NEW 3-ALKYLTHIO-2-O-CARBAMOYL-PROPANE-1.2-DIOL-1-O-PHOSPHOCHOLINES, AND PROCESSES FOR THEIR PREPARATION

Abstract: The present invention relates to new 3-alkylthio-2-0-­ carbamoyl-propan-1,2-diol-1-0-phosphocholines of the gen­ eral formula I and processes for their preparation.

Description: The present invention is related to new 3-alkylthio-2-0- carbamoyl-propan-1.2-diol-1-0-phosphocholines and processes for their preparation. The compounds of the invention correspond to the general formula I EMI1.1 wherein R1 signifies a straight chain saturated or unsaturated hydrocarbon residue with 1o to 20 carbon atoms, while R2 and R3 can be the same or different and signify a straight or branched chain, saturated or unsaturated hydrobarbon residue with 1 to 20 carbon atoms, phenyl, phenyl mono substituted by C1-3 alkyl, r 1-3 alkoxy, halogen or tri- fluoromethyl, or signify benzyl or hydrogen. Compounds of the invention are for example: 3-Hexadecylthio-2-0-methylcarbamoyl-propan-1.2-diol-1- O-phosphocholine, 2-0-Qthylcarbamoyl-3-hexadecylthio-propan-1.2-diol-1- O-phosphocholine, -3-hexadecylthio-2-0-p-ropylcarbamoyl-propan-1.2-djol-1- O-phosphocholine, 3-hexadecylthio-2-0-isopropylcarbamoyl-propan-1.2-diol-1-0- phosphocholine, 2-0-butylcarbamoyl-3-hexadecylthio-propan-1.2-diol-1 O-phosphocholine, 3-hexadecylthio-2-Q-pentylcarbamoyl-propan-1.2-djo O-phosphocholine, 3-hexadecylthio-2-0-hexylcarbamoyl-propan-1.2-diol-1- O-phosphocholine, 2-O-methylcarbamoyl-3-octadecylthio-propan-1,2-diol-1 O-phosphocholine, 2-0-ethylcarbamoyl-3-octadecylthio-propan-1.2-diol-1 O-phosphocholine, 3-octadecylthio-2-0-propylcarbamoyl-propan-1.2-diol-1 O-phosphocholine, 2-0-isopropylcarbamoyl-3-octadecylthio-propan-1.2-diol-1-0 phosphochol ine, 2-0-butylcarbamoyl-3-octadecylthio-propan-1.2-diol-1- O-phosphocholine, 3-octadecylthio-2-0-pentylcarbamoyl-propan-12-diol-1- O-phosphocholine, 2-0-heXylcarbamoyl-3-octadecylthio-propan-1.2-diol-1- O-phosphocholine, 2-0-methylcarbamoyl-3-oleylthio-propan-1.2-diol-1-0- phosphochol ine, 2-O-éthylcarbamoyl-3-linoleylthio-propan-1,2-diol-1-Ophosphocholine. 2-0-dimethylcarbamoyl-3-octadecylthio-propan-1.2-diol 1-O-phosphocholine, 2-0-dimethylcÅarbamoyl-3-hexadecylthio-propan-1.2-diol- l-0-phosphocholine, 2-0-decylcarbamoyl-3-hexadecylthio-propan-1.2-diol-1 O-phosphocholine, 3-hexadecylthio-2-0-undecylcarbamoyl-propan-1.2-diol 1-O-phosphocholine, 2-0-dodecylcarbamoyl-3-hexadecylthio-propan-1s2-diol- 1-O-phosphocholine, 3-hexadecylthio-2-0-tetradecylcarbamoyl-propan-1.2-diol- 1-O-phosphocholine, 2-0-hexadecylcarbamoyl-3-hexadecylthio-propan-1.2-diol-1-0- phosphochol ine, 3-hexadecylthio-2-0-octadecylcarbamoyl-propan-1.2-diol-1-0- phosphochol ine, 2-0-eicosylcarbamoyl-3-hexadecylthio-propan-1.2-diol-1-0- phosphocholine, 2-O-decylcarbamoyl-3-octadecylthio-propen-1,2-ciol-1-O phosphochol ine, 3-octadecylthio-2-0-undecylcarbamoyl-propan-1.2-diol-1-0 phosphochol ine, 2-0-dodecylcarbamoyl-3-octadecylthio-propan-1.2-diol-1-0 phosphochol ine, 3-octadecylthio-2-o-tetradecylcarbamoyl-propan-1,2-diol-q O-phosphocholine, 2-0-hexadecylcarbamoyl-3-octadecylthio-propan-1.2-diol-1-0 phosphochol ine, 2-0-octadecylcarbamoyl-3-octadecylthio-propan-142-diol-1-0- phosphocholine, 2-O-éfcosylcarbamoyl-3-octedecylthio-propan-1,2-diol-1-O phosphocholine, 3-hexadecyl thio-2-0-phenyl carbamoylpropan-1q2-diol-1-0 phosphochol ine, 2-0-(2-Eluorophenyl)-carbamoyl-3-hexadecylthio-propan-1.2- diol-1-O-phosphocholine, 2-0-(3-fluorophenyl)-carbamoyl-3-hexadecylthio-propan-1.2 diol-1-0-phosphocholine, 2-0-(4-fluorophenyl )-carbamoyl-3-hexadecylthio-propan-1.2 diol-1-0-phosphocholine, 2-0-(2-chlorophenyl)-carbamoyl-3-hexadecylthio-propan-1.2 diol-1-0-phosphochol ine, 2-0-(3-chlorophenyl)-carbamoyl-3-hexadecylthio-propan-1.2 diol-1-0-phosphochol ine, ¯-2-0-(4-chlorophenyl)-carbamoyl-3-hexadecylthio-propan-1.2- diol-1-0-phosphochol ine, 2-0-(4-bromophenyl)-carbamoyl-3-hexadecylthio-propan-1.2 diol-1-0-phosphocholine, 3-hexadecylthio-2-0-(2-methylphenyl)-carbamoyl-propan-1.2 diol-l-0-phosphochol ine, 3-hexadecylthio-2-O-(3-methylphenyl)-carbamoyl-propan-1,2 diol-1-0-phosphocholine, 3-hexadecylthio-2-0-(4-methylphenyl)-carbamoyl-propan-1.2- diol-1-0-phosphochol ine, 3-hexadecylthio-2-O-(2-methoxyphenyl)-carbamoyl-propen-1,2 diol-l-0-phosphochol ine, 3-hexadecylthio-2-0-(4-methoxyphenyl)-carbamoyl-propan-1.2 diol-1-0-phosphochol ine, 2-0-(2-othoxyphenyl)-carbamoyl-3-hexadecylthio-propan-1.2- diol-l-0-phosphochol ine, 2-O-(4-ethoxyphenyl)-carbamoyl-3-hexadecylthio-propan-1,2 diol-l-0-phosphocholine, 3-hexadecylthio-2-0-(2-trifluoromethylphenyl)-carbamoyl propan-12-diol-1-0-phosphocholine, 3-hexadecylthio-2-0-(3-trifluoromethylphenyl)-carbamoyl propan-1,2-diol-1-O-phosphocholine. 3-Oleylthio-2-0-phenylcarbamoyl-propan-1.2-diol-1-0- phosphochol ine, 3-linoleylthio-2-0-phenylcarbamoyl-propan-1.2-diol-1-0 phosphochol ine, 3-octadecylthio-2-O-phenylcarbamoyl-propan-1,2-diol-1-O phosphochol ine, 2-0-(2-Eluorophenyl)-carbamoyl-3-octadecylthio-propan-1.2- diol-1-0-phosphochol ine, 2-0-(3-fluorophenyl )-carbamoyl-3-octadecy0thio-propan-1 .2- diol-1-0-phosphochol ine, 2-O-(4-fluorophenyl)-carbamoyl-3-octadecylthio-propan-1,2 diol-1-0-phosphochol ine, 2-0-(2-chlorophenyl)-carbamoyl-3-octadecylthio-propan-1X2- diol-1-O-phosphocholine, 2-O-(3-chlorophenyl)-carbamoyl-3-octadecylthio-propen-1,2 diol-1-0-phosphochol ine, 2-0-(4-chlorophenyl)-carbamoyl-3-octadecylthio-propan-1.2 diol-1-0-phosphochol ine, 2-O-(4-bromophenyl)-carbamoyl-3-octadecylthio-propan-1,2diol-1-O-phosphocholine, 2-0-(2-methylphenyl)-carbamoyl-3-octadecylthio-propan-1.2 diol-1-0-phosphochol ine, 2-O-(3-methylphenyl)-carbamoyl-3-octadecylthio-propan-1,2diol-1-O-phosphocholine, 2-0-(4-methylphenyl)-carbamoyl-3-octadecylthio-propan-1.2diol-l-0-phosphocholine, 2-0-(2-methoxyphenyl )-carbamoyl-3-octadecylthio-propan12 diol-l-0-phosphocholine, 2-0-(4-methoxyphenyl)-carbamoyl-3-octadecylthio-propan 1.2-diol-1-0-phosphochol ine, 2-0-(2-ethoxyphenyl)-carbamoyl-3-octadecylthio-propan-1.2 diol-1-0-phosphochol ine, 2-O-(4-ethoxyphenyl)-carbamoyl-3-octadecylthfo-propan-1,2 diol-1-0-phosphocholine, 3-octadecylthio-2-0-(2-trifluoromethylphenyl)-carbamoylpropan-1,2-diol-1-O-phosphotholine, 3-octadecylthio-2-0-(3-trifluoromethylphenyl)-carbamoylpropan-1,2-diol-1-O-phosphocholine, 2-O-benzylcarbamoyl-3-octadecylthio-propan-1,2-diol-1-O phosphochol ine, 2-O-benzylcarbamoyl-3-hexadecylthio-propan-1,2-diol-1-O phosphochol ine. The compounds of the invention possess valuable pharmacological properties and are thus suitable for use as active ingredients in medicaments. Of the substances of the invention listed, some, e.g. 3-hexadecySthio-2-O-methyScarbamoyl-propan-1.2-diG1-l-O- phosphocholine, or 2-O-ethylcarbamoyl-3-octadecylthio- propan-1.2-diol-l-O-phosphocholine, are particularly preferred. The said compounds can be used for the treatment of high blood pressure, various rheumatic and some atherosclerotic conditions as well as for tumour therapy in humans. The compounds of formula I are administcred in the form of pharmaceutical preparations for enteral, oral, rectal as well as parenteral administration, and they contain the pharmaceutical active ingredients alone or together with a conventional pharmaceutically usable carrier material. Advantageously the pharmaceutical presentation of the active ingredient is in the form of single doses, which are adapted to the desired mode of administration, e.g. tablets, dragees, capsules, suppositories, granulates, solutions, emulsions or suspensions. The dosage of the compounds of formula I lies normally between 1 and looo mg. per dose, preferably between 1 to 10 mg. per dose, and can be administered once or oftener, preferably 2 to 3 times daily. Also preferred are compounds, e.g. 3-hexadecylthio-2-Ohexadecylcarbamoyl-propan-1. 2-diol-1-O-phosphocholine, which possess clear advantages compared with the natural or synthetic 1.2-diacyl-glycero-3-phosphocholines (erg. GB-PS 1,523,965) previously used in liposome technology, since they in contrast to the latter phospholipids, are resistant to phospholipase A2 and thus permit better transfer of the included active ingredient at the site of their - effect. The invented substances of the formula I in which R2 = H are prepared by reaction of the lyso-compounds II, wherein R1 has the meaning given in formula I, with the corresponding alkyl or aryl isocyanates of the formula III. EMI7.1 The reaction is usefully carried out in organic aprotic solvents e.g chloroform, acetone, dimethylformamide or mixtures thereof, with optional use of a catalyst, especially a Lewis base, e.g. triethylamine, pyridine, dimethylaminopyridine, dimethylformamide, at temperatures -between 0 and 100"C; preferably 400 to 600 C. As starting compounds of the formula II there may be mentioned: 3-Decylthio-propan-1,2-diol-1-O-phosphocholine, 3-undecylthio-propan-1.2-diol-1-0-phosphocholine, 3-dodecylthio-propan-1 .2-diol-1-0-phosphochol ine, 3-tridecylthio-propan-1 .2-diol-1-0-phosphochol ine, 3-tetradecylthio-propan-1,2-diol-1-O-phosphocholine, 3-pentadecylthio-propan-1.2-diol-1-0-phosphocholine, 3-hexadecylthio-propan-1.2-diol-1-0-phosphocholine, 3-heptadecylthic-propan-1,2-diol-1-O-phosphocholine, 3-octedecylthio-propan-1,2-diol-1-O-phosphocholine, 3-nonadecylthio-propan-12-diol -1-0-phosphochol ine, 3-ei-cosylthio-propan-1+2-diol-1-0-phosphocholine, 3-oleylthio-propan-1.2-diol-1-0-phosphochol ine, 3-1inoleylthio-propan-1.2-dlol-1-O-phosphocholine, and the lyso-compounds can be used in their R- or S-form or as a racemic mixture. As starting compounds of formula III there may be mentioned: methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, allyl isocyanate, butyl isocyanate, pentyl isocyanate, hexyl isocyanate, decyl isocyanate, undecyl isocyanate, dodecyl isocyanate, tridecyl iso cyanatej tetradecyl isocyanate, pentadecyl isocyanate, hexadecyl isocyanate, octadecyl isocyanate, nonadecyl isocyanate, eicosyl isocyanate, oleyl isocyanate, linoleyl isocyanate, phenyl isocyanate, 2-fluorophenyf isocyanate, 3-fluorophenyl isocyanate, 4-fluorophenyl isocyanate, 2-chlorophenyl isocyanate, 3-chlorophenyl isocyanate, 4-chlorphenyl isocyanate, 4-bromophenyl isocyanate, 2-methylphenyl isocyanate, 3-methylphenyl isocyanate, 4-methylphenyl isocyanate, 2-methoxyphenyl isocyanate, 4-methoxyphenyl isocyanate, 2-ethoxyphenyl isocyanate, 4-ethoxyphenyl isocyanate, 2-(trifluoromethyl)-phenyl isocyanate, 3-(trifluoromethyl)-phenyl isocyanate, benzyl i socyan ate. The 3-alkylthiopropan-1 .2-diol-1-0-phosphocholines of the formula II used as starting compounds can be synthesized from the corresponding 2-0-acyl-3-alkylthio-propan-1,2 diol-1-0-phosphocholines by conventional procedures, e.. by enzymatic splitting (Phospholipase A2) or mild alkaline hydrolysis. The 3- alkylthio-2-O-dialkylcarbamoyl-propan-1,2-diol-1-0 phosphocholines of the formula I can be synthesized from the said lyso-compounds II by reaction with dialkyl carbamic acid halides, especially with chlorides of the formula IV EMI9.1 such as N,N-dimethylcarbamic acid chloride, N-ethyl-N-methylcarbamic acid chloride, N,N-diethylcarbamic acid chloride, N-methyl-N-propylcarbamic acid chloride, N,N-dipropylcarbamic acid chloride, in inert organic solvents, e.g. chloroform, as well as solvent mixtures, with optional addition of conventional bases, e.g. tertiary amines, metal oxides, metal carbonates. The preparation of the compounds of the invention is described in greater detail by the following examples. The melting points were measured with a Buechi 510 melting point determination apparatus and are uncorrected. Example 1 3-Mexadecylthio-2-o-methylcarbamoyl-propan-1,2-diol-1-Ophosphocholine. a) 13-Bromoethyl- (3-hexadecylthio-2-hydroxypropyl) -phosphate. A mixture of 30 g of hexadecylthio-propan-1.2-diol and 300 ml of dry chloroform is cooled to OOC and a solution of 21.6 g of 6-bromoethylphosphoric acid dichloride in 25 ml of chloroform and a solution of 7.2 ml of pyridine in 25 ml of chloroform are simultaneously and slowly added dropwise to the mixture with stirring. After half an hour of further stirring another 7.2 ml of pyridine is added and the mixture is stirred for 12 hours at room temperature and, following addition of ice water, stirred for a further hour. The organic phase is separated, washed neutral ith water and sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is purified by column chromatography (silica gel//chloroform/methanol). Yield: 11.9 g. Mp: 197 to 1980 C. b) ss-Bromoethyl-(2-acetyloxy-3-hexadacylthiopropyl)-phosphate. 14 6 - g of B-bromoethyl- (3-hexadecylthio-2-hydroxy-propyl) phosphate is dissolved in loo ml of dry chloroform and the solution is treated with 7 ml of pyridine and 8.2 ml of acetic anhydride. After stirring at room temperature for 48 hours a little water is added and stirring continued for 15 minutes. The mixture is evaporated in vacuo and the residue is purified by column chromatography (silica gel//chloro form/methanol). Yield: 5.1 g. Mp: > 630C. c) 2-0-Acetyl-3-hexadecylthio-propan-1 .2-diol-1-0-phospho- choline. 1.8 g of ss-bromoethyl-(2-acetyloxy-3-hexadecylthiopropyl)- phosphate is dissolved in 3 ml of toluene, the solution is treated with 3 ml of a 20 % solution of trimethylainine in toluene and stirred for 3 hours at 60 C in a closed vessel. The reaction mixture is evaporated in vacuo and the residue purified by column chromatography (silica gel//chloroform/ methanol/water = 80/20/2, 40/20/2, 20/20/2 (v/v/v)). Field : 0.9 g. Mp : 246 to 249 C (dec). d) 3-Hexadecylthio-propan-1,2-diol-1-O-phosphocholine, 0.8 g of 2-O-acetyl-3-hexadecylthio-propan-1,2-diol-1-O- phosphocholine are dissolved in 15 ml of ethanol and 0.2 g of powdered potassium carbonate is added. After stirring for 48 hours, the salts are filtered off and washed with chloroform, the combined filtrates evaporated in vacuo and the residue purified by column chromatography (silica gel// chloroforn/methanol/water = 80/20/2, 50/20/2, 50/20/2, 40/20/2, 30/20/2, 20/20/2 (v/v/v)). Yield: o.4 g. Mp: 252 to 254 C. e) 3-Hexadecylthio-2-0-methylcarbamoyl-propan-1.2-diol-1-0- phosphocholine. 0.17 g of 3-hexadecylthio-propan-1,2-diol-1-O-phospho- choline is dissolved in lo ml of dry chloroform and l ml of dimethyl formamide, and 2 ml of methyl isocyanate is added. After stirring for 48 hours at 4o0C, the solution is evaporated in vacuo and the residue purified by column chromatography (silica gel//chloroform/methanol/water = 80/20/2, So/20/2, 40/20/2, 20/20/2 (V/V/V)). Yield: o.14 g. Np. 252 to 254 C. Example 2 2-O-Ethylcarbamoyl-3-hcxadecylthio-propa phosphocholine. 0.17 g of 3-hexadecylthio-propan-1,2-diol-1-O-phospho- choline are dissolved in 10 ml of dry chloroform, and 1 ml of dimethylformamide and 1 ml of ethyl isocyanate is added. After stirring for 48 hours at 4o0C, the solution is evaporated in vacuo and the residue purified by column chromatography (silica gel//chloroform/methanol/water = 80/20/2, 60/20/2, 40/20/2, 20/20/2 (V/V/V)). Yield: 0.15 g. Mp: 250 to 252 C. The following are prepared in a manner similar to examples 1 and 2: 3-Hexadecylthio-2-O-propylcarbamoyl-propan-1,2-diol-1-O phosphochol ine, 3-hexadecylthio-2-O-isopropylcarbamoyl-propan-1,2-diol-1-O phosphochol ine, 2-O-butylcarbamoyl-3-hexadecylthio-propan-1,2-diol-1-O phosphochol ine, 3-hexadecylthio-2-O-pentylcarbamoyl-propan-1,2-diol-1-O phosphochol ine, 3-hexadecylthio-2-O-hexylcarbamoyl-propan-1,2-diol-1-O phosphochol ine, 2-O-methylcarbamoyl-3-octadecylthio-propan-1,2-diol-1-O phosphochol ine, 2-0-ethylcarbamoyl-3-octadecylthio-propan-1.2-diol-1-0- phosphochol ine, 3-octadecylthio-2-0-propylcarhamoyl-propan-1.2-diol-1-0 phosphochol ine, 2-O-isopropylcarbamoyl-3-octadecylthio-propan-1,2-diol-1-O phosphochol ine, 2-O-butylcarbamoyl-3-octadecylthio-propan-1,2-diol-1-Ophosphocholine, 3-octadecylthio-2-0-pentylcarbamoyl-propan-1.2-diol-1-0 phosphochol ine, 2-0-hexylcarbamoyl-3-octadecylthio-propan-1 .2-diol-1-0- phosphochol ine, 3-linoleylthio-2-0-methyl carbamoyl-propan-1 02-diol-1-0- phosphochol ine, 2-0-ethylcarbamoyl-3-linoleylthio-propan-1.2-diol-1-0 phosphochol ine, 3-1inoleylthio-2-0-propylcarbamoyl-propan-1.2-diol-1-0- phosphochol ine, 2-0-butylcarbamoy-3-linoleylthio-propan-1.2-diol-1-0 phosphochol ine, 3-linoleylthio-2-0-pentylcarbamoyl-propan-1.2-diol-1-0- phosphochol ine, 2-O-hexylcarbamoyl-3-linoleylthio-propan-1,2-diol-1-O phosphochol ine, 2-0-methylcarbamoyl-3-oleylthio-propan-1.2-diol-1-0- phosphochol ine, 2-0-ethylcarbamoyl-3-oleylthio-propan-1.2-diol-1-0-phospho choline, 3-oleylthio-2-O-propylcarbamoyl-propan-1,2-diol-1-O phosphochol ine, 3-oleylthio-2-O-propylcarbamoyl-propan-1,2-diol-1-O choline, 3-oleylthio-2-0-pentylcarbamoyl-propan-1.2-diol-1-0- phosphochol ine, 2-0-hexylcarbamoyl-3-oleylthio-propan1 .2-diol-1-0-phospho- choline. Example 3 2-0-Hexadecylcarbamoyl- 1 -hexadecylthio-propan- 1. 2-diol- 1 -0-phosphocholine. A mixture of 100 mg of 2-O-hexadecylcarbamoyl-1-hexadecyl- thio-oropan-1,2-diol-1-O-phosphocholine, 200 ing. of hexa- -decyl isocyanate, -10 ml of chloroform and 1 ml of dimethyl formamide is stirred at 6o0C (48 hours). The excess alkyl isocyanate is hydrolyzed by addition of a little water and the mixture is substantially evaporated in vacuo. The residue is purified by column chromatography (silica gel// chloroform/methanol/water). Yield : 93 mg. MP : 220 to 225 C. The following are prepared by analogous methods: 3-Hexadecylthio-2-O-octadecylcarbamoyl-propan-1,2-diol-1-O -phosphocholine, 2-o-hexadecylcarbamoyl-3-octadecylthio-propan-l.2-d phosphochol ine, 3-octadecylthio-2-O-octadecylcarbamoyl-propan-1,2-diol-1-O phosphochol ine, 2-O-decylcarbamoyl-3-hexadecylthio-propan-1,2-diol-1-O phosphochol ine, 3-hexadecylthio-2-0-undecylcarbamoyl-propan-1.2-diol-1-0- phosphochol ine, 2-0-dodecyl carbamoyl -3-hexadecylthio-propan-1 .2-diol -1-0- phosphochol ine, 3-hexadecylthio-2-O-tetradecylcarbamoyl-propan-1,2-diol-1 0-phbsphochol ine, 2-0-eicosylcarbamoyl-3-hexadecylthio-propan-1.2-diol-1-0- phosphochol ine, 2-0-decylcarbamoyl-3-octadecylthio-propan-1 .2-diol -1-0- phosphocholine, 3-octadecylthio-2-0-undecylcarbamoyl-propan-1*2-diol-1-0- phosphochol ine, 2-0-dodecylcarbamoyl-3-octadecylthio-propan-1.2-diol-1-0- phosphochol ine, 3-octadecylthio-2-O-tetradecylcarbamoyl-propan-1,2-diol-1 O-phosphocholine, 2-O-eisosylcarbamoyl-3-octadecylthio-propan-1,2-diol-1-O phosphochol ine, 3-octadecylthio-2-O-oleylcarbamoyl-propan-1,2-diol-1-O phosphocholine, 2-O-linoleylcarbamoyl-3-octadecylthio-propan-1,2-diol-1-O phosphocholine, 3-hexadecylthio-2-O-oleylcarbamoyl-propan-1,2-diol-1-O phosphochol ine, 3-hexadecylthio-2-0-l inoleylcarbamoyl-propan-1 .2-diol-1-0 phosphochol ine, 2-O-oleylcarbamoyl-3-oleylthio-propan-1,2-diol-1-O-phesphocholine, 3-hexadecylthio-2-O-phenylcarbamoyl-1,2-diol-1-O-phosphocholine, 2-O-(2-fluorophenyl)-carbamoyl-3-hexadecylthio-propan-1,2 diol-1-0-phosphochol ine, 2-0-(3-fluorophenyl)-carbamoyl-3-hexadecylthio-propan-1.2 diol-1-0-phosphochol ine, 2-0-(4-fluorophenyl )-carbamoyl-3-hexadecylthio-propan-1.2- diol-1-0-phosphochol ine, 2-O-(2-chlorophenyl)-carbamoyl-3-hexadecylthio-propan-1,2 diol-1-0-phosphocholine, 2-O-(3-chlorophenyl)-carbamoyl-3-hexadecylthio-propan-1,2 diol-1-0-phosphochol ine, 2-O-(4-chlorophenyl)-carbamoyl-3-hexadecylthio-propan-1,2 diol-1-0-phosphochol ine, 2-0-(4-bromophenyl)-carbamoyl-3-hexadecylthio-propan-1.2 diol-1-0-phosphochol ine, 3-hexadecylthio-2-0-(2-methylphenyl)-carbamoyl-propan-1.2- diol-1-0-phosphochol ine, 3-hexadecylthio-2-O-(3-methylphenyl)-carbamoyl-propan-1,2 diol-1-0-phosphochol ine, 3-hexadecylthio-2-O-(4-methylphenyl)-carbamoyl-propan-1,2 diol-1-0-phosphochol ine, 3-hexadecylthio-2-0-(2-methoxyphenyl)-carbamoyl-propan-1.2 diol-1-0-phosphochol ine, 3-hexadecylthio-2-0-(4-methylphenyl)-carbamoyl-propan diol-1-0-phosphochol ine, 2-0-(2-ethoxyphenyl)-carbamoyl-3-hexadecylbhio-propan-1.2- diol-1-0-phosphochol ine, 2-O-(4-et hoxyphenyl)-carbamoyl-3-hexadecylthio-propan-1,2 diol-1-0-phosphochol ine, 3-hexadecylthio-2-0-(2-trifluoromethylphenyl)-carbamoyl- propan-1,2-diol-1-O-phosphocholine, 3-hexadecylthio-2-0-(3-trifluoromethylphenyl)-carbamoylpropan-1,2-diol-1-O-phosphocholine, 3-oleylthio-2-0-phenylcarbamoyl-propan-1.2-diol-1-0- phosphochol ine, 3-linoleylthio-2-O-phenylcarbamoyl-propan-1,2-diol-1-O phosphochol ine, 3-octadecylthio-2-0-phenylcarbamoyl-propan-1.2-diol-1-0 phosphochol ine, 2-O-(2-fluorophenyl)-carbamoyl-3-octadecylthio-propan-1,2 diol-1-0-phosphochol ine, 2-O-(3-fluorophenyl)-carbamoyl-3-octadecylthio-propan-1,2 diol-1-0-phosphochol ine, 2-O-(4-fluorophenyl)-carbamoyl-3-octadecylthio-propan-1,2 diol-1-0-phosphochol ine, 2-O-(2-chlorophenyl)-carbamoyl-3-octadecylthio-propan-1,2 diol-1-0-phosphochol ine, 2-O-(3-chlorophenyl)-carbamoyl-3-octadecylthio-propan-1,2 <RTI ID=16.8> diol-1-0-phosphochol ine, 2-O-(4-chlorophenyl)-carbamoyl-3-octadecylthio-propan-1,2 diol-1-0-phosphochol ine, 2-0-(4-bromophenyl)-carbamoyl-3-octadecylthio-propan-1.2- diol-1-O-phosphocholine, 2-0-(2-methylphenyl)-carbamoyl-3-octadecylthio-propan-1.2- diol-1-O-phosphocholine, 2-0-(3-methylphenyl)-carbamoyl-3-octadecylthio-propan-1.2- diol-1-0-phosphocholine, 2-0-(4-methyl phenyl )-carbamoyl-3-octadecylthio-propan-1.2diol-1-0-phosphocholine, 2-0-(2-methoxyphenyl ) -carbamoyl -3-octadecyithio-propan-1.2- dioi-1-0-phosphochoi ine, 2-0-(4-methoxyphenyl)-carbamoyl-3-octadecylthio-propan-1.2- diol-1-0-phosphocholine, 2-0-(2-ethoxyphenyl)-carbamoyl-3-octadecylthio-propan-1.2- diol-1-O-phosphocholine, 2-0-(4-ethoxyphenyl)-carbamoyt-3-octadecylthlo-propan-1.2- diol-1-0-phosphocholine, 3-octadecylthio-2-O-(2-trifluoromethylphenyl)-carbamoylpropan-1,2-diol-1-O-phosphocholine, 3-octadecylthio-2-0-(3-trifluoromethylphenyl)-carbamoylpropan-1,2-diol-1-O-phosphocholine, 2-0-benzylcarbamoyl-3-hexadecylthio-propan-1,2-diol-1-0- phosphocholine, 2-O-benzylcarbamoyl-3-octadecylthio-propan-1,2-diol-1-O phosphochol ine, Example 4 2-O-Dimethylcarbamoyl-3-hexadecylthio-propan-1,2-diol-1-Ophosphocholine. A mixture of 100 mg of 3-hexadecylthio-propan-1,2-diol 1-0-phosphocholine, 40 mg of dimethyl carbamic acid chloride and 60 mg of silver carbonate in 10 ml of chloroform is stirred for 24 hours at 50 C, the solvent taken off in vacuo and-the residue purified by column chromatography (silica. gel//chloroform/methanol/water). Yield: 83 mg. Np: 239 to 241 C. The following are prepared in a similar manner to example 4: 2-0-Dimethylcarbamoyl-3-octadecylthio-propan-1.2-diol-1-0 phosphochol ine, 2-0-dimethylcarbamoyl-3-eicosylthio-propan-1.2-diol-1-0- phosphochol ine.

Claims: PATENT CLAIMS: 1. 3-Alkylthio-2-O-carbamoyl-propan-1,2-diol-1-Ophosphocholines of the general formula I EMI18.1 wherein R1 is a member selected from the group consisting of the straight chain saturated and the straight chain unsaturated hydrocarbon residues with 10 to 20 carbon atoms, and R2 and R3 which may be the same or different from each other, are members selected from the group consisting of the straight chain saturated, the straight chain unsaturated, the branched chain saturated, and the branched chain unsaturated hydrocarbon residues with 1 to 20 carbon atoms, the unsubstituted phenyl group, the phenyl group mono-substituted by C1 3-alky1, C1 3-alkoxy, halogen or trifluoromethyl, the benzyl group and hydrogen. 2. 3-Alkylthio-2-O-carbamoyl-propan- 1.2-diol-l -O-phospho- cholines as claimed in claim 1, wherein R2 and R3 which maybe the same or different from each other, are members selected from the group consisting of the straight chain saturated, the straight chain unsaturated, the branched chain saturated, and the branched chain unsaturated hydro carbon residues with 1 to 10 carbon atoms, the unsubstituted phenyl group, the phenyl group mono-substituted by methyl, methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl, the benzyl group and hydrogen. 3. 3-Alkylthio-2-0-carbamoyl-propan- 1 .2-d iol- 1 -0-phospho- cholines according to claim 1 wherein R1 is a member selec ted from the group consisting of the straight chain satu rated hydrocarbon residues with 16, 18 or 20 carbon atoms, and R2 and R3 which maybe be the same or different from each other, are members selected from the group consisting of the methyl, ethyl and isopropyl residues and hydrogen. 4. 3-A1kySthio-2-0-carbamoy1-propan-l2-dio1-1-0-phospho- cholines as claimed in claim l, wherein R1 is a member selected from the group consisting of the straight chain saturated and straight chain unsaturated hydrocarbon resi dues with 10 to 20 carbon atoms, R2is a hydrogen atom, and R3 is a member selected from the group consisting of the straight chain saturated and the straight chain, unsaturated hydrocarbon residues with 10 to 20 carbon atoms, R1 and R3 being the same or different. 5. 3-Alkylthio-2-0-carbamoyl-propan-142-diol- 1 -0-phospho- cholines as claimed in claim 4, wherein R1 is a member selected from the group consisting of the straight chain saturated hydrocarbon residues with 16 or 18 carbon atoms, R2 is a hydrogen atom, and R3 is a member selected from the group consisting of the straight chain saturated hydro carbon residue with 16 or 18 carbon atoms, R1 and R3 being the same or different. 6. Process for the preparation of compounds of the formula I according to claims l to 5 wherein a lysocompound of the general formula II EMI20.1 wherein R1 has the meaning given in formula I of claim 1, is reacted in an aprotic organic solvent with optional addition of a Lewis base as catalyst, with an isocyanate of the formula III R3-N=C=O III wherein R3 has the meaning given in formula I in claim 1. 7. Process for the preparation of compounds of the formula I according to claims 1 to 5 wherein a lysocompound of the formula II is reacted in an inert organic solvent with optional addition of an acid acceptor, with the corresponding carbamic acid chlorides of the formula IV EMI20.2 wherein R2 and R3 have the same meaning as given in formula I of claim 1.

Inventors: BETZING, HANS, DR., LAUTENSCHLAGER, HANS-HEINER, DR., WINKELMANN, JOHANNES, DR., Lautenschläger, Hans-Heiner, Dr.
Applicants: A. NATTERMANN & CIE. GMBH
Application year: 1984
Main classification: C07F9
IPC codes: C07F9