AU682170B2 - Steroids for treating menopausal complaints - Google Patents

Description

1 Steroids for Treating Menopausal Complaints The invention relates to the use of steroids for the manufacture of a medicament for treating or preventing menopausal complains, especially for treating or preventing osteoporosis.

According to a first embodiment of this invention there is provided a method for the treatment or prophylaxis of menopausal complaints in a mammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of at least one compound having the general formula: R2R 3 IR4"

I

wherein RI represents O, or two hydrogen atoms; R 2 is hydroxy, optionally etherified or esterified; R3 is (2-6C)alkynyl, optionally substituted with hydroxy; R4 is CN or one of the hydrocarbon groups selected from (1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C)alkynyl, and (2-6C)alkylidene, each of said hydrocarbon groups may optionally be substituted with halogen, hydroxy or (1-6C)alkoxy; and R5 is hydrogen 15 or (1-6C)alkyl.

According to a second embodiment of this invention there is provided a steroid having the general fort..ala I o

I

wherein R1 represents O; R2 is hydroxy, optionzly etherified or esterified; R3 is (2- 6C)alkynyl, optionally substituted with hydroxy; R4 is CN, (2-6C)alkyl substituted with halogen, or (2-6C)alkenyl substituted with halogen; and R 5 is hydrogen or (1-6C)alkyL.

According to a third embodiment of this invention there is provided the steroid of general formula I, wherein R 1 is O; R 2 is hydroxy; R3 is ethynyl; R4 is (E)-ethylidene; and R5 is methyl.

According to a fourth embodiment of this invention there is provided a steroid having the general formula I INAULBC101057SAK S-

I

wherein R1 represents two hydrogens atoms; R2 is hydroxy, optionally etherified or esterified; R3 is (2-6C)alkynyl, optionally substituted with hydroxy; R4 is CN or one of the hydrocarbon groups selected from (2-6C)alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2- 6C)alkynyl, and (2-6C)alkylidene, each of said hydrocarbon groups may optionally be substituted with halogen, hydroxy or (1-6C)alkoxy; and R5 is (1-6C)alkyl, Many of the steroids according to this invention, which are used for the treatment of menopausal complaints, are known per se.

For instance, 11-alkyl steroid are known from USP 3,983,144. These steroids are described to have interesting anti-fertility activity. Other llp-alkyl steroids having anabolic, androgenic, and progestational activity are disclosed in USP 3,325,520. Related progestational compounds for menstrual and ovulation control are further known from Australian patent application AL 6614974, European patent application 0,145,493, and 15 USP 3,465,010. Steroids having unsaturated hydrocarbon groups at position 11 of the steroid skeleton are known from US 4,292,251, which patent discloses uterotropic and I 'ovulation inhibiting activity, and from above-mentioned EP 0,145,493.

It has now been found that compounds having the general formula: oo* i IN:LIBCIO1OS1SAK WO 94/18224 PCT/EP'94/00348 2 wherein

R

1 represents 0, or two hydrogens atoms;

R

2 is hydroxy, optionally etherified or esterified;

R

3 is (2-6 C) alkynyl, optionally substituted with hydroxy; R4 is CN or one of the hydrocarbon groups selected from (1-6 C) alkyl, (1-6 C) alkoxy, (2-6 C) alkenyl, (2-6 C) alkynyl, and (2-6 C) alkylidene, each of said hydrocarbon groups may optionally be substituted with halogen, hydroxy or (1-6 C) alkoxy; and

R

5 is hydrogen or (1-6 C) alkyl, can be used for treating or preventing postmenopausal complaints, and especially osteoporosis.

One of the most serious menopausal complaints is bone loss (osteoporosis), which characteristically affects women. The aim of this invention is to provide a medicament which is able to prevent bone loss, and possibly to increase bone mass, and further to treat climacteric complaints. Preferably the active ingredients of these medicaments have strong estrogen and weak or non-existing androgenic activity. Preferred medicaments further have favourable bleeding properties, do not induce endometrium proliferation, and have a favourable NDL/LDL (high/low density lipid) ratio.

In a preferred embodiment the compounds have the general formula I wherein R 1 represents 0 or two hydrogens atoms; R 2 is hydroxy; R 3 is ethynyl; R 4 is selected from the group consisting of methyl, (2-6 C) alkynyl, (2-6 C) alkylidene, and one of (2-6 C) alkyl, (2-7 C) alkoxyalkyl, (1-6 C) alkoxy, or (2-6 C) alkenyl, which may optionally be substituted with halogen; and R 5 is hydrogen or 11-6 C) alkyl.

More preferred is the use of steroids having the general formula I wherein: R 1 is 0; R 2 is hydroxy; R 3 is ethyn-

I,

WO 94/18224 PCT/EP94/0348 3 yl; R 4 is ethyl, 2-fluoroethyl, ethynyl, (2-6 C) alkenyl optionally substituted with fluorine, or (2-6 C) alkylidene optionally substituted with fluorine; and Rg is hydrogen or methyl. In the preferred embodiment R 5 is hydrogen.

Even more preferred is the use of steroids having the general formula I wherein: R 1 is 0; R 2 is hydroxy; R 3 is ethynyl; R 4 is ethyl or ethynyl; and R 5 is hydrogen.

The invention further relates to new steroids having the general formula I wherein:

R

1 represents 0;

R

2 is hydroxy, optionally etherified or esterified;

R

3 is (2-6 C) alkynyl, optionally substituted with hydroxy;

R

4 is CN, (2-6 C) alkyl p nn.J ysubstituted with halogen, or (2-6 C) alkenyl substituted with halogen; and

R

5 is hydrogen or (1-6 C) alkyl; or wherein

R

1 represents two hydrogens atoms;

R

2 is hydroxy, optionally etherified or esterified;

R

3 is (2-6 C) alkynyl, optionally substituted with hydroxy;

R

4 is CN or one of the hydrocarbon groups selected from (2-6 C) alkyl, (1-6 C) alkoxy, (2-6 C) alkenyl, (2-6 C) alkynyl, and (2-6 C) alkylidene, each of said hydrocarbon groups may optionally be substituted with halogen, hydroxy or (1-6 C) alkoxy; and

R

5 is (1-6 C) alkyl.

The steroids of general formula I wherein R 1 is O; R 2 is hydroxy; R 3 is ethynyl; R 4 is 2-fluoroethyl or 2-fluoroethenyl; and Rg is hydrogen are preferred steroids.

I

WO 94/18224 PCT/EP94/00348 4 Other preferred steroids are steroids of general formula I wherein R 1 represents two hydrogens atoms; R 2 is hydroxy; R 3 is ethynyl; R 4 is (2-6 C) alkyl, (2-6 C) alkylidene or (2-6 C) alkenyl, each of which groups may be substituted with fluorine; and R 5 is methyl.

In the definition of R2 the OH group may be etherified or esterified. The term etherified means that the hydroxy group is etherified with a lower alkyl group, preferably having 1-6 carbon atoms, such as methyl, ethyl, propyl, sec-butyl and the like. The term esterified means that the hydroxy group is esterified with a lower alkanoyl gioup, preferably having 2-6 carbon atoms, like acetyl, propionyl, and the like. In principle any ester suffices as long as the ester group cleaves when the compound is administered in vivo.

The (1-6 C) alkyl group in the definition of formula I is a branched or unbranched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, tert-butyl, pentyl and hexyl. Preferably the alkyl group is methyl (especially for R 5 and ethyl (especially for

R

4 The term (2-6 C) alkyl has the same meaning with the exception of methyl.

The (2-6 C) alkenyl group is a branched or unbranched alkenyl group having 2-6 carbon atoms, like vinyl, 2propenyl, and 1,3-butadienyl.

The (2-6 C) alkynyl group is a branched or unbranched alkynyl group having 2-6 carbon atoms, like ethynyl, propynyl, butynyl, and the like.

The (2-6 C) alkylidene group is a branched or unbranched alkylidene group having 2-6 carbon atoms, like ethylidene, propylidene, 2-methylpropylidene, and the like.

I

WO 94/18224 PCT/EP94/00348 The term halogen used in the definition of formula I means fluorine, chlorine, bromine or iodine. Fluorine is the preferred halogen.

The term (1-6 C) alkoxy means an alkoxy group, the alkyl moiety of which is a (1-6 C) alkyl group as previously defined.

The term (2-7 C) alkoxyalkyl means a (1-6 C) alkyl group as previously defined substituted by a (1-6 C) alkoxy group as previously defined, the total number of carbon atoms being between 2 and 7.

The new compounds of this invention can be prepared by condensation of 11-keto steroids of the general formula: O 3

II

wherein

R

1 represents 0;

R

2 is hydroxy, optionally etherified or esterified;

R

3 is (2-6 C) alkynyl, optionally substituted with hydroxy; and

R

5 is hydrogen or (1-6 C) alkyl; or wherein

R

1 represents two hydrogens atoms;

R

2 is hydroxy, optionally etherified or esterified;

R

3 is (2-6 C) alkynyl, optionally substituted with hydroxy; and

R

5 is (1-6 C) alkyl; the active groups of which are optionally protected, is condensed with a Wittig(-like) compound of the formula

R

4

'R

4 "CH-W, wherein R4'R 4 'C forms the group R 4 which is the optionally halogen, hydroxy, or(1-6 C) alkoxy WO 94/18224 PCT/EP94/00348 6 substituted (2-6 C) alkylidene group as previously defined, or R 4 wherein is (2-6 C) alkyl or (2-6 C) alkenyl optionally substituted with halogen, hydro.y, or (1-6 C) alkoxy, in which reactive groups can be protected by protective groups which are known in the art (see for example T.W. Green: Protective Groups in Organic Synthesis, Wiley, NY, 1981), and W is a Wittig, Wittig-Horner or Peterson-like moiety, optionally followed by halogenation and dehydration or by hydration, after which the compound obtained is converted into a nitrile or condensed with a Wittig(like) compound of the formula R 6 W, wherein W has the previously given meaning and R 6 is independently hydrogen, halogen or (1-6 C) alkyl, followed by hydroboration, optionally followed by alkylation, halogenation, or halogenation and dehydrohalogenation, or (partial) hydrogenation, after which optionally present protective groups are removed.

Suitable reagents are triphenylphosphoranes such as

R

4

'R

4 1 'CH-P(Hal)Ph 3 and the like, and suitable Peterson reagents are, for example, trimethylsilane reagents like

R

4

'R

4 '"C(MgHal)Si(CH 3 3 wherein Hal denotes a halogen like chlorine or bromine.

The steroids of the invention can be used to prevent and treat estrogen deficiency induced disorders such as menopausal complaints, as is demonstrated in the estrogen-induced bone loss assay. In this assay young mature female Wistar rats are ovariectomized and treated with the test compound for 1 month. After 1 month blood is collected and in the lithium-heparin plasma the bone turnover parameter (osteocalcin) is determined according to the method of Verhaeghe et al., J. Endrocrinol., i2Q, 143-151. At autopsy the right femur is dissected and the bone density of the distal part of the metaphyse is measured using an X-ray densitometric method. The bone density, in mm aluminum equivalent, is expressed in a WO 94/18224 PCTIEP94/00348 7 percentage relative to the intact control group which is 100 by definition, and to the ovariectomized control group which is 0 by definition.

The value for osteocalcin is defined as 100 for the ovariectomized group and 0 for the intact group.

Active compounds inhibit the bone turnover, and thus have an osteocalcin value lower than 100 Table I gives the results of this assay.

Table dose bone ,)steo- Ri R 2

R

3 R R5density calcin reference: O OH CE-CI H H 1000 24 this invention: 0 OH C=ECH C 2

H

5 H 64 94 -117 0 OH CE=CI CH 2 CJ. H 10 57 -78 0 OH CE-Ci CH 2

OCH

3 H1 250 66 0 OH CE-CI CH=CH 2 H 100 48 -52 0 OH CMMIT C-=H H 250 115 17 0 OH C=ECH CaN H 1000 113 0 OH CE=Ci CH 2 =CH CH 3 1000 90 0 OH CE=Ci OCH 3 Hi 1000 73 -46 O OH CE7CH CH 3 H 125 81.

0 OH CmCH CH 2

CH

2 F H 500 93 -59 O OH CE=CH CHCH 3 H 64 n O OH CECIL i'P'N H 125 119 -66 O OH CEiCIL C 2

H

5

CH

3 250 115

H

2 OH CrECIL Cl! 3 H 1000 80 -54

H

2 OHL CMCil CH 2 Cl H 10 43 -72

H

2 OH CmCH CH 2 C1 H 100 81 -112

H

2 OH Ce5CI CH=CH 2 Cl- 3 200 2

H

2 OH CE=CI C~sCH H 32 66 -17 WO 94/18224 PCT/EP94/00348 8 The compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0,001-10 mg per kg body weight. Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference, Gennaro et al., I.emington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture) the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.

For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.

Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.

The invention is further illustrated by the following examples.

Example 1 To a solution of 115 g of (7a,lla)-ll-hydroxy-7-methylestr-4-en-3,17-dione in 5 1 of acetone were added dropwise at 0.5 'C 110 ml of 8 N chromic acid. After stirring for 1 h 50 ml of propanol-2 were added, and min later the mixture was concentrated partially and diluted with 3 1 of water. After stirring for several WO 94/18224 PCT/EP94/00348 9 hours, the precipitate was filtered, taken up in a small volume of dichloromethane and dried with sodium sulfate, to give after evaporation of the organic solv~ent 107 g of triketone (7a)-7-methylestr-4-en-3 ,1l,17-trionle. Rf 0.54 (toluene-ethyl acetate 4-6 v/v).

A mixture of 115 g of (?ca)-7-methyles'L-r-4-en-3,ll,17trione, 8 g -if p-toluenesulfonic acid and 40 ml of eth-anedithiol in 1 1 of absolute ethanol was ref luxed for 1 h. After cooling the mixture was diluted with 1 1 of water and stirred in the cold for several hours. The precipitate was filtered and washed with 1 N NaOH, water and cold methanol. After drying 134 g of (7a)-3,3ethanedithio-7-methylestr-4-en-l1 17-dione were obtained. Rf 0.62 (toluene-ethyl acetate 8/2).

A solution consisting of 36 g of (7a)-3,3-ethanedi~thio- 7-methylestr-4-en-ll, 17-dione, 300 ml of dichloromethane, 85 ml of triethylorthoformate, 70 ml1 of' ethylene glycol and 2 g of p-toluenesulf onic acid was stirred for 7 h. Then the mixture was washed with sodium carbonate solution and dried, concentrated and passed through a silica gel column to provicle 44 g of product (7a)-3,3-ethanedithio-17, 17-ethylenedioxy-7methylestr-4-en, Rf 0.65 (toluene-ethyl acetate 8/2).

A mixture of 9.2 g of potassium tert-butoxide, 34.8 g of methyltriphenyiphosphonium bromide in 260 ml of toluene was ref luxed for 1 h. Then 7.8 g of (7a)-3,3-ethanedithio-17 ,17-ethylenedioxy-7-methylestr-4-en were added and the mixture was boiled f or another 2 h. Then the reaction was cooled, washed with water, dried and concentrated. The residue was chromatographed to give 6.1 g of (7a)-3,3-ethanedithio-17,17-ethylenedioxy-7methyl-l1-methylene-estr-4-en. Rf 77 (toluene-ethy2.

acetate 9/1).

WO 94/18224 PCT/EP94/00348 A mixture of 6.1 g of (7a)-3,3-ethanedithio-17,17ethylenedioxy-7-methyl-ll-methylene-estr-4-en, 90 ml of acetone, 50 ml of tetrahydrofuran and 3 ml of 6 N hydrochloric acid was stirred at ambient temperature.

After 1 h the mixture was diluted by addition of 700 ml of 5% sodium carbonate and stirred for h. The precipitate was filtered and dried to provide 5.4 g of (7a)-3,3-ethanedithio-7-methyl-l1-methylene-estr-4-en- 17-one. Rf 0.74 (toluene-ethyl acetate 9/1).

Acetylene gas was passed through a solution of 50 g of potassium tert-,ut(xide in 500 ml of dry tetrahydrofuran. After 2 h a solution of 30 g of (7a)-3,3ethanedithio-7-methyl-11-methylene-estr-4-sn-17-one in 400 ml of tetrahydrofuran was introduced dropwise at 0 After stirring for an additional 1 h the mixture was poured into 7 1 of water and stirred for an additional k h. The precipitates were filtered and dried to give 31 g of (7a,17a)-3,3-ethanedithio-17-hydroxy-7-methyl-11methylene-19-norpregn-4-en-20-yne. Rf 0.64 (tolueneethyl acetate 9/1).

To a solution of 8 g of sodium in 300 ml of liquid ammonia at -50 °C was added dropwise a solution of 16 g of (7a, 17u)-3,3-ethanedithio-7-methyl-l1-methylene-19norpregn-4-en-20-yn-17-ol in 75 ml of tetrahydrofuran.

After stirring tor 1 h, excess sodium was destroyed by addition of 10 ml of ethanol. After evaporation of ammonia, the residue was partioned between dichloromethane and water. The organic layer was separated, washed and dried. The material which left after evaporatiron of the solvent was chromatographed to provide 5.4 g of (7a, 17a)-7-methyl-1-meothylene-19-norpregn-4-en-20-yn-17-ol. Rf 0.59 (toluonG-ethyl acetate 9/1).

WO 94/18224 PCT/EP94/0034 1 1 Example 2 A mixture of 15 g of (7a,17a)-3,3-ethanedithio-7-methylll-methylene-19-norpregn-4-en-20-yn-17-ol, 300 ml of methanol, 20 ml of water, 6 g of calcium carbonate and 51 ml of methyl iodide was refluxed for 6 h. After filtration over Hy-flow, the filtrate was concentrated taken up in dichloromethane, washed, dried and evaporated. The remaining residue was chromatographed to provide 6.5 g of (7a,17a)-17-hydroxy-7-methyl-ll-methylene-19-norpregn-4-en-20-yn-3-one. Rf 0.40 (tolueneethyl acetate 9/1).

Example 3 To a solution of 134 g ot (7a)-3,3-ethanedithio-7methylestr-4-en-11,17-dione in 5 1 of dry tetrahydrofuran were added in portions 110 g of lithium tri-tertbutoxy aluminium hydride at 0-5 After stirring for 3 h the mixture was poured into 10 1 of ice water and acidified slightly by addition of 1 1 of 2 N hydrochloric acid. The product was extracted with ethyl acetate. After drying with sodium sulfate the organic material was treated with diethyl ether, to provide 133 g of essentially pure (7a,178)-3,3-ethanedithio-17hydroxy-7-methylestr-4-en-1-one. Rf 0.45 (tolueneethyl acetate 6/4).

To a solution of 132 g of (7a,17B)-3,3-etanthanedithio-17hydroxy-7-methylestx-4-in-ll-one in 800 ml of pyridine were added at 0 °C 182 ml of trimethylsilyl chloride.

After stirring for 1 h the mixture was poured into ice water and the product was extracted with ethyl acetate.

After washing, drying and evaporation of the solvent, the residue was co-evaporated with toluene and then treated with hexane to provide 137 g of (7a,178)-3,3- WO 94/18224 PCTEP94OO348 12 et%-hanedithio-7-inethyl-17-trimethylsilyloxy-estr-4 -en-1lone. Rf= 0.63 (toluene-ethyl acetate 6/4).

To a suspension of 334 q of raethoxymethyltriphenylphosphonium chloride in 6 1 of dry ether were added dropwise 600 ml of 1.6 M butyl lithium at 0.5 After stirring for 1 h a solution of 44.6 g of (7a,17B)-3,3ethaned4i thio-7 -methyl-i 7-trimethyls .lyloxy-estr-4 -en-lione in 1.5 1 of diethyl ether were added and the mixture was stirred fox. 24 h. The organic solution was then washed with water and dried. The residue which remained after concentration of the organic phase was partitioned betweeni hexane-methanol-water (1/0.7/0.3 and stirred for, 15 min. The hexane phase was dried and concentrated to provide 47 g of (7a,l7B)-3,3-ethanedithio-l1-methoxymetniylene-7-rnethyl-17-trimethylsilyloxyestr-4-en. Rf 0.50 (hexane-ethyl acetate 3/1).

To a solution of 265 g of (7c,17)-3,3-ethanedithio-11methoxymethylene-7-methyl-17-trimethylsilyloxy-estr-4-en in 800 ml of acetone were added 80 ml of concentrated bydrochloric acid and the mixture was stirred at room temperature. After 1 h the mixture was poured into water and extracted with ethyl acetate. After washing, drying and evaporation of the organic solvent, the remaining residue was passed through a silica gel column and eluted with dichloromethane-acetone 9/1 to provide 63 g of (7a#llB, 17B)-3, 3-ethanedithio-17-hydroxy-7-methylestr-4-en-l1-carboxaldehyde. Rf 0.38 (toluene-ethyl acetate 7/3).

To a solution of 55 g of (7a,113,17B)-3,3-ethanedithio- 17-hydroxy-7-methylestr-4-en-1l-carboxaldehyde and 165 ml of dihydropyrane iti 1100 ml of dry tetrahydrofuran were added 1.5 g of p-toluenesulfonic acid. After stirring f or 2 h the mixture was poured into 5 1 of sodium hydrogencarbonate solution and the product was WO 9418224 PCT/EP94/00348 13 extracted with ethyl acetate. After concentration of the organic phase (7a, 11,178)-3,3-ethanedithio-17-tetrahydropyranyloxy-7-methylastr-4-en-l-carboxaldehyde was isolated.

A mixture of 1 g of (7a,118,17B)-3,3-ethanedithio-17tetrahydropyranyloxy-7-methylestr--4-en-11-carboxaldehyde and 2 g of hydroxylamine hydrochloride in 12 ml of pyridine was stirred at 80 °C for 1 h. Then it was cooled, poured into water and extracted with ethyl acetate. After washing, drying and concentration 0.9 g of amorphous (7a,118,178)-3,3-ethanedithio-17-tetrahydropyranyloxy-7-methylestr-4-en-11-carboxaldehyde oxime were obtained. Rf 0.60 (toluene-ethyl acetate 8/2).

Dehydration of the oxime was effected by reacting,0.8 g of (7a,llB,17B)-3,3-ethanedithio-17-tetrahydropytonyloxy-7-methylestr-4-en-ll-carboxaldehyde oxime in 8 ml of acetic anhydride during 45 min. Concomitant replacement of the 17-tetrahydropyran ether by an acetate group was observed. The reaction mixture was poured into 50 ml of ice water and stirred for 30 min. After neutralization with 2 N sodium hydroxide and extraction with ethyl acetate 0.75 g of (7a,118,178)-3,3-ethanedithio-17acetyloxy-7-methylestr-4-en-ll-carbonitrile was obtained. Rf 0.58 (toluene-ethyl acetate 9/1).

The acetate functionality was siponified hy stirring 0.75 g of (7a,11B,178)-3,3-ethanedit .io-7-acetyloxy-7methylestr-4-en-ll-carbonitrile for 30 min -n a mixture of 20 ml of tetrahydrofuran and 10 ml of water containing 1 g of sodium hydroxide. The mixture was diluted and extracted with ethyl acetate. After drying and evaporation 0.50 g of (7a,lli,178)-3,3-ethanedithio- 17-hydroxy-7-methylestr-4-en-11-carbonitrile was obtained. Rf 0.34 (toluene-ethyl acetate 9/1).

WO 94/18224 PCT/EP94/00348 14 To a solution of 20 g of (7a,113,17B)-3,3-ethanedithio- 17-hydroxy-7-methylestr-4-en-l1-carbonitrile in 600 ml of dry dichloromethane were added 20 g of sodium acetate, followed by 85 g of pyridinium chlorochromate.

After stirring for 3 h the reaction turned out to be complete. Excess oxidant was removed by addition of ml of propanol-2. The mixture was filtered over Hy-Flow, concentrated and chromatographed to provide 13 g of (7a,11B)-3,3-ethanedithio-17-keto-7-methylestr-4-en-llcarbonitrile. Rf 0.75 (toluene-ethyl acetate 8/2).

Acetylene gas was passed through a solution of 10.5 g of potassium tert-butoxide in 60 ml of dry tetrahydrofuran for 1 h at 0 Then a solution of 9.3 g of (7a,llB)- 3,3-ethanedithio-17-oxo-7-methylestr-4-en-ll-carbonitrile in 100 ml of tetrahydrofuran were added dropwise. After stirring for 1 h at 0-5 °C the mixture was poured into 500 ml of saturated ammonium chloride solution and the product was extracted with ethyl acetate. After washing, drying and concentration 9.5 g of (7a,118,17a)-3,3-ethansdithio-17-hydroxy-7-methyl-19norpregn-4-en-20-yne-ll-car-cnitril was obtained. Rf 0.28 (toluene-ethyl acetate 9/1).

A mixture of 6.5 g of (7a,llB,17a)-3,3-ethanedithio-17hydroxy-7-methyl-19-norpregn-4-en-20-yne-ll-carbonitrile, 200 ml of methanol, 100 ml of tetrahydrofuran, 2.4 g of calcium carbonate, 8.5 ml of water, and 35 ml of methanol was refluxed for several hours, additional methanol was added from time to time and after disappearance of starting material the mixture was cooled, filtered and concentrated. The residue was passed through a silica column and provided 2.5 g of pure (7a,ll,l7a)-17-hydroxy-7-methyl-3-oxo-19-norpregn-4-en- M.p. 234 Rf 0.33 (tolueneethyl acetate 7/3).

WO 94/18224 PCTJIEP94/00348 Examuple 4 Hydroboration of the il-inethylene function in 3#3,17,17bis (ethylenedioxy -l-methylene-estr-5-en was accomplished as follows: To a solution of 2.18 ml of 10 M boron hydridedimethylsulf oxide complex in 10 ml of dry tetrahydrofuran wrere added at 0 *C 2.7 ml of cyclo-octadiene.

After additional ref lux for 1 h a solution of 2.7 g of 3,3 ,l7,17-bis(ethylenedioxy)-1l-methylene-estr--5-en in ml of tetrahydrofuran w~ere added. The mixture was stirred f or 16 h and then treated with 10 ml of sodium hydroxide, followed by 10 ml of 30% hydrogen peroxide. After stirring for an additional 4 h the mixture was poured into waier and the product extracted with dichioromethane. Final purification was achieved by chromatography to provide 2 g of (llB)-3,3,17,17-bis- Rf 0.25 (toluene-ethyl acetate 1/1).

To a suspension of 20 g of pyridinium chlorochromate in 200 ml of dichiorometharie were added 9.3 g of (11J3)- 3 ,3 ,17 ,17-bis (ethy,lenedicixy -,1l-(hydroxy-methyl) en in 100 ml of dichlornethane. Af, er stirring for I h 2 5excess oxidant was destroyed by addcition of 40 g of sodium hydrogensulf ite in 200 ml of water, f ollowed by extraction of the product with ethyl acetate. After drying and concentration of the organic phase the residue was purified by chromatography to provide 5.4 g of (liJ ,3,17417-bis(ethylenedi$oxy)-estr-5-en-l>carboxaldehyde. Rf 0.50 (hexane-ethyl acetate 1/1).

A solution of 1.6 M butyl lithium in hexane (44 ml) was added dropwise to a suspension of 24.4 g of chioromethyltriphenylphosphoniumn chloride in 500 ml of ether.

After stirring for 15 min a solution of 5.4 g of CuB8)- 3 3 17, 17-bis(ethylenedioxy)-estr-5-en-l1-earboxaldehyde WO 94/18224 PCT/EP94/00348 16 in 30 ml of tetrahydrofuran were added dropw:.se. After 12 h the mixture was poured into 0.5 1 of water and the organic phase was separated, washed, dried and concentrated. The residue was chromatographed to provide 3.7 g of E/Z (1.)-3,3,17,17-bis(ethylenedioxy)-ll-(2-chloro- Rf 0.4 (hexane-ethyl acetate 7/3).

To a suspension of lithium amide, prepared from 920 mg of lithium in 130 ml of ammonia were added at -45 °C a solution of 3.6 g of (llB)-3,3,17,17-bis- (ethylenedioxy)-1l-(2-chloroethenyl)-estr-5-en in 30 ml of tetrahydrofuran. After stirring for 1 h the excess reagent was destroyed by addition of 15 g of ammonium chloride, followed by evaporation of ammonia. The residue was partioned between dichloromethane and water; the organic phase was dried and concentrated and chromatographed to provide 1.8 g of (lB3)-3,3,17,17-bis- M.p. 200 Rf 0.45 (hexane-ethyl acetate 7/3).

A mixture of 8 g of (llB)-3,2,17,17-bis(ethylenedioxy)- 200 ml of acetone, 100 ml of methanol and 100 ml of tetrahydrofuran was treated with ml of 6 N hydrochloric acid and stirred overnight.

After treatment with sodium hydrogencarbonate and concentration, the residue was chromatographed to give 5.1 g of (118)-ll-ethynyl-estr-4-en-3,17-dione. Rf 0.48 (hexane-ethyl acetate 1/1).

A mixture of 2.7 g of potassium tert-butoxide in 12 ml of tetrahydrofuran and 5 ml of tert-butanol was placed under nitrogen and acetylene gas was bubbled through for h at 0 Then a suspension of 1.85 g of (118)-llethynyl-estr-4-en-3,17-dione in 5 ml of tetrahydrofuran was introduced, and stirring was prolonged for 1 h. The mixture was diluted with water (200 ml), neutralized by addition 'of 2 N hydrochloric acid and extracted with WO94/18224 PCT/EP9400348 17 ethyl acetate, dried and concentrated. The residue was chromatographed to provide 1.6 g of (118,17a)-l1ethynyl-17-hydroxy-19-norpregn-4-en-20-yn-3-one; M.p.

168 Rf 0.60 (hexane-ethyl acetate 1/1).

Example To a solution of 4 ml of borane methylsulfide (10M in tetrahydrofuran) in 20 ml of tetrahydrofuran were added dropwise 5 ml of 1,5-cyclo-octadiene. After stirring for 1 h a solution of 5 g of llB-vinyl-3,3,17,17-bisethyl- (obtained by selective Lindlar hydrogenation from (11B)-3,3,17,17-bis(ethylenedioxy)ll-ethynyl-estr-5-en) in 25 ml of tetrahydrofuran was added dropwise. After stirring for an additional hour ml of 15% aq sodium hydroxide and 20 ml of 30% hydrogen peroxide were added. After stirring overnight the product was extracted with ethyl acetate and the organic material thus obtained was purified by chromatography to give 3.4 g of 118-(2-hydroxyethyl)-3,3,17,17-bisethyl- M.p. 190 "C.

To a solution of 5 g of llB-(2-hydroxyethyl)-3,3,17,17bisethylenedioxyestr-5-ene in 7 ml of tetrahydrofuran were added at -30 °C 500 mg of 2,6-di-t-butylpyridine followed by 800 mg of trifluoromethanesulfonic anhydride. After stirring for an additional 15 min at 10 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran were added and the mixture was stirred for 2 h at room temperature and then poured into 30 ml of 10% sodium hydrogencarbonate solution.

Then the mixture was extracted with ethyl acetate and the organic material was purified by chromatography to give 600 mg of 11-(2-fluoroethyl)-,3,17,17-bisethyl- M.p. 196 "0.

I -II 91PI WO 94/18224 PCTEP94/00348 18 To a solution of 530 mg of 118-(2-fluoroethyl)- 3,3,17,17-bisethylenedioxy-estr-5-ene in a mixture of 3 ml of acetone and 3 ml of tetrahydrofuran were added 6 ml of 3M hydrochloric acid. After stirring for 2 h sodium hydrogencarbonate and water were added and the product was extracted with ethyl acetate. The residue obtained after evaporation of the solvent was treated with diispropyl ether to give 400 mg of 11B-(2-fluoroethyl)-estr-4-en-3,17-dione; M.p. 85 "C.

Acetylene gas was passed into a solution of 0.7 g of potassium tert-butoxide in 5 ml of tetrahydrofuran and 1 ml of tert-butanol. After 15 min a solution of 400 mg of 118-(2-fluoroethyl)-estr-4-en-3,17-dione in 5 ml of tetrahydrofuran was added. After stirring for an additional 15 min the solution was poured into water and the product was extracted with ethyl acetate. The organic material thus isolated was purified by column chromatography and treated with ether, to provide 320 mg of (lB,17a)-11-(2-fluoroethyl)-17-hydroxy-19-norpregn- 4-en-20-yn-3-one; M.p. 212 °C.

Example 6 To a solution of lithium diisopropylamide (prepared from 250 mg of diisopropylamine and 1.6 ml of a 1.6M butyl lithium-hexane solution) in 3 ml of tetrahydrofuran was added a solution of 600 mg of difluoromethyldiphenylphosphinoxide in 2 ml of tetrahydrofuran at -50 °C.

After stirring for 15 min a solution of 800 mg of (118)- 3,3,17,17-bis-(ethylenedioxy)-estr-5-en-ll-carboxaldehyde in 3 ml of tetrahydrofuran was added and the mixture was stirred overnight at room temperature. The reaction products were poured into water and extracted with ethyl acetate. Chromatography of the organic material provided 465 mg of 118-(2,2-difluoroethenyl)- WO 94/18224 PCT/FEP94/0034$ 19 3,3,17,17-bis-(ethylenedioxy)-estr-5-en; M.p. 180-181 aC A solution of 430 mg of above-mentioned product in a mixture of 3 ml of acetone and 2 ml of tetrahydrof uran was treated with 2 ml of 4N hydrochloric acid. Af ter stirring for 2 h the mixture was neutralized with solid sodium hydrogencarbonate and the product was extracted with ethyl acetate. The organic material thus obtained was crystallised frixn diisopropyl ether to provide 270 mg of llB-(2,2-difluoroethylene)-estr-4-en-3 ,17-dione; 1509C Acetylene gas was bubbled into a solution of 0. 48 g of potassium tert-butoxide in a mixture of 5 ml of tetrahydrofitran and 0.5 ml of t-butanol. After 15 min a solution of 250 mg of 111-(2,2-difluoroethylene)-estr-4en-3,17-dione in 3 ml of tetrahydrofuran aas added end min later the mixture was quenched with water and the product extracted with ethyl acetate.

The organic material thtis isolated was treated with diisopropyl, ether to provide 160 mg of (11B,17ca)-1l- (2 ,2-dif luoroethenyl )-17-hydroxy-19-norpregn-4-ene-20yn-3-one; M.p. 196 OC.

Example 7 A mixture cf E/Z 1113,3,3 ,17,17-bis-(ethylenedioxy)-11- (2-chloroethenyl)-estr-4-en Was separated on a silica column to provide the pure E-isomer 143 0 C) and, the Z-isomer (m.p 4 182 OC). Treatment of a solution of 3 g of (E)111,3,3,17,l7-bi-s-(ethylenedioxy)-l1-(2-chloroin 20 ml of acetone wich 3 ml of conc. hydrochloric acid during 1 h followed by neutralization with sodium hydrogencarbonate solution and ethyl acetate extraction provided the desired diketone WO 94/1822, PCTIEP94/00348 (13 2clrehnl et--n-3 (2.3 This product was dissolved in 10 ml of tetrahydrofuran and addedi dropwise to a solution of potassium acetylide in a mixture of 14 ml of tetrahydrof uran and 3 ml of tert-butanol (potassium acetylide was generated by passing acetylene gas into a solution of 2.9 g of potassium tert-butoxide in above-mentioned t-butanoltetrahydrofuran mixture). After stirring for h the mixture was quenched with water and the product was extracted with ethyl acetate. The organic material was purified by chromatography to provide 1.9 g of (ll E, 17a) -11- (2-chloroethenyl-17-hydroxy-19-norpregn- 4-en-2Q-yn-3-one; M.P. 180 OC.

Example 8 similarly as above-described were prepared: RI R 2 R R -C)

CCOH

C_=CH

C=2CH

C=ECH

C=_C1

C_=CH

CV-CH

C=_C1 C=ECi

C=_CH

CaCH CsCil

CMCH

CSCil CMCil 02115 HOCh3

(E)CHC

4

H

9 0113

ON

CH

2 00H 3

CH

3

CH=CH

2

ON

CH=C(CH

3 2

(Z)CH=CHF

CH

2

CH

2

F

H

H

OH

3

CH

3 0113 0'13

CH

3 0113

H

H

OH

3

H

H

11 0113 21,7 23 26,8 230 222 219 234 amorphous 221 1.65 223 208 212 215 151 208 01 OEOCH n-C 3

H

7

H

jj. WO 94/18224 PCT/EP94/00348 RR2 R 3 R4R 5 M.P. 0

C)

0 0 0 0 0 0 0 0 0 0

H

2

H

2

H

2

H

2

H

2

H

2

H

2

BOB

BOB

BOB

BOH

OBI

BOB

SOH

BOH

BOB

OH

OH

OH

OH

oHf

OH

OH

OH

OH

OH

QH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH-

OH

OH

OH

OH

OH

OH

OH

C=-CH

C=ECH

CE=CH

C=ECH

C=ECH

C=ECH

C=-CB

C=ECH

C=ECH

C=ECH

C=ECH

CaCH

C=ECB

C=ECH

C=ECU

C=ECH

C=ECH

CE-CH

CECH

CsCH CoCFI CaCH CmCH CmCH

C=ECH

CmCH

CE-CH

Ct',CH cCMCH CmCH CmCH

CE-CH

CmCH CmCil

CH=CF

2

CB=CHCB

3 (Z )CH=CHCB 3

(E)=CH-CB

3

CH

2

CH

2

F

CHi=CF 2 CH=CHC1.

(Z CHl=CHC1

(E)=CH-CH

2

F

(E)=CH-CH

2

F

C=ECH

(E)CHC

4

H

9

CN

C

2

B

5

CH

3

CH

2 0C1' 3

CH

3 CmCH

C=CH

2

(E)CHCH

3

(E)CHC

4

H

9 CECfl

C

2

H

5

CU

3

CN

CU

3

CH

2 0CH 3

CU

2

(Z)CH=CHF

CB

2

CH

2

F

n-C 3

H

7

CH=CF

2

CUCHCH

3

CH

3

H

B

CH

3

H

H

B

H

H

CU

3

CH

3 C .4 3

CU

3

CU

3

CU

3

CU

3

H

B

CU

3

H

H

OH

3

CH

3

CH

3

CU

3

CH

3

H

B1

CH

H

CU

3

H

H

169 168 169 235 212 196 180 186 116 120 172 120 119 134 107 98 135 145 172 217 133 151 243 183 amorphous 194 164 79 185 109 158 112 .4 CesCH (Z)CH=CHCfl 3 WO 94/18224 PCTIEP94/00348 22 JR,

R

BOH OH 8011i OH SOHl OH 30H OH BO0H OH BOll OH BOHl OH R3 R4R 5 M.P. (QC)

C-=CH

CE-CH

CE=CH

CE-CH

C=ECH

C=-CH

C=ECH

(TM=CH-CH

3

CH

2

CH

2 1'

CH=CF

2 CH=CHC1 Z) CH=CHCl1

(E)=CH-CH

2

F

=CH-CH

2

F

CH

3

H

H

H

H

H

CH

3 124 135 amorphous amorphous Example 9 A tablet having the following composition was prepared: 19-norpreqn-4-en-2U-yn-3-one 2.5 ng s).:arch 10 mg ascorbyl palmitate 0.2 mg maanesium stearate 0.5 mg lactose to make up to 100 mg Base granuleo were prepared by mixing the lactose with a portion of starch. The remainder of the starch was mixed to a slurry with water and added to the mixture. The whole was granulated and dried. These base granules were mixed with ascorbyl palmitate and the active ingredient, sieved, finely mixed with magnesium stearate and then tabletted.

Example A tablet having the same composit$dl as in Example 9 was prepared with (11fl47a)-Il-ethynyl-17-hydrcixy-19-norpregn-4-en-20-yl-3-one as active ingredient.

WO 94/18224 PCTIEP94/0034S 23 Excample 11 A tablet having the same composition as in Example 9 was prepared with (7a, lB, 17a)-ll-methylene-17-hydroxy-7methyl-19-norpregn-4-en-20-yn as active ingredient, by first mixing the active ingredient with 210 of the lactose and the ascorbyl palmitate and then mixing this mixture with the lactose, starch and starch slurry. The mixture was dried, finely mixod with magnesium stearaite 0 and tabletted.

Exanple 14".

A capsule having the following composition was preparedt norpregn-4 -en-2 Q-yn-3-one 2.5 mg starch 10 mg Aiscorbyl pa2.mitate 0,.2 mg 3 magnesium stearate 0.5 mg Avice 1 to make up to 100 mg The componea'ts were mixed with one another in the manner descristed in Example 9, granulated and filled into gelatin capsules.

Claims (12)

1. A method for the treatment or prophylaxis of menopausal complaints in a imammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of at least one compound having s the general formula: RR 3 R 4 wherein R, represents 0, or two hydrogen atoms; R 2 is hydroxy, optionally etherified or esterified; R 3 is (2-6C)alkynyl, optionally substituted withl e" hydroxy; R 4 is CN or one of the hydrocarbon groups selected from (1-6C)alkyl, 10 (l-6C)alkoxy, (2-6C)alkenyl, (2-6C):Jkynyl, and (2-6C)alkylidene, each of said hydrocarbon groups may optionally be substituted w 'h halogen, hydroxy or (l-6C)alkoxy; and R 5 is hydrogen or (1-6C)alkyl. 0 2. The method according to claim 1, wherein the mnopausal complaint is osteoporosis. is 3, The method according to claim I or 2, wherein the steroid has tho, general formula I wherein Ri represents 0 or two hydrogens atoms; R 2 is hydroxy; R 3 is ethynyl; R 4 is selected from the group consisting of methyl, (2-6C)alkynyl, (2-6C)alkylidene, and one of (2-6C)alkyl, (2-7C)alkoxyalkyl, (1-6C)alkoxy, or (2-6C)alkenyl, which may optionally be substituted with halogen; and R 5 is S 20 hydrogen or (l-6C)alkyl.

4. The method according to claim 1 or 2, wherein I'e steroid has the general formula I wherein R, is 0; Rz is hydroxy; R3 is ethynyl; R 4 is ethyl, 2-fluoroethyl, ethynyl, (2-6C)alkenyl optionally substituted with fluorine, or (2-6C)alkylidene optionally substituted with fluorine; and Rs is hydrogen or methyl, The method according to claim 1 or 2, wherein the steroid has the general formula I wherein R is 0; Rz is hydroxy; R 3 is ethynyl; R4 is ethyl or ethynyl; and R 5 is hydrogen.

6. A steroid having the general formula I iN W OLNIBOCG107 J0C 2 o 3 I wherein R1 represents 0; R2 is hydroxy, optionally etherified or esterified; R3 is (2- 6C)alkynyl, optionally substituted with hydroxy; R4 is CN, (2-6C)alkyl substituted with halogen, or (2-6C)alkenyl substituted with halogen; and R5 is hydrogen or (1-6C)alkyl.

7. The steroid of claim 6 wherein R1 is 0; R 2 is hydroxy; R3 is ethynyl; R4 is 2-fluoroethyl or 2-fluoroethenyl; and R5 is hydrogen.

8. The steroid of general formula I, wherein R1 is O; R2 is hydroxy; R3 is ethynyl; R4 is (E)-ethylidene; and R5 is methyl.

9. A steroid having the general formula I R2R3 R4y' 4 "'R S* wherein RI represents two hydrogens atoms; R2 is hydroxy, optionally etherified or esterified; R3 is (2-6C)alkynyl, optionally substituted with hydroxy; R4 is CN or one of the hydrocarbon groups selected from (2-6C)alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2- S 6C)alkynyl, and (2-6C)alkylidene, each of said hydrocarbon groups may optionally be substituted with halogen, hydroxy or (1-6C)alkoxy; and R5 is (1-6C)alkyl.

10. The steroid of claim 9 wherein R1 represents two hydrogens atoms; R2 is hydroxy; R3 is ethynyl; R4 is (2-6C)alkyl, (2-6C)alkylidene or (2-6C)alkenyl, each of which groups may be substituted with fluorine; and R5 is methyl.

11. A steroid having the general formula I substantially as hereinbefore described 20 with reference to any one of Examples 1 to 8.

12. A process for the preparation of the steroid of any one of claims 6 to 11, characterised in that an 11-keto steroids of the general formula: R2 R -A IR INA\LIC101057:SAK 26 wherein R1 is O; R 2 is hydroxy, optionally etherified or esterified; R3 is (2-6C)alkynyl, optionally substituted with hydroxy; and R 5 is hydrogen or (1-6C)alkyl or wherein R1 represents two hydrogen atoms; R2 is hydroxy, optionally etherified or esterified; R3 is (2-6C)alkynyl, optionally substituted with hydroxy; and R5 is (1-6C)alkyl; the active groups of which are optionally protected, is condensed with a Wittig(-like) compound of the formula R4'R4"CH-W, wherein R4'R4"C forms the group R4 which is the optionally halogen, hydroxy, or (1-6C)alkoxy substituted (2-6C)alkylidene group as previously defined, or R4',Li, wherein R4'" is (2-6C)alkyl or (2-6C)alkenyl optionally substituted with halogen, hydroxy, or (1-6C) alkoxy, in which reactive groups can be protected by protective groups which are known in the art, and W is a Wittig, Wittig-Horner or Peterson-like moiety, optionally followed by halogenation and dehydration or by hydraion, after which the compound obtained is converted into a nitrile or condensed with a Wittig(-like) compound of the formula R6W, wherein W has the previously given meaning and R6 is independently hydrogen, halogen or (1-6C)alkyl, followed by hydroboration, optionally followed by alkylation, halogenation, or halogenation and dehydrohalogenation, or (partial) hydrogenation, after which optionally present protective graups are removed. 13, A process for the preparation of a steroid having the general formula I substantially as hereinbefore described with reference to any one of Examples 1 to 8. 20 14. A steroid produced by the process of claim 12 or 13.

15. A pharmaceutical composition comprising the steroid of any one of claims 6 to 11 11,14 or 15 and pharmaceutically suitable auxiliaries.

16. A pharmaceutical composition for the treatment or prophylaxis of menopausal complaints in a mammal requiring said treatment or prophylaxis, substantially as 25 hereinbefore described with reference to Examples 9 to 12.

17. A method for the treatment or prophylaxis of menopausal complaints in a mammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of at least one compound according to any one of claims 6 to 11, 14 or 15 or of a composition according to claim 15 or 16. Dated 4 August, 1995 Akzo Nobel N. V. Patent Attorneys for the Applicant Nominated Person SPRUSON FERGUSON I "CZ A- 1 L [N:ALBC101057:SAK INTERNATION~AL SEARCH REPORT lntcrni. al Application No PCT/EP 94/00348 A. CLASSIFICATION OF SUBJECT MATITER IPC 5 C07J1/0O C07J41/00 C07J11/O0 A61K31/565 According to International Patent Classification (IPC) or to both national classification and JPC B. FIELDS SEARCHED Minimum documentation searched (classification syst,.m followed by classification symbols) IPC 5 C07J A61K Documentation searched other than mswmmum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international scarch (name of data base and, where practical, iearc'h terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X RECL.TRAV.CHIM. PAYS-BAS 6-11 vol. 94, no. 2 1975 pages 35 39 A.J..VAN DEN BROEK ET AL. 'li-ALKYLIDENE STEROIDS IN THE 19-NOR SERIES' see page 37; table I X NL,A,7 216 767 (AKZO N.V) 11 June 1974 6-11 see the whole document X EP,A,O 136 011 (E.R.PLUNKETT ET AL.) 3 1-11 April 1985 see page 3, line 15 -line 17 Y EP,A,IO 145 493 (THE UPJOHN COMPANY) 19 1-11 June 1985 see page 10, line 15 -page 11, line 16 [J Further documents are listed in the continuation of box C. [Lf Patent family mem~bers are listed in ianex Specal ateorie ofcitd clcumnts :T later document published sfter the international filing date document defining the general state of the art which is not oz M'o"ty date and not inconflict with the application but cormdered to be of paruicular relevcnce i 41 to undrstnd the principle or theory undelyinlg the invention EW eaifir document but published on or after the internaional WX document of particular, televan,%; the claimed invention filing date cannot be considered tiovell or cmanot be considered to WU document which may throw doubts on priority claim(s) or involve ara8 inventive step when 4,~e document is taken alone 'which is cited to establish the publication dat of aniother Y' document of particular relevance;, \he claimed invtntion citation or other special reason (as specified) cannot be considered to involve an inventive sto when the document referring to an oral disclosure, use, exhibition or document is combined with one or maore other such docu- other means ments, such combination being obvsomts to a person skled document published prior to the interntional filing date but in, tht art. later than the priority date claimed W document metober of the same patent family Date; of the actual completion of the international starch Date ofmrailin% of the international search report 1 June 1994 Name anid mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlama 2 NL 22801UW RI Awijk Tel. 3 1.1L) 340-2040,'l'Tx 31 651 p Theus, Fax: 31.70) 3401.3016 hu s H Form PCT11SA/210 (ascend shiut) (July 11n)~ page 1 of 3 INTERNATIONAL SEARCH REPORT Ilcmr ,^Apwvauon No PCT/EP 94/00348 C.(Contnuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with ndication, where appropnrte, of the relevant passages Relevant to claim No. Y EP,A,O 461 290 (HENNING BERLIN GMBH 1-11 CHEMIE- UND PHARMAWERK) 18 December 1991 see the whole document Y EP,A,O 474 374 (ORTHO PHARMACEUTICAL 1-11 CORPORATION) 11 March 1992 see the whole document Y EXPERIENTIA 1-11 vcl. 26, no. 7 1970 pages 762 763 S.BARAN ET AL. '11-BETA-METHYL-19-NORSTEROIDS: NOVEL PROGESTATIONAL HORMONES' see the whole document Y ACTA ENDOCRINOL. 1-11 vol. 115, no. 3 July 1987 pages 406 412 HOPPEN ET AL. 'THE INFLUENCE OF STRUCTURAL MODIFICATION ON PROGESTERONE AND ANDROGEN RECEPTOR BINDING OF NORETHISTERONE. CORRELATION WITH NUCLEAR MAGNETIC RESONANCE SIGNALS' see abstract Y J. STEROID BIOCHEM. 1-11 vol. 14, no. 2 February 1981 pages 175 183 E.W.BERGINK ET AL. 'BINDING OF A CONTRACEPTIVE PROGESTOGEN ORG 2969 AND ITS METABOLITES TO RECEPTOR PROTEINS AND HUMAN SEX HORMONE BINDING GLOBULIN' SUMMARY Y US,A,4 292 251 (OVERBEEK) 29 September 1-11 198:t cited in the application see the whole document Y US,A,3 465 010 (J.S.BARAN) 2 September 1-11 1969 cited in the application see the whole document Y US,A,3 325 520 (J.S.BARAN) 13 June 1967 1-11 cited in the application see the whole document Y US,A,3 983 144 (LEEMHUIS) 28 September 1-11 1976 cited in the application see the whole document Form PCT/ISA210 (continuaton of aseond shmet) (July 1992) page 2 of 3 I I II INTERNATIONAL SEARCH REPORT IntCMI, A AppIcAtioo No PCT/EP 94/00348 C.(Conununbon) D)OCUMENTS CONSIDERED TO BE RELEVANT Catoy C!atio of document, with indwrAt~on, where appropriate, of the relevant passages [ecatocli No. EP,A,0 337 938 (SANDOZ 18 October 1989 see -the whole document GB,A,2 ()58 564 (THE UPJOHN COMPANY) 15 April1 1981 see claim 2 NL,A,7 701 384 (AKZO 14 August 1978 see claim 1 NL,A,8 502 571 (AKZO 16 April 1987 see claims 1-8 DE,A,37 02 383 (SCHERING 4 August 1988 see page 13, line 13 GB,A,1 190 240 (G.D.SEARLE CO.) 29 April 1970 see claim 9 1-11 1-11 6 6 1-1i 6 FOemn PaCT/3110 (Continuation of Iecnd shoot) (July 1992) page 3 of 3 INTERNATIONAL ,,EWRH REPORT nen.?IpICAflN Informniion on patent IMMwY members nCT/EP 94/0pliat348N Patent document Publication Patent family Publicatkil cited in search report date member(s) date NL-A-7216767 11-06-74 AT-B- 367067 25-05-81, AU-A- 6326373 05-06-75 BE-A- 808391 07-06-74 CA-A- 1021318 22-11-77 CH-A- 614453 30-11-79 OE-AXC 2361120 12-06-74 FR-AB 2209577 05-07-74 GB-A- 1455270 10-11-76 JP-C- 1289124 14-11-135 JP-A- 50029548 25-03-75 JP-B- 59033600 16-08-84 4SE-B- 414771 18-08-80 US-A- 3927046 16-12-75 EP-A-0136011 03-04-85 US-A- 4826831 02-05-89 AU-B- 582540 06-04-89 AU-A- 3140584 07-02-85 CA-A- 1240927 23-08-88 JP-A- 60100520 04-06-85 EP-A-0145493 19-06-85 US-A- 4557867 10-12-85 AU-B- 572589 12-05-88 AU-A- 3574884 20-06-85 JP-A- 60149598 07-08-85 EP-A-0461290 18-12-91 DE-0- 59004243 24-02-94 EP-A-0474374 11-03-92 AU-A- 8166191 13-02-92 CA-A- 2048810 11-02-92 JP-A- 4230632 19-08-92 US-A-4292251 29-09"81 NL-A- 7701384 14-08-78 AU-B- 519916 07-01-82 BE-A- 863872 10-08-78 CA-A- 1109458 22-09-81 08~-A- 2805490 17-08-78 FR-A,B 2380300 08-09-78 GB-A- 1595661 12-08-81 JP-A- 53101357 04-09-78 LU-A- 79036 26-06-78 Form PCTflSAM20 (plant family annex) (July 1993) page 1 of 4 INTERNATIONAL SEARCH REPORT IMtMA Al Application No Infonniiaon on patent family membLrs C/P9034 Patent document PbiaonPatent family Publication cited in search report daemember(s) dame US-A-429225 1 SE-A- 7801539 11-08-78 US-A-3465010 02-09-69 BE-A- 706819 21-05-68 CH-A- 509297 30-06-7 1 CH-A- 512455 15-09--71 DE-A- 1618980 29-04-7 1 FR-M- 7830 25-05-70 FR-A- 1577245 08-08-69 GB-A- 1190240 29-04-70 NL-A- 6715790 24-05-68 OA-A- 2672 15-12-70 US-A-3325520 BE-A- 688389 18-04-67 BE-A- 690866 08-06-67 CH-A- 535751 15-04-73 DE-A- 1593444 30-07-70 DE-A- 1593468 03-09-70 FR-M- 5926 01-04-68 6050 20-05-68 GB-A- 1091999 GB-A- 1169938 05-11-69 US-A- 3299108 US-A-3983144 28-09-76 NL-A- 7317356 23-06-75 AU-B- 488962 1G-06-76 B9E-A- 823524 18-06-75 CA-A- 1038373 12-09-78 618182 15-07-80 OE-A- 2459706 26-06-75 FR-A 1 B 2255078 18-07-75 GB-A- 1495531 21-12-77 JP-A- 50093960 26-07-75 SE-B- 409716 03-09-79 SE-A- 7415888 23-06-75 EP-A-0337938 18-10-89 AU-A- 3131389 14-09-89 BE-A- 1002310 27-11-90 CH-A- 678814 15-11-91 DE-A- 3908130 05-10-89 FR-A- 2628321 15-09-89 Form PCT/lSAJ2Ia (patent family annex) (July 1993) page 2 of 4 I INTERNATIONAL SEARCH REPORT n Aplanono Intormauon on patent family Mmbers 7 CttEP 94/00348o N Patent document I Publication IPatent family Publication cited in search report date member(s) _T date EP-A-0337938 GB-A,B 2216420 11-10-89 JP-A- 2009820 12-01-90 NL-A- 8900610 02-10-89 SE-A- 8900875 15-12-89 GB-A-2058564 15-04-81 AU-A- 6184380 12-03-81 BE-A- 885113 05-03-81 DE-A- 30313545 02-04-81 FR-A,B 2464716 20-03-81 JP-A- 56049317 02-05-81 NL-A- 8004904 10-03-81 US-A- 4501754 26-02-85 NL-A-7701384 14-03-78 AU-B- 519916 07-01-82 BE-A- 863872 10-08-78 CA-A- 1109458 22-09-81 DE-A- 2805490 17-08-78 FR-A,B 2380300 08-09-78 GB-A- 1595661 12-08-81 JP-A- 53101,357 04-09-78 LU-A- 79036 26-06-78 SE-A- 7801539 11-08-78 US-A- 4292251 29-09-81 NL-A-8502571 16-04-87 NONE DE-A-3702383 04-08-88 AU-EB-, 616395 31-10-91 AU-A- 1111488 28-07-88 CA-A- 1326014 11-01-94 EP-A 3 B 0277089 03-08-88 JP-A- 63201197 19-08-88 US-A- 4870069 26-09-89 GB-A-1190240 29-,14-70 BE-A- 706819 21-05-68 CH-A- 509297 30-06-71 CH-A- 512455 15-09-7 1 DE-A-- 1618980 29-04-71 FR-Pr- 7830 25-05-70 FR-A- 1577245 08-08-69 NL-A- 6715790 24-05-68 Forin PC? jISA/210 (patent family annex) (July 1992) page 3 of 4 INTERNATIONAL SEARCH REPORT lniormitn on patent (AMlY Members InA nA .1 Application No PCT/EP 94/00348 Patent documn Pulcto I Patent family Publication cited in search eprdaeImember(s) date GB-A-1190240 OA-A- 2672 15-12-70 US-A- 3465010 02-09-69 F..miiM /IA/-Ott-uy ai-nM) Lluiy t2) page 4 of 4