FI89053C - New 11-methylene esters-15s and compositions containing the same for use as contraceptives - Google Patents

Description

! 89053

Novel 11-methylenestr-15-enes and compositions containing them for use in contraception

Divided by application 862970 5

The invention relates to 11-methylene estr-15-enes and to contraceptive compositions containing these estrenes.

In particular, the invention relates to 11-methylene-estra-10 4,15-dienes having an unsaturated hydrocarbon group at position 17a.

Steroids of this type are known. Accordingly, EP-A-0 051 762 describes 11-ethylene-18-methyl-estra-4,15-dien-3-ones substituted at the 17a-position with an ethynyl, chloroethynyl or propynyl group and in which in addition there is a 17B-OR1 group in which R2 is H or an acyl group. These steroids have potent progestogenic properties and few androgenic side effects.

A new class of 11-methylene-estr-15-enes having contraceptive activity has now been discovered. These new 11-methylene steroids have the general formula (I)

Wherein Rx is H or lower alkylcarbonyl, preferably H, R2 is ethynyl, vinyl, chloroethynyl, allyl or propynyl, of which ethynyl is preferred, and R3 is O or H2, preferably O.

The novel compounds of the formula I can be prepared by methods known per se. The starting materials are usually the corresponding 11-methylene-estr-4-en-17-ones described in NL-A-7 216 767, to which a double bond is formed between C-15 and C-16, followed, if desired, by the addition of substituent 5-5 supports at positions 3 and / or 17, if any.

The double bond between C-15 and C-16 can be formed by first microbiologically attaching the 15α-hydroxy group to the 11-methylene-estr-4-en-17-one compound and then performing dehydration.

15α-hydroxylation can be performed, for example

Fungi of the genus Penicillium, for example P. rais-trickii or P. patulum, or species of the genera Colletotrichum, Gibere or Glomerella, for example Colletotrichum antirrhini, Giberella baccata or Glomerella cingulata.

The dehydration is preferably performed by converting the 15α-hydroxy group to an acylate or sulfonate, followed by cleavage of the 15α-acyloxy or 15α-sulfonyloxy group to form a double bond between C-15 and C-16.

Suitable acyl groups include acetyl, trifluoroacetyl, propionyl, butyryl, heptanoyl and benzoyl.

Suitable sulfonyl groups include mesyl, ethanesulfonyl, propionylsulfonyl and p-tosyl.

The esterification of the 15α-hydroxy group is carried out in a conventional manner by reaction with an acid, anhydride or acid chloride in the presence of a strong acid such as p-toluenesulfonic acid or a base, for example a tertiary amine such as pyridine or 4- (dimethylamino) pyridine. at elevated temperature, if desired.

The sulfonylation is usually carried out with a suitable sulfonyl chloride in an anhydrous medium, for example dry pyridine, with dimethylformamide and sodium acetate.

3,89053

The substituent R 2 can be attached in a conventional manner by alkylation of the 17-oxo compound with an organometallic ethynyl, vinyl, chloroethynyl, allyl or propynyl compound.

Examples of such organometallic compounds are potassium acetylide, vinylmagnesium bromide, lithium chloroacetylide, allylmagnesium bromide and potassium methylacetylide. The organometallic compound can also be formed in situ, after which it is reacted with 17-10 ketones.

The 17α-vinyl compound can also be obtained by partial reduction of the 17α-ethynyl compound, for example with hydrogen, using a catalyst such as nickel, platinum or palladium with barium sulphate.

When a double bond is formed between C-15 and C-16, any 3-oxo group in the compound is temporarily protected in a conventional manner by formation of an acetal, for example an acetal from ethylene glycol, ethanedithiol or 2,2-dimethyl-1,3-propanediol.

The cleavage of the acetal (in the case of thioacetal after activation) can be carried out with acids, for example sulfuric acid, perchloric acid, hydrochloric acid or oxalic acid, preferably in alcoholic solution or acetone, if desired at elevated temperature.

The 3-dithioethylenedithioacetal group which may be present can also be cleaved by reduction, for example with sodium in ammonia or lithium in methylamine, to give a compound in which R3 is H2. In this reduction, the 17α-substituent having a triple bond, if present, is reduced to a substituent having a double bond, for example, 17α-ethynyl becomes 17α-vinyl. It is also possible to start from 3-deoxo-11-methylene-17-ketone to prepare the 3-deoxo-17α-ethynyl compound.

4,89053 The esterification of the 17β-hydroxy group can, if desired, be carried out in a conventional manner as described above for the 15α-hydroxy group.

The novel compounds of the invention, in particular 11-methylene-17α-ethynyl-17S-hydroxy-estra-4,15-dien-3-one, have better anti-ovulation properties when administered orally than the 18-methyl analogues described in EP-A-0 051 762. Furthermore, these new compounds are less androgenic than the corresponding 11-methylene compounds which do not have a double bond between C-15 and C-16 and which are described in NL-A-7 216 767. In particular receptor binding studies in human cell lines show that 11-methylene-17α-ethynyl-17β-hydroxy-estra-4,15-dien-3-one has a more favorable profile than the corresponding known compounds. The extremely low affinity for SHBG (steroid hormone binding globulin) is also significant. It is believed that a low affinity for SHBG lowers hepatic metabolic stress.

Compared to known 18-methyl compounds, these compounds also have the advantage that they are simpler to prepare. 18-methylsteroids are usually prepared by total synthesis. This complex method of preparation, in which racemates are formed, is not necessary for the preparation of these new compounds. Methods for preparing 18-methyl steroids are also known in which an 18-methyl group is attached to 13-methyl steroids, cf. for example NL-A-7 409 512 and NL-A-7 411 607. These reactions also do not need to be used in the preparation of the new steroids according to the invention.

The compounds of general formula I can be administered, parenterally or enterally, usually in admixture with excipients and, if desired, other ingredients, in the form of solutions, suspensions, emulsions or solid pharmaceutical preparations, such as tablets, pills and granules. They are particularly suitable for use in contraceptive preparations, either alone or in combination with an estrogen such as ethynyl estradiol or an estradiol-178 ester, for example estradiol-178-valale-5-estrate, estradiol-17β-decanoate or estradiol-17β-cyclooctyl acetate.

For oral administration, for example, tablets containing 0.02 to 0.4 mg of a compound of general formula I and 0.02 to 0.05 mg of ethynyl estradiol 10 (or an equivalent amount of estradiol 17B ester) are used, for example one tablet. tablet a day.

The following examples illustrate the invention.

Example 1 15 a) 11-Methylene-15α-hydroxy-estr-4-ene-3,17-dione 50 ml of a medium consisting of a mixture of glucose (10 g / l) and yeast extract (10 g / l) were placed to a refillable 250 ml Erlenmeyer flask. 20 Gomerella cingulata spores (ATCC 10534) were inoculated into the medium. It was then incubated for 2 days at 28 ° C with shaking.

The preculture thus obtained was inoculated into 2 liters of medium (containing 40 g / l glucose and 10 g / l carbon extract) in a 5 liter fermentor. The mixture was incubated with stirring (750 rpm) at 28 ° C at pH 5.0 for 16 hours while passing air (0.2 liters / liter of growth medium / minute). 11-Methylene-estr-4-ene-3,17-dione (0.6 g) suspended in 40 ml of Tween® (10%) was then added.

After 25 hours, the reaction mixture was extracted with methylene chloride / methanol 9: 1. The extract was evaporated to dryness and the residue was purified by chromatography on silica gel and crystallization from methanol.

0.26 g of 11-methylene-15α-hydroxy-estr-4-35-ene-3,17-dione were obtained, m.p. 237 ° C and [α] D = +294 (chloroform, c = 1%).

6 89053 b) 11-Methylene-estra-4,15-diene-3,17-dione-3-ethylenedithioacetal with 10.6 ml of ethanediol and 4.6 ml of boron trifluoride diethylate were added successively to a mixture cooled to 0-5 ° C. 5 to a suspension of 21.3 g of 11-methylene-15α-hydroxy-estr-4-ene-3,17-dione in 320 ml of methanol. After stirring for 6 hours at 0-5 ° C, the reaction mixture was poured into 4.5 liters of water and the precipitate was filtered off, washed neutral with water and dried in vacuo.

26.7 g of the thus obtained crude 11-methylene-15α-hydroxy-estr-4-ene-3,17-dione-3-ethylenedithioacetate were used in the next step without further purification. An analytical sample was obtained by crystallization from acetonitrile. Sp. 228 ° C; [α] D 20 +240 (in chloroform, c> 1%).

The crude product was dissolved in 172 ml of dry pyridine. 34.3 ml of methanesulfonyl chloride were added dropwise to this solution at 0-5 ° C over three quarters of an hour with good stirring under a nitrogen atmosphere. The mixture was stirred for 1.5 hours at 0-5 ° C, after which 139.5 ml of dry dimethylformamide and 82.5 g of anhydrous sodium acetate were added. After stirring for 5.5 hours at room temperature, the reaction mixture was poured into 5 liters of water. The precipitate was filtered off, washed thoroughly with water and dried in vacuo. After purification by chromatography on silica gel followed by crystallization from methylene chloride / acetonitrile, 17.4 g of 11-methylene-estra-4,15-diene-3,17-dione-3-ethylenedithioacetal were obtained; melting point 207.5 ° C; [α] D 20 - + 142 (chloroform; c = 1%).

C) 11-Methylene-17α-ethynyl-176-hydroxy-estra-4,15-dien-3-one-3-ethylenedithioacetal

A solution of 3.5 g of 11-methylene-estra-4,15-diene-3,17-dione-3-ethylenedithioacetal in 52.5 ml of dry tetrahydrofuran was added at -15 to -20 ° C with stirring to potassium acetylide. to a tetrahydrofuran solution of 7,89053 potassium acetylide prepared from 8.4 g of potassium tert-butylate in acetylene. The reaction mixture was stirred for another hour at this temperature while continuously introducing acetylene. A mixture of 10 ml of water and 10 ml of tetrahydrofuran was then added dropwise to the reaction mixture at -15 to -20 ° C. The reaction mixture was then poured into a mixture of 1 liter of saturated NaCl solution and 0.5 liters of water. The precipitate was filtered off, washed neutral with water and dried in vacuo. The product 10 was purified by chromatography on silica gel and crystallized from diethyl ether / hexane to give 2.6 g of 11-methylene-17α-ethynyl-17β-hydroxy-estra-4,15-dien-3-one-3-ethylenedithioacetal, m.p. 170.5 ° C; [α] D 20 = -21 (chloroform, c = 1%).

D) 11-Methylene-17α-ethynyl-178-hydroxy-estra-4,15-dien-3-one 1.41 g of potassium carbonate and 8.1 ml of methyl iodide were successively added to a suspension of 3 g of the dithioacetal of Example Ie) in a mixture. consisting of 76 ml of methanol-20 and 5 ml of water. The reaction mixture was refluxed for 20 hours, evaporated in vacuo to about 25 ml, further diluted with 250 ml of water and extracted with methylene chloride. The crude product was purified by chromatography on silica gel. The pure fractions were crystallized from hexane to give 1.5 g of 11-methylene-17α-ethynyl-17β-hydroxy-estra-4,15-dien-3-one; mp. 157 eC; [α] D 20 = -44 (chloroform, c = 1%).

Example II

a) 11-Methylene-estra-4,15-diene-3,17-dione-3-ethyl-30-dithioacetal-17-ethylenediacetal

A solution of 15 g of 11-methylene-estra-4,15-diene-3,17-dione-3-ethylenedithioacetal and 0.5 g of p-toluenesulfonic acid in 160 ml of methylene chloride, 320 ml of ethylene glycol and 48 ml of triethylorthoformate , boiled at reflux for 4 hours. The reaction mixture was worked up by extraction with β 89053 to give 16.9 g of 11-methylene-estra-4,15-diene-3,17-dione-3-ethylenedithioacetal-17-ethylenediacetal.

b) 11-Methylene-estra-4,15-dien-17-one-17-ethylene-diacetal

A solution of 14 g of 11-methylene-estra-4,15-diene-3,17-dione-3-ethylenedithioacetal-17-ethylenediacetal was added dropwise to a solution of 7.2 g of sodium in 280 ml of liquid. ammonia, for 30 minutes at -40 ° C, after which the mixture was stirred for a further 30 minutes at the same temperature. After further work-up and chromatography on silica gel, 9.2 g of 11-methylene-estra-4,15-dien-17-one-17-ethylenediacetal were obtained.

c) 11-Methylene-estra-4,15-dien-17-one A solution of 8.8 g of 11-methylene-estra-4,15-dien-17-one-17-ethylenediacetal in 175 ml of acetone and 0.9 ml of concentrated hydrochloric acid, was stirred for 1.5 hours at room temperature under a nitrogen atmosphere. Work-up by extraction and crystallization from ether gave 6.5 g of 11-methylene-estra-4,15-dien-17-one.

d) 11-Methylene-17α-ethynyl-estra-4,15-dien-176-ol 6 g of 11-methylene-estra-4,15-dien-17-one were ethynylated as described in Example Ie) to give 25 g of 2.1 g of 11-methylene-17α-ethynyl-estra-4,15-dien-17β-ol.

Example III

II-methylene-17a-ethynyl-estra-4,15-dien-17B-ol

Following the procedure described in Example I and starting from 11-methylene-estr-4-en-17-one, 11-methyl-30a-17α-ethynyl-estra-4,15-dien-17B-ol was prepared, with the possibility of omitting 3 oxo group protection and deprotection.

9 89053

Example IV

II-methylene-17a-allyl-17-hydroxy-estra-4,15-dien-3-one

By repeating Example I with the difference that the alkylation described in Example Ie was performed with allyl magnesium bromide, 11-methylene-17α-allyl-17β-hydroxy-estra-4,15-dien-3-one was obtained.

Example V

11-Methylene-17α- (1-propynyl) -17β-hydroxy-estra-10 4,15-dien-3-one

By repeating Example I, except that the alkylation described in Example Ie was performed with methylacetylene in the presence of butyllithium, 11-methylene-17α- (1-propynyl) -17β-hydroxy-estra-4,15-dien-3-15-one was obtained. .

Example VI

11-Methylene-17α-chloroethynyl-17β-hydroxy-estra-4,15-dien-3-one

Repeating Example I with the difference that the alkylation described in Example Ie was performed with 1,2-dichloroethylene in diethyl ether / tetrahydrofuran (8: 1) in the presence of methyllithium gave 11-methylene-17α-chloroethynyl-17β-hydroxy-estra-4 , 15-dien-3-one.

Example VII

25 11-Methylene-17α-ethynyl-17β-hydroxy-estra-4,15-dien-3-one-17β-acetate 1.8 g of 11-methylene-17α-ethynyl-17β-hydroxy-estra-4,15-dien-3 was reacted at room temperature with 10 ml of acetic anhydride in 15 ml of pyridine containing 150 mg of 4-dimethylaminopyridine. After 5 hours, the mixture was poured into ice water and worked up. The product was chromatographed on silica gel with acetone / hexane to give 1.6 g of 11-methylene-17α-ethynyl-17β-hydroxy-estra-4,15-dien-3-one-17β-acetate.

10 89053

Example VIII

In studies measuring the binding affinity of 11-methylene-17α-ethynyl-17α-hydroxy-estra-4,15-dien-3-one and its analogues with an 18-methyl group or no 5 double bonds at the 15-position, progesterone-, androgen and SHBG receptors, the following results were obtained:

Compound Receptor Affinity Target 10 ----- Δ15 18-CH3 Progetherlone Receptor Androgen Receptor SHBO Receptor (3-Ketodeositor (5α-Dihydro- (5α-DHT 100) Gestrel 100) Testosterone »100) 15 + - 114 2 1 80 7 3 + 1 + 1_99__2__5

Claims (6)

11 89053 11-methylene steroids of general formula (I) for use in contraception, wherein R 2 is H or lower alkylcarbonyl, R 2 is ethynyl, vinyl, chloroethynyl, allyl or propynyl and R 3 is O or H 2. Compounds according to Claim 1, characterized in that Rx is H. 3. A compound according to claims 1 or 2, which comprises R2, is etynyl. Compounds according to Claim 1 or 2, characterized in that R 2 is ethynyl. 4. A combination of patent claims 1, 2 or 3, 20 for the purposes of claim 1, wherein R3 is O. 5. 11-Methylene-17α-ethynyl-176-hydroxiestra-4,15-dien-3-one. Compounds according to Claim 1, 2 or 3, characterized in that R 3 is O. 5. 11-methylene-17α-ethynyl-17α-hydroxy-estra-4,15-dien-3-one. Composition for use in contraception, characterized in that it contains one or more compounds according to one of Claims 1 to 5. 12 89053 1. 11-methylsteroids for the preparation of the active compounds and with all the compounds of formula (I) 5 H * c. ORt VN -, - r, Rj color R2 is H or alkyl alkylcarbonyl, R2 is ethynyl, vinyl, chloroethyl, allyl or propynyl and R3 is O or H2. 15 2. Föreningar enligt patentkravet 1, kanne- tecknade därav, att R2 är H. 6. A composition for preventive measures having the effect of reversing the conditions of patent invention 1-5.