Patent GB-1290490-A (GB)
IPC: C07D295/12
Filed: 1969-12-16
Abstract: 1290490 Piperazine derivatives F HOFFMAN-LA ROCHE & CO AG 16 Dec 1969 [24 Dec 1968] 61246/69 Heading C2C The invention comprises novel piperazine derivatives of the Formula I wherein R 1  is amino, C 1-6  alkylamino, C 1-6  alkanoylamino, N-(C 1-6  alkyl)-C 1-6  alkanoylamino, or C 1-6  alkylsulphonylamino; R 2  is H or halogen; R 3  and R 4  each are H, OH, NH 2 , halogen, C 1-6  alkyl or C 1-6  alkoxy ; X is O or S; and Y is >CH 2 , >CH 2 OH, C 1-6  alkanoyloxymethylene, C 1-6  alkylsulphonyloxymethylene, arylsulphonyloxymethylene, or carbonyl, their pharmaceutical acceptable acid addition salts, and their preparation. The compounds are prepared by reacting ethers or thioethers of the Formula II wherein R<SP>1</SP> 1  is NO 2 , C 1-6  alkanoylamino, N-(C 1-6  alkyl)-C 1-6  alkanoylamino, and Z is halogen aryl or C 1-6  alkyl sulphonyloxy or, when taken together with Y and the terminal methylene group, is with the corresponding 4-phenylpiperazines, in which the benzene ring is optionally substituted by OH, NO 2 , halogen, C 1-6  alkyl or C 1-6  alkoxy, or reacting phenols or thiophenols, corresponding to Formula II above in which the radical CH 2 -Y-CH 2 -Z is replaced by H with compounds of the Formula V wherein R<SP>11</SP> 3  and R<SP>11</SP> 4  each are H, NO 2 , halogen, C 1-6  alkyl or C 1-6  alkoxy, or reacting compounds of the Formula II above in which Z is a 1 - piperazinyl radical with the appropriate halobenzenes, optionally substituted by R<SP>11</SP> 3  and/or R<SP>11</SP> 4 , or reacting compounds of the Formula VIII wherein Y<SP>11</SP> is CH 2  or CO, and A is halogen, C 1-6  alkylsulphonyloxy or arylsulphonyloxy with the corresponding anilines optionally substituted by R<SP>11</SP> 3  and/or R<SP>11</SP> 4 , or reacting compounds of Formula VIII above in which the two CH 2 CH 2 A radicals are replaced by hydrogen atoms with the corresponding N,N-bis-(A-ethyl)- anilines, optionally substituted by R<SP>11</SP> 3  and/or R<SP>11</SP> 4 , or reacting compounds of the Formula XII with compounds of the formula or reducing the corresponding dioxopiperazine derivatives, and in the resulting products reducing the nitro groups. If desired, in the resulting products acylamino groups may be hydrolysed, amino or C 1-6  alkylamino groups acylated, amino groups alkylated, carbonyl groups reduced to >CHOH and hydroxymethylene groups esterified. Epoxy compounds of Formula II above are obtained by reacting the appropriate phenols or thiophenols with epichlorohydrin. 41 - [3 - (1 - Aziridinyl) - 2 - hydroxypropoxy]- butyranilido and 2<SP>1</SP>- [3 - (1 - aziridinyl) - 2- hydroxypropoxy]acetanilide are made by reacting ethylene-imine with 4<SP>1</SP>-(2,3-epoxypropoxy)butyranilide and 2<SP>1 </SP>- (2,3 - epoxypropoxy)acetanilide respectively. 41 - [3 - (1 - Piperazinyl) - 2 - hydroxypropoxy)- acetanilide is obtained by hydrogenolysis of 4<SP>1</SP>- [3 - (4 - benzyl - 1 - piperazinyl) - 2 - hydroxypropoxy)-acetanilide resulting from the reaction between 41-(2,3-epoxypropoxy]acetanilide and 1-benzylpiperazine. 4<SP>1</SP>- (3 - Chloro - 2 - hydroxypropoxy)acetanilide is made by refluxing 4<SP>1</SP>-(2,3-epoxypropoxy)acetanilide with pyridine hydrochloride. 2 - {3 - [4 - (o - Methoxyphenyl) - 1 - piperazinyl]-propoxy}nitrobenzene is obtained by reacting o-anisidine with 2-{3-[bis-(2-chloroethyl) - amino]propoxy}nitrobenzene, resulting from the chlorination of 2 - {3 - [bis - (2 - hydroxyethyl)- amino]propoxy}nitrobenzene which is prepared by reacting 2-(3-bromopropoxy)nitrobenzene with diethanolamine. 2<SP>1</SP> - [3 - (4 - Phenyl) - 1 - (2,6 - dioxopiperazinyl) - 2 - hydroxypropoxy)acetanilide is made by reacting 4-phenyl-2,6-dioxopiperazine with 2<SP>1</SP>-(2,3-epoxypropoxy)acetanilide. 4<SP>1</SP> - {3 - [4 - (o - Nitrophenyl) - 1 - piperazinyl] - 2 - hydroxypropoxy}acetanilide is obtained by reacting 4<SP>1</SP>-[3-(1-piperazinyl)-2-hydroxypropoxy]acetanilide hydrochloride with o-chloronitrobenzene. 2<SP>1</SP> - [3 - Amino - 2 - hydroxypropoxy]acetanilide and 4<SP>1</SP> - [3 - amino - 2 - hydroxypropoxy)butyranilide are prepared by treating 2<SP>1</SP>-[2,3-epoxypropoxy] - acetanilide and 4<SP>1</SP> - [2,3 - epoxypropoxy]butyranilide respectively with a solution of ammonia in methanol. 2<SP>1</SP> - {3 - [2 - (o - Anisidino)ethylamino]- 2- hydroxypropoxy}acetanilide and 41 - {3 - [2- (o - anisodinoethyl)amino] - 2 - hydroxypropoxy} - butyranilide are obtained by reacting 21-(2,3- epoxypropoxy)acetanilide and 4<SP>1</SP>-(2,3-epoxypropoxy)butyranilide respectively with ethyleneimine and treating the resulting 2<SP>1</SP>-[3-(1- aziridinyl) - 2 - hydroxypropoxy]acetanilide and 41 - [3 - (1 - aziridinyl) - 2 - hydroxypropoxy]butyranilide with o-anisidine. 1 - Chloro - 2 - hydroxy - 3 - [4 - (o - methoxy - phenyl)-1-piperazinyl]propane is obtained by reacting 1-(o-methoxyphenyl)piperazine with epichlorohydrin. Pharmaceutical compositions, suitable for enteral or parenteral administration, contain the above novel compounds or acid addition salts thereof in admixture with pharmaceutically acceptable carriers. The compounds possess hypotensive activity.