DE19615819A1 - New 11beta-aryl-substituted 18-nor-steroid compounds - Google Patents

Abstract

11 beta -aryl-substituted 18-nor-steroid compounds of formula (Ia)-(Ic) are new. Ar = a group of formula (a); R = amino, (T)2N, TO, TS, OH, oximinomethyl, CN, CHO or acetyl; and T = 1-4C alkyl.

Description

The invention relates to new 11β-aryl-substituted 18-nor steroids general formula I.

of the general formula II

of the general formula III

wherein R is an amino, N-dialkylamino, alkoxy or an Al kylthio group each having 1 to 4 carbon atoms, a hydroxy, Oximinomethyl, cyano, formyl or an acetyl radical means.

Methods for producing the new derivatives are described as well as for the manufacture of their pharmaceutical compositions.

From the technical and patent literature (DE 44 17 880 (C.A. 124: 87 482; 1996), 18-nor steroids with an anti-hormonal effect are known.  

However, these compounds have no 4,9-diene structure and un differ by a completely different side chain on the C-17 and condensed, six-ring expanded unusually steroid framework.

The compounds according to the invention - 11β-aryl-substituted 18-nor- Steroids are new, their appearance and their biological effectiveness have not been described yet.

The invention has for its object new 11β-aryl-substituted To provide 18-nor steroids and procedures for their Show manufacturing.

The object is achieved in that new 11β-aryl substituted 18-nor steroids as set out in claims 1, 2 and 3, getting produced.

Preferred compounds according to the invention are, for example:
13β-bromo-14α, 17α-oxaethano-17-methyl-11β- (4′-dimethylamino phenyl) -gona-4,9-dien-3-one,
13β-bromo-14α, 17α-oxaethano-17methyl-11β- (4′-methoxyphenyl) -gona- 4,9-dien-3-one,
13β-bromo-14α, 17α-oxaethano-17-meth yl-11β- (4′-acetylphenyl) -gona- 4,9-dien-3-one,
13β-bromo-14α, 17α-oxaethano-17-methyl-11β- (4′-formylphenyl) -gona- 4,9-dien-3-one,
17α-hydroxymethyl-17-methyl-11β- (4′-dimethylaminophenyl) -gona- 4,9,13-trien-3-one,
17α-hydroxymethyl-17-methyl-11β- (4′-acetylphenyl) -gona-4,9,13-triene-3-one,
17α-hydroxymethyl-17-methyl-11β- (4′-cyanophenyl) -gona-4,9,13-trien-3-one,
17α-hydroxymethyl-17-methyl-11β- (4′-oximinomethylphenyl) -gona- 4,9,13-trien-3-one,
13ξ-14α, 17α-oxaethano-17-methyl-11β- (4′-dimethylaminophenyl) -gona- 4,9-dien-3-one,
13ξ-14α, 17α-oxaethano-17-methyl-11β- (4′-methylthiophenyl) -gona-4,9-dien-3-one,
13ξ-14α, 17α-oxaethano-17-methyl-11β- (4′-methoxyphenyl) -gona-4,9-dien-3-one,
13ξ-14α, 17α-oxaethano-17-methyl-11β- (4'-acetylphenyl) -gona-4, 9-dien-3-one.

The present compound also relates to pharmaceuticals Compositions containing at least one 11β-aryl substituted 18-nor steroid of the general formula I and / or II and / or III, these compositions being given if they contain suitable auxiliaries and carriers.

The compounds of the invention have an antigenic Effect profile and can therefore u. a. for reproductive control in the Hu man and veterinary medicine are used.

Furthermore, the compounds of the invention can because of their antigestagenic effectiveness in combination with progestogens and / or Estrogens in the form of multi-stage or combination preparations for hormonal contraception can be used.

Preferably the antigenic and gestagenic and / or estrogen components in contraceptive preparations administered orally together.

The term "progestogen" refers to any connection that the one Progesterone shows similar progestagenic effects.

Desogestrel or 3-keto-deso are preferred gestagens streel, Gestoden, Levonorgestrel and Norgestimate, Norethisterone, No rethisterone acetate, progesterone, chlormadinone acetate, cyproterone acetate, Medroxyprogesterone acetate, megestrol acetate, dydrogesterone, dienogest etc. into consideration.

The estrogens are synthetic estrogens, preferably from the Group ethinyl estradiol, mestranol and biogenic estrogens, preferred example from the group estradiol, estrone, estriol.  

The compounds according to the invention can also be used in preparations for Treatment of gynecological disorders and substitution therapy be used. Thanks to their favorable active profile, the new ones are Compounds suitable for the treatment of premenstrual complaints.

Furthermore, the pharmaceutical compositions with which he Compounds according to the invention for the treatment of endometriosis be used.

The pharmaceuticals of the invention are made with conventional solid or liquid gene carriers or diluents and the usual used pharmaceutical-technical auxiliaries accordingly the desired type of application with a suitable dosage in manufactured in a known manner.

The preferred preparations are in one dosage form, which is suitable for oral application.

Dosage forms of this type are, for example, tablets, film tablets ten, coated tablets, capsules, pills, powders and depot forms.

It is also possible to use the new compounds in suspensions or Incorporate solutions.

The use of the compounds according to the invention in the form of trans dermal systems is also given.

The compounds of the invention are also an intermediate product for the synthesis of other pharmacologically highly effective steroid products products.

The compounds of the invention are prepared according to claims 7 to 9.  

The compounds according to claims 1 to 3 are according to the invention from the 17 (R) -spirooxirane of the formula IV

accessible.

Compounds according to claim 1 are obtained by using the 17 (R) -spirooxirane in dipolar, aprotic solvents with Lewis Acids, for example in tetrahydrofuran, with aluminum chloride or in protic solvents, such as methanol, with mineral acids, Car bonic acids, preferably sulfonic acids, such as p-toluenesulfonic acid, for Gona-1,3,5 (10), 13-tetraene of the formula V

implements this in a Birch reduction known per se subjects in an aqueous organic solvent with the addition of egg Nes catalyst, for example in aqueous acetone using formation of dilute sulfuric acid, followed by an enol ether cleavage and by bromination / dehydrobromination, preferably in pyridine with Pyridine hydrobromide perbromide further to 13β-bromo-4,9-diene of the formula VI

implements.  

Surprisingly, there is no normal bromine addition to the 13 double bond to the dibromo product, but as a result of intramolecular ren nucleophilic attack of the alcohol function on the Bromonium structure The 13β-bromo-14α, 17α-oxaethano compound is formed.

Continuing the process, the 13β-bromo-4,9-diene of the formula VI with a suitable alcohol, preferably 1,3-propanediol Addition of trimethyl orthoformate and a catalyst, for example p-toluenesulfonic acid, ketalized, the ketal then ent neither with peracid or hydroperoxy compounds generated in situ, for example with 3-chloroperbenzoic acid in chlorinated coal water serstoffe, preferably in methylene chloride, in the 5α, 10α-epoxide transferred this in a manner known per se with aryl magnesium halo geniden and copper (I) catalysts, preferably copper (I) chloride in dipolar aprotic solvents, for example tetrahydrofu ran, converted to the corresponding 11β-aryl compounds and by ketal splitting and dehydration in water-containing organi rule solvents with the addition of a catalyst, preferably in acetone solution using p-toluenesulfonic acid or in methanolic solution using dilute mineral acid ren, converted into compounds of general formula I.

wherein R is an amino, N-dialkylamino, alkoxy or an alkylthio group each with 1 to 4 carbon atoms, a hydroxy, oximi nomethyl, cyano, formyl or an acetyl radical.

Compounds according to claim 2 are obtained by using the 17 (R) -spirooxirane in the above manner up to the 11β-aryl- 14α, 17α-oxaethano compounds and then in one Alcohol with alkali metal, preferably in isopropanol with sodium,  into the 11β-aryl-gona-9,13-dienes of the general formula VII

transferred to water by ketal splitting and dehydration containing organic solvents with the addition of a catalyst, preferably in acetone solution using p- Toluene sulfonic acid or in methanolic solution when using dilute mineral acids in compounds of general formula II transferred

wherein R is an amino, N-dialkylamino, alkoxy or an alkylthio group each with 1 to 4 carbon atoms, a hydroxy, oximi nomethyl, cyano, formyl or acetyl radical.

Compounds are obtained according to claim 3 by the 17 (R) -spirooxirane into the compound in the manner shown above of the formula V, which surprisingly compared to that of Bromine to olefins inert iodine in dipolar aprotic Solvents, for example terahydrofuran with the addition of a suitable oxidizing agent, preferably aqueous nitric acid, 13β-iodo-14α, 17α-oxaethano compounds of the formula VIII,

this, by means of hydrogenolysis with Raney nickel in dipolar aprotic Solvents, for example in 1,4-dioxane Converted 13ξ-14α, 17α-oxaethano steroids of the formula IX,

this by Birch reduction, enol ether cleavage, bromination / dehydro bromination, ketalization with isomerization, epoxidation and 11β- Arylation as well as ketal splitting and dehydration via the 13ξ-4.9- Serve Formula X

into the compounds according to claims 3 and 6 of the general formula III

wherein R is an amino, N-dialkylamino, alkoxy or an alkylthio group each with 1 to 4 carbon atoms, a hydroxy, oximi nomethyl, cyano, formyl or acetyl radical, transferred.  

In Fig. 1, the production route of the compounds according to the invention according to claims 1 to 3 is shown.

Fig. 2 shows in each case in detail the production route of the inventive compounds according to claims 1 and 2, Fig. 3 shows the manufacturing route of the inventive compounds according to claim 3.

Fig. 1

Fig. 2

Fig. 3

The preparation of the compounds of the general Formula I, II and III will be explained in more detail in the following examples tert, but are not limited by this.

The Roman numerals in parentheses indicate this the particular synthesis product shown in both the patent say, in the description of the manufacturing process as well as in the illustrations.

The Arabic numerals in brackets indicate this the particular synthesis product shown in Figure 2.

example 1 17α-hydroxymethyl-17-methyl-3-methoxy-gona-1,3,5 (10), 13-tetraene (V)

63.6 mmol (19.0 g) 3-methoxy-estra-1,3,5 (10) -triene-17 (R) -spirooxiran (IV) are dissolved in 90 ml of ketyl-dried tetrahydrofuran and cooled to -10 ° C . 63.7 mmol (8.5 g) of aluminum chloride are added to the cooled solution with stirring. After approx. 30-45 min. the reaction mixture is added to 150 ml of ice-water, the fine precipitate is extracted with methyl tert-butyl ether, the combined extracts are dried over sodium sulfate and concentrated. The resulting oil is purified by flash chromatography on silica gel (eluent toluene / ethyl acetate 32/1) and, if necessary, recrystallization from methanol. 8.5 g of solid product, mp. 78-80 ° C; [α] -25 ° (c = 1, CHCl₃).
The subsequent stages of Birch reduction and the enol ether cleavage are carried out in a known manner.

Example 2 13β-bromo-14α, 17α-oxaethano-17-methyl-gona-4,9-dien-3-one (VI)

61.8 mmol (17.7 g) 17α-hydroxymethyl-17-methyl-gona-5 (10), 13-diene-3- are dissolved in 150 ml pyridine and the solution cooled to -5 ° C. 123.4 mmol (39.5 g) of pyri are added to the cooled solution with stirring dinhydrobromide perbromide, dissolved in 150 ml of pyridine, was added dropwise. After When the dropping is complete, the temperature slowly increases to room temperature and finally increased to 40 ° C. Reak after about 4-5 hours the mixture is poured into ice-cold 2N HCl. The feinkri stalline yellowish precipitate is suctioned off, acid-free with water washed and dried in a desiccator over calcium chloride (vacuum) net. By flash chromatography on silica gel (eluent Tolu en / ethyl acetate 23/2) gives 7.5 g of a solid product. [α] -200 ° (c = 1, CHCl₃).

Example 3 13β-bromo-14α, 17α-oxaethano-17-methyl-3′3-propylenedioxy-gona- 5 (10), 9 (11) -diene (1)

9.9 mmol (3.6 g) 13β-bromo-14α, 17α-oxaethano-17-methyl-gona-4,9-dien-3-one (VI) are mixed in a mixture of 42 ml of 1,3-propanediol and 36 ml of tetrahydrofuran, and 27 mmol (≈ 3 ml) of trimethyl orthoformate and subsequently 15 mg of p-toluenesulfonic acid were added at room temperature. The mixture is stirred under protective gas (argon) for about 3.5 hours and the reaction solution is then poured into ice-cooled aqueous sodium hydrogen carbonate solution, the precipitate is filtered off with suction and finally dried over calcium chloride in a desiccator. 3.8 g of an amorphous product are obtained.
1 H-NMR: (ppm) 5.56 (m, 1.11-H) / CDCl₃

Example 4 13β-bromo-14α, 17α-oxaethano-17-methyl-5α, 10α-epoxy-3,3- propylenedioxy-gon-9 (11) -en (2)

9 mmol (3.8 g) 13β-bromo-14α, 17α-oxaethano-17-methyl-3,3-propylene dioxy-gona-5 (10), 9 (11) -diene are dissolved in 45 ml methylene chloride and 45 , 8 ul pyridine added. At room temperature, about 2.0 g of 3-chloroperbenzoic acid (70%) are added in portions. After about 2.5 hours, the reaction is stopped, the organic phase washed with sodium bicarbonate solution and concentrated. The 5α, 10α isomer is obtained from the oily epoxy mixture by flash chromatography on silica gel (eluent cyclohexane / ethyl acetate 4/1). 0.57 g of a very viscous oil is obtained.
1 H-NMR: (ppm) 6.00 (m, 1.11-H) / CDCl₃
The subsequent stage of the copper-catalyzed 11β-arylation is carried out in a known manner.

Example 5 13β-bromo-14α, 17α-oxaethano-17-methyl-11β- (4'-dimethyl aminophenyl) -gona-4,9-dien-3-one (I)

0.36 mmol (200 mg) 13β-bromo-14α, 17α-oxaethano-17-methyl-11β- (4'-dimethylaminophenyl) -3,3-propylenedioxy-gon-9 (10) -en-5α-ol dissolved in 5 ml of acetone, a small spatula tip of p-toluenesulfonic acid was added and the mixture was stirred at room temperature. After the reaction has ended, the mixture is poured onto ice-cooled sodium hydrogen carbonate solution, the precipitate is extracted with methyl tert-butyl ether and concentrated. After chromatographic purification, 106 mg of a slightly colored foam remain.
1 H-NMR: (ppm) 2.93 (s, 6, N (CH₃) ₂), 4.38 / 4.40 (m, 1.11α-H), 5.77 (s, 1,4-H ), 6.66 / 6.69-7.03 / 7.06 (m, 4, J = 8.8Hz, ArH).

Claims (10)

1. New 11β-aryl-substituted 18-nor steroids of the general formula I wherein
R is an amino, N-dialkylamino, alkoxy or an alkylthio group each having 1 to 4 carbon atoms,
a hydroxy, oximinomethyl, cyano, formyl or acetyl radical
means. 2. New 11β-aryl-substituted 18-nor steroids of the general formula II wherein
R is an amino, N-dialkylamino, alkoxy or an alkylthio group each having 1 to 4 carbon atoms,
a hydroxy, oximinomethyl, cyano, formyl or acetyl radical
means. 3. New 11β-aryl-substituted 18-nor steroids of the general formula III wherein
R is an amino, N-dialkylamino, alkoxy or an alkylthio group each having 1 to 4 carbon atoms,
a hydroxy, oximinomethyl, cyano, formyl or acetyl radical
means. 4. New 11β-aryl-substituted 18-nor steroids according to claim 1, namely
13β-bromo-14α, 17α-oxaethano-17-methyl-11β- (4′-dimethyl aminophenyl) -gona-4,9-dien-3-one
13β-bromo-14α, 17α-oxaethano-17methyl-11β- (4'-methoxyphenyl) -gona-4,9-dien-3-one
13β-bromo-14α, 17α-oxaethano-17-methyl-11β- (4'-acetylphenyl) - gona-4,9-dien-3-one
13β-bromo-14α, 17α-oxaethano-17-methyl-11β- (4'-formylphenyl) - gona-4,9-dien-3-one. 5.New 11β-aryl-substituted 18-nor steroids according to claim 2, namely
17α-hydroxymethyl-17-methyl-11β- (4′-dimethylaminophenyl) - gona-4,9, 13-trien-3-one,
17α-hydroxymethyl-17-methyl-11β- (4′-acetylphenyl) -gona- 4,9,13-trien-3-one,
17α-hydroxymethyl-17-methyl-11β- (4′-cyanophenyl) -gona- 4,9,13-trien-3-one,
17α-hydroxymethyl-17-methyl-11β- (4'-oximinomethylphenyl) - gona-4,9,13-trien-3-o n. 6. New 11β-aryl-substituted 18-nor steroids according to claim 2, namely
13ξ-14α, 17α-oxaethano-17-methyl-11β- (4′-dimethylamino phenyl) -gona-4,9-dien-3-one,
13ξ-14α, 17α-oxaethano-17-methyl-11β- (4′-methylthiophenyl) - gona-4,9-dien-3-one,
13ξ-14α, 17α-oxaethano-17-methyl-11β- (4′-methoxy phenyl) - gona-4,9-dien-3-one,
13ξ-14α, 17α-oxaethano-17-methyl-11β- (4'-acetylphenyl) -gona- 4,9-dien-3-one. 7. A process for the preparation of 11β-aryl-substituted 18-nor steroids according to claims 1 and 4, characterized in that

• - That the 17 (R) -spirooxirane of the formula IV in dipolar aprotic solvents with Lewis acids or in protic solvents with mineral acids, carboxylic acids or sulfonic acids
  to Gona-1,3,5 (10), 13-tetraene of the formula V implements
• carries out a Birch reduction in a manner known per se,
• - The product is subjected to an enol ether cleavage in an aqueous organic solvent with the addition of a catalyst
• - And by means of bromination / dehydrobromination to 13β-bromo-4,9-diene of the formula VI implements
• - ketalized with a suitable alcohol with the addition of orthoformic acid ester and a catalyst,
• - The ketal is then converted into the 5α, 10α-epoxide either with peracids or hydroperoxy compounds generated in situ in chlorinated hydrocarbons,
• - This 5α, 10α-epoxide in a known manner with aryl magnesium halides and copper (I) catalysts in dipolar aprotic solvents to the corresponding 11β-aryl-14α, 17α-oxaethano compounds
• - And by means of ketal splitting and dehydration in water-containing organic solvents with the addition of a catalyst in compounds of the general formula I. wherein
  R is an amino, N-dialkylamino, alkoxy or an alkylthio group each having 1 to 4 carbon atoms,
  a hydroxy, oximinomethyl, cyano, formyl or acetyl radical
  means
  transferred.

8. A process for the preparation of 11β-aryl-substituted 18-nor steroids according to claims 2 and 5, characterized in that

• - that the 17 (R) -spirooxirane of the formula IV is converted analogously to claim 7 to the 11β-aryl-14α, 17α-oxaethano compounds,
• - In an alcohol with alkali metal in the 11β-aryl-gona-9,13- dienes of the general formula VII convicted,
• - And by means of ketal splitting and dehydration in water-containing organic solvents with the addition of a catalyst in the general formula II R is an amino, N-dialkylamino, alkoxy or an alkylthio group each having 1 to 4 carbon atoms,
  a hydroxy, oximinomethyl, cyano, formyl or acetyl radical
  means
  transferred.

9. A process for the preparation of 11β-aryl-substituted 18-nor steroids according to claims 3 and 6, characterized in that

• - that the 17 (R) -spirooxirane of the formula IV is converted analogously to claim 7 to the 18-nor steroid of the formula V,
• - By means of iodine in dipolar aprotic solvents with the addition of a suitable oxidizing agent in 13β-iodo-14α, 17α-oxaethano compounds of the formula VIII convicted,
• - Using hydrogenolysis with Raney nickel in dipolar aprotic solvents to 13ξ-14α, 17α-oxaethano steroids of the formula IX implements
• - And also analogously to claim 7 by Birch reduction, enol ether cleavage, bromination / dehydrobromination, ketalization with isomerization, epoxidation and 11β-arylation as well as ketal cleavage and dehydration via 13ξ-4,9-dienes of the formula X. into the corresponding 13ξ-11β-aryl-4,9-dienes of the general formula III transferred.

10. Pharmaceutical compositions containing at least one 11β-aryl-substituted 18-nor steroid according to claims 1 to 3, optionally together with pharmaceutically acceptable auxiliaries and carriers.