# US 6,723,715 B1 · 14, 15-cyclopropanosteroids of the 19-norandrostane series, method for producing said compounds and pharmaceutical preparation containing said compounds

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- Number: US 6,723,715 B1
- Document ID: US6723715B1
- Status: Granted
- Kind: B1
- Application number: 10/148,159
- Filed: 2002-05-24
- Granted: 2004-04-20
- Earliest claimed: 1999-12-08
- Assignees: Schering Corporation
- Inventors: Sven Ring; Walter Elger; Guenter Kaufmann
- Web page: https://patentgrep.com/patent/US6723715B1

## CPC

- C07J 53/004: {3 membered carbocyclic rings}
- A61P 5/24: of the sex hormones
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 35/00: Antineoplastic agents
- C07J: STEROIDS (seco-steroids C07C)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to the new 14,15-cyclopropanoandrosteroids of the 19-norandrostane series of the general formula (I) their synthesis and to pharmaceutical compositions containing these compounds. The compounds of formula (I) have an interesting, mixed androgen/gestagen profile, the androgenic or gestagenic activity predominating, depending on the substitution.

## Claims

### Claim 1

14,15-cyclopranoandrostanes of the 19-norandrostane series of the formula (I)
wherein R1 is a hydrogen atom, a hydroxy group, C1-10-alkyl, a C1-10-alkyloxy, a C1-15 acyloxy, a C4-15-aryloxy, a C7-15-aralkyloxy or a C7-15-alkylaryloxy group;
R2 represents a hydrogen atom, a hydroxy group, a C1-10 alkyl group, a C1-10 acyl group, a C1-10 acyloxy group, a C6-15 aryl group, a C7-15 aralkyl group, a C7-15 alkylaryl group, a —(CH2)nCH2Y group with n=0, 1 or 2 and Y representing a halogen atom or a pseudohalogen; a (CH2)mCH═CH(CH2)pR6 group with m=0,1, 2 or 3 and p=0, 1 or 2 and R6 representing a hydrogen atom, a C1-10-alkyl group, a C6-15 aryl group, a C7-15 aralkyl group, a C7-15 alkylaryl group, a hydroxyl group, a C1-10 alkyloxy group, a C1-10 acyloxy group; a —(CH2)oC≡CR7 group with o=0, 1 or 2 and R7 representing a hydrogen atom, a halogen atom, a C1-10 alkyl group, a C6-15 aryl group, a C7-15 aralkyl group, a C7-15 alkylaryl group or a C1-10 acyl group; or
R1 and R2 together represent a keto group, a methylene group, a difluoromethylene group or, with inclusion of C-17, a spirooxirane or a 2,2-dimethyl-1,3-dioxolane;
R3 represents a hydrogen atom or an α-C1-10 alkyl group or β-C1-10 alkyl group;
R4 represents a halogen atom, a pseudohalogen, a hydroxy group or a perfluoroalkyl group;
R5 represents a C1-4 alkyl group,
wherein an α-cyclopropane or a β-cyclopropane group is between C-14 and C-15; and wherein optionally a 9,10-double bond is present and optionally an 11,12-double bond is present,
with the proviso that, if both the 9,10-double bond and the 11,12-double bond are present or if only the 11,12-double bond is present, then R4 can be a hydrogen atom in addition to said halogen atom, said pseudohalogen, said hydroxy group or said perfluoroalkyl group; and
with the further proviso that, if R5 is a methyl group, then R4 can be a hydrogen atom in addition to said halogen atom, said pseudohalogen, said hydroxy group or said perfluoroalkyl group;
or pharmaceutically tolerated salts thereof.

### Claim 2 (depends on 1)

The 14,15-cyclopranoandrostanes as defined in claim 1, wherein Y is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, an azide group or a rhodanide group.

### Claim 3 (depends on 1)

The 14,15-cyclopranoandrostanes as defined in claim 1, wherein R7 is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

### Claim 4 (depends on 1)

The 14,15-cyclopranoandrostanes as defined in claim 1, wherein R4 is a fluorine atom, a chlorine atom, a bromine atom, an azide group or a rhodanide group.

### Claim 5 (depends on 1)

The 14,15-cyclopranoandrostanes as defined in claim 1, wherein said R1 is a hydroxy group or an acyloxy group.

### Claim 6 (depends on 5)

The 14,15-cyclopranoandrostanes as defined in claim 5, wherein said acyloxy group is a formyloxy, an acetyloxy, a propionyloxy, a n-butyryloxy, an isobutyryloxy, a heptanyloxy or an undecanyloxy group.

### Claim 7 (depends on 1)

The 14,15-cyclopranoandrostanes as defined in claim 1, wherein R2 is a hydrogen atom or an alkyl group.

### Claim 8 (depends on 7)

The 14,15-cyclopranoandrostanes as defined in claim 7, wherein said alkyl group is a methyl group or an ethyl group.

### Claim 9 (depends on 1)

The 14,15-cyclopranoandrostanes as defined in claim 1, wherein R3 is a methyl group.

### Claim 10 (depends on 1)

The 14,15-cyclopranoandrostanes as defined in claim 1, wherein R4 is a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group or a trifluoromethyl group.

### Claim 11 (depends on 1)

The 14,15-cyclopranoandrostanes as defined in claim 1, wherein R5 is a methyl group or an ethyl group.

### Claim 12

A 14,15-cyclopranoandrostane selected from the group consisting of
4-chloro-17β-hydroxy-14α,15α-methylene-estr-4-ene-3-one,
4-chloro-17α-hydroxy-14α,15α-methylene-estr-4-ene-3-one,
4-chloro-17β-hydroxy-14β,15β-methylene-estr-4-ene-3-one,
4-chloro-17α-hydroxy-14β,15β-methylene-estr-4-ene-3-one,
4-bromo-17β-hydroxy-14α,15α-methylene-estr-4-ene-3-one,
4-bromo-17α-hydroxy-14α,15α-methylene-estr-4-ene-3-one,
4-bromo-17β-hydroxy-14β,15β-methylene-estr-4-ene-3-one,
4-bromo-17α-hydroxy-14β,15β-methylene-estr-4-ene-3-one,
4-fluoro-17β-hydroxy-14α,15α-methylene-estr-4-ene-3-one,
4-fluoro-17α-hydroxy-14α,15α-methylene-estr-4-ene-3-one,
4-fluoro-17β-hydroxy-14β,15β-methylene-estr-4-ene-3-one,
4-fluoro-17α-hydroxy-14β,15β-methylene-estr-4-ene-3-one,
4,17β-dihydroxy-14α,15α-methylene-estr-4-ene-3-one,
4,17α-dihydroxy-14α,15α-methylene-estr-4-ene-3-one,
4,17β-dihydroxy-14β,15β-methylene-estr-4-ene-3-one,
4,17α-dihydroxy-14β,15β-methylene-estr-4-ene-3-one,
4-trifluoromethyl-17β-hydroxy-14α,15α-methylene-estr-4-ene-3-one,
4-trifluoromethyl-17α-hydroxy-14α,15α-methylene-estr-4-ene-3-one,
4-trifluoromethyl-17β-hydroxy-14β,15β-methylene-estr-4-ene-3-one,
4-trifluoromethyl-17α-hydroxy-14β,15β-methylene-estr-4-ene-3-one,
17β-hydroxy-14α,15α-methylene-estra-4,9,11-triene-3-one,
17α-hydroxy-14α,15α-methylene-estra-4,9,11-triene-3-one,
17β-hydroxy-14β,15β-methylene-estra-4,9,11-triene-3-one and
17α-hydroxy-14β,15β-methylene-estra-4,9,11-triene-3-one.

### Claim 13 (depends on 1)

A method for the synthesis of the 14,15-cyclopranoandrostanes defined in claim 1, wherein, in 14,15-cyclopropanosteriods of the formula (II):
in which R1, R2, R3, R5 are as defined in claim 1, the 4,5 double bond is epoxidized with hydrogen peroxide under alkaline conditions and the resulting epoxide mixture is treated in a solvent with acids of the formula HR8, R8 being a halogen atom or a pseudohalogen atom, or reacted with catalytic amounts of a mineral acid, and the compound of the formula (I), as defined in claim 1, obtained above, is reacted with methyl 2,2-difluoro-2-(fluorosulfonyl) acetate in dimethylformamide in the presence of CuI.

### Claim 14 (depends on 13)

The method as defined in claim 13, wherein said halogen atom is a fluorine, chlorine or bromine atom.

### Claim 15 (depends on 13)

The method as defined in claim 13, wherein said pseudohalogen is an azide or a rhodanide group.

### Claim 16 (depends on 1)

A method for the synthesis of the 14,15-cyclopranoandrostanes defined in claim 1, wherein, compounds of the formula (III):
in which R1, R2, R3 and R5 are as defined in claim 1, are converted into the 14,15-cyclopranoandrostanes of the formula (I) with a 4,9,11-triene structure by ketalizing the compounds of the formula (III), hydrolyzing the ketal group of the thereby formed 5(10),9(11)-diene and reacting the 5(10),9(11)-diene-3-one obtained thereby with dichlorodicyanobenzoquinone.

### Claim 17 (depends on 1)

A pharmaceutical composition containing at least one of the 14,15-cyclopranoandrostanes defined in claim 1 and at least one additional ingredient selected from the group consisting of pharmaceutically tolerated inactive materials and vehicles.

### Claim 18 (depends on 1)

A method of hormone replacement therapy in a man or woman in need of said therapy, said method comprising administering to said man or said woman an effective amount of at least one of the 14,15-cyclopranoandrostanes as defined in claim 1 for said hormone replacement therapy.

### Claim 19 (depends on 1)

A method of controlling fertility of a human being, said method comprising administering to said human being an effective amount of at least one of the 14,15-cyclopranoandrostanes as defined in claim 1 for controlling said fertility.

### Claim 20 (depends on 1)

A method of treating a hormone-induced disease suffered by a man or a woman, said method comprising administering to said man or said woman an effective amount of at least one of the 14,15-cyclopranoandrostanes as defined in claim 1 for treating said hormone-induced disease.

### Claim 21 (depends on 20)

The method as defined in claim 20, wherein said hormone-induced disease is endometriosis, breast cancer or hypogonadism.