IE42058B1

IE42058B1 - Quaternary salts of d- homosteroids

Info

Publication number: IE42058B1
Application number: IE2344/75A
Authority: IE
Original assignee: Hoffmann La Roche
Priority date: 1974-10-29
Filing date: 1975-10-28
Publication date: 1980-05-21
Also published as: DK135316C; IE42058L; NO139736C; DE2547739A1; DK485975A; FI53711B; GB1498239A; AU8541875A; AR212436A1; ES442142A1; NZ178817A; NL7512661A; FI752825A; SE413248B; NO139736B; SE7512006L; LU73655A1; ATA819375A; CH602794A5; BE834925A

Abstract

1498239 D-homo steroid amine salts F HOFFMANN-LA ROCHE & CO AG 28 Oct 1975 [29 Oct 1974] 44288/75 Heading C2U The invention comprises the mono and bis quaternary salts of diamines of Formula I and also the acid addition salts of the monoquaternary salts (R1, R2, R4 and R5 are each H, C 1-10 alkyl or C 7-10 aralkyl, or NR1R2 or NR4R5 is a heterocyclic group; R3 is H or acyl; R6 is oxo (H, α-OR7) or (H, #-OR7) where R7 is H or acyl); and their preparation by salification of the diamines (e.g. with an alkyl halide) and if desired reducing a 17a-oxo group or acylating a 3- or 17ahydroxy group. 3# - Hydroxy - D - homo - 5α - androstan- 17a - one#3# - hydroxy - 17a,17a - ethylenedioxy- D - homo - 5α - androstane#3# - tosyloxy- 17a,17a - ethylenedioxy - D - homo - 5α - androstane#17a,17a - ethylenedixoy - D - homo - 5α- androst - 2 - ene#D - homo - 5α - androst - 2- en - 17a - one#17a - acetoxy - D - homo - 5α androsta - 2,17(17a) - diene#17α# - acetoxy- 2α,3α; 17a,17aα - diepoxy - D - homo - 5α- androstane#(i) 3α - hydroxy - 2#,17# - bis- (dimethylamino) - D - homo - 5α - androstan - 17aone or (ii) 3α - hydroxy - 2#.17# - dipiperidino- D - homo - 5α - androstan - 17a - one; then (ii)# 3α,17α# - dihydroxy - 2#,17# - dipiperidino - D- homo - 5α - androstane#3α,17a# - diacetoxy- 2#,17#-dipiperidino-D-homo-5α-androstane. 3#,17α# - Dihydroxy - D - homo - 5α - androstane - 3#,17α# - ditosyloxy - D - homo - 5α- androstane#D - homo - 5α - androsta - 2,17(17a)- diene#(i) 2α,3α; 17α,17aα - diepoxy - D- homo - 5α - androstane and (ii) its 17#,17a#- isomer; then (i) #3α,17aα - dihydroxy- 2#,17# - dipiperidino - D - homo - 5α - androstane#3α,17aα - diacetoxy - 2#,17# - dipiperidino-D-homo-5α-androstane. Anaesthetic parenteral compositions comprise a carrier and a compound of the invention.

Description

The present invention relates to steroids. More particularly, the invention is concerned with quaternary salts o£ D-homosteroids of the general formula , wherein R1, R2, R^ and R® each independently represent a hydrogen atom or a G3_3q1 2 alkyl or C^_^Q-aralkyl group or R and R 4 5 or R and R together with the N-atom to which they are;attached represent a hetero10 cyclic group; R2 represents a hydrogen £ atom or an acyl group; and R represents 7 7 an oxo, (β-H, ct-OR ) or (a-H, β-OR ) group in which R7 represents a hydrogen atom or an acyl group, at least one nitrogen atom being present in quaternised form, and acid addition salts of mono-quaternary salts of D-homosteroids of formula I.

The quaternary salts in accordance with the invention are preferably formed with alkyl .halides, especially alkyl halides such as methyl or ethyl bromide, chloride or iodide.

Examples of C1_^Q-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and isomers thereof, pentyl, hexyl, octyl and decyl. Examples of C7_1Q-aralkyl groups are benzyl and phenethyl. Examples of heterocyclic residues which may 12 4 5 be formed by R and R or R and R together with the N-atom to which they are attached are pyrrolidino, piperidino,' morpholino and piperazino.

The acid addition salts provided by the present invention can be formed with organic acids (e.g. alkanecarboxylic acids such as acetic acid or succinic acid, hydroxycarboxylic acids such as citric acid or aromatic carboxylic acids such as phenylacetic acid, benzoic acid or mandelic acid) or mineral acids (e.g. hydrochloric acid or sulphuric acid).

A preferred group of quaternary salts provided by the present invention comprises those of the general formula significance given earlier; one of R and 9 R represents an alkyl group and the other 20 represents a hydrogen atom or an alkyl group; and X© represents an anion, at least one nitrogen atom being present in quaternised form.

Especially preferred are the salts of formula II in which the groups -NiR1)(R2) and -N(R4)(R3) represent the piperidino group; R3 represents a hydrogen atom or a cj_4“ 7 alkanoyl group; R represents the grouping (H, OR ) wherein - 8 9 R represents a C1_4-alkanoyl group; R and R each represent a C1_4~alkyl group; and X represents bromine, chlorine or iodine.

According to the process provided by the present invention, the quaternary salts of the D-homosteroids of formula I and acid addition salt's of mono-quaternary salts of D-homosteroids of formula I are manufactured by quaternising one or . both amino groups of a D-homosteroid of formula I and, if desired, functionally modifying the group denoted by R®, acylating a 3-hydroxy group and/or converting a mono-quater15 nary salt obtained into an acid addition salt.

The quaternisation of a D-homosteroid of formula I can be carried out by adding a quaternising agent (e.g. an alkyl halide) to a solution of said D-homosteroid and working-up the resulting mixture; for example, by concentration of the solution and chromatography and/or recrystallisation of the residue. The mono-quaternary salts can be manufactured using stoichiometric amounts of a D-hoiiioSteroid of formula I and a quaternising agent and separating the desired product.

The acylation of a 3-hydroxy group can bo carried out in a manner known per se; for example, by treatment with an acyl halide or anhydride. - 4 42058 A 17a-oxo group can be reduced to the hydroxy group in a manner known per se; for example, with a complex metal hydride such as sodium borohydride, lithium aluminium hydride or lithium tri(tert-butoxy)-aluminium hydride. A 17a-hydroxy group can be acylated in the same manner as described earlier in connection with the acylation of a 3-hydroxy group.

A mono-quaternary salt of a D-homosteroid of formula I can be converted by treatment with an acid of the formula HX (e.g. one of the mineral acids or organic acids mentioned earlier) into a salt of such an acid.

The D-homosteroids of formula I can be prepared by reacting a 2α,3a;17a,l7aa-diepoxy-D-homo-5a-androstane of the general formula , wherein R represents a hydrogen atom or the acetoxy group, with an amine of the formula HNtR1) (R2) or I1N(R4) (R5) in which 12 4-5 R ,R ,R* and R3 have the significance given earlier. Xt is possible to prepare D-homosteroids of formula X in which R1 and 4 5 R are different from R and R . In this case, a diepoxide of formula III is reacted with an equivalent amount of an amine of the formula HNfR1)(R2) or HN(R4)(R^), whereby only one epoxide grouping reacts; In a subsequent reaction with an amine of the formula HN(R4)(R~*) or HNCR1)(R2), there is obtained a D-homosteroid Of formula I in which R and R are ' different'TromTi4 and R^T ' The preparation of 'the D-homosteroids of formula I and the diepoxides of formula III is more fully described in the Examples.

The quaternary salts of D-homosteroids of formula I and acid addition salts of mono-quaternary salts of 0-homosteroids of formula I possess valuable pharmacological properties.

They have an especially strong influence on the autonomic nervous system since they block the neuromuscular transmission, their duration of action being relatively short which is very desirable and advantageous. During this action, they cause no liberation of histamine or lowering of the blood pressure. They may accordingly be used in anaesthesis -in the same manner as the depolarisation-inhibiting muscle relaxants (M. . *· TJJ .... - .^,57 . of the curare type and may be administered in a manner known per se; preferably by intravenous injection, in which case a dosage in the range of 1-50 mg, preferably 2-25 mg or 5-10 mg, is conveniently administered initially and oan be supplemented by further dosages of 1-5 mg or below.

The quaternary salts of D-homosteroids of formula I and acid addition salts of mono-quaternary salts of D-homosteroids of formula I can, however, also be used, for example, in shock therapy as well as for lowering the muscle tone in the case of convulsive conditions of the striated muscles.

The testing of 3a,17ai?-diacetoxy-20,176-bis-(1-methylpiperidinio)-D-homo-5a-androstane dibromide in the narcotised cat for muscle relaxant activity yields the following results: Oosage mol/kg i.v. n. = 3 5 Δ% min. io-8 — — 3 χ 10-8 -90 10 io“7 -100 20 3 χ 10-7 -100 40 10 106 -100 60 n = Number of the test The quaternary salts of D-homosteroids of formula I and acid addition salts of mono-quaternary salts of D-homosteroids of formula I can be used, for example, in the form of pharma15 ceutical preparations which contain them in association with a compatible pharmaceutical carrier material which can be an organic or inorganic carrier material. - 7 42058 The following Examples illustrate the process provided by the present invention: Example 1 A solution of 225 mg of 3a,17a0-diaeetoxy-20,1705 dipiperidino-D-homo-5a-androstane in 2 ml of acetonitrile and ml of methyl bromide was kept for 170 hours at room temperature. Subsequently, the solvent was evaporated off under reduced pressure and the residue chromatographed on aluminium oxide (Activity III). Elution with isopropaiiol/ethyi acetate (2:1) yielded pure 3a, 17a0-diacetoxy-20,170-bis(1-methy 1piperidinio)-D-homo-5a-androstane dibromide which melted at 25O°-251°C after recrystallisation from methylene chloride/ ° acetone; [α]β = +51° (c - 0.1 in dioxane).

The starting material. can be prepared as follows: -Hydroxy-D-homo- 5a -androstan-17a -one was ketalised with ethyleneglycol/p-toluenesulphonic acid to give 17a,17aethyleriedioxy-30-hydroxy-D-homo-5d -androstane of melting point 196°-198°C, This ketal was converted With p-tosyl chloride/ pyridine into the 3-tosylate which, after heating in dimethyl sulphoxide ih the presence of potassium tert.butylate,. yielded 17a,17a-ethylenedioxy-D-homo-5a-androst-2-ene. This was hydrolysed with p-toluenesulphonic· acid in acetone/water to give D-homo-5a-androst-2-en-17a-one of melting point 131°-132°C and 25θ o faJjj·’ «= 0° (c=0.1 in dioxane) from which, by treatment with acetic anhydride in dioxane and catalytic amounts Of perchloric acid there was obtained. 17a-acetoxy-D-homo-5a-androsta-2,17(17a)- 8 42058 diene of melting point 140°-142°C. By reaction of this latter D-homosteroid with m-chloroperbenzoic acid in ether there was obtained 17a0-acetoxy-2a,3a;17a,17aa-diepoxy-D-homo-5aandrostane of melting point 183°-186°C; = +52° (c=0.1 in dioxane). .0 g of 17a8-acetoxy-2a,3a}17a,17aa-diepoxy-D-homo-5aandrostane were heated under reflux for 17 hours with 75 ml of piperidine and 25 ml of water. The mixture was then concentrated to half in a vacuum, treated with 200 ml of ice-water, acidified with concentrated hydrochloric acid and extracted with ether. The acidic-aqueous solution was made alkaline with 2-N sodium hydroxide and subsequently extracted three times with methylene chloride. These extracts were washed with water, dried over potassium carbonate and the solvent evaporated in a vacuum. The residue was recrystallised from acetone. There was obtained pure 3a-hydroxy-20,170-dipiperidino-D-homo-5a-androstan-17a-one of melting point 215°-220°C; 25° ta]jj = -5°(c=0.1 in dioxane).

A solution of 350 mg of 3a-hydroxy-20,170-dipiperidinoD-homo-5a-androstan-17a-one in 2 ml of tetrahydrofuran and 1 ml of methanol was treated with a solution of 165 mg of sodium borohydride in 0.5 ml of water. The solution was kept at room temperature for 24 hours and then treated with 20 ml of water. The crystalline precipitate was filtered off, dried in a vacuum and chromatographed over aluminium oxide with ether/hexane. Elution with ether/hexane (5:1) yielded pure 3a,17a0-dihydroxy-20,170-dipiperidino-D-homo-5a-androstane of melting point 225°-227°C5 [alp5’ = +19° (c = 0.1 in dioxane). 420 mg of 3a,17a0-dihydroxy-2ii,170-dipiperidino-D-homo5u-androstane were warmed to 90“0 for 60 minutes with 1 ml of acetic anhydride; The solution was evaporated to dryness in a vacuum and the residue Chromatographed on aluminium oxide.

Elution with benzene-yielded-amorphous—3a pITW-dlacefe’xy^e, 17(3-dipiperidino-D-Komo-5a-androstane which was pure according 25° to thin-layer chromatography; [α]β = -13° (c = 0.1 in ______dioxane) . -- - — ' — Example 2 A mixture of 92 mg of 3a,17aa-diacetoxy-20,170-dipiperidino-D-homo-5a-androstane, 1 ml of acetonitrile and ί ml of methyl bromide was kept at room temperature for 250·hours in a closed vessel» The solution was then evaporated to dryness under reduced pressure and the residue chromatographed Over aluminium oxide (Activity III). Elution with ethyl acetate/ isopropyl alcohol (4;1) yielded pure 3a,17aa-diacetoxy-2/3,170bis(1-methylpiperidinio)-D-homo-5a-androstane dibromide as a 25° colourless foam; [a]D = +28° (c = 0.1 in dioxane).

The starting material can be prepared as follows: 3 ,17aj3-dihydroxy-D-homo-5(X-androstane and jj-toluenesulphonyl chloride were reacted together in pyridine to give 3g,17ag-ditosyloxy-D-homo-Saandrostane which was converted by heating in dimethyl sulphoxide in the presence of potassium tert.butylate into the oco amorphous D-homo-5a-androsta-2,17(17a)-diene; [αίθ = +66°(c=0.1 in dioxane). This D-homosteroid was reacted in ether with tt-chlcroperbenzoic acid and yielded, as the main product, 2a,3aJ17«j17«*10 diepoxy-D-homo-5a-androstane of melting point 172°-173°C (from ° methanol); fat]p = +26° (c· = 0.1 in dioxane). Amorphous 25° 2a,3a;170,17a0-diepoxy-D-homo-5a-androstane, [σ]ρ = +39°(c=O.l in dioxane), was obtained as the by-product.

A mixture of 200 mg of 2a,3a;17a,17aa-diepoxy-D-homo-5aandrostane, 1 ml of piperidine and 0.3 ml of water was heated under reflux for 26 hours. For the working-up, the mixture 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 sodiun hydroxide and extracted with methylene chloride. This extract was washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on aluminium oxide (Activity in). Elution with ether contain15 ing 2% methanol yielded pure 3a,17aa-dihydroxy-20,170-dipiperidino-D-homo-5a-androstane of melting point 197°-199°C (from 25° acetone/hexane); [a)D = +22° (c = 0.1 in dioxane). 200 mg of 3a,17aa-dihydroxy-20,170-dipiperidino-D~homo5a-androstane and 0.5 ml of acetic anhydride were heated to 90°C for 2 hours. The mixture was evaporated to dryness under reduced pressure and the residue chromatographed over aluminium oxide (Activity II). Elution with benzene yielded pure, amorphous 3a,17aa-diacetoxy-20,170-dipiperidino-D-homo25° 5a-androstane; [α]θ = +16° (c = 0.1 in dioxane).

Example 3 g of 17a0-acetoxy-2a,3a;17a,17aa-diepoxy-D-homo-5a- 11 42058 androstane were heated to 200°C in an autoclave for 4 hours with a solution of 10 g of dimethylamine in 90 ml of ethanol and 10 ml of water. After working-up in the usual manner, there was obtained 3a-hydroxy-20,l70-bis-(dimethylamino)-D5 homo-5a-androstan-17a-one which was converted into the dimethobromide by treatment with methyl bromide in a manner analogous to that described in Example 1.

In an analogous manner, the dimethobromides of the following D-homosteroids were prepared: 3a-hydroxy-20,17010 bis-(diethylamino)-D-homo-5a-androstan-17a-0ne, 3c-hydroxy-20, 170-bis-(dipropylamino)-D-homo-5a-androstan-17a-one, 3άhydroxy-20,170-bis-(diisopropylamino)-D-homo-5a-androstan-17aone and 3a-hydroxy-20,170-bis-(dibutylamino)-D-homo-5a-androstan-17a-one.

Claims

1. ) Quaternary salts of D-homosteroids of the general formula 5 ently represent a hydrogen atom or a 1 2 alkyl or C 7 _ 1Q -aralkyl group or R and R 4 5 or R and R together with the N-atom to whioh they are attached represent a hetero3 cyclic group; R represents a hydrogen atom 10 or an acyl group; and R 6 represents an oxo, 7 7 (C-H, α-OR ) or (σ-H, (3-OR ) group in which R 7 represents a hydrogen atom or an acyl group, at least one nitrogen atom being present in quaternised form, and acid addition salts of mono-quaternary salts of D-homo15 steroids of formula I.

2. ) Quaternary salts of the general formula 4 2 0 5 8 g significance given in claim I; one of R g and R represents an alkyl group and the 5 other represents a hydrogen atom or an alkyl group; and X® represents an anion> at least one nitrogen atom being present in quaternised form.

3. ) Quaternary salts of formula II given in claim 2, wherein 12 4 5 the groups -N(R )(R ) and —N(R )(R ) represent the piperidino 10 group; R 3 represents a hydrogen atom or a C £ _ 4 -alkanoyl group; R® represents the grouping (H, OR^) in which R 1 8 9 represents a C £ _ 4 ~alkanoyl group; R and R each represent a C £ _ 4 -aLkyl group; and X represents bromine, chlorine or iodine. .15

4. ) 3u,17ai’.-Diacetoxy-20,170-bis- (1-methylpiperidinio) -Dhomo-5ct-androstane dibromide.

5. ) 3a,17aa-Diacetoxy-20,170-bis-(1-methylpiperidinio)-Dhomo-5a-androstane dibromide.

6. ) Λ process for the manufacture of the quaternary salts of 20 D-homosteroids of formula I given in claim 1 and acid addition salts of mono-quaternary salts of D-homosteroids of formula I 4 2 ο ο given in claim 1, which process comprises quaternising one or both amino groups of a D-homosteroid of formula I given in claim 1 and, if desired, functionally modifying the group denoted by R , acylating a 3-hydroxy group and/or converting ; 5 mono-quaternary salt obtained into an acid addition salt.

7. ) A process according to claim 6, wherein a quaternary salt as claimed in claim 2 is manufactured.

8. ) A process according to claim 6 or claim 7, wherein a quaternary salt as claimed in claim 3 is manufactured. 10

9. ) A process according to any one of claims 6 to 8 inclusive, wherein 3a,17a0-diacetoxy-20,170-dipiperidino-D-homo-5aandrostane is quaternised with methyl bromide to give 3a,l?a<5diacetoxy-2p,173-bis-(1-methylpiperidinio)-D-homo-5a-androstane dibromide. 15

10. ) A process according to any one of claims 6 to 8 inclusive, wherein 3a,17aa-diacetoxy-20,170-dipiperidino-D-homo-5aandrostane is quaternised with methyl bromide to give 3a,17aadiacetoxy-20,170-bis-(1-methylpiperidinio)-D-homo-5a-androstane dibromide. 20

11. ) A process for the manufacture of the quaternary salts of the D-homosteroids of formula X given in claim 1 and acid addition salts of mono-quaternary salts of D-homosteroids of formula I given in claim 1, substantially as hereinbefore described with reference to any one of the foregoing Examples. - 15 42058

12. ) Quaternary salts of the D-homosteroids of formula I given in claim 1 and acid addition salts of mono-quaternary salts of D-homosteroids of formula X given in claim 1, when manufactured by the process claimed in any one Of claims 6 to 5 11 inclusive.

13. ) A pharmaceutical preparation containing a quaternary salt of a D-homosteroid of formula I given in claim 1 or an acid addition salt of a mono-quaternary salt of a D-homosteroid of formula I given in claim 1 in association with a 10 compatible pharmaceutical carrier material.