IE61418B1 - Disaccharide derivatives - Google Patents

Disaccharide derivatives

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Publication number
IE61418B1
IE61418B1 IE53988A IE53988A IE61418B1 IE 61418 B1 IE61418 B1 IE 61418B1 IE 53988 A IE53988 A IE 53988A IE 53988 A IE53988 A IE 53988A IE 61418 B1 IE61418 B1 IE 61418B1
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Ireland
Prior art keywords
deoxy
compound
group
chloroform
phosphono
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IE53988A
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IE880539L (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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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 agentBACKGROUND 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 of natural lipid A include those described in Japanese Patent Application (OPI) Nos. 48497/84, 53295/86, and 227586/86 (the term “'OPI8' as used herein means ’“unexamined published Japanese patent application” ) Among them, 2-deoxy-6~0-(2~-deoxy-2~C(R)--3~dodeea~ noyloxytetradecanoylaminoJ-4-0-phosphono-3“-0-C (R)-4-tetradecanoyloxytetradecanoyl]-8-D-giucopyranosyl)-3-0-C(R)-3hydroxy tetradecanoyl3-2-[(R)-3-hydroxytetradecanoylaminol-IO-phosphono-a-D-glucopyranose disclosed in Japanese Patent Application (OPI) Mo. 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: wherein C0CH9CHR3(CH9) Me; R2 = C0CH?CHR4(CH?) Me; m, n = 8-12; R3, R4 = H, OH; R5, 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,y(1-6) D-glucosamine disaccharide 1,4'-bisphosphate, which is acylated at the 2'-amino and 3'hydroxyl groups with (R)-3-dodecanoyloxvtetradecanoyl and (R)-3-tetradecanovloxytetradecanoyl groups, respectively, and has (R)-3-hydroxytetradecanoyl groups at 2 amino and 3-hydroxyΊ groups. This compound exhibited full endotoxic activities identical to or sometimes stronger than those of a reference lipid A from an 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 position of phosphate (1-mono-, 4'-mono-, and 1,4'-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) - 2 £'\ 41 8 wherein R represents 9 wherein Z„ Z~ e, and Z each represents an alkylene group having from 1 to δ carbon atoms,, and R® represents a car boxyl group or a phosphonoxy group; .1 „2 „3 .. - 4 ,3„8 R , R, R , and R” each represents -COR g -COZ R , Q Q, Q G, I I 7 I l~ 3 8 7 -CO(CH J^CH-M-COR-CO(CH ) 1CH-N-COSJR°? -CO(CH ) 2OCOR'„ -co(ch2)^9ocoz3r8, -co(ch2)m2cor7, -co(CH2)n9coz3R8, Q, I1 “CO(CH2^2CO(CH2)yi3NCOR/ or -CO(C52> m9C0(CH2)n3NCOZ3R8, wherein R‘ represents an alkyl group having front 1 to 30 carbon atoms which may be substituted with one or more 3 hydroxyl groups, Z represents an alkylene group having from to 9 cartoon atoms, R represents a cycloalkyl group having from 3 to 12 cartoon atoms which may be substituted with one or more hydroxyl groups, Q represents a hydrogen atom, an alkyl group having from 1 to δ carbon atoms, -CONHg, -COOH or -CB'2OH, 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 10, and n2 and n3 each represents an integer of from 1 to 20; and R3 represents a hydrogen atom, a phosphono group or -CO(CH2COOH, wherein m represents 0 or an integer of from 1 to δτ 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.
DETAILED DESCRIPTION OE THE INVENTION The term alkylene group' as used herein means a methylene group, a polymethylene group, or a methylene or polymethylene group substituted with an alkyl group having from 1 to 6 carbon atoms. Specific examples of the alkylene group are methylene, ethylene, propylene, trimethylene, ethylethylene, tetramethylene, 2-methyl tetramethylene, 2,3dimethyl tetramethylene, 2-ethyl-3-methylpentamethylene and octaxnethylene groups, ©tc. In formula (I), the alkylene group as represented by Z, Z , E or Z preferably contains 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, nonyl, decyl, 3-ethylundecyl, 2“ethyl-4-methyltridecvl, tetradecyl, nonadecyl, tetraeicosyl, 2=ethyl-5~propvltetraeicosyl, and octaeicosyl groups. The alkyl group as represented by R preferably contains from 5 to 20 carbon atoms.
The term cycloaikyi group as used herein include, for example, .cyclopropyl, cyclobutyl, cycloheptyl, cyclohexyl, cycloheptyl, cvclodecyl, 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, and n2 and n3 each preferably represents an integer of from 1 to δ.
The compound of formula (I) include o- and 6-isomers due to the substituent 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 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., triethylamine, pyridine, N-methylamine, N-methyiglucamine, etc., or inorganic bases, hydroxide e.g., ammonia, sodium, potassium, calcium, magnesium^ etc.
Of the compounds of formula (l), preferred are those wherein R represents £R^ or CH ; R1, R2, R^, and Rf each represents COR Q Ql -COZ3 R8 , ‘ -CO ( CH„ ) , CH-B-COR7 , 2 HA -CO(CH2)nlCH-N-COZ3R8, -CO( CH2 )p2 COR7 or -CO(CH2)n2 CO A8 More preferred are those wherein R represents ZOPOiOH)^, and R“ , R7, R3, and R4 each represents -COR7 or Q Q, , , I I 7 -C0(CH9 )nl CH-N-COR .
Further preferred compounds are those, wherein R represents ZR^ wherein Z represents a methylene or an ethylene group and R® represents a carboxyl group or a phosphonoxy grouD. 7 7 R and R each represents -COR wherein R represents an alkyl group having from 1 to 30 carbon atoms, 4 0 0· R and R each represent f ?1 7 -CO(CH2)nlCH - N - CORZ wherein , reoresents 7 nl and R represents an 0(zero), Q and each represent a hydrogen atom alkyl group having from 1 to 30 carbon atoms or -COR wherein R carbon atoms, and R represents an alkyl group having from 1 to 30 represents a hydrogen atom.
The compounds according to the present invention can be prepared t’nrough various reaction routes. One example or the processes is illustrated below.
(II) wherein represents a hydrogen atom or a hydroxyl-protective group (i.e., a protective group for the hydroxyl group) ,Z1COOR14 represents ZCOOR14, ZOPO(OR13)2„ -CH “Z2COOR14 which can be removed by catalytic reduction or the like; R 1 , 13x Z OPO(OR )2 ; R11, and R31 each repre£2OPO(ORi3) Q? Q1 12 J1 sents -COR71, ~COZ3R81, -CO(C»2)n1 CH-NCOR71» -CO(CH2)n3 CH-NCOZ3R81, -CO(CH2)n2OCOR71, ~CO(CH9)n2OCOZ3R81,.
H 3 81 -CO(CH2)n2COR , -CO(CH2)n2COZ R , I 7i · 3 RU -CO( CH2 )n2CO( CH9 )n3 NCOR'“ or -CO( CH2) n2CO( CHQ) ^MCOZTR0--; A R represents a hydrogen atom, ~C0(Ca9)„COOR~ or PO(OR~ wherein R and R each represents a phosphonoprotective group which can be removed toy catalytic reduction; R14 represents a carboxyl-protective group which can 7-j be removed toy catalytic reduction; R - represents an alkyl group having from. 1 to 30 cartoon atoms which may toe substituted with one or more hydroxyl groups protected with a hydroxyl-protective group; R represents a eycloalkyl group having from 3 to 12 cartoon atoms which may toe substituted with one or more hydroxyl groups protected with a hydroxylprotective group; Q2 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, -COKH^, -COOR1’ or 91 16 -C«2-O-R , wherein. R represents a carboxyl-protective . . 15 group which can be removed by catalytic reduction; R‘ represents a phosphono-protective group which can be removed toy catalytic reduction; and R^l represents a hydroxyl-protective group which can be removed by catalytic reduction; i j 3 and Z, Z~, Z , Z , Q.. t nl, n2, n3, and m are as defined above.
The carboxyl-protective group which can be removed by catalytic reduction includes a benzyl group., etc., Which may be substituted with a halogen atom, a nitro group, a lower alkoxy group, etc. The phosphono-profective group which can be removed by catalytic reduction includes a phenyl group, a benzyl group, etc.., each of Which may be substituted with a halogen atom, a nitro group, a lower 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 nitro group, a lower alkoxy group, etc., a trichloroethoxycarbonyl group, a trichloro-t-butoxycarbonyl group, etc.
According to the above-described process, the compound of formula (II) is catalytically reduced in an inert solvent, e.g., tetrahydrofuren, methanol, ethanol, acetic 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 the like technique. The reduction reaction can usually be carried Out at a temperature of from room temperature (0 to 30eC) to SO°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 R11, R^1 or R^- contains therein a hydroxyl-protective group, such a protective group is preferably the one removable by catalytic reductionThe salt of the compound of formula (I) can be ob10 tained by adding a necessary amount of a base to the compound t followed by sedimentation, freeze-drying or the like means.
The process for preparing the starting compound represented by formula ¢11) can be selected appropriately depending on the kind of the substituents R10 and R51 as illustrated below.
HO (IIA) (IIB) (V) NHCOOCH,CC£3 (IXD) 14 , 13. wherein R represents an allyl group, ZCOOR ·, ZOPO(OR )2, 14 zZ COOR 13 Z~OPOR CH or CH R represents a hydroxylz2coor14 Z2OPOR13 7Ί 3 81 protective group; R represents -COR -, -COZ R -, 0, 0, ,2 |1 -CO(CH-) ,, CH-NCOR <& ni ,71 02 0ί I I* 3 8, -CO(CH-) θCH-NCOZ R ; 2 nl 3,,81 -CO(CHO) „ OCOR -, CO (CH2 )n2 OCOZ R , CO (CHO )„ .-, COR '2 n2 a2'n2 ,71 ,3,,81 -CO(CH.J -COZ R . —CO(CH-), 0CO(CH0) ., NCOR of *2 n2 2n2 ‘2-3 -C0{CH9)n9 CO(CH9)n3 NCOZ3R81,“ R19 represents ZCOOR14, 14 ,Z“COOR«Z1OPO(OR13 ), ZOPO(OR13)2, CH or CH Z 14 SPCOQR'* Z2OPO(OR13’ represents -COiCHj) COOR16 or PO(OR15)2; R92 represents a hydroxyl-protective group removable by catalytic reduction; and R11, R21, R31^ R12, R13. R14» R15, R16, Rzi R81, Z, Z1, 2 3 Z j, Z , nl, Q9 Q7 # a2s n3, and m are as defined above.
More specifically., the compound of formula (IV) is dissolved in an inert solvent (s..g-? methylene chloride, 15 acetic acid,, etc.,, either alone or combinations thereof) containing hydrogen bromide gas and allowed to react at 0°C fo room temperature for several tens minutes to about 24 hours to thereby substitute the acetyl group at the 1-posi1 2 tion of the sugar moiety by a bromine atom. The resulting bromo-substituted compound is dissolved in a dried solvent, 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 com20 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., pyridin®, 4-dimethylaminopyridine, triethylamine, etc., or reacted with a compound of formula HOR and a catalyst such as dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine to obtain the compound of formula (V) The compounds represented by formula (IIA) to (IID), i.e.« the starting compounds of formula (II)„ can then a synthesised from the thus obtained compounds of formula (v) and (V5) through the following reaction routes (A) to (D). Reaction Route (A)t A compound of formula (V) wherein R1® or R1' is dissolved or suspended in acetic acid, and a zinc powder is added thereto to effect reaction thereby removing the amino1 7 protective group at the 2’-positron and R' . 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 toe effected by a carbodiimide method, the Eintopf method, an active ester method, and the likeIn the above-described reaction for removal of protective groups, a trichloroefchoxycarbonyl group or a trii 7 chloro-t-butoxycarbonyl group is preferred as R , i.e., a protective group for a hydroxyl group. When has a hydroxyl-protective group in the molecule thereof, the same groups are preferred as the hydroxyl-protective group. Reaction Route (3)s A compound of formula (V) wherein R is an allyl group is treated in the same manner as in Reaction Route (A) 31 . . to remove R and then to bond R to the 2 ’ -positioned amino group. After protecting the 6’-positioned hydroxyl group with a protective group removable toy catalytic reduc25 tion, the compound is reacted with an iridium complex, e.g., 1,5-cyclooctadienebis(methyldiphenylphosphine)-iridium hexa14 fluorophosphate, etc», followed by hydrolysis-to remove the allyl group. The resulting compound is then reacted with O II 13 C1P(OR)9 to obtain the compound of formula (113)» Protection of the 6'-positioned hydroxyl group can be carried out, for example, by reacting with benzyloxymethyl chloride in an organic solvent,, e.g., anhydrous chloroform, anhydrous methylene chloride, etc», in the presence of an organic base, .e.g., pyridine, diisopropylethvlamine, etc», at room temperature for 1 to 2 days. The protection may also be effected by using benzyl trichloroacetimidate 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, tetrahydrofuran, etc., at about 50eC 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 II 13*? CIP(OR) is usually conducted in an anhydrous aprotic 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) s The compound of formula- (IXC) can be prepared by subjecting a compound of formula (V) to the same reactions of Reaction Route (A).
Reaction Route (D) The compound of formula (ΙΣΏ) can be prepared by subjecting the compound of formula (V ) to the same reactions of Reaction Route (B)» The compound of formula (IV) used as starting mate10 rial in the above-illustrated process can be synthesized according to known processes or the process disclosed in Japanese Patent Application (OPl) No™ 53295/86.
The compound of formula (III), the other starting material in the process, can be prepared by Reaction Route (a) or (b) shown below, selected according to the kind of Ί A the substituent R“ .
Reaction Route (a) v (XIII) (IX) I (XI) (nia) (Ilia') wherein X represents a halogen atom; Y represents a lower acyl group, a trichloroethoxycarbonyl group or a trichloro2 2 t-butoxycarbonyl group; W represents SOW , ZCOOW , or CH CH 4 -Z ON Jcoow3Χχχζ2αοοΝ3 13 -S'COOR··3 or CH 13 •zTCOOR ZCOOR14, CH or CH *s2coor14 .ZXOH i 4 13 W represents SOW., ZCOOR“ , R22 represents SOPO(OR13)9, .Z1OPO(ORJ’3).
‘Z2OPO(OR13).
; W represents ZOH or CH 13 W represents iZOJ?Q(QH' ) or Z20a ^/^OEOfOR13);, CH ? Y1 represents a trichloroethoxycarbonyl XSxZ2OPO(OR13)2 group or a trichloro-t-butoxycarbonyl group; W2 represents 10 an acetyl group, a benzoyl group, a benzyl group or a pchlorobenzyl group; W represents an alkyl group having from to 6 carbon atoms or a carboxyl-protective group removable by catalytic reduction; W* represents a hydrogen atom, a li 21 13 benzyl group or a p-chlorobensvl group; and R , R , R” , 14 1 2 R , Ζ,, Ζ , and Z are as defined above.
The compound of formula (VII) can'toe 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 WOH in the presence of mercury (II) cyanide, silver carbonate, mercury bromide, silver perchlorate or mercury (II) nitrate, or a mixture thereof. The compound of formula (VII) wherein W is a ZO-aeetyl group can be obtained by reacting a compound of formula (vie) with a compound of formula KOI· OH in the presence of hydrogen chloride, p-toluenesulfonle 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 trichloroethoxycarbon15 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 2positioned amino group. The resulting compound is then 1 1 condensed with a compound of formula R On according fo an 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 '2 COO20 alkyl or CH ^COO-alkyl is hydrolysed with sodium hydros^Z2COO-alkyl ide, etc™ to' remove the acyl and alkyl groups, and the resulting compound is reacted with a compound of formula X14 R xn the presence of an organic amine, e.g., triethylamine, 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 hydroxyl groups at the 4- and δ-positions of the compound of formula (IX) are protected using isopropvlidene to obtain the compound of formula (X).
The compound of formula (X) wherein W1 is a Z-Obensyl or ZO-p-ehlorobenzyl group is condensed with a coxapound of formula R“~~OB. and then the resulting compound is catalytically reduced to the compound wherein W1 is ZOHThe resulting compound is reacted with a compound of formula *1 3 X—PO(OR“ )^ in the presence of an organic amine, e.g™, triethylamine, 4-dimethylaminopyridine, pyridine, etc. to prepare the compound of formula (XI).
The compound of formula (X) wherein W1 is ZCOOR14 or ZXCOOR14 CH is condensed with the compound of formula 14 Z^COOR·*·^ R “OH to prepare the compound of formula (XI).
The compound of formula (Ilia) can toe obtained by hydrolysing the thus prepared compound of formula (XI) in water-containing acetic acid, e.g., a 50 to 90S by weight aqueous solution of acetic acid, or treating the compound with p-toluenesulfonic acid in methanol, ethanol, water or a mixture thereof.
The compound of formula (Ilia) wherein ,22 xs ' Z1OPO(OR13; n £O?O(OR )9 or CH i.e., the compound of ‘^2OPO(OR13L formula (Ilia) can be prepared as follows.
The compound of formula (VII) wherein W is ZO-acet^^γΛθ-acaty.. S'~ a-benzoyl yl, ΖΟ-benzoyl» CH or CH , and Y 'SX'x^20-acetyl ^''''^Z^O-bensoyl is a trichloroethoxycarbonyl or trichloro-t-butoxycarbonyl group is treated with aqueous ammonia to obtain the compound of formula (XII), which is then protected with isopropylidene to obtain the compound of formula (XIII). The resulting compound is condensed with the compound of formula -a 7 Ί XPO(OR~ then with the compound of formula R OH to prepare the compound of formula (XIV). The isopropylidene is removed from the resulting compound in the same manner as described above to prepare the compound of formula (XVa). yl 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 (IIIa“). 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 formula R OH. The isopropvlidene is then removed therefrom in the same manner as described above to prepare the compound of formula (Ilia').
The compound of formula (Ilia') wherein R and R are the same can also be obtained by removing Y^ from the compound of formula (XIII) and condensing the resulting compound with a fatty acid,,, followed by removing the iso™ propylideneReaction Route (b) s (XVII) O-allyl O-allyl (Illb) wherein R2\ and R'·'' are as defined above.
The compound of formula (XVI) is condensed with the oi compound of formula R OH to prepare the compound of formula 5 (XVII). After Y1 is removed in the same manner as described above, the compound is condensed with the compound of formula R ΌΗ to obtain the compound of formula (2CVIIX)» The isopropvlidene is then removed from the compound of formula (XVIII) in the same manner as described above to obtain the compound of formula (lllb)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 are superior as antitumor agents.
The invention also relates to pharmaceutical compositions comprising at least one compound of the inventions optionally together with conventional pharmaceutically acceptable carriers and/or adjuvants.
-/ The present invention is now illustrated m 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 I) preparation of 2-acetoxyethyl 3,4,6“tri-0-acetyl~2~ deoxy-2-(2,2,2-trichloroethoxycartoony lamino) -a -D-glucopvranoside To 5.00 g of 2-deoxy-2-(2,2,2-trichloroethoxycarbonvlamino)-D-glucose was added 5.0 mi of ethylene glycol and 0.5 ml 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 .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, was collected by filtration and washed with waterThe 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 recrystallized from ethanol to obtain 4.96 g of the entitled compound as a colorless prism.
Melting Point: 138 - 140°C +74»0° (c=12 chloroform) 2) Preparation of 2-acetoxyethyl 3,4,6-tri-o-acetyl“2deoxy~2-tetradecan.oylamin.o-a--D-glucopyranoside In SO ml of acetic acid was dissolved 4»SS g of the compound obtained in 1) above, and 7 g of a sine powder was 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 was removed by distillation under reduced pressure. The residue was dissolved in dioxane, and dioxane containing hydrogen chloride gas was added to the solution» The solvent was removed by distillation under reduced pressure, and the residue was dried.
The resulting oily product was dissolved in 70 ml of anhydrous methylene chloride, and 2 »88 ml of N-methylraorpholxne and 3.24 g of tetradecanoyl 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. 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 the residue was purified by silica gel column chromatography using, as eluent, a mixture of benzene and ethyl acetate at a ratio of 9/l (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-deoxv-2-tetradecanoylamino-a-D-glueopyranoside 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 methylate was added to the solution under ice-cooling, followed by stirring at room temperature for 30 minutes. Tetrahydrofuran was added thereto to dissolve the precipitate, the solution was neutralized with a strongly acidic ion exchange resin, Dowex-50 (ΈΥ type), and the resin was filtered off. The solvent was removed from the filtrate by distillation under reduced pressure. The residue was washed with diethyl ether, followed by filtration to give 3.02 g of the entitled compound as a white solid. Recrystallization from ethanolwater gave a purified product having a melting point of 158 to 160eC. +8.21° [c=0.8, tetrahydrofuran^water = 4::1 (v/v)] 4) Preparation of 2-hydroxyethyl 2-deoxy-4,5-0-isopropylidene-2-tetradecanoyXamino-a-D-glucopyranosida In 20 ml of dimethylformamide was dissolved 0.87 g of the compound obtained in 3) above, and 0.52 g of 2,2dimethoxypropane and 38 mg of p-toluenesulfonic acid monohydrate were added to the solution at room temperature. followed by stirring for 1.5 hours. After neutralizing with a 51 aqueous solution of sodium hydrogencarbonate, the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate, washed successively 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 using, as eluent, a 19/1 (v/v) mixture of chloroform 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*~(diphenylphosphonoxy)ethyl 2-deoxy-4,6O-isopropylidene-2-tetradecanoylamino-u-glucopyranoside In - 15 ml of anhydrous methylene chloride was dissolved 0.77 g of th® compound obtained in 4) above, and to the solution were added 0.48 g of diphenyl phosphorochloridate, 0.19 ml of pyridine, and 0.30 g of dimethylaminopyridine under ice-cooling. After stirring for 1 hour, the temperature of the mixture was returned to room temperature, and the stirring was continued for an additional one hour. To the reaction mixture, 0.17 g of diphenyl phosphorochloridate 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 distillation under reduced pressure. The residue was puri- 28 fied by silica gel column chromatography using a IS/l (v/v) mixture of chloroform and acetone as an eluent to obtain 0,.81 g of fhe entitled compound as a colorless viscous oil.. 6) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-3--0(N-dodecanoylglycyl)-2-tetradecanoylamino-a-D-glucopyranoside 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 dimethylaminopyrdine,» and 0-18 g of dieyelohexylcarbadiimide were added to the solution under ice-cooling - The mixture was stirred for 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 solution» and dried, over anhydrous sodium sulfate.
The solvent was removed by distillation under reduced pressure» and to the residue was 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 acetone and then a 19:1 (v/v) mixture of chloroform and methanol to obtain 0.51 g of the entitled compound as a colorless oily product.
CoOD s +46.2® (c-1,1, chloroform)WR-(CDC13)z g(ppm): 0,88 (5H, t), 1.26 (s), 2-07 (2H, t) , ; ' 2.27 <2H„ t), 4.84 (IH, d) f 5.18 (IH, ra), 7.2-7.4 (ΊΟΗ, ra) REFERENCE EXAMPLE 2 1) Preparation of 2-hyd.ro5 In 6 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-CD3OD, ca. 1:1), $(ppm): 4-78 (2H, s), 4.90 (IH, d) 2) preparation of 2-hydroxyethyl~2-deoxy-4,6~0-isopropyl= idene-2-( 2,2,2-trichloroethoxycarbonylamino) -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,S~ 0-isopropylidene~2-( 2,2,2-trichloroethoxycarbonylaminojα-D-gIucopyranoside The compound (1.12 g) obtained in 2) above was treated in the same manner as in Reference Example 1-5), and to th® resulting fraction were added diethyl ether and n-hexane. The precipitate formed was collected by filtration to obtain 1-23 g of the entitled compoundMelting Points 121 - 124“C [a]25: t46.4e (c-1,0, chloroform) 4) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy~4„6Q-isopropylidene-3-0-tetradecanoyl-2-(2,2,2-trichloroethoxycarbonylamino)-a-D-glucopyranoside 10 In 10 ml of anhydrous methylene chloride was dissolved 0.50 g of the compound obtained in 3) above, and 0.30 ml of pyridine, 0-22 g of tetradecanoyl chloride, and 20 ml of dimethylaminopyridine were added to th© solution,, followed by stirring for 2 hours- To tine reaction mixture 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.
Ca]^5s +36-1° (c~1.0, chloroform) ) Preparation of 2-(diphenylphosphonoxyJethyl 2-deoxy-2(N-dodecanoylglycyXamino j-4,6-0~isopropyXidene-3-0“ tetradecanovl-c-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 fewer a5 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 hydrogen carbonate aqueous solu.10 tion, 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-dodecanoylglycipe. To the mixture were added 0.17 g of dicvclohexylcarbodiimide and 32 mg of dimethylaminopyridine under ice-cooling. After 20 minutes., thus temperature of the mixture was returned to room temperature, and the mixture was allowed to react for 15 hours while stirring. Any insoluble matter · were removed by filtration, and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was purified by silica gel column chromatography using chloroform containing 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 Eaj2^. +28.1° (0=1.1, chloroform) 6) Preparation of 2-(diphenvlphosphonoxy)ethyl 2~deoxv-2“ (N-dodecanoylg lyeylamino) -3 -O-tetradecanoyl- c.Dg lucopyranoside 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 90eC- 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* --35..,1° (c-~l»l, chloroform) NMR (CDC13), 6(ppm): 0.90 (6H, t), 1-28 (s), 2.13 (2H, m) , 2.36 (2H, t), 4.90 (IH, d), 7.2-7-5 (10H, m) REFERENCE EXAMPLE 3 1) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-3-0(N-dodecanoyIglycyl)4,6-0-’isopropylidene-2~( 2,2,2-trichloroethoxycarbonyIamino)-ot“D~gIucopyranoside In 20 ml of anhydrous methylene chloride was dis33 solved 1.89 g of the compound obtained in Reference example 2-3), and 083 g of N-dodecanoylglvcxne, 0.17 g of dimethylaminopyridine, and 0.67 g of dicyclohexylcarbodiimide were added thereto under ice-cooling. After 30 minutes, the 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 was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 10:1 (v/v) mixture of chloroform and acetone as eluent fo obtain 2-80 g of the entitled compound as a colorless oily substance. 325 s -5-32.2® (c-^0.8» chloroform) D 2) Preparation of 2—(d ipheny Iphosphonoxv) ethyl 2-deoxy-3-0CN'~dodecanoylglycyl)-2-[6-(octanoylamino)hexanoylaraino3u-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 zinc 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 chloroform, washed successively with a 5% sodium hydrogencarbonate 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, 0.2δ g of 6-(octanoylamino)caproic acid was dissolved in. 7 ml of anhydrous tetrahydrofuran, and 0-16 g of 1-hydroxybenaotriasole and 0 21 g of dicyclohexylcarhodiimide 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 SO’C- The solvent was distilled off, and the residue was purified by silica gel column chromatography using successive eluents of a 10:1 (v/v) mixture of chloroform and acetone, a 20:1 (v/v) mixture of chloroform and methanol, and a 10:1 (v/v) mixture of chloroform and methanol to thereby obtain 0-56 g of the entitled compound as a colorless waxy substance.
Cc]25: -1-31-2° (c=l.l, chloroform) NMR (CDC1 )» 6(ppm): 0.88 (6H, t), 2.0-2.4 (6H, m)» 4-85 (IH, d), 7-2-7-4 (10H, m) REFERENCE EXAMPLE 4 Preparation of 2~(diphenylphosphonoxy)ethyl 2-deoxy-3-0(N-dodeeanoyl-N-methylglycyl) -2-[ (N-dodecanoyl-N-methylglycyl) amino] -α-17-glucopyranoside In 10 ml of acetic acid was dissolved 1.00 g of the compound obtained in Reference Example 2-3), and 0.5 g of a zinc powder was added to 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 was dissolved in chloroform, washed successively with a 5% aqueous solution of sodium hydrogencarbonate 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 sub15 stance and 1.21 g of N-dodecanoyl-N-methylglycine were dissolved in 10 ml of anhydrous methylene chloride. To the solution were added SO mg of dimthylaminopyridine and 0.92 g of dicyclohexylcarbodiimide under ice-cooling. After warming to room temperature, the mixture was stirred for 3 hours. The precipitated insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residual oily substance was purified by silica gel column chromatography successively using a S:1 (v/v) mixture of chloroform and acetone and a 19 sl (v/v) mixture of chloroform and methanol as eluent to obtain an oily substance. The resulting oily substance was dissolved in 40 ml of a 90% acetic acid aqueous solution, followed by stirring for 30 minutes under heating at 90uC 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 and methanol at a ratio of 50si (v/v) and then 20 si (v/v) to obtain 0.87 g of the entitled compound as an oily product. +34.9° (c-1.0, chloroform) NMR (CDCl,), 6 (pm): 0.,89 (6H, t), 1.28 (s), 2.36 (4H, m), 2.84 and 3.00 (total 3H, each s), 3.13 and 3.15 (total 3H, each s), 4.45 (2H, m), 4.87 (In, d), 7.2-7.4 (10H, m) REFERENCE EXAMPLE 5 1) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-3~0~ tetradecanoyl-2-(2,2,2~trichloroethoxycarbonylamino)-aD-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 diraeth20 ylarainopvridine 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, and the filtrate was concentrated under reduced pressure. The residual oily substance was subjected to silica gel column chromatography using a 10:1 (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 10:1 (v/v) mixture of chloroform and acetone and then a 10:1 (v/v) mixture of chloroform and methanol to obtain 0,61 g of an oily product. [g32^: +43.0® (c-l.2, chloroform) 2) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-2[ (N-dodecanoyl-D-isoglutaminyX) amino]-3-0-tetradecanoylG-D-glu copyranos ide The compound <0.47 g) obtained in 1) above was 15 treated with a zinc powder in an acetic acid solution aad then reacted with N-dodecanoyl-D-isoglutamine in the same manner as in Reference Example 3-2) to obtain 0.36 g of th® entitled compound as a white waxy substance. +38.70 (c=0-l, chloroform) NMR (CDC1_), 6(ppm): 0.88 (6H, t), 1.26 (s), 2.1-2.5 J (6H, m), 4.96 (IH, d), 5.18 (IH, d), 7.2-7.5 (10H, m) REFERENCE EXAMPLE 6 X) Preparation of 1,3-(diethoxycarbonyl)isopropyl 2-deoxy3 »4»6~tri-O-acetyl-2- (2,2,2-trichloroethoxycarbonyl- '* amino) -a^-D-glucopyranoside To 8 00 g of l»3(i.4»6-tetra-0“acetyl“2“deoxy-2(2,2 2-trichIoroethoxycarbonyIamino)-D-glucopyranose was 5 added a cooled acetic acid solution containing 25% hydrogen bromide at room temperature, followed by stirring for I hour. The reaction mixture was diluted with chloroform, washed successively with a 5% sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solu10 tion, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 72 ml of anhydrous methyla ene chloride. To the solution were added 8 g of anhydrous calcium sulfate, a suspension of 4.12 g of silver perchlo15 rate in 40 ml of anhydrous bensene, and 6-24 g of diethyl-3hydroxyglutarate under ice-cooling. The mixture was allowed to react at room temperature for 3 hours, followed by neutralizing with a 5% aqueous solution of sodium hydrogencarbonate» The insoluble matter was removed by filtration, and the filtrate was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, 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. Εα]^. 4-42-8° (c=0.7, chloroform)2) Preparation of 1,,3-(diethoxycarbonyl)isopropyl 2-deoxy2-tetradecanoylamino™3,4?6-tri0=acetyl-a~D~glucopyranoside The compound (4.00 g) obtained in 1) above was 5 treated with a zinc 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. 4-46-9® (c=0»16, chloroform) 3) Preparation of 1,3-(dibenzyloxycarbonyl)isopropyl 2deoxy-2-tetradecanoylamino-G-D-glucopyranosxd® In 30 ml of dioxane was dissolved 1-80 g of the compound obtained in 2) above, and -10 ml of water was added thereto. After cooling to 5®C, 15 ml of a IN potassium hydroxide aqueous solution was added to the solution- After stirring for 6 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 dimethylformamide, and 1 ml of benzyl bromide was added thereto. After stirring at 40®C for 3 hours, most of the dimethylformamide was removed by distillation under reduced pressure- The residue was extracted with benzene, and the benzene layer was washed successively with a 5% citric acid aqueous solution, a saturated sodium chloride aqueous solution, a 5% sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous 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 50:1:5 and then 50:1:15 to obtain 0.65 g of the entitled compound as a white waxy solid. +13-2° (c=0.51, chloroform) 4) Preparation of 1,3-(dibenzyloxycarbonyl) isopropyl 2deoxy-4, 6-0-isopropylidene-2-tetradecanoylamino-a-Dglucopyranoside 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. [a]p5; +3.3® (c=0.7, chloroform) ) Preparation of 1,3-( dltaenzyioxycarbonyl) isopropyl 2deoxy-3-0-tetradecanoyl-2-tetradecanoylamino-a-D-glucopyranosIde 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 O»53 g of the entitled compound as a white waxy solid. 4-32.8® (c=0,9 methanol) NMR (CDClg), 6(ppm): 0.88 (6H, t) , 1.26 (s), 4.94 (IH), .20 (43, s), 7.40 (103, s) REFERENCE EXAMPLE 7 Preparation of 1-3-(dibenzyloxycarbonyl) isopropyl 2-deoxy-3O- (N-dodeeanoylglycyl)-2-tetradecanoylamino-c-D-glucopvranoside In the same manner as in Reference Example 1-6), 0.50 g of the compound obtained in Reference Example S-4) was reacted with N-dodecanoylglycine, and the reaction pro10 duct was treated with a 90% acetic acid aqueous solution to obtain 0.53 g of the entitled compound as a waxy solid. [ούρ5; +36.9 (c-1.3, chloroform) NMR (CDClg), 6(ppra): 0.89 (63, t) , 1.26 (s), 2.1-2.3 (43, m), 2.5-2.9 (4H, m), 4.50 (IH, m) , - 4.97 (IH, d) , 5.07 (IH, m), 5.18 (4H), 7.40 (10H, s) REFERENCE EXAMPLE 8 1) Preparation of 2-acetoxyethyI 3,4,6~tri-0-acetyl~2deoxy ·2· -C5-- (octanoylamino)hexanoylaminojl- u-D-glueopyranoside In the same 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 5-(octanoylamino)caproic acid to obtain 2.84 g of the entitled compound as a waxy solid. Εα]25. +55-4° (0=1.1, chloroform) 2) Preparation of 2-hydroxyethyl 2-deoxy-2-[6-(oetanoylamino )hexanoyl amino] - α-b-g lucopyranoside In the same manner as in Reference Example 1-3), 5 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 Point: 156-1579C Ca]25. +78.8° (e=0.9, ethanol) 3) Preparation of 2-hydroxyethyl 2-deoxv-4,δ-O-isopropylidene“2-E6“(octanoylamino)hexanoylamino]“ u-D-glucopyranoside 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 5 : +35.2° ( g=I . 0, chloroform) 4) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-4,60-isopropylxdene~2-£6~ (octanoylamino)hexanoylamino3 -a-Dglu eopyranoside 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» Callus +26.7” (c=1.2, chloroform) ) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy~3-0“ dodecanoyl-2-L 6 - (octanovl amino) hexano yl amino] - cD-g luc opyranoside In the seme 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 SOS acetic acid aqueous solution to obtain 0-73 g of the entitled compound as an oily substance+37.30 (c=l.l, chloroform) NMR (CDC1,), 6(ppm)s 0-89 (Sn, ra), 2.10 (4H, xn), 2-33 (2H, ra), 3.20 (2H, ra), 4-30 (IH, ra), 4-46 (2H, ra), 4.85 (IH, d), 5.10 (IH, ra) REFERENCE EXAMPLE 9 1) Preparation of 2-acetoxyethyl 3,4,5-tri-0-acefyl~2“[ (R)3-benzyloxytetradecanoylamino3-2-deoxy-*a-D-glucopyranoside In the same manner as in Reference Example 2-5), 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 1.95 g of (R)~3benzyloxytetradecanoic acid to yield 3.70 g of the entitled compound as an oily substance.
NMR (CDC1 ), δ(ppm): 0.87 <3H, t, J=6Hz), 2-00 (3K, s), 2.02 (3H, s), 2-04 (3H, s), 2-08 (3H, s), 2.18 (2H, ra), 4-54 (2H, ABq, J=12Bte), 4.76 (IH, d, J=4Hz), 7.36 (5H, s) 2) Preparation of 2-hydroxvethyl 2-L(R)-3-benzyloxytetradecanoylamino]-2-deoxy-α-D-glucopyranoside In the same manner as in Reference Sxample 1-3), 3-68 g of the compound prepared in 1) above was reacted to obtain 2.49 g of the entitled compound as a pale brown •v - 44 powder. Recrystallised from water-ethanol.
Melting Points 125-127*C . [c]^5s +73.3° (c—0 9 methanol) 3) Prepartion of 2-hydroxyethyl 2-[(R)-3~benzyloxytetradecanoylamino]-2-deoxy-4,6-O-isopropylxdene-a-D-gilucopvranoside 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. [a]25: +31.4° (c=0»9, chloroform) ‘10 4) Prepartion of 2~(diphenylphosphonoxy)ethyl 2-[(R)-3benzylo xytetrade canoyl amino] -2 -deoxy-4,6 -0- i sopropy1idene-α -D-glucopyranoside In the same 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) above15 NMR (CDClg), 0(ppm)= 0.88 (3H, t, J=7Hz), 1.46 (3H, s) , 1.53 (3H, s), 2.47 (2H, d, J=6Hz), 4.2 (3H, ra), 4.53 (2H, ABq, J=12Hz), 4.64 (IH, d, J=4Hz), 7.2-7.4 (15H, m) ) Prepartion of 2-(diphenyIphosphonoxy)ethyl 3-O-[(R)-3benzyloxvtetradecanoyl)-2-[(R)-3-bensyloxytetradecanoylamino]-2-deoxy-a-D-glucopyranoside 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-bensyloxvtetradecanoic acid, and the rsac45 tion product was heated with a 90% acetic acid solution to obtain 1.23 g of the.entitled compound as a colorless oily substance. [g]2^s +31.4° (cl»2, chloroform) NMR (CDCIg), 6(ppm)s 0.88 (6H, t, J=7Hz), 2.34 (2H, d, J«6Hz), 2.6 (2H, m), 4-51 (2H, ABg, J—12Hz), 4.56 (2H, s), 4.71 (IH, d, J=4Hz), 5.13 (IH, m), 7.2-7.4 (20H. m) Reference example io Preparation of 2“(diphenylphosp'honoxy)ethyl 3-0-C(R)-3benzyloaytetradecanoyl]-2-deoxy-2-tetradecanoylaraino-a“Dglucopyranoside In the same manner as in Reference Example 1-6), the compound obtained in Reference Example 1-5) was reacted with (R)-3-benzyloxytetradacanoic acid, and the reaction product was heated in a 90% acetic acid solution to obtain the entitled compound'as an oily substance NMR (CDCIg), 0(ppm)s 0.89 (6H, t) , 2.06 (2H, t), 2.1-2.8 (2H, m), 4-85 (IH, d) , 5.14 (IH, t) , 7.1-7.3 (15H, m) REFERENCE EXAMPLE 11 Preparation of 2-(diphenylphosphonoxy)ethyl 2~C(R)-3-benzyl~ oxytetradecanoylamino3-2-deoxy-3-0-tetradscanoyl-o-D-glucopvranoside In the same manner as in Reference Example 1 6) .r 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 (CDCl3b 0(ppm): 0.88 (6H, t)t 2,3-2.4 (4H, ra), 4.52 (2H, d),, 4.72 (IH, d) 5.10 (IH, ra), 7.2-7.5 (15«, ra) REFERENCE EXAMPLES 12 TO 52 In the same.manner as described in Reference Exam. pies 1 to 11» the following compounds represented by formula (ilia) were prepared- (Ilia) Reference ExamplesR21 - · 12 -CO(CH2)5NHCO(CH?)gCK3 -CO(CH„),^C!k 2 JL& J Physical Properties 13 ι -COCH2MHCO(CH?)10CK3 -CO£ CH2)2NHCO(CH2)gCH3 14 -COCHjNHCO(CK2)10CK3 -CO(CH2)3NHCO(CH2)gCH3 / « CH, 3 15 -COCH2 NHCO £ CK2)χQCK3 1 -COCH?NCO£ CH2)10CH3 16 -COCK2NKCO(CH25,qCK3 =COCH?NCO(CH2) , qCH3 Co]25» +30.3* {cX.O, chloroform) NMR iCDClg), 4{ppm)i 0.33 (5H, fc) , 2,06 (2H, fc), 2.19 (2K, fc), 2.35 (2K, m), 3.10 (1H), 3.30 ilH), 4.3-4.5 (4H, ra), 4.83 (1H, d), 5.18 (1H, m), 7.2=7.4 (10K, ra) [c3q5s +24.38 (c^O.8, .chloroform) NMR (CDClg), 6(ppm)ι 0.88 (6H, t), 1.9-2.3 (6H, m), 3.25 (IK, m), 3.52 (1H, m), 3.74.5 (7H, ra), 4.84 (IK, d) , 5.20 (IK, t), 7.2=7,5 (10H, ta) Ea]?,5! +32.5° (c=»0,7 chloroform) NMR (CDCip, 6 (ppm) 3 0.88 (6K, t) , 2,0-2.4 (6H, ra), 4,83 (1H, d), .5,22 (1H, fc), 7.1t 7.5 (10H, ra) +33.8* (c»l,0, chloroform) NMR (CDC13) ,· δ (ppm) j 0.88 {6K, fc), l=2g(e), 2.2=2.4 (4H, ra), 2.98 (3H, s)J 4.35 (IK, d), 5,22 {IK, fc), 7.2=7,5 (10H, ra) Eo325i +31.4* (c°1.0, chloroform) NMR (CDClj), 6(ppra)s 0.38 (9.H, fc) / 1 = 25 (s), 2,2=2,4 (4H, m), 3,1=3,4 (2H, br), 4,84 (IHt d), 5.21 (IK, fc), 7.2=7;5 (lOH, m) Reference 1 1 Examples R21 RAA 17 -COCH2NHCO(CH?)χ qCH3 =co(ch2)2co(ch2)9ch3 18 1 -COCH2NHCO(CH2)10CH3 =COCH?OCO(CHg)10CH3 CH, . I 19 -COCH2 NHCO(CH2)χ qCH3 -CO(CK2)s NCO(CH2)gCH3 20 -COCH2NHCO(CH2),qCH3 S' -CO (CHj ) 5NHCO(Ck2) gCH. 21 CH, j 3 -COCK2NHCO(CH2),0CK3 -COCHNKCOCCSp1QCH3 Physical Properties Ca3D ! +29.6* (e“0<2, chloroform) NMR {CDCip, 6£ppm)t 0.88 (6K , t), 1.25 (a), 1.9-2.5 (3H, m), 3.51 (2H, m), 4.30 (IH, m), 5.20 (IK, si), 7.2-7.5 (10K, ra) ι +35.58 (cal.3, chloroform) NMR (CDClg), δ (ppm), 0.-90 (5K, t), 1.28 (a), 2.28 (2H, t), 2.40 (2H, t), 4.45 (e), 4.85 (IH, d), 5,22 (IH, ra), 7.2-7.5 (10H, m) t +14.3® (c=0,5, chloroform) NMR (CDCip, δ(ppm), 0.88 (6H, t) , 1.25 (a), 2.10 (2H, m), 2.30 (4H, m), 2.90, 2.96 (total 3H, each ε), 3.30 (2H, m), 4.84 (IH, d), 5.20 (IH, m), 7.2-7.5 (10H, ra) [c3^St +29.9* (c«0«5, chloroform) HMR (CDC13), $(ppm)j 0,89 (6H, t), 1,28 (s), 2.12 (413, m), 2.28 (2K> t), 3.18 (2H, m), 4.84 (IK, d), 7.2-7.4 (10H, ra) Ca3p5s +18.6 (c»1.3, chloroform) NMR {CDCip, δ (ppm) ι 0.88 (6K, t) , 2.30 (2H, t), 4,81 (IH, d), 5,23 (111, t), 7.2-7.6 (10H, m) Reference Examples .11 Physical Properties t in o -COCK,NHCO(CH?)χQCK3 3 -COCHgNKCO(CH2)χ QCH3 -COCH NHCO(CH.)_CH, 2 S 3 -COCH2mCO(CK23gCK3 -CO(CH2)2KHCO(CK2)0CH3 ^3/CH3 -COCHNCO{CH?)χ qCH3 =CO{CH,)2C0(CH?)2HHCO(CH2)gCHg -CO{CT2igCT3 =CO(CK2)8CK3 ~COiCH2),2CH3 Cc3^5 1 +29.1* (c«ol»0, chloroform) NMR (CDClg), (ppm)i 0,88 {SH, t) , 2.2-2.5, (4H, ra), 2.84» 2.93 (total 3H, each s), 4.91 (IH, d), 5,20 (IH, m), 7,2=7,5” (10H, ra) Ccj?*’ * +25.48 (c=0,37-, chloroform) JJ NMR (CDClg), δ(ppm)s 0.38 (6H, t), 1.2S (a), 3,48 (2H, m), 4,OS (2K, d)» 4.25 (IH, m)» 4.44 (2H, m), 4.81 (IH, d)» 5.20 (IH, t), 7.2=7.5 (10H, ra) * +46,8* (e=»l.l, chloroform) NMR (CDCI„), 6(ppm)j 0.89 (6H, t), 1.28 (s), J 2.08 (2H, ra), 2.28 (2H, t) , 4.84 (d, IH) , .20 (IH, m)» 7.2=7,4 (10H, m) { [c]^* ί +50.4* (c°1.0i chloroform) NMR (CDClg), 6{ppm)i 0.39 (SH, t)» 1.28 (a), 2.08 (2H, t), 2-,28 (2H, t), 4,84 (a, IH), .20 (1ΙΪ, a), 7.2-7,4 (10H, m) ΓαΥ^ί, 4-33.Q8 (c®0»S, chloroform) D NMR (CDClg), S(ppm)j 0.88 (SH, t), 1,26 (a), 2.0-2,5 (SH, m), 4,84 (IH, d) , 5.2S (IH, m), 7,2=7,5 (10H, ra) Reference Examples R21 R11 Physical Properties 27 -COCKj, NKCO ( CK2 ) 8CH3 ™CO£CHAoCE3 25 Γ°1ρ * +49.6* (c*«0.92, chloroform) NMR (CDC13)( 28 1 -CO(CH2)2CO{CH2)gCH3 -co(ch2)A2ch3 C°3p5 ι +33.0* (c*»0.4,'· chloroform) NMR (CDC13), 0(ppm)s 0..88 (6H, t), 1,28 (s), 2.09 (2K, t), 2.46 (2H, t), 2.56 (2H, t) , 2.80 (2H, ra), 4.84 (IK, d), 5.16 (IH, m), 7.2-7.5- (Ι0Η, m) i 29 CK3 CcO^s +29.8’ (c®0.45,’chloroform) tn 1 1 -COCH2N-CO(CH2)1QCH3 -CO{CH2)sNHCO(CH2)gCH3 NMR (CDCip, 6(ppm)i 0.88 (6H, t), 1.28 (a), 2.08 (4H, ra), 2.38 (2H, t), 3.16 (3H, a), 4.84 (IH, d), 5.18 (IH, m), 7.2-7.5 (10H, m) « 3P -CO(CK2h2CK3 -coίch25 5nhco£CK2)6ch3 CG3^ s +39.4’ (e=0«7s chloroform) NMR (CDC13), fi(ppm)j 0.38 (SH, t), 1.26 (s), 2.0-2.5 (6K, m), 4.85 (IH, d), 5.09 (IH, m), 7.2-7.5 (10H, ra) 31 -co ( ch2 ) 3mco ( ch2 ) 3ch3 £a]2S5 +41.3 (c«0.9, chloroform) NMR (CDC13), 6(ppm)i 0.38 (6H, t), 2.0-2.4 (6H, ra), 4.34 (IH, d), 5,09 (IH, in), 7.2- 7,5 (10H, ra) Reference Examples R21 . R11 32 K3 1 -COCH2NCO(CH2)χ0CH3 =CO(CH2)12CH3 33 t -CO(Oli2’l2Cii3 =CO{CH?)?NHCO{CH2)4CH 34 -CO(CH2)12CH3CH3 -coch2nco(CH2)1qCH3 35 ' CH,CK- 1 / -COCHNCO(CK2)?qCH3 1 “CO<CR2}12CH3 35 -CO(CH2)2CO(CH2)9CH3 -CO(CK2)2CO(CH2)3CK3 Physical Proparfclea Εβ]25, +25.43* {cniei4., chloroform) NMR (CDC13), 0(ppm)t 0.88 (6K, t), 1.28 (a), 2.08 (2H, m), 2,38 (2H, fc), 3.14 (3H, a), 4.83 (IH, d), 5.IS (IK, m), 7.2-7.9 (10H, m) Ca3|S, +37,4* (e«sl , 5, chloroform) NMR {CDCip, 0(ppm)j G.8S (6H, t) , 2.0-2.2, {4H, m), 2.34 (2H, t), 3,2-3.3 (2H, m), 4.85 (IK, d), 5,1-=5,2 (IH, m), 7,2-7.4 (10H, m) [a]23 44 2,7* (c1.8, chloroform) NMR {CDC13), 0(prm)i 0.9 0 (6B, fc) , 1,28 (a), 2.35 (4H, fc, 2„BSand 3,02 (total 3H, each s) , 4,4 2 (IK, m),4.4S (2H, m), 4 ,89 (IH, d) , .07 (IH, m), 7,2-7.4 (10H, ra) ( [c^S» +23.78 (c^O.8, chloroform) NMR iCDClj), 6(ppm)i 0,30 (SK, fc) , 2.05 (2H, fc), 2.34 (2H, t), 3.02 and 3,12 (total 3H, each e), 4.18 (IH, d), 5.24 (IH, fcj, 7,2=7,5 (10H, ra) (a)25 +24,0® (c=0,5, chloroform) NMR (CDClj), δ ί ppm) t 0,38 (SH, t),'l.26 (br), 2,3-2,8 (12H, m) ,4,2-4.5 £4H, ra), 4.82 (IH, d) , 5,18 (IH, ra), 5,55 (IK, ra), 7.2-7.5 (10H, ra) Reference Examples R21 11 RAA Physical Properties 37 -COCK,NHCO(CH21gCH3 “COiCH2512Cii3 £g32^s +39.1* (c“1.0, chloroform) NMR. (CDCIg), 0{ppm)i 0.89 (SH, t) , 1.28 (br), 2.08 (2H, t), 2.28 <2H, t), 4.84 (IH, d), 5.18 (IH, m), 7.2-=7.5 (10H, m) 38 » -COCHjiJHCO (CH2) iQCH3 [a]25, -Hl.0s {c^i,β, chloroform) NHR (CDCIg), δ(ppm)ι 0.89 (SH, t) , 1.29 (br), 2.08 (2H, t), 2.28 (2ΙΪ, fc) , 4.83 (IH, d), 5.18 (IH, ra), 7.2-7.5 (10H, m) 39 ch„ i 3 £g]2Si +29.4s (c«l,0, chloroform) -co2)2co(ch2)9ck3 COCH2NCO(CH2)1OCH3 ' · NMR (CDCIg), δ(ppm)j 0.88 (6KS t) , 1.26 (br), 2.2-=2.9 (8K, m), 3.02 and 3.10 (total 3K, each e), 4.46 (2H, m), 4.88 (IH, d), 5.16 (IH, ra), 7.2-7.5 (10H, ra) « 40, -CO(CH2)2CO(CK2)gCH3 -CO(CH2)gNHC0(CH2)gCH3 [cG2^, +25.0* (o=0.5, chloroform) 41 -COCH2CO(CH2)1qCH3 -CO(CH?)?NHCOίCH2)4CK3 · ία]q5ί »31.7®(c= 1.0, chloroform) ferenca 21 . II amplea _R__ »_ _Physical Properties_ -COCHgNHCOtCKjJ^ 0CH3 =COCH2NHCO(CH9)10CH3 Ca]|3; +18.6* ¢¢3=0.0, chloroform} NMR (CDCl,), 0(ppm)s 0.90 (SH, t) , ex «Μ {1K, d), 7.2-7.S (10H, in) tn . SG O to X υ o u tn es X o o u I tn rn x a o o I e« t CM tn X u tv: « X o es u o u I i/> •f es X o o u I to Reference 21 Examples K 47 CH, 1 3 -COCHNHCO(CH2)1QCH3 -CO{CH2)12CH3 48 1 -COtCHjlijCHj -CO(CHpi2CH3 49 -CH(CH_)rCH, 2 6 o -co(c:GirCH, £ 6 3 50 -CO(CH2)QCH3 =CO(CH2)eCH3 t 51 -CO(CH2)10CH3 -co(ch2)10ck3 Physical Properties_ Cc3~®j +20.4* (c“0.9, chloroform) D NMR {CDCip, δ (ppm) j 0.88 (3H, t), 2.22 (2H, t), 4,90' (IH, d), 5.22 (IH, m), 7.2-7.5 (10R, in) Call®» +40,8- (c«l.l, chloroform) D (c 3^® ϊ +49,48 (cel.2, chloroform) NMR (CDCip, 6{ppm)i 0.8δ (6H, m) s 2.08 (2H, fc) , 2.3S (2K, t), 4.85 (IH, d), 5.10 (IH, ra), 7,2-7.3 (10H, m) Cc 3q® « +46.1* (ceO.8, chloroform) β NMR (CDCip, δ(ppm)t 0.88 (6H, fc) , 2.07 (2H, fc), 2.35 (2K, fc), 4.35 (IH, d), 5.10 (IH, ra), 7,2-7,5 (10H, m) NMR (CDCip, δ (ppm)j 0.90 (6H, fc), 2.07 (2H, t), 2.35 (2H, t), 4.85 (IH, d) , 5.10 (IH, ra), 7.2--7,5 (Ι0Η, ra) cn cn Reference Examples -CO(CH2)14CH3 -CO(CH2)12CH3 »21 'COiaVl4CT3 R· -CO(CH?)1^NHCOCHj Physical Properties » +37,28 chloroform) NMR iCDClg), ipprob 0,09 (6H, t), 2.06 (2H, t), 2.32 {2H, t), 4.84 (1H, d), 5.10 (1H, Hi), 7.2-7.5 (10H, I») ,2¾ Ε°ϊρ · *28.5® t’ceO.S, chloroform) t In the seme meaner as described in Reference Examples 1 to 11, the following compounds represented by formula (Illb) were prepared- Reference Examplesrta18 ORr21 54 ^Ά-<Ο y >2 -=0(^2^2¾ ^=¾-(o) 55 6-OCH2COOCH2 -COCHgCHi CH2 ) 10CII3 5δ σ-OCHgCOO”CH? =co(ch2)12ch3 fo) R11 Physical Properties co(ch2)12ck3 Cc3^3 s -19.5* (e^O.9, chloroform) VCiiF-\O> ·. 1 \_ ~y COCHgCH(CH?)χ qCH3 t =25.68 (c®l.1, chloroform) COfCHjJ^CKj ϊϊΐ e ]p s § 34=558C Cj”. MS .98 (c^X b x j chloroform) / EXAMPLE 1 1) Preparation of 2-(diphenylphosphonoxv) ethyl 2-deoxy-6-0E2-deoxy-4-0-diphenylph'osphono-3-0- (N-dodecanoylglycyl) 6-0- (2,2,2-trichloroethoxycarbonyl) -2- (2,2,2-t.richloroethoxycarbonylaraino)- S-D-glucopyranosy 1]--3-0-(N-dodecanoylglycyl)-2-C ί N-dodecanoyl-N-methylglycyl)amino]-a-Dg1ucopyranoside In 2 ml of anhydrous methylene chloride was dissolved 370 mg of l-O-acetyl-2-deoxy—4-0-diphenylphosphono-35 0-(N-dodecanoylglycyl)-6-0-(2;2,2-trichloroethoxycarbonyl52- (2 , 2 , 2-trichloroethoxycarbonylamino) -D-glucopyranose, and 6 ml ox a cooled acetic acid solution containing 25% hydrogen bromide was added to' the solution at room temperature, followed by stirring for 1 hour. The reaction mixture was diluted with chloroform, washed successively with ice-water, a 5% sodium hydrogencarbonate aqueous solution, and a satul rated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue and 344 mg of 2-(diphenylphosphonoxy) ethyl 2-deoxy-3-0-(N-dodecanoylglycyl)-2-C(N-dodecanoyl-N-methylglycyl)amino]-a-D-glucopyranoside 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 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 usinge as eluent? a 10si (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. : +20-0° (c=1.0* chloroform) 2) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-6-0(2-deoxy-4-0-diphenylphosphono-3 -0- (M-dodecanoylglycyl) 2-[(N~dodecanoyl-N-methylglycyl)amino]-0-D-glucopyranoxy)-3 -O- (N-dodecanoylglycyl) -2«[ (N-dodecanoyl-Nmethylglycyl) amino]-α-D-glucopyranoside In 8 ml of acetic acid was dissolved 587 mg of th© compound prepared in 1) abover and 0.6 g of a sine powder was suspended In the solution* followed by stirring at room temperature for 2 hours. The Insoluble matter was removed by filtration* and th© filtrate waa washed with chloroform.
The solvent was removed by distillation under reduced pressure* and toluene was added to th® residue* 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 distil60 lation under reduced pressure to obtain an oily product.
Separately, 122 mg of N-dodecanoyl-N-methylglycine was dissolved in 3 ml of anhydrous tetrahydrofuran, and to the solution were added 77 mg of 1-hydroxybensotriazole and 103 mg 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 5 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 mixture was diluted with chloroform, washed with IN 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 10:1 (v/v) mixture of chloroform and acetone, then a 50:1 (v/v) 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=1.0, chloroform) 3) - preparation of 2-ohosDhonoxyethvl 2-deo:x'V6-0-( 2--deo.'Ky· 3-0-( gj-dodecanoylglycvl) -2-l (N-Sodecanoyl-N-methylglycyl) amino]-4-O-phosphono-g-D-glucopyranosyl )-3-0-( Ndodscanoylglycyl) -2-[ (SiJ-dodecanoyl-iJ-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 theretot followed by stirring under a hydrogen gas for 2 hoursThe catalyst was removed by filtration# and the filter cake was washed with a 8:3si (v/v) mixture (lower layer) of chloroform* methanol# and water. The filtrate and the washing were combined# and the solvent was removed therefrom by distillation under reduced pressure. The residue was purified by thin layer chromatography using a 6:4:0.7 (v/v) mixture of chloroform# methanol# and water as developing solvent* and then treated with a strongly acidic ion, exchange resin* Dowex 50“ ffif type) produced by Dow Chemical 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 Point: 165-170®C (gradually colored and turned to jelly) s +4-6 i’.c=0 7 chloroformsmethanol=3χ1 (v/v)] IR cm”1: 3400# 2930# 2850# 1750# 1675# 1650 KMR 3~CD3OD)» δ (ppm): 0.90 (12H, t)» 1.30 (s), . 2»29. (4Η» m), 2.44 (4H, t) . 2.94 and 3-11 (total 6He each s), 4-84 (1H, db 5.13 (IH, m) , .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 toy 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.
EXAMPLE 2 1) preparation of 2-(diphenylphosphonoxy)efhyl 2-deoxy-6~0~ [ 2-deoxy-4-0-diphenylph0sphono-3-0- (N-dodecanoylglycyl) $-0-(2,2» 2-trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonyl amino)-0-D-glucopyran©syl3-2-[6-(octanoylamino)hexanoylamino3-3-0-tetradecanoyl-a-D-glucopyranoside In the same manner as in Example 1-1)» 445 mg of 10-acetyl-2-deoxy-4-0-diphenylphosphono-3-0-(iFdodecanoylglycyl)-5-0-(2,2,2-trichloroethoxycarbonyl)-2-(2,2» 2-trichloroethokycarbonylamino)-D-gTycopyranose and 385 mg of 220 (diphenylp'hosphonoxy)ethyl 2-deoxy~2~E6-(octanoylamino)hexanoyIamino3-3-0~tetradecanoyl~a~D~glucopyranoside were reacted to obtain 650 mg of the entitled compound as an oily substance.
Ca]Q s +22.2® (c=1.0, chloroform) 2) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-6-OC2-deoxy-4-0-diphenylphosphono-3-0-(N-dodecanoylglycyl)2-tet radecanoylamino-B -D-glucopyranosyi ]--2-£ 6- (octanoylam.ino)hexanoylamino]-3-0-tetradecanoyl-a-x>-glucopyranoside In 10 ml of acetic acid was dissolved 620 mg 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 was removed by filtration, and solvent was removed toy distillation under reduced pressure, and the residue was dissolved in chloroform. The solution was washed successively with IN hvdro10 chloric acid, water, a 5% sodium hydrogencartoonate aqueous solution, and water, and dried ^over anhydrous magnesium sulfate· The solvent was removed toy concentration under reduced pressure, and the residue was dissolved in 10 ml of anhydrous tetrahydrofuran- To the solution were added 98 wig of tetradecanoic acid, 58 mg of l-hydroxybenzotriazole, and 90 mg of dicyclohexylcarbodiimide under ice-cooling, and the liquid temperature was gradually elevated up to room temperature, followed toy stirring for one night. The precipitated insoluble matter was removed toy filtration, and the filtrate was concentrated under reduced pressure- The residual solid was purified toy silica gel column chromatography using, as eluent, a 10:1 (v/v) mixture of chloroform and acetone and then a 30:1 (v/v) mixture of chloroform and methanol, and then powderized from acetonitrile to obtain 428 mg of the entitled compound as a white powder.
Melting Points 105107*0 [a]25. +24.7« (c=1.0, chloroform) 3) Preparation of 2-phosphonoxyethyi 2-deoxy-6-0-C2-deoxy4-0-phosphono-3-0-(N-dodecanoylglycyX)“2-tetradecanoylamino- β-b-g lucopyr ano syl3-2-C6-(octanoylamxno)hexanoylamino3-3-0-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 Point: 169-172°C (colored and turned to jelly) +19-5° ic=0.6„ chloroform:methanol = 3:1 (v/v)] IR V0'' cmfls 3405, 2925, 2855, 1740, 1645, 1560, 1460 max NMR (CDCl3)r o(ppm): 0-90 (12H, tC 1.30 (s), 2.1-2.-4 (10H, m), 3.19 <2H, t) , 5-17 (IH, t), 5.38 (IH, fc} The resulting compound was treated in the same manner 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[2-deoxy“4-0-diphenylphosphono-3-0-(4-oxotetradecanoyl6-0-(2,2,2-trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-6“D-glucopyranosyl]-3-0-(4-oxo~ tetradecanoyl)-2-tetradecanoylamino-a-D-glucopyranoside In the same manner as in Example 1-1), 435 mg of 10-acetyl-2-deoxy-4~0-diphenylphosphono-3-0-(4-oxotetradecanovl)-6-0- (2.-2,2-trichloroethoxycarbonyl)-2-(2,2,2-trichlo65 xoethoxycarbonylamino)-D-glucopyranose and 380 mg of 2-(diphenylphosphonoxy ) ethyl 2-deoxy- 3 0 (4-oxotetradecanoyl)-2tetradecanoylamino-σ -D-g lucopyza.no side were reacted to obtain 516 mg of the entitled compound as an oily substance. s +14.7® (c=0-03* chloroform) 2) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-6-0[2™deoxy-4-0-diphenylphosphono-3 -0- (4-oxotetradecanoyl) 2-tetradecanoylamino-B -D-glucopyranosyl ] -3-0- (4-oxotetradecanoyl)-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 tenperature 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 53 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-methylmorpholine under ice-cooling.
The mixture «as stirred at the same temperature for 30 minutes. The reaction mixture was diluted with chloroform* washed successively with IN hydrochloric acid and water* and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure* and the residue was purified by silica gel column'chromatography using, as eluant,» chloroform.and. then a 20sl (v/v) mixture of chloroform and methanol fo obtain 229 mg of the entitled compound as an oily substance» Ca]^5s +17-3° (e=0»2, chloroform) 3) Preparation of 2-phosphonoxyethyl 2-deoxy-6-0-[2-deoxy4-0-phosphono-3 ~Q (4-oxotetradecanoyl) -2-tetradecanoylamino- 3-D-giucopyranosyi]-3-0-(4-oxotetradecanoyl)-2fetradecanoylamino-c-D-glucopyranoside In 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 166-170*C (colored and jelly-like) IR VKBr cm1: 3406, 2926, 2854, 1710, 1662, 1557, 1470 max NMR (CDCIg-CDgOD) , o(ppm) s 0.88 · (3.2H, tb 1.26 2.22 <4H, mb 2»54 <4H, tb 2.64 <4H, sab 2.76 (4H, mb 15 5.16 (IH, tb 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 benzyloxycarbonylmethyl 2-deoxy-6~0-[2deoxy-4-0-diphenylphosphono-3-0-(N-dodecanoylglycy1)-60-(2,2,2-trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-g-D-glueopyranosyl]-3-0-tetradecanoyl-2-tetradecanoylamino-a-D-glucopyranos ide In the same manner as in Example 1-1), 303 mg of 10-acetyl-2-deoxy-4~0~diphenylphosphono-3-0-( N-dodecanovl67 glycyl 1-6-0-( 2,2,2-trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-D--glucopyranose and 217 mg of benzyloxycarbonylraethvl 2-deoxy-3-Q-tetr&decanoyl-2-tetradecanoylamiho-a-D-glucopyranoside were reacted to obtain 408 mg of the entitled compound as an oily substance.
C©3^3 * 5s +25.8* (e-1.0, chloroform) 2) Preparation of benzyloxycarbonylmethyl 2-deoxy-6-0-[2“ deoxy-4-0-diphenylphosphono-3-0- (N-dodecanoylg lycy 1 )-2tetradecanoylamino-6-D-glucopyranosyl]-3-0-tetradecanoyl-2-tetradecanoylamino-a-D-glucopyranoside In the same manner as in Example 1-2), 389 mg of the compound prepared in 1) above was reacted with tetradecanoic acid to obtain 293 mg of the entitled compound as an oily substance. +28.4* (¢=1.1, chloroform) D 3) Preparation of carboxymethyl 2-deoxy-6-0-t2-deoxy-3-0(M-dodecanoylg Ivey 1) -4 -O-phosphono-2-tetradecanoylamino3-D-glucopyranosyl '1-3-0- tetradecanoyl-2-tetradecanoylaraino-a-D-glucopyranoside In a mixture of 40 ml of tetrahydrofuran and. 1 ml of 15 water was dissolved 278 mg of the compound prepared in 2) above, and 0.3 g of 5% palladium-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 addi20 tional 2.5 hours. The catalyst was filtered, and the filtrate was distilled to remove the solvent. The residue was purified by thin layer chromatography using, as devel- 68 XO oping solvent, a lower layer of a 8:3:1 (v/v) mixture of chloroform, 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 vSx 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 (IK - 59 EXAMPLE 5 1) Preparation of 2-(diphenylphosphonoxy)ethyl 2-deoxy-6[2—deoxv-4-0-diphenylphosphono-3-0-(K-dodecanoylglycyl)6-0(2,2,2-trichloroethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylaraino)-6-D-glucopyranosyl]-4-0-diphenylphcsphono-3 -0- (N-dodecanoylglycyl) -2-C (N-dodeeanoyl-Nmethylglycyl) amino]-a-D-glucopyranoside In 5 ml of anhydrous methylene chloride was dissolved 500 mg of the compound prepared in Example 1-1), and .5 0.-04 ml of-pyridine, 139 mg of diphenylphosphorochlor idate, and 64 mg of 4-dimethylaminopyridine 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 aqueous solution. a saturated sodium hydrogencarbonate aqueous solution# and a saturated sodium 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 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]25s +21-9° (0=0.8# chloroform) 2) Preparation of 2-(diphenylphosphonoxv)ethyl 2-deoxy-o-O(2 -deo xv-4-0-d iphenylpho sphono)-3-0-(N-dodecanoylgIvcvl)-2-[N-dodecanoyl-N-methylglycvl) amino]-β-D-glucopvranosyl)-4-O-diphenylphosphono-3-0-(N-dodecanoylglycyl)-2-[ (N-dodecanoyl-N-methylglycyl)amino]-a-D-glucopyranoside In the same manner as in Example 1-2)# 350 mg of the - 70 compound obtained in 1) above was treated with a zinc powder in an acetic acid solution and then reacted with N-dodecanoyl-N-methylglycine to obtain 244 mg of the entitled compound as an- oily substance.
CoJq5: +3.5® (c=0-6, chloroform) 3) Preparation of 2-phosphonoxyethyl 2-deoxy-S-0-(2-deoxy3-0-(N-dodecanoylglycyl)-2-[(N-dodecanoyl-N-methylglycyl)amino]-4-0-phosphono-B-gXucopyranosyl)-3-0-(N-dodecanoylglycyl )-2-C( N-dodecanoyl-N-methylglycyl)amino]-4-0phosphono-α-D-glucopyranosid® Xn the same .manner as xn Example 1-3),, 238 mg of the compound prepared in 2) above was subjected to catalytic reduction to obtain 101 mg of the entitled compound as a white powder.
Melting Points 184-189C (colored and jelly-like) -4-3° Ec=0-6, chloroform sraethanol - 3:1 (v/v)] XR cm : 3280, 2900, 1740, 1660, 1640 NMR (CDC13-CD3QD), δ(ppm)s 0-89 (12H, t, u=7.0Hs), 20 1.28 (brs), 1.62 (8H, br), 2.242.31 (4H, ra), 2.40-2.42 (4H, m), 2-91-2.96, 3-09, 3»12 (total 6H, each s), 4.84 (IH, d), 5.19 (1H„ t), 5.31 (IH, t) EXAMPLE .S 1) Preparation of 2-(diphenyIphosphonoxy)ethyl 3-0-Γ(R)-3benzyloxytetradecanoyl]-2-C(R)-3-bensyloxytetradecanoyiamino] -’2-deoxy-6-0- (2-deoxy-4-0-diphenylphosphono-6“0~ (2,2,2-trichloroethoxycarbonyl)-2-¢2,2,2-trichloroethoxycarbonylami no) -3-0- [ (R) --3- (2,2»2-trxchloroethoxycar-’ bonyloxy) tetradecanoyi] - β-D-glueopyranosyl) - a-D-glucopyranoside In the same manner as in Example 1-1)» 409 mg of 10“acetyl-2-deoxy“4=0“d.lphenylphosphono-6-0“ ¢2,2,2-t richlo 5 roethoxye&rtoonyl )-2-(2,2,2-trichloroethoxycarbonylamino) -30-E (R)-3- (2,2,2-trichloroethoxycarbony lossy) tetradecanoyi] -D™ glucopyranose was 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-benz10 yloxytetradecanoyI]~2-C (Ri-3-benzyloxytetradecanoylamino]-2™ deoxy-c-D-glucopyranoside in fhe presence of mercury (II) cyanide to obtain 577 mg of the entitled compound as a pale yellow, viscous oily substance, CG]^S +20-2’ (c^O .,2,, chloroform) 2) Preparation of 2-(diphenylphosphonoxy)ethyI 3-O-[(R)-3bensyloxytetradecanoyl]“2-[(R)--3-benzyloxytetradecanoyi-amino]-2-deoxv-6-0-(2-deoxy-4“0-diphenylphosphono™3-O[(R)-3“hydroxytetradeeanoyl]-2“[(R)-3-hydroxytetradecanoylamino]-P-D-glucopyranosyl) -a-D-glucopyranoside 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-hydroxytetradecanoic acid to obtain 312 mg of the entitled compound as a colorless oily - 72 substance. s +6.3° (c=0.7* chloroform) 3) Preparation of 2-phosphonoxyethyl 2-deoxy-6-0-(2-deoxy3-0~[(R)-3-hydroxyttradecanovl]-2-C(R)-3-hydroxvtetradecanoylamlno]-4-0-phosphono-6-D-glucopyranosyl)-3-0[ (R)~3-hydroxytetradecanoyl3-2-E (R)-3“hydroxytetradecanoylamino]-c-D-glucopyranoside In the sane manner as in Example 4-3),. 294 mg of the 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 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.
Ca3^5. -1.8“ i£c“0.5* chloro form smethanpl = 3sl.(v/v)3 Melting Points 155-158OC (colored and jelly-like) IR af1: 3440, 2930, 2860, 1740, 1660 NMR (CDCl.-CD.OD)* 6(ppm): 0.90 (12H, t)g 2.3-2.5 (8H, m) , .2 (2Hf m) EXAMPLE 7 X) Preparation of 2-(diphenylphosphonoxyJethyl 4-O~[3(foenzyloxycarbonyl)propionyl]-2-deoxy-6-0“[2-deoxy-4-0diphenylphosphono-3-O-(N-dodecanoylglycyl)-6-0-(2*2*2trichloroethoxycarhonvl)-2-(2,2,2-trichloroethoxycarbonylamino)-6-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-6-0C2-deoxy-4-0-diphenylphosphono-3-0- (N-dodecanoylglycyl) -6-0 (21212-triehXorogthoxysarbonyl)-2-(2,2 /2-trichloroethoxycarI bonyland.no) -8 ~D-glucopyr anosyl 3-3-0- ί N-dodecanoy lglycy 1)-25 tetradecanoylamino-α-D-glucopyranoside, and 108 mg of monobenzyl succinate and 16 mg of of dxmethylaminopyridine were 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 the mix10 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. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column 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. Ea]^5: +35.60 (c=l.l, chloroform) 2) Preparation of 2-(dxphenylphosphonoxy)ethyl 4-O-C3(bensyloxycarbonyl)propionyl-2-deoxy-6-0-L2-deoxy-4-0diphenylphosphono-3-O- (N-dodecanoylglycyl) --2-tetradecanoylamino- S-D-glucopyranosylJ-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 zinc powder in an acetic acid solution, and the product was reacted with tetradecanoic acid to obtain 226 mg of the entitled compound - .74 as an oily substance. [©325: +29.6 (c=l-2, chloroform) 3) Preparation of 2-phosphonoxyethyl 4~o-(3-carboxypropionyl )-2-deoxy-6-0-C2-deoxy-3-0-(NF-dodecanoylglycyl )-40-phosphond-2-tetradeeanoyIamino~B~D-glucopyranosyl]~30-(N-dodecanoylglycyl)-2-tetradecanoylamino-u-D-glucopyranoside In the same manner as in Example 4-3),, 204 mg of the 5 compound prepared in 2) above was reacted to obtain 97 mg of the entitled compound as a white powder.
Melting Point: 150-155eC (colored and jelly-like) +24.4° (c=0.5, chloroform methanol “* 3:1 (v/v)) D IRV^cra1: 3300, 2925/ 2855, 1755, 1660, 1555 max NMR (CDCl.,-CD. OD), 0(onm): 0.89 (12H, t)„ 1-27 (s), 2.2-2.3 O * «3 (8H, ra),, 2.6-2.7 (4H, ra), 4. .18 (2H, ' mJ, 4.27 (2H, m), 4.61 (IH d). 4.82 (IH, d), 5.06 (IH, t) , 5.24 (IH, 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. (la) - 75 & !—I ft eo KI Z X w ac u χχ -COCH2NHCO(CH2)10CH3 -CO(CH2‘j12CH2 -COCK2NHCO(CH2)10CK3 -co(ch, oo ci a X 0 o oi ae X V Ci 03 o a £ pH 0 a XX •w XX • 03 O) o o M ffVl se 0 a o υ gG X XX 03 (3 s o Ul 0* u ^~X xx #x *55 03 oa 03 03 Prt S*a en en S3 eg G u u U •iaX ex x* O - - o o o a o u a a 8 1 1 ea se ea a ea fi a ©“ © o © -Ss oi n a SC 0 u o o eH χχ x*x d 03 OJ en en «*4 U 0 © 03 x>x XX H η O - o ** a © © ea 0—ss en MM ST. ea d S 0 a © en w Mm O-0 O o o a © © β ί 0 d Pl Ol oi on a se X © © a u o o o n-J X*X pH 03 03 ea ffi oa in m a o . « © © © g 2 3r o o 2 »-X o o u 03 o pi O © P □ o 03 pH © a © ea u en sc «ηχ XX en B*n ©—ss ,^-x X g g 03 03 s 9 ea eSi 03 oa se SC ea Pl I a 03 se 33 u o X x a © 33 o O tX XX © G—o U o o o o o o o O o u u u © © © o 8 8 c 1 n 1 8 8 Ol Ol se eg o u © o e-i &H XX e*X oa 03 Ol O) on a»n nn u*i S3 o u o a U XX xX 03 03 03 Ol © οι O rH pH wn o S3 U < XX XX u— -55 U«— SS 03 oa 03 1 03 en tfi S3 d I © O o I G XX o © I © xx o .© ©-a o © 353 os a © o I d Ol ts a u © o «Μ eH η» XX • Ol X ts u a o> o 8 en o a o—a F ea d SS a a en tW © 0—© o o © © S' a Ol d n Pl Ol Ol d eq^ eC o X u a © a © X u X u X o eM o ¢1 σ> o o © Φ Q nl pH XX pH 03 03 ea —» xx oa X O X u a © ea a u 03 X u 03 X o X u 03 a u O V Ol .o u Ol ~o © ea XX o o o u cn O X o o o 03 © *T< ϋ · 55 -™* § Oi Ol ea z g 03 Ol X U X u X u a © ea a 03 X Ol I X X X o © u u—o x-» o o ~o o o o o o u 1 ϋ o o o u u 1 o 1 σ> o OJ •5J· LO to «r— *— Example wo; 4 R R3 17 ' · ch3 -COCHNHCO(CH,), _CH, -CO(CH2i12=H3 18 -COCHgNHCO(CHg)x qCH3 =COCH2OCOiCH2)10CH3 19 -CO(CH,)_NHCO(CH,) -CH2 5 2 6 3 “CO ί CH2 3,, NHCO (CH2) g CK3 20 ' -CO(CH,),NHCO{CH-)-CH,' 2 2 2 8 3 “Co{ct2)1 ?ck3 21 -COCHgNHCO(CH2)i0CH3 ~CO(CH?3 ?co{ch23gCH2 22 -COCK 2NHCO(CHg)sCH3 -oo(ch2!10ch3 23 -cock2nhco(ch2)10ch3 -COi CH? i-CO( CHj ί jHHCO(ch2}6ch3 24 CH, i 3 -COCK2NCO(CH?)i0CH3 , ch3 -COCHgNCO{CHg3 x qCH3 25 -COCCHp^CH, ”CO(CH2)i2CH3 26 . ~CO(CH,)-NHCO(CHj-CH2 5 2 o 4 -co(ch2312ch3 CHq J 3 COCHNHCO(CH?)1QCH3 -CO(CKg)12CH3 COCHgNHCO(CHg) , QCH3 -COCHgOCO(CHg)1QCH3 CO(CH,).NHCO(CH,),CH, 2 5 2 '5 3 “CO(CH-)_NHCO(CH-)-CH. 2 5 2 6. CO(CH?5 gNHCOCCHg3QCH, =co(ch2J12ch3 COCHgNHCO ί CHg31C,CH3 -CO(CHg32CO(CHg}9CH3 COCH?NHCO{CHg)gCHg -C0(CH2)i0CH3 COCHgNHCOί CH?)i0CH3 =C0(CH2)2C0(CH2)2NHCO (ch2)6ch3 CH3 -COCHgNCO{CH? J 5 QCH3 ch3 —COCHgNCO(CHg310CH3 -COCHgNHCO (CH? 3 10cH3 -coSch2)12ch3 =CO(CH?)5NHCO(CH,)gCH3 -CO(CH2)i2CH3 Example MO»- 27 -coch2»hco(ch2)10ch3 -COiCH2)5NHCOiCH2)6CH3 28 -COCH2NHCO(CK2)10CK3 29 -COCH2NHCO(CH2)1QCH3 =co(CK2)3hhcoί ch2)8ch3 30 -COCH2NHCO(CH?5 1CjCH3 -CO(CK2)gNHCO(CK2i gCHg 31 -COCHjNHCO(CH2)1QCH3 “CO*CT2h2CK3 32 -COCH? NHCO(CH?) „ QCH3 CH2(CH2)la|CH3 -COCH^SCO£ CK2)1qCH3 33 “CO(CH2512CK3 -cot CB2 5 3hhco( ch2) s’ch3 34 -COCH2NHCO£ CH2)gCH3 -co{ch2)8ch3 35 -COCH?NHCO(CH2)gCH3 . ~CQ£CH2)sCH3 36 -coch2nhco(ch2),qch3 CH, . j ·* -COCHjHCOiCH2), 0CH, COCK?HHCO£ CH2)2 θΟΗ3 -cot CH?),. NHCO(CH2)gCH3 co£ch2)12ch3 -co(ch2)12ch3 COCK2NHCO( CH2) 1(jCH3 -COtCH2)3NHCO(CH2}sCH3 COCH?NKCO(CH2)1qCH3 -co£ch2)2nhco(ch2)8ch3 coch2nhco£ ch25, qCH3 -COCH2NHCO(CK2)iQCH3 COCHjHHCO(CH2)1QCH3 CH,(CK2>iocfl3 -COCHjHCO(CH2)10CK3 •CO£CH2)i2CH3 4 --co£ch2)3nhco(ch2)8ch3 COCHgNKCO£ CHgΪ g C«3 =OOtCH2)3CH3 =COCH2NHCO£ CH25 8CH3 =CO(CK2)aCH3 Γ3 -coch2m:-co£ ch2 ϊ , och3 ch, f3 -COCH?NCO(CH2)10CK3 ss ca CO &i.
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©S Ρ e-S a, ε ρ <0 κ ω r> fry» CBM 0 a o o iH e-®4 >-JX rf** cs X 03 X CJ X 0 03 o •H ^crf tsM b rf** X X a 03 0—0 CS x Ci X u X a •earf a o o o o a u 8 B » ο> υ Θ β-Μ *·* en X D o b*» erf eia CS cj cj «-4 id ca «·** rf-* «Τ-* 03 tM 03 X erf 0F« . Mm C~5M O cj u *rf* *erf o o o o a u 6 1 1 υ ο rf·*» Ρ5) Ο <*) »-»1 CC* p*9 6’·» u erf a 0 03 0 03 *·* &H *—rf «Η «·» rf-* feM erf / fcArt rf·* •S 03 O“0 03 w c? StM X 0 X 0 o e^rf 0 ** o o p o a 0 0 0 1 e s 9 Γ-Ί .ζ» η X ο ο β=$ PS Hf4 C-*-J Ο ο CS ,-1 Ci X Ο *^* Ο ο I C3 X ο X c X υ ο ο ι νη νο νο vo Ρ» X ο ο <*> Μ4 sAd Ο < 6Γ-3 rf®* erf 6*Μ ο *«rf ο υ ►Μ U & *οί brfi Γ—Μ υ *rrf ο ο I ea rf·* <μ ffC4 &Kj ο *lrf ο υ ι Λ 03 X n m a X 5*™ W o oa o CJ ·—J MS co biM rf** rf-* rf-* -u CM 03 O! CM X C«4 sJm X X u 0 o CJ «Mrf *-rf o o o o o 0 0 0 «X νο oo cn uo vo o r82 ο r> o> rf—* X Prf M>« 03 Q a 0 < 6 ¢-4 ' «-a rf’rta C-srt felV^ erf 03 03 o—0 rt* M-3 C4-S OM 0 0 MM *^rf o o o o 0 0 o 9 9 Ρ» Ρ?Μ *Μ Ο . ο «Π rf·* X «Α4 *03 CJ CJ X o CJ c-H «Η rf-S X erf MM CM 03 o-0 G=*M X *03 0 , u *^rf fc*j 0 o o o 0 0 0 β r~x ou co s^> I co CO I Example 2 3 1 NO. R* ir R R 74 -COCH?NHCO(CH?) 1 qCH? =CO(CH?)12CH3 -COCH? NHCO{CH?)1QCH3 -CO(CH2)i2CH3 -CH(CH2COOH) 75 -co2)12c«3 ^G/l2CH3 -c°(cb2)12cH3 -c°(CH2i12cH3 -CH(CK2COOH) 76 -c°(ca2)i2OH3 -CO(CH2)12CH3 -OO(OH2)12CH3 -CO(CH2)CH3 -CH?COOK Ρ» Example 4. 2 5 2 3 No; ·' - R RJ R* Rx 77 -co(ch2)2co(ch2)9ch3 =CO(CH2i12CH3 -COCOOK -CO(CHg)gCO(CHg39CH3 78 -COCHgNHCO(CHg3 χ QCK3 -COiCH2) CH3 »PO{OK)2 -COCHgNHCOi CHg)1QCH3 -co(ch2!12ch3 79 -COCHgNHCO(CH?)1QCK3 =CO(CH,)„NHCO(CH,)-CH, 2 5 2 © 3 ~po(oh)2 -COCHGNHCOί CH-), _CH, 2 2 XO 3 -c°(ch2)12ch3 80 -COCHgNHCO(CH?}iQCH3 -CO(CH,3s NHCO(CH?3 gCHg o^co- I 2 -COCHgNHCO(CHg)1QCH3 -c0ie»2»12CH3 Ή,COOH £ Physical properties of the compounds of Examples 8 to 80 ere as follows...
Example No. - _ physical properties__ Melting Point: 140»150®C (colored and jelly-like) s +13.3® (c-0,5 chloroformsmethanol = 3:1 (v/v)) IR cm1: 3400# 2930# 2855# 1750# 1660# 1560 NMR (CDC13-CD3OD), δ(ppm): 0.90 (12H, t)# 1-32 (s), 2-1-2.3 (8H, m)# 5-10 (IS, t) # 5-38 (IH# t) Melting Points 174-180°C (colored and jelly-like) E®3_j - +11.8® (cs=0.7, chloroform:methanol = 1:1 (v/v)) IR cm ~s 3425# 2930, 2854# 1745# 1675# 1470 NMR (CDCi^-CfbOD # δ(ppm): 0-89 (12H# t)# 1.28 (s), 2-27 (2Bt, t), 2.4-2.8 (12H, mb 2.93 (2H, m) 4- 81 (XH# mb 5.14 (XH# t)# 5-32 (IK# m) Melting Point: X59~167®C (colored and jelly-like) : +10-2® (c=0-6# chloroformsmethanol = 1:1 D (v/v)) IRvBr cm1; 3330# 2925# 2855# 1745# 1655# 1560 max 1470# 1025 NMR (CDC13~CD3OD)# δ(ppm)s 0-89 (X2H# t), 1.27 (s)„ 2-20 (6H# m), 2.46 (2H, t)# 2-6-2.8 (4H# mb 3»25 (2H, m)# 3-63 (1H, mb 3.71 (1H# m)# 3-90 (8H, mb 4.18 (4H# mb 4-75 (1H# d) # 5.13 (1H# t) - 24 (5H, t) - 85 Example No.
Physical Properties Melting Point; 165-171°C (colored and jelly-like) [a 3^5; 4-5.0° (c-0.5 chloroformsmethanol = 1:1 (v/v)) *3*· ei · IR cm s 3320, 2925, 2855, 1710, 1645, 1555 1470 NMR (CDCX_—CD_OD)» δ(pom): 0.89 (12H„ t), 1.27 3 3 (s), 2.17 (SH m)» 2.47 (4Η» m)» 2.60 (4Η» m) » 2.73 (4H, mb 4.25 (IH, q), 4.75 (IH, d), 5.12 (IH, t), 5.25 (IH, t) Melting Point: 169-173°C (colored and jelly-like) [α]χ ; +16.4° (c=0»7, chloroform;methanol = 3:1 D (v/v) ) IR cm x: 3425» 2925» 2855» 1735» 1645» 1555 NMR (CDC13-CD3OD), 6(ppm): 0-90 (12H, t)» 2.22.4 (10H, m), 3.18 (2H, t)» 5»16 (IH, t), 5.36 (IH, t) Melting Point; 161-165®C (colored and jelly-like) +9.2° (c-0.6, chloroform ί methanol := 3:1 (v/v)) IR vKBr cm**1: 3405» 2930» 2855» 1760» 1660» 1550 max NMR (CDC13~CD3OD), δ(ppm); 0.90 (12H, t), 2*22.5 (8H, m)» 2.96 and 3.04 (total 6Η» each s), 5.18 (IH, t), 5.34 (IH, t) - 86 Example No. _._Physical Properties_ Melting Points 144-147°C (colored and jelly-like) [α]β : -2.4° (c=0.8, chloroformsmethanol = 3;1 (v/v)) IR cm”1: 3405, 2925, lUCiJs 2855, 1745, 1655 , 1555 NMR (CDC13-CD3OD)„ 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 (1H, d) ,» 5.16 (1H, t) , 5.29 (IR, t) Melting Points 150-154®C (colored and jelly-like) s +16.8° (c=0.6, chloroform s me thanol = 3:1 (v/v)) IR vKBr cm1: 3450, 2930, 2860, 1745, 1675, 1675 max 1470 NMR (CDCl_~CDo0D) , 6(Dom) : 0-88 (12H, t) , 1.26 3 (br), 2.3-2.8 (18R, m), 2.96 and 3-10 and 3.18 (total 6H, each s), 5-16 (1H,, xn) „ 5.34 (1H, m) Melting Points 190-193C (colored and jelly-like) [a]-5.4® (c=0-7, chloroformsmethanol = 3 si (v/v)) IR vKBr cm1: 3305, 2925, 2855, 1750, 1650 max NMR (CDC13-CD3OD), 6(ppm): 0-90 (12H, t), 2.1-2.4 (8H, m), 5.16 (1H, t), 5.38 (1H, t) Example No. _Physical Properties_ bl Melting Points 175-177’C (colored and jelly-like) [a]D :· “2.2° (c=0-8„ chloroform:methanol = 3sl (v/v)) IR cm”1; 3310, 2925» 2855» 1745» 1660» 1555 max NMR (CDCI3~CD3OD)» 0(ppm)s 0.89 (12H, t)» 2.1-2.4 (8H, m)» 5.18 (1Η» t), 5.32 (IH, t) Melting Points 145-150“C (colored and jelly-like) [a]Q s +1.7° (c=0.6, chloroform;methanol = 3:1 (v/v)) IR vKBr cm1.· 3300» 2925» 2855» 1755» 1685, 1645 max 1555 NMR (CDC13-CD3OD)» 6(ppm): 0.90 (12H, t), 1.30 (s)» 2.29 (4H, t)» 2.48 (4H, t)» 4.73 (IH, d) » 4.84 (1Η» d)» 5.19 (1Η» t)» 5.32 (IH, t) Melting Points 165-168°C (colored and jelly-like) +10.2“ (c=0«5, chloroformsmethanol -3x1 (v/v)) IR vKBr cm1; 3310» 2930» 2865» 1735» 1645, 1555 max NMR (CDC13-CD3OD)» 6(ppm)s 0.90 (12Η» t-br)» 1.30 (s)» 2.20 (12H, t), 2.36 (4H, m) » 3.19 (8Η» t) » 4.68 (IH, d), 4.79 (IH, d)» 5.16 (IH, t) , 5.24 IH, t) - 88 Example No. __Physical Properties____ Melting Points 178-183*0 (colored and jelly-like) r.G3^5s +16.8* (c-0.5, chloroforms methanol = 3:1 (v/v)) IR cm-: 3315, 2925, 2855, 1735» 1660» 1570 NMR (CDClg-CDgOD), o(ppm): 0.88 (12H, t), 1.26 (s), 2-20 (8H, m), 5-18 (IH, t),2.56 (4H,m), 5.30 (IH, t) Melting Point: 151-160®C (colored and jelly-like) Cc3p°s +2.4® (e-0»3, chloroformsmethanol » 3:1 (v/v)) IR an‘j 3350, 2925, 2855, 1750, 1647, 1555 NMR (CDClg-CDgOD), 0(ppm)s 0.88 (12H, t), 1.26 (s), 2.2-2.7 (16H, m), 5.18 (IH, t), 5.30 (IH,. t) r Melting Point: 160-164®C (colored and jelly-like) 95· . +14.5* (c=0z, chloroform methanol ·- 3:1 (v/v)) IR cm1: 3330, 2930, 2860, 1755, 1660, 1565 max NMR (CDCXg-CDgOD), S(ppm): 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) +6.6* (c=0.3, chloroformsmethanol - 3:1 (v/v)) IR cm1: 3315, 2930, 2860, 1760, 1660, 1555 NMR (CDC13~CD3OD), δ(ppm): 0.88 (12H, t), 1.26 (s), 2.1-2.8 (20H, m), 5.20 (IH, t), 5.34 (IH, t) - 89 Example No.
Physical Properties Melting Point: 160-170°C (gradually colored and jelly-like) „25 [ct] τη v ·=· a.% KBr max +21.7° (c=0.6# chloroform smethanol = 3 si (v/v)) cm1: 3450,. 2930# 2860# 1760# 1675# 1470 (CDCl^-CD^OD) 0(ppm)s 0,30 (12H# t)#’l-32 (&), 2.43 (8H# mb 2.96 and 308 and 3.16 (total 12H# each m# s# s), 4.87 (2H# m) # 5.20 (1H# m)# 5.47 (IB# m) Melting Points 156-170°C (colored and jelly-like) 1-10.6° (e=l„0# chloro form smethanol = 3 si r -,25 Cc% = v) IR V' max cm 3330# 2925# 2855# 1745# 1660# 1560 ), 1.26 (CDC1„—CD_OD)# 6(ppm)s 0.88 (12H# «2 3 (sb 2.1 3-5-3-8 (4H 3.94 (6Hi mb 4.20 <4H# mb 4.79 (XH# d) # 5-19 (1H# t)# 5.25 (IB# t) Melting Points 160152°C (colored and jelly-like) [a]®· +12.9° (c=0.7# chloroformsmethanol = 3 si (v/v)) cm1: 3320# 2925# 2855# 1730# 1655# 1565 WR (CDC13-CD3OD), δ(ppm)s 0.90 (12H# t), 2.18 (8H# m)# 2.36 (4H, m), 3-20 (4H# m), 4.78 (1H# db .2 (2H# m ) KBr max - 90 Sxamole No. _Physical Properties__ Melting Points I62-X65OC‘ (colored and jelly-like) oe Ca3* s +10.7“ (c-0.5, chloroform smethanol: water = 8:3:1 (v/v) lower layer) IR \>roai cm1: 3315» 2925» 2860» 1760» 1645, 1555 NMR (CDC13-CD3OD)» δ(ppm)s 0.90 (12H, t)» 2-1-2.4 (12H, m), 3.1-3.3 (4H, t), 5.20 (IH, t) , 5.37 (IH, t) Melting Point; 160-164“C (colored and jelly-like) Cal^5· +14-1* (0=0.7, chloroform smethanol =3:1 (v/v)) KBr _-j IR vmax cm 3410» 2925» 2855» 1750» 1645» 1560 NMR (CDCl3-CD3ODb 6(ppm): 0.90 (12H, tb 2.1-2.4 (80» mb 5-18 (In, t)» 5.38 (IH, t) Melting Points X65-168°C (colored and jelly-like) [a]^5. ;8.6’ (c=0.7, chloroformsmethanol;water = D 6:4:1 (v/v)) KBr ! IR vmax cm : 3315» 3100» 2925, 2855» 1745» 1660, 1565 NMR (CDC13-CD3OD)» δ(ppm): 0.90 (12H# tb 2.2-2.5 (12H, mb 4.81 (1Η» d) » 5.19 (IH,. t) ,. 5.35 (IH,. t) - 91 Example No. __Physical Properties__ Melting Point; I77-185c’(gradually colored and jelly-like) • og Γα]“ s +3..,/B (c~0 S chloroformsmethanol:water = D 6;4;1 (v/v)) IR cm1; 3315* 2930* max 2855* 1750* 1660* 1560 NMR (CDC13“CD3OD)* δ(ppm); 0.88 (12H* tb 1 26 (s)* 2.1-2.5 (10H, m)* 5.18 (IH* tb 5.34 (IH* t) E® 3^» +2.4“ (chloroformsmethanolswaterstriethyl amine = 8s3;0.5;0.01 (v/v)) NMR (CDC1O—CD_OD)* 6(ppm): 0.90 (12H* tb 1.28 (s)* 2.1-2.4 (8H* mb 5.16 (IH* t) , 5.32 (IH* t) Melting Point; 17O-175°C (colored and jelly-like) 9s [a s 4-5*2** (c—0-6, chloroform smethanol - 3si (v/v)) =-1 IRV* cm ~s 3300* 2925* 2855* 1750* 1680* 1565 Xna3C NMR (CDC13-CD3OD) * δ (ppm) s 0.90 (12H* tb 1.30 (s)* 2.2-2.5 (8H* m), 5.20 (IH* m) * 5.37 (IH* m) Melting Points 182-185“C (colored and jelly-like) Ea 3^5 s +11..5° (c=0.7* chloroformsmethanoI = 3sl (v/v)) KBr ·, XRvmax cm : 3315* 2925* 2855* 1735* 1645* 1560 NMR (CDC1_—CD_OD)* δ (oom)s 0.90 (12H* t)* 2.1-2. 3 3 (12H* mb 3.1-3.3 (4H* mb 5.1-5.4 (2n„ m) - 92 Example E?o. ___Physical Properties_ Melting Point: 157-162°C (colored and jelly-like) C«3p5: +13-8° (c=0.5» chloroformsmethanol ~ 3:1 (v/v)) KBr -ί 2930, IR v ζ cm 3330,2860» 1755, 1660» 1565 iitciX / NMR (CDC13“CD3OD)» δ(ppm): 0.91 (12H, t)» 1-32 (s), 2-1-2.3 (8H, m), 5-10 (IH, t) » 5-38 (IH, t) Melting Points 168-172°C (colored and jelly-like) +14.6* (»1.0. chloroform =raethanol = 3 = 1 (v/v)) KBr Mmax cm x 3320» 2930» 2860, 1755, 1660» 1565 NMR (CDC! —CQ ODb δ (ppm) s 0.91 (12H, t)» 1.32 3 13 (br), 2-12-2.32 <8H, mb 5.18 (IH, m)» 5.36 (IH, m) Melting Point: 175-180*C (colored and jelly-like) IE® +9.9° ic-0-7,. chloro form: methanol = 3:1 (v/v)) KBr -ί IR vmax cm 3300» 2930» 2860» 1750, 1675» 1580 1560 KMR (CDC13-CD3OD)» δ(ppm): 0-89 (12H, t)» 1.30 (s), 2.2-2.5 (8H„ mb 2.95 and 3-12 (total 9H, each m), 4.85 (IH, d)» 5-18 (IH, t)» 5.35 (IH, m) - 93 Example No. _Physical Properties_ Melting Points 170-175*0 (colored and jelly-like) [c.1^. +14.9° (e=0.6, chloroformmethanol - 3x1 (v/v)) vmax cm1; 3400l! 330°' 2930* 2860* 1755* 1S75, 1575 NMR (CDClg-CDgOD) , 6(ppra): 0.91 (12H, t) ., 1.32 (sE 2-29 (2H, m) 2.43 (6H, m), 2.94 and 3.12 (total 9H, each m), 4.83 (IH, nt), 5.18 (IH, m), 5.44 (IH, m) Melting Point: 155-174*0 (colored and jelly-like) OG CcQjj . +9.2* (¢2=0.6, chloroform methanol ~ 3:1 (v/v)) IR vKBr CBa“l. 3310, 2930, max 2860, 1750, 1660, 1565 NMR (CDC13-CD3OD), δ (ppm): 0.88 (X2H, tE 1.25 (sE 2.1-2.4 (20H, m) , 2.94 (3H, s), 3 .04.(3H, a) 5.18 (IH, t), 5.36 (IH, t) Melting Points 170-186*0 (gradually colored and jelly-like) C IR cm_1s 3310, 2930, 2860, 1750, 1660, 1565 max NMR (CDClg-CDgOD), 6(ppm): 0.88 (12H, t) , 1.26 (s), 2.20 (8H, t), 2.43 (4H, t), 2.94 (1H, m)e 3.11 (6H, s), 3.19 (4H, m)a 4.81 (IH, m), 5.19 (XHj t), 5.38 (IH, t) - 94 Example No. ___Physical properties __ Melting Point: 184-186*C (colored and jelly-like) [a]29: +6.0“ (c=0.5# chloroform smethanol 3:1 (v/v)) IR cm: 3460# 1758,, 1662 NMR (CDC13~CD3OD) # δ (ppm) : 0.88 (12H# t) # 1-26 (s), 2.1 - 2.5 (8H»m), 2.94, 3.12 (total 6H,S) 4-,80 (1H,m), 5.18 (1H,- m), 5,,38 (1H, m) 41 Melting Points 155-165°C (gradually colored and jelly-like) fc. . +3,.2° (c=0.7# chloroformsmethanolswater --·· 6:4:1 (v/v)) IR cm1: 3320# 2930# 2850# 1760# 1645# 1565 lUG.i'k NMR (CDC1 -CD OD)# δ (ppmb 0.90 (12H, t)# 1.30 (s), 2.2 (12H, m), 3.18 (4H, t-tor) , 5.19 (XH# t)» .36 (1H# fc) Melting Point: 165-168°C (colored and jelly-like) +23.6° (c=06 chloroform:methanol -3:1 (v/v)) IRVmax cm 3450# 2925 * 2855« 1735’ 1^75# 1635 NMR (CDC13~CD3OD)# 0(ppm)s 0.90 (12H# t)# 1.30 (s) # 2.3-2.5 (8H# m) # 2.92 and 2-94 and 3..07 and 3.09 (total SH# s)# 4-74 (1H, m)# 4.87 (XH# d) # .14 (1H# t)# 5.38 (IR# t) - 95 Example NO. j_Physical Properties Melting Points 177-179°C (colored and jelly-like) +11.7® (c=0-7, chloroformsmethanol = 3si (v/v)) IR vgg cm1: 3310, 2860, 1734, 1659. 1560 NMR (CDC13-CD3OD), β(ppm)s 0.90 (12H, t) , 2.1-2-4 (12H, ra), 3.10 (4H, t), 5.1-5.3 (2H, ra) Melting Points 145~150°C (colored and jelly-like) Γα s +7.6° (o=0.8, chloroform smethanol = 3;1 (v/v)) IR cm1: 3300, 1760, 1665, 1555 max NMR (CDC13-CD3OD), δ (ppm) ϊ 0.90 (12H, t), 1.30 (s), 2.30 (8H, m), 4.84 (IH, d), 5.19 (IH, t), S.33 (IH, t) Melting Points 148-153°C (colored and jelly-like) [a]2^s +18-4* (c-0.9, chloroform smethanol = 3:1 (v/v)) IR cm-1: 3300, 1745, 1645, 1555 NMR (CDC13-CD3OD) , <5 (ppm) s 0.90 (12H, t) , 1-30 (s), 2.30 (8H, m), 4-86 (IH, d), 5-16 (IH, t) , .5-34 (IH, t) Example . No.
Physical Properties Melting Point: 155-158°C (colored and jelly-like) +11-6° (c=l»0,? chloroform smethanol = 3:1 (v/v)) vKBr CJfl-l 3320» 1745, 1645» 1555 max NMR (CDC1_—CD_OD), δ(ppm): 0.89 (12Η» t)» 1.30 3 (e), 2.1-2.4 (12H, m), 3-18 (4H, br)» 4-67 (IH, d), 5-2 (2H, ra) NMR (CDClg—CDgOD), δ(ppm)s 0-88 (12H, t), 1.26 (s), 1.9-2-1 (4Η» m), 2-2-2-4 (8H, mb 5.16 (1Η» t)» 5.30 (IH, t) Egj +4.3· (c=0.S» chloroform smethanol = 3:1 (v/v)) NMR (CDClg-CDgODb δ(ppm)s 0-1 (12H tb 1-26 Csb 1-9-2.2 (4H, mb 2.2-2.4 (8H, mb 4.80 (IH, ab 5.14 (IH, tb 5.30 (1Η» t) £c3“^ , 4.ΐ4„χθ (c=0.7» chloroform;methanol =water = D 8:3:0.5 (v/v)) NMR (CDClg-CDgODb (ppm)s 0-88 (6Η» tb 1.26 (s), 1-4-1-8 (mb 2.08 (4H, ra), 2.34 (4H, m)» 4.63 (1Η» db 4.78 (1H„ d) » 5-20 (2H, m) [a +16.6 0 (c=l. 0, chloroform smethanol:water = 8:3:0.5 (v/v)) 0.88 (SH, tb 1.26 (s)» 1.4-1.8 (mb 2-20 (4H, mb 2.36 (4H, m), 4.86 (IH, d), 5.14 (IH, t), 5.30 (IH, t) NMR (CDClg-CDgOD)» δ(ppm) - 97 Examole No. _Physical Propertxes__ Melting Points 148-153*C (colored and jelly-like) Eg]?,5 s +10-0” (e=0.7,f chloroform smethanol ~ 3:1 (v/v)) KBr -ί IR cm ~s 3320, 2925» 2855» 1745, 1645» 1565 NMR (CDC13~CD3OD)» δ (ppm);: 0.90 (12H, t), 1.30 (sb 2-2-2-3 (8Η» m)» 4.70 (1Η» d), 4.81 (IH, d)» 5.16 (IH, t)» 5.31 (IH, t) Melting Points 135-138“C (colored and jelly-like) Eaj25 ϊ +13-3’ (c=0-b chloroformsmethanol = 3 si (v/v)) IR aa-1: 3405, 2925» 2855» 1750» 1660» 1555 NMR 3~CD3ODb δ (ppm): 0-88 (12Η» tb 1.26 (hr)» 2.3-2.8 (24Η» mb 5.16 (IH, mb 5-30 (IH, ra) Melting Points 168-173*0 (colored and jelly-like) [al : +9.4® (c=0»5» chloro form smethanol = water = D 6:4si (v/v)) IR cm1: 3350, 2930» 1745, 1660» 1570 max NMR (CDC1„~CD_OD) » δ(ppm): 0.90 (12H, t) » 1.30 3 3 (s), 2.1-2-3 (10H, mb 3.18 (2H, t), 4.78 (2H, mb 5.18 (IH, tb 5.35 (IH, t) - 98 Example No. __Physical Properties____ Melting Point; 182-3.88°C (colored and jelly-like) +11.8” (c=0.7* chloroform;methanol ~ lsl (v/v)) IR vKBr cmS 3310, 2926, 2854, 1749, 1677, 1563 max NMR (CDC13~CD3OD)* δ(ppm); 0.89 (12H, t), 1.28 (s), 2.28 (4H* m), 2.4-2.8 (8H, m)* 3.09, 3-13 (total 6H* each s), 3.6-4.3 (m) * 4»82 (IH, d) * .12 (IH, t), 5.34 (IH, t) Melting Point; 160-165*C (colored and jelly-like) IE®3«° ϊ +16.8® (c=0-5, chloroformxmethanol = 3;1 D (v/v)) tCPv a cm -= · 3330* 2925* 2855* 1735* 1645* 1550 max NMR (CDCb-CD^ODb δ (ppm) x 0.89 (12H, tb 1-27 3 «3» (sb 2.1-2.4 (XOH, mb 3.16 (12H* tb 4.27 (IH* qb 4.76 (IH, d) * 4.79’(IH, d) * 5.12 (IH, dd) * 5.33 (IH* t) Melting Point; 158-162®C (colored and jelly-like) +13.09 (c=0.4* chloroform xmethanol = 3:1 (v/v)) -IR VK3r cm1; 3328, 2926* 2854* 1749, 1659, 1563 max NMR (CDC13-CD3OD)* δ(ppm)x 0.89 (12H* t), 1.27 (s), 1.5-1.6 (8H, ra), 2.1-2.3 (8H* m) * 5.14 (IH, t)* 5.32 (IH* t) - 99 Example No. _Physical Properties_ Melting Point: 168-172’C (colored and jelly-like) Cc]25: +14-2° (c=0.6, chloroformsmethanol = 3:1 (v/v)) IR cm1; 3320, 2925, 2855, 1750, 1660, 1565 NMR (CDC13“CD3OD), 6(ppm): 0-81 (12H, t), 1-18 (a), 1-5-1.6 (8H, a), 2.0-2.2 (8H, m), 5-05 (IH, t), 5-23 (IH, t) Melting Point: 184-187“C (colored and jelly-like) Ca]^*; +15.4® (c=0.S, chloroformsmethanol = 1:1 (v/v)) IR vK3r cm1: 3430, 2930, 2855, 1755, 1660, 1565, max 1470, 138559' Melting Point; X78-182°C (colored and jelly-like) Cc]25: +9.5 (¢=0.6, chloroformsmethanol = 1:1 (v/v)) ί IR cm*: 3405, 2930, 2855, 1760, 1660, 1555, 1470, 1205, 1025» NMR (CDC13“CD3OD), δ(ρρπ)ϊ 0.89 (12H, t) , 1.27 (a), 1.61 (ra), 2-12-2-36 (10H, m), 2.91, 3.03 (total 3H, each s), 4.77 (IH, d), 5-14 (IH, t) .32 (IH, t) - 100 Example No.
Physical Properties · Melting Points 192-198*0 (colored and jelly-like) [cd25s +7.8* (c=0.5, chloroformsmethanol = 1:1 (v/v)) IR vmax cm~1: 3355’ 2θ3θ* 2855' 1745* 166°* 1565 1470, 1385, 1210 NMR (CDC13-CD3OD), δ(ppm): 0.89 (I2H, t), 1.28 (s), 1-60 (m), 2.12-2.38 (10H, m), 3.16 (2H, t), 3.53 (2H, ra), 3.62 (IH, m) t 3.72 -(IH, m), 3,90 (8H, a), 4.16 (6H, m), 4.23 (IH, q), 4-59 (IH, d) 5.15 (IH, t), 5.21 (IH, t) Melting Point: 194-195*0 (colored and jelly-like) [cjj25 s +7.2* (c=0«8, chloroform methanol = 1:1 (v/v)) aCBX 71 IR Emax CT· 3320, 2930, 2855, 1745, 1660, 1555 1025 NMR (CDCl -CD^OD), 3 3 δ(ppm): 0.89 (12H, t), 1.2/ (®) , 1.60 (m), 2.03-2.35 (12H, m), 3.16 (5H, m), 3.50 (2H, m), 3.54 (IH, m), 3.72 (IH, m), 3.88 (2H, m), 4.15 (5Hf m), 4-27 (IH, q), 4.77 (IH, d) 5.15 (IH, t), 5.23 (IH, t) - 101 Example NO.
Physical Properties Melting Point: 177-182C (colored and jelly-like) Ca3^s +11.6° (c=0,5 chloroform smethanol = 3 si (v/v)) KBr -ι IR Vmax cm 's 3330, 2925, 2855, 1755, 1650, 1555, 1470 NMR (CDC13“CD3OD), o(ppm)s 0.89 (I2H, t), 1.27 (s), 2.13-2.27 (10H, m) , 3.16 (2H, t), 4-74-4-77 (2H, t), 5.15 (IH, t), 5-32 (IH, t) Melting Points 173-177°C (colored and jelly-like) 4-95 * (e-0.5, chloroform smethanol? water = 6s4sl (v/v)) KBr -i IR VmeiX cm s 3330, 2925-, 2855, 1755, 1660, 1565 NMR (CDC13-CD3OD), 0(ppm)s 0.89 (12H, t), 1-27 (s), 2.1-2-3 (10H, ra), 3.17 (2H, ra), 4-29 (IH, q), 4.75 (IH, d), 4-77 (IH, d), 5.14 (IH, dd), 5-38 (IH, dd) NMR (CDC13-CD3OD), δ (ppm): 0-90 (12H, t), 1-26 (s), 2.1-2-5 (3H ra), 4.83 (XH, d), 5-1-5-4 (2H, m) Melting Points 148-I5XeC (colored and jelly-like) NMR (CDCl —CD OD), 6(ppm): 0.90 (12H, t) , 1.26 J J (s), 2.10-2.50 (8H, m) , 4.82 (IH, d), 5-1-5-3 (2H, m) - 102 Example No. _Physical Properties__ Melting Point: 166.-5-168*. 5 *C (gradually colored and jelly-like) NMR (CDC13 -CDgOD)» δ(ppm): 0.90 (12H, , t)» 1*26 (s), 2*16 (2Η» tb 2*32 (4H, m)» 2.50 (2Η» d)» 4*82 (IH, d), 5*16 (1Η» tb 5*32 (IH, t) Malting Points 155-T58°C (colored and jelly-like) Eg . +1.5® (c=0.5,, chloroform smethanol = 3:1 (v/v)) KBr IR cm 3400» 2930» 2860,. 1740» 1660 WR (CDCX3~CD3OD)» δ(ppm): 0.90 (12Η» t)» 2.3-2.5 (8Η» m)» 5.2 (2Η» ra) Melting Points 153*5-155.O^C (gradually browncolored and jelly-like) Ecs +13.3° (e=0.6„ chloroformsmathanol = 9:1 (v/v)) KB**· *3 1RSnax c“”“s 3445» 2530» 1740» 1660» 1560 NMR (CDC1 -CD-OD)» δ(ppm): 0.90 (12H)» 2-10-2.26 3 (4Η» ra)» 2*26-2.46 (4H, m) Melting Point: 156-158»5°C (gradually brown-colored and jelly-like) Ea ]25 s +16.5° (c=0*9» chloroformsmathanol = 9si (v/v)) IRv^ οηΛ 3450» 2930» 1735» 1660» 1560 XUo.Ji NMR (CDC13-CD3OD)» δ (ppm): 0.89 (12Η» t)» 1*30 (s)» 2.10-2*45 (8H, m), 5,20 (m) - 103 Example No. ;_Physical Properties_ Melting Points 148-152°C (gradually brown-colored and jelly-like) -1-14,.5° (c=0,9 chloroform smethanol - 9:1 (v/v)) KBr IR vmax cm ~s 3450# 2930# 1745# 1650# 1560 NMR (CDC1_-CD_OD)# 6(ppm)s 0.90 (12H# t)# 1-30 3 (s)# 2 10-2,50 (SH# mb 5.10-5.35 (2H# m) Melting Points 156-158.5°C (gradually brown-colored and jelly-like) C«3^5 +14.1° (c~09 chloroform smethanol = 9:1 (v/v)) KBr _·, IR Vjnax cm h 3350# 2930# 1730# 1660# 1560 NMR (CDC13-CD3OD)# δ(ρρη): 0·90 (12H# tb 1-30 (s)# 2.1-2.5 (8H# a»)# 5.1-5.3 (2H, m) Melting Points 184-1889C (gradually brown-colored and jelly-like) [ajljps +8-3* IR cm1: 3455# 2925# 1745# 1665# 1555 max NMR (CDC13-CD3OD) # 6(ppm) : 0.89 (12H# t) # 2.1-2.5 (8H# mb 5..1-5.4 (2H# m) - 104 Example Nol ._Physical Properties__ Melting Points 159-171”C (colored and jelly-like) E® 3^5 s +6.2“ (c=1.22«. chloroform xmethanol = 3:1 (v/v)) NMR (CDCI3~CD3OD) , δ (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) Melting Points 140-I45°C (colored and jelly-like) Fd3^5 . +10.3“ (c-0 6* chloroformxmethanol = 3:1 (v/v)) KBr , IR vmax cm‘: 3330* 2925* 2855* 1755* 1645* 1550 NMR (CDC1 -CD.OD) * <5(Opm)s 0.90 (12H* t) * 1.30 J J (s)* 2.1-2.3 (8H* m) * 2.6-3.0 <4H* m)* 4-89 (IH* d) * 4.99 (IH* d)* 5.09 (IH* t)* 5.45 (IH* t) Melting points 142~147eC (colored and jelly-like) [a3^5. +11.7® (c=0-7, chloroformsmethanol - 3x1 (v/v)) NMR (CDC13-CD3OD)* 6(ppm)s 0.90 (12H* t)* 1.30 (s)* 2.1-2.4 (8H* m)* 5.10 (IH* t)* 5.30 (IH* t) Melting Points 145-148“C (colored and jelly-like) [a3^5 . +14.2® (c=0»5* chloroformxmethanol = 3x1 (v/v)) KB’V’ _ Ί IR cm 3450* 2925* 2855* 1740* 1640 XncUC NMR (CDC13~CD3OD)* δ(ppm): 0.90 (12H* t, J=6 Hz) 2.1-2-4 (8H* m)* 4-80 (IH, d* J=4 Hs) * 5.24 (2H* m) - 105 Example No77 Physical Properties· Melting Point: 149-153°C (colored and jelly-like) [α]25. +20.6® (c=0.31 chloroform smethanol - Isl (v/v)) KBr -i IRvm cm ! 3406, 2926, 2854, 1746, 1662, 1557 NMR (CDC13-CD3OD), 6(ppm): 0.89 (12H, t) , 1.27 (s), 2-23 (4H, m), 2-46 (SH, m), 2.59 (3H, m)„ 2-68 (3H, ffl), 4.89 (IH, d) , 5.16 (IH, t), 5-25 (IH, t), 5.38 (IH, t) Melting Points 170-175°C (colored and jelly-like) fe325; +12-6 (c-05 chloroformsmethanolswater 6:4:1 (v/v)) frCR’y «ι IRVmax 3320, 2925, 2855, 1755, 1660, 1560 NMR (GDC13-CD30D), 6(ppm.)s 0.89 (12H, t) , 1.27 C®5, 2.1-2-3 (SHV'm), 3-18 (4H, m), 4.72 (IH, fi), 5.23 (IH, t), 5-33 (IH, dd) Melting Points 172-175°C (colored and jelly-like) 25 s +12.6 (c-0.5, chloroform:methano1:water 6:4:1 (v/v)) IR ca-1: 3320, 2920, 2850, 1755, 1655, 1550 NMR (CDCK-CD-OD), <5(opm): 0.89 (12H. t) 1.27 3 (s), 2-1-2.3 (10H, m), 3-16 (2H, m) , 4.28 (IH, q) 4.35 (1H, q), 4.69 (IH, d), 4.80 (IH, d), 5-21 (IH, t), 5-32 (IH, t) 106 Physical Properties Example No.
Melting Points 170-175’’C (colored and jelly-like) +20,2* (c=0-5 chloro form s methanol - 3 si (v/v)) IR cm1». 3330, 2930, 2855, 1755, 1655, 1555, 1470 NMR (CDClg-CDgOD), 6(ppm): 0.89 (12H, t), 2.152.3 (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 (XH, f), 5.30 (IH, t) 107 TEST EXAMPLE Fibrosarcoma cells (Meth A) (2 x 10 ) induced in a BALB/c mouse by methyl chlolanfhrene were intracutaneously implanted to the flank of seven 3AL3/c mice per group. A 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 Pg/ml solution or suspension. The solution or suspension was administered to the mice at a dose level of 100 Ug/mouse through the tail vein on the 7th,. 12th„ and 21st days from the implantationThe 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 weight of the control group (non-treated group) and multiplying th© quotient by 100For comparison» the same evaluation was made by using Compound A as a comparative compound. The results obtained are shown in Table 1. - 108 Table 1 Compound of Example Compound A Control Antitumor Effect -19 100 It can be seen from Table 1 that th© compounds 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 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 - 109 a dose level of 50 pg/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 pg/kg-b.w. The results obtained are shown in Table 2.
Table 2 Compound of Example Dose Level 1 (pg/kg) 50 8 50 25 50 32 50 45 SO Compound A 5 As is apparent from Number of Dead Rabbits/ Number of Test Animals 0/3 0/3 0/3 0/3 0/3 4/4 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.

Claims (9)

CLAIMS A compound represented by formula (I) s Z~R° wherein R represents ZR° or Ci Z 2 R 6
1 9 wherein Z, Γ, and Z each represents an alkylene group having from 1 to 6 carbon atoms, and R 8 represents a carχ· 9 9 Λ boxyl group or a phosphonoxy group? R , R , R , and R Q CX each represents “COR 7 , -€ΟΖ 3 Β 8 , CO(CH„) CH-N-COR 7 , 2. Nl Q Q. II 1 -CO( CH ? ) n3 CH-N-COZ 3 R 8 , -CO( CH 2 ) ^OCOr' , -CH( CH 2 OCOZ 3 R 8 , -CO(CH-) -COR 7 , -CO(CH-) _COZ 3 R 8 , -CO(CH ) CO(CH„) NCOR 7 j. π / z τ\ λ 2 π 2 /%-i4 2 n2 Q 2 n3 ~CO(CH ) CO(CH ) .NCOS^R®, wherein R 7 represents an 2 n2 2 n3 alkyl group having from 1 to 30 carbon atoms which may be - 111 -. substituted with one or more hydroxyl groups,. z3 represents an alkylene group having from 1 to S carbon atoms, R represents a eycloalkyl 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 δ carbon atoms, -GONH^, -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 and n3 each represents an xnteger of from 1 to 20» and R represents a hydrogen atom, a phosphono group or -COiCHjl^COOH, wherein m represents 0 or an integer of from 1 to 5 S and the salts thereof.
2. A compound as claimed in claim 1» wherein R repre.3¼ 6 sents ZR or CH ; and R 1 » R^, r^ , and R 4 each Q Q, 7 3 8 I 1 1 7 represents COR » -C02 o R , -CO(CH,J CH-N-COR » 2 nl Q CL I l· -CO(CH 2 ) n1 CH-N-COZ 3 R 8 » -CO(CH2)n2COR 7 or -CO( CH2 ) n2 COZ 3 R 8 3. A compound as claimed in claim 2» wherein R repre12 3 4 sents ZOPO(OH) 2 ; and R » R , R » and R each represents -COR Z or —CO(CH„) , 2 nl Q Ql I I CH-NCOR 7 . - 112 4. A compound as claimed in claim 1 or claim 2 wherein R represents ZR wherein Z represents a methylene or an ethylene group and R 5 represents a carboxyl group or a phosphonoxy group, 13 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 ! ~C0(CH 2 )nl CH - N - COR 7 wherein nl represents 0 (zero), Q and Q, each represents a 7 ί 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 ς carbon atoms, and R represents a hydrogen atom. 5. The compounds as claimed in claim 2, which are: 1,3-dicarboxyisopropyl 2-deoxv-6-0-[2-deoxy-3-0-(N-dodecanoylglycyl)-4-0-phosphono-2-tetradecanoylamino-B-D-glucopyranosyl]-3-0(N-dodecanoylglycvl)-2-tetradecanovlamino-“-D-glucopvranoside: 2-phosphonoxyethyl 2-deoxy-5-0~[2-deoxv-3-0-(N-dodecanoylglycyl)4~0-phosphono~2-tetradecanoylamino-B-D-glucopyranosyl]-3-0(N-dodecanoylglycyl)=2-tetradecanoylamino-a-D-glucopyranoside; 2-phosphonoxyethyl 2-deoxy-5-0-[2-deoxy-3-0-(N-dodecanoylglycyl)2- (N-dodecanoyl-N-methyl~glycylamino)-4“0-phosphono-B-D-glucopyranosyl]~
3. - 0-(N-dodecanoylglycyl)-2-(N-dodecanoyl-N-methylglycylamino)-a-Dglucopyranoside: 2-phosphonoxyethyl 2-deoxy-6-0-[2-deoxy-3-0-(N-dodecanoylglycyl )
4. - 0-phosphono-2-tetradecanoy1anrino-B-D-glucopyranosyl]-3-0~ - 113 (i'S-dodecanoyl glycyl)-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-Dg1ucopyranosv1]-3~0~[(R)3-hydroxytetradecanoy1]-2-[(R)-3-hydroxvtetradecanoy1ami no]-a-D-glucopyranosi de; carboxymethyl 2-deoxy-0-0-[2-deoxy-3-O-(i'ldodecanoylglycyl) 4-0-phosphono-2“tetradecanoylamino-e-D-glucopvranosyl]-3“0-tetradecanoyl -2“tetradecanoylamino-a-D-glucopyranos ide,· 2-phosphonoxyethyl 2-deoxy-
5. -0-[2-deoxy-2-(6“Octanoylaminohexanoylamino)-4-0-phosphono-3-0-tetradecanoyl-B-D-glucopyranosyl]2- (5“octanovlaminohexanoyl)amino-3-0-tetradecanoyl-a-D-glucopyranoside; 2-phosphonoxyethyl 2-deoxy-5-0-[2-deoxy-3-0-(M-dodecanoylglycyl)4-0-phosphonO“2-tetradecanoylamino-B-D“glucopyranosyl]-3-0-(iV dodecanoylglycyl)-2-[(5-octanoylamino)-hexanoylamino]-a-D-gluco~ pyranoside; 2-phosphonoxyethyl 2-deoxy-5-0-[2-deoxy-4-0-phosphono-3-0tetradecanoyl-2-tetradecanoylamino-B-D-glucopyranosyl]3- 0-(N-dodecanoy1glycy1-2~tetradecanoylami no-α-D-g1ucopyranos ide; 2-phosphonoxyethyl 2-deoxy-5-0-[2-deoxy~3-0-(S^-dodecanoylglycyl)4- 0-phosphono-2-tetradecanoy1amino-B-D-g1ucopyranosv1]-2-(8-hexanoy1ami nooctanoy1ami no)-3-0-tetradecanoyl-α-D-g1ucopyranos ide: 2-phosphonoxyethyl 2-deoxy-6-0-[2-deoxy-2-(8-hexanoylaminooctanovlamino)-4-0-phosphonO“3“0-tetradecanoyΙ-β-D-glucopyranosv1]-2-(8~hexanov1ami nooctanoy1ami no)-3-0-tetradecanoyl-a -D-g1ucopyranos i de; 2-phosphonoxyethyl 2-deoxy-6-0-[2-deoxy-2-(lhl-dodecanoyl-iV methylglycylamino)-3-0~(4“Oxotetradecanoyl)-4-0-phosphono-B -D-glucopyranosvl]-3-0-(H-dodecanoylglycyl )-2-(S1-dodecanoyl-N-methylg1ycy1ami no)-α-D-g1ucopyranos i de; - 114 2-phosphonoxyethyl 2-deoxy-6-0-[2-deoxy-3-0-(4-oxotetradecanoyl)-4-0-phosphono-2-tetradecanoylamino-g-D-glucopyranosyl]-3-0(N-dodecanoylglycyl)-2-tetradecanoy1 amiηο-α-D-glucopyranoside; 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-octanoy1 ami no)-hexanoyl-amino]-a~ D-g1ucopyranos i de.
6. A process for preparing the compound of the claims 1 to 5 characterized in that a compound of the general formula II OR (II) wherein R represents a hydrogen atom or a hydroxyl-protective group; β'θ represents ZCOOR^, Z0P0(0R^) 2 , -CH COOR - 115 z 1 opo(or 3 ) o R^ ( and R 3 ^ each represents -COR 7 \ -C0Z 3 R 8 , or ? ί 3 . Z'OPO(OR ) I 1 1 “1 -CO(CH 2 ) nl CH-NCOR a } Q- Q, Il 3 81 -CO(CH 2 ) nl CH-NCOZ R . -CO(CH 2 ) n2 OCOR 71 , ~C0(CH2)n20C0Z 3 R 81 , ~CO(CH2) n2 COR 71 , -C0(CH 2 ) n2 C0Z 3 R 81 , Q 1 V 1 I Tl ' 3 81 —CO(CH ) CO(CH ) NCOR 71 or co ^ CH 2^ n 2 CO ^ CH 2 hi3 NCOZ R R 31 represents a hydrogen atom, -C0(CH9) COOR 18 or PO(OR 15 )9, 12 13 z m ά wherein R~ and R each represents a phosphonoprotective group; 14 71 R represents a carboxyl-protective group; R represents an alkyl group having from 1 to 30 carbon atoms which may be substituted with one or more hydroxyl groups protected with a hydroxyl-protective group; - 115 Rl R represents a c\/cloalkyl group having from 3 to 12 carbon atoms which mav be substituted with one or more hydroxyl groups protected with a hydroxyl-protective group; Q represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, -CONI^, -COOR^ or -CH 9 -O-R^, wherein R* 5 represents a carboxyl-protective group; 15^ 91 R represents a phosphono-protective group; R represents a 12 3 1 hydroxyl-protective group and Ζ, Ζ , Ζ , 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 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.
8. A pharmaceutical composition comprising at least one of the compounds of claims 1 to 5, optionally together with conventional pharmaceutically acceptable carriers and/or adjuvants.
9. A process for preparing the pharmaceutical composition of claim 8 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.
IE53988A 1988-02-26 1988-02-26 Disaccharide derivatives IE61418B1 (en)

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