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1. WO2006102308 - BETA-LACTAMYL VASOPRESSIN V1B ANTAGONISTS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

WHAT IS CLAIMED IS:
1. A method for treating a disease responsive to antagonism of vasopressin Vib receptors, the method comprising the step of administering an effective amount of a compound to a patient in need of relief from the disease, where the compound is of the formula



and pharmaceutically acceptable salts thereof, wherein
A is a carboxylic acid, an ester, or an amide;
B is a carboxylic acid, or an ester or amide derivative thereof; or B is an alcohol or thiol, or a derivative thereof;
R1 is hydrogen or C1-Cg alkyl;
R2 is hydrogen, alkyl, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting Of -CO2R8 and -CONR8R8 , where R8 and R8 are each independently selected from hydrogen and alkyl;
R3 is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom; and
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl.
2. The method of claim 1 wherein the compound is of the formula:



and pharmaceutically acceptable salts thereof, wherein A and A' are each independently selected from -CO2H, or an ester or amide derivative thereof;
n is an integer selected from 0 to about 3;
R1 is hydrogen or C1-C6 alkyl;
R2 is hydrogen, alkyl, alkoxy, alkylthio, cyano, foπnyl, alkylcarbonyl, or a substituent selected from the group consisting Of-CO2R8 and -CONR8R8', where R8 and R8' are each independently selected from hydrogen and alkyl;
R is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom; and
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl.
3. The method of claim 1 wherein the compound is of the foπnula:



and pharmaceutically acceptable salts thereof, wherein
A is -CO2H, or an ester or amide derivative thereof;
Q is oxygen; or Q is sulfur or disulfide, or an oxidized derivative thereof; n is an integer from 1 to 3;
R1 is hydrogen or Ci-C6 alkyl;
R2 is hydrogen, alkyl, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl, or a substiruent selected from the group consisting Of -CO2R8 and -CONR8R8 , where R8 and R8' are each independently selected from hydrogen and alkyl;
R3 is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl; and
R5 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, and optionally substituted aminoalkyl.
4. The method of any one of claims 1 to 3 wherein R1 is hydrogen or methyl.
5. The method of any one of claims 1 to 3 wherein R1 is hydrogen.
6. The method of any one of claims 1 to 3 wherein R2 is hydrogen or methyl.
7. The method of any one of claims 1 to 3 wherein R2 is hydrogen.
8. The method of any one of claims 1 to 3 wherein R3 is selected from the group consisting of:



wherein R10 and R11 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, triphenylmethoxy, and the like; and R12 is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted aryloyl, and the like.
9. The method of claim 8 wherein R3 is selected from the group consisting of:

10. The method of claim 8 wherein R 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 any one of claims 1 to 3 wherein R4 is selected from the group consisting of:



wherein Y an electron withdrawing group, and R is hydrogen, halo, alkyl, or alkoxy.
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 any one of claims 1 to 3 wherein R is optionally substituted arylalkyl or optionally substituted arylalkenyl.
17. The method of any one of claims 1 to 3 wherein R4 is is arylalkyl or arylalkenyl.
18. The method of any one of claims 1 to 3 wherein R4 is arylalkenyl.
19. The method of any one of claims 1 to 3 wherein A is -CO2R5; where R5 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(C1-C4 alkyl), and R6R7N-(C2-C4 alkyl); where R6 and R7 are each independently selected in each instance, where R6 is selected from the group consisting of hydrogen or alkyl; and R7 is selected from the group consisting of alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R6 and R7 are taken together with the attached nitrogen atom to form an optionally substituted heterocycle.
20. The method of claim 19 wherein the optionally substituted heterocycle 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 hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aryloyl.
21. The method of claim 2 wherein the stereochemistry at C(ά) is (S).
22. The method of claim 3 wherein the stereochemistry at C(θ!) is (R).
23. The method of claim 2 wherein n is 1 or 2.
24. The method of claim 2 wherein n is 2.
25. The method of claim 3 wherein n is 1 or 2.
26. The method of claim 3 wherein n is 1.
27. The method of claim 2 wherein A is an amide of a primary amine
28. The method of claim 27 wherein the primary amine is an optionally substituted arylalkylamine.
29. The method of claim 27 wherein the primary amine is an optionally substituted arylmethyl, 1 -arylalkyl, or 2-arylalkyl, where aryl is selected from the group consisting of fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

30. The method of claim 27 wherein the primary amine is an optionally substituted arylcycloalkylamine, where aryl is selected from the group consisting of fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
31. The method of claim 27 wherein the primary amine is an optionally substituted 1-arylcyclopropylamine, 1-arylcyclopentylamine, 2-arylcyclopentylamine,

1-arylcyclohexylamine, or 2-arylcyclohexylamine, where aryl is selected from the group consisting of fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
32. The method of claim 27 wherein the primary amine is an optionally substituted partially hydrogenated bicyclic aromatic amine.
33. The method of claim 27 wherein the primary amine is an optionally substituted indanylamine, tetrahydronaphthylamine, tetrahydroquinoline, or
tetrahydroisoquinoline.
34. The method of claim 2 wherein A' is an amide of an optionally substituted morpholine, pyrrolidine, piperidine, piperazine, homopiperazine, or quinuclidine.
35. The method of claim 2 wherein A1 is an amide of 2-substituted pyrrolidine, 3 -substituted pyrrolidine, 4-substituted piperazine, 4-substituted piperidine, or 4-substituted homopiperazine, where said substituents are selected from the group consisting of alkyl, cycloaklyl, pyrrolidinyl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidinyl, piperdin-4-yl, and piperazinyl.
36. The method of claim 2 wherein A1 is an amide of an optionally substituted primary alkylamine, heterocyclylamine, or heterocyclylalkylamine.
37. The method of claim 3 wherein A is an amide of an optionally substituted morpholine, pyrrolidine, piperidine, piperazine, homopiperazine, or quinuclidine.
38. The method of claim 3 wherein Q is oxygen or sulfur.
39. The method of claim 3 wherein Q is oxygen.
40. The method of any one of claims 1 to 3 wherein the disease state is selected from the group consisting of anxiety, depression, obsesive-compulsive disorder, and impulsivity.

41. The method of any one of claims 1 to 3 wherein the disease state is anxiety.
42. The method of any one of claims 1 to 3 wherein the disease state is depression.
43. The method of any one of claims 1 to 3 wherein the disease state is a stress-related affective illness.