Unsaturated 14,15-cyclopropanoandrostanes, method for their preparing, compounds, pharmaceutical composition

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention describes unsaturated 14,15-cyclopropanoandrostanes of the general formula (I):

wherein R1 means hydrogen atom (H), hydroxy-group (OH); R2 means hydroxy-group (OH), hydrogen atom (H); R3 means hydrogen atom (H), (C1-C10)-alkyl at α- or β-position; R4 means halogen atom (F, Cl, Br) or pseudohalogen group (azide, rhodanide), hydroxy-group (OH), perfluoroalkyl; R5 means (C1-C4)-alkyl; if double bond is at 1,2-position then R4 can mean hydrogen atom (H). Also, invention relates to a method for preparing these compounds and pharmaceutical compositions containing these compounds. Compounds of the formula (I) are compounds eliciting gestagenic and/or androgenic effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 1 tbl, 9 ex

 

The present invention relates to new unsaturated 14,15-cyclopropanemethanol, the way they are received and containing these compounds in pharmaceutical compositions.

Unsaturated 14,15-cyclopropaneacetic the following formula

known from the application DE 19827523.4 (PCT/DE99/01794), which has an earlier priority in comparison with the present application, but which was published after the filing of this application.

In the above formula

R1denotes a hydrogen atom, a hydroxyl group, alkyloxy, acyloxy, aryloxy, aralkylated or alkylammonium, balance-OCONHR9or -- OCOOR9where R9represents a hydrogen atom, alkyl, aryl, Aracely or alcylaryl the remainder in each case with 1-10 carbon atoms,

R2means

is a hydrogen atom, hydroxyl group, alkyl, acyl, aryl, Uralkaliy, alcylaryl group with 1-10 carbon atoms,

- the remainder -(CH2)nCH2Y, where n denotes 0, 1 or 2, a Y is an atom of fluorine, chlorine, bromine or iodine, cyano, azide or rhodanate group, residue OR10or-SR10where R10represents a hydrogen atom, alkyl, aryl, Aracely or alcylaryl residue with 1-10 carbon atoms or acyl residue COR9where R 9represents alkyl, aryl, Aracely or alcylaryl the remainder in each case with 1-10 carbon atoms, a residue OR9where R9represents a hydrogen atom, alkyl, aryl, Aracely or alcylaryl the remainder in each case with 1-10 carbon atoms,

- the remainder -(CH2)m-CH=CH(CH2)n-R8where m denotes 0, 1, 2 or 3 and n represents 0, 1 or 2, a R8represents a hydrogen atom, alkyl, aryl, Aracely or alcylaryl the remainder in each case with 1-10 carbon atoms or a hydroxyl group, alkoxygroup or alloctype in each case with 1-10 carbon atoms,

- the remainder -(CH2)OWith≡CR11where o denotes 0, 1 or 2, and R11represents a hydrogen atom, fluorine atom, chlorine, bromine or iodine, alkyl, aryl, Uralkaliy, alcylaryl or acyl residue, in each case with 1-10 carbon atoms, or

R1and R2denote independently from each other keto-, methylene, deformationof group,

between C-6 and C-7 may be a double bond,

between C-14 and C-15 is αor β-cyclopropane group X, where X represents CZ2-group, where Z denotes a hydrogen atom, fluorine, chlorine, bromine or iodine,

R3and R4denote independently each other a hydrogen atom, alkyl g is the SCP in α or β-position with 1-10 carbon atoms, and

R5denotes an alkyl group with 1-3 carbon atoms.

From application EP 0768316 A1 known steroids with 14,15-methylene group, which have Progesteronum action and thus can be used in combination with at least one suitable for this purpose estrogen for hormonal contraception and menopausal hormone replacement therapy (GST), as well as for the treatment of endometriosis or estensively tumors.

In contrast to this prior art, the present invention was based on the task to get new unsaturated 14,15-cyclopropaneacetic.

This problem is solved by using unsaturated 14,15-cyclopropanemethanol General formula (I)

where

R1denotes a hydrogen atom, hydroxyl group, With1-10alkyl,

With1-10alkyloxy-From1-15acyloxy-From4-15aryloxy-From7-15aralkylated or7-15alkylammonium,

R2means

is a hydrogen atom, hydroxyl group, With1-10alkyl, C1-10acyl, C1-10acyloxy-From6-15aryl, C7-15aracelio or7-15alcylaryl group,

- the remainder -(CH2)nCH2Y, where n denotes 0, 1 or 2, a Y is a halogen atom, especially a fluorine atom is, chlorine, bromine or iodine, pseudohalogen, first of all, cyano, azide or rhodanate group,

- the remainder -(CH2)m-CH=CH(CH2)p-R6where m denotes 0, 1, 2 or 3, p represents 0, 1 or 2, and R6represents a hydrogen atom, a C1-10alkyl, C6-15aryl, C7-15Uralkaliy or7-15alcylaryl residue or a hydroxyl group, a C1-10alkyloxy or1-10alloctype,

- the remainder -(CH2)oC≡CR7where o denotes 0, 1 or 2, a R7represents a hydrogen atom, a halogen atom, especially a fluorine atom, chlorine, bromine or iodine, With1-10alkyl, C6-15aryl, C7-15Uralkaliy,7-15alcylaryl or1-10acyl residue, or

R1and R2together denote keto-, methylene, deformationof or group, including C-17, form spirometry or 2,2-dimethyl-1,3-dioxolane,

between C-1 and C-2 may be a double bond,

between C-14 and C-15 is αor β-cyclopropane group,

R3denotes a hydrogen atom or a C1-10alkyl group αor β-position

R4denotes a halogen atom, especially a fluorine atom, chlorine or bromine, or pseudohalogen primarily rhodanate or azide group, or a hydroxyl or performanceline group,

Rsub> 5stands With1-4alkyl group,

if in position 1,2 is a double bond, R4in addition to the above values may represent a hydrogen atom, and their pharmaceutically acceptable salts.

Unexpectedly, it was found that proposed in the invention unsaturated 14,15-cyclopropaneacetic General formula (1) are compounds with gestagenna and/or androgenic action.

In the context of the present invention pharmaceutically acceptable salts are salts of alkali or alkaline earth metals, especially sodium, potassium or ammonium. These salts can be obtained by well known from the prior art standard technologies and methods.

Under the concept of "1-4-, respectively, With1-10alkyl group" in the context of the present invention refers to an alkyl residue with a branched or unbranched chain with 1-4, respectively 1-10 carbon atoms. As examples of such can be called methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene or tert-boutelou, n-pentelow, isopentanol, n-hexoloy, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl group.

Under the concept of "1-10alkoxygroup" in the context of the present invention refers to cyclica the Kai or acyclic group, the alkyl residue contains from 1 to 10 carbon atoms, while the term "cyclic group" also refers to a heterocyclic group, which may contain in the ring one or two atoms heteroatoms which may be selected from the group including a nitrogen atom, an oxygen atom and a sulfur atom. Examples of such groups are methoxy group, ethoxypropan or n - or isopropoxy, ISO - or tert-butoxypropan, (1’-methoxy)cyclopentane-, respectively tetrahydropyranyloxy.

Under the concept of "1-10-, respectively, With1-15acyl, respectively alloctype" in kontekste the present invention refers to a residue with 1-10, respectively 1-15 carbon atoms alkenylboronic acid with unbranched or branched chain, such as formic acid, acetic acid, propionic acid, butane acid, isobutane acid, heptane acid or undecanoate acid.

Under the concept of "6-15aryl group" in the context of the present invention refers to a substituted or unsubstituted aryl residue with 6 to 15 carbon atoms, such as phenyl group, substituted phenyl group, such as halofantrine group or nitroaniline group, or naftalina group.

The term "C4-l5alloctype" in the context of the present invented what I mean carbocyclic or heterocyclic residue with 4 to 15 carbon atoms. Examples thereof are benzoyloxy, 1 - or 2-naftiluksusnaya, 2 - or 3-uranylacetate group, 2 - or 3-taylortype, 2-, 3 - or 4-pyridinylamino.

Under the concept of "7-15alcylaryl group" in the context of the present invention refers to aryl residue, a substituted alkyl residue, which together contain from 7 to 15 carbon atoms, while the aryl residue may carry other substituents, such as halogen atom. Examples of such groups are coloririna group (methylphenylene group), galatella group, ethylenimine group, dimethylaniline group or trimethylaniline group.

Under the concept of "7-15alkylammonium" in the context of the present invention refers to an elongated one oxygen atom "C7-15kalkilya group, such as 3-, 4-methylphenoxy.

Under the concept of "7-15kalkilya group" in the context of the present invention refers to an alkyl residue, a substituted aryl residue, which together contain from 7 to 15 carbon atoms, while the aryl residue may carry other substituents such as halogen atom. Examples of such groups are free or substituted aromatic residue benzyl group such as benzyl group or halobenzene group.

the od of the concept of " 7-15arancelaria" in the context of the present invention refers to an elongated one oxygen atom "C7-15kalkilya group, such as benzyloxy.

The term "halogen" in the context of the present invention refers to a fluorine atom, chlorine, bromine or iodine.

The term "pseudohalogen" in the context of the present invention refers to lanata, rhodanate, cyano, or azide group.

The term "perferably balance" in the context of the present invention refers to alkyl fluoride residue branched or non-branched chain with 1 to 3 carbon atoms, and as examples of when this can be called triptorelin, pentatration, getattr-n-sawn or heptafluoroisopropyl group.

R1means preferably hydroxyl or alloctype, primarily hydroxyl group, formyloxy, acetyloxy, propionyloxy, n-butyryloxy, isobutyryloxy, heptyloxy or undecyloxy.

If R2denotes a residue -(CH2)nCH2Y, n preferably represents 1, a Y preferably represents a fluorine atom, cyano - or rhodanate group.

If R2denotes a residue -(CH2)mCH=CH(CH2)p-R6then m preferably denotes 1, and R6preferred is entrusted represents a methyl or ethyl group or a methoxy - or ethoxypropan.

If R2denotes a residue -(CH2)oC=CR7, preferably denotes 1, a R7preferably represents a fluorine atom or a methyl or ethyl group.

R2particularly preferably denotes a hydrogen atom or a C1-6alkyl group, especially methyl or ethyl group.

R3preferably stands With1-4alkyl residue, particularly preferably a methyl group.

R4preferably represents fluorine atom, chlorine or bromine or triptorelin or hydroxyl group.

R5preferably denotes a methyl or ethyl group.

Most preferred are the following compounds:

1) 4-chloro-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one,

2) 4-chloro-17α-hydroxy-14α,15α-medienanstalt-4-EN-3-one,

3) 4-chloro-17β-hydroxy-14β,15β-medienanstalt-4-EN-3-one,

4) 4-chloro-17α-hydroxy-14β,15β-medienanstalt-4-EN-3-one,

5) 4-bromo-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one,

6) 4-bromo-17α-hydroxy-14α,15α-medienanstalt-4-EN-3-one,

7) 4-bromo-17β-hydroxy-14β,15β-medienanstalt-4-EN-3-one,

8) 4-bromo-17α-hydroxy-14β,15β-medienanstalt-4-EN-3-one,

9) 4-fluoro-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one,

10) 4-fluoro-17α-hydroxy-14α ,15α-medienanstalt-4-EN-3-one,

11) 4-fluoro-17β-hydroxy-14β,15β-medienanstalt-4-EN-3-one,

12) 4-fluoro-17α-hydroxy-14β,15β-medienanstalt-4-EN-3-one,

13) 4,17β-dihydroxy-14α,15α-medienanstalt-4-EN-3-one,

14) 4,17α-dihydroxy-14α,15α-medienanstalt-4-EN-3-one,

15) 4,17β-dihydroxy-14β,15β-medienanstalt-4-EN-3-one,

16) 4,17α-dihydroxy-14β,15β-medienanstalt-4-EN-3-one,

17) 4-trifluoromethyl-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one,

18) 4-trifluoromethyl-17α-hydroxy-14α,15α-medienanstalt-4-EN-3-one,

19) 4-trifluoromethyl-17β-hydroxy-14β,15β-medienanstalt-4-EN-3-one,

20) 4-trifluoromethyl-17α-hydroxy-14β,15β-medienanstalt-4-EN-3-one,

21) 17β-hydroxy-14α,15α-medienanstalt-1,4-Dien-3-one,

22) 17α-hydroxy-14α,15α-medienanstalt-1,4-Dien-3-one,

23) 17β-hydroxy-14α,15α-medienanstalt-1,4-Dien-3-one,

24) 17β-hydroxy-14β,15β-medienanstalt-1,4-Dien-3-one,

25) 17α-hydroxy-14β,15β-medienanstalt-1,4-diene-C-he,

26) 4-chloro-17α-hydroxy-14α,15α-medienanstalt-1,4-Dien-3-one,

27) 4-chloro-17β-hydroxy-14α,15α-medienanstalt-1,4-Dien-3-one,

28) 4-chloro-17β-hydroxy-14β,15β-medienanstalt-1,4-Dien-3-one and

29) 4-chloro-17α-hydroxy-14β,15β-medienanstalt-1,4-Dien-3-one

Proposed in the invention compounds and their pharmaceutically acceptable salts can be obtained in the following way, which is that in the compounds of General formula (II)

where R1, R2, R3and R5have the above values, and between C-14 and C-15 is αor β-cyclopropane group, the double bond in position 4,5 epoxidized hydrogen peroxide under alkaline conditions and the obtained epoxy mixture is treated in suitable for this purpose solvent acids of General formula HR8where R8may be a halogen atom or pseudohalogen.

Another possibility of obtaining 4-Poslednij compounds is the addition of bromine to compounds of General formula (II) using bromine, N-bromosuccinimide or N-bromoacetamide in a mixture of acetic acid/simple ether in the presence of a proton acceptor, such as kallidin (X.S. Fei and others J. Chem. Soc. Perkin Trans. 1: 1139-1142 (1998)).

4-hydroxy-substituted can be obtained by the interaction of the above-mentioned epoxy mixed with catalytic amounts of a mineral acid, such as sulfuric acid (P.S. Furth and other J. Enzyme Inhibition, 1990, T. 4, 131-135).

Compounds of General formula (I) with an additional double bond in position 1,2 can be easily obtained by methods known in the art, such as degidio is the W 4-EN-3-one system using 2,3-dichloro-5,6-disinsertion in an appropriate solvent, for example, dioxane, toluene or tert-butanol.

4-cryptomelane compounds of General formula (I) can be obtained by the interaction of the above 4-Poslednij compounds of General formula (I) with methyl ether of 2,2-debtor-2-(persulfonic)acetic acid in dimethylformamide in the presence of Cul (X.S. Fei and others J. Chem. Soc., Perkin Trans. 1: 1139-1142(1998)).

The initial compounds of the formula (II) can be obtained by known methods or by the method described in the application DE 19827523.4 (PCT/DE99/01794). In this application also described the introduction of residues, which are analogues presented in this description of the residues R1, R2, R3and R5.

The object of the present invention are also pharmaceutical compositions for oral, rectal, subcutaneous, intravenous or intramuscular use, which together with conventional carriers and diluents contain at least one compound of General formula (I) and/or an acid additive salt as the active substance.

The proposed invention in pharmaceutical preparations together with used to produce conventional solid or liquid carriers and/or diluents and the conventional in such cases, auxiliary substances as provided for the method of introducing the issue in the appropriate dosage. To obtain preferably the second oral dosage forms are made preferably tablets, tablets, film-coated, tablets, capsules, pills, powders, solutions or suspensions, as well as preparations in the form of a depot, i.e. the prolonged action.

Along with this can be applied parenteral dosage forms such as injectable solutions or suppositories.

Dosage forms, tablets can be obtained, for example, by mixing the active substance with known auxiliary substances such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, lubricating agents such as magnesium stearate or talc, and/or reagiruyushchimi agents (agents that provide depot-forms), such as carboxypolymethylene, carboxymethylcellulose, acatitla cellulose or polyvinyl acetate. Tablets can also consist of several layers.

Tablets can be produced by coating on cores produced analogously to the tablets, vehicles commonly used in covers for tablets, for example polyvinylpyrrolidone or shellac, gum Arabic, talc, titanium dioxide or sugar. When this shell beans can also consist of several layers, which can be used, for example, the above-mentioned excipients.

To improve the Oia taste solutions and suspensions, containing proposed in the invention, the active substance can be mixed with substances such as saccharin, cyclamate or sugar, and/or flavorings such as vanillin or orange extract. In addition, they can be mixed with auxiliary suspendresume agents such as sodium carboxymethyl cellulose, or preservatives, such as n-hydroxybenzoic acid.

Capsules can be produced by mixing the drug with a carrier, such as lactose or sorbitol, and filling the mixture into capsules.

Suppositories are made preferably by mixing the active substance with suitable for these purposes carriers, such as neutral fats or polyethylene glycol or their derivatives.

The pharmaceutical composition may further be a designed for percutaneous introduction of the composition, such as transdermal therapeutic system (TDS) or gels, ointments or sprays, or nasal compositions, such as nasal sprays or nasal drops.

Proposed in the invention unsaturated 14,15-cyclopropaneacetic General formula (I) are compounds with hormonal (gestagenna and/or androgenic action.

For example, the compound of General formula (I), where R1denotes a hydroxyl group, R2and R3 represent a hydrogen atom, R5denotes a methyl group, X represents CH3group, and 14,15-cyclopropane ring is in the α-position, namely 4-chloro-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one is an androgen.

It was found that the substance 4-chloro-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one 42±3% is associated with androgen receptor in the prostate of rats (comparative substance: 17β-hydroxy-17α-methylestra-4,9,11-trien-3-one; R 1881), whereas the relationship with the progesterone receptor in the uterus of rabbits virtually no space. In the test on Hershberger managed to reveal the noticeable androgenic activity, while gestagenna action in the test for continuation of the pregnancy has not occurred.

From the experiments the results of the open multilateral possible use of the present invention compounds of General formula (I) to control fertility in men, when conducting hormone replacement therapy (GST) in women and men, or for treatment due to the action of hormones diseases in men and women, such as endometriosis, breast cancer, or hypogonadism.

Examples

Example 1

17β-hydroxy-4,5-epoxy-14α,15α-methylenedioxy-3-one

Obtaining 4,5-epoxides

2 g 17β-hydroxy-14α,15α-matieland the OST-4-EN-3-one are dissolved in 80 ml of methanol and at 0° With mixed with 26 ml of a solution of hydrogen peroxide (35%). Then added with stirring to 5.2 ml of 10%sodium hydroxide solution and stirred at 0°C for 30 hours, the Reaction solution is mixed with 50 ml of dichloromethane and 25 ml of water and separate the organic phase. Next washed policecontributing solution of thiosulfate, dried and concentrated to dryness. The remainder is a mixture of 4α,5α-, 4β,5β-epoxides, and it is used at the subsequent stage without further purification.

Example 2

17α-hydroxy-4,5-epoxy-14α,15α-methylenedioxy-3-one

The above compound can be obtained from 17α-hydroxy-14α,15α-medienanstalt-4-EN-3-one analogously to example 1.

Example 3

4-chloro-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one

1.5 g 17β-hydroxy-4,5-epoxy-14α,15α-methylenedioxy-3-one are dissolved in 150 ml of acetone and 0°mixed with 5.5 ml of concentrated hydrochloric acid. After 24 h at 0°the mixture is neutralized with soda solution and the acetone is distilled off. The residue is extracted with dichloromethane. The organic extracts are dried and concentrated. After crystallization from ethanol 4-chloro-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one.

1H-NMR: 0,12 (1H, dd, J=5,5, 3,3 Hz, CH2-bridge)and 0.22 (1H, dd, J=8,2, 5.5 Hz, CH2-bridge), 0,99 (3 is, s, H-18), of 1.30 (3H, s, H-19), 3,49 (1H, dd, J and 9.3 and 7.1 Hz, H-17).

Example 4

4-chloro-17α-hydroxy-14α,15α-medienanstalt-4-EN-3-one

17α-hydroxy-14α,15α-medienanstalt-4-EN-3-one is subjected to transform as in example 3.

1H-NMR: 0,32 (1H, dd, J=7,7, a 4.9 Hz, CH2-bridge), to 0.72 (1H, dd, J=4,4, 3,3 Hz, CH2-bridge), 0,99 (3H, s, H-18), of 1.29 (3H, s, H-19), 3,80 (1H, d, J=6.0 Hz, H-17).

Example 5

4,17β-dihydroxy-14α,15α-medienanstalt-4-EN-3-one

3.5 g of epoxy mixture, 17β-hydroxy-4,5-epoxy-14α,15α-methylenedioxy-3-one (stage 1) is dissolved in 50 ml of acetic acid containing about 2. % concentrated sulfuric acid. The solution for 3 days incubated at 10°C. thereafter, the solution is mixed with 200 ml of ethyl ether, acetic acid and neutralized with soda solution. Then the organic phase is dried and concentrated. The residue is dissolved in 100 ml of methanol, mixed with 4 g of potassium hydroxide and within 1 hour and heated under reflux. Then the solution is allowed to cool, neutralized with 50%acetic acid, poured into 1 l of water and the crystals separated using a suction filter. In this way receive 4,17β-dihydroxy-14α,15α-medienanstalt-4-EN-3-one.

1H-NMR: 0,13 (1H, dd, J=5,6, and 3.2 Hz, CH2-bridge), 0,24 (1H, dd, J=8,3, 5.6 Hz, CH2-bridge), 0,99 (3H, s, H-18), of 1.30 (3H, s, H-19), 3,50 (1H, dd, J=9,4, 6,8 Hz, H-17), 6,10 (1H, s, 4-OH).

Example 6

4-bromo-17β-g is droxi-14α ,15α-medienanstalt-4-EN-3-one

The target connection receive similarly, to obtain 4-chloro-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one, however instead of hydrochloric acid used 48%Hydrobromic acid.

1H-NMR: 0,12 (1H, dd, J-5,5, 3,3 Hz, CH2-bridge), 0,21 (1H, dd, J an 8.4, 5.4 Hz, CH2-bridge), and 1.00 (3H, s, H-18), of 1.33 (3H, s, H-19), 3,49 (1H, dd, J=9,3 and 7.1 Hz, H-17).

Example 7

4-trifluoromethyl-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one

1.5 g of 4-bromo-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one are dissolved in 180 ml of dimethylformamide and stirred with 1 g Cul and 2.8 ml of methyl ether of 2,2-debtor-2-(persulfonic)acetic acid at 75°C for 12 hours

After processing the mixture and chromatographic purification receive 4-trifluoromethyl-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one.

1H-NMR: 0,14 (1H, dd, J=5,5, 3.0 Hz, CH2-bridge), and 0.25 (1H, dd, J=8,2, 5.8 Hz, CH2-bridge), and 1.00 (3H, s, H-18), 1,32 (3H, s, H-19), 3,51 (1H, m, H-17).

19F-NMR: -55,3 (3F, s, 4-F3C).

Example 8

17β-hydroxy-14α,15α-medienanstalt-1,4-Dien-3-one

4 g 17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one for 6 days stirred in 160 ml of toluene with 3.2 g of 2,3-dichloro-5,6-disinsertion at 85°C. Then, using a suction filter the precipitate is filtered off, washed with a small amount of toluene and the filtrate concentrate is their dryness. The residue is purified by chromatography, and thus receive 17β-hydroxy-14α,15α-medienanstalt-1,4-Dien-3-one.

1H-NMR: 0,13 (1H, dd, J=5,6, and 3.2 Hz, CH2-bridge), 0,24 (1H, dd, J=8,3, 5.6 Hz, CH2-bridge), and 0.98 (3H, s, H-18), of 1.35 (3H, s, H-19), a 3.50 (1H, m, H-17), the 6.06 (1H, m, H-4), to 6.22 (1H, dd, J=12,09, 1.65 Hz, H{2}),? 7.04 baby mortality (1H, d, J=9.9 Hz, H-1).

Example 9

4-chloro-17β-hydroxy-14α,15α-medienanstalt-1,4-Dien-3-one

This compound is obtained from 4-chloro-17β-hydroxy-14α,15α-medienanstalt-4-EN-3-one analogously to example 6.

1H-NMR: 0,13 (1H, dd, J=5,6, and 3.2 Hz, CH2-bridge), 0,24 (1H, dd, J=8,3, 5.6 Hz, CH2-bridge), and 0.98 (3H, s, H-18), of 1.35 (3H, s, H-19), a 3.50 (1H, m, H-17), to 6.22 (1H, dd, J=12,09, 1.65 Hz, H{2}),? 7.04 baby mortality (1H, d, J=9.9 Hz, H-1).

Regarding toxicity, the applicant informs the following. To determine the Toxicological properties of the claimed compounds was performed with the program DR, which uses the results of a worldwide examination of the structural elements of chemical substances that can be toxic to humans, and analyzes substances in the presence of the so-called "structural alerts". The use of this program there was no evidence of toxicity for compounds of formula I. a Brief description of the program DER see in the application.

With respect to biological properties, the applicant informs that on the basis of the results of the Tobit animal tests can confirm androgenic action of the two compounds, namely, the compound No. 1 (example 3) and the compound No. 13 (example 5), which was tested in a test Hershberger (rshberger) on immature orientirovannyh rats at doses of 1 mg/animal/day subcutaneously for 7 days. In the control group was used lonaprisan and orientirovannyh animals. The test Hershberger (analysis) is a recognized method of analysis (recommended OD-organization for economic cooperation and development) and due to the growth of androgen-dependent tissues can confirm androgenic and, accordingly, antiandrogennoe chemicals. He is recognized as a method of searching in vivo (screening) androgen agonists or antagonists by measuring changes to the relevant organs or tissues, such as prostate, seminal vesicles and muscle, levator anus, castrated (orientirovannyh) male rats.

The essence of the method consists in the following. Features and dimensions the extension of the sex glands (seminal vesicles and prostate and muscle, levator anus, depends on the presence of androgens. Accordingly, castration leads to atrophy of these organs. If after castration introduce androgens, increase in the mass extension glands can conclude about the presence of androgenic compounds. Immature with the IWAC (line WIST, Tierzucht GmBH Schonwalde, Germany) weighing 40-50 g were orientational (ORH). The control group consisted of intact animals, but they were lonaprisan (LO). The control group, the ORH group and LR group (n=5) were administered the compounds obtained. The analyzed compounds were administered at a dose of 1.0 mg/individual/day subcutaneously. Sample volume was 0.2 ml/individual/day. After 24 hours after 7 injections, animals were scored.

As can be seen from the following table 1, both of the analyzed compounds on the basis of the growth of the prostate gland, seminal vesicles and muscles, levator anus, have unexpectedly high androgenic effect compared to untreated castrated animals (ORH) and, accordingly, linearizovannykh animals. The test Hershberger immature orientirovannyh the male rats, the dose of 1.0 mg/individual/day, subcutaneously, 7 injections (6 animals)

Table 1
The prostate gland (mg)Seminal vesicles (mg)Lev. Ani (mg)
4-chloro-17β-hydroxy-14α, 15α-medienanstalt-4-EN-3-one607875
Group LO522132
Group ORH8731

The prostate gland (mg)Seminal vesicles (mg)Lev. ani (mg)
4,17 β-dihydroxy-14α, 15α-medienanstalt-4-ene-on629480
Group LO482040
Group ORH9640

Based on these data, the compound 13 (4,17β-dihydroxy-14α,15α-medienanstalt-4-EN-3-one) affinity for the androgen receptor is AR=32%. Binding to the receptor was determined by the method of competitive binding specific radioactiveman (3H) hormone (label) and the analyzed compounds with the receptor in the cytosol of the cells of target organs. This was achieved by saturation of the receptor and equilibrium reactions. Label and analyze the connection (competitive) in ascending concentrations were incubated at 0-4°C for 18 h with fractions cytosol containing the receptor. After separation of unbound label on the suspension of charcoal-dextran for each concentration was measured by the proportion of label associated with the receptor, and the curve of the concentration dependence was determined IC50. The relative molar affinity binding (R control is connected to the I=100%) was determined by dividing the IC 50control and analyze connections (X100%). For androgen receptor used the following incubation conditions: prostate cytosol castrated animal; the prostate was stored at -30°; buffer solution: D containing 10% glycerol and 2 μm triaminobenzene; label:3H-metabolon, 4 nm; reference substance: metribolone (100%).

1. Unsaturated 14,15-cyclopropaneacetic General formula (I)

where

R1denotes a hydrogen atom, hydroxyl group,

R2denotes a hydrogen atom, hydroxyl group,

R3denotes a hydrogen atom or a C1-10alkyl group αor β-position

R4denotes a halogen atom, especially a fluorine atom, chlorine or bromine or pseudohalogen primarily rhodanate or azide group, or a hydroxyl or performanceline group,

R5stands With1-4alkyl group, provided that if in position 1, 2 is a double bond, R4in addition to the above values may represent a hydrogen atom, and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, where R1represents a hydroxyl group.

3. Compounds according to claim 1 or 2, where R2isone of the hydrogen atom.

4. The compound according to any one of claims 1 to 3, where R3represents a methyl group.

5. Compounds according to any one of claims 1 to 4, where R4represents a fluorine atom, chlorine or bromine or triptorelin or hydroxyl group.

6. Compounds according to any one of claims 1 to 5, where R5represents a methyl or ethyl group.

7. Compounds according to claim 1 of the group, including

1) 4-chloro-17β-hydroxy-14α, 15α-medienanstalt-4-EN-3-one,

2) 4-chloro-17α-hydroxy-14α, 15α-medienanstalt-4-EN-3-one,

3) 4-bromo-17β-hydroxy-14α, 15α-medienanstalt-4-EN-3-one,

4) 4,17β-dihydroxy-14α, 15α-medienanstalt-4-EN-3-one,

5) 4-trifluoromethyl-17β-hydroxy-14α, 15α-medienanstalt-4-EN-3-one,

6) 17β-hydroxy - 14α, 15α-medienanstalt-1,4-Dien-3-one,

7) 4-chloro-17β-hydroxy-14α,15α-medienanstalt-1,4-Dien-3-one.

8. Method of preparing compounds according to any one of claims 1 to 7, characterized in that compounds of General formula (II)

where R1, R2and R5have specified in claim 1 values and between C-14 and C-15 is αor β-cyclopropane group, the double bond in position 4, 5 epoxidized by hydrogen peroxide in alkaline conditions, the obtained epoxy mixture is treated in appropriate rest retele acids of General formula HR 8in which R8may be a halogen atom, especially a fluorine atom, chlorine or bromine, or pseudohalogen primarily rhodanate or azide group, or subjected to interaction with catalytic amounts of a mineral acid and, if necessary, the obtained 4-poslednie compounds of General formula (I) is subjected to interaction with the methyl ether of 2,2-debtor-2-(persulfonic)acetic acid in dimethylformamide in the presence of ul in the presence Si and/or if necessary, the resulting compound of formula (I) is subjected to dehydrogenation with 2,3-dichloro-5,6-disinsertion in an appropriate solvent.

9. Pharmaceutical compositions with gestagennami and/or androgenic activity that contains at least one compound of General formula (I) according to any one of claims 1 to 7, optionally together with pharmaceutically acceptable excipients and carriers.

10. Compounds of General formula (I) according to any one of claims 1 to 7 for the control of fertility in men, when conducting hormone replacement therapy for men and women or to treat due to the action of hormones diseases in men and women, such as endometriosis, breast cancer, or hypogonadism.

11. Compounds of General formula (I) according to any one of claims 1 to 7 for use as therapeutic active substances.



 

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