Patent GB-1411767-A (GB)
Title: Triazoloquinazolines
IPC: C07D487/04
Filed: 1972-12-13
Abstract: 1411767 Triazoloquinazolines SANDOZ Ltd 13 Dec 1972 [17 Dec 1971] 57419/72 Heading C2C Triazoloquinazolines of the general formula wherein one of P and Q is a nitrogen atom and the other is a group in which R 2  is hydrogen atom or a C 1-4  alkyl group, either (a) n is 0, 1, 2 or 3 and R is F, Cl or Br or a C 1-3  alkyl, C 1-3  alkoxy, nitro or trifluoromethyl group, provided that (i) when n is 2 or 3, the radicals R are the same or different, (ii) when n is 2 or 3, each R is other than a nitro or trifluoromethyl group and (iii) when n is 3, each R is a C 1-3  alkoxy group, or (b) n is 2 and the radicals R are located on adjacent carbon atoms and together form a methylenedioxy group and either (c) R 1  is a -OR 3  group in which R 3  is a C 1-6  alkyl, allyl, methylallyl or propargyl group, a -ZNR 4 R 5  group in which Z is a straight or branched chain C 1-4  alkylene group and each of R 4  and R 5  is a C 1-3  alkyl group, or a group of the formula wherein m is 0, 1, 2 or 3 and p is 2, 3, 4 or 5, or (d) R 1  is a -NR 6 R 7  group in which either (e) R 6  is a hydrogen atom and R 7  is a hydrogen atom, a C 1-5  alkyl, C 1-4  alkoxy-C 1-4  alkyl, allyl, methylallyl, propargyl or C 3-6  cycloalkyl group or a -ZNR 4 R 5  group, or (f) R 6  and R 7 , together with the N atom to which they are attached, form a di-C 1-3  alkylamino, diallylamino, di(methylallyl)amino or dipropargyl group or a group of the formula in which X is a direct bond, -CH 2 -, -O- or =NR 8 , in which R 8  is a hydrogen atom or a C 1-3  alkyl group, and x and y are 0 or 1, provided that X is a direct bond when x or y is 0, provided that when Q is a N atom and P is a =CH- group, then R 1  is a -OR 3  group or a -NR 6 <SP>1</SP>R 7 <SP>1</SP> group, in which either R 6 <SP>1</SP> is a hydrogen atom and R 7 <SP>1</SP> is a C 1-4  alkoxy-C 1-4  alkyl or C 3-6  cycloalkyl group, or R 6 <SP>1</SP> and R 7 <SP>1</SP>, together with the N atom to which they are attached, form a group of the formula VI in which one or both of x and y is 0, and acid addition salts thereof are prepared (A) by reacting a halotriazoloquinazoline of the general formula with a compound of the general formula HNR 6 <SP>11</SP>R 7 <SP>11</SP> to give a triazoloquinazoline of the general formula P<SP>11</SP>, Q<SP>11</SP>, R 6 <SP>11</SP> and R 7 <SP>11</SP> being the same as P,Q, R 6  and R 7  except that when Q<SP>11</SP> is N and P<SP>11</SP> is =CH-, then R 6 <SP>11</SP> and R 7 <SP>11</SP> are as R 6 <SP>1</SP> and R 7 <SP>1</SP> and Y being Cl or Br; (B) by reacting a halotriazoloquinazoline of the general formula with a compound of the general formula MOR 3 <SP>11</SP> to give a triazoloquinazoline of the general formula wherein either R 2 <SP>111</SP> is a C 1-4  alkyl group and R 3 <SP>11</SP> is as R 3  or R 2 <SP>111</SP> is H and R 3 <SP>11</SP> is as R 3 1, and M is H or an equivalent of an alkali or alkaline earth metal cation, the process being effected, when MOR 3 <SP>11</SP> is a free alcohol, in the presence of an inert organic base or under anhydrous conditions and in the presence of an inert inorganic base; (c) by reacting a hydrazine of the general formula with a compound of the general formula R 2 <SP>1</SP>C[O(CH 2 ) 2 CH 3 ] 3  under substantially anhydrous conditions to give a triazoloquinazoline of the general formula wherein either (i) R 2 <SP>1</SP> is a C 1-4  alkyl group and R 6 <SP>111</SP> and R 7 <SP>111</SP> are as R 6  and R 7  or (j) R 2 <SP>1</SP> is H and R 6 <SP>111</SP> and R 7 <SP>111</SP> are as R 6 <SP>1</SP> and R 7 <SP>1</SP>, and z is 0 or 1; (D) by reacting a halotriazoloquinazoline of the general formula with a compound of the general formula MOR 3  to give a triazoloquinazoline of the first general formula above wherein R 1  is -OR 3 , provided that when Q is N in the starting material, the process is effected using a compound MOR 3  in which M is H, in the presence of an inert organic base, under anhydrous conditions and under controlled time and temperature conditions, and that when P is N in the starting material and a compound MOR 3  in which M is H is used, the process is effected in the presence of an inert organic base or under anhydrous conditions and in the presence of an inert inorganic base; or (E) by rearranging a triazoloquinazoline of the first general formula above wherein P is under basic conditions or by heating in the presence of an organic acid or to a temperature above the melting point of the starting material to give a triazoloquinazoline of the first general formula above wherein Q is followed optionally by salification of a resulting free base or conversion of a resulting acid addition salt to the corresponding free base. Triazoloquinazolines of the first general formula above wherein R 1 ,P and Q are replaced by R 1 <SP>1</SP>, P<SP>1</SP> and Q<SP>1</SP>, respectively, which are as R 1  P and Q except that when P<SP>1</SP> is N and Q<SP>1</SP> is =CH-, then R 1 <SP>1</SP> is -OR 3 <SP>1</SP> in which R 3 <SP>1</SP> is a group of the Formula IV or -NR 6 R 7 , and acid addition salts thereof are novel. Novel halotriazoloquinazolines of the general formula wherein either P<SP>111</SP> is in which R 2 <SP>11</SP> is a C 1-4  alkyl group and Q<SP>111</SP> is N, or P<SP>111</SP> is N and Q<SP>111</SP> is are prepared (α) when P<SP>111</SP> is by reacting a hydrazine of the general formula with a compound of the general formula R 2 <SP>11</SP>C[O(CH 2 ) 2 CH 3 ] 3  or (#) when Q<SP>111</SP> is by chlorinating or brominating a ketone of the general formula which is prepared by rearranging and hydrolysing a halotriazoloquinazoline of the general Formula VII in which P is 2 - Cyclopropylamino - 4 - hydrazino - 6,7- dimethoxyquinazoline is prepared by reacting 2- chloro - 4 - hydrazino - 6,7 - dimethoxyquinazoline with cyclopropylamine. Pharmaceutical compositions having hypotensive and antiinflammatory activity comprise, as active ingredient, one of the novel triazoloquinazolines or halotriazoloquinazolines as defined above or, where appropriate, a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier. Reference has been directed by the Comptroller to Specification 1,374,769.