Patent GB-1460532-A (GB)
Title: Thiazole dardiovascular agents
IPC: A61K31/425
Filed: 1974-03-21
Abstract: 1460532 Thiazole derivatives SYNTEX (USA) Inc 21 March 1974 [22 March 1973 14 March 1974] 12707/74 Addition to 1410511 Heading C2C  The invention comprises compounds of the formula  wherein R<SP>1</SP> and R<SP>2</SP> are H, (C 1 -C 6 ) alkyl, (C 3 - C 7 ) cycloalkyl, (C 2 -C 6 ) alkenyl, aryl, arylalkyl, (C 1 -C 6 ) alkylaryl, hydroxyl(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl- (N-heterocyclic having 5 to 7 ring atoms including one or two N, O or S atoms, at least one of said atoms being N) and groups having the formulae or wherein n is an integer from 1 to 4, and R<SP>11</SP> and R<SP>12</SP> are H or (C 1 -C 6 ) alkyl; or R<SP>1</SP> and R<SP>2</SP> together with the N atom to which they are joined form a nitrogen heterocycle having from five to seven ring atoms having one or two heteroatoms selected from nitrogen, oxygen and sulphur and wherein at least one of said heteroatoms is nitrogen or R<SP>1</SP> and R<SP>2</SP> form a substituted nitrogen heterocycle having from five to seven ring atoms including one or two hetero-atoms selected from nitrogen, oxygen and sulphur and wherein at least one of said heteroatoms is nitrogen and having one or two substituents independently selected from lower alkyl, and hydroxy(lower alkyl); Z is a substituent on the thiazole ring at either the 4- or 5-position selected from the groups having the formulas wherein one of R<SP>3</SP> or R<SP>4</SP> is independently selected from alkyl having from seven to 12 carbon atoms; cycloalkyl having from three to 12 carbon atoms; terminally substituted alkyl group having from two to 12 carbon atoms having one substituted terminal carbon having a substituent selected from hydroxy, acyloxy having from two to 12 carbon atoms and alkoxy having from one to six carbon atoms; and groups having the formulas -(CH 2 ) n+1 NR<SP>8</SP>R<SP>9</SP> or -(CH 2 ) n R<SP>10</SP>, wherein n is an integer of from one to four, R<SP>8</SP> and R<SP>9</SP> are independently selected from hydrogen and alkyl groups having from one to four carbon atoms and R<SP>10</SP> is cycloalkyl having from three to eight carbon atoms; and the other of R<SP>3</SP> or R<SP>4</SP> is selected from hydrogen; alkyl having from one to 12 carbon atoms; cycloalkyl having from three to 12 carbon atoms; phenyl, lower phenylalkyl wherein the alkyl moiety has from one to six carbon atoms, substituted phenyl and substituted lower phenylalkyl wherein said phenyl ring has one or two substituents independently selected from hydroxy, lower alkyl, lower alkoxy and halo; terminally substituted alkyl group having from two to 12 carbon atoms having one substituted terminal carbon atom having a substituent selected from hydroxy, acyloxy having from two to 12 carbon atoms and alkoxy having from one to six carbon atoms; and groups having the formulas -(CH 2 ) n+1 NR<SP>8</SP>R<SP>9</SP> or -(CH 2 ) n R<SP>10</SP> wherein n is an integer of from one to four, R<SP>8</SP> and R<SP>9</SP> are independently selected from hydrogen and alkyl groups having from one to four carbon atoms and R<SP>10</SP> is cycloalkyl having from three to eight carbon atoms; and wherein when one of R<SP>1</SP> or R<SP>2</SP> is the group then R<SP>3</SP> and R<SP>4</SP> can each be independently selected from hydrogen; alkyl having from one to 12 carbon atoms; cycloalkyl having from three to 12 carbon atoms; phenyl, lower phenylalkyl wherein alkyl moiety has from one to six carbon atoms, substituted phenyl and substituted lower phenylalkyl wherein said phenyl ring has one or two substituents independently selected from hydroxy, lower alkyl, lower alkoxy and halo; terminally substituted alkyl group having from two to 12 carbon atoms having one substituted terminal carbon atom having a substituent selected from hydroxy, acyloxy having from two to 12 carbon atoms and alkoxy having from one to six carbon atoms; and groups having the formulas  -(CH 2 ) n+1 NR<SP>8</SP>R<SP>9</SP> or -(CH 2 ) n R<SP>10</SP> wherein n is an integer of from one to four, R<SP>8</SP> and R<SP>9</SP> are independently selected from hydrogen and alkyl groups having from one to four carbon atoms and R<SP>10</SP> is cycloalkyl having from three to eight carbon atoms; with the proviso that when Z is then R<SP>4</SP> is not H; and pharmaceutically acceptable salts thereof. They may be obtained by (1) reacting a compound of the formula with an amino-derivative or N-heterocyclic derivative having the appropriate R<SP>1</SP> and R<SP>2</SP> substituents, or (2) when one of R<SP>1</SP> and R<SP>2</SP> is H by hydrolysing a compound of formula wherein R<SP>5</SP> and R<SP>6</SP> are independently selected from hydrogen, (C 1 -C 6 ) alkyl, arylalkyl or together with the carbon atom to which they are joined form a cycloalkyl having from five to seven carbon atoms; and R<SP>7</SP> is hydrogen, (C 1 -C 6 ) alkyl, aryl or arylalkyl. Therapeutic compositions comprise compounds of Formula I either alone or in combination with other pharmaceutically compatible medicaments together with conventional carriers. In particular the compounds of Formula I may be used in conjunction with the thiazoloxymethylene oxazolidine derivatives which form the subject of Specification 1,460,534.