Patent GB-1390658-A (GB)
Title: Thiazolopyrimidine derivatives
IPC: C07D239/50
Filed: 1972-11-10
Abstract: 1390658 Thiazolo[5,4-d]pyrimidines DR KARL THOMAE GmbH 10 Nov 1972 [11 Nov 1971 5 Oct 1972 (2)] 52050/72 Heading C2C Novel thiazolo[5,4-d]pyrimidines of the general formula wherein R 1  is a hydrogen atom or phenyl or C 1-3  alkyl group and each of R 2  and R 3  is a piperazino or 1,4-diazacycloheptan-1-y1 group optionally substituted at the 4-position by an acyl, carbamoyl, benzyl, C 1-3  alkyl or C 2-3  hydroxyalkyl group, or a morpholino, hexahydro-1,4-oxoazepin-4-yl, thiomorpholino, 1- oxido - thiomorpholino, 1,1 - dioxido - thiomorpholino, hexahydro - 1,4 - thiazepin - 4 - yl, 1 - oxido - hexahydro - 1,4 - thiazepino - 4 - yl, 1,1 - dioxido - hexahydro - 1,4 - thiazepin - 4- yl, N - hydroxyalkylamino, N,N - di(hydroxyalkyl)amino, N - methoxyalkyl - N - hydroxyalkylamino, N - alkyl - N - hydroxyalkylamino, N - alkyl - N - (dihydroxyalkyl)amino, N -cycloalkyl - N - (dihydroxyalkyl)amino, N - hydroxyalkyl - N - (dihydroxyalkyl) - amino or aminoalkylamino group, the C skeleton of each of the above heterocyclic groups being either unsubstituted or substituted by one or two C 1-3  alkyl groups, and acid addition salts thereof are prepared (a) by reacting a thiazolo[5,4-d]pyrimidine of the general formula wherein one of Z 2  and Z 3  is a radical replaceable by an R 2  or R 3  radical upon reaction with an appropriate amine and the other is the same or as R 2  or R 3 , with an amine of the general formula R 2 H or R 3 H; (b) when one of R 2  and R 3  is a 1-oxido-thiomorpholino, 1,1-dioxidothiomorpholino, 1 -oxido-hexahydro- 1 ,4-thiazepin-4-yl or 1,1-dioxido-1,4-thiazepin-4-yl group which is optionally substituted by one or two C 1-3  alkyl groups and the other is not an optionally substituted thiomorpholino or hexahydro-1,4-thiazepin-4-yl group, by oxidizing the corresponding compound of the first general formula above wherein at least one of R 2  and R 3  is a thiomorpholino or hexahydro-1,4-thiazepin-4-yl group, optionally substituted by one or two C 1-3  alkyl groups; (c) when one of R 2  and R 3  is a thiomorpholino or hexahydro-1,4-thiazepin-4-yl group, optionally substituted by one or two C 1-3  alkyl groups and the other is not a group containing an S-oxide radical or a piperazino or 1,4-diazacycloheptan-1-yl group substituted in the 4-position by an acyl or carbamoyl group, by reacting the corresponding compound of the first general formula above wherein at least one of R 2  and R 3  is an S-oxide-containing group with a hydrohalic acid, and (d) by reacting a 5-amino-6-mercaptopyrimidine of the general formula with a carboxylic acid of the general formula R 1 -COOH or an amide thereof; followed optionally by salification of the product with an acid. Thiazolo[5,4 - d]pyrimidines of the second general formula above are prepared (a) when one of Z 2  and Z 3  is a hydrogen atom and the other is as R 2  or R 3 , by reacting the corresponding compound in which each of Z 2  and Z 3  is a halogen atom with an amine of the third or fourth general formula above at a relatively low temperature, (b) when one of Z 2  and Z 3  is an alkoxy, phenoxy or alkylthio group and the other is a halogen atom or as R 2  or R 3 , by reacting the corresponding compound in which at least one of Z 2  and Z 3  is a halogen atom with an alkali metal alkoxide, phenolate or an alkylmercaptide, (c) when one of Z 2  and Z 3  is an alkylsulphinyl or alkylsulphonyl group and the other is a 1-oxido- or 1,1 .dioxido-thiomorpholin-4-yl group, by oxidizing the corresponding compound in which one of Z 2  and Z 3  is an alkylthio group and the other is a thiomorpholino group, (d) when one of Z 2  and Z 3  is an alkoxy group and the other is as R 2  or R 3 , by reacting the corresponding compound in which one of Z 2  and Z 3  is a halogen atom and the other is as R 2  or R 3  with an amine of the third or fourth general formula above and (e) when one of Z 2  and Z 3  is a halogen atom and the other is as R 2  or R 3 , by saponifying the corresponding compound in which one of Z 2  and Z 3  is an alkoxy group and the other is as R 2  or R 3  with an acid and reacting the resulting hydroxy - amino - thiazolo[5,4 - d]pyrimidine with a phosphoryl halide at an elevated temperature. 2 - N - Formylpiperazino - 4 - (1 - oxidothiomorpholino) - 5 - nitro - 6 mercaptopyrimidine is prepared by reacting 2,4,6-trichloropyrimidine with thiomorpholine, reacting the resulting 2,6 - dichloro - 4 - thiomorpholinopyrimidine with N-formylpiperazine, reaching the resulting 2-N- formylpiperazino - 4 - thiomorpholino - 6 -chloropyrimidine with conc. H 2 SO 4 /HNO 3  and reacting the resulting 2 - N - formylpiperazino - 4 - (1- oxidothiomorpholino) - 5 - nitro - 6 - chloropyrimidine with hydrogen sulphide in the presence of sodium. It may be reduced with sodium dithionite to give the corresponding 5-amino derivative or heated in the presence of hydrogen sulphide to give the corresponding 4-thiomorpholino-5-amino derivative. Pharmaceutical compositions having blood pressure-lowering and antithrombotic activity comprise, as active ingredient, a thiazolo[5,4-d]- pyrimidine of the first general formula above or a physiologically compatible acid addition salt thereof, in association with a pharmaceutical carrier or excipient, and may be administered orally, rectally or parenterally.