Note: Descriptions are shown in the official language in which they were submitted.
RAN 4104/136
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
R6 R5
R' ~`R4
R2~ ~
R30 R
, 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
R 0
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 -
.~ ,~. .. .
- ,
. ~ : .~ . ......
1050009
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
- 5 -
~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
10-7 -100 20
3 x 10- -100 40
10-6 -100 60
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:
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)- ~:
,~ :
-- 8 --
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;
25
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-
-- 10 --
~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-
-- 11 --
~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.
- 12 -
