Note: Descriptions are shown in the official language in which they were submitted.
OS~7~
The present invention relates to steroids. More particularly, the
; invention is concerned with D-homosteroids, a process for the manufacture
thereof, pharmaceutical preparations containing same and starting materials
used in the manufacture of said D-homosteroids.
The D-homosteroids provided by the present invention have the fol-
lowing general formula
OR17a~
R 3 ¦ R17a~ -
R3
~:'
wherein R represents an oxo~ ~H,H) or (a-H, ~-O-acyl) grouping,
R13 represents a lower alkyl group, R17a~ represents a hydrogen
10atom or an acyl or lower alkyl group and R17aa represents a
hydrogen atom~ a lower alkyl group or an ethynyl, l-propynyl,
vinyl, chloroethynyl, butadlynyl or propadienyl group and wherein
the broken line m the A-ring denotes an additional carbon-
carbon bond in the 4,5- or 5(10)-position.
According to the process provided by the present invention,
the D-homosteroids of formula I ar~ manufactured by
,.
''''''
.
''''
'.;
~ ,
- 2 - ~
.~.,, `'
. . . : . . . . . . . ~, : , . ~ . . ... . .
i~5'~7~i~
(a) hydrolysing a compound of the general formula
~Rt7afl
~ 1""~17a~ .
~ 3 (II)
- , wherein Rl3, R17a~ and R17a~ hav th
significance given earlier and R3l
represents a moiety hydrolysable to form
a 3-keto-~4 or 3-keto-~5(10) grouping,
or
(b) r~acting a compound of the general formula
R13 ~
(III)
32~--
R
: ~lO , wherein Rl3 and the broken line in the
.
A-ring have the significance given earlier
and R3 represents a (H,H~ or ~a-H, ~-0-
acyl) grouping,
- with an organometallic compound furni~hing a group denoted by
Rl7aa
: or
(c) reducing the keto group in a compound of formula
~ I hereinbefore to a hydroxy group.
':
-- 3 --
~05'~
As used in this specificatlon, the term "acyl" denotes,
in particular, an acyl group derived from an organic acid;
for example, an alkanecarboxylic acid such as acetic acid,
propionic acid, caproic acid or valeric acid, oxalic acid,
succinic acidO citric acid or an aromatic carboxylic acid such
as benzoic acid.
A lower alkyl group can contain up to 7 carbon atoms and
can be straight chain or branched-chain. Examples of such
lower alkyl groups are the methyl, ethyl, propyl, isopropyl
1~ and butyl groups and isomers of the latter. Preferred lower
alkyl groups denoted by R13 are the methyl and ethyl groups.
Examples for the moiety denoted by R31 are 3-alkoxy
(e.g. 3-methoxy)-~2'5'(10~, 3-alkylthio (e.g. 3-methylthio~-
~ ~ 3-seC-amino (~.~. pyrrolidino)-~2~5~(lO)~ 3-alkylene-
I5 dioxy (e.g. ethylenedioxy)-A5(10), -~4 or -~5, or 3--alkylene-
dithio (e.g. 3-ethylenedithio)-~5(10), -A4 or -~5 groupings.
A preferred group of D-homosteroids of formula I are
those wherein R3 represents an oxo grouping, R13 represents a
methyl or ethyl group and the double bond in ring A is present
in the 4,5 position. More especially preferred are such D-
homosteroids of formula I wherein R17aa represents a hydrogen
atom or an ethynyl, chloroethynyl or butadiynyl group and
R17a~ represents a hydrogen atom.
Examples of D-homcsteroids of formula I in whlch R3
represents a (H,ll) or (~-H, ~-0-acyl) grouping are:
17a~-hydroxy-13-methyl-gona-4,16-diene;
~sz~
17aa-ethynyl-17a~-hydroxy~13-methyl-gona-4,16-diene;
17aa-ethynyl-13-ethyl-17a~-hydroxy-gona-4,16-diene;
17a~-acetoxy-17aa-ethynyl-13-ethyl-gona-4,16-diene;
3~,17a~-diacetoxy-13-methyl-gona-4,16-diene;
3~,17à~-diacetoxy-17aa-ethynyl-13-methyl-gona-4,16-
diene and
3~,17a~-diacetoxy-17aa-ethynyl-13-ethyl-gona-4,16-diene.
~he hydrolysis of a compound of formula II according to
embodiment (a) of the present process can be carried out in a
manner known per se u~ing an acid; for example, a mineral
acid ~uch as hydrochloric acid or a carboxylic acid such as
oxalic acid. A particularly suitable hydrolysis medium is an
aqueous-alcoholic solutlon ~e.q. methanol/water) which may
contain other solvents (e.g. chloroform).
The reaction of a compound of formula III with an
organometallic compound according to embodiment (b) of the
present process can be carried out in a manner known per se.
The organometallic compound can be a Grignard compound (e.g.
ethynylmagnesium bromide, proW nylmagnesium bromide or vinyl
m2gnesium~bromide) or an alkali organometallic compound such
as sodium acetylide, potassium acetylide, lithium acetylide or
vinyllithium.
The reduction of a compound of formula III according to
embodiment (c) of the present process can be carried out in a
~5 manner known per se with complex metal hydrides [e.g. di(lower
alkyl)-aluminium-hydrides such as diisobutylaluminium hydride;
tri(lower alkoxy)-aluminiums such as triisopropoxyaluminium;
_ 5 _
- . . . . ..
- ~ .. . .: , ,, :
. :,: . . :: ': . . . ; ... . ..
.. ., , ,. . ~ , ,
~OS;~76~3
lithium aluminium hydride; sodium aluminium or sodium (boro)
hydride; trimethoxy- or tributoxy-(lithium aluminium hyd-
ride)]. Suitable solv~nts for this reduction are hydrocar-
bons such as cyclohexane, benzene and toluene or ethers such
as diethyl ether and tetrahydrofuran.
The starting materials of formulae II and III can be
prepared as follows or in an analogous manner.
A) Pre~ration of 3-methoxy-D-homo-l9~nor-17aa-pregna-
2,5(10),16-trien~20-yn~17a-ol.
a) A boiling solution of 44 g of 3-methoxy-D-homooestra-
1,3,5(10)-trien-17a-one in 100 ml of dichloromethane and 200
ml of methanol was treated wi*h a suspension of 62 g of cupric
bromide in 40 ml of methanol and 30 ml of dichloromethane and
the mixture was stirred for 5 hours under reflux. The
crystalline precipitate wa~ flltered over Speedex under
suction, rlnsed with dlchloromethane and the filtrate was
concentrated to dryness on a rotary evaporator. The residue
was taken up ln dichloromethane, wa~hed three times with water
and the aqueous pha3es were extracted twice more with di-
chloromethane. The organic phases were dried over sodium
~ulphate and concentrated on a rotary evaporator. The crude
17~-bromo-3-methoxy-D-homooe~tra-1,3,5(10)-trien-17a-one was
crystalllsed from dlchloromethane/hexane; melting point
183-184C; [a]25 = +32 (c = 1.0 in chloroform).
.
b) A solution of 49 g of 17~-bromo-3-methoxy-D-homoQestra-
1,3,5(10)-trien-17a one in 400 ml of dimethylformamide was
treated with 43.5 g of lithium bromide and with 18.5 g of
Trc~de~ ~
-- 6 --
1~3SZ7~1~
lithium carbonate and the mixture stirred at 110C ~bath
temperature) for 10 hours under argon. The mixture was
poured on to ice-water and extracted three times with di-
chloromethane. The organic extracts were back-washed twice
with water, dried over sodium sulphate and concentrated on a
rotary evaporator. The last traces of dimethylformamide were
removed at 70C/0.5 Torr. Crystallisation from dichloro-
methane/acetone gave 3-methoxy-D-homooestra-1,3,5(10),16-
tetraen-17a-one; melting point 161D-162C; [~]25 = +o (c =
lo 1. o in chloroform).
c) A solution of 36.5 g of 3-methoxy-D-homooestra-1,3,5-
(10),16-tetraen-17a-one in 750 ml of absolute tetrahydrofuran
was treated portionwise with 3.8 g of lithium aluminium
hydride while stirring in an argon atmosphere at 0-5C.
After stlrring at oC for 2 hours, the mixture was treated
carefully with ethyl acetate and then with ice-water and
filtered over Speedex~under suction. The filtrate was
extracted three times with ethyl acetate, the organic phases
washed twice with water, dried over sodium sulphate and con-
centrated to dryness on a rotary evaporator. Crystallisationof the crude product from ether/hexane yielded 3-methoxy-D-
hom00estra-1,3,5(10),16-tetraen-17a~-ol; melting point
100-101C; [a]D = ~8 (c = 1.0 in chloroform).
d) A solution of 33 g of 3-methoxy-D-homooestra-1,3,5(10),
16-tetraen-17~-ol in 300 ml o~ absolute tetrahydrofuran and
300 ml of tert.butanol was added dropwise withln 15 minute~ to
750 ml of absolute liquid ammonia at -33C. 10.2 g of ~odium
were added portionwise to the milky suspenFion. The dark-
.. .
-- 7 --
:: - - . . . , . , ~;
-: . .. . ~
105;~7f~1~
blue mixture was stirred for 2 hours at -33C, carefully
treated with 100 ml of methanol and freed from ammonla by
slowly warming to room temperature. The mixture was poured
on to ice-water and extracted with dichloromethane~ The
organic phases were back-washed twice with water, dried over
sodium sulphate and evaporated to dryness on a rotary evapor-
ator. Crystallisation from ether/hexane yielded 3-methoxy-
D-homooestra-2,5~10),16-trien-17a~-ol; melting point 119-
120C; [~]D5 = ~90 ~c = 1.0 in chloroform).
e) A solution of 16 g of 3-methoxy-D-homooestra-2,5(10),16-
trien-17a~-ol in 200 ml of benzene was treated with a suspen
sion of 50 g of silver carbonate on Speedex [M. FPtizon et al
J. Org. Chem. 36, 1341 (1971)] in 400 ml of benzene and the
mixture was heated to reflux for 3 hours under argoi~. The
black precipitate was filtered off~under suction, rli~sed with
ether and the filtrate concentrated to dryness on a rotary
evaporator. Crystallisation from ether/hexane yielded 3-
methoxy-D-homooestra-2,5(10),16-trien-17a-one; melting point
149-151C; [a]25 = -86 (c = 0.95 in chloroform).
:
f) A solution of 3.7 g of 3-methoxy-D-homooestra-2,5(10),
16-trien-17a-one in 75 ml of absolute tetrahydrofuran was
treated with 3.4 g of lithium acetylide-ethylenediamine
complex and the mixture was stirred for 90 minutes at 25C
under argon. The mixture was poured on to ice--water and
extracted three times with ether/ethyl acetate (ca 1:1). The
organic phases were washed with water, dried over sodium
sulphate and evaporated to dryness on a rotary evaporator.
There was obtained 3-methoxy-D-homooestra-2,5(10),16-trien-
- 8 ~
:
l~)S'~7~!3
17a-one; melting point 139-140C (from hexane); [~]25 =
-86 (c = 0.816 in chlorofonm)
B) Preparation of 13-ethyl-3-methoxy-D-homo-18~19-dinor-
17aa-pregna-2~5(1~0~ L~ 0-yn-17a-ol
.
a~ A boiling solution of 25 g of 13-ethyl-3-methoxy-D-
homogona-1,3,5(10)-trien-17a-one / prepared from 13-e~hyl-3-
methoxygona-1,3,5(10)-trien-17-one by 1~ conversion in~o the
corresponding 17-cyanohydrin and 2) reduction of the cyano-
hydrin to the corresponding primary amine and N-nitrosation
with nitrous acid with ~imultaneous ring extenslon ~see Helv.
24 295E (1941)] 7 in 50 ml of dichloromethane and 100 ml of
methanol was treated with a suspension of 36.2 g of cupric
bromide in 20 ml of dichloromethane and 20 ml of methanol and
^~ the mixture was stirred for 18 hours under reflux. The
1~;
crystalline precipitate was flltered over Speedex~under
suction, thoroughly rinsed with dichloromethane and the
filtrate was evaporated to dryness on a rotary evaporator.
The residue wa~ taken up in dichloromethane, wa~hed three
times with water an~ the aqueous phaseR were extracted a
~further twice with dichloromethane. After drylng over ~odlum
sulphate the dichloromethane solutions were concentrated on a
rotary evapox~tor, the 13-ethyl-17-bromo~3-methoxy-D-homo-
oeRtra-1,3,5(10~-tri~n-17a-one.cry~talllsing out. Further
cry~talline a-bromoketone was obtained from the mother liquors
after ~hrom~tography on 1 kg of silica gel with benzene/2%
ethyl acetate as the eluant. 28 g of a-bromoketone were
dlssolved in 400 ml of d$methylformamide, treated with 20.4 g
of lithium brom1de and 8.3 g of lithium carbonate and the
mixture was 3tirred at 110C (bath temperature) for 7 hours
~527~;~
under argon. The mixture was poured on to ice-water and
extracted once with ether/dichloromethane (2:1) and twice wi~h
ether. The organic extracts were back-washed twice with
water, dxied over sodium sulphate and evaporated on a rotary
evaporator. After chromatography on 700 g of silica gel with
benzene as the eluant and crystallisation from dichloro-
methane/acetone, there was obtained 13-ethyl-3-methoxy-D-
homogona-1,3,5(10),16-tetraen-17a-one; melting point 169-
170C; [al2sg = -20 (c = 0.103 in dioxane).
b) A solution of 12 g of 13-ethyl-3-methoxy-D-homogona-
1,3,5(10),16-tetraen-17a-one in 400 ml of absolute tetra-
hydrofuran was treated portionwise with 1.6 g of lith1um
aluminium hydride under an argon atmosphere while stirring at
0~-5C. After stirring at 0C for 60 minutes, the mixture
was treated carefully with ethyl acetate, then with ice-water
and ~iltered over Speedex under suction. The filtrate was
extracted three times with ethyl acetate, the organic phases
washed twice with water, dried over sodium sulphate and
evaporated to dryness on a rotary evaporator. After chro-
matography of the crude product on 1 kg of silica gel (0.06-
0.2 mm) wlth hexane/ethyl acetate (7:1) as the eluant, there
was obtained 13-ethyl-3-methoxy~D~homogona-1,3,5~10),16-
tetraen-17a~-ol; meltlng point 138-139C (from ether); ~a]
589 = +1~ (c = 0.099 in dloxane).
c) A solutlon of 9 g of 13-ethyl-3-methoxy-D-homogona-
1,3,5(10),16-tetraen-17a~-ol ln 100 ml of absolute tetra-
hydrofuran and 100 ml of tert.butanol was added dropwise
within 20 minutes to 250 ml of absolute liquid ammonia at
-- 10 --
-- `--
105'~'7~B
-33C. 4.5 g of sodium were added portionwise ~o the milky
suspension. The dark-blue mixture was stirred for 4.5 hours
at -33C, treated carefully w~th 50 ml of methanol and freed
from ammonia by slowly warming to room temperature. The
mixture was poured on to ice-water and extracted three times
with dichloromethane. The organic phases were back-washed
twice with water, dried over sodium sulphate and evaporated to
dryness on a rotary evaporator. There was ob~ained 13-ethyl-
i 3-methoxy-D-homogona-2,5(10),16-trien-17a~-ol; meltin~ point
166-170C (from dichloromethane~.
c) A solution of 1 g of 13-ethyl-3-methoxy-D-homogona-2,5
~-A~ (lo) ,16-trien-17a~-ol in 100 ml of benzene was treated with a
suspension of 15 g of sllver carbonate on Speedex in ca 100 ml
of benzene and the mixture was heated at reflux under argon
for 48 hours. The mixture was filtered, the filtrate evap-
.
orated and the residue chromatographed on 30 g of Alox neutral
(actlvlty III) using benzene for the elution, there being
obtained 13-ethyl-3-methoxy-D homogona-2,5(10),16-krlen-17a-
one; melting point 168-172C.
e) A solutlon of 0.9 g of crude 13~ethyl-3-methoxy-D-
homogona-2,5(10),16-trien-17a-one in 20 ml of absolute tetra-
hydrofuran was added to a suspension of ethynylmagneslum
bromide prepared from 1 g of magnesium shavings, 4 ml of ethyl
bromide and excess dry acetylene in 30 ml of tetrahydrofuran.
The mixture was stirred under acetylene for 20 hours at 25C,
carefully decomposed with ice-water and filtered over Speede
under suction. The filtxate was extracted three times with
ether, the organic phases washed wlth water, dried over mag-
-- 1 1 --
, . . . ... . .
,
~52t768
nesium sulphate and evaporated to dryness on a rotary evap-
orator to give 13-ethyl-3-methoxy-D-homo-18,19-dinor-17aa-
pregna-2,5(10)-16-trien-20-yn-L7a-ol.
C) ~ aration of 13-ethyl=17a-hydroxy-D-homo-l8
dinor-17a~pre~na-5(10~,16-dien-20-yn-3-one _t~leneketal.
a~ A suspension of 3.1 g of 13-ethyl-3-methoxy-D-homogona-
2,5(10),16-trien-17a~-ol in 30 ml of dichloromethane and 25 ml
of ethyleneglycol was reduced to a volume of ca 30 ml on a
rotary evaporator and treated with 15 ml of glacial acetic
acid. After stirring for 18 hours under argon at 25C, the
homogeneous solution was poured on to ice-cold aqueous 3-N
sodium hydroxide and the alkaline phase extracted three tlmes
with ether. The organic phases were washed three times with
water, dried over magnesium sulphate and concentrated to dry-
ness on a rotary evaporator. ~fter chromatography on 120 g
of silica gel (0.06-0.2 mm) with hexane/ethyl acetate ~5:1) as
the eluant, there was obtained amorphous 13-ethyl-I7a~-hyd-
roxy-D-homogona-5(10),16-dien~3-one ethyleneketal.
b) A solution of 3.68 g of 13-ethyl-17a~-hydroxy-D-homo
gona-5(10),16-dien-3 one ethyleneXetal ln 60 ml of pyridine
was treated at 5~C with 30 ml of a 1 molar solution of chro-
~ mium trloxlde in pyridine/water (10:1). After stlrring for
: ,_a 18 hours at 25C, the mixture was treated with ice-water and
ether, filtered over Speedex~ nder a vacuum and the aqueous
phase of the filtrate extracted three times with ether. The
organic phases were washed three tlmes with water, dried over
magnesium sulphate and evaporated on a rotary evaporator.
After chromatography on 100 g of silica gel (0.06-0.02 mm)
.
- 12 -
, ,, , . i. . , , i, ; :
~L~5'~716~3
with hexane/ethyl acetate as the eluant, there was obtained
13-ethyl-D-homogona-5(10),16-diene-3,17a-dione 3-ethylene-
ketal; melting point 86-88C (from ether); [a~589 - ~52
(c = 0.105 in dioxane).
c) A ~olution of 2.6 g of 13 ethyl D-homo-5(10),16-diene-
3,17a-dione 3-ethyleneketal ln 30 ml of absolute tetrahydro-
furan was added to a ~u~pen~lon of ethynylmagnesium bromide
prepared from 2 g of magneslum ~havlngs, 8 ml of ethyl bromide
and excess dry acetylene in 100 ml of tetrahydrofuran. The
mixture wa~ stirred under acetylene at 25C for 20 hours,
carefully decomposed with ice-water, covered with ether and
converted lnto a homogeneou~ two-phase system by the addltion
of aqueous 3-N sulphurlc acid. The aqueous phase was ex-
tracted three time~ with ether, the organic extracts washed
once wlth aqueous bicarbonate fiolu~10n and once with water,
dried over mag~eslum ~ulphate and evaporated to drynes~ on a
rotary:evaporator. Thexe was ob~alned crude 13~ethyl-17a-
:~: hydroxy-D-homo-18,19-dlnor-17aa-pregna-5(10),16-dlen-20-yn-3-
one ~ethyleneketal in the form of a yellow foam.
D)
dlen-3-one ethyleneketal.
13.3 ml of a ca 0.75~M olutloA of dlisobutylaluminlum
hydride ln:toluene were added at 0C wlth 3tlrring under argon
to a olutlon of 3.3 y o~ D~homooe~tra-5(10),16-diene-3,17a-
dione 3-ethyleneketal in 50 ml of benzene. A~ter ~tirring
for 45 mlnute3 at 0C, the mlxture was poured on to ice-water
and extr~cted thr~e time~ with ether. The organic phases
were back-washed twlce wlth water, drled over sodium sulphate
- 13 -
.
i27~i8
and concentrated on a rotary evaporator. Crystallisation
from ether followed by chromatography of the mother liquor on
silica gel yielded respectively 2.85 g and 0.37 g of 17a~-
hydroxy-D-homooestra-5(10),16-dien-3-one ethyleneketal;
melting point 166-168C.
E) Preparation of 13-ethyl-17a~hydrox~_ homogona-
5~10),16-dien-3-one 3-ethyleneketal.
13.3 ml of a ca 0.75-M solution of diisobutylaluminium
hydride in toluene were added at 0C with stirring under argon
to a solution of 3.4 g of 13-ethyl-D-homogona-5(10),16-diene-
3,17a~dione 3-ethyleneketal in 50 ml of benzene. After
stirring for 60 minutes at 0C, the mixture was poured on to
ice-water and extracted three times with ether. The organic
phases were washed twice with water, dried over sodium sul-
phate and concentrated on a rotary evaporator. After chro-
matography on silica gel, there were obtained 3.2 g of amor-
phous 13-ethyl-17a~-hydroxy-D-homogona-5(10),16-dien-3-one
3-ethyleneketal.
The D-homosteroids of formula I possess a hormonal
activity, i.e. a strongly gestagenic and ovulation-inhibitory
activity. They can be used, for example, as fertility inhib-
itors or cycle regulators. For this, dosages of 0.01-0.1 mg/
kg may be administered. Furthermore, an androgen1c activity
has been observed, especially in D-homosteroids of formula I
i R17aa represents a hydrogen atom-
The D-homosteroids of formula I can be used in the form
of pharmaceutical preparations which contaln them in as~ocia-
- 14
, - . . ~ ~ ,; ..... , . ... " .... .. . .. . .... . . .
~5~7~il5
tion with a compatible pharmaceutical carrier whlch can be an
organic or inorganic, inert carrier material suitable for
enteral or parenteral administration such as, for example,
water, gelatine, gum arabic, lactose, starch, magnesium stea
rate, talc, vegetable oils, polyalkyleneglycols, petroleum
jelly etc. The pharmaceutical preparations can be made up in
a solid form (e.g~ ~s tablets, dragées, suppositories or
capsules) or in a ll~uid form (e.g. as solutions, suspensions
or emulsions).
.
- 15 -
: . ,J
,, , , . :~ ,i .,
7~
The following Examples illustrate the present invention: ~
,:
Example 1
A solution of 3.9 g of crude 3-methoxy D-homo-19-nor-
. 17aa-pregna-2,5(10),16-trien-20-yn-17a-ol in 90 ml of methanol
and 50 ml of chloroform was treated with 1.8 g of oxalic acid
in 50 ml of water. After stirring at ~5C ~or 3 hours, the
~ mixture was poured on to an ice-cold aqueous bicarbonate
solution, the methanol was removed on a rotary evaporator and
the aqueous phase was extracted three times witll ether/ethyl
10 acetate (1:1). The organic phases were washed twice with
water, dried over sodium sulphate and concentrated to dryness
on a rotary evaporator. After chromatography on 250 g of
A Alox~(neutral III) with dlchloromethane as the eluant, there
was obtained 17a-hydroxy-D-homo-l9-nor-I7aa-pregna-5~10),16-
dien-20-yn-3-one; melting point 182-184C ~from hexane~;
C~]589 = -31 (c = 0.100 in dioxane).
. :
Exam~le_2
.
A solution of 3.2 g of crude 3-methoxy-D~homo-l9-nor-
17a-pregna 2,5(10),16-trien-20-yn-17a-ol in 40 ml of methanol
was treated with 1.6 ml of concentrated hydroahloric acid and
with 2 ml of w~ter and kept at 25C for 18 hour~. The mix
ture was poured on to brine, extracted three times with di-
chloromethane, the organic phases were washed once wlth bi-
carbonate solution, dried over sodium sulphate and concen-
trated to dryness on a rotary evaporator. After chromat-
ography on 150 g of Alox~(neutral III) with hexane/ethyl
- 16 -
: : . .
~5;~6~3
acetate (4:11 as the eluant, there was obtained 17a-hydroxy-D-
homo-l9-nor-17aa-pregna-4,16-dien-20-yn-3-one; melting point
190-191C; [a]259 = -202 (c = 0.102 in dioxane).
Example 3
A solution of 3 g of crude 13-ethyl-17a-hydroxy-D-homo-
18,19-dinor-17aa-pregna-5(10),16-dien-20-yn-3-one ethylene-
ketal in 40 ml of methanol was treated with 0.5 ml of con-
centrated hydrochloric acid and 1 ml of water. After stan-
ding at 25~C for 2.5 hours, the mixture was neutralised with
an aqueous bicarbonate solution, the methanol was removed on a
rotary evaporator and the aqueous residue was extracted with
dichloromethane. The organic phases were washed with water, ~`-
dried over sodium sulphate and concentrated to dryness on a
rotary evaporator. After chromatography on 100 g of Alox~
~ ~ 15 (neutral II) with dichloromethane as the eluant, there was
; obtained 13-ethyl-17a-hydroxy-D-homo-18,19-dinor-17aa-pregna-
4,16-dien-20-yn-3-one; melting point 227-230C (from di-
chloromethane/methanol); L~]2589 = -197 (c = 0.072 in di-
oxane).
Exam le 4
A solutlon of 0.9 g of crude 13-ethyl-3-methoxy-D-homo-
18,19-dinor-17a-pregna-2,5(10),16-trien-20-yn~17a-ol in 20 ml
of methanol was treated wlth 0.4 ml of concentrated hydro-
chlorlc `acld and 1 ml of water. After 4 hours, the mixture
was worked up as described in Example 3. There was obtained
13-ethyI-17a-hydroxy-D-homo-18,19-dinor-17a~-pregna~4,16-dien-
20-yn-~-one.
- 17 -
-
. . ~.
~05'~7~3
Example 5
A suspension o~ 3.2 g of 17aJ~-hydroxy-D-homooestra-
5(]0),16-dien-3-one ethyleneketal in 15 ml of methanol was
treated with 4 ml of l-N and with 0.4 ml of concentrated
aqueous hydrochloric acid and the mixture stirred at 0C for
15 hours, a homogeneous solution resulting. The methanol was
evaporated on a rotary evaporator, the residue was treated
with ice-water and ~hen extracted three times with dlchloro-
methane. After washing with bicarbonate solution, drying
, . . ..
over sodium sulphate and concentration on a rotary evaporator,
the crude product obtained was adsorbed on 100 g of silica gel
(0.~6-0.2 mm). Elution with dichloromet}lane~l% ether yielded
2.5 g of 17a~-hydroxy-D-homooestra-4,16-dien-3-one; melting
point 132-133C; ~a]559 = +29 (c = ~.100 in dioxane).
~ ~ .
; ~ 15 Example 6
A solution of 3 g of 3-methoxy-D-homooestra-2,5(10),16-
trien-17a~-ol in 150 ml of methanol was treated with 30 ml of
.~
l-N aqueous hydrochloric acid and kept at 25C for 15 hours.
The methanol was evaporated on a rotary evaporator and the
aqueous residue extracted thrae times with dichloromethane.
The organic phases were washed with bicarbonate solutlon,
dried over sodium sulphate and concentrated on a rotary evap-
orator. There were obtained 2.8 g of 17a~-hydroxy-D homo-
oestra-4,16-dlen-3-one; melting point 132-133C.
Example 7
A solution of 3.14 g of 13-ethyl-3-methoxy-D-homogona-
.
- 18 -
: . ~ -- ., . - ~ . . . . . .
: ........ .. :.................... . . .
7~8
2,5(10),16-trien-17a~-ol in 150 ml of methanol was treated
with 10 ml of 1-N and with 3 ml of concentrated aqueous hydro-
chloric acid and stirred at 25C'C for 12 hours. The methanol
was evaporated on a rotary evaporator and the aqueous residue
S extracted three time~ wlth dichloromethane. The organic
phases were washed wlth bicarbonate solutlon, drled over
sodium sulphate and concentrated on a rotary evaporator.
~- There were obtalned 2.9 g of 13-ethylw17a~-hydroxy-D-homogon~-
4,16-dien-3-one; melting point 191-192C.
r.
Exam~le 8
~, ` A suspension of 3.2 g of 13-ethyl-17a~-hydroxy-D-homo-
gona-5(103,16-dien-3-one in 20 ml of methanol waC~ treated with
5 ml of l-N and 0.3 ml of concentrated aqueou3 hydrochloric
acid and stlrred for 2 hours. The homogeneous ~olution wa~
kept at +5C for 2.5 day~, after which 0.93 g of crystalline
13-ethyl-17a~-hydroxy-D-homogona-4,16-dlen-3-one had separ-
ated. After the usual working-up of the filtrate and chro-
matography on silica gel, there were obtained a further 1.0 g
of 13-ethyl-17~-hydroxy-D-homogona-~,16-dien-3-on~; melting
point 191-192C; [a]589 - ~12~ ~c = 0~101 in dioxane).
i
12 ml o a ca 2-M ethereal solution of n-butyllithium
were added while stirring under argon at -20C to a olution
of 1.16 g of trans-1,2-dlchloroethylene ln 20 ml of ether.
After stirring at -20C for 30 minutes a olutlon of 1 g o
'~ D-homooectra-5(10),16-d~ene-3,17a-dione 3-e~hyleneketal in 20
"
.
-- 19 _ ,.
7~8
ml of ether was added with stirring and the mixture stirred
for 2 hours at 0C and for 1.5 hours at 25C. The mixture
was poured on to an ice-cold aqueous ammonium chloride solu-
tion and extracted three times with ether. The organic
phases were washed with water, dried over sodium sulphate and
concentrated on a rotary evaporator. The 1.5 g of crude
substance obtained were crystallised from dichloromethane/
ether to give 0.48 g of 13-ethyl-21-chloro-17a-hydroxy-D-homo-
18,19-dinor 17aa-pregna-5(10),16-dien-20-yn-3-one ethylene-
ketal, a fur~her 0.47 g of same being obtained after chro-
matography of the mother liquor on silica gel; melting point
191-192C; [a]589 = -143 (c = 0.102 in dioxane).
A solution of 0.5 g of 13-ethyl-21-chloro-17a-hydroxy-D-
homo-18,19-dinor-17aa-pregna-5(10),16-dien 20-yn-3-one ethyl- .
eneketal in 20 ml of methanol was treated with 10 ml of l-N
aqueous hydrochloric acid and stirred at 25C for 24 hours.
: After removal of the methanol on a rotary evaporator, the
residue wàs partitioned between ether and aqueous bicarbonate
solution, the ethereal phases were washed with water, dried
over sodium sulphate and concentrated on a rotary evaporator.
crystallisation from ether/hexane yielded 0.35 g of 13-ethyl-
21-chloro-17a-hydroxy-D-homo-18,19-dinor-17aa-pregna-4,16-
dien~20-yn-3 one; melting point 198-199C; [a]589.
Example 10
7.5 ml of a ca 1.5-M solution of methylllthium were
added with stirring under argon at 0C to a solution of 3.4 g
of D-homooestra-5(10),16-diene-3,17a-dione 3-ethyleneketal in
- 20 -
, .' ' ' , ' ', . ''. ' . , ' , ,., ~ ' ' ' ' '
10~'~761!3
20 ml of tetrahydrofuran. After stirring at 0C for 1 hour
the mixture was poured on to ice-water and extracted four
times with ether. The ethereal phases were washed with
water, dried over sodium sulphate and evaporatored on a rotary
evaporator. The 4 g of crude substance obtained were adsor-
bed on 150 g of silica gel (0.06-0.2 mm) and eluted with di-
chloromethane to give 2.8 g of amorphous 13-ethyl-17a~-
hydroxy-17a-methyl-D-homogona-5~10),16-dien-3-one ethylene-
ketal.
A solution of 2.5 g of 13-ethyl-17a~-hydroxy-17a-methyl-
D-homogona-5(10),16-dien-3-one ethyleneketal in 30 ml of
methanol was treated with a solution of 0.25 g of oxalic acid
in 10 ml of water and kept at 5C for 4 days and at 25C for
24 houxs~ The mixture was made slightly alkaline with an
aqueous ammonia solution, the methanol was removed on a rotary
evaporator and the aqueous residue was extracted with di-
chloromethane. The organic phases were washed with water,
- dried over sodium sulphate and evaporated on a rotary evap-
; orator. The residue was adsorbed on 150 g of silica gel
(0.06-0.2 mm) and eluted with benzene to give 0.12 g of 13-
ethyl-17a~-hydroxy-17a-methyl-D-homogona-4,16-dien-3-one;
melting point 159-160C; ~a]589 ~ ~54 (c = O.o99 in di
oxane). -
The fo:Llowing Example illu~trates a pharmaceutical
preparation containing a D-homosteroid of formula I:
Example A
A tablet for oral administration of the following com-
- 21 -
71~8
position can be manufactuxed:
13-Ethyl-17a-hydroxy-D-holmo-18,19-
dinor-17aa-pregna-4,16-dilen-20-yn-
3-one 1 mg
Lactose 60 mg
Starch 37 mg
Talcum 1~8 mg
Magnesium stearate 0,2 mg
Total weight 100 mg
- 22 -
. ~ . ... .
.
