BETA-LACTAMYLALKANOIC ACIDS FOR TREATING PREMENSTRUAL DISORDERS

• US 20090170825A1
• Filed: 03/21/2006
• Published: 07/02/2009
• Est. Priority Date: 03/22/2005
• Status: Active Grant

• Current Assignee: Azevan Pharmaceuticals, Inc.
• Original Assignee: Azevan Pharmaceuticals, Inc.
• Inventors: Miller, Marvin J., Koppel, Gary A.
• Granted Patent: US 9,597,314 B2
• Time in Patent Office: Days
• US Class Current: 514/210.20
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 of the sex hormones

Abstract

0-lactamyl alkanoic acids are described. Methods for treating various premenstrual disorders using or more O-lactamyl alkanoic acids are also described.

Claims

1. A method for treating a premenstrual disorder, the method comprising the step of administering an effective amount a compound to a patient in need of relief from the disorder, where the compound is of the formula

2. The method of claim 1 wherein the compound is of the formula:

3. The method of claim 1 wherein the compound is of the formula:

5. The method of claim 1 wherein R¹ is hydrogen.

7. The method of claim 1 wherein R² is hydrogen.

8. The method of claim 1 wherein R³ is selected from the group consisting of:

10. The method of claim 8 wherein R³ is selected from the group consisting of:

11. The method of claim 8 wherein R³ is:

12. The method of claim 8 wherein R¹⁰ is optionally substituted aryl, and R¹¹ is hydrogen:

13. The method of claim 1 wherein R⁴ is selected from the group consisting of:

14. The method of claim 13 wherein Y is halo.

15. The method of claim 13 wherein R is hydrogen or methoxy.

16. The method of claim 1 wherein A is —

CO₂R⁵;

where R⁵ is hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(C₁-C₄ alkyl), or R⁶R⁷N—

(C₂-C₄ alkyl);

where R⁶ is selected from the group consisting of hydrogen and alkyl; and

R⁷ is selected from the group consisting of alkyl, cycloalkyl, optionally substituted aryl, and optionally substituted arylalkyl;

or R⁶ and R⁷ are taken together with the attached nitrogen atom to form an optionally substituted heterocyclyl.

17. The method of claim 16 wherein the optionally substituted heterocyclyl is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl;

where said piperazinyl or homopiperazinyl is also optionally N-substituted with R¹³;

where R¹³ is independently selected in each instance from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aryloyl.

18. The method of claim 1 wherein A is monosubstituted amido, disubstituted amido, or an optionally substituted nitrogen-containing heterocyclylamido.

19. The method of claim 18 wherein heterocyclyl is selected from the group consisting of tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, and quinuclidinyl;

where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C₁-C₄ alkyl or optionally substituted aryl(C₁-C₄ alkyl).

20. The method of claim 1 wherein A is C(O)NR¹⁴X—

, where R¹⁴ is hydrogen, hydroxy, alkyl, alkoxycarbonyl, or benzyl; and

X is alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C₁-C₄ alkyl), R⁶R⁷N—

, or R⁶R⁷N—

(C₂-C₄ alkyl);

where R⁶ is selected from the group consisting of hydrogen and alkyl; and

R⁷ is selected from the group consisting of alkyl, cycloalkyl, optionally substituted aryl, and optionally substituted arylalkyl;

or R⁶ and R⁷ are taken together with the attached nitrogen atom to form an optionally substituted heterocyclyl.

21. The method of claim 1 wherein A is an amide of an optionally substituted nitrogen-containing heterocycle.

22. The method of claim 21 wherein the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl.

23. The method of claim 21 wherein the nitrogen-containing heterocycle is substituted with R¹⁰, R², R⁶R⁷N—

, or R⁶R⁷N—

(C₁-C₄ alkyl);

where R⁶ is selected from the group consisting of hydrogen and alkyl; and

R⁷ is selected from the group consisting of alkyl, cycloalkyl, optionally substituted aryl, and optionally substituted arylalkyl;

or R⁶ and R⁷ are taken together with the attached nitrogen atom to form an optionally substituted heterocyclyl;

wherein R¹⁰ and R¹² are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, and triphenylmethoxy.

24. The method of claim 21 wherein the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, and 1,2,3,4-tetrahydroisoquinolin-2-yl.

25. The method of claim 2 wherein A′

is C(O)NR¹⁴X—

, where R¹⁴ is hydrogen, hydroxy, alkyl, alkoxycarbonyl, or benzyl; and

X is alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C₁-C₄ alkyl), R⁶R⁷N—

, or R⁶R⁷N—

(C₂-C₄ alkyl);

where R⁶ is selected from the group consisting of hydrogen and alkyl; and

R⁷ is selected from the group consisting of alkyl, cycloalkyl, optionally substituted aryl, and optionally substituted arylalkyl;

or R⁶ and R⁷ are taken together with the attached nitrogen atom to form an optionally substituted heterocyclyl.

26. The method of claim 2 wherein A′

is an amide of an optionally substituted nitrogen-containing heterocycle.

27. The method of claim 26 wherein the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl.

28. The method of claim 26 wherein the nitrogen-containing heterocycle is substituted with R¹⁰, R², R⁶R⁷N—

, or R⁶R⁷N—

(C₁-C₄ alkyl);

where R⁶ is selected from the group consisting of hydrogen and alkyl; and

R⁷ is selected from the group consisting of alkyl, cycloalkyl, optionally substituted aryl, and optionally substituted arylalkyl;

or R⁶ and R⁷ are taken together with the attached nitrogen atom to form an optionally substituted heterocyclyl;

wherein R¹⁰ and R¹² are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, and triphenylmethoxy.

29. The method of claim 26 wherein the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, and 1,2,3,4-tetrahydroisoquinolin-2-yl.

30. The method of claim 3 wherein R^5″

is optionally substituted arylalkyl.

32. The method of claim 2 wherein n is 1 or 2.

33. The method of claim 3 wherein n is 1.

34. The method of claim 2 wherein A and A′

are each independently selected from the group consisting of monosubstituted amide, disubstituted amide and optionally substituted nitrogen-containing heterocyclylamide.

4. (canceled)

6. (canceled)

9. (canceled)

31. (canceled)