17-substituted steroids useful in cancer treatment

• US 5,604,213 A
• Filed: 09/30/1994
• Issued: 02/18/1997
• Est. Priority Date: 03/31/1992
• Status: Expired due to Term

• Current Assignee: BTG International Limited (Boston Scientific Corporation)
• Original Assignee: British Technology Group Ltd. (Boston Scientific Corporation)
• Inventors: Potter, Gerard A., Hardcastle, Ian R., Barrie, Susan E., Jarman, Michael
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Bottino, Anthony
• Application Number:
  US08/315,882
• Time in Patent Office: 872 Days
• Field of Search: 540/95, 514/176
• US Class Current: 514/176
• CPC Class Codes: C07J 13/005 with double bond in position 16 (17)
• CPC Class Codes: C07J 31/006 not covered by C07J31/003
• CPC Class Codes: C07J 41/0005 the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
• CPC Class Codes: C07J 43/003 not condensed
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Abstract

Compounds of the general formula (1) ##STR1## wherein X represents the residue of the A, B and C rings of a steroid, R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R¹⁴ represents a hydrogen atom and R¹⁵ represents a hydrogen atom or an alkyl or alkoxy group of 1-4 carbon atoms, or a hydroxy or alkylcarbonyloxy group of 2 to 5 carbon atoms or R¹⁴ and R¹⁵ together represent a double bond, and R¹⁶ represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, in the form of the free bases or phannaceutically acceptable acid addition salts, are useful for treatment of androgen-dependent disorders, especially prostatic cancer, and also oestrogen-dependent disorders such as breast cancer.

Claims

1. A compound of the formula (I) ##STR27## wherein X represents the residue of the A, B and C rings of a steroid selected from the group consisting of

androstan-3α

- or 3β

-ol,

androst-5-en-3α

- or 3β

-ol,

androst-4-en-3-one,

androst-2-ene,

androst-4-ene,

androst-5-ene,

androsta-5,7-dien-3α

or 3β

-ol,

androsta-1,4-dien-3-one,

estra-1,3,5[10]-trien-3-ol,

α

-androstan-3-one,

androst-4-ene-3,11-dione,

6-fluoroandrost-4-ene-3-one,

androstan-4-ene-3,6-dione,

each of which, where structurally permissible, can be further derivatised in one or more of the following ways;

to form 3-esters

to have one or more carbon to carbon ring double bonds in any of the 5,6-, 6,7-, 7,8-, 9,11- and 11,12-positions

as 3-oximes

as 3-methylenes

as 3-carboxylates

as 3-nitriles

as 3-nitros

as 3-desoxy derivatives

to have one or more hydroxy, halo, C_1-4 -alkyl, trifluoro-methyl, C_1-4 -alkoxy, C_1-4 -alkanoyloxy, benzoyloxy, oxo, methylene or alkenyl substituents in the A, B, or C-ring

to be 19-nor;

R represents a hydrogen atom or an alkyl group of 1-4 carbon atoms;

androsta-3,5-diene,

androsta-3,5-diene-3-ol,

estra-1,3,5[10]-triene and

estra-1,3,5[10]-trien-3-ol,

α

-androstan-3-one;

androst-4-ene-3,11-dione,

6-fluoroandrost-4-ene-3-one,

androstan-4-ene-3,6-dione,

each of which, where structurally permissible, can be further derivatised in one or more of the following ways;

to form 3-esters

to have one or more carbon or carbon ring double bonds in any of the 5,6-, 6,7-, 7,8-, 9,11- and 11,12-positions

as 3-oximes

as 3-methylenes

as 3-carboxylates

as 3-nitriles

as 3-nitros

as 3-desoxy derivatives

to have one or more hydroxy, halo, C_1-4 -alkyl, trifluoro-methyl, C_1-4 -alkoxy, C_1-4 -alkanoyloxy, benzoyloxy, oxo, methylene or alkenyl substituents in the A, B, or C-ring

to be 19-nor;

R represents a hydrogen atom or an alkyl group of 1-4 carbon atoms;

R¹⁴ represents a hydrogen atom, a halogen atom or an alkyl group of 1 to 4 carbon atoms;

each of the R¹⁵ substituents independently represents a hydrogen atom or an alkyl or alkoxy group of 1-4 carbon atoms, a hydroxy group or an alkylcarbonyloxy group of 2 to 5 carbon atoms or together represent an oxo or methylene group or R¹⁴ and one of the R¹⁵ groups together represent a double bond and the other R¹⁵ group represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms; and

R¹⁶ represents a hydrogen atom, halogen atom, or an alkyl group of 1 to 4 carbon atoms, in the form of the free bases or pharmaceutically acceptable acid addition salts, but excluding 3β

-acetoxy-17-(3-pyridyl)androsta-5,14,16-triene, 3β

,15α

- and 3β

,15β

-diacetoxy-17-(3-pyridyl)androsta-5,16-diene and 3β

-methoxy-17-(3-pyridyl-5α

-androst-16-ene.

3. A compound according to claim 1, which is saturated and unsubstituted at the 11- and 12-positions.

5. A compound according to claim 1 wherein R represents a hydrogen atom.

9. A pharmaceutical composition comprising a compound of claim 1 in association with a pharmaceutically acceptable carrier or diluent.

10. A pharmaceutical composition comprising a compound of claim 3 in association with a pharmaceutically acceptable carrier or diluent.

11. A pharmaceutical composition comprising a compound of claim 1 wherein R represent a hydrogen atom in association with a pharmaceutically acceptable carrier or diluent.

2. A method of treating an androgen-dependent or estrogen-dependent disorder which comprises administering to a patient in a therapeutically effective dose a compound of the formula (1):

##STR28## wherein X represents the residue of the A, B and C rings of asteroid selected from the group consisting of

androstan-3α

- or 3β

-ol,

androst-5-en-3α

- or 3β

-ol,

androst-4-en-3-one,

androst-2-ene,

androst-4-ene,

androst-5-ene,

androsta-5,7-dien-3α

or 3β

-ol,

androsta-1,4-dien-3-one,

androsta-3,5-diene,

androsta-3,5-dien-3-ol,

estra-1,3,5[10]-triene and

R¹⁴ represents a hydrogen atom, a halogen atom or an alkyl group of 1 to 4 carbon atoms;

each of the R¹⁵ substituents independently represents a hydrogen atom or an alkyl or alkoxy group of 1-4 carbon atoms, a hydroxy group or an alkylcarbonyloxy group of 2 to 5 carbon atoms or together represent an oxo or methylene group or R¹⁴ and one of the R¹⁵ groups together represent a double bond and the other R¹⁵ group represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms; and

R¹⁶ represents a hydrogen atom, halogen atom, or an alkyl group of 1 to 4 carbon atoms, in the form of the free bases or pharmaceutically acceptable acid addition salts.

16. A method according to claim 2 wherein the patient has prostatic cancer.

17. A method according to claim 2 wherein the patient has breast cancer.

18. A method according to claim 2 wherein the compound defined in claim 2 is saturated and unsubstituted at the 11- and 12-positions.

19. A method according to claim 2 wherein the compound is selected from the group consisting of:

17-(3-pyridyl)androsta-5,16-dien-3β

-ol,

17-(3-pyridyl)androsta-3,5,16-triene,

17-(3-pyridyl)androsta-4,16-dien-3-one,

17-(3-pyridyl)estra-1,3,5[10],16-tetraen-3-ol,

17-(3-pyridyl)-5α

-androst-16-en-3α

-ol

and their acid addition salts and 3-esters.

20. A method according to claim 2 wherein the compound is a 3β

-alkanoyloxy-17-(3-pyridyl)androsta-5,16-diene wherein the alkanoyloxy group has 2 to 4 carbon atoms.

21. A method according to claim 2 wherein the compound is 3β

-acetoxy-17-(3-pyridyl)androsta-5,16-diene.

22. An orally ingestible solid composition or a sterile injectable liquid composition comprising respectively a solid or liquid pharmaceutically acceptable carrier or diluent and a compound as defined by general formula (1) of claim 2.

4.

17-(3-Pyridyl)androsta-5,16-dien-3β

-ol,

17-(3-pyridyl)androsta-3,5,16-triene,

17-(3-pyridyl)androsta-4,16-dien-3-one,

17-(3-pyridyl)estra-1,3,5[10],16-tetraen-3-ol,

17-(3-pyridyl)-5α

-androst-16-en-3α

-ol

and their acid addition salts and 3-esters.

12. A pharmaceutical composition comprising a compound of claim 4 in association with a pharmaceutically acceptable carrier or diluent.

6.

17-(3-Pyridyl)-5α

-androst-16-en-3-one,

17-(3-pyridyl)-androsta-4,16-diene-3,11-dione,

17-(3-pyridyl)-androsta-3,5,16-trien-3-ol,

6α

- and 6β

-fluoro-17-(3-pyridyl)androsta-4,16-dien-3-one,

17-(3-pyridyl)androsta-4,16-dien-3,6-dione,

3α

-trifluoromethyl-17-(3-pyridyl)androst-16-en-3β

-ol

and their acid addition salts and 3-esters.

13. A pharmaceutical composition comprising a compound of claim 6 in association with a pharmaceutically acceptable carrier or diluent.

7. 3β

-Alkanoyloxy-17-(3-pyridyl)androsta-5,16-dienes in which the alkanoyloxy group has from 2 to 4 carbon atoms.

14. A pharmaceutical composition comprising a compound of claim 7 in association with a pharmaceutically acceptable carrier or diluent.

8. 3β

-Acetoxy-17-(3-pyridyl)androsta-5,16-diene.

15. A pharmaceutical composition comprising a compound of claim 8 in association with a pharmaceutically acceptable carrier or diluent.