Patent GB-1473591-A (GB)
Title: Vinylic and acetylenic pyridines and their n-oxides
IPC: C07D263/42
Filed: 1974-06-11
Abstract: 1473591 Vinylic and acetylenic pyridines and their N-oxides MERCK & CO Inc 11 June 1974 [15 June 1973 18 April 1974 26 April 1974] 25858/74 Headings C2C and C2P The invention comprises novel compounds (I) and their pharmaceutically acceptable salts, in which m is 0 or 1; x is 0, 1, 2 or 3; A is or -C# C-, where R<SP>7</SP> is hydrogen, chlorine or fluorine; each of R<SP>1</SP> and R<SP>2</SP> is hydrogen or C 1-3  alkyl; R<SP>3</SP> is (a) hydrogen, (b) -SO 3 H, (c) -PO 3 H 2 , (d) amidino, (e) N-(C 1-4  alkyl) 2 , (f) -CH 2 CH(NH 2 )COOH, (g) ethoxycarbonylmethyl, (h) where E represents (1) adamantyl, (2) C 3-8  cycloalkyl, (3) C 1-5  alkoxy, (4) C 2-6  alkyl, (5) N- (C 1-4  alkyl) 2 , (6) phenyl, (7) 2-acetoxyphenyl, (8) 2 - hydroxy - 4 - (2,4 - difluorophenyl)- phenyl, (9) 3 - chloro - 4 - allyloxybenzyl, (10) α - methyl - 4 - isobutylbenzyl, (11) α- methyl - 3 - phenoxybenzyl, (12) α - methyl - 3- benzoylbenzyl, (13) 1 - (6 - methoxynaphth - 2- yl)ethyl, (14) α - methyl - 3 - fluoro - 4 - phenylbenzyl, (15) 2 - (3 - chloro - 4 - cyclohexylbenzoyl)ethyl, (16) 2 - (3 - trifluoromethylanilino)phenyl, (17) 2 - (2,3 - dimethylanilino)- phenyl, (18) 2 - (2,6 - dichloro - 3 - methylanilino)phenyl, (19) 2 - (3 - trifluoromethylanilino - 3 - pyridyl, (20) 2 - (2 - methyl - 3- chloroanilino)-3-pyridyl, or (i) where G represents (1) C 1-4  alkoxy, (2) -S- (alkali metal) or (3) wherein L represents (1) -(CH 2 ) 1-5 -, (2) phenylene, or (3) (m) -S-R<SP>8</SP>, wherein R<SP>8</SP> represents (1) -C(CH 3 ) 2 CH(NH 2 )COOH, (2) C 1-5  alkyl, (3) C 2-5  alkenyl, (4) phenyl-C 1-3  alkyl, (5) phenyl, (6) C 2-5  alkynyl, (7) 2-carboxyphenyl, or (8) R<SP>4</SP> is hydrogen, C 1-3  alkyl, phenyl, chloro, carboxy, C 1-3  alkoxycarbonyl, fluoro; and R is (a) C 1-3  alkyl, (b) hydroxy, (c) (d) hydroxy-C 1-3  alkyl; and (e) when one R is hydroxy adjacent to the group, the oxygen and sulphur thereof may be joined together through a group of formula wherein R<SP>5</SP> and R<SP>5</SP>α are the same or different and each is hydrogen, C 1-6  alkyl, phenyl, dimethylphenyl, or difluorophenyl, or taken together, R<SP>5</SP> and R<SP>5</SP>α represent =O or =S. When R<SP>3</SP> is -SO 3 H and -PO 3 H 2  the compounds exist as internal salts (Ia) and (Ib) and cyclic isomers of certain of the compounds (I) are also described, e.g. as shown in the relationship between (Ic) and (Id) Many standard methods are described for preparing the novel compounds. In particular, 2- methyl - 3 - hydroxy - 5 - vinyl - 4 - pyridylmethylthio-phosphonic acid internal salt is made by acidifying sodium 2 - methyl - 3 - hydroxy - 5- vinyl - 4 - pyridylmethylthiophosphorothioate which is itself obtained by interacting trisodium phosphorothioate and 2-methyl-3-hydroxy - 4 - chloromethyl - 5 - vinylpyridine hydrochloride. Salts (of ylide type) from triphenylphosphine and 2-methyl-3-hydroxy-4- acetylthiomethyl - 5 - chloromethylpyridine, 2- methyl - 3 - hydroxy - 4 - mercaptomethyl - 5- chloromethylpyridine, bis - [2 - methyl - 3- hydroxy - 5 - chloromethylpyridin - 4 - methyl]- disulphide or 2 - methyl - 3 - acetoxy - 4- acetylthiomethyl - 5 - chloromethylpyridine are obtained by interacting triphenylphosphine and the stated pyridine compound. Pharmaceutical preparations having antiinflammatory action and especially suitable for treating rheumatoid arthritis contain (I) as active ingredient. Administration is orally, parenterally, rectally or topically.