Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-12
2004-07-20
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S577000
Reexamination Certificate
active
06765004
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel tricyclic vasopressin receptor antagonists. By interrupting the binding of the peptide hormone vasopressin to its receptors, the antagonists are useful for treating conditions involving increased vascular resistance and cardiac insufficiency.
BACKGROUND OF THE INVENTION
Vasopressin is a nonapeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through the vascular V-1 and renal V-2 receptor subtypes. The functions of vasopressin include contraction of uterine, bladder and smooth muscle; stimulation of glycogen breakdown in the liver; release of corticotropin from the anterior pituitary; induction of platelet aggregation; and central nervous system modulation of behaviors and stress responses. The V-1 receptor mediates the contraction of smooth muscle and hepatic glycogenolytic and central nervous system effects of vasopressin. The V-2 receptor, presumably found only in the kidney, effects the antidiuretic actions of vasopressin via stimulation of adenylate cyclase.
Elevated plasma vasopressin levels appear to play a role in the pathogenesis of congestive heart failure (P. A. Van Zwieten,
Progr. Pharmacol. Clin. Pharmacol
. 1990, 7, 49). As progress toward the treatment of congestive heart failure, nonpeptide vasopressin V-2 receptor antagonists have induced low osmolality aquaresis and decreased peripheral resistance in conscious dogs with congestive heart failure (H. Ogawa,
J. Med. Chem
. 1996, 39, 3547). In certain pathological states, plasma vasopressin levels may be inappropriately elevated for a given osmolality, thereby resulting in renal water retention and hyponatremia. Hyponatremia, associated with edematous conditions (cirrhosis, congestive heart failure, renal failure), can be accompanied by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Treatment of SIADH-compromised rats with a vasopressin V-2 antagonist has corrected their existing hyponatremia (G. Fujisawa,
Kidney Int
. 1993, 44(1), 19). Due in part to the contractile actions of vasopressin at its V-1 receptor in the vasculature, vasopressin V-1 antagonists have reduced blood pressure as a potential treatment for hypertension as well.
Thus, vasopressin receptor antagonists are useful as therapeutics for 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.
SUMMARY OF THE INVENTION
The present invention is directed to compounds represented by the following general formula (I):
wherein:
A is selected from C(O), SO
2
or CH
2
; preferably, A is C(O);
a represents a single or double bond;
X is selected from hydrogen, halogen, acyl, C
1
-C
10
alkyl, arC
1
-C
10
alkyl, C
1
-C
10
alkylsulfonyl, arylsulfonyl, C
1
-C
10
alkylaminoC
1
-C
6
alkyl, SO
3
H or ═O when a is a single bond; preferably, X is hydrogen, SO
3
H, or ═O;
Y is selected from hydrogen, C
1
-C
6
alkyl, arC
1
-C
6
alkyl, C
1
-C
6
alkylcarbonyl, C
1
-C
6
alkoxycarbonyl, arylcarbonyl, C
1
-C
6
alkylsulfonyl, arylsulfonyl,
C
1
-C
6
alkylaminocarbonyl; preferably, Y is hydrogen;
Z is selected from N or CH;
R
1
is selected from hydrogen, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, halogen, amino C
1
-C
10
alkyl or nitro;
R
2
is selected from hydrogen, NR
3
COAr, NR
3
CO-heteroaryl, NR
3
Ar, 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, OCH
2
—Ar, OCH
2
-heteroaryl or NR
3
CH
2
Ar; wherein the Ar group may be unsubstituted or substituted with one to three substituents independently selected from C
1
-C
10
alkyl, C
1
-C
10
alkoxy, fluorinated C
1
-C
10
alkyl, fluorinated C
1
-C
10
alkoxy, halogen, cyano, hydroxy, amino, nitro, C
1
-C
10
alkylamino, or unsubstituted, mono-, di- or tri-substituted phenyl, wherein the substituents on the phenyl are independently selected from C
1
-C
10
alkyl, C
1
-C
10
alkoxy, fluorinated C
1
-C
10
alkyl, fluorinated C
1
-C
10
alkoxy, halogen, cyano, hydroxy, amino, nitro, C
1
-C
10
alkylamino, or heteroaryl; and wherein the heteroaryl group may be unsubstituted or substituted with one to three substituents independently selected from C
1
-C
10
alkyl, halogen, aryl, heteroaryl, C
1
-C
10
alkoxy, C
1
-C
10
alkylamino, arylamino, nitro or hydroxy; preferably, R
2
is NR
3
COAr; more preferably, R
2
is NHCOAr wherein the Ar group is phenyl substituted with unsubstituted, mono-substituted or di-substituted phenyl wherein the substituents on the phenyl are independently selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy, fluorinated C
1
-C
4
alkyl, fluorinated C
1
-C
4
alkoxy, halogen, cyano, hydroxy, amino, nitro, C
1
-C
4
alkylamino, or heteroaryl; most preferably,
R
2
is NHCOAr wherein the Ar group is substituted phenyl wherein the substituent on the phenyl is selected from phenyl or tolyl;
R
3
is selected from hydrogen or C
1
-C
10
alkyl; preferably, R
3
is hydrogen or methyl; more preferably, R
3
is hydrogen; and,
R
4
is selected from hydrogen, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, halogen, fluorinated C
1
-C
10
alkyl (e.g., trifluoromethyl) or fluorinated C
1
-C
10
alkoxy (e.g., trifluoromethoxy);
and pharmaceutically acceptable salts thereof.
Exemplifying the invention is the compound of formula (I) selected from:
6-[4-[[(4′-Methyl-2-biphenyl-)carbonyl]amino]benzoyl]-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indole;
6-[4-[[(2-Methyl-3-furanyl)carbonyl]amino]benzoyl]-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indole;
6-[4-[[(4′-Methyl-2-biphenyl-)carbonyl]amino]benzoyl]-1-methyl-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indole;
6-[4-[[(4′-Methyl-2-biphenyl-)carbonyl]amino]benzoyl]-1-acetyl-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indole;
6-[4-[[(2-Biphenyl-)carbonyl]amino]benzoyl]-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indole;
6-[4-[[(2-Biphenyl-)carbonyl]amino]benzoyl]-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]-2-indolone;
6-[4-[[(2-Biphenyl-)carbonyl]amino]benzoyl]-2-chloro-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indole;
6-[4-[[(2-Biphenyl-)carbonyl)amino]benzoyl]-2-(N,N-dimethylaminomethyl)-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indole;
6-[4-[[(2-Biphenyl-)carbonyl]amino]benzoyl]-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indole-2-sulfonic acid; or,
6-[4-[[(2-Biphenyl-)carbonyl]amino]2-chlorobenzoyl]-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indole-2-sulfonic acid;
and pharmaceutically acceptable salts thereof.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Illustrating the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
Exemplifying the invention is a method of treating a condition mediated by a vasopressin receptor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
An example of the invention is 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
Greco Michael N.
Hecker Leonard R.
Hoekstra William J.
Maryanoff Bruce E.
Matthews Jay M.
Coleman Brenda
Ortho-McNeil Pharmaceutical , Inc.
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