CA1052768A

CA1052768A - D-homo steroids

Info

Publication number: CA1052768A
Application number: CA237,710A
Authority: CA
Inventors: Andor Furst; Marcel Muller; Rudolf Wiechert; Ulrich Kerb; Jurg A.W. Gutzwiller
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1974-10-18
Filing date: 1975-10-15
Publication date: 1979-04-17
Also published as: DK137088C; KE3062A; NO142349C; NO143503C; IL48239A0; BE834597A; NO143503B; ES441863A1; LU73595A1; FI53974B; AT348697B; HK40580A; PL100429B1; FR2287902A1; FR2287902B1; CH606113A5; IE42024B1; ZA756243B; MY8100137A; FI752797A

Abstract

ABSTRACT OF THE DISCLOSURE
The D-homosteroids provided by the present invention have the following general formula (I) wherein R3 represents an oxo, (H,H) or (.alpha.-H, .beta.-O-acyl) grouping, R13 represents a lower alkyl group, R17a.beta. represents a hydrogen atom or an acyl or lower alkyl group and R17a.alpha. represents a hydrogen atom, a lower alkyl group or an ethynyl, 1-propynyl, vinyl, chloroethynyl, butadiynyl or propadienyl group and wherein the broken line in the A-ring denotes an addi-tional carbon-carbon bond in the 4,5- or 5(10)-position.
The compounds are obtained by methods known per se and are hormonally active.

Description

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~ -~:' 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.

':

~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~ ~

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-.. .

:: - - . . . , . , ~;
-: . .. . ~

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 -- `--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-, . . . ... . .
, ~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) .

, ,, , . 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 .

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-, - . . ~ ~ ,; ..... , . ... " .... .. . .. . .... . . .

~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).

.

: . ,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 : : . .

~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.

-. . ~.

~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-.

: . ~ -- ., . - ~ . . . . . .
: ........ .. :.................... . . .

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 , .' ' ' , ' ', . ''. ' . , ' , ,., ~ ' ' ' ' ' 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-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 . ~ . ... .

.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufacture of D-homosteroids of the general formula (I) wherein R3 represents an oxo, (H,H) or (.alpha.-H, .beta.-O-acyl) grouping, R13 represents a lower alkyl group, R17a.beta. represents a hydrogen atom or an acyl or lower alkyl group and R17a.alpha. represents a hydro-gen atom, a lower alkyl group or an ethynyl, 1-propynyl, vinyl, chloroethynyl, butadiynyl or propadienyl group and wherein the broken line in the A-ring denotes an additional carbon-carbon bond in the 4,5- or 5(10)-position, which process comprises (a) hydrolysing a compound of the general formula (II) , wherein R13, R17a.beta. and R17a.alpha. have the significance given above and R31 represents a moiety hydrolysable to form a 3-keto-.DELTA.4 or 3-keto-.DELTA.5(10) grouping, or (b) reacting a compound of the general formula (III) , wherein R13 and the broken line in the A-ring have the significance given above and R32 represents a (H,H) or (.alpha.-H, .beta.-O-acyl) grouping, with an organometallic compound furnishing a group denoted by Rl7a.alpha., or (c) reducing the keto group in a compound of formula III given earlier in this claim to a hydroxy group.
n

2) A process according to claim 1, wherein a D-homosteroid of formula I wherein R3 represents an oxo, (H,H) or (.alpha.-H, .beta.-O-acyl) grouping, R13 represents a lower alkyl group, R17a.alpha.
represents a hydrogen atom or an acyl or lower alkyl group and R17a.alpha. represents an ethynyl, 1-propynyl, vinyl, chloroethynyl or propadienyl group and wherein the broken line in the A-ring denotes an additional carbon-carbon bond in the 4,5- or 5(10)-position is manufactured according to embodiment (a) or (b) of said process.

3. A process according to claim 1, wherein a D-homosteroid of formula I wherein R 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 is manufactured.

4. A process according to claim 2, wherein a D-homosteroid of formula I wherein R3 represents an oxo grouping, R 3 represents a methyl or ethyl group and the double bond in ring A is present in the 4,5-position is manufactured.

5. A process according to claim 1, wherein a D-homosteroid of for-mula I wherein R17a.alpha. represents a hydrogen atom or an ethynyl, chloroethynyl or butadinynyl group and R17a.alpha. represents a hydrogen atom is manufactured.

6. A process according to claim 3, wherein a D-homosteroid of for-mula I wherein R17a.alpha. represents a hydrogen atom or an ethynyl, chloroethynyl or butadinynyl group and R17a.beta. represents a hydrogen atom is manufactured.

7. A process according to claim 1 for the preparation of 17a-hydroxy-D-homo-19-nor-17a.alpha.-pregna-5(10),16-dien-20-yn-3-one which comprises hydrolys-ing3-methoxy-D-homo-19-nor-17a.alpha.-pregna-2,5(10),16-trien-20-yn-17a-ol.

8. A process according to claim 7, wherein the hydrolysis is carried out by means of oxalic acid in aqueous-methanolic medium.

9. A process according to claim 1 for the preparation of 17a-hydroxy-D-homo-19-nor-17a.alpha.-pregna-4,16-dien-20-yn-3-one which comprises hydrolysing 3-methoxy-D-homo-19-nor-17a.alpha.-pregna-2,5(10),16-trien-20-yn-17a-ol.

10. A process according to claim 9, wherein the hydrolysis is carried out by means of hydrochloric acid in an aqueous-methanolic medium.

11. A process according to claim 1 for the preparation of 13-ethyl-17a-hydroxy-D-homo-18,19-dinor-17a.alpha.-pregna-4,16-dien-20-yn-3-one which com-prises hydrolysing 13-ethyl-17a-hydroxy-D-homo-18,19-dinor-17a.alpha.-pregna-5(10),16-dien-20-yn-3-one ethyleneketal.

12. A process according to claim 11, wherein the hydrolysis is carried out by means of hydrochloric acid in an aqueous-methanolic medium.

13. A process according to claim 1 for the preparation of 17a.beta.-hydroxy-D-homooestra-4,16-dien-3-one which comprises hydrolysing 17a.beta.-hydroxy-D-homooestra-5(10),16-dien-3-one ethyleneketal.

14. A process according to claim 13,wherein the hydrolysis is carried out by means of hydrochloric acid in an aqueous-methanolic medium.

15. A process according to claim 1 for the preparation of 13-ethyl-17a.beta.-hydroxy-D-homogona-4,16-dien-3-one which comprises hydrolysing 13-ethyl-3-methoxy-D-homogona-2,5(10),16-trien-17a.beta.-ol.

16. A process according to claim 15, wherein the hydrolysis is carried out by means of hydrochloric acid in an aqueous-methanolic medium.

17. A process according to claim 1 for the preparation of 13-ethyl-21-chloro-17a-hydroxy-D-homo-18,19-dinor-17a.alpha.-pregna-4,16-dien-20-yn-3-one which comprises hydrolysing 13-ethyl-21-chloro-17a-hydroxy-D-homo-18,19-dinor-17a.alpha.-pregna-5(10),16-dien-20-yn-3-one ethyleneketal.

18. A process according to claim 17, wherein the hydrolysis is carried out by means of hydrochloric acid in an aqueous-methanolic medium.

19. A process according to claim 1 for the preparation of 13-ethyl-17a.alpha.-hydroxy-17a-methyl-D-homogona-4,16-diene-3-one which comprises hydrolys-ing 13-ethyl-17a.beta.-hydroxy-17a-methyl-D-homogona-5(10),16-dien-3-one ethylene-ketal.

20. A process according to claim 19, wherein the hydrolysis is carried out by means of axalic acid in an aqueous-methanolic medium.

21. A D-homosteroid of the general formula(I) defined in claim 1, when-ever prepared according to the process of claim 1 or by an obvious chemical equivalent thereof.

22. A D-homosteroid of formula (I) defined in claim 1, wherein R3 re-presents an oxo, (H,H) or (.alpha.-H, .beta.-0-acyl) grouping, R13 represents a lower alkyl group, R17a.beta. represents a hydrogen atom or an acyl or lower alkyl group and R17a.alpha. represents an ethynyl, 1-propynyl, vinyl, chloroethynyl or propa-dienyl group and wherein the broken line in the A-ring denotes an additional carbon-carbon bond in the 4,5- or 5(10)-position, whenever prepared according to the process of claim 2 or by an obvious chemical equivalent thereof.

23. A D-homosteroid as defined in claim 3, whenever prepared according to the process of claim 3 or by an obvious chemical equivalent thereof.

24. A D-homosteroid as defined in claim 4, whenever prepared according to the process of claim 4 or by an obvious chemical equivalent thereof.

25. A D-homosteroid as defined in claim 5, whenever prepared according to the process of claim 5 or by an obvious chemical equivalent thereof.

26. A D-homosteroid as defined in claim 6, whenever prepared according to the process of claim 6 or by an obvious chemical equivalent thereof.

27. 17a-Hydroxy-D-homo-19-nor-17aa-pregna-5(10),16-dien-20-yn-3-one, whenever prepared according to the process of claim 7 or 8 or by an obvious chemical equivalent thereof.

28. 17a-Hydroxy-D-homo-19-nor-17a.alpha.-pregna-4,16-dien-20-yn-3-one, when-ever prepared according to the process of claim 9 or 10 or by an obvious chemical equivalent thereof.

29. 13-Ethyl-17a-hydroxy-D-homo-18,19-dinor-17a.alpha.-pregna-4,16-dien-20-yn-3-one, whenever prepared according to the process of claim 11 or 12 or by an obvious chemical equivalent thereof.

30. 17a.alpha.-Hydroxy-D-homooestra-4,16-dien-3-one, whenever prepared ac-cording to the process of claim 13 or 14 or by an obvious chemical equivalent thereof.

31. 13-Ethyl-17a.beta.-hydroxy-D-homogona-4,16-dien-3-one, whenever prepared according to the process of claim 15 or 16 or by an obvious chemical equi-valent thereof.

32. 13-Ethyl-21-chloro-17a-hydroxy-D-homo-18,19-dinor-17a.alpha.-pregna-4,16-dien-20-yn-3-one, whenever prepared according to the process of claim 17 or 18 or by an obvious chemical equivalent thereof.

33. 13-Ethyl-17a.beta.-hydroxy-17a-methyl-D-homogona-4,16-dien-3-one, when-ever prepared according to the process of claim 19 or 20 or by an obvious chemical equivalent thereof.