PROCEDEU PENTRU PREPARAREA UNOR DERIVATI CHINAZOLINICI

摘要

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) R1 is a hydrogen atom or a lower alkyl group; (R2) n represents 1 to 3 optional substituents, each R2 being a hydroxy or lower alkoxy group, and n being 0 to 3, or any two of the moieties R2 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 -Z1-COR3 wherein Z1 is -CH 2 - or R3 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 R4 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 R4 is as defined above and R5 is a group as defined for R3 above or is a group of the formula in which R7 is a hydrogen atom or a lower alkyl group and R6 is a group as defined for R4 above, or R6 and R7 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 Z2 is Z1 or -O-, and R6 and R7 are as defined above, provided that when Z2 is R4 and R7 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 R3, R6 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 R9 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 NR4CONHR6 or NR4CSNHR6, reacting a compound V: in which X is -(CH 2 ) p - with an isocyanate R6NCO or isothiocyanate R6NCS when R6 is not hydrogen or with sodium or potassium cyanate or thiocyanate in acid when R6 is hydrogen; (3) where in I X is -(CH 2 ) p - and Y is either -NR4COR3, -NR4SO 2 R5 or -NR4CONR6R7, reacting a compound V with either (a) a haloformate or acyl halide Q2COR3 where Q2 is chloro or bromo, (b) a halosulphonate, sulphonyl halide or sulphamyl halide Q2SO 2 R5; (c) a carbamyl halide R6R7NCOQ2 where R6 and R7 are both other than hydrogen or (d) an anhydride or pyrocarbonate (R3CO) 2 O; (4) where in I X is -(CH 2 ) p - and Y is -OCONHR6 or -OCSNHR6, reacting a compound VI: where X is -(CH 2 ) p -, with an isocyanate R6NCO or isothiocyanate R6NCS (R6 # H) or sodium or potassium cyanate or thiocyanate in the presence of acid where R6 is hydrogen; (5) where in I X is -CH 2 ) p - and Y is -NHCONR6R7 or -NHCSNR6R7, 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 R6R7NH; (6) where in I X is -(CH 2 ) p -, Y is -NR4COR3 and R3 is other than lower alkoxy, substituted lower alkoxy and aryloxy, reacting a compound V with an R3COOH ester of N-hydroxysuccinimide; (7) where in I Y is -CH 2 CONR6R7, reacting a compound IX: where Q3 is a good leaving group, with a compound R6R7NH; (8) where in I X is -(CH 2 ) p - and Y is -NR4COR3, R3 being a lower alkyl substituted by an amino group defined above, reacting a compound X where X is -(CH 2 ) p - and Q4 is lower alkyl substituted by chloro or bromo, with a compound R8R9NH; (9) where in I ring C is unsaturated and Y is thus CH 2 COR3, -CH 2 CONR6R7 or -CH 2 CSNR6R7, 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 COR3, -CH 2 CONR6R7 or -CH 2 CSNR6R7; (10) when in I Y is -CH 2 CONR6R7, reacting a compound XII: with N-hydroxy succinimide in the presence of a dehydrating agent to form an ester followed by reaction with R6R7NH, 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 withα-bromoacetyl bromide. Pharmaceutical compositions of the compounds I with the usual excipients show cardiac stimulant activity when administered orally or parenterally.