Estradiol prodrugs

• US 7,534,780 B2
• Filed: 05/20/2005
• Issued: 05/19/2009
• Est. Priority Date: 05/21/2004
• Status: Expired due to Fees

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Bayer Schering Pharma AG (Bayer AG)
• Inventors: Ring, Sven, Droescher, Peter, Wyrwa, Ralf, Reddersen, Gudrun, Hillisch, Alexander, Elger, Walter, Schneider, Birgitt
• Primary Examiner(s): Badio; Barbara P
• Application Number:
  US11/133,431
• Publication Number:
  US 20050288267A1
• Time in Patent Office: 1,460 Days
• Field of Search: 552/626, 514/182
• US Class Current: 514/182
• CPC Class Codes: C07J 1/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane

Abstract

The invention relates to estradiol prodrugs of general formula (I), in which group Z is bonded to the steroid,

process for their production, pharmaceutical compositions that contain these compounds, as well as their use for the production of pharmaceutical agents with estrogenic action.

Claims

1. An estradiol compound of formula (I)

2. A compound according to claim 1, wherein n is 0, 1 or 2.

3. A compound according to claim 1, wherein R¹ represents a radical —

SO₂NH₂ or —

NHSO₂NH₂.

4. A compound according to claim 3, wherein R¹ represents a group —

SO₂NH₂.

5. A compound according to claim 1, wherein either R¹, R² or R³ a group —

SO₂NH₂.

6. A compound according to claim 1, wherein

if R¹ means—

SO₂NH₂ or —

NHSO₂NH₂, then R², R³, X, and X¹, independently of one another, stand for a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group, or

if R² means—

SO₂NH₂ or —

NHSO₂NH₂, then R¹, R³, X, and X¹, independently of one another, stand for a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group, or

if R³ means—

SO₂NH₂ or —

NHSO₂NH₂, then R¹, R², X, and X¹, independently of one another, stand for a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group.

7. A compound according to claim 1, wherein, independently of one another,

R⁵, R⁶, R⁷ and R⁸ in each case represent a hydrogen atom,

R⁹ represents a hydrogen atom or a fluorine atom,

R¹¹ represents a hydrogen atom or a fluorine atom,

R¹⁰ represents a hydroxy group, a methoxy group, a trimethylsilyloxy radical, a tert.-butyldimethylsilyloxy radical, a benzoate radical, an acetate radical, a propionate radical, a valerate radical, a (trans-4-n-butyl) cyclohexylcarboxylate radical, a cyclopentylpropionate radical or a group Z,

R¹² represents a hydroxy group, a methoxy group, a trimethylsilyloxy radical, a tert.-butyldimethylsilyloxy radical, a benzoate radical, an acetate radical, a propionate radical, a valerate radical, a (trans-4-n-butyl) cyclohexylcarboxylate radical, a cyclopentylpropionate radical or a group Z,

R¹⁴ represents a hydrogen atom, and

R¹⁵ represents a hydrogen atom, a methoxy group, or an ethoxy group.

8. A compound according to claim 1, wherein n is 0.

9. A compound according to claim 1, wherein n is 2.

10. A compound according to claim 1, wherein n is 3.

11. A compound according to claim 1, wherein n is 4.

12. A compound according to claim 7, wherein, independently of one another,

R¹⁰ represents a hydroxy group, a methoxy group, a trimethylsilyloxy radical, a tert.-butyldimethylsilyloxy radical, a benzoate radical, an acetate radical, a propionate radical, a valerate radical, a cyclopentylpropionate radical or a group Z, and

R¹² represents a hydroxy group, a methoxy group, a trimethylsilyloxy radical, a tert.-butyldimethylsilyloxy radical, a benzoate radical, an acetate radical, a propionate radical, a valerate radical, a cyclopentylpropionate radical or a group Z.

13. A compound according to claim 1, wherein

R¹ is a radical —

SO₂NH₂ or —

NHSO₂NH₂,

wherein

R², R³, X, and X¹ stand for a hydrogen atom, a halogen atom,

a nitrile group, a nitro group, a branched or straight chain, unsubstituted C_1-5-alkyl group, a C_pF_2p+1 group with p=1-3, a group OC(O)—

R²⁰, COOR²⁰, OR²⁰, C(O)NHR²⁰ or OC(O)NH—

R²¹,

wherein

R²⁰, and R²¹ are a branched or straight chain, unsubstituted C_1-5-alkyl group, a mono or bicyclic C_3-8-cycloalkyl group, an unsubstituted C₆ to C₁₅ aryl group, an unsubstituted C_1-4-alkylene aryl group, an unsubstituted C_1-4-alkylene-C_3-8-cycloalkyl group or an unsubstituted C_3-8-cycloalkylene-C_1-4-alkyl group, and

R²⁰ R in addition can mean a hydrogen, or

R² is a radical —

SO₂NH₂ or —

NHSO₂NH₂,

wherein

R¹, R³, X, and X¹ stand for a hydrogen atom, a halogen atom,

a nitrile group, a nitro group, a branched or straight chain, unsubstituted C_1-5-alkyl group, a C_pF_2p+1 group with p=1-3, a group OC(O)—

R²⁰, COOR²⁰, OR²⁰, C(O)NHR²⁰ or OC(O)NH—

R²¹,

wherein

R²⁰, and R²¹ are a branched or straight chain, unsubstituted C_1-5-alkyl group, a mono or bicyclic C_3-8-cycloalkyl group, an unsubstituted C₆ to C₁₅ aryl group, an unsubstituted C_1-4-alkylene aryl group, an unsubstituted C_1-4-alkylene-C_3-8-cycloalkyl group or an unsubstituted C_3-8-cycloalkylene-C_1-4-alkyl group, and

R²⁰ in addition can mean a hydrogen, or

R³ is a radical —

SO₂NH₂ or —

NHSO₂NH₂,

wherein

R¹, R², X, and X¹ stand for a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a branched or straight chain, unsubstituted C_1-5-alkyl group, a C_pF_2p+1 group with p=1-3, a group OC(O)—

R²⁰, COOR²⁰, OR²⁰, C(O)NHR²⁰ or OC(O)NH—

R²¹,

wherein

R²⁰, and R²¹ are a branched or straight chain, unsubstituted C_1-5-alkyl group, a mono or bicyclic C_3-8-cycloalkyl group, an unsubstituted C₆ to C₁₅ aryl group, an unsubstituted C_1-4-alkylene aryl group, an unsubstituted C_1-4-alkylene-C_3-8-cycloalkyl group or an unsubstituted C_3-8-cycloalkylene-C_1-4-alkyl group, and

R²⁰ addition can mean a hydrogen.

14. A compound according to claim 1, wherein

R¹ is a radical —

SO₂NH₂ or —

NHSO₂NH₂,

wherein

R², R³, X, and X¹ stand for a hydrogen atom, a halogen atom,

a nitrile group, a nitro group,

a branched or straight chain, substituted or unsubstituted C_1-5-alkyl group, wherein the substituent on the C_1-5-alkyl group is a halogen atom, a hydroxy group, or a nitrile group,

a C_pF_2p+1 group with p=1-3, a group OC(O)—

R²⁰, COOR²⁰, OR²⁰, C(O)NHR²⁰ or OC(O)NH—

R²¹,

wherein

R²⁰, and R²¹ are

a branched or straight chain, substituted or unsubstituted C_1-5-alkyl group,

wherein the substituent on the C_1-5-alkyl group is a halogen atom, a

hydroxy group, or a nitrile group,

a mono or bicyclic C_3-8-cycloalkyl group,

a substituted or unsubstituted C₆ to C₁₅ aryl group, wherein the substituent on the aryl group is a halogen atom or a nitro group,

a substituted or unsubstituted C_1-4-alkylene aryl group, wherein the substituent on the C_1-4-alkylene aryl group is a halogen atom,

a substituted or unsubstituted C_1-4-alkylene-C_3-8-cycloalkyl group, wherein the substituent on the C_1-4-alkylene-C_3-8-cycloalkyl group is a halogen atom, or

a substituted or unsubstituted C_3-8-cycloalkylene-C_1-4-alkyl group, wherein the substituent on the C_3-8-cycloalkylene-C_1-4-alkyl group is a halogen atom,

and

R²⁰ in addition is hydrogen, or

R² is a radical —

SO₂NH₂ or —

NHSO₂NH₂,

wherein

R¹, R³, X, and X¹ stand for a hydrogen atom, a halogen atom,

a nitrile group, a nitro group,

a branched or straight chain, substituted or unsubstituted C_1-5-alkyl group,

wherein the substituent on the C_1-5-alkyl group is a halogen atom, a hydroxy group, or a nitrile group,

a C_pF_2p+1 group with p=1-3, a group OC(O)—

R²⁰, COOR²⁰, OR²⁰, C(O)NHR²⁰ or OC(O)NH—

R²¹,

wherein

R²⁰, and R²¹ are

a branched or straight chain, substituted or unsubstituted C_1-5-alkyl group, wherein the substituent on the C_1-5-alkyl group is a halogen atom, a hydroxy group, or a nitrile group,

a mono or bicyclic C_3-8-cycloalkyl group,

a substituted or unsubstituted C₆ to C₁₅ aryl group, wherein the substituent on the aryl group is a halogen atom or a nitro group,

a substituted or unsubstituted C_1-4-alkylene aryl group, wherein the substituent on the C_1-4-alkylene aryl group is a halogen atom,

a substituted or unsubstituted C_1-4-alkylene-C_3-8-cycloalkyl group, wherein the substituent on the C_1-4-alkylene-C_3-8-cycloalkyl group is a halogen atom, or

a substituted or unsubstituted C_3-8-cycloalkylene-C_1-4-alkyl group, wherein the substituent on the C_3-8-cycloalkylene-C_1-4-alkyl group is a halogen atom,

and

R²⁰ in addition is hydrogen, or

R³ is a radical —

SO₂NH₂ or —

NHSO₂NH₂,

wherein

R¹, R², X, and X¹ stand for a hydrogen atom, a halogen atom,

a nitrile group, a nitro group,

a branched or straight chain, substituted or unsubstituted C_1-5-alkyl group,

wherein the substituent on the C_1-5-alkyl group is a halogen atom, a hydroxy group, or a nitrile group,

a C_pF_2p+1 group with p=1-3, a group OC(O)—

R²⁰, COOR²⁰, OR²⁰, C(O)NHR²⁰ or OC(O)NH—

R²¹,

wherein

R²⁰, and R²¹ are

a branched or straight chain, substituted or unsubstituted C_1-5-alkyl group,

wherein the substituent on the C_1-5-alkyl group is a halogen atom, a hydroxy group, or a nitrile group,

a mono or bicyclic C_3-8-cycloalkyl group,

a substituted or unsubstituted C₆ to C₁₅ aryl group, wherein the substituent on the aryl group is a halogen atom or a nitro group,

a substituted or unsubstituted C_1-4-alkylene aryl group, wherein the substituent on the C_1-4-alkylene aryl group is a halogen atom,

a substituted or unsubstituted C_1-4-alkylene-C_3-8-cycloalkyl group, wherein the substituent on the C_1-4-alkylene-C_3-8-cycloalkyl group is a halogen atom, or

a substituted or unsubstituted C_3-8-cycloalkylene-C_1-4-alkyl group, wherein the substituent on the C_3-8-cycloalkylene-C_1-4-alkyl group is a halogen atom,

and

R²⁰ in addition is hydrogen.

15. A compound according to claim 1, which is

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

3-Acetoxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

3-tert.-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoyl-4′

-chloro-benzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,4′

-dichloro-5′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-methoxy-5′

-sulfamoylbenzoate,

3-tert.-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β

-yl 2′

-methoxy-5′

-sulfamoylbenzoate

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,3′

-dimethoxy-5′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoyl-4′

-chloro-benzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,4′

-dichloro-5′

-sulfamoyl-benzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamatobenzoate,

3-Benzoyloxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

17β

-(n-Pentanoyloxy)estra-1,3,5(10)-trien-3-yl 3′

-sulfamoylbenzoate,

17β

-Benzoyloxyestra-1,3,5(10)-trien-3-yl 3′

-sulfamoylbenzoate,

17β

-Hydroxyestra-1,3,5(10)-trien-3-yl 4′

-sulfamoylbenzoate,

17β

-Hydroxyestra-1,3,5(10)-trien-3-yl 2′

,3′

-dichloro-5′

-sulfamoylbenzoate,

17β

-Hydroxyestra-1,3,5(10)-trien-3-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

3-Methoxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-sulfamoylbenzoate,

3-Benzoyloxyestra-1,3,5(10)-trien-17β

-yl 2′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,3′

-dimethoxy-5′

-sulfamoylbenzoate,

Estra-1,3,5(10)-triene-3,17β

-diyl bis(3′

-sulfamoylbenzoate),

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoyl-4′

-chloro-benzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,4′

-dichloro-5′

-sulfamoyl-benzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamatobenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,3′

-dimethoxy-5′

-sulfamoylbenzoate,

3-tert.-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-sulfamoylbenzoate, or

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-sulfamoylbenzoate.

16. A compound according to claim 1, which is

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

3-Acetoxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

3-tert.-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoyl-4′

-chloro-benzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,4′

-dichloro-5′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-methoxy-5′

-sulfamoylbenzoate,

3-tert.-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β

-yl 2′

-methoxy-5′

-sulfamoylbenzoate

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,3′

-dimethoxy-5′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoyl-4′

-chloro-benzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,4′

-dichloro-5′

-sulfamoyl-benzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamatobenzoate,

3-Benzoyloxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

17β

-(n-Pentanoyloxy)estra-1,3,5(10)-trien-3-yl 3′

-sulfamoylbenzoate,

17β

-Benzoyloxyestra-1,3,5(10)-trien-3-yl 3′

-sulfamoylbenzoate,

17β

-Hydroxyestra-1,3,5(10)-trien-3-yl 4′

-sulfamoylbenzoate,

17β

-Hydroxyestra-1,3,5(10)-trien-3-yl 2′

,3′

-dichloro-5′

-sulfamoylbenzoate,

17β

-Hydroxyestra-1,3,5(10)-trien-3-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

3-Methoxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-sulfamoylbenzoate,

3-Benzoyloxyestra-1,3,5(10)-trien-17β

-yl 2′

-sulfamoylbenzoate,

2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,3′

-dimethoxy-5′

-sulfamoylbenzoate,

Estra-1,3,5(10)-triene-3,17β

-diyl bis(3′

-sulfamoylbenzoate),

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoyl-4′

-chloro-benzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,4′

-dichloro-5′

-sulfamoyl-benzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamatobenzoate,

2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,3′

-dimethoxy-5′

-sulfamoylbenzoate,

3-tert.-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-sulfamoylbenzoate, or

3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-sulfamoylbenzoate,

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition according to claim 17, further comprising a steroidally active compound which is not a compound of formula (I).

19. A pharmaceutical composition according to claim 18, wherein the additional steroidally active compound is a gestagen, an antigestagen or a mesoprogestin.

20. A pharmaceutical composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier.

21. A method for hormone replacement therapy in women, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 17.

22. A method for birth control in women, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 17.

23. A method for treating endometriosis, breast cancer, prostate cancer or hypogonadism, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 17.

24. A method for hormone replacement therapy in women, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 20.

25. A method for birth control in women, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 20.

26. A method for treating endometriosis, breast cancer, prostate cancer or hypogonadism, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 20.