Note: Descriptions are shown in the official language in which they were submitted.
- - ~069~
The present invention relates to a hitherto un-
known group of compounds, the 18,18-difluorosteroids, and,
. in particular, to processes for the manufacture of the
compounds of the general formula
CHF2 IOR3
St F ~ --R4 (Ia)
.,, ~ .
~` - wherein R3 denotes a hydrogen atom or a lower alkanoyl
` group and R4 denotes a hydrogen atom or a lower aliphatic
:~ hydrocarbon radical, especially a lower alkyl radical,
above all the methyl radical and ethyl radical, or the
ethinyl radical, and St denotes a radical of the partial
formula
- R5 ~ R60 ~ 'R7 ~ R7
(Stl) (St2) (St'2)
R ~ .
~ UO ~ (SC3~ ;
: wherein R5 denotes the oxo group or a hytrogen atom con-
jointly with an esterified hydroxyl group, or especially
. ,
,. ' q~-
,,, . . . :
- . , . . . - - - . -':, - . . . : -
- . - - ~ . . - , .. : . .. . . .
,. . ~ ;~
. ', ' . ~ ,: '~ ' ' ' ' . : ~
. ~ - . -
,. .- : - , , ~ . ~.: : , -
- . : ., -, . ., - .. .
,
` 1069118
.
with a free hydroxyl group, or denotes two hydrogen atoms,
R6 denotes a hydrogen atom or a lower alkyl group, espe-
cially the methyl group, R7 denotes a hydrogen atom or the
methyl group, and R denotes a hydrogen atom or the methyl
group, it being possible for an additional 1,2-double bond
also to be present in compounds of the partial formula St
in which R is the methyl group.
Wherever it is used in connection with an organic
radical, the term ~'lower" designates a corresponding radical
with at mo8t 7, but preferably with 1 to 4, carbon atoms.
A lower alkyl radical is, for example, a n-propyl,
~-propyl, n-butyl, i-butyl, sec.-butyl or tert.-butyl radical
or a branched or preferably straight-chain pentyl, hexyl or
~eptyl radical, but above all an ethyl or methyl radical.
A lower aliphatic hydrocarbon radical is to be regarded as
a lower alkyl radical, for example one of those already
mentioned, or an analogous radical which in addition contains
one or two multiple bonds, that i8 to say double bonds or
acetylenic bonds, such as, or example, a lower alkenyl, lower
alkinyl and allenyl radical, for example a vinyl, allyl, meth-
allyl, propargyl, hexadiinyl and, above all, ethinyl radical.
An esterified hydroxyl group is derived, in par-
ticular, from a carboxylic acid customary in steroid chemi-
stry, for example a monocarboxylic acid with at most 18
carbon atoms, such as aliphatic carboxylic acids, especially
.. .. . .. .. ~ .
: .
' ' ~ .
10691~8
from formic acid or a lower alkanecarboxylic acid, the
lower alkyl radical of which is one of those mentioned above,
primarily propionic acid, butyric acid, isobutyric acid,
valeric acid, isovaleric acid, oenanthic acid and diethyl-
acetic acid and, above all, caproic acid, trimethylacetic
acid and acetic acid.
e new 18,18-difluorosterolds according to the Invention
can be used as intermediates for the synthesis of valuable
pharmaceutical active substances, especially for honmone
therapy and for fertility control, and also a8 additives in
animal feeds. A number of the steroids, for example the com-
pounds singled out for special mention hereinafter, at the
same time themselves exhibit a biological activity and, accor-
d~ngly, can be used direct as acti~e substances in the above-
mentioned fields of applicaticn.
. . , , -- .
Compounds to be singled out, because of their advan-
tageous biological properties, from the compounds of the
formula Ia are those in which St represents a radical of the
partial formula Stl. These compounds are distinguished as
highly active sex hormones. On the one hand, they have a
central action in that they block the secretion of pituitary
gonadotrophins; on the other hand, they also have a peri-
pheral action on the male and the female sexual functions,
as can be demonstrated by animal experiments. Because of
these advantegeous biological properties, the compounds
.. .. " . . .. , . , ~ . . ..
~0 69 ~ 18
can be used in medicine for all indications involving
sex hormones, but especially as preparations for inhibiting
gonadotrophin secretion and/or for controlling fertility.
Compounds to be singled out particularly are 17~-acetoxy-18,18-
difluoro-oestr-4-en-~-one, whlch in a dose of 0.01 mg/animal -~
(capon , comb test, local application) exhibits a marked andro-
genic activity and in a dosage range of from 0.01 to 0.1 mg/kg
(rat , ovulation test, subcutaneous administration) inhibits
ovulation, and 17a-ethinyl-18,18-difluoro-l?~-h~ o~ 3-one,
whlch in a dosage range of from 0.03 to 0.3 mg1kg (rabbit ,
Clauberg test, perorally) exhibits a distinct gestagenic
. . .
ac~ivity and in a dosage range of from 0.3 to 1 mg/kg (rat ,
ovulation test, perorally) inhibits ovulation.
Compounds which should also be mentioned because
of their advantageous biological properties are those amongst
the compounds of the formula Ia in which St represents a
.
radical of the partial formula St2.
These compounds are also distinguished as highly
active sex hormones. They have a central action and greatly
inhibit the secretion of pituitary gonadotrophins. In addi-
tion, they also have a strong peripheral, especially oestro-
genic activity, as can be shown by animal experiments.
Because of these advantageous biological properties, they
can be used as therapeutic preparativns in medicine for all
- ' '
~ .
... ... .. . . . . . .
. .: .:, - . .
':~,, ' ' ~ . -
., . . , ~ . , .
....
,
1069118
- 6 -
,,
the indications usual for oestrogens, but especially to
inhibit gonadotrophin secretion andtor to control fertility.
The 18,18-difluorosteroids according to the in-
vention are obtained according to a novel chemical process,
which is characterised in that in a corresponding 17-ketone
of the general formula III
'~:HF2
St ~ ~ (III)
.
where~n S~ has the meanings indicated for Stl, St2, St'2
and St3, the 17-oxo-group is reduced to a hydroxyl group,
optionally with a simultaneous introduction of a lower
;~ aliphatic hydrocarbon radical into the 17a-position, and,
if a compound of the formula Ia is required in which a
hydroxyl group in the 3- and/or 17-position is in an esteri-
fied form, a resulting product having a corresponding free
A~ hydroxyl group is esterified.
h~
The reduction of the 17-oxo group to the hyd-ccyl
group is carried out in a manner which is in itself known
and advantageously diborane or complex hydrides, especially
those of aluminium or boron with an alkali metal or alkaline
earth metal, such as, for example, sodium aluminium hydride,
calcium borohydride and lithium borohydride, but especially
lithium aluminium hydride and above all sodium borohydride, or
:
~ . . .
: . . - - .
. . , .. . ~ .. ~ -.
.. . : . . . .. .
- . ,:
- . .
.
. ~ -. .. . ... .
10~9118
-- 7 --
derivatives thereof in which one or more hydrogen atoms are
replaced by lower alkoxy radicals, such as sodium methoxy-
borohydride and especi~lly Iithium tri-tert.-butoxy-aluminium
hydride, are advantageously used for this purpose. The
choice of the solventandcEthe reduction conditions depends
on the reducing agent used and is in accordance with the
generally known principles. If a selective reduction of the
17-oxo group is required, the other oxo groups are protected
temporarily as ketals or enol ethers; when a 3-oxo-~4-,grou-
ping is present, the procedure can also be such that this
grouping is reduced simultaneously and then selectively
dehydrogenated, for example with manganese dioxide, back to
the 3-oxo-~4-grouping.
The reduction of the 17-oxo group with simulta-
neous introduction of a lower aliphatic hydrocarbon radical,
for example one of those mentioned initially, is carried out
in a manner which is in itself known by reacting the 17-oxo
compound with a corresponding organo-metallic compound.
If the hydrocarbon radical to be introduced is a lower
alkyl radical, a ¢rignard compound, for example a lower
alkyl-magnesium halide, such as methylmagnesium bromide or
methylmagnesium iodide, or lower alkyllithium, such methyl-
lithium, is preferred as the organometallic compound; if
a l-alkinyl radical, especially the
,
.,
., .; . . ~
,
. . . . - - - ~ . .
.
- . - , . . . , - , . -
. '' : . .. - . ,:. '.... . . ~ .~ ~
0 69 il8
ethinyl radlcal, is to be introduced, a oorrespondlng al~ali
metal compound, for example sodium acetylide or potassium
acetylide or, in particular, lithium acetylide, is advantageously
used. In the latter case it is particularly advantageous
to use lithium acetylide in the form of lts complex with
ethylenediamine. Also in this case, the other oxo groups must
be protected in a manner analogous to that described above
for the selective reduction.
The ketalisation and the formation of enol ethers,
which are to be carried out, if necessary, in order to
protect the oxo groups, are also effected ~
in a manner which is in itself known, especially under the
conditions of acid catalysis and optionally using dehydratin~
agents or azeotropic distillation. For ketalisation,
for example, lower alkanols, such as methanol or ethanol, and
especially a- and ~-glycols, such as 1,2- or 1,3-propanediol
and 1,2_ or 2,3-butanediol, and, above all, ethylene glycol,
.. . .
or reactive derivatives of these alcohols, such as acetals or
ketals, especially those in which the carbonyl component is
readily volatile, such as, for example, 2,2-dimethyl-1,~-
dioxolane, are used. Corresponding thioketals are obtained
analogously, but starting from the sulphur analogues of the
abovementioned alcohols, above all from l,?-ethanedithiol or
a reactive derivati~e thereof. - In order to form the
enol ethers, an ortho-ester of a lower alkanol, especially of
methanol or ethanol, with a lower aliphatic carboxylic acid,
,
.
,. , , :, : , :, - : -: . . . . : :
: -~0 69 11 8
_ 9 _
.`~ '
.
` especially formic acid, is preferably used as the reagent;
particularly preferred reagents are methyl orthoformate and,
above all, ethyl orthoformate. In the case of
; an oxo group conjugated with a double bond, the formation of
the ketal or enol ether ~ay also be accompanied by a shi~t
of the double bonds, for example in the case of the 3-oxo-~4
~ grouping the 4,5-double bond migrates into the 5,6-position.
; The subsequent liberation of the temporarily
protected oxo groups in the resulting process products is
carried out in a manner which is in itself known, preferably
by hydrolysis. Both enol ethers and ketals are prefer-
ably hydrolysed under the conditions of acid catalysis in the
presence oP an inorganic acid, for example sulphuric acid, or
a hydrogen halide acid, such as hydrochloric acid, hydrobromic
acld or hydriodic acid, or of an organic acid, for example a
sulphonic acid, such as p-toluenesulphonic acid cr sulphosali-
cylic acid, or of a strong carboxylic acid, such as oxalic
acid or formic acid.
The subsequent esterification or etherification of
hydroxyl groups in the resulting compounds is also effected
ln a manner ~rhich is in itself kno~. For esterification,
for example, the compound to be esterified is treated with an
excess of the aoid itself, such as with formic acid, or with
a reactive derivative thereof, for example with a derivative
of one of the abovementioned acids, especially with an
.~ . .
.; . .
~ ' ' ' - .
,~ .
.. ..
. - , : . . :
.
.
.. , , .. ,
~0 69 1 1 8
.
- 10 --
anhydride or acid halide, advantageously in the presence of
a tertlary base, rsuch as pyridine, quinollne or N-ethyl-
piperldine; For etherification, for example, thc com~ounds
to be
etherified are treated with reactive derivatives of
alcohols, for example with esters of strong acids, such
as ~alides, sulphates of sulphonic acidesters~ it being
possible to use, in particular, one of the above mentioned
alcohols as the alcohol component. Preferably, the reaction
is carried out in the presence of basic agents.
Those compounds of the formula Ia in which St has
the meaning of St2 can also be prepared advantageously in
a manner which is in itself known, for example as described
below, by aromatisation of a resulting corresponding compound
of the formula Ia, in which St represents a radical of the
partial formula St2 asdefined above, and, if a compound is
required in which R6 is lower alkyl, by subsequent etheri-
fication of a resulting 3-hydroxy compound at the 3-hydroxyl
in a manner describe above.
The aromatisation is carried out in a manner which
is in itself known by reacting a l9-nor-~4-3-oxo compound,
optionally in the form of a 3-enol ether thereof, with a
.. ..
~ quinone, such as chloranil or especially 2,3-dichloro-5,6-
; dicyano-1,4-benzoquinone, by which means, by rearrangement
.
. ~ .
.: : , . . : . . . . ....... .
r~
10 69118
- 11 - ,
of the 3-oxo-1,4-diene grouping first formed, aromatisation
of the A ring can take place in the same step, the 3-hydro-
xy-1,3,5(10)-triene grouping being formed.
Alternatively, the compounds of the formula Ia
wherein St has the meaning of Stl in whi-ch R5 is an oxo group
can be obtained when in a corresponding resulting compound
of the formula Ia, wherein St represents a radical of the
partial formula St3 as defined above, the 3-hydroxyl group
is oxidised in a known manner, for example as described
below, especially by the Oppenauer oxidation, to the 3-oxo
group, the double bond being simultaneously shifted into
the 4,5-position.
Oxidising agents are compounds of 6-valent chromium,
~uch as chromium trioxide, chromic acid and the alkali metal
salts thereof,Lower alkanecarboxylic acids, such as acetic
acid or proplonic acid, or pyridine or acetone, optionally
diluted with a halogenated lower alkane, such as dichloro-
methane or chloroform, and/or in the presenoe o~ ~queous
sulphurlc acid, ad~antageously are use~ às the ~eaction
~ medium.Apreferred alternative is the Oppenauer oxldatlon,
that is to say oxidation with a ketone, such as acetone or
cyclohexanone, under the catalytic action o~ an aluminium
lower alkoxide, such as aluminium isopropylate; .
.
.
.. . ..
,,
: . ~ , . ' . :.
' .. . : . . . ' , :
. . - ~
.
: . . . . . ... . . . . .
, . . ~. .
~, :
- - 1069~18
- 12 -
the Oppenauer oxidation is particularly advantageous in
that the double bond in the 5,6-position migrates
spontaneously into the 4,5-position. i -
The invention also relate~ to those embodiments of the
above processes in which a compound obtained as an intermediate
at any stage is used as the starting material and the missing
~teps are carried out or in which a starting material is fonmed
under the reaction conditions.
The starting materials of formula III for the pro-
cesses of the present invention are manufactured in a manner
which is described in our co-pending Canadian Patent Appli-
cation Ser. No. 232,334. Appropriately, those starting ma-
terials which contain the substituents mentioned particularly
above, and especially those starting materials which lead to
the final products described specifically or highlighted by
! formulae herein, are used.
'
.
... ~ - . . . ..
- - .. . . .. . : - . - . ~
. - : ,
:, ~ . ` . :
.
- 1069118
- 13 -
m e present invention also relates to the production
of pharmaceutical preparations, and of contraceptives for
humans and mammals, which contain the new pharmacologically
active substances, described above, of the present invention
as active substances, together with a pharmaceutical excipient.
Organic or inorganic substances which are suitable for enteral,
for example oral, or parenteral administration or for topical
application are used as the excipients. Substances which
can be used to form the excipients are those which do not
react with the new compounds, such as, ~or example, water,
gelatine, lactose, starch, magnesium stearate, talc, vegetable
oils, benzyl alcohols, gum, polyalkylene glycols, white petrol-
eum jelly, cholesterol and other known medicinal excipients.
m e pharmaceutical preparations can be in the solid form, for
example as tablets, dragees or capsules, or in the liquid or
semi-liquid form as solutions, suspensions, emulsions, oint-
ments or creams. Optionally, these pharmaceutical prepara-
-- tions are sterilised and/or contain auxiliaries, such as pre-
servatives, stabilisers, wetting agents or emulsifiers, salts
to regulate the osmotic pressure or buffers. They can also
contain other therapeutically valuable or biologically active
substances.
me following Examples describe the invention in more
detail, but do not limit it to what is described therein.
The tempera~ures are given in degrees Centigrade.
,
'' '' ~ .
, . . . , : , . .
. .. . ,,., . - . . , . . : :
. : . . ~ , .: , , . . - ~ : :
0691 18
- 14 -
Example 1
After adding 22 ml of a 10% strenght potassium
hydroxide solution, a solution of 2.3 g of 18,18-difluoro-
androst-5-ene-3~,17~-diol diacetate (crude product) in 130 ml
of methanol is stirred for 1 hour at room temperature, whilst
passing nitrogen through the solution. me reaction mix-
ture is then concentrated to about 60 ml in an aspirator
vacuum and taken up in ethyl acetate and the mixture is
washed with 1 N hydrochloric acid and with water until neut-
ral, dried and evaporated in an aspirator vacuum. The crude
.18,18-difluoro-androst-5-ene-3~,17~-diol is suspended, with-
out purification, in 80 ml of toluene, the suspension 7S
treated with 8 ml of cyclohexanone and 2.2 g of aluminium iso-
propylate and the mixture is refluxed for 45 minutes with
stirring. The cooled reaction mixture is worked up by diluting
it with ethyl acetate and washing it successively with satura-
ted Seignette salt solution (potassium sodium tartrate solu-
tion) and with water. The washings are further extracted with
ethyl acetate and the organic phases are dried and evaporated
in an aspirator vacuum. The amorphous residue is then chromato-
graphed over 100 times the amount by weight of silica gel.
Elution with a mixture of hexane/ethyl acetate(3:1) gives
successively, in approximately equal amounts by weight, 18,18-
difluoro-androst-4-ene-3,17-dione, which after recrystalli-
sation from acetone/hexane melts at 161-163C, and 18,18-di-
.
.. . . . .. .
. ~ . . . . . . - . .
- - .
. . . . -
, . . . . . -
... : . .. . . ~ . - - , .
- ~ ' : . ' - -... . . - . : .' : - , :
69 ~ ~ 8
- 15 -
uoro-17~-hydroxy-androst-4-en-3-one o~ melting point 183-184C
(recrystallised from acetone/hexane).
Example 2
500 mg of 18,18-difluoro-androst-4-ene-3,17-dione
are dissolved in 20 ml of dioxane and, after adding 1 ml of
orthoformic acid ethyl ester and 30 mg of p-toluenesulphonic
acid, the mixture is stirred ~or 8 hours at room temperature.
The reaction mixture is then poured into.water (containing
traces of pyridine) and extracted twice with ethyl acetate :~
and the extracts are washed until neutral, dried and evapora-
ted in an aspirator vacuum. The crude amorphous enol ether
(3-ethoxy-18,18-difluoro-androsta-3,5-dien-17-one) is dis-
solved direct in 30 ml of absolute ether and the solution is
added dropwise to an ethereal solution of methyl magnesium
iodide prepared from 300 mg of magnesium turnings and an equi-
valent amount of methyl iodide, whilst stirring and cooling.
The reaction mixture is refluxed for 2 hours and
then worked up in the customary manner. ~le crude carbinol
is subjected to hydrolysis direct, without purification.
For this purpose, the compound is dissolved in 10 ml of 66%
~trength acetic acid and the solution is stirred for 2 hours
at 30C. It is then diluted with water and extracted with
e~hyl acetate and the extracts are washed until neutral
(twice with saturated sodium bicarbonate solution and with
water), dried and evaporated in an aspirator vacuum. Chroma-
- .
: . . . .-, - . -
, : .,-; .. . - .
, . - :
:, . ., , ,. ... ~. . ...
0 69 11 8
- 16 -
tography of the crude product over 100 tires the amount by
weight of silica gel (system: hexane/ethyl acetate, 3:1)
gives 18,18-difluoro-17~-hydroxy-17-m~thyl-androst-4-en-3-one.
Example 3
250 mg of 18,18-difluoro-17~-hydroxy-oestr-4-en-3-one
are dissolved in 1 ml of pyridine, 1 ml of acetic anhydride is
added to the solution and the mixture is left to stand for 15
hours at room temperature. me reaction mixture is then
poured into ice water, the mixture is extracted twice with
ethyl acetate, washed until neutral, dried~and evaporated in
an aspirator vacuum. After one crystallisation oE the crude
product from ether/hexane, pure 18,18-di1uoro-17~-hydroxy-
oestr-4-en-3-one acetate of melting point 108-110C is ob-
tained.
Example 4
280 mg of 18,18-difluoro-oestr-4-ene-3,17-dione, 10 ml
of dioxane, 0.5 ml of ortho~o~ic acid ethyl ester and 16 mg
o~ p-toluenesulphonic acid are stirred for 6 hours at room
temperature, li6ht being excluded. me reaction mixture is
poured into 40 ml of water (containing 4 drops of pyridine),
the mixture is extracted twice with ethyl acetate and the
organic layer is washed with water and a saturated sodium
chloride solution until neutral, dried and evaporated in
an aspirator vacuum. ~le resulting amorphous 3-ethoxy-18,i8-
difluoro-oest~3,5-dien-17-one is then dissolved in 6 ml of
dioxane and the solution is added dropwise in the course of
..
' --',,, ; ,
'
- 1069118
.
20 minutes to a solution, which is saturated with acetylene,
of 1.8 g of lithium ace~ylide-ethylenediamine complex in
18 ml of diox~ne, whilst at the same time passing acetylene
through the solution. The reaction mixture is then stirred
at room temperature for a further 15 minutes and saturated
ammonium chloride solution and ethyl acetate are then added
with coo~ing and the organic phase is washed successively
with 1 N hydrochloric acid and with a saturated sodium chloride
solution, dried and evaporated in an aspirator vacuum. In
order to dissolve the resulting yellowish amorphous residue in
5 ml of tètrahydrofurane, 2.5 ml of a 3:7 mixture of concen- -
trated hydrochloric acid and water are then added and the mix-
ture is stirred for 1 hour at room temperature. After adding
ethyl acetate, the organic layer is washed with sodium bicar-
bonate solution and water until neutral (subsequent extraction
with ethyl ace~ate)-, dried and evaporated in an aspirator ~-
vacuum. The residue is chromatographed over 100 times the
amount of silica gel, using hexane/ethyl acetate (2:1) as the
eluant, to yield 18,18-difluoro-17-hydroxy-19-nor-17a-
pregn-4-en-20-in-3-one (17~-ethinyl-18,18-difluoro-19-nor-
testosterone), which after recrystallisation from methylene
chloride/hexane melts at 244-252C.
In spectrum: 3550, 3280, 1670, 1620 and 1055 cm 1.
NMR spectrum: 2.63 ppm, singlet, (C-21), 5.84 ppm, broads~et
(C-~), 6.13 ppm, triplet, JHF = 54 Hz (C-18).
.
.
, - ~ . . .. . . . .
... . - ~ .
. . .
~ 10 69 1 1 8
- 18 -
Example 5
A solution of 300 mg of 18,18-difluoro-3-methoxy-
oestra~,5(10)-trien-17-one in 12 ml of dioxane is added
dropwise in the course of 30 minutes to a solution, saturated
with acetylene, of 1.5 g of lithium acetylide-ethylenediamine
complex in 10 ml of dioxane, whilst at the same time passing
acetylene through the solution. m e reaction mixture is
stirred at room temperature for a further 60 minutes and
treated, whilst cooling, with saturated ammonium chloride
~olution and with ethyl acetate. m e organic phase is
washed successively with 1 N hydrochloric acid and with a
saturated sodium chloride solution, dried and evaporated in
an aspirator vacuum. The residue is chromatographed over silica
gel with a mixture of hexane/ethyl acetate (9:1) as the eluant
afording 17-ethinyl-18,18-difluoro-3-methoxy-oestra-1,3,5
(10)-trien-17~-ol, which after recrystallisation from acetone/
hexane has a melting point of 167-168C.
.. . .
,. . -
, . ~
'' . - ~ ~
