Patent GB-1332008-A (GB)
Title: Piperazine derivatives their preparation and pharmaceutical compositions containing them
IPC: C07D295/092
Filed: 1971-09-28
Abstract: 1332008 Piperazine derivatives PFIZER Ltd 28 Sept 1971 [23 Nov 1970] 55647/70 Addition to 1325876 Heading C2C The invention comprises novel piperazine derivatives of the Formula I wherein R is R<SP>6</SP>R<SP>7</SP>NCON(R<SP>8</SP>)-, R<SP>6</SP>R<SP>7</SP>NCSN(R<SP>8</SP>)-, R<SP>6</SP>R<SP>7</SP>NSO 2 N(R<SP>8</SP>)-, R<SP>6</SP>R<SP>7</SP>NCO-, R<SP>6</SP>R<SP>7</SP>NCS, R<SP>6</SP>R<SP>7</SP>NSO 2 -, wherein R<SP>6</SP>, R<SP>7</SP> and R<SP>8</SP> are H, C 1-6  alkyl, aryl or aryl- C 1-6  alkyl, or R<SP>4</SP>OCON(R<SP>5</SP>)-, wherein R<SP>4</SP> is C 1-6  alkyl and R<SP>5</SP> is H or C 1-6  alkyl, or CN, COOH, C 1-6  alkoxycarbonyl, or N-aminocarbamoyl; R<SP>1</SP> is H, halogen, OH, OCH 3  or C 1-6  alkyl; R<SP>2</SP> is H or C 1-6  alkyl, R<SP>3</SP> is halogen, C 1-6  alkyl or C 1-6  alkoxy; n is 0, 1 or 2; and X is O or S; the esters of those compounds in which R<SP>2</SP> is H; and the N-oxides and pharmaceutically acceptable acid addition salts thereof. The novel compounds are prepared by one of the following methods: (1) Compounds in which R<SP>2</SP> is H and in which R<SP>1</SP> is as above except OH by reacting the appropriately substituted 1-phenoxy (or phenylthio)- 2,3-epoxypropane with the corresponding N- phenylpiperazines. (2) By reacting the appropriate phenoxy or phenylthio substituted propylene chlorohydrins or ethers thereof with the corresponding N- phenylpiperazine. (3) By reacting suitably substituted phenoxy- or phenylthiopropanolamines or ethers thereof with the corresponding N,N-bis-(2- chloroethyl)anilines. (4) Compounds in which R is COOH by hydrolysing the corresponding compounds in which R is carbamoyl or C 1-6  alkoxycarbonyl. (5) Compounds in which R is C 1-6  alkoxycarbonyl by esterifying the corresponding compounds in which R is COOH.  (6) Compounds in which R is NHCONH 2  or NHCSNH 2  by reacting the corresponding compounds in which R is NH 2  with alkali metal cyanates or thiocyanates, respectively. (7) Compounds in which R is N-aminocarbamoyl by reacting the corresponding compounds in which R is C 1-6  alkoxycarbonyl with hydrazine hydrate. (8) Compounds in which R<SP>1</SP> is OH by hydrogenolysis of the corresponding benzyl ethers. (9) Compounds in which R<SP>2</SP> is alkyl and esters of compounds in which R<SP>2</SP> is H by alkylation and esterification of the corresponding compounds in which R<SP>2</SP> is H. 1 - (2 - Aminophenoxyl) - 3 - [4 - (2 - methoxyphenyl) - piperazin - 1 - yl] - propan - 2 - ol hydrochloride is obtained by hydrolysing 1-(2- acetamidophenoxy) - 3 - [4 - (2 - methoxyphenyl)- piperazin-1-yl]-propan-2-ol, resulting from the reaction between 1-(2-acetamidophenoxy)-2,3- epoxypropane and 1-(2-methoxyphenyl)-piperazine. 1 - (4 - Benzyloxy - 2 - carbamoylphenoxy) - 3- [4 - (2 - methoxyphenyl)piperazin- 1 - yl] - propan- 2-ol is obtained by reacting 1-(4-benzyloxy-2- carbamoylphenoxy) - 2,3 - epoxypropane with 1-(2-methoxyphenyl)-piperazine. Pharmaceutical compositions, suitable for oral or parenteral administration, contain the above novel compounds and suitable carrier therefor. The compounds possess anti-hypertensive activity.