Patent GB-1425347-A (GB)
Title: N-thienylmethylbenzomorphanes and n-thienylmethylmorphinanes
IPC: A61K31/485
Filed: 1973-04-11
Abstract: 1425347 2 - Thienylmethyl - 2<SP>1</SP> - hydroxybenzomorphanes; N - thienylmethyl - 3 - hydroxymorphinanes BOEHRINGER INGELHEIM GmbH 11 April 1973 [12 April 1972] 17458/73 Heading C2C The novel benzomorphanes and morphinanes of Formula I: wherein R represents H, CH 3  or CH 3 CO, preferably H, and R 1  and R 2  independently represent H or a C 1-3  alkyl group or together represent a -(CH 2 ) 4 - group and their acid addition salts may be prepared by: (a) reacting a compound of Formula II: in which R 1  and R 2  are as defined above and R 3  represents a hydrogen atom or an alkyl, aralkyl or acyl group with a compound of Formula III: in which X is an atom or group removable as an anion, to obtain a compound of Formula Ia: wherein R 3  is as defined above and when R 3  in said compound represents a group R 3 <SP>1</SP> (defined as for R 3  but other than H, CH 3  or CH 3 CO-), converting said compound of Formula Ia into a compound of Formula I in which R is H and then, if desired, methylating or acetylating to obtain a compound in which R is CH 3  or CH 3 CO; (b) reacting a compound of Formula II (above) with a compound of Formula V: in the presence of either hydrogen and a hydrogenation catalyst or formic acid to obtain a compound of Formula 1a as defined above which is converted to a compound of Formula I as described in (a); (c) reduction of a compound of Formula VII: wherein R 1  and R 2  are as defined above and R 3  is as defined above to a compound of Formula Ia as defined above which is converted to a compound of Formula I as described in (a); (d) reaction of a compound of Formula IX: wherein R 1 , R 2 , R 3  and X are as defined above and R 4  is an atom or group removable under the conditions of a Hofmann elimination, e.g. phenethyl-1,2-diphenylethyl or naphthylethyl, with a strong alkali to produce a compound of Formula Ia (above) which is converted to a compound of Formula I as described in (a); (e) cyclization of a compound of Formula XIa or Xlb: wherein R 1 , R 2  and R 3  are as defined above and Y is an atom or group removable as an anion, preferably halogen, to obtain a compound of Formula Ia which is converted to a compound of Formula I as described in (a); (f) decarboxylation of a compound of Formula XII, preferably using copper powder/quinoline to obtain a compound of Formula Ia which is converted to a compound of Formula I by the means described in (a); (g) methylation or acetylation of a compound of Formula I in which R is H or (h) dealkylation, dearalkylation or deacylation of a compound of Formula Ia in which R 1 , R 2  and R 3  are as defined above. 2 - (5 - Carboxy - 2 - thienylmethyl) - 2<SP>1</SP> - hydroxy - 5,9α - dimethyl - 6,7 - benzomorphane is obtained by saponification of the corresponding 2 - (5 - carboxymethyl - 2 - thienylmethyl) compound which is in turn obtained by alkylation of 2<SP>1 </SP>- hydroxy - 5,9α - dimethyl - 6,7 - benzomorphane with 5 - chloromethylthiophen - 2- carboxylic acid methyl ester.  N - (2 - Thienoyl) - 3 - hydroxymorphinane; 2- (2 - thienoyl) - 2<SP>1</SP> - (2 - thienoyloxy) - 5,9α - dimethyl - 6,7 - benzomorphan; 2 - (2 - thienoyl)- 21 - acetoxy - 5 - n - propyl - 6,7 - benzomorphane and 2 - (2 - thienoyl) - 2<SP>1</SP> - (2 - thienoyloxy) - 5- ethyl - 9α - methylbenzomorphane are prepared by reaction of the corresponding free OH and NH compounds by reaction with thiophen-2- carboxylic acid chloride. 2 - [2 - (α - Naphthyl)ethyl] - 2 - (3 - thienylmethyl) - 2<SP>1</SP> - hydroxy - 5,9α - dimethyl - 6,7 - benzomorphanium bromide is prepared by reaction of 3 - bromomethylthiophen with 2 - [2 - (α- naphthyl)ethyl] - 2<SP>1</SP>- hydroxy - 5,9α - dimethyl- 6,7-benzomorphan. 1 - (2 - Thienylmethyl and 1 - (3 - thienylmethyl) - 2<SP>1</SP>- (p - methoxybenzyl) - 3,4 - dimethyl- 4 - hydroxypiperidine hydrochlorides are prepared by reaction of 2-(p-methoxybenzyl)-3,4-dimethyl - 4 - hydroxypiperidine with 2 - chloromethylthiophen. Pharmaceutical compositions having central nervous system activity, particularly as antidote for opiates, for oral, rectal, parenteral or enteral administration, comprise at least one compound of Formula I or physiologically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient.