Patent GB-1177840-A (GB)
Title: 2-Thiopyrimidine Nucleosides
Inventor: SHEN TSUNG-YING
IPC: A61K31/70
Filed: 1967-12-29
Abstract: 1,177,840. 2-Thiopyrimidine nucleosides. MERCK & CO. Inc. 29 Dec., 1967 [3 Jan., 1967], No. 59089/67. Heading C2C. The invention comprises compounds of the general Formula I wherein R is a hydrogen atom or a C 2-6  alkanoyl or a benzoyl radical which may be substituted by nitro, halo or alkoxy groups, R<SP>11</SP> is a hydrogen atom or a methyl radical substituted by one or more phenyl or substituted phenyl groups, or a C 2-6  alkanoyl or a benzoyl radical which may be substituted by nitro, halo or alkoxy groups, Y is OH, SH, NH 2  or NR<SP>3</SP>R<SP>4</SP>, where R<SP>3</SP> and R<SP>4</SP> are hydrogen or lower alkyl C 1-5 , or NHOH and Z is hydrogen, halogen, lower alkyl C 1-5 , halogenated lower alkyl C 1-5  or NR<SP>3</SP>R<SP>4</SP>, where R<SP>3</SP> and R<SP>4</SP> are as defined above. They are prepared by treating a compound of the formula wherein R<SP>1</SP> and Z are as defined above, with hydrogen sulphide in a solvent in the presence of an organic base at a temperature within the range of 95-115 C. 5<SP>1</SP>-O-Trityluridine is prepared by reacting uridine with trityl chloride in the presence of dry pyridine. 5<SP>1</SP>-O-p-nitrobenzoyl-, 5<SP>1</SP>-O-benzoyl and 5<SP>1</SP>-O-acetyl-uridine are prepared analagously using the appropriate alkanoyl chloride. 5<SP>1</SP>-OTrityluridines substituted in the 5-position by -CH 3 , -NHCH 3 , -CF 3 , -F, -Br or I are prepared from the correspondingly substituted uridine and trityl chloride. 2,2<SP>1</SP> - Anhydro - 1 - (5<SP>1</SP> - O - trityl - # - D-arabinefuranosyl) uracil optionally substituted in the 5-position by -CH 3 , -NHCH 3 , -F, -Br or I is prepared by reacting the appropriate 5<SP>1</SP>-O- trityl uridine with thiophosgene in the presence of a base. 1 - (5<SP>1</SP> - O - Trityl - # - D - arabinosyl) - 2 - thiouracil, optionally substituted in the 5-position by -CH 3 , -NHCH 3 , -F, -Br or I is prepared by reacting the corresponding 2,2<SP>1</SP>-anhydro compound above with hydrogen sulphide. 1 - (# - D - Arabinofuranosyl) - 2 - thiouracil, optionally substituted in the 5-position by -CH 3 , -NHCH 3 , -F, -Br or I is prepared by reacting the 5<SP>1</SP>-O-trityl compound above with aqueous acetic acid. The triacetyl (2<SP>1</SP>,3<SP>1</SP>,5<SP>1</SP>) derivatives may subsequently be prepared by reaction with acetic anhydride. 1 - (2<SP>1</SP>,3<SP>1</SP>,5<SP>1</SP> - O - Triacetyl - # - D - arabinofuranosyl)-2,4-dithiouracil optionally substituted in the 5-position by -CH 3 , -NHCH 3 , -CF 3 , F, Br or I is prepared by reacting the appropriate 2-thiouracil with phosphorus pentasulphide. 1 - (# D - Arabinofuranosyl) - 2 - thiocytosine is prepared by reacting 1-(2<SP>1</SP>,3<SP>1</SP>,5<SP>1</SP>-O-triacetyl- # - D - arabinofuranosyl) - 2,4 - thiouracil with anhydrous ammonia. When reacted with hydroxylamine, mono C 1-3  alkylamines and di C 1-2  alkylamines the corresponding 1-(#-D- arabinofuranosyl) - 2 - thio - 4 - hydroxyaminopyrimidine or -4 - mono C 1-3  alkylaminopyrimidines or -di C 1-2  alkylamine pyrimidines are obtained. 2,2<SP>1</SP> - Anhydro - (1 - # - D - arabinofuranosyl)- cytosine (as its imino tautomer) is prepared by treating the 2,4-dithiouracil derivative above with methanolic ammonia, followed by treatment with ethereal HCl to obtain the hydrochloride or by reacting 1- (#-D-arabinofuranosyl)- 2-thio-cytosine with bromine to obtain the hydrobromide. 1 - (# - D - Arabinofuranosyl)cytosine is obtained by reacting the 2,4-dithiouracil derivative above with concentrated ammonium hydroxide. (2,2<SP>1</SP> - Anhydro 1- # - D - arabinofuranosyl) uracil hydrobromide is obtained by reacting 1 - (# - D - arabinofuranosyl) - 2 - thiouracil with bromine. Opthalmic compositions comprising as active ingredient a compound of Formula I, wherein Y is NH 2-  and R<SP>11</SP>, R and Z are as defined above, together with a pharmaceutically acceptable carrier are applied topically. When used as a solution it also contains sufficient salts to be essentially isotonic and have a pH in the range 6À5-7À5.