Diazepine antiallergy agents

Claim 1

A process for making a compound of formula (I), (II) or (III). wherein A represents a fused benzene, pyridine, naphthalene, quinoline, thiophene, benzothiophene, pyrazole or isothiazole ring, which ring or rings being optionally substituted by 1 or 2 substituents independently selected from C, - C 4 alkyl; C 4 -C 7 cycloalkyl halo; perfluoro - (C 1 - C 4 alkyl); cyano; (Ci - C 4 alkoxy)-carbonyl; nitro; amino; amino substituted by (C 1 - C 4 alkyl) sulfonyl, amino substituted by (C 1 - C 4 alkyl) oxalyl; C, - C 4 alkoxy - (Ci - C 4 alkyl) imino; hydroxy(C 1 -C 4 alkyl), (C 1 -C 4 alkoxy)-C 1 -C 4 alkyl, (C 1 -C 4 alkoxy)-(C 2 -C 4 alkoxy)-C 1 -C 4 alkyl, -CONR 5 R 6 wherein R 5 and R 6 are each independently H or C 1 -C 6 alkyl, or R 5 is H or C 1 -C 4 alkyl and R 6 is C 3 -C 7 cycloalkyl, or 2-pyridyl, or R 5 and R 6 are joined together to form, with the nitrogen atom to which they are attached, a morpholino, pyrrolidino or piperidino group; and phenyl, thienyl or pyridyl optionally substituted by halogen, cyano, trifluoromethyl, (C 1 - C 4 alkoxy) carbonyl or carbamoyl, X is 0, S or NH Y is 1, 4 phenylene or a group of formula R 1 is H or C, - C 4 alkyl optionally substituted by a substituent selected from phenyl, halophenyl, pyridyl, (C 1 - C 4 alkoxy) carbonyl, and di- (C 1 -C 4 alkyl) amino or C 2 -C 4 alkyl substituted by hydroxy or by one or two C 1 -C 4 alkoxy groups or is (CH 2 ) n CONR 7 R 8 where n = 1-4 and R 7 and R 8 are each independently H or C 1 -C 4 alkyl. R 2 is H or C, - C 4 alkyl; R 3 is H or C 1 - C 4 alkyl; B represents a fused 5-membered heterocyclic ring containing from 1 to 4 nitrogen atoms or a fused 6 - membered heterocyclic ring containing two nitrogen atoms said fused 5- or 6-membered ring being optionally substituted by 1 or 2 substituents independently selected from C, - C 4 alkyl, C, - C 4 haloalkyl, halo and oxo; and "Het" is either a 5-membered aromatic heterocyclic ring containing two or three nitrogen atoms or a pyridine ring; which ring may optionally be fused to a benzene or pyridine ring or to a further 5 - membered aromatic heterocyclic ring, at least one of said heterocyclic rings optionally containing a sulphur or oxygen atom and at least one of said rings optionally being substituted with from one to three substituents independently selected from C, - C 4 alkyl, C, - C 4 alkoxy, halo, CF 3 , CN and formyl; and wherein the dashed line represents an optional bond; or a pharmaceutically acceptable salt thereof, which comprises: (a) reacting a compound of formula (IV) with a keto-ester of formula (V) to produce a compound of formula (IV'): wherein R 1 is H or C, -C4 alkyl, Q is a leaving group, and A, Y and Het are as defined above except that A is not substituted by an amino or carbamoyl group, and cyclising compound (IV') to produce a compound of formula (I'): (b) if necessary, reacting compound (I') with phosphorus pentasulphide to produce a compound of formula (le): (c) if necessary, reacting compound (le) with ammonia to produce a compound of formula (I) in which R 1 is H or C 1 -C 4 alkyl, X is = NH and the dashed line represents a bond, (d) if necessary reacting a compound from (c) in which R 1 is H with an alkyl propiolate to form a compound of formula (II) in which B is a pyrimidone ring, (e) if necessary, reacting compound (le) in which R 1 is H with an alkyl carbazate and cyclising the product to form a compound of formula (II) in which B is a 3-oxo-1,2,4-triazole ring, (f) if necessary, reacting compound (le) in which R' is H with hydrazine and either: (1) diazotising the hydrazide obtained to yield a compound of formula (II) in which B is a fused tetrazole ring, or (2) reacting the hydrazide obtained with an alkyl formate of formula R 4 C(OAlk) 3 wherein Alk is an alkyl group and R 4 is H, C 1 -C 4 alkyl or haloalkyl to produce a compound of formula (II) in which B is a substituted or unsubstituted 1,2,4-triazole ring, or (3) reacting the hydrazide obtained with trifluoroacetic acid to produce a compound of formula (II) in which B is a 1,2,4-triazole ring substituted by a trifluoromethyl group, (g) if necessary, reacting compound (le) in which R 1 is H with an acetal of aminoacetaldehyde or a homologue thereof to produce a compound of formula (II) in which B is an unsubstituted or substituted imidazole ring, (h) if necessary, reacting compound (le) in which R 1 is H with propargylamine or a homologue thereof to produce a compound of formula (II) in which B is a substituted imidazole ring, (i) if necessary, reacting compound (le) in which R 1 is H with ethanolamine or an analogue thereof followed by cyclisation to produce a compound of formula (II) in which B is a substituted or unsubstituted imidazoline or tetrahydropyrimidine ring, (j) if necessary, reacting a compound of formula (I) produced as above in which R' is H with a substituted or unsubstituted alkyl halide, halo-substituted carboxylic acid ester, or halo-substituted amine or amide to produce a compound of formula (I) in which R 1 is other than H, (k) if necessary, alkylating a compound of formula (I), (II) or (III) obtained as above in which R 2 and R 3 are H to produce a compound of formula (I), (II) or (III) in which at least one of R 2 and R 3 is an alkyl group, (I) if necessary, reducing a compound of formula (I), (II) or (III) obtained as above in which ring A bears a nitro substituent to yield a corresponding compound of formula (I), (II) or (III) in which ring A bears an amino substituent, (m) if necessary, reacting a compound of formula (I), (II) and (III) obtained as above in which ring A bears a halo substituent with carbon monoxide and an amine in the presence of a catalyst to yield a corresponding compound of formula (I), (II) or (III) in which ring A bears a carbamoyl substituent, (n) if necessary, reducing a compound of formula (I), (II) or (III) obtained as above in which the dashed line represents a bond to produce a compound of formula (I), (II) or (III) in which said bond is absent, and (o) if necessary, reacting a compound obtained as above with an acid to produce a pharmaceutically acceptable salt.