NO139736B - ANALOGICAL PROCEDURES FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE NEW 3ALFA, 17A-DIACETOXY-2BETA, 17BETA-BIS (1-ALKYLPIPERIDINO) -D-HOMO-5ALFA-ANDROSTANE DIHALOGENIDES - Google Patents

Description

The present invention relates to an analogous process for the production of new 3a,17a-diacetoxy-2(3,173-bis-(1-alkyl-piperidino)-D-homo-5a-androstane dihalides with the general formula I

where R" denotes alkyl with 1-4 carbon atoms and X denotes chlorine, bromine or iodine, the method being characterized by what is stated in the characterizing part of claim 1.

Preferred compounds of formula I are those where R 1 is methyl and the dibromides are particularly preferred.

The compounds of formula I can be prepared in a manner known per se by treating each compound of the general formula II with an alkyl halide with 1-4 carbon atoms, preferably methyl bromide in a suitable solvent and subsequent work-up of the reaction mixture, e.g. by evaporation of the solution and chromatography and/or recrystallization of the evaporation residue.

The compounds present here have valuable pharmacological properties. They have a particularly strong influence on

the autonomic nervous system as they block the neuromuscular transmission and the duration of the effect is relatively short which is highly desirable and beneficial. In addition, they do not cause the release of histamine and no lowering of blood pressure. The compounds can therefore, like the depolarisation-inhibiting muscle relaxants of the curare type, be used in anesthesia and can be given in a manner known per se, preferably by intravenous injection, with a dose of the order of 1 - 50 mg, preferably 2-25 mg or 5-10 mg to which further doses of 1-5 mg or lower can be added.

The compounds converted here can e.g. also used in shock therapy and for lowering muscle tone in spasms in the striated muscles.

When examining 3a , 17a|3-diacetoxy-23,17fJ-bis (1-methylpiperidino)-D-homo-5a-androstane dibromide (compound A) with regard to its muscle relaxant effect in anesthetized cats, the results stated below are obtained in table I. In relation to the structurally closest known compound, 3a, 17(3-diaceotksy-2|3,163-bis-piperidino-5a-androstane-dimetho-bromide which is known under the name Pancuronium bromide and is described in Danish patent no. 114,688, compound A excels by having a shorter duration of action with the same potency, which is a highly desired therapeutic effect. The results of the comparison trials appear in Table I below.

n denotes the number of trials.

Because of the particular advantages associated with 3a,17a(3-diacetoxy-33,173-bis(1-methylpiperidino)-D-homo-5a-androstane dibromide and 3a,17aa-diacetoxy-23,173-bis(1-methylpiperidino ) - D-homo-5a-androstane dibromide preferred embodiments of the method according to the invention involve 3a,17a3-diacetoxy-23,173-dipiperidino-D-homo-5a-androstane being reacted with methyl bromide to 3a,17a3-diacetoxy-23, 17|3-bis (1-methylpiperidino)-D-homo-5a-androstane dibromide, or that 3a,17aa-diacetoxy-23/173-dipiperidino-D-homo-5a-androstane is reacted with methyl bromide to 3a,17aa- diacetoxy-23/173-bis(1-methylpiperidino)-D-homo-5α-androstane dibromide.

The compounds included here can e.g. are used in the form of pharmaceutical preparations that contain them in admixture with a suitable, pharmaceutical, organic or inorganic, inert carrier material.

The method according to the invention is illustrated in more detail by the following examples:

Example 1

A solution of 225 mg of 3a,17a(3-diacetoxy-2(3,17(3-dipiperidino-D-homo-5a-androstane) in 2 ml of acetonitrile and 2 ml of methyl bromide was kept for 170 hours at room temperature. Then the solvent was evaporated under reduced pressure and the residue chromatographed on alumina (act. III). Pure 3a,17a3-diacetoxy-2p,173-bis-(1-methylpiperidinio)-D-homo-5a-androstane dibromide was eluted with isopropanol-acetic ester 2: 1, which after recrystallization from methylene chloride-acetone melted at 250-251°C.

[a]^ = +51° (c = 0.1 in. dioxane) .

Preparation of the starting material: 33-hydroxy-D-homo-androstan-17-one was catalyzed with ethylene glycol/p-toluenesulfonic acid to 17a,17a_ethylenedioxy-33-hydroxy-D-homo-androstane, melting point 196-198°C. This compound was converted with p-tosyl chloride/pyridine into the 3-tosylate, which after heating in dimethylsulfoxide in the presence of potassium tertiary butylate gave the compound 17a,17a-ethylenedioxy-D-homo-5a-androst-2-ene. This was hydrolyzed with p-toluenesulfonic acid in acetone-water to . D-homo-5a-androst-2-en-17a-one, melting point 131-132°C, [a]^<5> = 0° and from there was obtained with acetic anhydride in dioxane and catalytic amount of perchloric acid 17a-acetoxy -D-homo-5a-androsta-2,17(17a)-diene with melting point 140-142°C. By reacting this compound with m-chloroperbenzoic acid in ether, 17ap-acetoxy-2a,3a; 17a,17aa-diepoxy-D-homo-5a-androstane, melting point 183-186°C, [a]^<5>° = +52° obtained.

15.0 g of 17ap-acetoxy-2a,3a^17a,17aa-diepoxy-D-homo-5a-androstane was heated with 75 ml of piperidine and 25 ml of water for 17 hours under reflux. The reaction mixture was then concentrated to half in vacuo, mixed with 200 ml of ice water, acidified with conc. hydrochloric acid and extracted with ether. The acidic aqueous solution was made alkaline with 2N sodium hydroxide solution and then extracted 3 times with methylene chloride. This extract was washed with water, dried with pot ash and the solvent evaporated away in a vacuum. The residue was recrystallized from acetone. Pure 3a-hydroxy-23,173-dipiperidino-D-homo-5a-androstan-17a-one with melting point 215-220°C is obtained. [a]^<5>° = -5°.

A solution of 350 mg of 3α-hydroxy-2β,17β-dipiperidino-D-homo-5oc-androstan-17α-one in 2 ml of tetrahydrofuran and 1 ml of methanol was mixed with a solution of 165 mg of sodium borohydride in 0.5 ml of water. The solution was kept for 24 hours at room temperature and then mixed with 20 ml of water. The crystalline precipitate was filtered off, dried in vacuo and chromatographed with ether-hexane over alumina. With ether-hexane 5:1, pure 23,17(3-dipiperidino-3a,17ap-dihydroxy-D-homo-5a-androstane, melting point 225-227°C, was eluted. [a]^<5>° = + 19° (c = 0.1 in dioxane).

420 mg of 3a,17a3-dihydroxy-23,17p-dipiperidino-D-homo-5a-androstane were heated with 1 ml of acetic anhydride for 60 minutes at 90°C. The reaction solution was evaporated to dryness in vacuo and the residue chromatographed on alumina. With benzene, pure, amorphous 3a,17ap-diacetoxy-2p,17p-dipiperidino-D-homo-5a-androstane could be eluted by thin-layer chromatography. [a]^<5>° = -13° (c = 0.1 in dioxane).

Example 2

A mixture of 92 mg of 3a,17aa-diacetoxy-23,173-dipiperidino-D-homo-5a-androstane, 1 ml of acetonitrile and 1 ml of methyl bromide was stored for 250 hours in a closed apparatus at room temperature. The reaction solution was then evaporated to dryness under reduced pressure and the residue chromatographed over alumina (Act. III). Pure 3α,17α-diacetoxy-23,173-bis-(1-methylpiperidindo)-D-homo-5α-androstane dibromide was eluted as a colorless foam with ethyl acetate-isopropyl alcohol (4:1). [a]p5 = +28° (c = 0.1 in dioxane).

Preparation of the starting material: 3p,17ap-dihydroxy-D-homo-5a-androstane sulfochloride was converted in pyridine to 3p,17a(3-ditosyloxy-D-homo-5a-androstane which on heating in dimethylsulfoxide in the presence of potassium tertiary butylate converted to the amorphous D-homo-5a-androsta-2,17(17a)-diene

([a]^ = +66°) . This compound was reacted in ether with m-chloroperbenzoic acid and gave as main product 2a,3a$17a,17aa-diepoxy-D-homo-5a-androstane, melting point 172-173°C (methanol), [oc]^5 <= > +26° (c = 0.1 in dioxane). Amorphous 2a,3a517p,17aa-diepoxy-D-homo-5a-androstane was obtained as a by-product, [a]^ = +39°.

A mixture of 200 mg of 2a,3a517a,17aa-diepoxy-D-homo-5a-androstane, 1 ml of piperidine and 0.3 ml of water was heated under reflux for 26 hours. For work-up, it was poured into ice water, acidified with dilute hydrochloric acid and extracted twice with ether. The acidic, aqueous solution was then made alkaline with dilute caustic soda and extracted with methylene chloride. This extract was washed with water, dried with Na 2 SO 4 and evaporated under reduced pressure.

The residue was chromatographed on aluminum oxide (Act. III). With ether and 2% methanol, pure 3a,17aa-dihydroxy-23,173,dipiperidino-D-homo-5a-androstane with melting point 197-199°C (acetone-hexane) was eluted. [a]^° = +22° (c = 0.1 in dioxane).

200 mg of 3α,17α-dihydroxy-23,17β-dipiperidino-D-homo-5α-androstane and 0.5 ml of acetic anhydride were heated for 2 hours at 90°C. The reaction mixture was evaporated to dryness under reduced pressure and the residue chromatographed over alumina (Act. II). Pure, amorphous 3α,17aa-diacetoxy-23,173-dipiperidino-D-homo-5α-androstane was eluted with benzene. [a]D = +16 (c = 0.1 in dioxane).

Claims (3)

1. Analogous process for the preparation of therapeutically active 3α,17α-diacetoxy-23,173-bis(1-alkylpiperidino)-D-homo-5α-androstane dihalides of the general formula I where R denotes alkyl with 1-4 carbon atoms and X denotes chlorine, bromine or iodine, characterized in that a compound of the general formula II is reacted with an alkyl halide with 1-4 carbon atoms in a suitable solvent. 2. Method according to claim 1, characterized in that 3a,17a3-diacetoxy-23,173-dipiperidino-D-homo-5a-androstane is reacted with methyl bromide to 3a,17a&-diacetoxy-23,173-bis(1-methylpiperidino)-b- homo-5α-androstane dibromide. 3. Process according to claim 1, characterized in that 3a,17aa-diacetoxy-23,173-dipiperidino-D-homo-5a-androstane is reacted with methyl bromide to 3a,17aa-diacetoxy-23,173-bis(1-methylpiperidino)-D-homo- 5α-androstane dibromide.