CA1050009A - Steroids - Google Patents
SteroidsInfo
- Publication number
- CA1050009A CA1050009A CA238,187A CA238187A CA1050009A CA 1050009 A CA1050009 A CA 1050009A CA 238187 A CA238187 A CA 238187A CA 1050009 A CA1050009 A CA 1050009A
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- CA
- Canada
- Prior art keywords
- alpha
- beta
- group
- homo
- formula
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Abstract
ABSTRACT
A process for the manufacture of quaternary salts of D-homosteroids of the general formula
A process for the manufacture of quaternary salts of D-homosteroids of the general formula
Description
10~0009 The present invention relates to s~eroids. More par-ticularly, the invention is concerned with quaternary salts of D-homosteroids of the general formula R' ~`R4 R2~ ~
, wherein Rl, R2, R4 and R5 each independ-ently represent a hydrogen atom or a Cl lO-7-lo~aralkYl group or Rl d 2 or R4 and R5 together with the N-atom to which they are attached represent a hetero-: lO cyclic group; R3 represents a hydrogen atom or an acyl group; and R6 represents an oxo, (~-H, a-OR7) or (a-H, ~-oR7) group in which R7 represents a hydrogen atom or an acyl group, : at least one nit~ogen atom bein resent in quaternised form, ~ ~ phar~acec~C~//4 ~ecc~J~4 and~acid addition sa~tts of mono-quaternary salts of D-homo-steroids of formula I.
The quaternary salts in accordance with the invention are preferably formed with alkyl halides, especially Cl 4-ZO a1kyl halides such as methyl or ethyl bromide, chloride oriodide, .,, ~
--2-- ~7--Mez/17.9.1975 lOSO~O9 EXamples of Cl_lO-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and isomers thereof, pentyl, hexyl, octyl and decyl. Examples of C7_10-aralkyl groups are benzyl and phenethyl. Examples of heterocyclic resid~es which may be formed by Rl and R2 or R4 and ~5 together with the N-atom to which they are attached are pyrrolidino, piperidino, morpholino and piperazino.
The acid addition salts provided by the present inven-tion can be formed with organic acids (e.g. alkanecarboxylic acids such as acetic acid or succinic acid, oxycarboxylic 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 lS present invention comprises those of the general formula n6 o9 ~i"R 4 R30 2 x~) ~ 2 R3 R4 R5 and R6 have the s gnificance given eàrlier; one of R and R represents an alkyl group and the other represents a hydrogen atom or an alkyl group; and X ~ represents an anion.
.
~sooo9 ~ specially preferred are the salts of formula II in which the groups -N(Rl)(R2) and -~(R4)(R5) represent the piperidino group; R3 represents a hydrogen atom or a Cl_4- alkanoyl group; R6 represents the grouping (H,oR7) wherein R7 represents a Cl 4-alkanoyl group; R and R9 each represent a Cl 4-alkyl group; and X represents bromine, chlorine or iodine.
According to the process provided by the present invention, the quate~nary salts of the D-homosteroids of formula I and pharmaceutically acceptable acid addition salts 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 b~ R6, acylating a 3-hydroxy group and/or converti.ng a mono-quater-nary salt obtained into a pharmaceutically acceptable acid addition salt.
Thus according to this invention there is provided aiprocess for the manufacture of quaternary salts of D~homosteroid9 of the general formula R6 R5 .
N ~ I R4 wherein Rl, R2, R4~and R5 each independently represent a hydrogen atom or a ~ -Cl 1O-alkyl or C7 1O-aralkyl group or R and R2 or R4 and R5 ~ogether withthe ::
20 N-atom to which they are attached represent a hetero cyclic group; R3 ~.
represents a hydrogen atom or an acyl group; and R represents an oxo, .
(~ -K~ 0( -oR7) or ~ ~ oR7~ group in which R7 nepresents a hydrogen atom or an acyl group, at least one nitrogen atom being present in quaternised form, and of acid addition salt of mono-quaternary salts of D-homo-..
~, A~w ~ - 4 -.~ ,~. .. .
- , . ~ : .~ . ......
steroids o~ formula I, which process comprises 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-quaternary salt obtained into a pharmaceutically acceptable 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 DLhomosteroid of formula I and a quaternising agent and separating the desired product.
The acylation of a 3-hydroxy group can be carried out in a manner known per se; for example~ by treatment with an acyl halide or anhydride.
~os~009 A 17a-oxo group can be reduced to the hydroxy group in a manner known per se; for example, with a compl~x metal hydride such as sodlum borohydride, lithium alu~inium hydride or lithium tri(tert-butoxy~-aluminium hydride. A 17a-hydroxy S group can ~e 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.~. one of the mineral acids or organic acids mentioned earlier) into a salt of such an acid.
The D-homoste~oids of formula I can be prepared by reacting a 2~,2a;17a,17aa-diepoxy-D-homo-5a-androstane of the general formula R Q
~ t~ (III) ; H
.-:
lS , wherein R represents a hydrogen atom or the acetoxy group, with an amine of the formula HN(Rl)(R2) or HN(R4)(R5) in which : R and R5 have the significance given earlier. It is pos-sible to prepare D-homosteroids of formula I in which Rl and R2 are different from R4 and R5. In this case, a diepoxide of formuIa III is reacted with an equivalent amount of an ~osooo9 amine of the formula HN(Rl)(R2) or HN(R4)(R5), whereby only one epoxide grouping reacts. In a su~sequent reaction with an amine of the formula HN(R4)(R5) or HN(Rl)(R ), there is obtained a D-homosteroid of formula I in which Rl and R2 are different from R4 and R5. The preparation of the D-homo-steroids of formula I and the diepoxides of formula III is more fully described in the Examples.
The quaternary salts of D-homostèroids of formula I and acid addition salts of mono-quaternary salts of D-homosteroids of formula I possess valuable pharmacological properties.
They have an especially strong influence on the autonomic nervous system since they block the neuromuscular transmis-sion, their duration of action being relatively short which is -very desirable and advantageous. During this action, they lS cause no liberatlon 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 of the curare type and may be adminlstered in a manner known per se; preferably by ~ntravenous injection, in which case a dosage in the ra~ge of 1-50 mg, preferably 2-25 mg or 5-10 mg, is conveniently administered lnitially and can be supplemen-ted 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.
~050009 T~e testing of 3a,17a~-diacetoxy-2~,17~-bis-(1-methyl-piperidinio)-D-homo-5a-androstane dlbromide in the narcotised cat for muscle relaxant activity yields the following results;
~osage mol/kg i.v. n = 3 10 8 __ min.
3 x 10-8 -go 10 3 x 10- -100 40 n = Number of the test The quaternary salts of D-homosteroids of formula I and ac.id addition salts of mono-quaternary salts of D-homosteroids of formula I can ~e used, for example, in the form of pharma-15 ceutical preparations which c~ntain th~m in association with acompatible pharmaceutical carrier material which can be an ~ organic or inorganic carrier material.
:; ~
~ .
: ~ .
~ ~ .
:
., ~ _ 7 _ .
~OS0009 The following Examples illustrate the process provided by the present invention:
Example 1 A solution of 225 mg of 3a,17a~-diacetoxy-2~,17~-dipiperidino-D-homo-5a-androstane in 2 ml of acetonitrile and
, wherein Rl, R2, R4 and R5 each independ-ently represent a hydrogen atom or a Cl lO-7-lo~aralkYl group or Rl d 2 or R4 and R5 together with the N-atom to which they are attached represent a hetero-: lO cyclic group; R3 represents a hydrogen atom or an acyl group; and R6 represents an oxo, (~-H, a-OR7) or (a-H, ~-oR7) group in which R7 represents a hydrogen atom or an acyl group, : at least one nit~ogen atom bein resent in quaternised form, ~ ~ phar~acec~C~//4 ~ecc~J~4 and~acid addition sa~tts of mono-quaternary salts of D-homo-steroids of formula I.
The quaternary salts in accordance with the invention are preferably formed with alkyl halides, especially Cl 4-ZO a1kyl halides such as methyl or ethyl bromide, chloride oriodide, .,, ~
--2-- ~7--Mez/17.9.1975 lOSO~O9 EXamples of Cl_lO-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and isomers thereof, pentyl, hexyl, octyl and decyl. Examples of C7_10-aralkyl groups are benzyl and phenethyl. Examples of heterocyclic resid~es which may be formed by Rl and R2 or R4 and ~5 together with the N-atom to which they are attached are pyrrolidino, piperidino, morpholino and piperazino.
The acid addition salts provided by the present inven-tion can be formed with organic acids (e.g. alkanecarboxylic acids such as acetic acid or succinic acid, oxycarboxylic 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 lS present invention comprises those of the general formula n6 o9 ~i"R 4 R30 2 x~) ~ 2 R3 R4 R5 and R6 have the s gnificance given eàrlier; one of R and R represents an alkyl group and the other represents a hydrogen atom or an alkyl group; and X ~ represents an anion.
.
~sooo9 ~ specially preferred are the salts of formula II in which the groups -N(Rl)(R2) and -~(R4)(R5) represent the piperidino group; R3 represents a hydrogen atom or a Cl_4- alkanoyl group; R6 represents the grouping (H,oR7) wherein R7 represents a Cl 4-alkanoyl group; R and R9 each represent a Cl 4-alkyl group; and X represents bromine, chlorine or iodine.
According to the process provided by the present invention, the quate~nary salts of the D-homosteroids of formula I and pharmaceutically acceptable acid addition salts 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 b~ R6, acylating a 3-hydroxy group and/or converti.ng a mono-quater-nary salt obtained into a pharmaceutically acceptable acid addition salt.
Thus according to this invention there is provided aiprocess for the manufacture of quaternary salts of D~homosteroid9 of the general formula R6 R5 .
N ~ I R4 wherein Rl, R2, R4~and R5 each independently represent a hydrogen atom or a ~ -Cl 1O-alkyl or C7 1O-aralkyl group or R and R2 or R4 and R5 ~ogether withthe ::
20 N-atom to which they are attached represent a hetero cyclic group; R3 ~.
represents a hydrogen atom or an acyl group; and R represents an oxo, .
(~ -K~ 0( -oR7) or ~ ~ oR7~ group in which R7 nepresents a hydrogen atom or an acyl group, at least one nitrogen atom being present in quaternised form, and of acid addition salt of mono-quaternary salts of D-homo-..
~, A~w ~ - 4 -.~ ,~. .. .
- , . ~ : .~ . ......
steroids o~ formula I, which process comprises 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-quaternary salt obtained into a pharmaceutically acceptable 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 DLhomosteroid of formula I and a quaternising agent and separating the desired product.
The acylation of a 3-hydroxy group can be carried out in a manner known per se; for example~ by treatment with an acyl halide or anhydride.
~os~009 A 17a-oxo group can be reduced to the hydroxy group in a manner known per se; for example, with a compl~x metal hydride such as sodlum borohydride, lithium alu~inium hydride or lithium tri(tert-butoxy~-aluminium hydride. A 17a-hydroxy S group can ~e 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.~. one of the mineral acids or organic acids mentioned earlier) into a salt of such an acid.
The D-homoste~oids of formula I can be prepared by reacting a 2~,2a;17a,17aa-diepoxy-D-homo-5a-androstane of the general formula R Q
~ t~ (III) ; H
.-:
lS , wherein R represents a hydrogen atom or the acetoxy group, with an amine of the formula HN(Rl)(R2) or HN(R4)(R5) in which : R and R5 have the significance given earlier. It is pos-sible to prepare D-homosteroids of formula I in which Rl and R2 are different from R4 and R5. In this case, a diepoxide of formuIa III is reacted with an equivalent amount of an ~osooo9 amine of the formula HN(Rl)(R2) or HN(R4)(R5), whereby only one epoxide grouping reacts. In a su~sequent reaction with an amine of the formula HN(R4)(R5) or HN(Rl)(R ), there is obtained a D-homosteroid of formula I in which Rl and R2 are different from R4 and R5. The preparation of the D-homo-steroids of formula I and the diepoxides of formula III is more fully described in the Examples.
The quaternary salts of D-homostèroids of formula I and acid addition salts of mono-quaternary salts of D-homosteroids of formula I possess valuable pharmacological properties.
They have an especially strong influence on the autonomic nervous system since they block the neuromuscular transmis-sion, their duration of action being relatively short which is -very desirable and advantageous. During this action, they lS cause no liberatlon 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 of the curare type and may be adminlstered in a manner known per se; preferably by ~ntravenous injection, in which case a dosage in the ra~ge of 1-50 mg, preferably 2-25 mg or 5-10 mg, is conveniently administered lnitially and can be supplemen-ted 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.
~050009 T~e testing of 3a,17a~-diacetoxy-2~,17~-bis-(1-methyl-piperidinio)-D-homo-5a-androstane dlbromide in the narcotised cat for muscle relaxant activity yields the following results;
~osage mol/kg i.v. n = 3 10 8 __ min.
3 x 10-8 -go 10 3 x 10- -100 40 n = Number of the test The quaternary salts of D-homosteroids of formula I and ac.id addition salts of mono-quaternary salts of D-homosteroids of formula I can ~e used, for example, in the form of pharma-15 ceutical preparations which c~ntain th~m in association with acompatible pharmaceutical carrier material which can be an ~ organic or inorganic carrier material.
:; ~
~ .
: ~ .
~ ~ .
:
., ~ _ 7 _ .
~OS0009 The following Examples illustrate the process provided by the present invention:
Example 1 A solution of 225 mg of 3a,17a~-diacetoxy-2~,17~-dipiperidino-D-homo-5a-androstane in 2 ml of acetonitrile and
2 ml of methyl bromide was kept for 170 hours at room tempera-ture. Subsequently, the solvent was evaporated off under reduced pressure and the residue chromatographed on aluminium oxide (Activity III). Elution with isopropanol/ethyl acetate (2:1) yielded pure 3a,17a~-diacetoxy-2B,17~-bis(l-methyl-piperidinlo)-D-homo-5a-androstane dibr~mide which melted at 250-251C after recrystallisation from methylene chloride/
~ ]25 = ~51 ~c = o.l in dioxane).
The starting material can be prepared as follows:
~ ]25 = ~51 ~c = o.l in dioxane).
The starting material can be prepared as follows:
3~-Hydroxy-D-homo-androstan-17-one was ketalised wlth ~ ethyleneglycol/p-toluenesulphonic acid to give 17a,17a-: ethylenedioxy-3~-hydroxy-D-homo-androstane of melting point : ~196-198C. This ketal was converted with p-tosyl chloride/
~ pyridine into the 3-tosylate which, after heating in dimethyl : 20 sulphoxi~e in the presence of potassium tert.~utylate, 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 mèlting point 131-132C and [a]25 = o from which, by treatment with acètic anhydride in dioxane and catalytic amounts of perchloric acid there was obtained 17a-acetoxy-D-homo-5a-androsta-2,17~17a)- ~:
,~ :
lOSOOO9 dlene of melting point 140-142DC. By reaction of this lat-ter D-homosteroid with m-chloroperbenzolc acid ~n ether there was obtained 17a~-acetoxy-2a,3~;17~,17aa-diepoxy-D-homo-5-androstane of melting point 183-186C; [a]25 = ~52.
15.0 g of 17a~-acet~xy-2a,3a;17,17aa-diepoxy-D-homo-5a-androstane were heated under reflux for 17 hours with 75 ml of piperidine and 25 ml of water. The mixture was then concen-trated to half in a vacuum, treated wlth 200 ml of ice-w~ter, acidified with concentrated hydrochloric acid and extracted with ether. The acidic-a~ueous solution was made alkaline with 2-N sodium hydroxide and ~ubse~uently extracted three times wl th methylene chloride. ~hese extracts were washed wlth water, dried over potassium carbonate and the solvent evaporated in a vacuum. The resldue was recrystallised from acetone. There was obtained pure 3a-hydroxy-2~,17~-dipiper-idino-D-homo-5a-androstan-17a-one of melting point 215-220C;
A solution of 350 mg of 3a-hydroxy-2B,17~-dipiperidino-D-homo-5~-androstan-17a-one in 2 ml of tetrahydrofuran and 1 ml of methanol was treated with a solutlon of 165 mg of sod~um 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 preclpitate was filtered off, dried in a vacuum and chromatographed over aluminium oxide with ether/hexane. Elution with ether/hexane (5:1) yielded pure 3a,17a~-dihydroxy-2~,17~-dipiperidino-D-homo-5a-androstane of melting point 225-227C; [a~25 = ~19 (c = ~.1 in dioxane).
, .
_ g _ ~05~009 420 mg of 3,17a~-dihydroxy-2~17l~-dipipcridino-~-homo-5a-androstane were warmed to 90C for 60 minutes Wit~ nl o~
acetic anhydride. The solution was evaporated to dryness in a vacuum and the residue chromatographed on aluminium oxide.
Elution with benzene yielded amorphous 3~,17a~~diacetoxy-2~, 17~-dipiperidino-D-homo-5a-androstane which was pure according to thin-layer chromatography; ~a]25 = -13 (c = 0.1 in dioxane).
ExamP~e ?
A mixture of 92 mg of 3a,17aa-diacetoxy-2~,17~-dipip-eridino-D-homo-5a-androstane, 1 ml of acetonitrile and 1 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~,17~-bis(l-methylpiperidinio)-D-homo 5a-androstane dibromide as a colourless foam; [a~DS = +28 (c = 4.1 in dioxane).
The starting material can be prepared as follows:
3~17a~-dihydroxy-D-homo-5a-androstane sulphochloride was reacted in pyridine to give 3~,17a~-ditosyloxy-D-homo-5~-androstane which was converted by heating in dimethyl sulph-oxide in the presence of potassium tert.butylate into the amorphous D-homo-5a-androsta-2,17(17a)-diene; [a]D5 = +66.
This D-homosteroid was reacted in ether with m-chloroper-benzoic acid and yielded, as the main product, 2a,3a;17a,17aa-~oso~o9 diepoxy-D-homo-5a-androstane of melting point 172-173C (fro~
methanol); ~a725 = +26U (c = 0.1 in dioxane). Amorphous 2a,3a;17~,17a~-diepoxy-D-homo-5a-androstane, ~a~D = ~39' was obtained as the by-product.
A mixture of 200 mg of 2a,3a;17a,17aa-diepoxy-D-homo-5a-androstane, 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 on to ice-water, acidified with dilute hydroch:Loric acid and extracted twice with ether. The acidic-aqueous solution was then made alkaline with dilute sodium 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 a~uminium oxide (Activity III). Elution with ether contain-lS ing 2% methanol yielded pure 3a,17a-dihydroxy-2~,17~-dipip-eridino-D-homo-5-androstane of melting point 197-199C (from acetone/hexane); la]25 = ~22 (c = 0.1 in dioxane).
200 mg of 3a,17aa-dihydroxy-2~,17B-dipiperidino-D-homo-5a-androstan~ and 0.5 ml of acetic anhydride were heated to 90C for 2 hours. The mixture was evaporated to dryness under reduced pressure and the residue chromatographed over aluminlum oxide (Acti~ity ~I~. Elution with benzene yielded pure, amorphous 3a,17aa-diacetoxy-2~,17~-dipiperidino-D-homo-Sa-androstane; la]D5 = +16 (c = 0.1 in dioxane).
Exam~le 3 10 g of 17a~-acetoxy-2a,3a;17a,17aa-diepoxy-D-homo-5a-~osooas androstane were heated to 200C 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-2B,17~-bis-(dimethylamlno)-D-homo-5a-androstan-17a-one which was converted into the di-methobromide 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 ~ere prepared: 3a-hydroxy-2~,17~-bis-(diethylamino)-D-homo-5a-andro~tan-17a-one, 3a-hydroxy-2~, 17~-bis-(dipropylamino)-D-homo-5a-androstan-17a-one, 3a-hydroxy~2~,17B-bis-(diisopropylamlno)-D-homo-5a-androstan-17a-one and 3a-hydroxy-2~,17~-bls-(dlbutylamino)-D-homo-Sa-andro-stan-17a-one.
~ pyridine into the 3-tosylate which, after heating in dimethyl : 20 sulphoxi~e in the presence of potassium tert.~utylate, 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 mèlting point 131-132C and [a]25 = o from which, by treatment with acètic anhydride in dioxane and catalytic amounts of perchloric acid there was obtained 17a-acetoxy-D-homo-5a-androsta-2,17~17a)- ~:
,~ :
lOSOOO9 dlene of melting point 140-142DC. By reaction of this lat-ter D-homosteroid with m-chloroperbenzolc acid ~n ether there was obtained 17a~-acetoxy-2a,3~;17~,17aa-diepoxy-D-homo-5-androstane of melting point 183-186C; [a]25 = ~52.
15.0 g of 17a~-acet~xy-2a,3a;17,17aa-diepoxy-D-homo-5a-androstane were heated under reflux for 17 hours with 75 ml of piperidine and 25 ml of water. The mixture was then concen-trated to half in a vacuum, treated wlth 200 ml of ice-w~ter, acidified with concentrated hydrochloric acid and extracted with ether. The acidic-a~ueous solution was made alkaline with 2-N sodium hydroxide and ~ubse~uently extracted three times wl th methylene chloride. ~hese extracts were washed wlth water, dried over potassium carbonate and the solvent evaporated in a vacuum. The resldue was recrystallised from acetone. There was obtained pure 3a-hydroxy-2~,17~-dipiper-idino-D-homo-5a-androstan-17a-one of melting point 215-220C;
A solution of 350 mg of 3a-hydroxy-2B,17~-dipiperidino-D-homo-5~-androstan-17a-one in 2 ml of tetrahydrofuran and 1 ml of methanol was treated with a solutlon of 165 mg of sod~um 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 preclpitate was filtered off, dried in a vacuum and chromatographed over aluminium oxide with ether/hexane. Elution with ether/hexane (5:1) yielded pure 3a,17a~-dihydroxy-2~,17~-dipiperidino-D-homo-5a-androstane of melting point 225-227C; [a~25 = ~19 (c = ~.1 in dioxane).
, .
_ g _ ~05~009 420 mg of 3,17a~-dihydroxy-2~17l~-dipipcridino-~-homo-5a-androstane were warmed to 90C for 60 minutes Wit~ nl o~
acetic anhydride. The solution was evaporated to dryness in a vacuum and the residue chromatographed on aluminium oxide.
Elution with benzene yielded amorphous 3~,17a~~diacetoxy-2~, 17~-dipiperidino-D-homo-5a-androstane which was pure according to thin-layer chromatography; ~a]25 = -13 (c = 0.1 in dioxane).
ExamP~e ?
A mixture of 92 mg of 3a,17aa-diacetoxy-2~,17~-dipip-eridino-D-homo-5a-androstane, 1 ml of acetonitrile and 1 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~,17~-bis(l-methylpiperidinio)-D-homo 5a-androstane dibromide as a colourless foam; [a~DS = +28 (c = 4.1 in dioxane).
The starting material can be prepared as follows:
3~17a~-dihydroxy-D-homo-5a-androstane sulphochloride was reacted in pyridine to give 3~,17a~-ditosyloxy-D-homo-5~-androstane which was converted by heating in dimethyl sulph-oxide in the presence of potassium tert.butylate into the amorphous D-homo-5a-androsta-2,17(17a)-diene; [a]D5 = +66.
This D-homosteroid was reacted in ether with m-chloroper-benzoic acid and yielded, as the main product, 2a,3a;17a,17aa-~oso~o9 diepoxy-D-homo-5a-androstane of melting point 172-173C (fro~
methanol); ~a725 = +26U (c = 0.1 in dioxane). Amorphous 2a,3a;17~,17a~-diepoxy-D-homo-5a-androstane, ~a~D = ~39' was obtained as the by-product.
A mixture of 200 mg of 2a,3a;17a,17aa-diepoxy-D-homo-5a-androstane, 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 on to ice-water, acidified with dilute hydroch:Loric acid and extracted twice with ether. The acidic-aqueous solution was then made alkaline with dilute sodium 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 a~uminium oxide (Activity III). Elution with ether contain-lS ing 2% methanol yielded pure 3a,17a-dihydroxy-2~,17~-dipip-eridino-D-homo-5-androstane of melting point 197-199C (from acetone/hexane); la]25 = ~22 (c = 0.1 in dioxane).
200 mg of 3a,17aa-dihydroxy-2~,17B-dipiperidino-D-homo-5a-androstan~ and 0.5 ml of acetic anhydride were heated to 90C for 2 hours. The mixture was evaporated to dryness under reduced pressure and the residue chromatographed over aluminlum oxide (Acti~ity ~I~. Elution with benzene yielded pure, amorphous 3a,17aa-diacetoxy-2~,17~-dipiperidino-D-homo-Sa-androstane; la]D5 = +16 (c = 0.1 in dioxane).
Exam~le 3 10 g of 17a~-acetoxy-2a,3a;17a,17aa-diepoxy-D-homo-5a-~osooas androstane were heated to 200C 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-2B,17~-bis-(dimethylamlno)-D-homo-5a-androstan-17a-one which was converted into the di-methobromide 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 ~ere prepared: 3a-hydroxy-2~,17~-bis-(diethylamino)-D-homo-5a-andro~tan-17a-one, 3a-hydroxy-2~, 17~-bis-(dipropylamino)-D-homo-5a-androstan-17a-one, 3a-hydroxy~2~,17B-bis-(diisopropylamlno)-D-homo-5a-androstan-17a-one and 3a-hydroxy-2~,17~-bls-(dlbutylamino)-D-homo-Sa-andro-stan-17a-one.
Claims (8)
1) A process for the manufacture of quaternary salts of D-homosteroids of the general formula (I) , wherein R1, R2, R4 and R5 each independ-ently represent a hydrogen atom or a C1-10-alkyl or C7-10-aralkyl group or R1 and R2 or R4 and R5 together with the N-atom to which they are attached represent a hetero cyclic group; R3 represents a hydrogen atom or an acyl group; and R6 represents an oxo, (.beta.-H, .alpha.-OR7) or (.alpha.-H, .beta.-OR7) group in which R7 represents a hydrogen atom or an acyl group, at least one nitrogen atom being present in quaternised form, and of acid addition salts of mono-quaternary salts of D-homo-steroids of formula I, which process comprises guaternising one or both amino groups of a D-homosteroid of formula I and, if desired, functionally modifying the group denoted by R6, acylating a 3-hydroxy group and/or converting a mono-quaternary salt obtained into a pharmaceutically acceptable acid addition salt.
2) A process according to claim 1, characterized in that a quaternary salt of the formula (II) wherein R1, R2, R3, R4, R5 and R6 have the significance given in claim 1;
one of R8 and R9 represents an alkyl group and the other represents a hydrogen atom or an alkyl group; and X? represents an anion, is manufactured.
one of R8 and R9 represents an alkyl group and the other represents a hydrogen atom or an alkyl group; and X? represents an anion, is manufactured.
3) A process according to claim 2, characterized in that a quaternary salt of formula II given in claim 2, wherein the groups -N(R1)(R2) and -N(R4)(R5) represent the piperidino group; R3 represents a hydrogen atom or a C1-4-alkanoyl group; R6 represents the grouping (H, OR7) in which R7 represents a C1-4-alkanoyl group; R8 and R9 each represent a C1-4-alkyl group;
and X represents bromine, chlorine or iodine, is manufactured.
and X represents bromine, chlorine or iodine, is manufactured.
4) A process according to claim 1, wherein 3.alpha.,17.alpha..beta.-diacetoxy-2.beta.,17.beta.-dipiperidino-D-homo-5.alpha.-androstane is quaternised with methyl bromide to give 3.alpha.,17.alpha..beta.-diacetoxy-2.beta.,17.beta.-bis-(1-methylpiperidino)-D-homo-5.alpha.-androstane dibromide.
5. A process according to claim 1 wherein 3.alpha.,17a.alpha.-diacetoxy-2.beta.,17.beta.-dipiperidino-D-homo-5.alpha.-androstane is quaternised with methyl bromide to give 3.alpha.,17a.alpha.-diacetoxy-2.beta.,17.beta.-bis-(1-methylpiperidinio)-D-homo-5.alpha.-androstane dibromide.
6. Quaternary salts of the D-homosteroids of formula I given in claim 1 and pharmaceutically acceptable acid addition salts of mono-quaternary salts of D-monosteroids of formula I given in claim 1, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
7. 3.alpha.,17a.beta.-diacetoxy-2.beta.,17.beta.-bis-(1-methylpiperidino)-D-homo-5.alpha.-androstane dibromide, when manufactured by the process claimed in claim 4 or by an obvious chemical equivalent thereof.
8. 3.alpha.,17a.alpha.-diacetoxy-2.beta.,17.beta.-bis-(1-methylpiperidino)-D-homo-5.alpha.-androstane dibromide, when manufactured by the process claimed in claim 5 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1446974A CH602794A5 (en) | 1974-10-29 | 1974-10-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050009A true CA1050009A (en) | 1979-03-06 |
Family
ID=4401103
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA238,187A Expired CA1050009A (en) | 1974-10-29 | 1975-10-23 | Steroids |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS51125267A (en) |
| AR (1) | AR212436A1 (en) |
| AT (1) | AT349161B (en) |
| BE (1) | BE834925A (en) |
| CA (1) | CA1050009A (en) |
| CH (1) | CH602794A5 (en) |
| DD (1) | DD123332A5 (en) |
| DE (1) | DE2547739A1 (en) |
| DK (1) | DK135316B (en) |
| ES (1) | ES442142A1 (en) |
| FI (1) | FI53711C (en) |
| FR (1) | FR2289175A1 (en) |
| GB (1) | GB1498239A (en) |
| HU (1) | HU174161B (en) |
| IE (1) | IE42058B1 (en) |
| IL (1) | IL48219A (en) |
| LU (1) | LU73655A1 (en) |
| NL (1) | NL7512661A (en) |
| NO (1) | NO139736C (en) |
| NZ (1) | NZ178817A (en) |
| PL (1) | PL100305B1 (en) |
| SE (1) | SE413248B (en) |
| ZA (1) | ZA756169B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2362648A (en) * | 2000-05-23 | 2001-11-28 | Univerzita Palackeho V Olomouc | Triterpenoid derivatives |
| EP1465914B1 (en) | 2002-01-18 | 2008-12-17 | Regents Of The University Of Minnesota | Triterpene quaternary salts as biologically active surfactants |
-
1974
- 1974-10-29 CH CH1446974A patent/CH602794A5/xx not_active IP Right Cessation
-
1975
- 1975-09-29 ZA ZA00756169A patent/ZA756169B/en unknown
- 1975-09-30 IL IL48219A patent/IL48219A/en unknown
- 1975-09-30 NZ NZ178817A patent/NZ178817A/en unknown
- 1975-10-10 FI FI752825A patent/FI53711C/en not_active IP Right Cessation
- 1975-10-21 AR AR260869A patent/AR212436A1/en active
- 1975-10-23 CA CA238,187A patent/CA1050009A/en not_active Expired
- 1975-10-24 DE DE19752547739 patent/DE2547739A1/en not_active Withdrawn
- 1975-10-27 LU LU73655A patent/LU73655A1/xx unknown
- 1975-10-27 JP JP50128445A patent/JPS51125267A/en active Pending
- 1975-10-27 FR FR7532779A patent/FR2289175A1/en active Granted
- 1975-10-27 SE SE7512006A patent/SE413248B/en unknown
- 1975-10-28 DK DK485975AA patent/DK135316B/en not_active IP Right Cessation
- 1975-10-28 AT AT819375A patent/AT349161B/en not_active IP Right Cessation
- 1975-10-28 GB GB44288/75A patent/GB1498239A/en not_active Expired
- 1975-10-28 IE IE2344/75A patent/IE42058B1/en unknown
- 1975-10-28 PL PL1975184292A patent/PL100305B1/en unknown
- 1975-10-28 HU HU75HO1849A patent/HU174161B/en unknown
- 1975-10-28 NO NO753616A patent/NO139736C/en unknown
- 1975-10-28 DD DD189086A patent/DD123332A5/xx unknown
- 1975-10-28 BE BE161295A patent/BE834925A/en unknown
- 1975-10-28 ES ES442142A patent/ES442142A1/en not_active Expired
- 1975-10-29 NL NL7512661A patent/NL7512661A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AT349161B (en) | 1979-03-26 |
| CH602794A5 (en) | 1978-08-15 |
| FI53711B (en) | 1978-03-31 |
| NZ178817A (en) | 1978-06-02 |
| DK135316B (en) | 1977-04-04 |
| FR2289175B1 (en) | 1980-05-30 |
| LU73655A1 (en) | 1977-05-31 |
| FR2289175A1 (en) | 1976-05-28 |
| AR212436A1 (en) | 1978-07-14 |
| SE413248B (en) | 1980-05-12 |
| NO753616L (en) | 1976-04-30 |
| FI752825A (en) | 1976-04-30 |
| DD123332A5 (en) | 1976-12-12 |
| NO139736B (en) | 1979-01-22 |
| PL100305B1 (en) | 1978-09-30 |
| AU8541875A (en) | 1977-04-07 |
| NL7512661A (en) | 1976-05-04 |
| IL48219A0 (en) | 1975-11-25 |
| DE2547739A1 (en) | 1976-05-06 |
| SE7512006L (en) | 1976-04-30 |
| JPS51125267A (en) | 1976-11-01 |
| GB1498239A (en) | 1978-01-18 |
| IE42058B1 (en) | 1980-05-21 |
| IE42058L (en) | 1976-04-29 |
| IL48219A (en) | 1979-01-31 |
| FI53711C (en) | 1978-07-10 |
| DK485975A (en) | 1976-04-30 |
| DK135316C (en) | 1977-08-22 |
| ATA819375A (en) | 1978-08-15 |
| ZA756169B (en) | 1976-09-29 |
| BE834925A (en) | 1976-04-28 |
| ES442142A1 (en) | 1977-04-01 |
| NO139736C (en) | 1979-05-09 |
| HU174161B (en) | 1979-11-28 |
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