IL42600A - Bis-piperazino-androstane derivatives and a process for the preparation thereof - Google Patents

Description

NEW BISTPIPERAZINO-ANDROSTANE DERIVATIVES AND A PROCESS FOR THE PREPARATION THEREOF ftlchtor Qetleon <£r -T& This invention relates to novel 2β ,160-bis-pi perazino-androstane derivatives having the general form pounds.

In the above formulae alkanoyl R represents hydrogen or a C^_g group, R1 represents a alkvl group, vinyl group, allyl group hydroxyethyl group, or (C^^-alkano lo )-ethyl group R2 represents hydrogen, a C^g alkyl group, allyl group or benzyl group, 42600/2 - 3 - X and Y together may form an oxo. roup, and Z represents a chloride, bromide, iodide, hydroxy, mesyloxy, or tosyloxy anion.

The compounds of the general formula (I) possess valuable biological activities, the salts of the general formula (II), however, are of greater importance. Among the compounds of the general formula (II) 2p,^-bis(4-methyl-4-allyl-l-piperazinyl)-3 -l7p-diacetoxy-5 -androstane dibromide is particularly preferred, since it exerts a curare-like, neomuscu-lar blocking (non depolarizing) activity, and inhibits the transfer of nerve stimuli onto the striated muscles. The activity of this compound exceeds many times that of D-tubo-curanine or pancuronium bromide. The novel compound does not cause hystamine liberation, has ah hypotensive side-effect, and its effect can be suspended upon neostigmine administration. Compared to the known nondepolarizing substances, the effect of the new compound sets in more quickly, and the duration of its effect is like to that of tubocuranine · The new compound has no hormonal activity.

U.S. Patent Specif cation No. 3553212 describes certain 2p,16p-diamino andhostanes. There are described three types of heterocyclic amines namely the morpholino, piperidino and pyrolidine groups. However, no piperazine amine was disclosed in said specification.

It has been found that the 20,16p-bis-piperazino-andro-stane derivatives accordin to the present invention have a substantially higher activity than the best compound disclosed 42600/2 in said specification namely the pancuranium-bromide.

The new compounds of the invention can be used first of all in the surgery, as well as a muscle relaxant agent in intubation narcosis. The novel compounds can further be used in the shock therapy, and for the reduction of muscular tonus in spasmodic conditions of the striated musculature.

The novel 2p,16p-bisppiperazino~androstane derivatives of the general formula (I), or their salts of the general formula (II) can be prepared, according to the invention, as follows t 20, 542 to 545 /195S/3 with is propenyl acetate and epox- idizihg the thus-formed 17-acetoxy-5c<-androst-2 ,16-diene with perbehzoic acid.

According to the process of the invention 2o(,- 3o<,16< ,17o(-diepoxy-17p-acetoxy-5<--ahdrostane of the formula Clli Vis reacted with a piperazine derivative of the general formula (iV ) in an aqueous medium generally at e, temperature of 70 to 160°C, under atmospheric or super- atmospheric pressure. The reaction terminates within a period of 35 hours to 5 days. When the reaction terminates the excess of the piperazine derivative is distilled off in vacuo, the residue is triturated with water , and the solids are filtered off. When piperazine derivatives of higher boiling points are Used, the reaction mixture is preferably worked up by admixing it with water and filtering off the separated precipitate. The thus-obtained crude bis-piperazino compounds can be purified by acidic-alkaline' precipitation, recrystallization, or both.

The thus-obtained 2 ,16p-bis-piperazino-3« --hydroxy-i7-oxo-5e<-androstane derivatives of the general formula CI) can be subjected to reduction , if desired. The reduction can be carried out in an inert solvent, in the presence of an alkali metal borohydride , such as sodium borohydride , alkali metal aluminium hydride, such as lithium aluminium hydride , or alkali metal alkoxy aluminium hydride, such as sodium-bis-2-methoxyethoxy-lithium aluminium hydride . The reaction is conducted preferably at room temperature. - - - - - rilized, if necessary.

The pharmaceutical compositions may also contain auxiliary agents, such as salts for adjusting the osmotic pressure, buffers, etc. The pharmaceutical corn- positions can be prepared by known methods.

When preparing an injectable composition the active agents Csuch as 2/3 ,16p-bis-(4-methyl-'+-allyl-l- -piperaziny1) -3cx, 170-diacetoxy-5oC-androstane dibromide) is dissolved in pyrogen-free physiological saline or in bi- distilled water, the solution is sterilized, and filled into ampoulles under sterile conditions.

The invention is further elucidated by the follow ing non-limiting Examples.

Example 1 100 g. of 17-oxo-5o<-androst-2-ene are dissolved in 300 ml. of freshly distilled isopropenyl acetate, thereafter 'a. mixture of 1 ml. of concentrated sulfuric acid and 50 ml. of isopropenyl acetate is added to the solu- tion. The reaction mixture is heated slowly and gradually, Within about 1.5 hours , to the boiling point, and the acetone liberated in the reaction is continuously distilled off using a mirror column of 80 cm. length, filled with Raschig rings. After about 6 hours of distillation the mixture is cooled to room temperature, and poured into 0Q0 ml. of ice water. After some hours of standing the separated precipitate is filtered off, and washed thoroughly with ice-cold water. The wet precipitate is dissolved mixture is heated at 120 °C external temperature for 70 hours under nitrogen atmosphere, thereafter the excess of N-methyl-piperazine is distilled off in vacuo, the residue is triturated with acetone, the solids are filtered 6ff , and washed with ice-cold acetone. The obtained crude product is mixed with twofold amount of acetone i and the mixture is boiled fo some minutes . Thereafter the mixture is cooled to 0°C, the separated white, crystalline product is collected by filtration , arid dried in vacuo until constant weigt . ··. .;. ■:, .···':·· ' ;·.'; 4 1? |. C63% of 2 , 16p -bis-C*-methy1-1-piper- aziho)-3oC-hydroxy-17-oxo-5o(-androstane are obtained, m.pVi 195-197°C Analysis: Calculated for C2gH5002Ni+ .2H20 ί C: 66.6 % H: 10.3% N: 10.7% Found: C: 66.4% H: 10.5% . N: 10.5%.

; Example 5 5.8 g. of 2|3 ,168-bis-(4-methyl-l-piperazinyl) - -3cf,17p-dihydroxy-5o<-androstane are dissolved in a mixture of 20 ml. of acetic anhydride and 5 ml. of glacial acetic acid, and 0.5 g. of zinc chloride are added to the solution. The reaction mixture is stirred at room temperature for 3 hours , thereafter it is poured into 250 ml. of ice water'. The mixture is cautiously alkalinized CpH = = '9-10 D at 0°C, the separated precipitate is filtered off, and washed well with cold water. The obtained pasty substance is dissolved in ether, the solutio is dried over sodium sulphate, filtered, and the filtrate is mixed with a five-fold amount of silica gel. The mixture is filtered, the filtrate is evaporated, and the residue is triturated with petroleum ether. The white, fluffy precipit 5 g. (.71%·) of 2B ,16p-bis-C4-methyi-i-piperazin- yl)-3«,17p-diacetoxy-5ος-androstane are obtained.

Analysis : Calculated for C: 69.2 % H: 9.7 % N: 9.7 % Found: C: 69.0 % N: 9.8 % N:10 % Example 6 4.5 g. of 2Θ ,16|3-bis-(4-hydroxyethyi-l-piper- azinyl' -3c<,,17p-dihydroxy-5o(-androstane are dissolved in a mixture of 25 ml. of acetic anhydride and 5 ml. of glacial acetic acid, and 0.5 g. of zinc chloride are added to the reaction mixture. The mixture is stirred for 4 hours at room temperature * thereafter it is poured into 250 ml. of ice water. The mixture is cautiously alkalin- ized to pH 9-10 at 0°C. The separated precipitate is filtered off, and washed well with cold Water; The obtained crude product is dissolved in ether, the solution is dried over sodium sulfate, filtered, and the filtrate is treated with a five-fold amount of silica gel. The adsorbent is filtered off, and the filtrate is evaporated . The residue is triturated with a mixture of ether and petroleum ether, the white fluffy precipitate is filtered off, arid dried in vacuo until constant weight. 4.4 g. (81%) of 2β ,16B-bis-C4-acetoxy-ethyl-l- -piperazinyn-3c>{,17p-diacetoxy-5o<-andr0s,tane are obtained. . ■ ..·.

Anal sis : Found: C: 65.2 % H: 8.7 % N: 7.8 % Analysis : Calculated for ^7H7o04 ¾Cl2.2H20: C: 65.6% H: 8.6 % Cl": 8.2 %a Found: C: 65.4% H: 8.3 % Cl~: 8% Example 9 t g. of 2p,16p-bis-(4-methyl-l-piperazinyl.)- -3o( jl7p-diacetoxy-5o<-androstane are dissolved in a mixture of 140 ml. of methylene chloride and 20 ml. of nitro- methane, and 9 ml. of methyl bromide are added to the sol tion. The reaction mixture is left to stand at room tempo ure for 2 days in a pressure tube. The tube ie vented, ai> the separated solid, a "trimethobromide" by-product, formed in some per cents, is removed by filtration. Th^ filtrate is diluted with ether, the separated solids are filtered off, and recrystallized from a mixture of nr-thyl-ene chloride and ether. 4.5 g. C81 %) of 2p,16/3-C4-dimethyi-l-piperazin yl)-3ors17p-diacetoxy-5o{-androstane dibromide are obtained; m.p. : 252-25i4°C.

Analysis : Calculated for C35H62°HNl+Br2 * 2H2° : C: 53.J-? % H: 8.3 % Br": 20.9 % Found : % H: 8.8 % ' Br": %.

Example 10 0.6 g. of 2β ,16B-bis-C4-methyl-l- i erazinyl)--3 Analysis: Calculated for C35H6()02NuBr2.2H20 : C: 54.9 % H: 8.3 % Br": 20.9 % Found: C: 54.7 % H: 8.4 % Br": 20.7 % Example 11 0.7 g. of 2B,16p-bis-C4-methyl-l-piperazinyD--3of,17p-dihydroxy-5 • Analysis : Calculated for C35H62°2N2C12' 2H20: C: 62.2 % H: 9.7 % C1 : 10.5 % Found: C: 62.1 % H: 9.8 % Cl": 10.5 % Example 12 C: 58. i+ % H: 7.7 % Br": 16.6 % Found: C: 58.1 H: 7.8 % Br": 16.3 %.

Example l 0.6 g. of 2β ,16 -bis-C4-hydroxyethyl-l-piper- azinyl)-3x-hydroxy-17-oxo-5(*-androstane are dissolved ;n a mixture of 25 ml. of acetonitrile and 5 ml. of chloroform* and 4 ml. of allyl bromide are added to the solution. The reaction mixture is boiled for 2.5 hours, then it is cooled to room temperature, and diluted with ether to threefold volume. The separated white, crystalline substance is filtered off, and recrystallized from a mixture of ethanol and ether. 0.75 g. (88 %") of 2β ,16B-bis-(U-hydroxyethyl~ -4-allyl-l-piperazinyl) -3c(-hydroxy-17-oxo-5oC-androstane: dibromide are obtained; m.p.: 218-220°C.

Analysis: Calculated for C^Hg^N^B^ .2H20 : C: 53.8 % H: 7.7 ¾ Br": 19.4 % Found: C: 53.5 H: 7.5 % Br~ : 19.2 %.

Example 15 0.5 g. of 2β ,16@-bis-(4-hydroxyethyl-l-piper--azinylJ -3σ(, 17p-dihydroxy-5e<-androstane are dissolved in a mixture of 30 ml. of acetonitrile and 5 ml. of chloroform, and 1 ml. of allyl bromide are added to the solution. The reaction mixture is boiled for 2.5 hours, then it is cooled to room temperature, and diluted with ether to threefold volume. The separated white, crystalline

Claims (1)

1. WHAT WE CLAIM IS: 1. A 2|3 ,16f3-bis-piperazino-androstane deriv- having the general formula CI) alkanoyl R represents hydrogen or a C^_g eeyi group, R^ represents ~~.a C^_& alkyl group, vinyl group, allyl group ΌΟ- hydroxyethyl group,, or (C^^alkanoyloxy )-ethyl group R2 represents hydrogen, a C-^g alkyl group, allyl group or benzyl group, X stands for hydrogen, alkanoyloxy Y represents hydroxy or a C1_g efce-y-ieoty- group, or X and Y together may form an oxo group, and i e mide iodide h drox mes lox / formula (IV) is carried out in aqueous medium. 19. A process as claimed in Claim 17 or 18, in which the reaction using a piperazine derivative of the general formula (IV) is carried out at 70 to 160°C, 5 preferably at 80 to 120°C. 20. A process as claimed in any of point.- a/ to d/ of Claim 17 , in which acylation is carried out :u. the presence of a Lewis acid, preferably of zinc chloric 21. A process as claimed in any of points a/ 0 to d/ of Claim 17, in which acylation is carried out at room temperature. 22. A process as claimed in Claim 17 , point o7 or in any of Claims 19 to 20, in which the second acyla tion is carried out with an acylating agent other than 5 that used in the first acylation step. 23. A procees as claimed in any of points a/ to d of Claim 17 or in any of Claims 19 to 20, in which the acylation is carried out using an acetylating agent. 24. A process as claimed in any of points b/ 0 to e/ of Claim 17, in which reduction is carried out in the presence of an alkali metal borohydride, preferably sodium borohydride, an alkali metal aluminium hydride, preferably lithium aluminium hydride, or an alkali metal - -alkoxy-aluminium hydride, preferably sodium-bis-2-meth™ 5 oxyethbxy-lithium aluminium hydride . 25. A process as claimed in any of points b/ to e of Claim 17 , or in Claim 24 , in which reduction is carried out at room temperature. 26. A process as claimed in any of points b/ o e of Claim 17 or in any of Claims 2 to 25, in which tuents have the" same meaning as defined in Clai-n 1 -is admixed with a carrier or diluent. 32. A compound of the general formulae (I) or (II) substantially as defined in Claims 1 to 16 , with particular reference to the Examples. 33. A process as claimed in Claims 17 to 29 substantially as hereinbefore described with particular' reference to the Examples. For the Applicants Dr. Yitzhak Hess