PHOSPHOLIPID DERIVATIVES, PROCESS FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION OF THE SAME

Abstract: New phospholipid derivatives represented by the formula: wherein R¹ is alkoxy or alkenyloxy; R² is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio, thiadi­ azolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrupted by a -NHCO- group; and is unsaturated or saturated 5-7 membered he­ terocyclic group which may contain additional N, O or S atom(s), and may have 1 to 3 substituent(s); provided that R¹ alkoxy having 15 or more carbon atoms when is a pyridyl group, and pharmaceutical­ ly acceptable salt thereof, which exhibit antitumor activity.

Description: PHOSPHOLIPID DERIVATIVES, PROCESSES FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION OF THE SAME This invention relates to phospholipid derivatives. More particularly, it relates to new phospholipid derivatives which have antitumor activity, to processes for the preparation thereof, and to pharmaceutical composition comprising the same for therapeutical treatment of cancer in human beings. Accordingly, one object of this invention is to provide new and useful phospholipid derivatives. Another object of this invention is to provide processes for preparation of phospholipid derivatives. A further object of this invention is to provide useful pharmaceutical composition comprising said phospholipid derivatives as an antitumor agent. Still further object of the present invention is to provide a therapeutical method of treating cancer. The object phospholipid derivatives of the present invention are novel and include the compound of the formula (I) EMI2.1 wherein R1 is alkoxy or alkenyloxy; R2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio thiadiazolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrupted by a -NHCO- group; and EMI2.2 is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,O or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxyClower)alkyl groups; provided that R1 is alkoxy having 15 or more carbon atoms when EMI2.3 is a pyridyl group, and pharmaceutically acceptable salt thereof. In the above and subsequent description of the present specification, suitable examples and illustrations for the various definitions to be included within the scope of the invention are explained in details as follows. The term "lower" is intended to mean 1 to 6 carbon atom(s) and the term "higher" is intended to mean 7 to 25 carbon atoms, unless otherwise indicated. Suitable "alkoxy" for R1 is straight or branched one containing 1 to 25 carbon atoms and may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, eicosyloxy, heneicosyloxy, docosyloxy,- tricosyloxy, tetracosyloxy, pentacosyloxy and the like, among which the preferable alkoxy for R1 is the higher one having 13 or more carbon atoms. Suitable "alkenyloxy" for R1 is the one containing at least one double bond in the above exemplified "alkoxy" group for R1. More particularly, vinyloxy, allyloxy, 1propenyloxy, isopropenyloxy, l-methylallyloxy, 1,2 or 3butenyloxy, 1,2,3 or 4-pentenyloxy, 1,2,3,4 or 5-hexenyloxy, heptenyloxy, octenyloxy, nonenyloxy, decenyloxy, undecenyloxy, dodecenyloxy, tridecenyloxy, tetradecenyloxy, pentadecenyloxy, hexadecenyloxy, heptadecenyloxy, octadecenyloxy, nonadecenyloxy, eicosenyloxy and the like are exemplified as suitable alkenyloxy for R1. More preferable "alkenyloxy" is 8-hexadecenyloxy, 9-octadecenyloxy, 9,12-octadecadienyloxy, or the like. "Halogen" for R2 includes chlorine, bromine, iodine and fluorine. Suitable "lower alkoxy" for R2 and "lower alkoxy" moiety in the "ar(lower)alkoxy" and "lower alkoxycarbonylamino" for R2 are the ones containing 1 to 6 carbon atoms among the aforementioned alkoxy. Suitable "aryl" moiety in the "ar(lower)alkoxy", "aryloxy" and "arylthio" for R2 may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like. Suitable "lower alkyl" moiety in the "lower alkylthio", "lower alkylsulfonyl" and "lower alkylureido" for R2 may include straight or branched ones containing 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. Suitable "thiadiazolylthio" for R2 may include l,3,4-tiadiazol-5-ylthio, l,3,4-thiadiazol-4-ylthio, 1,2 ,4-thiadiazol-5-ylthio, 1,2 ,4-thiadiazol-4-ylthio, and the like. Suitable "lower alkylene" for A is straight or branched one containing 2 to 6 carbon atoms and may include ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like. These "lower alkylene" may optionally be interrupted by a -NHCO- group at any portion therein. Suitable "unsaturated or saturated 5 - 7 membered heterocyclic group which may contain additional N,O or S atom(s)" for EMI4.1 may include 1-pyrrolyl, 1-imidazolyl, 3-imidazolyl, l-pyrazolyl, 2-pyrazolyl, l-pyrrolidinyl, 1-pyrrolinyl, 1-imidazolidinyl, 2-imidazolin-l-yl, l-pyrazolidinyl, 3-pyrazolin-l-yl, l,3,4-triazol-l-yl, l,2,4-triazol.l-yl, l-pyridyl, l-pyrazinyl, l-pyrimidinyl, l-pyridazinyl, 1,2,4-triazin-l-yl, piperidino, 1 piperazinyl, 3-oxazolyl, 2-isoxazolyl, morpholino, 3thiazolyl, 2-isothiazolyl, 1,4-thiazin-4-yl, 5,6-dihydro1,4-thiazin-4-yl, l-homopiperazinyl, homopiperidino, homomorpholino and the like. The heterocyclic ring as mentioned above may have 1 to 3 substituent(s) selected from the group consisting of aforementioned lower alkyl, lower alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, pentylamino, hexylamino, N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, etc.), aforementioned lower alkoxy, aforementioned halogen, hydroxy, carboxy, lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) and hydroxy±lower)alkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.). It is to be noted that the pharmaceutically acceptable salt of the object compound (I) includes an intramolecular salt as illustrated by the formula (I') and intermolecular salts as illustrated by formula (I"), (1tt?) and (I""). EMI5.1 (in which R1, R2, A, EMI5.2 are each as defined above, Y is an anion residue of an acid, and B is a cation residue of a base). The salt of type (I') may be a betain-type salt such as a pyridinio- or a piperazinio-phosphate and the like. The salts of type (I"), (I"') and (I"") may include intermolecular onium salts such as an acid addition salt (e.g. a pyridinium- or a piperazinium-salt and the like), and a salt of the hydrogen phosphate with a base (e.g. a metal salt etc.). Suitable anion residue of an acid for Y includes an inorganic and organic ones such as a halide anion (e.g. chloride-, bromide-, or iodide-anion etc.), a hydroxide anion, a sulfate anion, a sulfonate anion (e.g. methanesulfonyloxy-, benzenesulfonyloxy-, tosyloxy-, or camphorsulfonyloxy-anion etc.), a carboxylate anion (e.g. trifluoroacetoxy- or hydrogen tartaroyloxy-anion etc.). Suitable cation residue of a base for B includes an alkali metal ion (e.g. sodium- or potassium-ion, etc.) and the like. The pharmaceutically acceptable salt of the object compound (I) includes a hydrate and solvate thereof, too. With regard to the object compounds [I], it is to be noted that the compounds [I] include all of the possible optical isomers due to the asymmetric carbon atom in the molecule of the compounds [I]. And further, it is to be noted that all of the chemical formulas of the l-propanol moiety are shown by formula (A) in this specification instead of formula (B) for abbreviation sake. EMI6.1 The object compound (I) and its salt of the present invention can be prepared by the following processes. Process 1 EMI6.2 or its salt Or its salt Process 2 EMI6.3 or its salt or its salt Process 3 EMI7.1 or its salt or its salt Process 4 EMI7.2 or its salt or its salt wherein R1, R2, A and EMI7.3 are eachas defined above, X1 and X2 are each an acid residue, EMI7.4 a is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,O or S atom(s), and may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups, R3 is lower alkyl, and R4 is a protective group of hydroxy. Suitable "acid residue" for X1 and X2 may include halogen (e.g. fluorine, chlorine, bromine, iodine), acyloxy (e.g. benzenesulfonyloxy, tosyloxy, etc.), and the like. Suitable "unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,O or S atom(s), and may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl group" for EMI8.1 is the same as the one for EMI8.2 except the number of the substituents. Suitable "lower alkyl" for R3 is the same as mentioned before. Suitable "protective group of hydroxy" for R4 is a conventional protective group such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxy carbonyl, etc.), benzyloxycarbonyl, alkanoyl (e.g. formyl, acetyl, etc.), ar(lower)alkyl(e.g.benzyl, trityl etc°) and the like. The processes for preparing the object compounds (I) and salts thereof of the present invention are explained in detail in the following. Process 1 The object compound (I) and its salt can be prepared by reacting a compound (II) or its salt with a compound (III) or its salt. The suitable salts of the compound (II) are the metal salts as exemplified before for the compound (I). The suitable salts of the compound (III) are the inorganic or organic acid salts as exemplified before for the compound (I). This reaction is usually carried out in a solvent such as acetone, methanol, tetrahydrofuran, chloroform, benzene or any other solvent which does not adversely affect the reaction. When the compound (III) or its salt is liquid, the compound (III) or its salt can be used as a solvent, too. The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under heating. In case that the object comPound (I) has a quarters nitrogen atom in the group of EMI9.1 (e.g. pyridinio) and it is obtained in an acid addition salt form in the present reaction, the resulting acid addition salt can be optionally converted to its intramolecular salt by a conventional method, for instance, by treating the acid addition salt with an ion-exchange resin, silver acetate, or the like. Process 2 The compound (Ia) and its salt can be prepared by reacting a compound (Ib) or its salt with a compound (IV) The suitable salts of the compounds (Ia) and (Ib) can be referred to those as exemplified before for the compound (I). This reaction is preferably carried out in the presence of an organic or inorganic base, for example, cyclohexylamine, di- or tri-(lower)alkylamine (e.g. trimethylamine, triethylamine, dimethylamine, etc.), pyridine, metal hydroxide (e.g. sodium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), or the like. The reaction is usually carried out in a solvent such as methanol, ethanol, acetone, benzene or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under warming or heating. In case that the object compound. (Ia) is obtained in an acid addition salt form in the present reaction as mentioned before, the resulting acid addition salt can be optionally converted to its intramolecular salt according to the procedures as described in the above Process 1. Process 3 The object compound (Ic) and its salt can be prepared by subjecting a compound (V) or its salt to the elimination reaction of the protective group on the hydroxy group. The suitable salts of the compound (V) and (Ic) can be referred to those as exemplified before for the compound (I). The elimination reaction is carried out by a conventional method such as solvolysis (e.g. hydrolysis, alcoholysis etc.), reduction or the like in accordance with a kind of the protective group. Among these methods, when the protective group is a lower alkoxycarbonyl, benzyloxycarbonyl or ar(lower)al kanoyl, rzivöLysis is prierable method. More specifically, hydrolysis by using a base or an acid is the most preferable. Suitable base may include an organic or inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, etc.), alkali metal carbonate or bicarbonate (e.g. sodium carbonate, sodium bicarbonate, etc.), alkali metal alkoxide (e.g. sodium methoxide, potassium methoxide, etc.), organic amine (e.g. methylamine, diethylamine, pyrrolidine, etc.), and the like. Suitable acid may include an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, and the like. The reaction is usually carried out in a solvent such as water, methanol, ethanol, propanol, dimethylformamide or any other solvent which does not adversely affect the reaction, or a mixture thereof. The reaction temperature is not critical, but the reaction is preferably carried out under mild condition such as under cooling at ambient temperature or under warming in order to avoid the hydrolysis of phosphate. Process 4 The object compound (I) and its salt can be prepared by reacting a compound (VI) or its salt with a compound (III) or its salt. The suitable salts of the compound (VI) are the salts with an acid as exemplified before for the compound (I). The reaction can be carried out by substantially the same manner as that of Process 1. The object compound prepared by the above-mentioned processes can be isolated from the reaction mixture and purified by a conventional method. The object compound (I) in a free form can optionally be converted to its salt, and the object compound in an intramolecular salt form can also be converted to its acid addition salt by conventional manner. Some of the starting compounds (II), (V) and (VI) are novel, and can be prepared by process as shown in the following Examples or processes chemically equivalent thereto. The following pharmacological test data show that the object compounds (I) of the present invention exhibit high anti-tumor activity. Test Method A Groups of six female BALB/c mice, aged 12 weeks and weighing 19 - 21 g were used. Fibrosarcoma Meth A (hereinafter referred to as Meth A) was successively transferred every 7 days into BALB/c mice by intraperitoneal inoculation of the ascites cells thereof and the Meth A in the ascites cells as harvested 6 days after the inoculation was used as tumor cells. Each of the BALTIC mice was inoculated intradermally with 1 x 105 Meth A cells in 0.05 ml Hanks solution. Test compound was dissolved in 0.5% methylcellulose saline solution, and was intratumorally injected to each of the mice in doses of 100 pg/mouse once daily from Day 1 to Day 4 postimplant. The control group was given with a vehicle alone in the same way. The antitumor effectiveness of the test compound was estimated by tumor growth inhibition (1-T/C). T: Mean diameter of the growing tumor of the medicated group C: Mean diameter of the growing tumor of the control group Results of Test Method A EMI13.1 <tb> Compounds <SEP> *a <SEP> fob <SEP> *b <tb> Example <SEP> No. <SEP> Day <SEP> Day <SEP> Day <SEP> Day <SEP> Day <SEP> Day <tb> <SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21 <SEP> la <SEP> 21 <tb> <SEP> 1 <SEP> 0 <SEP> 0 <SEP> 100 <SEP> 100 <SEP> 6/6 <SEP> 6/6 <tb> <SEP> 3-(1) <SEP> 0 <SEP> 0 <SEP> 100 <SEP> 100 <SEP> 6/6 <SEP> 6/6 <tb> <SEP> 3-(13) <SEP> 7.9 <SEP> 12.5 <SEP> 37 <SEP> 31 <SEP> 0/6 <SEP> 0/6 <tb> <SEP> 3-(21) <SEP> 0 <SEP> 0 <SEP> 100 <SEP> 100 <SEP> 6/6 <SEP> 6/6 <tb> <SEP> <RTI ID=13.9> 3-(22) <SEP> 2.9 <SEP> 5.6 <SEP> 77 <SEP> 68 <SEP> 3/6 <SEP> 3/6 <tb> <SEP> 3-(23) <SEP> 2.8 <SEP> 5.3 <SEP> 77 <SEP> 70 <SEP> 316 <SEP> 3/6 <tb> <SEP> 3-(25) <SEP> 0.8 <SEP> 1.3 <SEP> <SEP> 94 <SEP> 93 <SEP> 5/6 <SEP> 5/6 <SEP> <tb> <SEP> 3-(30) <SEP> 1.6 <SEP> 2.8 <SEP> 85 <SEP> 84 <SEP> 4/6 <SEP> 4/6 <tb> <SEP> 9-(4) <SEP> 0.8 <SEP> 2.3 <SEP> 92 <SEP> 86 <SEP> 4/6 <SEP> 4/6 <tb> *a : Mean df two diameters of the growing tumor (mm) *b : Tumor growth inhibition (%) [(1-T/c)x100] *c : Ratio of tumor free mice [Number of tumor free mice/ Number of mice used as a group) Test Method B Groups of eight female BALB/c mice, aged 8-9 weeks and weighing 18.0-22.5 g were used. Fibrosarcoma Meth A (hereinafter referred to as Meth A) was successively transferred every 7 days into BALBIc mice by intraperitoneal inoculation of the ascites cells thereof and the Meth A in the ascites cells as harvested 6 or 7 days after the inoculation was used as tumor cells. Each of the BALB/c mice was inoculated intrapleurally with 5 x 105 Meth A cells in 0.1 ml Hanks solution. Test compound was dissolved in phosphate buffer saline solution, and was injected into pleural cavity to each of the mice in doses of 100 g/0.05 ml/mouse three times, i.e. before 14 days, after 1 hour and after 3 days of tumor implantation. The control group was given with a vehicle alone in the same way. The antitumor activity of the test compound was estimated by comparing mean survival time of the two groups. T : Mean survival time of the medicated group C : Mean survival time of the control group Results of Test Method B EMI14.1 <tb> Compound <SEP> Mean <SEP> survival <SEP> time <SEP> Anti-tumor <SEP> activit <tb> Example <SEP> No. <SEP> (Day) <SEP> (%) <SEP> *d <SEP> <tb> <SEP> 1 <SEP> 22.0 <SEP> 367 <tb> <SEP> 3= <SEP> 2Q.5 <SEP> 342 <tb> <SEP> 3-(2) <SEP> 21.0 <SEP> 350 <tb> <SEP> 3-(3) <SEP> 19.0 <SEP> 317 <tb> <SEP> 3-(73 <SEP> 14.5 <SEP> 325 <tb> <SEP> 3-(9) <SEP> 21.0 <SEP> 350 <tb> <SEP> 3-(10) <SEP> 25.5 <SEP> 364 <tb> <SEP> 3-(12) <SEP> 20.0 <SEP> 333 <tb> <SEP> 3-(14) <SEP> 19.5 <SEP> 325 <tb> <SEP> 3-(15) <SEP> 26.0 <SEP> 433 <tb> <SEP> 3-(16) <SEP> 21.0 <SEP> 350 <tb> <SEP> 3-(18) <SEP> 19.5 <SEP> 325 <tb> <SEP> 3-(19) <SEP> 19.0 <SEP> 317 <tb> <SEP> 3-(26) <SEP> > 39.0 <SEP> > 650 <SEP> <tb> <SEP> 3-(29) <SEP> 18.5 <SEP> 264 <tb> <SEP> 3-(31) <SEP> 21.5 <SEP> 358 <tb> <SEP> 5-(2) <SEP> 25.5 <SEP> 364 <tb> <SEP> 8-(4) <SEP> 25.0 <SEP> 417 <tb> 10-(6). <SEP> 24.0 <SEP> < 400 <SEP> <tb> 11-(2) <SEP> 21.0 <SEP> 350 <tb> <SEP> *e <SEP> 14.5 <SEP> 242 <tb> *d : T/C x 100 *e : (rac)-l-Q-Octadecyl-2-O-methyl-glYcer l¯3- phosphorylcholine which is described in British Patent No. 1583661. As being apparent from the above test results, the object compound (I) of the present invention is useful as an antitumor agent. The effective ingredient may usually be administered with a dose of 0.1 mg/kg to 500 mg/kg, 1 to 4 times a day in a preparations such as tablet, granule, powder, capsule, syrup, injection, suppository and the like. However, the above dosage may be increased or decreased according to the age, weight or conditions of the patient or the administering method. The above mentioned pharmaceutical preparations can be prepared in a conventional manner by using conventional carriers and additives. The present invention is illustrated by the following Examples in more detail. Example 1 EMI15.1 A mixture of (rac)-l-O-octadecyl-2-O-methyl-glycerol-3 (2-bromoethyl)phosphate (2.18 g) and pyridine (10 ml) was stirred at 1000C for one hour, and then the solvent was removed under reduced pressure. The residue was pulverized from acetone. The powder was dissolved in a mixture of 90% aqueous methanol (20 ml) and chloroform (4 ml), and the mixture was treated with silver acetate (1.36 g) for 30 minutes. The precipitates were removed by filtration and washed with methanol. The filtrate and washings were combined and-evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (66 g, elution by chloroform-methanol-water, 65:25:4) to give 1.15 g of (rac)-1-O-octadecyl-2-O-methyl-glycerol- 3-[2-(1-pyridinio3ethylphosphate, which was recrystallized from chloroform-acetone, yield 0.99 g (colorless crystals).m.p. 84.5 tO 890C. I.R. (Nujol) : 3380, 1590, 1220, 1080 cm 1 N.-M.R. (CD3OD) ppm : 0.90-1.75 (35H, m), 3.42 (3H, s), 3.48-4.95 (llH, m3, 8.10-9.00 (5H, m) Anal. Calcd. for C29H54O6NPH2O : C: 62.01, H: 10.04, N:2.49 Found C: 61.32, H: 9.99, N:2.51 Example 2 EMI16.1 A mixture of (rac)-1-O-octadecyl-2-O-methyl-glycerol-3- (2-bromoethyl)phosphate (1.09 g) and morpholine (2 ml) was stirred for 4 hours at ambient temperature, and then the mixture was evaporated to dryness. The residue dissolved in a mixture of chloroform-methanol-water (1:2:1) was passed through a mixed ion-exchange column, containing Amberlite IRC-50 (Trade name, manufactured by Rohm G Haas) (H ) (3 g) and Amberlite IR-45 (Trade name, manufactured by Rohm X Haas) (OH-)(6 g) to give 1.25 g of (rac)-l-O octadecyl-2-O-methyl-glycerol-3 (2-morpholinoethyl)phosphate, which was purified by column chromatography on silica gel (30 g, elution by chloroform-methanol, 9:1X9:2) and recrystallized from chloroform-acetone, yield 0.95 g (colorless solid). m.p. 450C I.R. (Nujol) : 3350, 1220, 1115 cm 1 N.M.R. (CD30D) ppm : 0.7-1.9 (35H, m), 2.4-2.9 (6H, m), 3.2-4.2 (13H, m), 3.47 (3H, s) Example 3 The following compounds were prepared according to the similar manners to those of Examples 1 and 2. EMI17.1 (rac) -l-O-Octadecyl-2-O-ethyl-glycerol-3- [2- (4- methyl-l-piperazinyl)ethyl]phosphate. m.p. 1150C I.R. (Nujol) : 3400, 1645, 1215, 1090, 1055 cm N.M.R. (CD3OD) ppm : 0.90 (3H, t, J=5.5Hz), 1.07-1.69 (35H, m), 2.71 (3H, s), 2.80-4.19 (20H, m), 4.74 (1H, m) Anal. Calcd. for C30H63N206P.H20 C: 60.37, H: 10.99, N: 4.69 Found C: 60.15, H: 11.34, N: 4.50 EMI17.2 (rac)-1-O-Hexadecyl-2-O-methyl-glycerol-3-[2-(4- methyl-l-piperazinyl)ethyl]phosphate. m.p. 125 to 1280C I.R. (Nujol) : 3350, 1220 cm 1 N.M.R. (CD30D) ppm : 0.9 (3H, m), 1.0-1.8 (28H, m), 2.68 (3H, s), 2.76-3.16 (9H, m), 3.3-4.2 (10H, m), 3.46 (3H, s) Anal. Calcd. for C27H57N206P.H2O C: 58.45, H: 10.71, N: 5.05 Found C: 58.28, H: 11.07, N: 5.05 EMI18.1 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-C4- ethyl-1-piperazinyl)ethyl]phosphate. m.p. 150 to 1550C I.R. (Nujol) : 3350, 1210, 1050 cm 1 N.M.R. (CD30D) ppm : 0.89 C3H, t, J=5.5Hz), 1.05-1.69 C35H, m), 2.79-3.14 (12H, m), 3.34-3.56 (4H, m), 3.44 (3H, s), 3.83-4.13 C4H, m), 4.68 (1H, m) Anal. Calcd. for C30H63N2O6P.H20 C: 60.37, H: 10.98, N: 4.69 Found C: 60.68, H: 11.08, N: 4.62 EMI18.2 (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1- piperazinyl)ethyl)phosphate. m.p. 2080C I.R. (Nujol) : 3350, 1625, 1220, 1070 cm 1 N.M.R. (CD30D) ppm : 0.90 (3H, t, J=5.5Hz), 1.05-1.68 (32H, m), 2.58-2.89 (6H, m), 3.00-3.34 (6H, m), 3.47 (3H, s), 3.36-4.09 (6H, m), 4.74 (1H, m) Anal. Calcd. for C28H59N206P.H20 C: 59.13, H: 10.81, N: 4.93 Found C: 59.42, H: 10.82, N: 4.89 EMI19.1 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4- hydroxypiperidino)ethyl)phosphate. m.p. 2100C I.R. (Nujol) : 3200, 1215, 1055 cm 1 N.M.R. (CD30D) ppm : 0.90 (3H, t, J=5.5Hz), 1.07-1.66 (32H, m), 1.69-2.25 (4H, m), 3.13-3.68 (10H, m), 3.46 (3H, s), 3.79-4.29 (5H, m), 4.71 (1H, m) Anal. Calcd. for C29H60NO7P.1/2H2O C: 60.60, H: 10.70, N: 2.44 Found C: 60.75, H: 11.11, N: 2.43 EMI19.2 (rac) -l-O-Octadecyl-2-0-methyl-glycerol-3- [2(4- methylpiperidino)ethyl]phosphate. m.p. 97 to 100 C I.R. tNujol) : 3400, 1220, 1040 cm1 N.M.R. (CD3OD) ppm: 0.90 (3H, t, J=5.5Hz), 1.04 (3H, d, J=5Hz), 1.09-1.49 C32H, m), 1.50-2.01 (4H, m), 2.85-3.69 (llH, m), 3.46 (3H, s), 3.82-4.01 C2H, m), 4.06-4.29 (2H, m), 4.71 (1H, m) Anal. Calcd. for C30H62N06P.l/2H20 C: 62.91, H: 11.09, N: 2.45 Found C: 62.79, H: 11.05, N: 2.45 EMI20.1 (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2- [4-(2-hydroxyethyl) l-piperazinyljethyl]phosphate, m.p. 196 to 1990C I.R. (Nujol) : 3120, 2200, 1210, 1050 cm 1 N.M.R. (CD3OD) ppm : 0.90 C3H, t, J=5.5Hz), 1.07-1.81 (32H, m), 2.78-3.22 (10H, m), 3.26-3.65 (6H, m), 3.46 (3H, s), 3.69-3.85 (2H, m), 3.85-3.99 (2H, m), 4.00-4.21 (2H, m), 4.75 (1H, m) Anal. Calcd. for C30H63N207P.l/2H20 C: 59.60, H: 10.69, N: 4.52 Found C: 59.82, H: 10.71, N: 4.65 EMI21.1 (rac)-l-O-Hexadecyl-2-O-benzyl-glycerol-3-[2-(4- methyl-l-piperazinyl)ethyl]phosphate. waxy solid. I.R. (Film) : 3350, 2700, 1640, 1200,,1050 cm N.M.R. (CD30D) ppm : 0.88 (3H,t, J=5.5Hz), 1.08-1.83 (28H, m), 2.62 (3H, s), 2.68-3.13 (8H, m), 3.30-3.63 (4H, m), 3.66-4.20 (6H, m > , 4.67 (2H, s), 4.70-4.98 (1H, m), 7.17-7.50 (5H, m) Anal. Calcd. for C33H61N206P.H20 C: 62.83, H: 10.06, N: 4.44 Found C: 62.86, H: 9.57, N: 4.46 EMI21.2 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4- methyl-l-pyridinio)ethyl]phosphate. m.p. 134 C I.R. (Nujol) : 3350, 1640, 1240 cm N.M.R. (CD30D) ppm : 0.86-1.66 (35H, m), 2.68 (3H, s), 3.42 (3H, s), 3.20-4.86 (llH, m), 7.96 (2H, d, J=7.5Hz), 8.84 (2H, d, J=7.5Hz) Anal. Calcd. for C30H56NO6P.H2O C: 61.66, H: 10.16, N: 2.39 Found C : 61.45, H: 10.70, N: 2.31 EMI22.1 (rac)-1-O-Octadecyl-2-O-methyl- glycerol-3- (2- (3-methyl- 1- pyridinio)ethyl]phosphate. m.p. 1700C I.R. (CHCl3) : 3650, 3300, 2850, 1635 cm N.M.R. (CD30D) ppm : 0.89 C3H, t, J=6Hz), 1.06-1.70 C32H, m), 2.60 (3H, s), 3.44 C3H, s), 3.28-4.93 (11H, m), 8.03 (1H, dd, J=6.5Hz, 7Hz), 8.87 (lH, d, J=6.5Hz), 8.92 (1H, s) Anal. Calcd. for C30H56N06P.3/2H20 C: 59.78, H: 10.20, N: 2.32 Found C: 59.69, H: 10.04, N: 2.26 EMI22.2 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4- dimethylamino-1-pyridinio)ethyl]phosphate. m.p. 2080C (dec.). I.R. (Nujol) : 3350, 1650, 1570, 1230 cm 1 N.M.R. (CD30D) ppm : 0.90-1.72 (35H, m), 3.27 (6H, s), 3.45 (3H, s), 3.12-4.56 (llH, m), 7.06 (2H, d, J=8Hz), 8.27 (2H, d, J=8Hz) Anal. Calcd. for C31H59N206P.2H20 C: 58.93, H: 10.05, N: 4.43 Found C: 59.16, H: 10.42, N: 3.97 EMI23.1 (rac) -l-O-Octadecyl-2-O-methyl-glycerol-3- [2- (1- pyridazinio)ethyl]phosphate. m.p. 740C I.R. (Nujol) : 3350, 1600, 1245 cm 1 N,M.R. (CD30D) ppm : 0.88-1.76 (35H, m), 3.36-5.06 (llH, m), 3.42 (3H, s), 8.34 (2H, m), 9.48 (1H, m), 9.76 (1H, m), Anal. Calcd. for C28H53N206P.H20 C: 59.76, H: 9.85, N: 4.98 Found C: 59.24, H: 9.96, N: 4.83 EMI23.2 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1- imidazolyl)ethyl]phosphate. m.p. 2380C (dec.). I.R. (Nujol) : 3100, 1260, 1120, 1085, 1050, 930, 850, 770 cm 1 N.M.R. (CD3 OD-CDC13) ppm : 0.5-2.2 (35H, m), 3.14-3.6 (5H, m), 3.40 (3H, s), 3.6-3.96 (2H, m), 3.96-4.3 (4H, m), 6.92 (1H, s), 7.08 (1H, s), 7.62 (1H, s) Anal. Calcd. for C27H53N206P.H2O C: 58.87, H: 10.24, N: 5.09 Found C: 58.50, H: 9.67, N: 4.89 EMI24.1 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-(2- piperidinoethyl)phosphate. m.p. 122 to 1300C I.R. (Nujol) : 3400, 1660, 1230, 1120, 1085, 1070, 1055, 1020 cm-1 N.M.R. (CD30D) ppm : 0.6-2.0 (41H, m), 3.0-3.68 (llH, m), 3.44 C3H, s), 3.8-4.0 (2H, m), 4.04-4.3 (2H, m) Anal. Calcd. for C29H60N06P.2H2O C: 59.46, H: 11.01, N: 2.39 Found C: 59.30, H: 11.03, N: 2.28 EMI24.2 (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(N- methyl-4-morpholino)ethyl]phosphate. hygroscopic solid. m.p. 580C I.R. (Nujol) : 3350, 1625, 1220 cm 1 EMI25.1 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2 (4-methyl-l-piperazinyl)ethyl]phosphate. m.p. 132 to 136 C I.R. (Nujol) : 3350, 1650, 1210, 1050 cm 1 N.M.R. (CD30D) ppm : 0.6-1.8 (35H, m), 2.68 (3H, s), 2.76-3.2 (10H, m), 3.2-3.7 (5H, m), 3.46 (3H, s), 3.7-4.2 (4H, m) Anal. Calcd. for C29H61N206P.2H20 C: 57.97, H: 10.91, N: 4.66 Found C: 58.48, H: 11.23, N: 4.62 EMI25.2 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(3- chloro-l-pyridinio)ethyl]phosphate. m.p. 192"C I.R. (Nujol) : 3350, 1625, 1240 cm 1 N.M.R. (CD30D) ppm : 0.92 (3H, t, J=6Hz), 1.04-1.72 (32H, m), 3.46 (3H, s), 3.40-4.92 (llH, m), 8.18 (1H, dd, J=6Hz, 7Hz), 8.74 (1H, d, J=7Hz), 9.06 (1H, d, J=6Hz), 9.36 (1H, s) EMI26.1 (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2- (l-methyl-2-pyrazolio)ethyllphosphate. m.p. 218 C I.R. (Nujol) : 3370, 1675 (s), 1240 cm N.M.R. (CD3OD) ppm : 0.90 (3H, t, J=6Hz), 3.46 (3H, s), 4.25 (3H, s), 3.38-4.84 (llH, m), 6.84 (1H, dd, J=3Hz, 4Hz), 8.38 (1H, d, J=3Hz), 8.48 (1H, d, J34Hz) Anal. Calcd. for C28H55N206P.3/2H20 C: 58.61, H: 10.18, N: 4.48 Found C: 58.49, H: 10.27, N: 4.63 EMI26.2 (rac)-1-O-Octadecyl-2-O-ethyl-glycerol-3-[2-(1- pyridinio)ethyl]phosphate. m.p. 190 to 195 C I.R. (CHCl3) ppm : 3300, 1635, 1240 cm -l N.M.R. (CD3OD) ppm : 0.89 (3H, t, J=6.5Hz), 1.09-1.49 (35H, m), 3.28-4.97 (13H, m), 8.08-9.13 (5H, m) Anal. Calcd. for C30H56N06P.l/2H20 C: 61.83, H: 9.86, N: 2.40 Found C: 61.27, H: 10.10, N: 2.17 EMI27.1 (sac)-l-O-Octadecyl-2-O-benzyl-glycerol-3-[2-(1- pyridinio)ethyl]phosphate. m.p. l130C (dec.) I.R. (Nujol) : 3370, 1230 cm 1 N.M.R. (CD30D) ppm : 0.85 (3H, m), 1.0-2.0 (32H, m), 3.20-4.4 (llH, m), 4.68 (2H, s), 7.36 (5H, brs), 8.04-8.92 (5H, m) Anal. Calcd. for C35H58NO6P.2H2O C: 64.01, H: 9.53, N: 2.14 Found C: 63.73, H: 9.37, N: 2.10 EMI27.2 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3- [2-(l-methyl- 1,2,4-triazol-4-io)ethyl]phosphate. m.p. 2000C (dec.) I.R. (CHC13) : 3280, 3130, 2900, 2850, 1580 cm 1 N.M.R. (CDC13) ppm : 0.89 (3H, t, J=SHz), 1.12-1.87 (32H, m), 3.40 (3H, s), 4.18 (3H, s), 3.20-4.87 (llH, m), 9.05 (1H, s), 11.10 (1H, s) Anal. Calcd. for C27H54N306P.1/2HO C: 58.25, H: 9.96, N: 7.55 Found C: 58.68, H:10.16, N: 7.07 EMI28.1 (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(3- thiazolio)ethyIlphosphate. m.p. 218-to 2200C I.R. (CHCl3) : 3300, 2900, 2850, 1660, 1460 cm 1 N.M.R. (CD30D) ppm : 0.90 (3H, t, J=5Hz), 1.09-1.58 (32H, m), 3.45 (3H, s), 3.23 4.97 (11H, m), 8.28 (1H, m), 8.51 (1H, m), 10.15 (1H, m) Anal. Calcd. for C27H52N06PS.2H20 C: 55.36, H: 9.63, N: 2.39 Found C: 55.47, H: 9.29, N: 2.33 EMI28.2 (rac3-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(3-ethoxy- -carbonyl-1-pyridinio)ethyl]phosphate. m.p. 140 C (dec.) I.R. (CHCl3) : 3300, 2900, 2850, 1740, 1460 cm-1 N.M.R. (CD30D) ppm : 0.91 (3H, t, J=5.5Hz), 1.07-1.72 (32H, m), 1.48 (3H, t, J=7Hz), 3.27-5.10 (llH, m), 4.58 (2H, q, J=7Hz), 3.46 (3H, s), 8.34-9.67 (4H, m) Anal. Calcd. for C32H58N08P.3/2H20 C: 59.79, H: 9.56, N: 2.18 Found C: 60.07, H: 9.59, N: 2.00 EMI29.1 (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(3- hydroxymethyl-l-pyridinio)ethyl]phosphate. m.p. 160 C (dec.). I.R. (CHC13) : 3200, 2900, 2850, 1635, 1460 cm 1 N.M.R. (CD3OD) ppm : 0.91 (3H, t, J=6Hz), 1.12-1.70 C32H, m), 3.28-4.98 (11H, m), 3.45 (3H, s), 4.89 (2H, s), 8.14 (1H, t, J=8Hz), 8.62 (1H, d, J 8Hz), 8.97 (1H, d, J=8Hz), 9.02 (1H, s) Anal. Calcd. for C30H56N07P.3/2H20 C: 59.98, H: 9.90, N: 2.33 Found C: 60.14, H: 10.38, N: 2.26 EMI29.2 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1-methyl3-imidazolio)ethyl]phosphate. m.p. 240 to 2480C I.R. (CHCl3) : 3300, 2900, 2850, 1570, 1460 cm 1 N.M.R. (CD3OD) ppm : 0.90 (3H, t, J=6Hz), 1.12-1.67 (32H, m), 3.25-4.72 (llH, m), 3.45 (3H, s), 3.95 (3H, s), 7.57 (1H, m), 7.66 (1H, m), 8.95 (1H, s) Anal. Calcd. for C28H55N2O6P.H2O C: 59.55, H: 10.17, N: 4.96 Found C: 59.37, H: 10.69, N: 4.75 EMI30.1 (rac)-1-O-Hexadecyl-2-O-benzyl-glycerol-3-[2-(1- pyridinio)ethyl)phosphate. m.p. 1600C (dec.) I.R. (Nujol) : 3350, 3050, 1640, 1230, 1100, 1070 cm N.M.R. (CD30D3 ppm : 0.7-1.0 (3H, m), 1.0L1.8 (28H, m), 3.2-4.46 (llH, m), 4.74 (2H, s), 7.20 C5H, s), 8.12-9.00 (5H, m), Anal. Calcd. for C33H54NO6P.2H20 C: 63.13, H: 9.31, N: 2.23 Found C: 63.91, H: 9.18, N: 2.19 EMI30.2 (rac)-l-O-Hexadecyl-2-O-methyl-glycerol-3-[2-(1- pyridinio)ethyl]phosphate. m.p. 1570C (dec.) I.R. (Nujol) : 3370, 1640, 1245, 1130, 1080 cm N.M.R. (CD30D) ppm : 0.92 (3H, t, J-5.5Hz), 1.04-1.80 (28H, m), 3.48 (3H, s), 3.30-4.96 (11H, m), 8.22-9.12 (5H, m) Anal. Calcd. for C27H50NO6P.3/2H20 C: 59.76, H: 9.84, N: 2.58 Found C: 59.78, H: 9.97, N: 2.62 EMI31.1 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1- homopiperazinyl)ethyl)phosphate. waxy solid. I.R. (Nujol) : 3400, 1620, 1210, 1050 cm 1 EMI31.2 (rac)-1-O-Octadecyl-1,3-propanediol-3-[2-(1-pyridinio)- ethyl]phosphate. m.p. 2030C (dec.) I.R. (Nujol) : 3390, 1685, 1640, 1490 cm 1 N.M.R. (CD3OD) ppm : 0.89 (3H, t, Js6Hz), 1.05-1.57 (32H, m), 1.78 (2H, m), 3.23-4.93 (lOH, m), 7.94-9.03 (2H, m) Anal. Calcd. for C28H52N05P. 3/2H2O C: 62.19, H: 10.25, N: 2.59 Found C: 62.27,!H: 10.49, N: 2.53 EMI31.3 (rac)-1-O-Octadecyl-glycerol-3-[2-(1-pyridinio)ethyl]- phosphate. m.p. 1500C (dec.). I.R. (Nujol) : 3410, 1635, 1235 cm EMI32.1 (rac)-1-O-Octadecyl-2-methylthio-1,3-propanediol-3- C2-(l-pyridinio)ethyIlphosphate, m.p. 194 to 1950C. I.R. (Nujol) : 3350, 1635, 1240 cm 1 EMI32.2 (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4- dimethyl-1-homopiperazinio)ethyl]phosphate. m.p. 21 to 2140C I.R; (Nujol) : 3330, 1240, 1095 cm 1 EMI32.3 (rac)-1-O-Tetradecyl-2-O-methyl-glycerol-3-[2-(1- pyridinio)ethyl]phosphate. m.p. 1590C I. R. (Nujol) : 3370, 1640, 1240 cm 1 N.M.R. (CD3OD) ppm : 0.91 (3H, t, J=5.5Hz), 1.04-1.70 (24H, m), 3.20-4.88 (llH, m), 3.43 (3H, s), 8.04-9.02 (5H, m) Anal. Calcd. for C25H46N06P.3/2H2O C: 58.34, H: 9.59, N: 2.72 Found C: 58.67, H: 9.49, N: 2.66 EMI33.1 (rac)-1-O-Tetradecyl-2-O-methyl-glycerol-3-[2-(4- methyl-l-piperazinyl)ethyl]phosphate. waxy solid. I.R. (Film) : 3400, 2800, 1650, 1220, 1050 cm 1 N.M.R. (CD30D) ppm : 0.89 (3H, t, J=5.5Hz), 1.10-1.82 (24H, m), 2.70 (3H, s), 2.77-4.27 (18H, m), 3.47 (3H, s), 4.67-4.98 (1H, m) Anal. Calcd. for C25H53N2O6P.l/2H2O C: 58.00, H: 10.51, N: 5.41 Found C: 57.82, H: 10.31, N: 5.39 EMI33.2 (rac)-l-O-Tridecyl-2-0-methyl-glycerol-3-[2-(4- methyl-l-piperazinyl)ethyl]phosphate. N.M.R. (CD30D) ppm : 0.9 (3H, m), 1.0-1.7 (22H, m), 2.68 (3H, s), 2.76-3.16 (9H, m), 3.3-3.7 (6H, m), 3.46 (3H, s), 3.7-4.2 (4H, m) Example 4 (1) To a mixture of (rac)-l-O-octadecyl-3-O-trityl-glycerol (11.74 g), triethylamine (3.03 g), and 4-dimethylamino pyridine (0.25 g) in dry 1,2-dichloroethane (110 ml) was added p-toluenesulfonyl chloride (5.70 g) in one port ion at ambient temperature. After being stirred for 17 hours at the same temperature, the mixture was washed with water, an aqueous sodium bicarbonate solution, 5% aqueous sulfuric acid, and water respectively. The organic layer was dried and evaporated to dryness. The residue was crystallized from methanol to yield 9.7 g of (rac) -l-O-octadecyl-3-O-trityl-glycerol-2-tosylate. m.p. 540C. I.R. (Nujol) : 1640, 1150 cm- (2) To a solution of phenol (5.75 g) in dry N,N-dimethyl formamide (150 ml) was added potassium tert-butoxide (6.85 g) followed by stirring for 10 minutes at ambient temperature. To the resultant solution containing potassium phenoxide was added (rac)-1-O-octadecyl-3- O-trityl-glycerol-2-tosylate (15.03 g). The mixture was heated for 1.5 hours at 1000C, cooled in an ice bath, and poured into a mixture of benzene, ethyl acetate, and water. The organic layer was washed with 1% aqueous sodium hydroxide solution and water, dried, and evapo rated. The residue was purified by column chromatography on silica gel (393 gelution by a mixture of benzene and n-hexane, 1:4 - 1:2) to yield 10.1 g of (rac)-l-O octadecyl-2-O-phenyl-3-O-trityl-glycerol as a colorless oil. -l I.R. (Film) : 3060, 2930, 2850, 1595, 1235, 1115 cm (3) To a solution of (rac)-l-O-octadecyl-2-O-phenyl-3-O trityl-glycerol (10.0 g) in methylene chloride (100 ml) was added trifluoroacetic acid (11 ml) in one portion. After the yellow solution was stirred for 20 minutes at ambient temperature, ice water was added under vigorous stirring. The organic layer was washed with an aqueous sodium bicarbonate solution and water, dried, and evaporated under reduced pressure. The residue was treated with n-hexane to remove triphenylcarbinol by filtration. The filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (120 g, elution by chloroform) to yield 4.48 g of (rac)-l-O-octadecyl-2-O-phenyl-glycerol as a waxy solid. -l I.R. (Film) : 3000, 2920, 1595, 1210 cm (4) To a solution of 2-bromoethyldichlorophosphate (3.30 g) in dry chloroform (6 ml) was added, dropwise over 20 minutes, a solution of (rac)-l-O-octadecyl-2-O-phenyl- glycerol (4.42 g) and triethylamine (1.92 g3 in dry chloroform (6 ml) at 0 to 5 C. After the addition was completed, the mixture was allowed to warm to ambient temperature, stirred for 2 hours, and then cooled in an ice bath. To the resultant thick solution containing (rac)-l-O octadecyl-2-0-phenyl-glycerol-3-(2-bromo chlorophosphate was added dropwise a mixture of water (5 ml) and pyridine (10 ml) below 150C. The resulting solution was allowed to warm to ambient temperature followed by stirring for 30 minutes. The solvents were then evaporated under reduced pressure. The residue was dissolved in aqueous sodium bicarbonate solution and diethyl ether. The aqueous phase was washed with diethyl ether, adjusted to pH 1 with 10% hydrochloric acid, and extracted twice with diethyl ether - ethyl acetate (50%). The organic layer was washed with water, dried, and evaporated under reduced pressure to yield 6.7 g of (rac) -l-O-octadecyl-2-O-phenyl-glycerol-3-(2- bromoethyl)phosphate (oil). I.R. (Film) : 2920, 2850, 1595, 1235 cm EMI36.1 (rac)-l-O-Octadecyl-2-O-phenyl-glycerol-3-(2-(1 pyridinio)ethyl]phosphate (2.24 g) was obtained by reacting the above obtained compound of Example 4-(4) (3.05 g) with pyridine (9 ml) according to similar manner to those of Example 1 and 2. m.p. 196 to 2000C I.R. (Nujol) : 3380, 1635, 1595, 1585 cm 1 N.M.R. (CD30D) ppm : 0.90 (3H, m), 1.02-1.72 (32H, m), 3.25-4.88 (llH,m), 6.77-7.38 (5H, m), 7.89-9.03 (5H, m) Anal. Calcd, for C34H56NO6P.2H2 C: 63.62, H: 9.42, N: 2.18 Found C: 63.75, H: 9.02, N: 2.16 Example 5 (1) To a stirred suspension of (rac)-l-O-octadecyl-2 O-methyl-glycerol-3-(2-aminoethyl)phosphate (5.3 g) in dry chloroform (88 ml) was added bis(trimethylsilyl) acetamide (4.47 g) in one portion with stirring at ambient temperature followed by stirring for another one hour. The resulting solution was cooled in an ice bath and a solution of chloroacetyl chloride (1.37 g) in dry chloroform (22 ml) was dropwise added during a period of 5 minutes with stirring. After stirring for 3 hours at 50C, the reaction mixture was washed with aqueous hydrochloric acid and with brine, dried, and evaporated under reduced pressure. The residue was crystallized from n-hexane to yield (rac)-1-O-octadecyl- 2-O-methyl-glycerol-3-t2-chloroacetylaminoethyl)phosphate. m.p. 67 to 700C. I.R. (Nujol) : 3300, 1640, 1220 cm 1 EMI37.1 (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1- pyridinioacetylamino)ethyl]phosphate(1.9g) was obtained by reacting the above obtained compound (2.0 g) of Example 5-(1) with pyridine according to similar manners to those of Example 1 and 2. m.p. 224 to 2260C. I.R. (Nujol) : 3350, 3200, 1675 cm 1 N.M.R. (CD30D) ppm : 0.88 (3H, m), 1.12-1.49 (32H, m), 3.24-4.09 (llH, m), 3.46 (3H, s), 5.47 (2H, s), 8.14-8.96 (5H, m) Anal. Calcd. for C31H57N207P.H2O C: 60.17, H: 9.61, N: 4.53 Found C: 60.04, H: 9.85, N: 4.54 Example 6 (1) (rac)-1-O-Octadecyl-2-methylthio-3-O-trityl-1,3 - propanediol (6.17 g) was obtained as an oil by reacting (ract-l-O-octadecyl-3-O-trityl-glycerol-2-tosylate (7.3 g) with sodium methylmercaptide (10 ml, 15% in water) in a similar manner to that of Example 4-(2). N.M.R. (CC14) ppm : 0.86 (3H, t, J=6Hz), 1.02-1.70 (32H, m), 1.96 (3H, s), 2.70 (1H, m), 3.25 (2H, d, J=6Hz), 3.30 (2H, t, J=6Hz), 3.55 (2H, d, J=6Hz), 7.00-7.56 (1SH, m) (2) To a solution of (rac)-l-O-octadecyl-2-methylthio-3-O trityl-1,3-propanediol (2.8 g) in chloroform (22.5 ml) was dropwise added, during a period over 20 minutes, a solution of m-chloroperbenzoic acid (1.94 g) in chloroform (30 ml) under cooling at 50C and the mixture was stirred for one hour at the same temperature. The precipitates were filtered off and washed with a small quantity of chloroform. The combined filtrates were washed with an aqueous sodium sulfite solution, an aqueous sodium bicarbonate solution, and water respecti vely. The organic layer was dried and evaporated to yield 3.19 g of (rac)-l-O-octadecyl-2-methylsulfonyl-3- O-trityl-l,3-propanediol as a thick oil. I.R. (Film) : 3030, 2920, 2850, 1595, 1350 cm (3) (rac) -l-O-Octadecyl-2-methylsulfonyl-l,3-propanediol (5.3 g) was obtained as an oil by reacting the above obtained compound of Example 6-(2)(8.92 g) with tri fluoroacetic acid (10.9 ml) in a similar manner to that of Example 4-(3). N.M.R. (CC14) ppm : 0.90 (3H, m), 1.07-1.78 (32H, m), 2.88 (3H, s), 2.97-3.33 (2H, m), 3.45 (2H, dd, J=6Hz), 3.82 (2H, d, J=6Hz), 3.72-4.10 (2H, m) (4) (rac) l-O-Octadecyl-2-methylsulfonyl-l,3-propanediol- 3-(2-bromoethyl)phosphate (1.58 g) was prepared as an oil by reacting the above obtained compound of Example 6-(3) with 2-bromoethyldichlorophosphate (4.10 g) in a similar manner to that of Example 4-(4). I.R. (CHC13) : 3450, 3300, 2900, 1460, 1300, 1190 cm EMI39.1 (rac)-l-O-Octadecyl-2-methylsulfonyl-1,3-propanediol 3- [2-(l-pyridinio)ethyl]phosphate (1.6 g) was obtained by reacting the above obtained compound of the Example 6-(4) (2.2 g) with pyridine (6.6 ml) according to similar manners to those of Examples 1 and 2. m.p. 168 to 1720C. I.R. (Nujol) : 3350, 1465, 1295 cm 1 N.M.R. (CD3OD) ppm : 0.89 (3H, m), 1.08-1.43 (32H, m), 3.00 (3H, s), 3.18-4.89 (llH, m), 8.13-9.00 (SH, m) Anal. Calcd. for C29H54NO7PS- 3/2H2 C: 56.29, H: 2.26, N: 9.28 Found C: 56.23, H: 2.21, N: 9.59 Example 7 (1) (rac)-1-O-Octadecyl-2-phenylthio-3-O-trityl-1,3- propanediol (9.9 g) was obtained as an oil by reacting the above obtained compound Example 4-(1)(10.32 g) with thiophenol (3.08 g) in a similar manner to that of Example 4-(2). I.R. (Film) : 3050, 2920, 2850, 1445, 1100 cm (2) (rac) -l-O-Octadecyl-2-phenylthio-1,3-propanediol (6.7 g) was obtained as an oil by reacting the above obtained compound o-e Example 7-(1) (12.1 g) with trifluoroacetic acid (12.1 ml3 in a similar manner to that of Example 4-(3). I.R. (Film) : 3450, 3020, 2930, 1463, 1213 cm I (3) (rac) -l-O-Octadecyl-2-phenylthio-l,3-propanediol- 3-(2-bromoethyl)phosphate (3.59 g) was obtained as an oil by reacting the above obtained compound of Example 7-(2) (5.55 g) with 2-bromoethyldichlorophosphate (4.0 g) in a similar manner to that of Example 4-(4). I.R. (CHCl3) : 3400, 3010, 2920, 1210 cm EMI40.1 (rac) -l-O-Octadecyl-2-phenylthio-1,3-propanediol-3- (2-(1-pyridinio)ethyl]phosphate (2.5 g) was obtained by reacting the above obtained compound of Example 7-(3) (4.1 g) with pyridine (12.3 ml) according to similar manners to those of Examples 1 and 2. m.p. 194 to 196"C. I.R. (Nujol) : 3350, 1630, 1580 cm N.M.R. (CD30D) ppm : 0.89 (3H, m), 1.04-1.63 (32H, m), 3.15-4.92 (llH, m), 7.05-7.51 (5H, m), 8.04-9.02 (SH, m) Anal. Calcd. for C34H56NO5PS. 3 /2H2O C: 62.94, H: 9.16, N: 2.16 Found C: 63.16, H: 9.19, N: 2.17 Example 8 (1) (rac)-1-O-Octadecyl-2-(1,3,4-thiadiazolyl-2-thio)- 3-O-trityl-l,3-propanediol (4.61 g) was obtained as an oil by reacting (rac)-l-O-octadecyl-3-O-trityl- glycerol-2-tosylate (7.37 g) with 2-mercapto-1,3,4 thiadiazole(l.30 g) in a similar manner to that of Example 4-(2). I.R. (Film) : 2920, 2850, 1595, 1050 cm 1 (2) (rac)-1-O-Octadecyl-2-(1,3,4-thiadiazolyl-2-thio)- 1,3-propanediol (2.29 g) was obtained by reacting the above obtained compound of Example 8-(1)(4.o g) with trifluoroacetic acid (4 ml) in a similar manner to that of Example 4-(3). m.p. 950C. I.R. (Nujol) : 3300, 1590 cm 1 (3) (rac)-1-O-Octadecyl-2-(1,3,4-thiadiazolyl-2-thio)-1,3- propanediol-3-(2-bromoethyl)phosphate (2.16 g) was obtained as an oil by reacting the above obtained compound of Example 8-(2)(2.22 g) with 2-bromoethyl dichlorophosphate (1.57 g) in a similar manner to that of Example 4-(4). I.R. (Film) : 2920, 2850, 1600, 1240 cm EMI41.1 (rac)-1-O-Octadecyl-2-(1,3,4-thiadiazolyl-2-thio)-1,3- propanediol-3-[2-(1-pyridinio3ethyl3phosphate (1.08 g) was obtained by reacting the above obtained compound of the Example 8-(3)(2.10 g) with pyridine (20 ml) according to similar manners to those of Examples I and 2. m.p. 203 to 2050C. I.R. (Nujol) : 3350, 1630, 1240 cm 1 N.M.R. (CD30D) ppm : 0.90 (3H, t, J=S.5Hz), 1.04 1.64 (32H, m), 3.36-4.94 (llH, m), 8.14-9.10 (5H, m), 9.42 (lH, s) Anal. Calcd. for C30H52N305PS2-H2O C: 55.62, H: 8.40, N: 6.49 Found C: 55.65, H: 8.82, N: 6.18 Example 9 (1) (rac)-1-O-Octadecyl-2-chloro-3-O-trityl-1,3- propanediol (1.66 g) was obtained by reacting (rac) l-O-octadecyl-3-O-trityl-glycerol-2-tosylate (3.0 g) with lithium chloride (0.85 g) in a similar manner to that of Example 4-(2). m.p. 68 to 710C. I.R. (Nujol) : 1595 cm 1 (2) (rac)-l-O-Octadecyl-2-chloro-l,3-propanediol (3.3 g) was obtained by reacting the above obtained compound of Example 9-(1) (5.59g) with trifluoroacetic acid (6 ml) in a similar manner to that of Example 4-(3). m.p. 40 to 410C. I.R. (Nujol) : 3320, 1465 cm 1 (3) (rac)-1-O-Octadecyl-2-chloro-1,3-propanediol-3-(2 bromoethyl)phosphate (3.92 g) was obtained as a waxy solid by reacting the above obtained compound of Example 9-(2)(3.48 g) with 2-bromoethyldichlorophosphate (3.01 g) in a similar manner to that of Example 4-(4). I.R. (CHCl3) : 2900, 2840, 2300, 1220 cm 1 EMI42.1 (rac)-l-O-Octadecyl-2-chloro-1,3-propanediol-3-t2- (l-pyridinio)ethyl]phosphate (2.73 g) was obtained by reacting the above obtained compound of Example 9-(3)(3.80 g) with pyridine (7 ml) according to similar manners to those of Examples 1 and 2. m.p. 203 to 2050C. I.R. (Nujol) : 3350, 1240 cm 1 N.M.R. (CD3OD) ppm : 0.89 (3H, t, J=5Hz), 1.04-1.70 (32H, m), 3.34-4.44 (llH, m), 7.92-9.04 (5H, m) Anal. Calcd. for C28H51NO5CP.H2O C: 59.40, H: 9.44, N: 2.47 Found C: 59.17, H: 9.59, N: 2.51 Example 10 (1) (rac) -l-O-Octadecyl-2-azido-3-O-trityl-l,3-propanediol (12.2 g) was obtained by reacting (rac)-l-O-octadecyl- 3-O-trityl-glycerol-2-tosylate (14.7 g) with sodium azide (3.9 g) in a similar manner to that of Example 4-(2). m.p. 47 to 490C. I.R. (Nujol) : 2100, 1595 cm (2) (rac)-1-O-Octadecyl-2-azido-1,3-propanediol (6.24 g) was obtained as a waxy solid by reacting the above obtained compound of Example 10-(1) (13.5 g) with trifluoroacetic acid (13.5 ml) in a similar manner to that of Example 4-(3). I.R. (CHCl3) : 3450, 2900, 2850, 2200 cm (3) (rac) -l-O-Octadecyl-2-azido-l,3-propanediol-3- (2- bromoethyl)phosphate (4.90 g) was obtained as an amorphous solid by reacting the above obtained com pound of Example 10-(2)(6.10 g) with 2-bromoethyl dichlorophosphate (5.15 g) in a similar manner to that of Example 4-(4). I.R. (CHC13) : 2120, 1460, 1215 cm 1 (4) A solution of (rac)-l-O-octadecyl-2-azido-1,3 propanediol-3-(2-bromoethyl)phosphate (6.7 g) in a mixture of ethyl acetate (40 ml), chloroform (30 ml), and acetic acid (20 ml) containing 10% palladium on charcoal (2.0 g) was hydrogenated at 3 atm. hydrogen pressure for 8 hours. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (130 g, elution by CHC13, 5% methanol in chloroform, 10% methanol in chloroform, and chloroform:methanol: water, 65:25:4, v/v/v) followed by crystallization from methanol to yield 2.27 g of (rac)-l-O-octadecyl 2-amino-1,3-propanediol-3-(2-bromoethyl)phosphate. m.p. 2100C, I.R. (Nujol) : 3350, 1220 cm 1 (5) To a solution of the above obtained compound of Example 10-'C4)(1.65 g) and dry pyridine (1.5 g) in dry methylenechloride (20 ml) was added, dropwise over 20 minutes, a solution of methyl chloroformate (0.34 g) in dry methylene chloride (5 ml) at 50C. After 3 hours, the solution was allowed to stand for 17 hours at ambient temperature, and then washed with aqueous hydrochloric acid and water, dried, and evaporated. The residue was purified by column chro matography on silica gel (30 g, elution by chloroform) to yield 1.20 g of (rac)-1-O-octadecyl-2-ethoxy- carbonylamino-1,3-propanediol-3-C2-bromoethyl)phosphate as an amorphous solid. I.R. (CHC13) : 3270, 1715, 1250 cm 1 EMI45.1 (rac)-l-O-Octadecyl-2-ethoxycarbonylamino-l,3 propanediol-3-[2-(1-pyridinio)ethyl]phosphate (0.60 g) was obtained by reacting the above obtained compound of Example 10-(5)(1.15 g) with pyridine (6 ml) accord ing to similar manners to those of Examples 1 and 2. m.p. 175 to 1760C (dec.). I.R. (Nujol) : 3470, 1710, 1635, 1240 cm N.M.R. (CD30D) ppm : 0.89 (3H, t, J=5.5Hz), 1.10 1.70 (35H, m), 3.32-4.88 (13H, m), 8.08-8.98 (5H, m) Anal.Calcd. for C H N O P. 3 /2H20 31 57 2 7 C: 59.31, H: 9.63, N: 4.46 Found C: 59.57, H: 9.64, N: 3.97 Example 11 (1) To a suspension of (rac)-l-O-octadecyl-2-amino-1,3 propanediol-3- (2-bromoethyl)phosphate (2.20 g) in dry methylene chloride (30 ml) was added bis(tri methylsilyl)acetamide (2.0 g) in one portion. After the mixture was stirred for 5 hours at ambient tem perature, a solution of methyl isocyanate (0.79 g) in dry methylene chloride (2 ml) was added therein. After standing overnight, the mixture was washed with aqueous hydrochloric acid and twice with water, dried, and evaporated. The residue was triturated in methanol to yield 1.66 g of (rac)-l-O-octadecyl-2- (N' -methylureido) -l,3-propanediol-3- (2-bromoethyl) - phosphate. m.p. 950C. I.R. (Nujol) : 3320, 1630, 1230 cm 1 EMI46.1 (rac)-l-O-Octadecyl-2-(N'-methylureido)-1,3-propanediol 3-C2-(l-pyridinio)ethylphosphate (0.65 g) was obtained by reacting the above obtained compound of Example 11 (I) (1.64 g) with pyridine (S ml) according to similar manners to those of Examples 1 and 2. m.p. 1890C (dec.) I.R. (Nujol) : 3330, 1635, 1235 cm N.M.R. (CD30D) ppm : 0.90 (3H, t, J=5.5Hz), 1.04 1.70 (32H, m), 2.67 (3H, s), 3.32-4.88 (llH, m), 8.10-9.00 (SH, m) Anal. Calcd. for C30H56N306P.H20 C: 59.67, H: 9.68, N: 6.96 Found C: 59.43, H: 9.99, N: 6.79 Example 12 (1) (rac) -1-0- (Octadec-cis- 9-enyl) - 2-O-methy1- 3-0- trityl-glycerol (9.4g) was obtained as an oil by - methylation of (rac)-l-O-(octadec-cis-9-enyl) 3-O-trityl-glyceroi (8.94g) with methyl iodide(2.83g). I.R. (Film) : 3050, 2920, 2850, 1445 cm (2) (rac)-1-O- (Octadec-cis-9-enyl)-2-O-methyl-glycerol t4.08 g was obtained as an oil.by reacting the above obtained compound of Example 12-(1) (9.4 g) with trifluoroacetic acid (9.4 ml) in a similar manner to that of Example 4-(3). I.R. [Film]: 3400, 2900, 2850, 1460 cm 1 (3) (rac) -1-0- (Octadec-cis-9-enyl) -2-0-methyl-glycerol- 3-(2-bromoethyl)phosphate (5.39g) was obtained by reacting the above obtained compound of Example 12-(2)(4.0 g) with 2-bromoethyldichlorophosphate (4.07 g) in a similar manner to that of Example 4-(4). I.R. (Film) : 2900, 2850, 1460, 1230 cm 1 EMI47.1 (rac3-1-O-(Octadec-cis-9-enyl3-2-O-methyl-glycerol- 3-[2-(l-pyridinio)ethyl]phosphate (1.9 g) was obtained as an oil by reacting the above obtained compound of Example 12- (3) (2.2 g) with pyridine accordi to similar manners to those of Example 1 and 2. I.R. (Film) : 3350, 3030, 2900, 2820, 1630, 1460, 1230 cm 1 N.M.R. (CD3OD) ppm : 0.89 (3H, m), 1.08-1.71 (24H, m), 1.81-2.23 (4H, m), 3.41 (3H, s), 3.45-5.39 (13H, m), 8.08-8.97 (5H, m) Anal. Calcd. for C29H52NO6P. 3 /2H2O C: 61.24, H: 9.75, N: 2.46 Found C: 61.31, H: 9.81, N: 2.40 Example 13 EMI48.1 A mixture of (rac)-l-O-octadecyl-2-O-methyl-glycerol-3 (2-morpholinoethyl)phosphate (3.05 g), cyclohexylamine (1.17 g) and methyl iodide (6.64 g) in ethanol (45 ml) was refluxed for 7 hours. The reaction mixture was evaporated under reduced pressure and the residue was triturated in acetone. The obtained powder was dissolved in 90% aqueous methanol (50 ml), and the solution was treated with silver acetate (4.02 g) for 30 minutes at room temperature. The precipitates were filtered off and washed with methanol. The filtrate and washings were combined and evaporated to dryness. The residue was purified by column chromatography on silica gel (60 g, elution by chloroform-methanol-water, 65:25:4) to give 1.62 g of (rac)-l-O-octadecyl-2-O-methyl-glycerol-3- [2- (N-methyl-4-morpholinio)ethyl]phosphate, which was recrystallized from chloroform-acetone. yield 1.19 g (hygroscopic solid). m.p. 580C. I.R. (Nujol) : 3350, 1625, 1220 cm 1 Anal. Calcd. for C29H6007NP.3/2 H2O C: 58.75, H: 10.71, N: 2.36 Found C: 58.38, H: 10.79, N: 2.37 Example 14 The following compounds were obtained according to a similar manner to that of Example 13. EMI49.1 (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4- dimethyl-l-homopiperazinio)ethyl]phosphate. m.p. 210 to 2140C. I.R. (Nujol) : 3330, 1240, 1095 cm N.M.R. (CD3OD) ppm : 0.90 (3H, m), 1.09-2.22 (34H, m), 2.73-4.79 (19H, m), 3.17 (6H, s), 3.46 (3H, s) Anal. Calcd. for C31H65N2O6P. 5 /4H2O C: 60.51, H: 11.01, N: 4.55 Found C: 60.53, H: 11.07, N: 4.43 (2) (rac)-1-O-Octadecyl-2-O-ethyl-glycerol-3-t2-(4 methyl-1-piperazinyl)ethyl]phosphate. m.p. 115 C. I.R. (Nujol) : 3400, 1645, 1215, 1090, 1055 cm (3) (rac)-1-O-Hexadecyl-2-O-methyl-glycerol-3-[2-(4 methyl-1-piperazinyl)ethyl]phosphate. I.R. (Nujol) : 3350, 1220 cm (4) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4- ethyl-1-piperazinyl)ethyl]phosphate. I.R. (Nujol) : 3350, 1210, 1050 cm 1 (5) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-[4-(2 hydroxyethyl)-1-piperazinyl]ethyl]phosphate. m.p. 196 to 1990C. I.R. (Nujol) : 3120, 2200, 1210, 1050 cm 1 (6) (rac)-l-O-Hexadecyl-2-O-benzyl-glycerol-3-[2-(4- methyl-l-piperazinyl)ethyl]phosphate. I.R. (Film) : 3350, 2700, 1640, 1200, 1050 cm (7) (rac)-l-O-Tetradecyl-2-O-methyl-glycerol-3-[2-(4- methyl-l-piperazinyl)ethyl]phosphate. I.R. (Film) : 3400, 2800, 1650, 1220, 1050 cm (8) (rac)-1-O-Tridecyl-2-O-methyl-glycerol-3-[2-(4-methyl l-piperazinyl)ethyl]phosphate. Example 15 EMI50.1 To a solution of (rach-l-O-octadecyl-2-O- methoxycarbonyl-glycerol-3- (2-pyridinioethyl)phosphate (1.0 g) in methyl alcohol (20 ml) was dropwise added during a period over one minute lN-aqueous sodium hydroxide solution (2 ml) at ambient temperature. After stirring for 1.5 hours at the same temperature, the mixture was evaporated under reduced pressure. The resultant residue was dissolved in a mixture of chloroform-methyl alcoholwater t20 ml, 1:2:1 v/v/v) and passed through a mixed ion-exchange column (Amberlite IRC-50(H+) 3.7 g, IR-45(OH-! 7.3 g). After washing the column with the same solvents, the combined eluates were evaporated to dryness. Purification of the obtained residue was carried out by column chromatography on silica gel (54 g, elution by chloroform-methyl alcohol-water, 65:25:4, v/v/v). The combined eluates containing the desired product were evaporated to dryness and the residue was crystallized from a mixture of chloroform and acetone to yield 0.53 g of Crac)-l-O-octadecyl-glycerol-3-[2-(l-piridinio)ethyl] - phosphate as a colorless solid. m.p. 1500C (dec.). I.R. (Nujol) : 3410, 1635, 1235 cm N.M.R. (CD3OD) ppm : 0.9 (3H, t, J=5Hz), 1.0-1.8 (32H, m), 3.08-4.88 (llH, m), 8.12-8.94 (5H, m) Anal. Calcd. for C28H52NO6P.2H2O C: 59.44, H: 9.97, N: 2.48 Found C: 59.11, H: 9.66, N: 2.43 Example 16 (1) (rac) -1-O-Octadecyl-2-methylthio-l,3-propanediol (2.68 g) was obtained as a waxy solid by reacting (rac)-l-O-octadecyl-2-methylthio-3-O-trityl-1,3- propanediol (5.59 g) with trifluoroacetic acid (5.6 ml) in a similar manner to that of Example 4-(3). I.R. (Film) : 3300, 1460 cm EMI51.1 To a solution of (rac)-l-O-octadecyl-2-methylthio1,3-propanediol (2.68 g) and triethylamine (0.87 g) in dry benzene (35 ml) was added a solution of 2 chloro-2-oxo-1,3,2-dioxaphospholidine (1.22 g) in dry benzene (5 ml) during 5 minutes at 50C under stirring. After the addition, the mixture was allowed to warm to ambient temperature and stirred for 2 hours further. The precipitates were filtered off and washed with a small quantity of dry benzene. The combined filtrate and washings were evaporated under reduced pressure and the residue was dissolved in dry pyridine (6 ml). The resultant mixture was heated for 1.5 hours at 1000C and then evaporated to dryness. The residue was tri turated in acetone to give a crude product, which was purified by column chromatography on silica gel (80 g. elution by a mixture of chloroform-methyl alcohol water, 65:25:4, v/v/v) followed by recrystallization from a mixture of chloroform and acetone to yield 0.55 g of (rac)-l-O-octadecyl-2-methylthio-1,3- propanediol-3-[2-(l-pyridinio)ethyl]phosphate. m.p. 194 to 1950C. I.R. (Nujol) : 3350, 1635, 1240 cm 1 N.M.R. (CD30D) ppm : 0.91 (3H, t, J=5.5Hz), 1.04 1.64 C32H, m), 2.-14 (3H, s), 2.89 (1H, m), 3.38-4.90 t1OH, m), 8.06-9.06 (5H, m) Anal. Calcd. for C29H54NO5PS. 5 /2H2 C: 59.35, H: 9.79, N: 2.38 Found C: 59.03, H: 9.59, N: 2.28 Example 17 The following compounds were obtained according to a similar manner to that of Example 16. (1) (rac)-l-O-Octadecyl-2-O-ethyl-glycerol-3-[2-(4 methyl-l-piperazinyl)ethyl]phosphate. I.R. (Nujol) : 3400, 1645, 1215, 1090, 1055 cm (2) (rac)-l-O-Hexadecyl-2-O-methyl-glycerol-3-[2-(4 methyl-l-piperazinyl)ethyl]phosphate. I.R. (Nujol) : 3350, 1220 cm 1 (3) (rac) l-O-Octadecyl-2-O-methyl-glycerol-3- [2- (4- ethyl-l-piperazinyl)ethyl]phosphate. I.R. (Nujol) : 3350, 1210, 1050 cm (4) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1 piperazinyllethyllphosphate. I.R. (Nujol) : 3350, 1625, 1220, 1070 cm (5) (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4- hydroxypiperidino)ethy)phosphate. I.R. (Nujol) : 3200, 1215, 1055 cm (6) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4 methylpiperidino) ethyl]phosphate. I.R. (Nujol) : 3400, 1220, 1040 cm (73 (rac) -1-O-Octadecyl-2-O-methyl-glycerol-3- [2- [4-(2-hydroxyethyl3-1-piperazinylZethyl3phosphate. I.R. (Nujol) : 3120, 2200, 1210, 1050 cm (8) (rac)-l-O-Hexadecyl-2-O-benzyl-glycerol-3-[2-(4 methyl-1-piperazinyl)ethyl]phosphate. I.R. Film3 : 3350, 2700, 1640, 1200, 1050 cm (9) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3- [2-(4- methyl-l-pyridinio3ethyl3phosphate. I.R. (Nujol) : 3350, 1640, 1240 cm 1 (10) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-[3- methyl-l-pyridinioJethyl]phosphate. I.R. (CHC13) : 3650, 3300, 2850, 1635 cm (11) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4 dimethylamino-1-pyridinio)ethyl]phosphate. I.R. (Nujol) : 3350, 1650, 1570, 1230 cm (12) (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1 pyridazinio3ethyl]phosphate. I.R. (Nujol) : 3350, 1600, 1245 cm 1 (13) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1- imidazolyl)ethyl]phosphate. I.R. (Nujol) : 3100, 1260, 1120, 1085, 1050, 930 cm (14) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-(2- piperidinoethyl) phosphate. I.R. (Nujol) : 3400, 1660, 1230, 1120, 1085, 1070, 1055, 1020 cm 1 (15) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(N- methyl-4-morpholinio)ethyl]phosphate,hygroscopic solid. I.R. (Nujol) : 3350, 1625, 1220 cm 1 (16) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(4- methyl-1-piperazinyl)ethyl]phosphate. I.R. (Nujol) : 3350, 1650, 1210, 1050 cm 1 17) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(3- chloro-1-pyridinio)ethyl]phosphate. I.R. (Nujol) : 3350, 1625, 1240 cm 1 (18) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2- (l-methyl-2-pyrazolio)ethyl]phosphate. I.R. (Nujol) : 3370, 1675 (s), 1240 cm (19) (rac)-1-O-Octadecyl-2-O-ethyl-glycerol-3-[2-(1- pyridinio)ethyl]phosphate. I.R. (CHCl3) : 3300, 1635, 1240 cm 1 (20) (rac)-1-O-Octadecyl-2-O-benzyl-glycerol-3-[2-(1- pyridinio) ethyl] phosphate. I.R. (Nujol) : 3370, 1230 cm (21) (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(l- methyl-1,2,4-triazol-4-io)ethyl]phosphate. I.R. (CHC13) : 3280, 3130, 2900, 2850, 1580 cm 1 (22) (rac)-l-O-Octadecyl-2-O-methyl-glycerol-3-[2-(3 thiazolio)ethyl]phosphate. I.R. (CHC13) : 3300, 2900, 2850, 1660, 1460 cm 1 (23) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(3- ethoxycarbonyl-1-pyridinio)ethyl]phosphate. I.R. (CHCl3) : 3300, 2900, 2850, 1740, 1460 cm 1 (24) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(3- hydroxymethyl-1-pyridinio)ethyl]phosphate. I.R. (CHC13) : 3200, 2900, 2850, 1635, 1460 cm 1 (25) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1- methyl-3-imidazolio)ethyl]phosphate. I.R. (CHC13) : 3300, 2900, 2850, 1570, 1460 cm 1 (26) (rac)-1-O-Hexadecyl-2-O-benzyl-glycerol-3-[2-(1- pyridinjo) ethyl] phosphate. I.R. (Nujol) : 3350, 3050, 1640, 1230,1100, 1070 cm (27) (rac)-1-O-Hexadecyl-2-O-methyl-glycerol-3-[2-(1- pyridinio3ethyl3phosphate. I.R. (Nujol) : 3370, 1640, 1245, 1130, 1080 cm 1 (28) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2- (1-homopiperazinyl)ethyl]phosphate. waxy solid. I.R. (Nujol) : 3400, 1620, 1210, 1050 cm 1 (29) (rac)-1-O-Octadecyl-1,3-propanediol-3-[2-(1-pyridinio)- ethylaphosphate. I.R. (Nujol) : 3390, 1685, 1640,1490 cm 1 (30) (rac) -l-O-Octadecyl-2-O-methyl-glycerol-3- [2- (4-dimethyl-1-homopiperazinio) ethyl] phosphate. I.R.(Nujol) : 3330, 1240, 1095 cm 1 (31) (rac) -l-O-Tetradecyl-2-O-methyl-glycerol-3- [2(1- pyridinio) ethyl] phosphate. I.R. (Nujol) : 3370, 1640, 1240 cm (32) Crac)-l-O-Tetradecyl-2-O-methyl-glycerol-3-[2-(4 methyl-l-piperazinyl)ethyl]phosphate. waxy solid. I.R. (Film) : 3400, 2800, 1650, 1220, 1050 cm 1 (33) Crac)-l-O-Tridecyl-2-O-methyl-glycerol-3 [2- (4- methyl-1-piperazinyl)ethyl]phosphate. (34) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-[2-(1- pyridinio)ethyl]phosphate. I.R. (Nujol) : 3380, 1590, 1220, 1080 cm 1 (35) (rac)-1-O-Octadecyl-2-O-methyl-glycerol-3-(2- morpholinoethyl)phosphate. I.R. (Nujol) : 3350, 1220,1115 cm 1 (36) (rac)-1-O-Octadecyl-2-O-phenyl-glycerol-3-[2-(1- pyridinio)ethyl]phosphate. I.R. (Nujol) : 3380, 1635, 1595, 1585 cm 1 (37) (rac) -l-O-Octadecyl-2-methylsulfonyl-l,3-propanediol- 3-[2-(1-pyridinio)ethyl]phosphate. I.R. (Nujol) : 3350, 1465, 1295 cm 1 (38) (rac)-1-O-Octadecyl-2-phenylthio-l,3-propanediol- 3-[2-(1-pyridinio)ethyl]phosphate. I.R. (Nujol) : 3350, 1630, 1580 cm 1 (39) (rac)-1-O-Octadecyl-2-(1,3,4-thiadiazolyl-2-thio)- 1,3-propanediol-3-[2-(1-pyridinio)ethyl]phosphate. I.R. (Nujol3 : 3350, 1630, 1240 cm 1 (40) (rac)-1-O-Octadecyl-2-chloro-1,3-propanediol-3- [2-(1-pyridinio)ethyl]phosphate. I.R. (Nujol) : 3350, 1240 cm- (41) (rac)-1-O-Octadecyl-2-ethoxycarbonylamino-1,3- propanediol-3-[2-(1-pyridinio)ethyl]phosphate. I.R. (Nujol) : 3470, 1710, 1635, 1240 cm 1 (42) Crac)-1-O-Octadecyl-2-(N'-methylureido).1,3 propanediol-3-[2-(1-pyridinio)ethyl3phosphate. I.R. (Nujol) : 3330, 1635, 1235 cm 1 (43) (rac)-1-O-(Octadec-cis-9-enyl)-2-O-methyl-glycerol- 3-[2-(1-pyridinioZethyl3phosphateO I.R. (Film) : 3350, 3030, 2900, 2820, 1630, 1460, 1230 cm-1

Claims: What is claimed is 1. A compound of the formula: EMI58.1 wherein R1 is alkoxy or alkenyloxy; R2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio thiadiazolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrupted by a -NHCO- group; and EMI58.2 is unsaturated or saturated 5-7 membered heterocyclic group which may contain addi tional N,O or S atoms), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups; provided that 21 is alkoxy having 15 or more carbon atoms when EMI58.3 is a pyridyl group, and pharmaceutically acceptable salt thereof. 2. A comPound of claim 1, wherein EMI58.4 is saturated 5-7 membered heterocyclic group which may contain additional N, O or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy (lower) alkyl groups. 3. A compound of claim 2, wherein R1 is alkoxy; R2 is lower alkoxy or ar(lower)alkoxy; A is lower alkylene: and EMI59.1 is saturated 6 or 7 membered heterocyclic group which may contain additional N or 0 atom(s) and may have 1 to 3 sub stituent(s) elected from the group consisting of lower alkyl, hydroxy and hydroxy (lower) alkyl groups. 4. A compound of claim 3, wherein R2 is lower alkoxy. 5. A compound of claim 4. wherein EMI59.2 is morpholino, piperazinyl, piperidino or homopiperazinyl which may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, hydroxy and hydroxy(lower)alkyl groups. 6. A compound of claim 5, which is (rac)-l-O-octadecyl 2-O-methyl-glycerol-3-[2-(N-methylmorpholinio)ethyl3- phosphate. 7. A compound of claim 5, which is (rac3-l-O-hexadecyl- 2-O-methyl-glycerol-3-[2-(4-methyl-1-piperazinyl)- ethyl3phosphate. 8. A compound of claim 5, which is (rac) -l-O-octadecyl-2-O-methyl-glycerol-3- [2- (4- methyl-l-piperazinyl)ethyl]phosphate. 9. A compound of claim 3, wherein R2 is ar(lower)alkoxy. 10. A compound of claim 9, which is (rac)-l-O-hexadecyl- 2-O-benzyl-glycerol-3-[2-(4-methyl-1-piperazinyl) ethyl3phosphate. 11. A compound of claim 1. wherein EMI60.1 is unsaturated 5-7 membered hetero cyclic group which may contain addi tional N, O or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy (lower) alkyl groups. 12. A compound of claim 11, wherein R1 is alkoxy having 15 or more carbon atoms or alkenyloxy; R2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio thiadiazolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrupted by a a -NHCO- group; and EMI60.2 is unsaturated 5 or 6 membered heterocyclic group which may contain additional N or S atom(s) and may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, halogen, lower alkoxycarbonyl and hydroxy(lower) alkyl groups. 13. A compound of claim 12, wherein R1 is alkoxy having IS or more carbon atoms. 14. A compound of claim 13, wherein R2 is lower alkoxy. 15. A compound of claim 14, which is (rac)-1-O-octadecyl-2-O-methyl-glycerol-3-[2- (l-pyridinio3ethylphosphate. 16. A compound of claim 14, which is (rac)-1-O-octadecyl-2-O-methyl-3-[2-(3-methyl-1- pyridinio)ethyl]phosphate. 17. A compound of claim 14, which is (rac)-l-O-octadecyl-2-O-methyl-glycerol-3-[2-(1- pyridinioacetylamino)ethyl]phosphate. 18. A compound of claim 14, which is (rac)-1-O-octadecyl-2-O-methyl-glycerol-3-[2-(4- methyl-1-pyridinio)ethyl]phosphate. 19. A compound of claim 13, wherein R2 is ar(lower)alkoxy. 20. A compound of claim 19, which is (rac)-l-O-hexadecyl-2-O-benzyl-glycerol-3-[2-(l pyridinjo) ethyl]phosphate. 21. A compound of claim 13, wherein R2 is hydroxy. 22. A compound of claim 21, which is (rac)-l-O-octadecyl-glycerol-3-[2-(1-pyridinio)ethyl] phosphate. 23. A compound of claim 13, wherein R2 is thiadiazolylthio. 24. A compound of claim 23, which is (rac)-l-O-octadecyl-2-(l,3,4-thiadiazol-2-ylthio) - 1,3-propanediol-3-[2-(1-pyridinio)ethylphosphate. 25. A compound of claim 13, wherein R2 is lower alkoxycarbonylamino. 26. A compound of claim 25, which is (rac) -l-O-octadecyl-2-ethoxycarbonylamino-l,3- propanediol-3-[2-(1-pyridinio)ethyl]phosphate. 27. A process for preparing a compound of the formula: EMI62.1 wherein R1 is alkoxy or alkenyloxy; R2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio, thiadiazolylthio, lower alkyl sulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrrupted by a -NHCO- group ; and EMI63.1 is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,O or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower) alkyl groups; provided that R1 is alkoxy having 15 or more carbon atoms when EMI63.2 is a pyridyl group, and pharmaceutically acceptable salt thereof, which comprises (13 by reacting a compound of the formula: EMI63.3 wherein R1, R2 and A are each as defined above, and is an acid residue, or its salt with a compound of the formula: EMI63.4 wherein EMI63.5 is as defined above, or its salt to provide a compound of the formula: EMI63.6 wherein R1, R2, A and EMI64.1 are each as defined above or its salt, or (2) by reacting a compound of the formula: : EMI64.2 wherein R1, R2 and A are each as defined above, and EMI64.3 is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,O or S atom(s), and may have 1 to 2 substituentts) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower) alkyl groups, or its salt with a compound of the formula: X2-R3 (IV) wherein R3 is lower alkyl, and X2 is an acid residue, to provide a compound of the formula: EMI64.4 wherein R , R2, A, R3 and EMI65.1 are each as defined above, or its salt, or (3) by subjecting a compound of the formula: : EMI65.2 wherein R1, A and EMI65.3 are each as defined above, and R4 is a protective group of hydroxy, or its salt to an elimination reaction of the protective group to provide a compound of the formula: EMI65.4 wherein Rl, A and EMI65.5 are each as defined aDove, or its salt, or (4) by reacting a compound of the formula: EMI65.6 wherein R1, R2 and A are each as defined above, or its salt with a compound of the formula: EMI66.1 wherein EMI66.2 is as defined above, or its salt to provide a compound of the formula: EMI66.3 wherein Rl, R2, A and EMI66.4 are each as defined above, or its salt. 28. A pharmaceutical composition comprising an effective amount of a compound of the formula: EMI66.5 wherein R1 is alkoxy or alkenyloxy; R2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio, thiadiazolylthio, lower alkyl sulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrupted by a -NHCO- group; and EMI66.6 is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,O or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups; provided that R1 is alkoxy having 15 or more carbon atoms when EMI67.1 is a pyridyl group, or pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable, substantially nontoxic carrier or excipient. 29. A method for treating cancer which comprises by administering a compound of the formula: EMI67.2 wherein R1 is alkoxy or alkenyloxy; R2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio, thiadiazolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrupted by a -NHCO- group; and EMI67.3 is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,O or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups; provided that R1 is alkoxy having 15 or more carbon atoms when EMI68.1 is a pyridyl group, or pharmaceutically acceptable salt thereof, to human beings.

Inventors: NAMIKI, TAKAYUKI, OKU, TERUO, SHIMAZAKI, NORIHIKO, TERAJI, TSUTOMU, TODO, EISHIRO
Applicants: FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1982
Main classification: C07F9
IPC codes: C07F9, C07C43, C07D285