Non-peptide GnRH agents

• US 6,218,426 B1
• Filed: 03/01/1999
• Issued: 04/17/2001
• Est. Priority Date: 03/05/1998
• Status: Expired due to Fees

• Current Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Anderson, Mark Brian, Polinsky, Alexander, Gregor, Vlad Edward, Hong, Yufeng
• Primary Examiner(s): Killos, Paul J.
• Application Number:
  US09/259,206
• Time in Patent Office: 778 Days
• Field of Search: 514/255, 514/337, 514/323, 514/448, 514/471, 514/663, 514/634, 548/496, 548/495, 549/72, 549/461, 549/483, 549/487, 564/161, 564/170, 564/237, 560/190
• US Class Current: 514/448
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 279/12 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/16 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 261/10 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/00 Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/71 attached in position 5
• CPC Class Codes: C07D 307/91 Dibenzofurans; Hydrogenated dibenzofurans
• CPC Class Codes: C07D 317/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/70 attached in position 2
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

Abstract

Non-peptide GnRH agents capable of inhibiting the effect of gonadotropin-releasing hormone are of the following general formula, where X₁, X₂, Y, and are defined variables:

Such compounds and their pharmaceutically acceptable salts, multimers, prodrugs, and active metabolites are suitable for treating mammalian reproductive disorders and steroid hormone-dependent tumors as well as for regulating fertility, where suppression of gonadotropin release is indicated. Methods for synthesizing the compounds and intermediates useful in their preparation are also described.

Claims

1. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a GnRH agent selected from the group consisting of compounds of the Formula I;

wherein;

Z is a group selected from substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, CH₂OR and C(O)OR, where R is substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, and where the number of carbon atoms present in Z ranges from 1 to 12;

Y is a lipophilic group selected from substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, where the number of carbons atoms present in Y ranges from 6 to 20;

X₁ is a structural unit connecting CH₂NC(O), X₂, Y, and Z in three-dimensional space that is selected from substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl such that the atom count in the chain portion of the unit linking the central nitrogen to X₂ ranges from 3 to 8; and

X₂ is a basic group having a pK_a greater than about 8 and is guanidinyl, amidinyl, or amino, unsubstituted or substituted with one or more lower alkyls; and

pharmaceutically acceptable salts, multimers, prodrugs, and active metabolites thereof; and

(b) a pharmaceutically acceptable carrier or diluent.

2. A pharmaceutical composition according to claim 1, wherein Z is a substituted or unsubstituted furyl, pyrrolyl, naphthyl, thienyl, pyridyl, C₃-C₈ cycloalkyl, C₁-C₈ alkyl, CH₂CF₃, or CF₃.

3. A pharmaceutical composition according to claim 1, wherein Z is furyl, pyrrolyl, thienyl, or CF₃.

4. A pharmaceutical composition according to claim 1, wherein Y is substituted or unsubstituted phenyl, naphthyl, saturated or partially saturated naphthyl derivative, dibenzylfuryl, saturated or partially saturated dibenzylfuryl derivative, quinolinyl, isoquinolinyl, quinoxalinyl, saturated or partially saturated cycloalkyl, or fused polycyclic alkyl.

5. A pharmaceutical composition according to claim 1, wherein Y is 4-isopropylphenyl, 4-N,N-dimethylaminopropyloxyphenyl, 2,4,5-triethoxyphenyl, 2,3-dibenzyloxyphenyl, 2-(4′

-chlorophenyloxy)phenyl or a partially or fully saturated thereof, or 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl.

6. A pharmaceutical composition according to claim 1, wherein Y is

7. A pharmaceutical composition according to claim 1, wherein X₁ is alkylene, alkylene-(C_5-6-cycloalkyl)-alkylene, or alkylene-(C_5-6-aryl)-alkylene.

8. A pharmaceutical composition according to claim 7, wherein X₁ is selected from the group consisting of:

9. A pharmaceutical composition according to claim 1 wherein the X₂ group has a pK_a greater than about 9.

10. A pharmaceutical composition according to claim 1, where X₂ is guanidinyl.

11. A pharmaceutical composition according to claim 1, wherein the GnRH agent is selected from the group consisting of:

or a pharmaceutically acceptable salt, multimer, prodrug, or active metabolite thereof.

12. A pharmaceutical composition according to claim 1, wherein the compounds of the Formula I are selected from compounds of the formula:

13. A pharmaceutical composition according to claim 1, wherein the compounds of the Formula I are selected from compounds of the formula:

14. A method for regulating the secretion of gonadotropins in mammals, comprising administering a therapeutically effective amount of a GnRH agent selected from the group consisting of compounds of the Formula I:

wherein;

Z is a group selected from substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroraryl, CH₂OR, and C(O)OR, where R is substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, and where the number of carbon atoms present in Z ranges from 1 to 12;

Y is a lipophilic group selected from substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, where the number of carbon atoms present in Y ranges from 6 to 20;

X₁ is a structural unit connecting CH₂NC(O), X₂, Y, and Z in three-dimensional space that is selected from substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl such that the atom count in the chain portion of the unit linking the central nitrogen to X₂ ranges form 3 to 8; and

X₂ is a basic group having pK_a greater than about 8, and is guanidinyl, amidinyl, or amino, unsubstituted or substituted with one or more lower alkyls, and pharmaceutically acceptable salts multimers, prodrugs, and active metabolites thereof.

15. A method according to claim 14, wherein the compounds of the Formula I are selected from compounds of the formula:

16. A method according to claim 14, wherein the compounds of the Formula I are selected from compounds of the formula: