Tricyclic benzodiazepines as vasopressin receptor antagonists

• US 7,317,005 B2
• Filed: 02/10/2004
• Issued: 01/08/2008
• Est. Priority Date: 01/19/1999
• Status: Expired due to Fees

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Inventors: Dyatkin, Alexey B., Maryanoff, Bruce E., Hoekstra, William J., Matthews, Jay M.
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US10/775,675
• Publication Number:
  US 20040242866A1
• Time in Patent Office: 1,428 Days
• Field of Search: 514/220, 540/497, 540/559
• US Class Current: 514/220
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

The invention is directed to tricyclic benzodiazepines useful as vasopressin receptor antagonists for treating conditions involving increased vascular resistance and cardiac insufficiency. Pharmaceutical compositions comprising tricyclic benzodiazepines of the present invention and methods of treating conditions such as hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention are also disclosed.

Claims

1. A solid oral dosage form comprising

(a) a compound of the formula (I) or (II):

2. The solid oral dosage form of claim 1 wherein “

HET”

of formula II is selected from the group consisting of thiophene, furan, pyrrole and pyridine;

A is —

C(O)—

;

Ar is naphthyl, wherein naphthyl is optionally substituted with from one to four substituents independently selected from trifluoromethyl, trifluoromethoxy, —

NH—

C₁–

C₄ alkyl and —

N—

(C₁–

C₄ alkyl)₂ (wherein the alkyl groups on the amino may be the same or different);

R₂ is NR₄COAr;

R₄ is selected from the group consisting of hydrogen and methyl.

3. The solid oral dosage form of claim 1 wherein R₄ is hydrogen.

4. The solid oral dosage form of claim 1 wherein the compound is of formula (III):

5. The solid oral dosage form of claim 4 wherein Y is selected from the group consisting of CH₂ and CH as part of an olefin;

X is selected from the group consisting of CH₂, CH as part of an olefin, O and S;

with the proviso that if Y is CH as part of an olefin, then X is CH as part of an olefin;

A is —

C(O)—

;

Z is CH;

Ar is phenyl, wherein phenyl is optionally substituted with from one to four substituents independently selected from C₁–

C₈ alkyl, C₁–

C₈ alkoxy, fluorinated C₁–

C₈ alkyl, fluorinated C₁–

C₈ alkoxy, C₁–

C₈ aralkyl (wherein optionally the alkyl or aryl portions are independently substituted and the alkyl portion may be substituted with at least one fluorine and/or the aryl portion may be independently substituted with from one to two substituents selected from halogen, C₁–

C₄ alkyl, C₁–

C₆ alkylthio and hydroxyl), C₁–

C₈ aralkoxy (wherein optionally the alkoxy or aryl portions are independently substituted and the alkoxy portion may be substituted with at least one fluorine and/or the aryl portion may be independently substituted with from one to two substituents selected from halogen, C₁–

C₄ alkyl, C₁–

C₆ alkylthio and hydroxyl), halogen, cyano, hydroxy, amino, nitro, C₁–

C₈ alkylamino, C₁–

C₄ dialkylamino (wherein the alkyl groups on the amino may be the same or different), (halo)_1-3(C₁–

C₈)alkylthio, C₁–

C₈ alkylsulfonyl, C₁–

C₈ alkylthio, C₁–

C₈ alkylsulfinyl, heteroaryl (optionally substituted with one to two substituents independently selected from C₁–

C₈ alkyl) and phenyl (optionally substituted with from one to two substituents independently selected from C₁–

C₄ alkyl, C₁–

C₄ alkoxy, fluorinated C₁–

C₄ alkyl, fluorinated C₁–

C₄ alkoxy, halogen, cyano, hydroxy, amino, nitro, C₁–

C₄ alkylamino, C₁–

C₄ dialkylamino (wherein the alkyl groups on the amino may be the same or different), C₁–

C₄ alkylsulfonyl, C₁–

C₄ alkylthio, and C₁–

C₄ alkylsulfinyl);

and (b) a pharmaceutically acceptable carrier.

34. The solid oral dosage form of claim 1 selected from the group consisting of

10-[4-[[(2-Biphenyl)carbonyl]amino]benzoyl]-10,11-dihydro-5H-piperidino[2,1-c][1,4]benzodiazepine;

10-[4-[[(2-Biphenyl)carbonyl]amino]benzoyl]-10,11-dihydro-5H-(tetrahydropyridino)[2,1-c][1,4]benzodiazepine;

(RS)-2-Phenyl-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(S)-2-(4-Hydroxyphenyl)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(S)-2-Phenyl-4-hydroxy-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(S)-2-(3-Hydroxyphenyl)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(S)-2-Phenyl-5-hydroxy-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-2-thienyl)-4-fluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2,6-Dimethyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2,3-Dimethyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-phenyl)-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(R)-2-Phenyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methoxy-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[2-methoxy-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2,3,4,5-Tetrafluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Chloro-5-trifluoromethyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Fluoro-3-chloro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(Difluoromethylthio)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[2-hydroxy-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-hydroxy-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12h)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-phenyl)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-N-[3-methyl-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-phenyl)-N-[3-methyl-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methyl-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-phenyl)-N-[3-fluoro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(8-methoxy-1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(8-fluoro-1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(9-chloro-1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(8,9-difluoro-1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(8-methyl-1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(8-chloro-1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-chloro-4-(8-fluoro-1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(10-methyl-1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-3,5-Dimethyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Iodo-3-methyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-3,5-Dichloro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-3-iodo-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(2-Fluoro-phenyl)-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(S)-2-Phenyl-N-[3-dimethylamino-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

and pharmaceutically acceptable salts thereof.

36. A method of treating a condition selected from hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

37. The method of claim 36, wherein the condition is congestive heart failure.

38. The method of claim 36, wherein the therapeutically effective amount of the compound is about 0.1 to about 300 mg/kg/day.

45. The solid dosage form of claim 34 wherein the compound is (S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide and pharmaceutically acceptable salts thereof.

6. A solid oral dosage form comprising (a) a compound of the formula (IV):

7. The solid oral dosage form of claim 6 wherein the carrier is selected from the group consisting of diluents, granulating agents, lubricants, binders, glidants, and disintegrating agents.

27. The solid oral dosage form of claim 6 wherein R₆ is selected from the group consisting of hydrogen, C₁–

C₄ alkyl, C₁–

C₄ alkoxy, phenyl (wherein the phenyl is optionally substituted with from one to two substituents independently selected from the group consisting of C₁–

C₄ alkyl, C₁–

C₄ alkoxy, fluorinated C₁–

C₄ alkyl, fluorinated C₁–

C₄ alkoxy, halogen, cyano, hydroxy, amino, nitro, C₁–

C₄ alkylamino, C₁–

C₄ dialkylamino (wherein the alkyl groups on the amino may be the same or different), C₁–

C₄ alkylsulfonyl, C₁–

C₄ alkylthio and C₁–

C₄ alkylsulfinyl);

heteroaryl (optionally substituted with one to two substituents independently selected from the group consisting of C₁–

C₄ alkyl and halogen), heteroaryl(C₁–

C₈)alkyl (wherein the heteroaryl portion is optionally substituted with one to two substituents independently selected from C₁–

C₈ alkyl), (halo)_1-3(C₁–

C₄)alkylthio and halogen.

28. The solid oral dosage form of claim 6 wherein R₆ is selected from the group consisting of hydrogen, C₁–

C₄ alkyl, phenyl (optionally substituted with from one to two substituents independently selected from the group consisting of C₁–

C₄ alkyl, C₁–

C₄ alkoxy, halogen and hydroxy), heteroaryl (optionally substituted with one to two substituents independently selected from C₁–

C₄ alkyl), (halo)_1-3(C₁–

C₄)alkylthio and halogen.

29. The solid oral dosage form of claim 6 wherein R₆ is selected from the group consisting of hydrogen, methyl, phenyl (optionally substituted with from one to two substituents independently selected from the group consisting of methyl, methoxy, fluorine and hydroxy), thienyl (optionally substituted with methyl), difluoromethylthio, fluorine, chlorine and iodine.

30. The solid oral dosage of claim 6 wherein R₇ is one to three substituents independently selected from the group consisting of hydrogen, fluorine, chlorine, iodine, hydroxy, C₁–

C₆ alkyl, C₁–

C₆ alkoxy and fluorinated C₁–

C₆ alkyl.

31. The solid oral dosage form of claim 6 wherein R₇ is one to three substituents independently selected from the group consisting of hydrogen, fluorine, chlorine, iodine, hydroxy, C₁–

C₄ alkyl, C₁–

C₄ alkoxy and fluorinated C₁–

C₄ alkyl.

32. The solid oral dosage form of claim 6 wherein R₇ is one to three substituents independently selected from the group consisting of hydrogen, fluorine, chlorine, iodine, hydroxy, C₁–

C₂ alkyl, C₁–

C₂ alkoxy and fluorinated C₁–

C₂ alkyl.

33. The solid oral dosage form of claim 6 wherein R₇ is one to three substituents independently selected from the group consisting of hydrogen, fluorine, chlorine, iodine, hydroxy, methyl, methoxy and trifluoromethyl.

42. A method of treating a condition selected from hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 6.

43. The method of claim 42, wherein the condition is congestive heart failure.

44. The method of claim 42, wherein the therapeutically effective amount of the compound is about 0.1 to about 300 mg/kg/day.

8. A solid oral dosage form comprising (a) a compound of formula (IVa):

9. The solid oral dosage form of claim 8 wherein the carrier is selected from the group consisting of diluents, granulating agents, lubricants, binders, glidants, and disintegrating agents.

10. A solid oral dosage form comprising (a) a compound of formula (I):

11. The solid oral dosage form of claim 10 wherein the carrier is selected from the group consisting of diluents, granulating agents, lubricants binders, glidants, and disintegrating agents.

12. The solid oral dosage form of claim 10 wherein A is —

C(O)—

.

13. The solid oral dosage form compound of claim 10 wherein Z is CH.

14. The solid oral dosage form of claim 10 wherein R₁ is one to two substituents independently selected from the group consisting of hydrogen, C₁–

C₄ alkyl, C₁–

C₄ alkoxy, and halogen.

15. The solid oral dosage from of claim 10 wherein R₁ is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, chlorine, and fluorine.

16. The solid oral dosage from of claim 10 wherein Ar is phenyl optionally substituted with from one to four substituents independently selected from the group consisting of C₁–

C₈ alkyl, C₁–

C₈ alkoxy, fluorinated C₁–

C₈ alkyl, fluorinated C₁–

C₈ alkoxy, C₁–

C₈ aralkyl (wherein the alkyl portion is optionally substituted with at least one fluorine and the aryl portion is optionally substituted with from one to two substituents independently selected from the group consisting of halogen, C₁–

C₄ alkyl, C₁–

C₆ alkylthio and hydroxy), C₁–

C₈ aralkoxy (wherein the alkoxy portion is optionally substituted with at least one fluorine and the aryl portion is optionally substituted with from one to two substituents independently selected from the group consisting of halogen, C₁–

C₄ alkyl, C₁–

C₆ alkylthio and hydroxy), halogen, cyano, hydroxy, amino, nitro, C₁–

C₈ alkylamino, C₁–

C₄ dialkylamino (wherein the alkyl groups on the amino may be the same or different), C₁–

C₈ alkylsulfonyl, C₁–

C₈ alkylthio, (halo)_1-3(C₁–

C₈)alkylthio, C₁–

C₈ alkylsulfinyl, heteroaryl (optionally substituted with one to two substituents independently selected from the group consisting of C₁–

C₈ alkyl and halogen), heteroaryl(C₁–

C₈)alkyl (wherein the heteroaryl portion is optionally substituted with one to two substituents independently selected from C₁–

C₈ alkyl) and phenyl (optionally substituted with from one to two substituents independently selected from the group consisting of C₁–

C₄ alkyl, C₁–

C₄ alkoxy, fluorinated C₁–

C₄ alkyl, fluorinated C₁–

C₄ alkoxy, halogen, cyano, hydroxy, amino, nitro, C₁–

C₄ alkylamino, C₁–

C₄ dialkylamino (wherein the alkyl groups on the amino may be the same or different), C₁–

C₄ alkylsulfonyl, C₁–

C₄ alkylthio and C₁–

C₄ alkylsulfinyl).

17. The solid oral dosage form of claim 10 wherein Ar is phenyl optionally substituted with from one to four substituents independently selected from the group consisting of C₁–

C₈ alkyl, C₁–

C₈ alkoxy, fluorinated C₁–

C₈ alkyl, halogen, hydroxy, (halo)_1-3(C₁–

C₈)alkylthio, heteroaryl (optionally substituted with one to two substituents independently selected from the group consisting of C₁–

C₈ alkyl and halogen) and phenyl (optionally substituted with from one to two substituents independently selected from the group consisting of C₁–

C₄ alkyl, C₁–

C₄ alkoxy, halogen and hydroxy).

18. The solid oral dosage from of claim 10 wherein Ar is phenyl optionally substituted with from one to four substituents independently selected from the group consisting of C₁–

C₄ alkyl, C₁–

C₄ alkoxy, fluorinated C₁–

C₄ alkyl, halogen, hydroxy, (halo)_1-3(C₁–

C₄)alkylthio, heteroaryl (optionally substituted with one to two substituents independently selected from the group consisting of C₁–

C₄ alkyl and halogen) and phenyl (optionally substituted with from one to two substituents independently selected from the group consisting of C₁–

C₄ alkyl, C₁–

C₄ alkoxy, halogen and hydroxy).

19. The solid oral dosage from of claim 10 wherein Ar is phenyl optionally substituted with from one to four substituents independently selected from the group consisting of C₁–

C₄ alkyl, C₁–

C₄ alkoxy, fluorinated C₁–

C₄ alkyl, halogen, hydroxy and (halo)_1-3(C₁–

C₄)alkylthio, heteroaryl (optionally substituted with one to two substituents independently selected from the group consisting of C₁–

C₄ alkyl and halogen) and phenyl (optionally substituted with from one to two substituents independently selected from the group consisting of C₁–

C₄ alkyl, C₁–

C₄ alkoxy, halogen and hydroxy).

20. The solid oral dosage form of claim 10 wherein R₂ is selected from the group consisting of NR₄COAr, NR₄CO-heteroaryl, NR₄Ar, CH═

CH—

Ar, CF═

CH—

Ar, CH═

CF—

Ar, CCl═

CH—

Ar, CH═

CCl—

Ar, CH═

CH-heteroaryl, CF═

CH-heteroaryl, CH═

CF-heteroaryl, —

CCl═

CH-heteroaryl, CH═

CCl-heteroaryl and NR₄CH₂Ar.

21. The solid oral dosage form of claim 10 wherein R₂ is selected from NR₄COAr.

22. The solid oral dosage form of claim 10 wherein R₂ is selected from NHCOAr.

23. The solid oral dosage of claim 10 wherein R₃ is selected from the group consisting of hydrogen, acyl, C₁–

C₈ alkyl, ar(C₁–

C₈)alkyl, C₁–

C₈ alkoxycarbonyl, C₁–

C₈ alkylsulfonyl, fluorinated(C₁–

C₈) alkyl and arylsulfonyl.

24. The solid oral dosage of claim 10 wherein R₃ is selected from the group consisting of hydrogen, acyl, C₁–

C₄ alkyl, ar(C₁–

C₄)alkyl and trifluoro(C₁–

C₄)alkyl.

25. The solid oral dosage form of claim 10 wherein R₃ is selected from the group consisting of hydrogen, formyl, methyl, isopropyl, benzyl and trifluoroethyl.

26. The solid oral dosage form of claim 10 wherein R₅ is one to two substituents independently selected from the group consisting of hydrogen, methyl, methoxy, chlorine, fluorine, hydroxy, dimethylamino and trifluoromethyl.

35. The solid oral dosage form of claim 10 selected from the group consisting of

(RS)-2-(3-Thienyl)-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(3-Thienyl)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(3-Thienyl)-N-[3-fluoro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(2-Thienyl)-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-2-thienyl)-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-2-thienyl)-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(1,3,4,12a-tetrahydro-2,2-dioxo-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(1,3,4,12a-tetrahydro-2-benzyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(1,3,4,12a-tetrahydro-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(1,3,4,12a-tetrahydro-2-formyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-isopropyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2,3-Dimethyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2,6-Dimethyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-phenyl)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methoxy-phenyl)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(3-Methoxy-phenyl)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-fluoro-4-(1,3,4, 12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[2-methoxy-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-,Methyl-phenyl)-N-[2-methoxy-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-phenyl)-N-[3-trifluoromethyl-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-phenyl)-N-[2-methyl-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-N-[3-methoxy-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methoxy-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methyl-phenyl)-N-[3-methoxy-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-N-[4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methyl-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-(2,2,2-trifluoroethyl)-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2,3,4,5-Tetrafluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-5-fluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-3-chloro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2,3-Dichloro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2,6-Dichloro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-5-fluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-3-fluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-5-fluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-4-fluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-fluoro-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methyl-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methoxy-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-hydroxy-4-(1,3,4,12a-tetrahydro-6H-[1,4]thiazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Methyl-5-fluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-5-fluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(4-Methoxy-phenyl)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-(3-Methoxy-phenyl)-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-4-fluoro-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-4-methoxy-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

(RS)-2-Phenyl-5-methoxy-N-[3-chloro-4-(1,3,4,12a-tetrahydro-6H-[1,4]oxazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide;

and pharmaceutically acceptable salts thereof.

39. A method of treating a condition selected from hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 10.

40. The method of claim 39, wherein the condition is congestive heart failure.

41. The method of claim 39, wherein the therapeutically effective amount of the compound is about 0.1 to about 300 mg/kg/day.

46. The solid dosage form of claim 35 wherein the compound is (RS)-2-Phenyl-N-[3-chloro-4-(1,3,4,12a-tetrahydro-2-methyl-6H-[1,4]pyrazino[4,3-a][1,4]-benzodiazepin-11(12H)-yl-carbonyl)phenyl]benzamide and pharmaceutically acceptable salts thereof.