Dihydropyridine anti-ischaemic and antihypertensive agents

Claim 1

A process for preparing a 1,4-dihydropyridine of the formula wherein R is aryl or heteroaryl; R 1 and R 2 are each independently C 1 -C 4 alkyl or 2-methoxyethyl; Y is -(CH 2 ) n -, -CR 2 CH(CH 3 )- or -CH 2 C(CH 3 ) 2 -; X is a 5 or 6 membered nitrogen containing aromatic heterocyclic ring which may optionally be substituted by one or more C 1 -C 4 alkyl, phenyl, benzyl, CN -N(R 3 ) 2 , (CH 2 ) m CO 2 H, (CH 2 ) m CO 2 (C 1 -C 4 alkyl) or (CH 2 ) m CON(R 3 ) 2 groups wherein each R is independently H or C l -C 4 alkyl and m is 0 or 1; and n is 1 to 3 when X is linked by a ring carbon atom or 2 or 3 when X is linked by a ring nitrogen atom; and their pharmaceutically acceptable acid addition salts, which comprises: (a) reacting the following compounds together:- 1 2 where R, R , R , X and Y are as defined above; or (b) reacting compounds of the formulae:- or (c) reacting an azide of the formula:- wherein R, R 1 , R 2 and Y are as defined above, with a C 1 -C 4 alkyl ester of acetylenedicarboxylic or propiolic acid to yield those compounds of formula (I) wherein X is a 1,2,3-triazolyl group substituted with C0 2 (C 1 -C 4 alkyl) groups, and optionally reacting with concentrated ammonium hydroxide, hydrolysing or decarboxylating to give those compounds of formula (I) wherein X is a 1,2,3-triazolyl group substituted with CONH 2 or CO 2 H or which is unsubstituted; or (d) reacting an amine of the formula:- 1 2 where R, R 1 , R 2 and Y are as defined above with N,N-dimethylformamide azine to give the compound of formula (I) wherein X is a 1,2,4-triazolyl group; or (e) reacting a compound of the formula:- where R, R 1 , R 2 and Y are as defined above with tri-n-butyltin. azide to give the compound of formula (I) wherein X is a 5-tetrazolyl ring, and optionally alkylating or reacting with a chloroformate or alkyl haloalkanoate to yield the compounds wherein X is substituted with a C l -C 4 lower alkyl or (CH 2 ) m CO 2 (C 1 -C 4 alkyl) group wherein m is 0 or 1 and optionally hydrolysing or reacting the esters with ammonia to give the compounds wherein X is substituted with (CH 2 ) m CO 2 H or (CH 2 ) m CONH 2 respectively; or (f) reacting a compound of the formula:- wherein R, R 1 , R and Y are as defined above with a compound of the formula:- wherein hal is halo and Q is H, C 1 -C 4 lower alkyl, phenyl,benzyl or (CH 2 ) m CO 2 (C 1 -C 4 lower alkyl) and m is 0 or I to give compounds of the formula (I) wherein X is a group of the formula:- and Q is as previously defined, and optionally hydrolysing or reacting the compounds where Q is (CH 2 ) m CO 2 (C 1 -C 4 alkyl) with ammonia to obtain the compounds where X is substituted with (CH 2 ) m CO 2 H or (CH 2 ) m CONH 2 respectively; or (g) reacting a compound of the formula:- wherein R, R 1 , R 2 and Y are as defined above with 2-methylisothiourea to give the compounds of formula (I) wherein X is 3-amino-1,2,4-triazol-5-yl, or (h) reacting a compound of the formula (VIII) with hexahydro-2,4,6-trimethyl-s-triazine to obtain compounds of the formula (I) wherein X is 2,4,5-trimethyl-(lH)-imidazol-l-yl, or with ethyl 2-amino-2-cyanoacetate and trimethyl orthoformate to obtain the compounds of formula I wherein X is 5-amino-4- ethoxycarbonylimidazol-1-yl; or (i) reacting a compound of the formula:- 2 wherein R, R , R 2 , Q and Y are as defined above with phosphorus pentoxide to give the compound of formula (I) wherein X is 1,3,4-oxadiazol-1-yl or with para-methoxyphenylthionophosphine to give the compounds wherein X is 1,3,4-thiadiazol-2-yl, and optionally hydrolysing or reacting the compound wherein Q is (CH 2 ) m CO 2 (C 1 -C 4 alkyl) with ammonia to give the compounds where X is substituted with (CH 2 ) m CO 2 H or (CH 2 ) m CONH 2 respectively; or (j) reacting a compound of the formula:- wherein R, R 1 , R 2 and Y are as defined above with phosphorus oxychloride to give the compounds of formula (I) wherein X is 5-amino-1,3,4-thiadiazol-2-yl, or (k) reacting a compound of the formula (VIII) with hexane-2,5-dione to obtain compounds of the formula (I) wherein X is 2,5-dimethylpyrrol-1-yl; and in each case optionally forming a pharmaceutically acceptable acid addition salt of the product.