqueous solution,, a saturated sodium chloride- aqueous solution,, a 5% sodium hydrogencarbonate aqueous solution,, and a saturated sodium chloride aqueous 5 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, as eluent,, a mixture of chloroform,, methanol,, and acetone at a volume ratio of 50sis5 and then 50:Is 15 to 10 obtain 0.65 g of the entitled compound as a white waxy solid, Cct-§-13.,2s (c=0.51» chloroform) D 4) Preparation of 1,3 -(dibenzyloxycarbonyl} isopropyl 2-deoxy~4„6~0~isopropylidene-2-tetradecanoylamino~a~D~ g Ixicopyr anos ide In 10 ml of acetone was dissolved 0.64 g of the 15 compound obtained in 3) above and treated in the same manner as in Reference Example 1-4) to obtain 0,54 g of the entitled compound as an oily substance. ?5 [cOD ; +3»3B (c=0.7,» chloroform) ) Preparation of 1,3-(dibenzyloxycarbonyl)isopropyl 2-deo%y-3-0-tetradecanoyl-2~tetradecanoylaniino-a~D-gluco-pyranoside In the same manner as in Reference Example 1-6)? 0-48 g of the compound obtained in 4) above was reacted with tetradecanoic acid, and the reaction product was heated in a 90% acetic acid aqueous solution to obtain 0.53 g of the entitled compound as a white waxv solid. [a]^5 : +32-8® (c=0.9 methanol) MMR (CDClg), 6 (ppa) s 0-88 ( SH - t) , 1-26 (a J , 4-94 (1H) „ -20 (43, s)$ 7.40 (10H, s) REFERENCE EXAMPLE ? Preparation of 1 >3-(dibenzyloxycarbonyl)isopropyl 2-deoxy-3-O- (N-dodeeanoylglycyl)-2-tet.radecanoylamijio- a-D-gluco-pyranoside In the same manner as in Reference Example 1-6) „ 0-60 g of the compound obtained in Reference Example 6-4) was reacted with N~dodecanoylglycine, and the reaction pro-■10 duct was treated with a 90% acetic acid aqueous solution to obtain 0-63 g of the entitled compound as a waxy solid. Cci]q5: +36.9" (c-1.3,, chloroform} NMR <CDC1 }, 6(ppm)s 0-89 (6H, t) , 1-26 (s), 2-1-2-3 (4H, m), 2.5-2.9 (4H, m), 4.50 (1H, m), 15 • 4.97 (1H, d), 5-07 (1H» m), 5-18 (4H)^ 7-40 (10H, s) REFERENCE EXAMPLE 8 1) Preparation of 2-acetoxyethyl 3,4,6-fcri-0-acetyl-2-deoxy-2- C 6 - (octanoylamino )heasanoyXamino3 - o-D-g luco- pyranoside In the seme manner as in Reference Example 2-5), 20 3-00 g of the compound obtained in Reference Example 1-1) was treated with a zinc powder in an acetic acid solution,, and the reaction product was reacted with S~(oetanoylamino)-caproic acid to obtain 2.84 g of the entitled compound as a ~ 42 " waxy solid..
CoGpSj +55 -4* (c=l .1, chloroform) 2) Preparation of 2■ -hydroxy©thy1 2-deoxy-2-[6-(octanoyl~ amino )hexanoyl amino] - ct-ib-g lucopyranoside In the same manner as in Reference Example 1-3) 2-82 g of the compound obtained in 1) above was reacted to yield 1*66 g of the entitled compound as a white powder.
Melting Points 155-1579C [a]25. +78-8° (c=0.9, ethanol) 3) Preparation of 2-hydroxvethyl 2-deoxy-4,6-O-isopropyl- idene-2*~[6-(oetanoylamino)hexanQylamino]~ » D-glaco-pyranoside In the same manner as in Reference Example 1-4), 1.60 g of the compound prepared in 2) above was reacted to yield 1-48 g of the entitled compound as an oily substance -[a 1:^ : +35.2° (c=l.0, chloroform) 4) Preparation of 2~(diphenylphosphonoxy)ethyl 2-deoxy-4,6-0-isopropylidene-2-C6-(octanoylamino)hexanoylamino]~ct-D-glucopyranoside In the same manner as in Reference Example 1 ~5) „ 1»26 g of the compound obtained in 3) above was reacted to obtain 1 -35 g of the entitled compound as an oily substance- Ca3?^ s +26.7® (c=l .2* chloroform) ) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-3-0-dodecanoy 1- 2-C 6 - (oc t anoyl amino) hexanovl amino] - ct-D-g luc o-pyranoside In the same manner as in Reference Example 1-6),, 0»65 g of the compound obtained in 4) above was reacted with dodecanoic acid,, and the reaction product was heated in a 90% acetic acid aqueous solution to obtain 0*73 g of tiie entitled compound as an oily substance- [a]^5: +37„3S (c~l«1/ chloroform) D _ NMR (CDC1-) , 6(ppm)s 0.89 (SH, ta), 2.10 (4H., m), 2.33 (2H, J in), 3.20 (2H, m) „ 4.30 (IE, m), 4.46 (2H, m) , 4.85 (1H, d) , 5.10 (1H, m) REFERENCE EXAMPLE 9 1) Preparation of 2-acetoxyethyl 3»4,6-tri-0~acetyl-2-[ (R)-* 3-benzyloxytetradecanoylamino]~2-deoxy-a~D-gluco-pyranoside "10 In the same manner as in Reference Example 2-5), 3.00 g of the compound obtained in Reference Example 1-1} %?as treated with a zinc powder in an acetic acid solution,, and the reaction product was reacted with 1.95 g of (R)~3-benzyloxytetradecanoic acid to yield 3.70 g of the entitled 15 compound as an oily substance.
NMR CCDClg),* 6(ppn): 0.87 (3H» t, J»6Hs)« 2-00 (3H, a), 2.02 (3H, s)4, 2.04 (3H# s) , 2.08 (3H, s), 2.18 (2H, m), 4-54 (2H, ABq, J=12Hz), 4.76 (1H, d„ J=4Hz), 7.36 20 {5H, s) 2) Preparation of 2~hydroxvethyl 2-C(R)~3~benzyloxytetra~ decanoylamino]-2 ~deo xy- a- D~g lucopyranos ide In the same manner as in Reference Example 1-3), 3 »S8 g of the compound prepared in 1) above was reacted to obtain 2.49 g of the entitled compound as a pale brown v powder. Recrystallised from water-ethanol~ Melting Points 125-127"C . [cO|5s +73«.3° (c=0»S«, methanol) 3) Prepartion of 2~hydroxyethyl 2~-[(R)-3-benzyloxytetra- decanoyl amino] -2 -dao xy~ 4 a, 5 -O-isopropyl iden e™ a-D-g lucopyranos ids In the same manner as in Reference Example 1-4), 0 -98 g of the entitled compound was obtained as a, colorless oily substance from 1-20 g of the compound prepared in 2) above. fc]25s +31.4° (c=0-9* chloroform) 4) Prepartion of 2~(diphenylphosphonoxy)ethyl 2-[(R)-3-benzyloxytetradecanoylaraino3~2-deoxy-4,»6-0-isopropyl-idene-ot -D-glucopyranoside la the seme manner as in Reference Example 1-5) , 0.98 g of the entitled compound was obtained as a colorless oily substance from 0-83 g of the compound prepared in 3) above- NMR CCDC13) , 6 (ppra) = 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) ) Prepartion of 2~(diphenylphosphonoxy)ethyl 3-0-C(R)-3-benzyloxytetradecanoyl)-2™[ (R)-3-bensyloxytetradecanoyl-amino]-2-deoxy~ a-D-gluscopyranoside In the same manner as in Reference Example 1-6), 0.96 g of the compound obtained in 4) above was reacted with 0.59 g of (R)-3-benzyloxvtetradecanoic acid, and the reac- 45 - tion product was heated with a 90S acetic acid solu tion to obtain 1.23 g of the.entitled compound as a colorless oily substance. +31*40 (c~1..2it chloroform) KHR (CDClg), 6(ppm)s 0.88 (6H, t, J»7Hs), 2.34 (2H, d, J»6Hz), 2.6 (2H, m)f 4-51 (2H, ABg, J**12Hz), 4.56 (2H* s), 4.71 (1H, d, J»4Hz), 5.13 (1H, m), 7-2-7-4 (20H. n) REFERENCE EXAMPLE 10 Preparation of 2 - (diphenylphosphonoxy)ethyl 3 0 [(R) 3 benzyloxytetradecaneyl]-2-deoxy-2-tetradecanoylasd.no-ci-d-glucopyranoside In the same manner as in Reference Example 1-6), the compound obtained in Reference Example 1-5) was reacted with (R) ~3~benzy3L©xy tetradecanoic acid, and the reaction product, was heated in a 90% acetic acid solution to obtain the entitled compound"as an oily substances NMR (CDClg), SCpp^ls 0,89 (6H, t), 2.06 (2H, t) , 2.1-2.8 (2H, m), 4-85 (1H, d) , 5-14 (1H, t) , 7-1-7-3 (15H, ra) REFERENCE EXAMPLE 11 Preparation of 2-(diphenylphosphonoxy)ethyl 2-C (R)-3-benzyl~ oxytetradecanoylamino3~2~deoxy-3~0~tetradecanoyl-Ci-D-gluco-pyranoside In the same manner as in Reference Example 1-6), the compound prepared in Reference Example 9-4) was reacted with tetradecanoic acid „ and the reaction product was heated in a 90% acetic acid aqueous solution to obtain the entitled compound as a colorless oily substance-NMR (CDC1 ), 6(ppm): 0-88 (6H, t), 2.3-2.4 (4H, m) , 4-52 (2H, 6.), 4-72 (1H, d) , 5.10 (1H, m), 7-2-7-5 (15H, m) REFERENCE EXAMPLES 12 TO 52 In the saxse .manner as described in Reference Examples 1 to 11, the following compounds represented by formula (ilia) were prepared- HO—CH» O /0R2l\ K-A o (Ilia) HO NHR' 0(CH0>-2—0~P( 11 12 -CO(CH2)5NHCO(CH2}gCK3 -CO(C8.).4CH. i Xd $ 13 I -coch2nhco(ch,)10ch3 -co(ch2) 2nhco(ch2)ach3 14 -COCH2nhco(CH2}10CH3 ' -co(ch2)3khco(ch2)gck3 CH3 I -COCH2 mico (CU2} x qCK3 =*C0CH2HC0(CH2 It 1QCH2 j '2^iIC|?2 16 -coch2nhco(ch2310ch3 -coch2nco(ch2)10ch3 Physical Properties Co3^®« +30.3* (c"1.0, chloroform) NMR (CDC13), 8{ppm}i 0.39 (6H, t), 2,06 (2H» t), 2.19 (2R, t), 2.33 (2K, m), 3.10 (IH), 3.30 i IH) f 4=3-4,5 (4H, in), 4.65 (IH, d), 5,18 (IH, m), 7,2=7.4 (10H, m) [g3q58 +24.3* (c*0.8, .chloroform) NMR (CDCi„), 6 (ppm)j 0.80 (6H, t), 1,9-2.5 £ (6H, m), 3.25 (IH, m), 3.S2 (IH, in), 3.7-4.5 (7H, ra), 4.84 (IB, d), 5.20 (IK, t), 7.2-7,5 ClOH, ra) Ce]?LS» +32.5° (c«0.7 chloroform) o NMR (CDC13), 6(ppm)3 0.88 (6H, t), 2.0-2.4 (6H, m), 4.83 (IH, d), 5.22 (IH, t), 7.1- t 7.5 (10H, in) +33.8* (c>l.O, chloroform) MMK (CDC13),- 6(ppm)i 0.88 (6K, t), 1.22(a), 2.2-2.4 (4H, ra), 2.98 (3H, s)] 4.35 {IH, d), .22 {IH, t), 7.2=7,5 (10H, m) Ee]ESi +31e4* (enl.O, chloroform) P NMR (CDC13), 6 (ppra) s 0.9B (9.H, t) / 1 = 26 (s), 2.2=2,4 (4H, m), 3.1=3.4 (2H, br), 4.84 (IH, d), S.21 (IH, t), 7.2-7;5 (10H, m) Reference Examples R 17 -coch2 nhcot ch2}t qch3 18 -coch2nhco(ch2)1qch3 19 -COCH2NHCO(CH2)i0CH3 -coch2nhco{ch2),qch3 21 -cock2nhco(ch2),qck3 =co C ch2)9co(ck2)9ck3 =COCH,OCO(CH2}10CH3 ch- .
I -1 -co(ch2)5nco(ch2)fich3 §< -cotchj}sNHCO(ch2)gch3 -cochnhco(ch2)1qch3 Physical Properties Ca3D i +29.6* {cO < 2, chloroform) NMR £CDClj 31 a £ppm)I 0.88 (SH, t), 1,25 (a), 1.9-2.5 (SH, in), 3<51 (2H, m), 4.80 (IH, m), ,20 (IH, m), 7.2-7.5 (10H, m) Co 3p®i +3 5.5s (e-1.3,"chloroform) NMR (CDClg), 6 (ppm) j 0.-90 (6H, t), 1.28 (s), 2.28 (2H, t), 2.40 (2H, t), 4.45 (o), 4.85 (IH, d), 5.22 (IH, m), 7.2-7.5 (10H, m) laDp5 i +14.3* (c«0.5, chloroform) NMR (CDC13), S(ppm)i 0.88 (SH, t) , 1.26 (s) , 2.10 (2H, m), 2.30 (4H, m), 2.90, 2.94 (total 3H, each s), 3.30 (2H, in), 4 .84 (IH, A), 5.20 (IH, m), 7.2-7.5 (10H, m) [a]" t +29.9' (c=0.5, chloroform) NMR (CDC13), o(ppm)j 0.89 (6K, t), 1.28 (s), 2.12 (4H, m), 2.28 (2K; t), 3.18 (2H, m), 4.84 (IH, d), 7.2-7.4 (10H, sr.) [a]p5 * +18.6 (c=l .3, chloroform) NMR (CDC13), «(ppm)i 0.88 (SH, t), 2.30 (2H, t), 4.81 (IH, d), 5.23 (IH, t), 7.2-7.6 (1GH, m) («! 'HOT) S'L*=Z'L ' (ui "HI) 9Z3 £ '(P 'HI) ^8e fr ' *H9) S'Z-O'Z '(b) SZ'1 ' ("* 'H9) 88'0 « (UKid) $ '{EIDOD> hhn (uuojo^oms '9»QsO) sQ'ZZ-\- 5 (ui 'HOI) VL-Z' L 1C® 'HI) 0Z3S '(HI 'p) frB'fr 'it 'HZ) 8Z*-Z '(!■ 'HZ) 80eZ '(e) 8Z* I ' (* 'H9) 68s 0 « (uidd) 9 '{£TDCID) MHH (uaojoaomo 'o*T=o) ,fr'OS+ » s°Co] 1 (m 'KOI) f'L-Z'L * <ui ' Kl) OZsS '(HI 'P) V8'V '{% 'HZ) 8Z* Z ' («i 'HZ) 80*Z ' (o) 82 = 1 ' (:» *H9) 68*0 ' (Uidd) 9 ' (CIDdD) HHK (uuojoaoiip 'VT-o) ,9*9fr+ 'Sg£°3 (w 'HOT) S'L-Z'L ' (3 'HI) OS'S <{P 'HI) IS'fr '(«« 'HZ) Wfr ' (ui 'HT) SZ'fr ' (P 'HZ) 90* fr ' (« 'HZ) QV'Z '(e) 92*1 ' (H 'H9) 88*0 3C^^)9 ' (STOaD) HWN (uuojoaoiHO #-££3Q=o) ,fr'SZ+ «--Cal] 23 C (w 'HOI) S'L~Z'L ' (ui 'HI) OZ'S ' (P 'HI) 16' V '(o ipse 'HE ) £6'Z 'VQ'Z '(«i 'Hfr) 'S'Z-Z'Z '(3 *H9) 88s0 quKfd) * {£10Q0} HHH (uuojoiomo '0«I»3) ,I*6Z+ ' CjC°3 sdT^aedoad isofsAqfi SHDE1(ZHO)OD~ SHO0(SHD)OD= SHD8{ZKD)OD" SHD9{ZHD)ODHH*(SHD)OD*(CHD)OD' EHD°1(ZEO)0DMHDOD- £HD8(SHD)ODHM2(2HD)OD- 9Z EHD9(SHD)ODHH2HDOD- SZ I o in EHDS(2HD)ODHKZHDOD- VZ ' EHD°T(SHD)ODHHSHDOD~ £ Z SHD°1(ZHD)ODHK SHDOD- ZZ Reference Examples 27 .21 R' 11 -COCH2NKCO(CK2>qCH3 .CO£CH2}i0CH3 28 »co(ch2)2co(ch259ch3 -CO(CH2>^2CHS I cn 29 ck. -cochjn-co(ch2)1qch3 -CO{CH2) ,.NHCO(C«2) gCH3 3 p -COtCHjJu^ -co(CH2)gnhco{ch2)6chs 31 -CO(CH2)12CH3 •CO(CR2)3HHCO(CH2)gCH3 Physical Properties t +49.6* (c-0.92, chloroform) NMR (CDC13), 6(ppm)i 0.89 (6H, t), 1.28 (a), 2.08 (2H, t), 2.28 (2H, t), 4.84 (IH, d), 5.20 (IH, m), 7.2-7.4 (10K, m) Cc3^i +33.0' (c*0.4> chloroform) NMR {CDC13 ), 6 (ppm) i 0..88 (6H, t), 1.28 (s), 2.09 (2H, t), 2.46 (2H, t), 2.56 (2H, t), 2.80 (2H» m)( 4.84 (IH, d), 5.16 (IH, m), 7.2-7,5" (10H, m) 8 +29.8' (c®0.45,' chloroform) NMR (CDC13), 6(ppm)t 0.88 (6H. t), 1.28 (a), 2.08 (4Ht ra), 2.38 (2H, t), 3.16 (3H, a), 4.84 (IH, d), 5.18 (IH, m), 7.2-7.5 (10H, m) « Co]?,5 i +39.4' (c-0.7, chloroform) . NMR (CDClj), 6(ppm)i 0.38 (SH, t), 1.26 (s), 2.0-2.5 (6H, m), 4.85 (IH, d), 5.09 (IH, m), 7.2-7 .5 ClOH, m) Ca3D i +41.3 (c»0.9, chloroform) NMR (CDC13), 6(ppm)i 0.88 (6H, t), 2.0-2.4 "(SB, m) t 4.84 (IH, d), 5.09 (IH, in), 7.2-1®S C10H, m) Reference Examples 32 .21 CH. .11 -COCH2NCO(CH2)xqCH3 =CO(CH2)12CH3 33 -C°(CH2)12CH3 -CO{ch,)?hhco(ch2)4ch3 34 -C°(CK2)12CR3 ch. 'coch2nco(ch2)10ch3 CH-CK- i / -COCHNCO(CK2) CK3 *C0«CK25'I2CH3 36 -co(ch2>2co(ch2j9ch3 -co(ch2)2co(ch2i3ch3 _ Physical Proparfclaa Co3|5 « "!"2S ,43'"' {cnl«14$ chloroform) mn (CDC I ^) s 6 (ppm) I 0.88 {SH, t) , 1,28 (a)» 2=08 {2H, m), 2,38 (2H, t), 3,14 (SH, a), 4.83 {IH, d), 5.19 (IH, m), 7,2-7.? (10H, m) Za]2s , 37 ,4• {e«1.5, "'chloroform) NMR (CDC13), a(ppm)j 0,SS (6H, t), 2.0-2,2, (4H, m), 2.34 (2H, t), 3,2-3.3 (2H, m), 4.85 (IH, A), 5,1-5.2 (IH, m), 7.2-7.4 (10H, m) [a]p® +4 2,7* (c=l,8f chloroform) NMR (CDC13) , <S (ppra) i 0.9 0 (6K, t) , 1.28 (s) , 2.36 (4H, fc, 2.86 and 3,02 (total 3H, ach s) , 4 ,4 2 (IK, m) , 4 ,4 S (2H, m), 4 .89 (IH, d) , 5.07 (IH, ro), 7.2-7.4 (10R, m) i +23®78 (c*0>3f chloroform) HHR (CDC13), 6(ppm)i 0,90 {6K, t), 2.06 (2H, t), 2.34 (2H, t), 3.02 and 3.12 (total 3H, each b), 4.18 (IH, A), 5.24 (IH, t), 7,2=7,5 (10H, m) |o!qS +24,0® (c>0.5, chloroform) NMR (CDClj) «{ppra) t 0=3S (6H, t) , 1.26 (br), 2,3-2,8 (12H, m), 4,2-4.5 (4H, n), 4.82 (IH, d), 5,18 (IH, m)t 6,56 (IK, m), 7.2-7.5 (10H, m) sT o g aT - > « OJ Sag ***** « <PH Jf" - o o MS « y O O O <J g£ 33 <H O "X . &5 S5 t-j d mo m *% «>-» M U *"» „ OS W ' O—S3 JM fS SS £3 <M W o o W 3 a W U ^ »u« o o o o o V V V V V CO o o OS w a o 0 1 e*> £3 a o <3-4 - OS SE O o o CM M O o u fj §s o ON OS se o o o CO £ u 0 a 1 « K u a\ OS M O C3 o OS s o o o <»1 X cj o CM £ u o cj fM X cj o cj f-n 00 n cti o o t? Referencs Examples ,21 42 - coch2 mco {CK?) 1 0 chg ,11 =COCH2»KCO(CH, )1(jCH3 43 -CO(CH-2)gHHCO(CK2}gCH3 -CCfCH^gNHCtXCHjJgCHg 44 -co(ch2)12ch3 COOCK2C6a5 'CO(CR2)2CRNHCO(CR2)qCH3 45 -coca. 46 -co(ch2)12ch3 =coch ,2MHCOCH2— Physical Properties Ccs]^ss +16.6* Ce^O.S, chloroform} KMR (CDCi3), 8 (ppm)i 0.90 (SH? t) , 1.28 (s)» 2=0-2,3 (4H, mi, 4=85 (IH, d) , 5=24 (IH, t), 7.2-7.5 (10H, m) [cal^3 i +31.S* (e=l .2,' chloroform) NMR (CDClg), 6(ppm)i 0*88 (6H, t), 1.28 (a), 2.0-2.2 (6Kt m), 2.35 (2H, ra), 3.1-3.3 {4H," m}, 4.85 (IH, d), 5.17 (IH, m), 7.2-7.4 (10H, raj CaD^s +37.78 (e=>0 = S, chloroform) NMR (CDC13), 6 (ppm)s 0.8S (SH, t), 1.26 (s), 2 = 0-2.2 (6H, m), 2 = 30 (2Hf t), 4.82 (1H, d), 5.14 (2Hf s) i 7.2-7.5 {15H, in) i Co3pSi +42.I8 (c-1.3, chloroform) NMR (CDClj), 6(ppm)i 0.90 (3H» t), 1.26 (s), 1.3-1.8 (br), 2.00 [a), 2.34 (2H, m), 4.84 (1H, d), 7.2-7.5 {10H, m) C°]^Ss +34.3* (c»1.6, chloroform) NMR (CDC13), 6{ppm)§ 0.88 (3H» fc), 1.26 (s), 1.3-1.8 (br), 2.04 (m)» 2.35 (2H, t), 4.88 (18, d), 7.2-7.5 (10K, in) Reference 21 Examplea R 47 CK, l 3 -COCHNHCO {CH2) 1 qCH3 -co {chg ) £ gch^ 48 ~CO(CK2512CH3 ' "CO*CIVi2°H3 49 -CH(CH2)sCH3 "CO(Ca2igCH3 so -co(ch2)qch3 =co{ch2)8ch3 51 -co(ch2)10ch3 -COICH2)10CH3 ' Physical properties Eo t +20.4* (c«0.9, chloroform) D NMR (CDC13}, <5 (ppm) i 0.86 (3H, t), 2.22 (2H# t), 4.90 (IH, d), S.22 (IH, m), 7.2-7.5 (10H, ffl) [ai +40.84 (c»l.l, chloroform) D ■«». +49.4* (c-1.2, chloroform) NMR (CDCI3), 6(ppm)t 0.8S (6H« m), 2.08 (2Hj t)f 2.36 (2H, t), 4.85 (IH, d), 5.10 (IH, m), 7.2-7.5 (10H, m) Ca i +46. 1* (c«=0.8, chloroform) e NMR (CDC13), « (ppm)i 0.88 (6H, t), 2.07 (2H, t), 2.35 (2K, t), 4.85 (IH, d) » 5.10 (IH, iri), 7.2-7.5 (10H, m) NMR (CDC135, 6 (ppm)i 0.90 {6H, t), 2.07 (2H, t), 2.35 (2H, t), 4.85 (IH, d), 5.10 (IH, m), 7.2-7.5 (10H, m) Referenca 2i 11 Examples ; R ' R 52 -CO(CH2)14CH3 ' =CQ(CH2)14CH3 53 -CO(CH2) 12,CH3 -COCCH?),nHHCOCH3 cr\ 1 / Physical Properties Co3^ * +37.2* chloroform) HHR (CDC13), (ppm)i 0=89 (6H, t), 2.06 (2H, t), 2,32 {2H, t), 4=04 (IH, d), 3,10 (IH, m)f 1,2-7,5 ClOH; m) [c]Q i *28,5® fc«0.S, chloroform) In the sesae manner as described in Reference Examples 1 to 11, the following compounds represented toy formula (Illb) were prepared- Reference Examples OR r a 54 $-0«(CH2)20P(0- 3, =-CO{CH2< 55 B-OCH2COOCH2 OCH, »COCH2CH(CH2)10CK3 UI 00 56 C£-OCK2COO"CH9 =CO(CH2)12CH3 / R11 K Phvaleal Prooartiea »CO(CH5l1?CH3 Cc3^5 « -19.5* (en0.9, chloroform) OCH, i-^O) IiWsvlt r n/ =C0CH2CH(CH2)xqCK3 CgIq s =25.6s {e«l,i, chloroform) -C0CCH2}I2CH3 m.p.i 54-55*C C«J«. -MS..®8 chloroform) 0 EXAMPLE 1 1) Preparation of 2-(diphenylphosphonoxv)athyl 2-deoxv-6-0~ jf 2 -deo sy-4 -0-d iphe ny Iph'o sphono- 3 -O- (NF-dodec&noylglycyl) -6-0-{2,2,2-trichloroethoxycarbonyl)-2-{2,2,2-trichloro-ethoxycarbonylamino)- (J-D-glucopyranosyl]-3-0-(N-dodeca~ noylglycyl}-2-C(N-dodecanoyl~N-methylglycylJ amino]-a-D-g1ucopyranoside In 2 ml of anhydrous methylene chloride was dissolved 370 mg of l"-0-acetyl~2~deoxy-4-0-diphenylphosphono-3-5 0- C N-dodecanoylglycyl} -6-0- (2 ,22-trichloroethoxycarbonyl 5 -2- C 2 „ 2,2—trxchloroethoxycarbonylamino} -D-g lucopyranos e, and 6 ml of a cooled acetic acid solution containing 25% hydrogen bromide was added to the soltation at room temperature, followed by stirring for 1 hour. The reaction mixture was 10 diluted with chloroform, washed successively with ice-water,, a 5% sodium hydrogencarbonate aqueous solution^ and a s&tu- i rated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent, was removed toy distillation under reduced pressure. The residue and 344 mg of 15 2-Cdiphenylphosphonoxy)ethyl 2-deoxy-3-0-C N-dodecanoylglyc-yl)-2-C C N-dodecanoyl-N-methylglycyl)amino]-a-D-glucopyra-noside were 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 20 was heated to 50 to 60°C and stirred for 3 hours - The insoluble matter was removed by filtration through Celite, and the filtrate was washed successively with a 5% potassium iodide aqueous solution and a saturated sodium chloride ~ 5S ~ aqueous solution,, and dried over anhydrous sodium sulfate. The solvent was distilled off,, and.the residue was purified by silica gel column chromatography using, as eluent, a 10:1 (v/v) mixture of chloroform and acetone', followed by a 50si (v/v) mixture of chloroform and methanol, and followed by a 20si (v/v) mixture of chloroform and methanol to thereby obtain 599 mg of the entitled compound as an oily substance. icad^. 4-20-0* (c=1.0, chloroform) 21 Preparation of 2 - Cdiphenylphosphonoxy)ethyl 2~d@oxy-S-0~ C 2-deoxy~4~o~diphenylphosphQno-3 -0- ( if-dodecanoylglycyl) -2—[ C ST-aodecanpyl-N-methylglycyl J amino] ~3~-D-gluco~ pyranoxyJ~3 ~q~ (N-dode canoylg Ivcy 1} -2~[ (NF-dodecanoyl-N- methy1glycy1}amino]-a-D~glucopyranos ids In Q ml of acetic acid was dissolved 587 mg of the compound prepared in 1) aboveand 0.6 g of a zinc powder was suspended in the solution, followed by stirring at room temperature for 2 hours- "She insoluble matter was removed by filtration# and the filtrate was washed with chloroform. ittxe solvent ^-as removed by distillation under reduced pressure* and toluene was added to the residue,y followed by distillation to remove the solvent. Addition of toluene and subsequent distillation were repeated three times in total# and the residue was dissolved in chloroform_ The chloroform layer was washed successively with IN hydrochloric acid* a 5% sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate» The solvent was removed by distil- 60 ~ lation under reduced pressure to obtain an oily product.
Separately,, 122 mg of M-dodecanoyl -M-~me thylglycine was dissolved in 3 ml of anhydrous tetrahydrofuran„ and to the solution were added 77 mg of l-hydroxybenzotriazole and 5 103 sag of dicyclohexylcarbodiimide# followed by stirring on an ice bath.. Thirty minutes later,, the liquid temperature was returned to room temperature., and the stirring was continued for an additional 3 hours. The precipitated crystals were removed by filtration., The above prepared oily substance was dissolved in ml of anhydrous methylene chloride,, and the filtrate was added thereto under ice-cooling. The temperature of the mixture was returned to room temperature„ and the mixture was stirred at that temperature for 1.5 hours. The reaction 15 mixture was diluted with chloroform# washed with lKf hydrochloric acid* dried over anhydrous sodium sulfate* and' then distilled to remove the solvent™ The residue was purified by silica gel column chromatography using,, as eluent,, a 10si (v/v) mixture of chloroform and acetone,, then a 50:1 (v/v) 20 mixture of chloroform and methanol? and finally a 20si (v/v) mixture of chloroform and methanol to yield 445 mg of the entitled compound as an oily substance. [a]25; +19-2® (c=l.Of chloroform) D - 61 ~ 3) - preparation of 2-ohosoho.no xvethvl 2-deoxv-6-0-(2-deoxy-3~0-(^-dodecanoylglycyl)-2-l(9ode c a noy1-N-me thy1- glycvl)amino]~4-0~phosphono™g~D~glucopyranosyl)-3-0-(N-dodeeanoylglyeyl) -2~£ (N~dodecanoyl~N~methylglycyl) - " amino] -a-D-glucopyranoside In a mixture of 50 ml of tetrahydrofuran and 2-5 ml of water was dissolved 424 mg of the compound prepared in2) above# and 0-2 g of platinum dioxide was added thereto 5 followed by stirring under a hydrogen gas for 2 hours -The catalyst was removed by filtration, and the filter cake was washed with a 8s3sl (v/v) mixture (lower layer) of chloroform,8 methanol, and water,, The filtrate and the washing were combined, and the solvent was removed therefrom 10 by distillation under reduced pressure. The residue was purified by thin layer chromatography using a 6 s 4 s 0»7 (v/v) mixture of chloroform, methanol# and water as developing solvent# and then treated with a strongly acidic ion ex-change resin# Dowesc 50" C"H" type) produced by Dow Chemical 15 Co.# Ltd.). The solvent was removed by distillation under reduced pressure, and the residue was suspended in dioxane. Freeze-drying of the suspension gave 204 mg of the entitled compound as a white powder.
' Melting Points 165-170®C (gradually colored and turned to jelly) [c^d : +4-6 [c=0»7,,, chloroformsmethanol=3s 1 (v/v)] IR cm"*11 3400„ 2930 „ 2850, 1750, 1675, 1650 - 62 NMR (CDC13~CD30D), 6(ppm) : 0.90 (12H, t), 1.30 (s), . 2»29. (4H, m), 2.44 (4H, t) . 2.94 and 3-11 (total 6H* each s), 4-84 (1H» d), 5.18 (IH, hi) , 5 5.34 (IH, m) A part of the resulting product was dissolved in a 3si (v/v) mixture of chloroform and methanol, and the solution was adjusted to a pH of about 9 with triethylamine, followed by concentration under reduced pressure. The residue was dissolved in a 0.1% triethylamine aqueous solution, followed by filtration through a millipore filter-The filtrate was freeze-dried to produce a triethylamine salt of the entitled compound as a white powder. 3XAMPLE 2 IS 1) Preparation of 2-(diphenylphosphonoxy) ethyl 2-deoxy-6~0~ £2-deoxy-4-0-diphenylphO3phono-3~0- (N-dodecanoylglycyl) -6~0~{ 2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-trichloroethoxycarbonyl amino)-0-D-glucopyrariosyl3-2-[6-(octanoy1- amino)liexanaylaminoj^3-0~tetradeestt©yl-a-D~gl,aco-pyranoside In the same manner as in Example 1-1), 445 mg of 1-0-acetyl-2-deoxy-4-0-diphenylphosphono-3-0-(N-dodecanoylglycyl ) —S-O-(2,2,2-trichloroethoxycarbonyl)-2-(2,2,2-tri-chloroethoxycarbonylamino)~D~gXycopyranose and 385 mg of 2- (diphenylphosphonoxy)ethyl 2-deoxy-2»C6-(octanoylamino)hexa-noylamino3-3-0~tetradecan.oyl~a~d~glucopyranoside were reacted to obtain 650 mg of the entitled compound as an oily substance.
Ca3d ' +22«2° (c=! »0chloroform) 2) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-6-Q-[2-deoxy-4-0-diphenylphosphono-3-0~ C N-dodecanoylglycyl} -2~tetradecanoylamino-S -D-glucopyranosyl ] -2- [ 6-1 oct&noyi-aroino)hexanoylaminoi]"3-0- tetradecanoyl-a~D~g lucopyranos ide In 10 ml of acetic acid was dissolved 620 rag of the compound prepared in 1} above, and 1-5 g of a zinc powder was suspended therein,, followed by stirring at room temperature for 3 hours. Any insoluble .matter Mas removed by filtration, and solvent '«'£s removed by distillation under reduced pressure, and the residue was dissolved in chloroform. 'The solution was washed successively with IN hydrochloric acid, water, a 5% sodium hydrogencarbonate aqueous solution, and water, and dried ^over anhydrous magnesium sulfate. fee solvent was removed by concentration under reduced pressure, and the residue was dissolved in 10 ml of anhydrous tetrahydrofuran. To the solution were added 93 rag of tetradecanoic acid, 58 mg of l-hydroacybenzotriazole, and 90 mg of dicyclohexylcarbodiimide under ice-cooling, and the liquid temperature was gradually elevated up to room temperature, followed by stirring for one night. 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, as eluent, a 10si (v/v) mixture of chloroform and acetone and then a 30 s 1 (v/v) mixture of chloroform and methanol, and then powderized from acetonitriia to obtain 428 nig of the entitled compound as" a white powder.
Melting Points 105-107°C rcO^-'s +24.7® (c=1.0, chloroform} 3) Preparation of 2-phosphonoxyethyl 2-deoxy-S~0~[2~deoxy-4-0-phosphono-3-0-(N-dodeeanoylglycyl)-2~tetradecanoyl-amino- B-b-glucopyranosyl 3 -2-L 6- (octanoy lamino) hexanoy 1-amino]-3-0-tetradecanoyl-a-D~glucopyranoside In the same manner as in Example 1-3), 350 mg of the compound prepared in 2) above was reacted to obtain 162 mg of the entitled compound as .a white powder™ Melting Points 169-172®€ {colored and turned to jelly) CcGj^s +19-5® |[c=0.6, chloroformsmethanol = 3:1 {v/v)] IR VKBx e«f~s 3405* 2925, 2855, 1740, 1645, 1560,, 1460 max NMR (CDC1 ), 6(ppro5: 0-90 Cl2H,-tj; 1,30 (s), 2.1-2-4 (1QH, J n), 3.19 C2H, t), 5.1.7 (IH, t) , 5.38 (IH# t) The resulting compound was treated in the same man ner as in Example 1-3) to obtain a triethylamine salt of the entitled compound as a white powder.
EXAMPLE 3 1) prepartion of 2-(diphenylphosphonoxy)ethyl 2-deoxy-6-0-C2-deoxy-4-0-diphenylphosphono-3 -0- (4-oxotetradecanioyX-6-0-(2,2,2-trichloroethoxycarbonyl)-2-(2,2,2-trichloro-eth03tycarbonylamino5-3~D-glucopyranosyl]~3-0-(4-oxo~ tetradecanoyl)-2-tetrsdecanoylamino-(x-D-giucopyranoside In the same manner as in Example 1-1) t, 435 mg of 1- 0-acetyl~2"deoxy~4-0-diphenylphosphono-3~0-(4-oxotetradeca-noyl )-6~0- (2,2, 2-trichloroethoxycarbonyl)-2- (2,2, 2-trichlo- roethoxycarbonylamino) -D-glucopyranose and 380 mg of 2~(diphenylphosphonoxy )ethyl 2-deoxy-3~0~(4-oxotetradecanoyl)-2- tetradecanoylamino~K~D~glueopyranoside were reacted to obtain SIS mg of the entitled compound as an oily substance.. [<x: +14-7° (c=0-03, chloroform) 2) Preparation of 2~(diphenylphosphonoxy)ethyl 2-deoxy-S-O-E2«deoxy-4«0~diphenyIphosphono-3 -0- (4~oxotetradecanoyl)-2-tet.ra*deeanoylamino-f3 -D-glucopyranosyl 3 -3-D- (4-oxo-fcetradecanoyl)-2-tetradecanoylamino-a-D-glucopyranoside In 5 ml of acetic acid was dissolved 510 mg of the compound prepared in 1) above, and 0»5 g of a sine powder was suspended in the solution., followed by stirring at room 10 temperature for 1-5 hours. The insoluble matter was removed by filtration# and the filtrate was distilled under reduced pressure. The resulting residue-was diluted with chloroform, washed successively with IN hydrochloric acid, a 5% sodium hydrocarboncarbonate aqueous solution, and water, IS 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 to the solution were added 88 mg of tetradecanoyl chloride and 2 ml of N-raethyIraorpholine under ice-cooling -20 The mixture was stirred at the same temperature for 30 minutes- The reaction mixture was diluted with chloroform^, washed successively with IN hydrochloric acid and waters and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the •n ~ 66 - residue was purified by silica gel.column"chromatography ■asing, as eluent, chloroform.and. then a 20si (v/v) mixture of chloroform arid methanol to obtain 229 mg of the entitled compound as an oily substance. ta]^5s +17-3° Cc=0.2, chloroform) 3) Preparation of 2-phosphonoxyethyl 2-deoxy-6-0-£ 2-deoxy- 4-0-pb.osphono-3 -O - (4-oxotetradecanoyl) -2-tetradecanoyl-amino-B-b-glucopyranosyl]-3-0-(4-oxotetradecanoyl)-2- tetradacanoylamino- a-D-glucopyranos ide la the same manner as in Example 1-3}, 225 mg of the compound prepared in 2) above was reacted and treated to obtain 91 mg of the entitled compound as a white powder., Melting Points 166~X70*C (colored and jelly-like) IR vKBr cm"1? 3406, 2926, 2854, 1710, 1662, 1557, 1470 max NMR CCDCIg-CD^OD), o (ppm)s 0,88■(12H, fc) , 1.26 (s), 2,22 (4H*> JftK 2-54 (4H, t), 2.64 (4H, ffl), 2.76 (4H, m)', 5,.16 (IH, t), 5-30 (IH, t) The resulting compound was treated in the same manner as in Example 1-3} to obtain a triethylamine salt thereof as a white powder.
EXAMPLE 4 1) Preparation of benzyloxycarbonylraethyl 2-deoxv-6-0-[2-deoxy-4-0-diphenylphosphono-3~0- (N-dodecanoylglycyl) -6-O—(2,2,2-trichloroethoxycarbonyl)-2-(2,2,2-trichloro- ethoxycarbonylamino)-B-D-giucopyranosyl3-3-0-tetradeca-noyl-2-tetradecanoyl amino- a-D-glucopyranoside In the same manner as in Example 1-1),, 303 mg of 1- 0-acetyi-2-deoxy-4~0~diphenylphosphono-3-0~(N-dodecanoyl- glycyl)-6-0-( 2,2,2-trichloroethoxycarbonyl) -2-( 2,2»2-tri- chloroethoxycarbonylamino) -D-glucopyranose and 217 mg of benzyloxycarbonylmethyl 2»deoxy-3-0-tetradecanoyl-2--tetra- decanoylamiho-cx-D-glucopyranoside were reacted to obtain 408 mg of the entitled compound as an oily substance« ml5: 4-25 «8e (e-i .0, chloroform) D 2) Preparation of benzyloxycarbonylmethyl 2~deoxy-S-0-[2-deoxy-4-0-diphenvlphosphono-3-0- {N-dodecanoylg lycy 1) ~2 -tetradecanoylamino-8-D-glucopyranosyl]-3~0-tetradeca-noyl~2-tetradecanoylamino-a-I>-glucopyranoside In the same manner as In Example 1-2), 389 rag of the compound prepared in 1) above was reacted with tetradecaiioic acid to obtain 293 sag of the entitled compound as an oily substance* [a]^ : -1-28 Cc=l. 1 , chloroform) D 33 Preparation, of c&rboxymethyl 2-deoxy-6-O- [ 2-deoxy-3-O-C N-dodecanovlg lycy 1) -4 -0-phosphono~2~tetradecanoylaraino-S-D-glucopyranosyl]-3~0~tefcradecanoyl-2—tetradecanoyl-amino-a-D-glucopyranoside In a mixture of 40 ml of tetrahydrofuran and 1 al of water was dissolved 278 mg of the compound prepared in.'2) above, and Q«3 g of 5% palladiura~on~carbon was added thereto, followed by stirring under a hydrogen gas for 1 hour. Then, 150 mg of platinum dioxide -was added thereto,, and the stirring under a hydrogen gas was continued for an additional 2-5 hours. The catalyst -was filtered, and the filtrate was distilled to remove the solvent,. The residue %?as purified by thin layer chromatography using,, as devel oping solvent.,, a lower layer of a 8:3:1 (v/v) mixture of chloroforms methanol, and water and then treated with a strongly acidic ion exchange resin, Dowex 50 (H type). The active fraction was distilled to remove the solvent, and the residue was suspended in dioxane. The suspension was freeze-dried to obtain 68 mg of the entitled compound as a white powder.
Melting Points 150-155°C (colored and jelly-like) IR cm1: 3400, 2925, 2855, 1745, 1650, 1470 NMR (CDC13), 6(ppm): 0-90 (12H, t)» 1-30 (s), 2.1-2.4 (8H, m) , 4«82 (2H* m),, 5.22 (IH, t) , 5.37 (IH, t).
EXAMPLE R 1) Preparation of 2~(diphenylphosphonoxy)ethyl 2~deoxy-6.-- [2-deoxv-4-0~diphenylphosphono-3-0-{N-dodecanoylglycyl)-S-O- (2,2,2-trichloroethoxvcarbonyl)-2-{2,2,2-t.ricliloro-ethcxycarbonylamino) -6 -D~glucopyranosyl]~4-0-diphenyl-phosphono-3-0-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-Nf-raefchylglycyl)amino]-a~D-glucopyranoside In 5 ml of anhydrous methylene chloride was dissolved 500 sag of the compound prepared in Example 1-1J, and .5 0 *04 ml of pyridine.. 139 mg of diphenylphosphoroc'hlor idate * and 64 rag of 4~diraethylaminopyridine were added thereto in ■this order at room temperature, followed by stirring overnight- The reaction mixture was diluted with methylene chloride, washed successively with a 10% hydrochloric acid 10 aqueous solution,, a saturated sodium "hydrogencarbonate aqueous solution,? and a saturated sodioa chloride aqueous solution* and dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under reduced pressure, and the residue was purified by silica gel column 15 chromatography using a 40:1 (v/v) mixture of chloroform and methanol as eluent to obtain 368 mg of the entitled compound as an oily substance™ [a 3~ 5 . +21. 9 ° (c=0«8chloroform) 2) Preparation of 2-(diphenylphosphonoxv) ethyl 2-deoxy-o-O-(2 -deo xv-4-0-d iDhenyloho sphono)-3-0-(H-dodecanoylglyc-yl)-2-[ l<J-dodecanoyI-N~methylglycyl) amino]-ft-D-gluco-pyranosyl)-4-O-dipher.ylphosphono-3-O-(N-dodecanoylglyc— yl)-2-[ (N-dodecanoyl-N-methylglycyl)amino]-a-D-glucopyranos ide In the same manner as in Example 1-2), 350 mg of the compound obtained xn 1) above was treated with a sine powder in an acetic acid solution and then reacted with N-dodeca- noyl-N^-raethylglycine to obtain 244 mg of the entitled compound as an- oily substance. [cOp"5: +3.5° (c=0-6, chloroform) 3) Preparation of 2~phosphonoxyethyl 2-deoxy-6-0-(2-deoxy-3-0-(N-dodecanoylglycyl)-2-[(N-dode canoy1-N-methylglyc-yl) amino] -4-0-phosphon.o-P-glucopyranosyl) -3-0- (N-dodecanoylglycyl )—2—CC N-dodecanoyl-N-methylglycyl)araino]-4-0-■ phosphono-a-D-glucopyranos ide In the same •manner as in Example 1-3),, 238 mg of the compound prepared in 2) above was subjected to catalytic reduction, to obtain 101 rag of the entitled compound as a white powder..
Melting Points 184-185"C (colored and jelly-like) -4-3° £c=0-6» chloroformsmsthanol ~ 3:1 (v/v) J IR Gm - 3280, 2900, 1740, 1660, 1640 NMR CeDCl3-CD3OD)* 6(ppm)s 0-89 (12H, t, J=7.0Hz), 1.28 (brs), 1.62 (8H, br), 2.24-2.31 (4H# hi) r 2.40-2.42 (4H, m), 2 «91-2»96 , 3-09, 3-12 (total 6H, each s)« 4.84 (IH, d), 5.19 (IH, t), 5.31 (IH, t) EXAMPLE.6 ' 1) preparation of 2-(diphenylphosp'honoxy)ethyl 3-0~[(R)~3~ benzyloxytetradecanoyl]-2~C (R)-3-benzyloxytetradecanoyl~ amino] -2-deoxy-6-0- (2 ~d aoxy-4-0- d iphenyIpho sphono~ 6-O-C 2,2,2-trichloroethoxycarbonyl)-2-(2,2,2-trichloroeth-oxycarbonyiaxnino) -3-0-C {R)~3~ (2 „ 2,2 -1 r iclilor oe thoxyca r« bonyloxy) tetradecanoyl] - 3-D-glucopyranosyl) - a-D-g lucopyranos ide In the same manner as in Example 1-1), 409 mg of 1-0-acetyl-2-deoxy-4-0-diphenylphosphono~6-0- (2*2 ,.2-triclilo-■ 5 roethoxycarbonyl} -2- (2 , 2,2-trichloraethoxycarbonylaxnino) -3-O-T(R)-3-(2,2,2~trichloroethoxvcarbonyloxy)tetradecanoyl]-D~ glucopyranos® %?as reacted with hydrogen bromide to obtain an oily substance, and the resulting oily substance was reacted with 370 mg of 2- (diphenylphosphonoxy) ethyl 3-0-[ (R)-3-benz- yloxytetradecanoyl]-2-[ (R)-3-benzyloxytetradecanoylamino]-2- deoxv-o-D-glucopyranoside in the presence of mercury (II) cyanide to obtain 577 mg of the entitled compound as a pal® yellow, viscous oily substance, !*£j25, +20-2° (gsO.2, chloroform) D 2) Preparation of 2-(diphenylphosphonoxy)ethyl 3-0-E(R)~3« bensyloxytetradecanoyl]~2-[ (R)~3-benzyloxytetradecanoyl~ amino]-2-deoxv-6-0«(2-deoxy-4-0-diphenylphosphono™3-0-[(R)-3-hydroxytetradecanoyl]-2-[{R)-3-hydroxytetradeca-noylamino]-3-D-glucopyranosyl) - ct-D-g lucopy r ano side In the same manner as in Example 1-2),, 555 mg of the compound prepared in 1) above was treated with a zinc powder in an acetic acid solution, and the reaction product was reacted with 93 mg of (R)-3-hvdroxytetradecanoic acid to 20 obtain 312 mg of the entitled compound as a colorless oily substance™ £a]^: +6.3° (c^O.7, chloroform) - 3) Preparation of 2 -phosphonoxyethyl 2-deoxy-6-0- (2-deoxy-3-0-[ (R)-3-hydroxyttradecanoyl]-2-C (R)-3-hydroxytetra-decanoylamino] -4-0-phosphono~8-D-glucopyranosyl) -3-0-t (R)~3-hydroxytetradecanoyl3-2-C (R)-3-hydroxytetradeca~ noylamino] -G-D-gliuicopyranGside In the same manner as in Example 4-3), 294 mg of the 5 compound prepared in 2) above was catalytically reduced in the presence of a 5% palladium-on-carbon catalyst to obtain the entitled compound* The compound was treated with a 0.1% triethylamine aqueous solution to obtain 76 mg of a triethylamine salt of the entitled compound as a white powder. A 10 part of the product was treated with a strongly acidic ion exchange resin to obtain the entitled compound in a free form as a white powder- The following data are of the free compound™ C°3^s -1.8* Ec»0.5„ chloroform=methanol = 3sl .(v/v)3 15 Melting Points 155-1580C (colored and jelly-like) IR ^ cm"1: 3440, 2930, 2860, 1740, 1650 NMR (CDC1--CD.OD), 6(m>m) : 0.90 (12H, t), 2.3-2.5 (8H, m) , 3 J .2 (2H, m) example 7 1) Preparation of 2-(diphenylphosphonoxy)ethyl 4-0-[3- (bensyloxycarbonyl)propionyl3-2-deoxy-6-0-[2-deoxy-4-0-diphenylphosphono-3-0-(N-dodecanoylglycyl)-6-0-(2„2,2-trichloroethoxycarbonvl)-2-(2 e2,2-trichloroethoxycar-bonylamino)-B-D-glucopyranosyl]-3-0-(N-dodecanoylglycyl) -2-tetradecanoylamino-a-D-glucopyranoside In 6 ml of anhydrous methylene chloride was dis- 73 - solved 483 mg of 2-(diphenylphosphonoxy) ethyl 2~deoxy-6-0-C2-deoxy-4-0-diphenylphosphono~3-Q<~ (M-dodecanoylglycyl) -S-o (2,2,2-trichloroethoxycarbonyl )-2~(2,2 /2-tr ichloroethoxycar- i bony 1 amino) -0 ~I>-glucopyranosyl3-3-0- (N-dodecanoylglycyl)-2- tetr&decanoylamino-cx-D-glucopyranoside,, and 108 mg of mono-bensyl succinate and 16 mg of of d ime thy 1 aminopyr id xne we re added to the solution- To the solution was added 107 mg of dicyclohexylcarbodiimide under ice-cooling. The liquid temperature was returned to room temperature, and trie mix-10 ture was stirred for 1 hour- The insoluble matter was removed toy filtration, and the filtrate was washed with IN hydrochloric acid, and dried over anhydrous sodium sulfate, liie solvent was removed by distillation trader reduced pressure, and the residue was purified by silica gel column 15 chromatography using, as eluent, 10% acetone-containing chloroform and then 3% methanol-containing chloroform to obtain 113 mg of the entitled compound as an oily substance. [<y.]~5s +35«6* (c»l.1, chloroform) 2) Preparation of 2-(diphenylphosphonoxy)ethyl 4-0-[3~ (benzyloxvcarbonyl) propionyl-2 -deoxy-6 -O™ £ 2-deoxy-4 -0- diphenylphosphono-3-O- (H-dodecanoylglycyl) ~2~tetr&deca-noylamino- $-D-glucopyranosyl3-3~0~ (N-dodecanoylglycyl) - 2-tetradecanoylamino~a~D-glucopyranoside In the same manner as in Example 1-2), 327 mg of the compound prepared in 1) above was treated with a sine powder in an acetic acid solution, arid the product was reacted with tetradecanoic acid to obtain 226 mg of the entitled compound - .74 - as an oily substance. [a]25 . +29.6° (c=l-2, chloroform). 3) Preparation of 2-phosphonoxyethyl 4-0-(3-carboxypro- pionyl )-2-deoxy~6-0-C2-deoxy--3-b~( N-dodecanoylglycyl)-4-O-phosphonb-2-tetradecanoylamino- 3-D-glucopyranosyl] -3-0- C H-dodecanoylglycyl) -2-tetradecanoylamino- cu-o~g lucopyranos ide In the same manner as in Example 4-3),, 204 mg of the compound prepared in 2) above w&s reacted to obtain 97 mg of the entitled compound as a white powder» Melting Points 150-155°C (colored and jelly-like) [o3^5. +24-4® (c=0.5, chloroformsmethanol = 3si (v/v)) D IR V*3* cm"1: 3300» 2925/ 2855, 1755, 1660, 1555 max NMR (CDCln—CD-OD)t 6(Dram): 0-89 (12H, t), 1-27 (s), 2-2-2-3 o ^ d (8H, m), 2-6-2-7 |4H, m), 4-18 (2H, m), 4-27 (2H, m), 4-61 (IH,' d), 4.82 (IH, d), 5.06 (IH* t), .24 CIH* t), 5.30 (IH, t) EXAMPLES 8 TO 80 In the same manner as described in Examples 1 to 7 * the following compounds represented by formula (la) were prepared.
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Example Hoi -■ ■ Physical Propierties 8 Melting Points 140-150°C (colored and jelly-like) Ca : +13.3* (c-0.6, chloroforms methanol = 3:1 (^/v)) IR Vma3C cm"1: 3400, 2930, 2855, 1750, 1660, 1560 NMR (CDC13-CD30D), 6(ppm): 0.90 (12H, t), 1.32 (s), 2.1-2.3 {8H, m), 5-10 {IH, t), 5.,38 (IH, t) [a30 s +11.8° Cc~0»7„ chloroform:methanol = 1:1 Melting Points I74-180°C (colored and jelly-like) C c~0-7 (v/v)) ICS v* *1 • IE cm i 3425, 2930, 2854, 1745, 1675, 3,470 NMR tCDCi^-CD.,OD ' , 6(ppn)s 0.89 (12H, t) , 1.28 3 & (s), 2.27 (2H# fcj, 2.4-2*8 (12H, m)» 2.93 (2H, m) 4.81 (IH, m), 5.14 (IH, t), 5.32 (IH, at) Melting Point: 159-167"C (colored and jelly-like) Cct : +10«2S (c-0 . 3, chloroform^methanol - 1:1 D (v/v)) IR vKBr cm'1; 3330? 2925, 2855, 1745, 1655, 1560 max 1470, 1025 NMR (CDC13~CD30D), 6(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 (IH, m), 3.71 (IH, m), 3.90 (8H» m), 4.18 (4H, m), 4-76 (IH, d), 5.13 (IH, t)r 5.24 (5H, t) Physical Properties Melting Points 165~171°C (colored and jellv-like) n-S-O4 (c=0 - 6 , chloroforms methanol = 1:1 (v/v)) 5C"B *3** i * IR vma; cm" : 3320„ 2925, 2855, 1710, 1645, 1555 iUaX 1470 NMR (CDCl ~CD„OD) , 6 (pom) : 0.89 (12H, t) , 1.27 3 3 (s), 2 .17 (SH m), 2.47 (4H, rn), 2.60 (4H, m) , 2.73 (4H,-n), 4.25 (1H» q) , 4.75 (IH, d), 5.12 (IH, t), 5.25 (IH, t) Melting Point: 169-173 °C (colored and jelly-like) [a]" ;; +16.4s (c=0-7, chloroform;methanol = 3:1 D (v/v)) KB** — i IR u„ cm x% 3425, 2925, 2855, 1735, 1645, 1555 NMR (CDC1_—CD-OD), <5 (ppm) s 0.90 (12H, t) , 2.2- 3 3 2.4 (10H, m), 3.18 (2H, t), 5.16 (IH, t) , 5.36 (IH, t) Melting Points 161-165°C (colored and jelly-like) [a]^: +9.2° (c-0.6, chloroform: methanol = 3:1 (w/v)) IR vKBr cm"1: 3405, 2930, 2855, 1/60, 1660, 1550 max MMR (CDCl_—CDo0D) , 6(pdhi)s 0.90 (12H, t) , 2.2-3 3 2.5 (8H, m)0 2.96 and 3.04 (total 6H„ each s) , 5.18 (IH, t), 5.34 (IH, t) Example Physical Properties 14 Melting Points 144—147°C (colored and jelly-like) [a] : -2 »4° (c=0 »8, chloroformsmethanol = 3;1 (v/v)) IR cm"1? 3405, 2925, 2855, 1745, 1655, 1555 NMR (CDC13~CD30D) e, 6 (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 (IH, d), 5.16 (IH, t), 5.29 (IH, t) Melting Point: 150-154°C (colored and jelly-like) [oGd s +16.8° (c=0.6, chloroform:methanol - 3 si (v/v)) JR vKBr cm-l; 3450 2930, 2860,, 1745, 1675, 1675 max 1470 NMR (CDC1--CD-0D) , 6(DK>m) : 0-88 (12H, t) , 1 »26 J O (br), 2-3-2-8 (18H, xn), 2.96 and 3-10 and 3.18 (total 6H* each s) , 5-16 (IH, m), 5-.34 (IH, m) 16 Melting Points 190-193°C (colored and jelly-like) [a]^: ~5.4° (c=0-/e, chloroform ^methanol = 3:1 (v/v)) IR vKBr cm"1: 3305, 2925,, 2855, 1750, 1650 max NMR (CDCl3-CD3OD), 6(ppm): 0-90 (12H, t), 2.1-2.4 (8H, m), 5,16 (IH, t), 5.38 (IH, t) Example No.
Physical Properties '' Melting Points 175-177°0 (colored and jelly-like) [a]D s -2.2° (c=0 -8,, chloroform: methanol = 3 si (v/v)) IR cm"1: 3310, 2925, 2855t, 1745, 1660, 1555 luaX NMR (CDC13-CD30D), 6(ppm)s 0.89 (12H, t) , 2.1-2.4 (8H, m), 5.18 (IH, t), 5.32 (IH, t) 18 Melting Points 145-150"C (colored and jelly-like) [a]^: +1.7° (c=0.6, chloroform^methanol = 3 si (v/v)) -j IR v cm" s 3300, 2925, 2855, 1755, 1S85, 1645 max 1555 NMR (CDC13-CD30D), 6(ppm): 0.90 (12H, t), 1.30 (s), 2.29 (4H, t), 2.48 (4H, t), 4.73 (IH, d) , 4.84 (IH, d), 5.19 (IH, t), 5.32 (IH, t) 19 Melting Points 165-1S3°G (colored and jelly-like) CaU^* +10.2° (c=0 « 5,, chloroform ^methanol =3:1 (v/v)) IR vKBr cm"1; 3310, 2930, 2865, 1735, 1645, 1555 max NMR (CDCl3-CD3OD), 6(ppm); 0.90 (12H, t-br), 1.30 (s), 2.20 (12H, t), 2.36 (4H, m) , 3.19 (8H, t)„ 4.68 (IH, d), 4.79 (IH, d), 5.16 (IH, t) , 5.24 IH, t) Example No. 21 22 23 Physical properties Melting points 1/8-183WC (colored and jelly-like) [s +16.8* (c=0».5, chloroform:methanol = 3si KBr - i IE v cm - HISLX (v/v)) 3315» 2925, 2855, 1735, 1660, 1570 (CDC13-CD30D), 6(ppm): 0.88 (12H, t), 1,26 (s), 2-20 , 5.18 (IH, t) , 2.56 (4H,m), 5.30 (1H, t) M Lting Points 151-160^'C (colored and jelly-like) 25 D KBr -1 IR vmax 010 f2-4° (c-0-3, chloroform :methanol = 3si (v/v)) 3350, 2925, 2855, 1750, 1647, 1555 1-26 NMR (CDCl_-CDo0D), O(ppm)s 0-88 (12H, t) If %&t $ 2.2-2.7 (16H, hi), 5-18 (IH, t), 5-30 (IH,. t) Melting Point = 160~164®C (colored and jelly-like) "5K • Cc3p s +14.5° (c=0-7, chloroform sxnethanol •- 3 = 1 ( v/ •) ) IR VKBr cm"1! 3330, 2930, 2860, 1755, 1660, 1565 max NMR (CDClg-CDgOD), $(ppra); 0-90 (12H, t), 1.32 (s), 2.1-2.3 (8H, m), 5.10 (IH, t) 5-38 (IH, t) Melting points 168-174°C (colored and jelly-like) i25 C«3 D +6-6° (c=0*3f chloroform^methanol = 3si (v/v)) IR vlar, cm"": 3315, 2930, 2860, 1760, 1660, 1555 AUclX NMR (CDC1 -CD OD), 6(ppm): 0-88 (12H, t), 1.26 3 o (s), 2.1-2-8 (2OH, m), 5.20 (IH, t), 5.34 (IH, t) Physical Properties Melting Points 160-170°C (gradually colored and jelly-like) [^ s +21 «7° (c^O.6,,. chloroform: methanol = 3si (v/v)) tQJy i IR vmax cm"": 3450,, 2S30, 2860, 1760, 1S75, 1470 NMR {CDCi -CD OD) 6(ozm)s 0.90 (12H, t),*l»32 3 3 (s), 2.43 (8H, m), 2.96 and 3»08 and 3.16 (total 12H, each m, s, s) ,, 4.87 (2H, m) , 5.20 (IH# m) , 5.47 (1H» m) Melting Point: 1S6-170°C (colored and jelly-like) Lci] ^ % +10.6- {c=l -0chloroform:methanol = 3si D (v/v)) V„«C cm"": 3330, 2925, 2855, 1745, 1660, 1560 IttaX .
NMR (CDC1-—CD_OD), 6 (pom): 0.88 (12H, t), 1.26 3 (s), 2-1-2.4 (8H, m), 3.5-3 -8 (4H, m) , 3.94 (6H, m), 4.20 <4H, m), 4.79 (IB, d), 5.19 (IH, t), 5.25 (IH, t) Melting Points 160-162 °C (colored and jelly-like) [aTj~ ^ z +12.9° (c=0.7, chloroform:methanol - 3 si (v/v)) IR V*?* cm"1: 3320, 2925, 2855, 1730, 1655, 1565 luclX NMR (CDCl3-CD3OD) , 6 (ppm); 0.90 (12H, t) , 2.18 (8H, m), 2.36 (4H, m), 3.20 (4H? m) , 4.78 (IH, d) , 5.2 (2Ht m) Example iS?o,„ physical Properties- 27 Melting Points 162-165°C" (colored and jelly-like) Cot 3^ s +10.7* (e-0»6, chloroform ^methanolswater = 8s3sl (v/v) lower layer) IR v^fx on""1® 3315, 2925, 2860, 1760, 1645, 1555 NMR (CDCl3-CD3OD), 6(ppm): 0-90 (12H, t), 2-1-2.4 (12H, m), 3-1-3.3 (4H, t), 5.20 (IH, t), 5-37 (IH, t) 28 Melting Points 160-164*C (colored and jelly-like) Ca3^* •3-14.1° (c=0-7, chloroform^methanol =3:1 (v/v)) KBr _i IR vmax cm -s 3410, 2925, 2855, 1750, 1645, 1560 NMR (CDC13-CD30D), 6(ppm): 0.90 (12H, t), 2.1-2.4 (8H,r m)f 5-18 (IH, t) , 5.38 (IH, t) 29 Melting Points 165-168°C (colored and jelly-like) Ecil^x +8.6° {c-0.7, chloroformrmethanol:water = D 6:4:1 (v/v)) KBr n IR \>max cm : 3315, 3100, 2925, 2855, 1745, 1660, 1565 NMR (CDCl3-CD3OD), 6(ppm): 0-90 (12H, t), 2.2-2.5 (12H, in), 4-81 (IH, d) „ 5-19 (IH, t) 5.35 (IH, t) Example Mo- Physical Properties Melting Point: 177-185"C~(gradually colored and jelly-like) [oO~ s +3 -7e (c^O.S, chloroformsmethanol:water = 6=4:1 (v/v)) IR vf?C cm"1: 3315? 2930, 2855, 1750, 1660, 1560 max NMR (CDClg-CDgOD), 6(ppm): 0-88 (12H, t), 1.26 (s), 2.1-2-5 (10H, m), 5-18 (IH, t), 5.34 (IH, t) 31 C® 3^* = +2.4° (chloroform:me-thanol:water:triethyl amine = 8 s 3 s0.5:0*01 (v/v)) NMR (CDC10—CD_0D), 6(ppm) : 0.90 (12H, t), 1.28 J 3 (s), 2-1-2.4 (8H, m), 5.16 (IH, t), 5.32 (IH, t) 32 Melting Points 170™175°C (colored and jelly-like) Cos ] ■ s +5.2*' C c=0 - 6, chloroform smethanol - 3.1 (v/v)) IRv" r, cm 3300, 2925, 2855, 1750, 1680, 1565 NMR (CDC1 -CDgOD) , 6 (ppsa) : 0.90 (12H, t) , 1.30 (s), 2.2-2.5 (8H, m), 5.20 (IH, m), 5.37 (IH, m) 33 Melting Points 182-185°C (colored and jelly-like) Ccx 3~^ = ■ +11-5° (c=0.7, chloroform:methanol = 3:1 0 (v/v)) KBr IRvmax cm A: 3315, 2925, 2855, 1735, 1645, 1560 NMR (CDC1 -CD OD), 6 (ppm)s 0-90 (12H, t), 2.1-2-4 J Cr (12H, m), 3.1-3-3 (4H, m),, 5.1-5-4 (2H„ m) Example Ho" Physical Properties 34 Melting points 157~162eC (colored and jelly-lilce) [a +13 «8° (c=0»5, chloroform smethanol = 3 si (v/v)) KBr 2930, IR v t cm x: 3330-2860, 1755, 1660, 1565 lilaA j NMR (CDCl3-CD3OD), 6(ppm): 0.91 (12H, t), 1-32 (s), 2-1-2.3 (8H, m)t 5-10 (IH, t), 5-38 (IH, t) Melting Point: 1S8~172°C (colored and jelly-like) Ca s +14.6° (c~l .0,, chloroform smethanol = 3 si (v/v)) KBr IR vmax cm : 3320, 2930, 2860, 1755, 1660, 1565 NMR (CDC1 -Cp.OOK 6 (ppm)': 0.91 (12H, t) , 1.32 3,3 (br)t 2-12-2.32 C8H, m), 5.18 (IH, n), 5.36 (IH, sq) 36 Melting Point: 175-180"C (colored and jelly-like) £a j|25. +9.9° (c=0«7, chloroform smethanol = 3 si (v/v)) IR vmax cm"1: 3300, 2930, 2860, 1750, 1675, 1580 1560 NMR (CDC13-CD30D), 6(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 (IH, d), 5-18 (IH, t), 5.35 (IH, m) Example Mo» Phvsical Properties 37 Melting Points 170-175®C (colored and jelly-like) Cclf: +14 ® 9 ° (0=0.6# chloroform smethanol - 3 si (v/v)) IR vj®* cm™1? 3400, 3300, 2930, 2860, 1755, 1675, 1575 NMR (CDCl3-CD3OD), 6(ppm): 0.91 (12H, t), 1.32 (-8)/'-2.29 (2H, m), 2.43 (6H, m), 2.94 and 3.12 (total 9H, each hi) , 4.83 (IH,, m), 5.18 (IH, m) ... 5.44 (IH, m) 38 Melting Points 166-174*C (colored and jelly-like) 2 ^ i +9.2° (e-0.6* chloroform smethanol - 3 si (v/v)) IE vKBr cm"1: 3310, 2930, 2860,, 1750 , 1660, 1565 max NMR (CDClg-CDgOD) , 6 (ppm) s 0.88 (12H, t).„, 1.26 (s), 2.1-2-4 (20H, m), 2.94 (3H, s), 3.04. (3H, a), 5.18 (IH, t) , 5.36 (IH,, t) 39 Melting Points 170~186°C (gradually colored and jelly-like) DO". +7.8® (c-1-1, chloroform smethanol = 3sl (v/v)) IR v55 cm-1: 3310, 2930, 2860, 1750, 1660, 1565 max NMR (CDCl3-CD3OD), 6(ppm)s 0»88 (12H, t), 1.26 (s), 2.20 (8H, t), 2•43 (4H, t), 2.94 (IH, m), 3.11 (6H, s), 3.19 (4H, m), 4.81 (IH, m) , 5.19 (1H,~ t) , 5.38 (IH, t) - 94 _ Example No.
Physical properties 40 Melting Points 184-186®C (colored and jelly-like) +6.0B (c~Q «, 5 e chloroform smethanol = 3sl (v/v)) IR cm"1: 3460, 1758, 166 2 NMR (CDC13~CD30D), 6 (ppm) : 0-88 (12H, t) , 1-26 (s), 2.1 - 2.5 (8Hjn)s 2„94s 3.12 (total 6H,S) 4.80 (1H,m), 5.18 (IH,- m), 5„38 (IH, m) - 41 Melting Points 155-165°C (gradually colored and jelly-like) O 2"^ • +8.2° (c=0.7* chloroform smethanol s water = 6:4:1 {v/v)) IR cm*"1: 3320, 2930, 2850, 1760, 1645, 1565 Kiel 3k • NMR (CDC1 -CD3OD), ofppmlc 0,90 (12H, t), 1.30 (s), 2.2 (X2H, m), 3.18 C4H, t-tor), 5.,19 (IH, t)» 5.36 (IH, t) 42 Melting Point: 165-168°C {colored ana jelly-like) [a]" s +23-S0 (c-0.6, chloroformsmethanol - 3:1 (v/v)) IR vma^ cm~ s 3450, 2925, 2855,, 1735, 1675, 1635 NMR (CDC13~CD30D), 6(ppm): 0.90 (12H, t), 1-30 (s), 2.3-2.5 (8HC m), 2.92 and 2«94 and 3.07 and 3.09 (total 6He, s) , 4-74 (IH, m) . 4.87 (IH, d) , 5.14 (IH, t), 5»38 (IH, t) Example No, Phvsical Properties 43 Melting Points 177-17S"C (colored and jelly-like) (c=0.7 (v/v)) Caj". (c=0.7* chloroform smethanol = 3si r" IR cm"1.- 3310, 2860, 1734, 1659, 1560 MR (CDC13-CD30D), 6(ppm): 0.S0 (12H, t), 2,1-2-4 (12H, m), 3 .10 (4H, t), 5.1-5.3 (2H, hi) 44 Melting Point: 145-150UC (colored and jelly-like) Ca 'j" s +7.6° (e-0 8 , chloroform ^methanol = 3 = 1 (v/v)) IR vic3r chi™1 s 3300, 1760, 1665, 1555 max NMR (CDCl3-CD3OD), 6 (ppm) : 0»90 (12H, t) . 1.30 (s), 2.30 (8H, m)# 4-84 (3LH, d), 5.IS (IH, t) , 5.33 (1H» t) 45 Melting Points 148-153°C {colored and jelly-like) C^3p^s 4-18-4® (c~0.9, chloroform smethanol = 3 si !. */*«')) IR v*®* cm"1: 3300, 1745, 1645, 1555 UlaX NMR (CDC13-CD30D) , 6 (ppm) : 0.90 (12H, t) «, 1.30 (s), 2.30 (8H, m), 4.86 (IH, d) , 5-16 (IH, t), .5.34 (IH, t) Physical Properties Melting Points 155-158eC (colored and jelly-lilce) [a s +11 -6° (c~l • 0 - chloroformsmethanol = 3 s 1 (v/v)) IR vKBr cm"1: 3320# 1745, 1645, 1555 max NMR (CDC1_—CD_OD), <5 (ppm) s 0.89 (12H, t), 1.30 3 3 Cs), 2.1-2.4 (12H, m), 3-18 (4H, br), 4-67 (IH, d), 5-2 (2H, m) NMR (CDC13-CD30D), <5 (ppm) s 0-88 (12H, t) , 1.26 Cs), 1 -9-2-1 (4H, m), 2.2-2-4 (8H, m), 5.16 (IH, t)t 5.30 (IE# t) [c t +4■»3 ° (c—0.8, chloroform smethanol = 3 s 1 (v/v)) &1MR £CDClg-CDgOD) # 6 (ppm) s 0-88 (12H, t) „ 1.26 (s)r 1.9-2.2 (4H« n), 2.2-2.4 (8H, m) „ 4.80 (IH, d), 5.14 (IH# tj, 5.30 (IH, t) +14.1° Cc~0.7# chloroform smethanol: water = D 8:3:0.5 (v/v)) NMR (CDC13~CD30D), 6(ppm)s 0»88 (SH, t), 1.26 Cs), 1.4-1-8 (m)# 2.08 (4H# m)# 2.34 (4H# m) # 4.63 (IH, d) , 4.78 (IH, d) , 5.20 (2H, m) [a; +16.6° (c=l 0P chloroform smethanol:water = 8 s 3:0 - 5 (v/v)) NMR (CDC13-CD30D), 6(ppm): 0.88 (6H, t) , 1.26 (s). 1.4-1.8 (m), 2.20 (4H„ m), 2.36 (4H, m)f 4.86 (IH» d)# 5.14 (lHf t), 5.30 (IH, t) Example Mol Physical Properties 51 Melting Points 148-153"C {colored and jelly-like) L<x3q5 = +10-0* (e=0,7 chloroform ^methanol ~ 3si (v/v)) KBr -i IR cm *s 3320, 2925, 2855, 1745, 1645, 1565 NMR (CPC13~CD30D), 6(ppm): 0.S0 (12H, t), 1«30 (s), 2-2-2-3 (8H, m), 4-70 (IH, d), 4.81 (IH, d) , 5.16 (IH, t), 5.31 (IH, t) 52 Melting Points 135~138#C (colored and jelly-like) [a 3?^ s -4-13.3° (c=0-l, chloroform:methanol - 3si (v/v)) IR vg; cm"1; 3405, 2925, 2855, 1750, 1660, 1555 NMR CCDC1_~CD.0D) , 6 (ppm) : 0-88 |12H, *) , 1.26 J (br), 2.3-2.8 (24H, m) , 5.16 (IE, m). 5-30 (ih, m) 53 Melting Point: 158-173"C (colored and jelly-like) s +9.4° (c=0.5# chloro£orm:methanol:water = ~D 6:4:1 (v/v)) IR v?r cm"-1: 3350„• 2930, 1745, 1660, 1570 max NMR (CDCl —CD OD), 6(ppm): 0.90 (12H, t), 1.30 3 j (s) , 2.1-2-3 (10H, xn), 3-18 (2H, t) , 4.78 (2H, m) , 5.18 (IH, t), 5-35 (IH, t) Physical properties Melting Points 182-3.88 °C (colored and jelly-like) DO*. 4-11.8" (c=0.7, chloroform smethanol ~ X s 1 (v/v)) IR vKBr cm"1: 3310, 2926, 2854, 1749, 1677, 1563 max NMR (CDCl3~CD3OD), 6(ppm)s 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), 4-82 (IE, d), 5-12 (IH, t), 5-34 (IH, t) Melting Points 160-165®C (colored and jelly-like) +16.8® (c=0 - 5, chloroform smethanol = 3 = 1 (v/v)) IR vKBx can"1: • 3330,, 2925-, 2855, 1735, 1645, 1550 max MMR (CDClg-CDgOD) , 6 Cppa) s 0-89 (12H. t) # 1.27 (s), 2-1-2-4 ClOH, m), 3.16 (12H, t.) , 4.27 (IH, q>, 4.76 (IH, d), 4.79'CIH, d), 5,12 (IH, dd), 5.33 (IH, t) Melting Points 158-162®C (colored and jelly-like) [oO?^ : +13.09 (e=0.4, chloroformsmethanol = 3si (v/v)) ■ IR vBr cm"1: 3328, 2926, 2854,- 1749, 1659, 1563 max HMR (CDC13-CD30D), 6(ppm)s 0.89 (12H, t), 1-27 (s) ,= 1.5-1.6 (8H/ m) „ 2.1-2.3 (8H, m) , 5-14 (IH, t), 5.32 (IH, t) Physical Properties Melting Points 158-172°C (colored and jelly-like) Ce]*s +14-2° (c=0«S, chloroform smethanol = 3 si (v/v)) IH era**1: 3320, 2925, 2855, 1750, 1660, 1565 luax MMR (CDCl3"CD3OD) 6 (ppm) s 0.81 (12H,, t) , 1.18 (s), 1-5-1.6 (8H , m), 2.0-2.2 (8H, m), 5.05 (IH, t)# 5.23 (IH, t) Melting Points 184-187°C (colored and jelly-like) Ca3*- +15.4° {c=0.6, chloroformsmethanol = 1:1 (v/v)) IR v*31 cm"1: 3430, 2930, 2855, 1755, 1660, 1565, max 1470, 1385- Melting Points 178-182°C (colored and jelly-like) C(x3q5 = +9.5° Cc=0.6, chloroform smethanol = I si (v/v)) KB-5- i IH >f * cm"': 3405, 2930, 2855, 1760, 1660, 1555, IICaA 1470, 120 5, 1025.
KMR (CDCl3-CD3OD), 6(ppm): 0.89 (12H, t), 1.27 (s), 1.61 (m), 2-12-2-36 (10H, m), 2.91, 3.03 (total 3H, each s), 4,77 (IH, d)„ 5-14 (IH, t) 5.32 (IH# t) Example No.
Physical properties 60 Melting Points 152-198"C (colored and jelly-like) [cs]*s +7-8° (c=0«5,, chloroform smethanol = 1x1 (v/v)) IR vmax cm~1- 3355, 2930, 2855, 1745, 1660, 1565, 1470* 1385, 1210 NMR (CDCl3~CD3OD), 6(ppm): 0.89 (12H, fc), 1-28 (s),, 1.60 (in), 2.12-2.38 (10H, m), 3-16 (2H, t) , 3.53 (2K, m), 3.52 (IH, m), 3-72 -(IH, m), 3,90 (8H, a), 4.16 (SH, m), 4.23 (1H» q) » 4-59 (IH, d) , 5.15 {IH, t), 5.21 (IH, t) 61 Melting Point: .194-195 °C (colored and jelly-like) [a3* : 4-7.2'* (c?=0.8, chloroformrmetnanol = 1 = 1 (v/v)) IR vmax cm"1: 3320, 2930, 2855, 1745, 1660, 1555, 1025 NMR (CDCl3~CD3OD), 6(ppm)s 0.89 (12H, t) , 1»27 (s), 1.60 (m), 2.03-2.35 (12H, m), 3-16 (5H, m), 3.50 (2H, la), 3.54 (IH, hi), 3-72 (IH, m) , 3.88 (2H, m), 4.15 (5Hf m), 4-27 (IH, q) 4.77 (IH, d), 5.15 (IE, t) , 5.23 (IH,. t) Physical Properties Melting Points 177-182°C (colored and jelly-like) C°0D : 4-11.6° (e=0-5 , chloroform smethanol = 3 si (v/v)) KBr IR Vmax cm *s 3330, 2925, 2855, 1755, 1650, 1555, 1470 NMR (CDC13-CD30D), 6{ppm) s 0.89 (X2H, t), 1.27 (s) , 2.13-2.27 (10H, in), 3-IS (2E, t), 4-74-4-77 (2H, t), 5.15 (IH, t), 5-32 {IH, t) Melting Points 173-177"C (colored and jelly-like) +9-5s (e~0.5, chloroform:methanolswater = D 6:4:1 (v/v)} KBr -i XR Vmex cm s 3330, 2925-, 2855, 1755, 1660, 1565 NMR (CDCl3-CD3OD), 6(ppm): 0,89 (12H, t), 1.27 (3), 2.1-2-3 ClOH, m), 3.17 (2H„ m), 4-2S (IH, q), 4.75 (1H« d), 4-77 ClH, d) , 5.14 (IH, dd), 5-38 (1H„ dd) NMR (CDC13-CD30D), 6(ppra)s 0-90 (12H, t), 1-26 (s), 2.1-2-5 (8H, m), 4.83 (IH, d), 5-1-5-4 (2H, m) Melting Points 148-151nC (colored and jelly-like) NMR (CDCl —CD OD)„ 6(ppm): 0.90 (12H, t), 1-26 3 3 (s), 2.10-2.50 (8H» m)„ 4.82 (lHe d), 5-1-5-3 (2H, m) Physical properties Melting Points 166-5-168*.5°C (gradually colored and jelly-like) NMR (CDC13-CD30D) , 6 (pe®0 : 0-90 (12H, t) , 1-26 (s), 2-16 (2H, t) ,, 2-32 (4H, m) 2-50 (2H, d) , 4-82 (IH, <3.) , 5 .16 (IH, t) , 5-32 (IH, t) Malting Points 155~158°C (colored and jelly-like) [a s +1.519 (c=0 - 5, chloroform smethanol = 3 zl {"/■/)) KBr IR vmax cm 3400, 2930, 2860, 1740, 1660 MR (CDClg-CDgOD)f 6(ppm)s 0-90 (12H, t), 2.3-2.5 (8H, m), 5.2 (2H, m) Melting Points 153.5-155 .CC (gradually brown-colored and jelly-like) [a 3*: +13.3° (c—0-6, chloroformsmethanol = 9sl (v/v) ) -a 1Rviax c"~~s 3445, 2530, 1740, 1660, 1560 NMR (CDCl -CD-OD), 6(ppm): 0-90 (12H), 2-10-2.26 d J (4H, m), 2.26-2.46 (4H, hi) Melting Points 156-158»5°C (gradually brown-eolor-ed and jelly-like) [a 3* : +16-5° (0=0*9, chloroform smethanol = 9 si (v/v)) cm"1: 3450, 2930, 1735, 1660, 1560 ludiC NMR (CDC13~CD30D), 6 (ppm); 0.89 (12H, t), 1-30 (s) -e 2.10-2-45 (8H, m) , 5 -J20 (m) Physical Properties Melting Points 148-152°C (gradually brown-colored and jelly-like) [ci]^5s +14-5'' (c=0.9, chloroform smethanol = 9sl (v/v)) KBr IR vmax cm 3450, 2930, 1745, 1650, 1560 MMR (CDCi_—CD_OD) , 6(ppaa) : 0.90 (12H, t) , 1-30 o o (s), 2-10-2.50 (8H, m), 5-10-5.35 (2H, m) Melting Points 156-158.5°C (gradually brox^rs,-colored and jelly-like) CcO^- +14.1° (c-0.9/ chloroform^methanol = 9sl (v/v)) KBr _ 'j IR era "s 3350, 2930; 1730, 1660,, 1560 NMR CCPCl3»CD3OD) , 6(ppra) = 0.90 (12H, t.) , 1.30 (s) jf 2-1-2.5 CSH, m), 5*1-5.3 _ (2H, m) Melting Points 184-1889C (gradually torovn-colored and jelly-like) [a]", +8-3° (c~0-7, chloroform) IR cm"1: 3455, 2925* 1745, 1665, 1555 lUGiC NMR (CDC13-CD30D) , 6(ppra) : 0.89 (12H, t), 2.1-2.5 (8H, m), 5.1-5.4 (2H, m) Example No".
Physical Properties 73 Melting Points 169-171°C (colored and jelly-like) [ct s +6*2® (c=1.22, chloroform smethanol = 3:1 (v/v)) NMR (CDC13»CD30D) , 6 (ppm) : 0.90 (12H, t) , 1.26 (s) „ 2.1-2»6 (8H, m) , 4.80 (IH, d) , 5.16 (IH, t) , 5.34 (IH, t) 74 Melting Points 140~145°C (colored and jelly-like) [a 3^ s +10.3 s (c-0»6 f chloroform smethanol = 3:1 (v/v)) IR vma* cm"1! 3330,» 2925, 2855, 1755, 1645, 1550 NMR (CDCl -CD.,OD) , 6(opra) : 0-90 (12H, t) , 1.30 3 3 (a) t 2.1-2.3 (8K, m), 2-6-3-0 (4H, m}, 4-89 (IH, d), 4-99 (IH, d), 5.09 (IH, t), 5.45 (IH, t) 75 Melting Points 142-147°C (colored and jelly-like) i +11 .7* {c=0-7, chloroform smethanol - 3:1 (v/v)) NMR (CDC13-CD30D) , 6 (ppm) : 0.90 (12H, t) , 1-30 (s), 2.1-2.4 (8H, m)., 5-10 (IH, t) , 5.30 (IH, t) 76 Melting Points 145-148°C (colored and jelly-like) [00^5 . +-14,2a (c=0 . 5, chloroform smethanol = 3 s 1 (v/v)) IR v " cm 3450„ 2925, 2855, 1740, 1640 inax NMR (CDCl3~CD3OD)0 6(ppm): 0.90 (12H, t, J=6 Hz), 2.1-2-4 (8Hf m), 4.80 (IH, d, J=4 Hs)e 5.24 (2H, m) - Example No- Physical Proper-ci.es- [ct 3^ s +20 «6B (c=0-31, chloroform smethanol = Isl 77 Melting Points 149-153°C (colored and jelly-like) (c=0»3 (v/v)) vmax cm"1*. 3406, 2926, 2854, 1746, 1662, 1557 (CDC13-CD30D), 6(ppm): 0.89 (12H, t), 1-27 (s), 2-23 (4H, m), 2-46 (SH, m)2.59 (3H, m), 2-68 (3H, m), 4.89 (IH, d) , 5.16 (IH, t), 5-25 (IE, t), 5.38 (IH, t) 78 Melting Points 170-175°C (colored and jelly-like) Ife325» h-12.6® (c-0.5, chloroform smethanol :water = 6:4:1 (v/v)) IR vmax cm~"- 3320, 2925, 2855, 1755, 1660, 1560 MMR (CDC13-CD30D), 6 (ppm) - 0.89 (i2H, t) , 1.27 (s)# 2.1-2-3 (8H',"m), 3-18 (4H, m), 4.72 (IH, d), 5.23 (IH, t), 5-33 (IH, dd) 79 Melting Points 172-175°C (colored and jelly-like) (c-0... 5, chlo: 6 s4:1 (v/v)) DOp s +12.6° (c-0.5, chloroform smethanol:water IR v*?* era"1? 3320, 2920, 2850, 1755, 1655, 1550 UMaX MMR (CDCl -CD.OD), <5 (pom) : 0.89 (12H, t) , 1.27 3 3 (s), 2-1-2.3 (10H, m) , 3-16 (2«, m), 4.28 (IH, q) , 4.35 (IH. q), 4.69 (IH, d), 4.80 (IH, d), 5-21 (IH, t), 5-32 (IH, t) Example Mo, Physical Properties 80 Melting Points 170~175°C (colored and jelly-like) s +20»2S (e=0.5, chloroform:methanol - 3si (v/v)) IR v^?: cm"1; 3330» 2930, 2855, 1755, 1555, 1555, max 1470 NMR (CDCl3~CD3OD), 6(ppm) : 0.89 (12H, t) , 2.15-2»3 (10H, m), 2.6-2-7 (4H, m), 3.17 (2H, m)„ 4.58 (IH, d) 4.83 (IH, d) , 5.07 (IH, t) , 5.23 (IH, t), 5.30 (IH, t) TSST EXAMPLE Fibrosarcoma cells (Meth A} (2 x 10 ) induced in a BMiB/c mouse by methyl chlolanthrene were in.tracutaneously implanted to the flank of seven BAL3/c mice per group- A 5 triethylamine salt of each of the compounds according to the present inventin as shown in Table 1 below was dissolved or suspended in a 0®1% (v/v) triethylamine aqueous solution to prepare a 500 Vg/ml solution or suspension* The solution or suspension was administered to the x-aice at a dose level of 10 100 Pg/mouse through the tail vein on the 7th.. 12th, and 21st days from the implantation- The antitumor effect {%} on growth of the fibrosarcoma was determined by dividing the average tumor weight of the test group on the 21st day by the average tumor 15 weight of the control group (non-treated group) and multiplying the quotient by 100 - For comparison, the same evaluation was made by using Compound A as a comparative compound- The results obtained are shown in Table 1.
Table 1 Compound of Examole Antitumor Effect (%) 1 19 2 13 3 8 9 11 32 24 43 7 46 8 53 6 Compound A Control 100 It can toe seen from Table 1 that the compounds 15 according to the present invention exhibit antitumor activity equal or higher than Compound A.
TEST EXAMPLE 2 A triethylamine salt of each of the compounds according to the present invention as shown in Table 2 below 20 was dissolved or suspended in a 5% (w/v) glucose aqueous solution containing 0.1 (v/v) triethylamine to prepare a 100 pg/ml solution or suspension. The solution or suspension was administered to three NSW male rabbits per group at a dose level of 50 yg/kg-b.w- "through the ear vein for consecutive three days. The toxicity was evaluated by the number of dead animals after 24 hours from the final administration/the number of test animals. For comparison, Compound A was administered at. a level of 5 yg/kg-b. The results obtained are shown in Table 2» Table 2 Compound of Example 1 8 25 32 45 Compound A Dose Number of Dead Rabbits/ Level Hurnber of Test. Animals (yg/kg) 50 0/3 50 0/3 50 0/3 50 0/3 50 0/3 4/4 As is apparent from Table 2,, -the compounds according to the present invention have toxicity lower than 1/10 of that of Compound A and thus prove excellent in safety. - 1 1 0' -

Claims (5)

CLAIMS 10 15 20 25 1- A compound represented by formula (I)s ho-ch (HO)2P0 (I) NHR nhr" wherein R represents ZR6 or zxr6 Z2RS I O wh'erein Zr Z", and each represents an alkylene group having from 1 to 6 carbon atoms, and R® represents a car- 1 • ^ ^ id boryl group or a phosphonoxy group? R , R g R , and R" Q Q-s I I each represents -cor7, -COZ3R8P -co(ch_) , ch-n-cor', 2 nl q q, II -co(ch2) ^^ch—n-coz3r8* -co(ch2) ^jcor' , -ch(ch2) 9ocoz3r8, Q, -CO(CH_) ,cor7, -CO(CH-) _c0z3r8, ~CO(CH„) CO(CH ) NCOR7 2 n2 2 rs.2 2 n2 2 n3 30 -CO(CH ) CO(CH ) NCOS3R8„ wherein R7 represents an 2 n2 2 n3 alkyl group having from 1 to 30 carbon atoms which may be - 111 - substituted with one or snore hydroxyl groups,, . g3 represents an alkylene group having from 1 to 9 carbon atoms,, R represents a cycloalkyl group having from 3 to 12 carbon atoms Which may be substituted with one or more hydroxyl groups,, Q represents a hydrogen atom,, an alkyl group having from 1 to 6 carbon atoms, -GOMH^<» -COOH or -CH^OH,, represents a hydrogen atom or an alkyl group having from 1 to 20 carbon atoms, nl represents 0 or an integer of from 1 to 20, and n2 5 and n3 each represents an integer of from 1 to 20? end R represents a hydrogen atom,, a phosphono group or -CO(CH^} ^COORwherein m represents 0 or an integer of from 1 to 5S and the salts thereof. 20 15 2- A compound as claimed in claim 1, wherein R repre- sents EE6 or CH j and R1 , R2a> R3 „ and R4 each . _ z r Q Q, 7 3 8 I 1 7 represents -COR , -COS^R , -c0(ch_) ,ch-n-cor , 2 nl Q Q, i |* -co(ch2)nl ch-n—c033r8, -co(ch2 >n2.cor7 or -co(ch2)r2coz3r8. 3. A compound as claimed in claim 2„ wherein R repre- 12 3 4 25 sents z0p0(0h)2? and R » R , r „ and R each represents Q Qi -cor7 or -co(ch ) , J:h-n-cor7. 2 nl - 112 - 4. A compound as claimed in claim 1 or claim 2 wherein R represents 6 ZR wherein Z represents a methylene or an ethylene group and R^ represents a carboxyl group or a phosphonoxy group,
1-j 7 7 R and R each represents -COR wherein R represents an alkyl group having from 1 to 30 carbon atoms, 2 4 R and R each represents Q - Ql I I ~C0(CH2)nl CH - N - COR? wherein nl represents 0 (zero), Q and Q, each represents a 7 s hydrogen atom and R represents an alkyl group having from 1 to 30 carbon atoms or 7 7 -COR wherein R represents an alkyl group having from 1 to 30 5 carbon atoms, and R represents a hydrogen atom. 5. The compounds as claimed in claim 2, which are: 1,3-dicarboxyisopropvl 2-deoxy-6-0-[2-deoxy-3-0»(M~dodecanoyl-glycyl)-4-0-phosphono-2-tetradecanoylamino-B-D-glucopyranosyl]-3-0- (N-dodecanoylglycy1)-2-tetradecanoylamino-a-D-glucopyranoside; 2-phosphonoxyethvl 2-deoxy-6-0~[2-deoxy-3-0-(N-dodecanoylglycyl) 4~0-phosphono~2-tetradecanoy1amino-3-D-glucopvranosvl]-3-0-(N-dodecanoyIglycy1)-2-tetradecanoy1amino-a-D-glucopvranoside; 2-phosphonoxvethyl 2-deoxy~5~0-[2-deoxy-3-0-(N-dodecanoylglycyl) 2-(N-dodecanoyl-M-methyl-glycylamino)-4-0-phosphono-B-D-glucopvranosy 3-0-(N-dodecanoylglycyl)~2-(N-dodecanoyl-N-methylglycylamino)-a-D-glucopyranoside* 2-phosphonoxyethvl 2-deoxy~6-0-[2~deoxy-3-0~(N-dodecanoylglycyl) 4-0-phosphono-2-tetradecanoylamino-B-D-glucopyranosyl]-3-0- - 113 - (N-dodecanoylglvcyl) -2-tetradecanoyl ami no-ct-D-glucopyranos i de ; 2-phosphonoxyethyl 2-deoxy-6»0-[2-deoxy-3-0-[(R)-3-hydroxytetra~ decanoyl]-2-[(R)-3-hydroxytetradecanoylamino]~4-0-phosphono-g-D-g1ucopyranosy1]-3-0-[(R)-3-hydroxvtetradecanoy1]-2-[(R)-3-hvdroxytetra-decanoy1ami no]~a-D~glucopyranosi de; carboxymethyl 2-deoxy-6-0-[2-deoxy-3-0-(N-dodecanoylglycyl)-4-0-phosphono-2-tetradecanoylamino-3-D-glucopvranosyl]-3-0-tetradecanoy 1-2-tetradecanoylamino-a~D-glucopyranoside; 2-phosphonoxyethvl 2-deoxy-6-0-[2-deoxy-2-(6**octanoylamino-hexanoylamino)-4-0-phosphono»3-0-tetradecanoyl-g-D-glucopvranosy1]- 2-(6-octanoylaminohexanoyl)amino-3-0-tetradecanoyl-a-D-glucopyranoside; 2-phosphonoxyethyl 2~deoxy-6-0-[2-deoxy-3-0-(N-dodecanoylglycyl)-4-0-phosphono~2-tetradecanoylamino-$-D-glucopyranosyl]-3-0~(N-dodecanoylglycyl)~2-[(5-octanoylamino)-hexanoylamino]-a-D-gluco~ pvranoside;
2-phosphonoxyethyl 2-deoxy-6-0~[2~deoxy-4-0-phosphono~3-0-tetradecanoyl~2~tetradecanoylamino-B-D-glucopyranosyl]~
3-0-(IN-dodecanoy 1 g lycy 1~2~tetradecanoy1ami no-a-D-g1ucopyranos i de; 2-phosphonoxyethyl 2-deoxy-6-0-[2-deoxy~3-0-(N-dodecanoylglycyl)- 4-0-phosphono-2-tetradecanoy1ami no-B-D-g1ucopyranosy1]-2-(8-hexanoy1-ami nooctanoy1ami no)-3-0-tetradecanoy1-a~D-g1ucopyranos i de: 2-phosphonoxyethyl 2-deoxy-6~0-[2-deoxy--2-(8-hexanoyl-ami nooctanoy1ami no)~4~0-phosphono-3-0-tetradecanoy1-p-D-g1ucopyranosy 1 ]-2-(8~hexanov1aminooctanoy1ami no)-3-0-tetradecanoy1-a -D-g1ucopyranos i de; 2-phosphonoxyethyl 2-deoxy-6~0-[2-deoxy-2-(H-dodecanoyl-N-methylglycylamino)-3-0~(4-oxotetradecanoyl)-4-0-phosphono-e -D-glucopyranosyl]-3-0-(H-dodecanoylglycyl)-2-(INI-dodecanoyl-N«-methyl~ g1ycv1ami no)-a-D-g1ucopyranosi de; - 114 -■ 2-phosphonoxyethyl 2-deoxy-6-0-[2-deoxy-3-0-(4-oxotetra-decanoyl)-4-0-phosphono-2-tetradecanoylamino-3-D-g1ucopyranosy1]-3-0-(N-dodecanoylglycyl)=2-tetradecanoylamino-a-D-glucopyranoside; 5 2-phosphonoxyethyl 2-deoxy-6-0-[2-deoxy-3-0-(N-dodecanoylglycyl)-
4-0-phosphono-2-tetradecanoylamino-3-D-glucopyranosyl]-3-0-(M-dodecanoylglycyl)-2-[6-N-methyl-N-octanoylamino)-hexanoyl-amino]-a~ D-g1ucopyranos i de. 10 6. A process for preparing the compound of the claims 1 to 5 characterized in that a compound of the general formula II 15 (R12°, 31 OR 10 20 NHR (II) 25 wherein R^ represents a hydrogen atom or a hydroxyl-protective group; R1^ represents ZC00R14, Z0P0(0R1^)2, 30 Z1COOR1 -CH 35 - 115 - or 1 13 z opo(or" )o ? "• 3 . 2"opo(or ) R^, R^, and R3^ each represents -COR^, -COZ^R8', Q~ Q, I 1 -1 -CO(CH,1 tCB-ITCOR'1-, J, i»-s. Q_ Q, II 3 81 -CO(CH2)nlCH-NCOZ R -C0(CH2)n20C0R71, -C0(GH2)n20C0Z3R81, -C0(CH2)n2C0R71, -C0(CH2)n2C0Z3R81, Q1 ?1 I ti I 3 81 —CO(CH ) CO(CH ) NCOR or ~co^CH2^ n2C°^CH2 ^ n3NCOZ R 1 R represents a hydrogen atom, -C0(CH^) COOR or P0(0R )0, 12 13 wherein R~ and R each represents a phosphonoprotective group; .V.-. ® 14 71 R represents a carboxvl-protective group; R represents an alkyl group having from 1 to 30 carbon atoms which may be substituted with one or more hvdroxyl groups protected with a hydroxyl-protective group; - 116 - Ol R represents a cycloalkvl group having from 3 to 12 carbon atoms which mav be substituted with one or more hydroxyl groups protected with 2 a hydroxyl-protective group; Q represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, -CONI^, -COOR^ or
5 -Ct-U-O-R^1, wherein R1® represents a carboxyl-protective group; 1 *5 91 R represents a phosphono-protective group; R represents a 12 3 1 hydroxyl-protective group and Z, Z , Z , Z , Q , nl, n2, n3 and m are as defined in claim 1, is catalytically reduced with hydrogen in an inert solvent and, if desired, the so obtained compound of formula I is 10 converted to a salt thereof. 7. The compounds of claims 1 to 5 for use in a method for treatment of the human or animal body. 15 8. A pharmaceutical composition comprising at least one of the compounds of claims 1 to 5, optionally together with conventional pharmaceuticallv acceptable carriers and/or adjuvants. 9. A process for preparing the pharmaceutical composition of claim 8 20 characterized in that at least one compound of claims 1 to 5 is provided in a suitable administration form, optionally with incorporation of a conventional carrier and/or adjuvant. 25 TONKINS & CO. 30 i <9 35 - 117 -
IE53988A 1988-02-26 1988-02-26 Disaccharide derivatives IE61418B1 (en)

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