Patent GB-1460389-A (GB)
Title: 4-substituted quinazoline cardiac stimulants
IPC: C07D211/58
Filed: 1975-01-06
Abstract: 1460389 4-Substituted quinazoline cardiac stimulants PFIZER Ltd 24 July 1975 [25 July 1974 6 Jan 1975] 32805/74 and 416/75 Heading C2C The invention comprises novel compounds of the Formula I: wherein (i) R<SP>1</SP> is a hydrogen atom or a lower alkyl group; (R<SP>2</SP>) n  represents 1 to 3 optional substituents, each R<SP>2</SP> being a hydroxy or lower alkoxy group, and n being 0 to 3, or any two of the moieties R<SP>2</SP> constituting a methylenedioxy or ethylenedioxy group attached to adjacent positions of ring A; (ii) X represents -(CH 2 ) p - wherein p is 1 to 3, -CH=CH- or -CH 2 . CH=CH-; (iii) Y is attached to the 3- or 4-position of ring C and represents either: (a) a group of the formula -Z<SP>1</SP>-COR<SP>3</SP> wherein Z<SP>1</SP> is -CH 2 - or R<SP>3</SP> is a lower alkyl group optionally substituted by an amino (as hereinbefore defined), hydroxy, lower alkoxy, aryl, or heteroaryl group; a lower alkenyl- or lower alkynyl-methyl group; a lower alkoxy group optionally substituted by an amino (as hereinbefore defined), aryl, heteroaryl, lower alkoxy or hydroxy group; an aryl group; an aryloxy group; or a heteroaryl group; and R<SP>4</SP> is a hydrogen atom; a lower alkyl group optionally substituted by an amino (as hereinbefore defined), lower alkoxy, hydroxy, carbethoxy, aryl or heteroaryl group; a lower alkenyl- or lower alkynyl-methyl group; an aryl group or a heteroaryl group; (b) a group of the formula wherein R<SP>4</SP> is as defined above and R<SP>5</SP> is a group as defined for R<SP>3</SP> above or is a group of the formula in which R<SP>7</SP> is a hydrogen atom or a lower alkyl group and R<SP>6</SP> is a group as defined for R<SP>4</SP> above, or R<SP>6</SP> and R<SP>7</SP> taken together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic ring; or, (c) a group of the formula wherein Z<SP>2</SP> is Z<SP>1</SP> or -O-, and R<SP>6</SP> and R<SP>7</SP> are as defined above, provided that when Z<SP>2</SP> is R<SP>4</SP> and R<SP>7</SP> taken together may represent -(CH 2 ) 2 -, -(CH 2 ) 3 - or an o-phenylene group; and (iv) R is a hydrogen atom or a lower alkyl group attached to the same carbon atom as Y; provided that when X is -CH=CH- or -CH 2 CH=CH-, R is absent and Y is wherein R<SP>3</SP>, R<SP>6</SP> and R' are as defined above, Y being attached to an unsaturated ring carbon atom; and their pharmaceutically acceptable acid addition salts. In the above compounds "lower" indicates up to 6 carbon atoms in the radical, aryl and heteroaryl include those radicals substituted by lower alkyl, lower alkoxy, hydroxy, halogen or acetamido, and "amino" means -NR 8 R 9 , wherein R 8  is H or lower alkyl, and R<SP>9</SP> is H, lower alkyl, or aryl substituted lower alkyl or -NR 8 R 9  is a saturated monocyclic heterocyclic group. The compounds may be prepared by (1) reacting a compound III: wherein Q is a good leaving group with an amine IV: (2) wherein I X is -(CH 2 ) p - and Y is NR<SP>4</SP>CONHR<SP>6</SP> or NR<SP>4</SP>CSNHR<SP>6</SP>, reacting a compound V: in which X is -(CH 2 ) p - with an isocyanate R<SP>6</SP>NCO or isothiocyanate R<SP>6</SP>NCS when R<SP>6</SP> is not hydrogen or with sodium or potassium cyanate or thiocyanate in acid when R<SP>6</SP> is hydrogen; (3) where in I X is -(CH 2 ) p - and Y is either -NR<SP>4</SP>COR<SP>3</SP>, -NR<SP>4</SP>SO 2 R<SP>5</SP> or -NR<SP>4</SP>CONR<SP>6</SP>R<SP>7</SP>, reacting a compound V with either (a) a haloformate or acyl halide Q<SP>2</SP>COR<SP>3</SP> where Q<SP>2</SP> is chloro or bromo, (b) a halosulphonate, sulphonyl halide or sulphamyl halide Q<SP>2</SP>SO 2 R<SP>5</SP>; (c) a carbamyl halide R<SP>6</SP>R<SP>7</SP>NCOQ<SP>2</SP> where R<SP>6</SP> and R<SP>7</SP> are both other than hydrogen or (d) an anhydride or pyrocarbonate (R<SP>3</SP>CO) 2 O; (4) where in I X is -(CH 2 ) p - and Y is -OCONHR<SP>6</SP> or -OCSNHR<SP>6</SP>, reacting a compound VI: where X is -(CH 2 ) p -, with an isocyanate R<SP>6</SP>NCO or isothiocyanate R<SP>6</SP>NCS (R<SP>6</SP> # H) or sodium or potassium cyanate or thiocyanate in the presence of acid where R<SP>6</SP> is hydrogen; (5) where in I X is -CH 2 ) p - and Y is -NHCONR<SP>6</SP>R<SP>7</SP> or -NHCSNR<SP>6</SP>R<SP>7</SP>, reacting a compound VII: where X is -CH 2 ) p - with phosgene or thiophosgene in the presence of base to convert the NH 2  group to -NCO or -NCS, and thereafter reacting the product with R<SP>6</SP>R<SP>7</SP>NH; (6) where in I X is -(CH 2 ) p -, Y is -NR<SP>4</SP>COR<SP>3</SP> and R<SP>3</SP> is other than lower alkoxy, substituted lower alkoxy and aryloxy, reacting a compound V with an R<SP>3</SP>COOH ester of N-hydroxysuccinimide; (7) where in I Y is -CH 2 CONR<SP>6</SP>R<SP>7</SP>, reacting a compound IX: where Q<SP>3</SP> is a good leaving group, with a compound R<SP>6</SP>R<SP>7</SP>NH; (8) where in I X is -(CH 2 ) p - and Y is -NR<SP>4</SP>COR<SP>3</SP>, R<SP>3</SP> being a lower alkyl substituted by an amino group defined above, reacting a compound X where X is -(CH 2 ) p - and Q<SP>4</SP> is lower alkyl substituted by chloro or bromo, with a compound R<SP>8</SP>R<SP>9</SP>NH; (9) where in I ring C is unsaturated and Y is thus CH 2 COR<SP>3</SP>, -CH 2 CONR<SP>6</SP>R<SP>7</SP> or -CH 2 CSNR<SP>6</SP>R<SP>7</SP>, reacting a compound XI: wherein X is -(CH 2 ) 2 - or -(CH 2 ) 3 - with a phosphonate, (lower alkoxy) 2 P(O)Y or (aryloxy) 2 P(O)Y, wherein Y is -CH 2 COR<SP>3</SP>, -CH 2 CONR<SP>6</SP>R<SP>7</SP> or -CH 2 CSNR<SP>6</SP>R<SP>7</SP>; (10) when in I Y is -CH 2 CONR<SP>6</SP>R<SP>7</SP>, reacting a compound XII: with N-hydroxy succinimide in the presence of a dehydrating agent to form an ester followed by reaction with R<SP>6</SP>R<SP>7</SP>NH, optionally followed by acid addition salt formation. In the above processes any substituent which would interfere in the process are initially protected and subsequently the protecting group removed. 4 - [4 - Aminopiperidino] - 6,7 - dimethoxyquinazoline is prepared by reacting 4-chloro-6,7- dimethoxyquinazoline with 4-(trifluoroacetylamino) piperidine to form 4-(4-trifluoroacetamidopiperidino) - 6,7 - dimethoxy-quinazoline followed by hydrolysis of the amide group. 4 - [4 - (2 - Pyridylmethylamino) piperidino]- 6,7 - dimethoxy-quinazoline and 4 - (4 - methylamino - piperidino) - 6,7 - dimethoxy - quinazoline are prepared by reacting 4-chloro-6,7-dimethoxy-quinazoline with 4-piperidone ethylene ketal hydrochloride to yield 4-(4-oxopiperidino)- 6,7-dimethoxy-quinazoline which is reacted with 2-aminomethylpyridine or methylamine followed by reduction with sodium borohydride. 4 - [4 - (α - Bromoacetamido) piperidino] - 6,7- dimethoxy-quinazoline is prepared by reacting 4- (4 - aminopiperidino) - 6,7 - dimethoxy quinazoline with α-bromoacetyl bromide. Pharmaceutical compositions of the compounds I with the usual excipients show cardiac stimulant activity when administered orally or parenterally.