Patent GB-1259005-A (GB)
IPC: C07D401/06
Filed: 1969-02-04
Abstract: 1,259,005. Cyclic amidines. SCHERICO Ltd. 4 Feb., 1969 [9 Feb., 1968], No. 5937/69. Heading C2C.  Novel cyclic amidines of the general formula wherein n is 0, 1 or 2, U is a pyridine, pyrimidine or thiazole. ring which is attached to the adjacent carbon atom at position 2, or a pyrazine. ring, and may be substituted by a C 1-6  alkyl, trifluoromethyl or C 1-6  alkoxy group and/or a halogen atom, V is a phenyl, thienyl or pyridyl ring which may be substituted by a C 1-6  alkyl, trifluoromethyl, C 1-6  alkoxy or dialkylamino group and/or a halogen atom, Y is a hydrogen atom or a hydroxyl, C 1-6  alkyl, alkoxy or acyloxy group, R 1  is a hydrogen atom or a C 1-6  alkyl, aminoalkyl, hydroxyalkyl, aralkyl or acyl group and each of R 2 , R 3 , R 4  and R 5  is a hydrogen atom or a C 1-6  alkyl group, or two of R 2 , R 3 , R 4  and R 5 , taken together with the atom or group separating them, form a saturated carbocyclic ring having 5-7 carbon atoms, and acid addition salts thereof are prepared (a) by condensation of a cyclic amidine of the general formula  or an acid addition salt thereof with a compound of the general formula T 2 -P, wherein one of T 1  and T 2  is the ring U and the other the ring V and one of P and Q is a metallic or metalcontaining residue of an organometallic compound and the other is a reactive organic or inorganic ester residue; (b) by intramolecular condensation of a cyclic amidine of the general formula  wherein U<SP>1</SP> is the group required for completing the ring U and Z is a hydroxyl group, or a tautomer or salt thereof; (c) by intermolecular condensation of a cyclic amidine of the general formula where T 3  is a group consisting of part of the structural elements of ring U and two reactive groups, with a second reactant providing the remaining part of the structural elements of the ring U and two reactive atoms or groups, the reactive groups being halogen, oxo, hydroxy, thioxo, amino or imino; (d) by intramolecular condensation of an amine of the general formula or a salt or N-acyl derivative thereof; (e) by condensation of a carboxylic acid of the general formula or a functional derivative thereof at the carboxy group with an amine of the general formula or a functional derivative thereof at either or both of the amino groups; (f) when Y is an acyloxy group, by esterification of the corresponding compound wherein Y is a hydroxyl group; (g) when Y is an alkoxy group, by etherification of the corresponding compound wherein Y is a hydroxyl group; (h) when R 1  is an acyl group, by acylation of the corresponding compound wherein R 1  is a hydrogen atom; and (i) when Y is a hydroxyl group, by oxidation of the corresponding compound wherein Y is a hydrogen atom ; followed optionally by conversion of a resulting free base to a corresponding acid addition salt or vice-versa. Thiocarboxamides having a central carbon atom attached to the rings U and V, the atom or group Y and a thiocarbamoyl group are prepared by treatment of the corresponding cyanide with hydrogen sulphide. The said cyanide is prepared by reaction of a cyanide of the general formula VYC-CN with a compound having the ring U attached to a chlorine atom in the 2-position, in the presence of sodium amide.  N - (# - Aminoethyl)-α-(2 - pyridyl) - p - chlorophenylacetamide is prepared by reaction of methyl α - (2 - pyridyl) - p - chlorophenylacetate with ethylenediamine. 2 - (α - Amidino - p - chlorobenzyl) - #<SP>1</SP> - imidazoline is prepared by reaction of p-chlorobenzyl cyanide with N-methyl-N-phenyl-cyanamide in the presence of sodium amide, treatment of the resulting p-chlorophenyl-malononitrile with hydrogen sulphide, reaction of the α - (p - chlorophenyl) - α - cyano - thioacetamide thus obtained with ethylenediamine and treatment of the 2-(α-cyano-p-chlorobenzyl)-#<SP>1</SP>-imidazoline so produced with hydrogen chloride, followed by ammonia in ethanol. Malondialdehyde is prepared by hydrolysing malonaldehyde tetramethylacetal with 1% hydrochloric acid at 20-25 C. Pharmaceutical compositions having antidepressant and anti inflammatory activity comprise, as active ingredient, a cyclic amidine of the above general formula or a pharmaceutically acceptable acid addition salt thereof, in admixture with an acceptable pharmaceutical carrier, and may be administered enterally or parenterally.