Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-02
2002-12-03
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S211090, C540S523000, C540S552000
Reexamination Certificate
active
06489321
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel nonpeptide substituted vasopressin receptor antagonists. More particularly, the compounds of the present invention interrupt the binding of the peptide hormone vasopressin to its receptors and are therefore useful for treating conditions involving increased vascular resistance and cardiac insufficiency.
BACKGROUND OF THE INVENTION
Vasopressin is a nonpeptide 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 could be useful as therapeutics in the conditions of hypertension, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, and water retention.
SUMMARY OF THE INVENTION
The present invention is directed to compounds represented by the following formula I:
wherein
R
1
is selected from —COOH, formyl, o-mesylate, —SO
2
OH, alkoxysulfonyl, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, —NR
4
R
5
, —OH, cyano, N-morpholino, alkoxy, aralkoxy, alkylcarbamoyl, substituted alkylcarbamoyl, alkoxycarbonyl, substituted alkoxycarbonyl, —NHCOR
6
and —CONR
7
R
8
, wherein
R
4
, R
5
, R
6
, and R
8
are independently selected from the group consisting of H, alkyl, and aryl;
A is S, SO or SO
2
;
X is CH
2
or carbonyl;
Z is CH
2
, SO
2
or carbonyl, with the proviso that X is not CH
2
when Z is CH
2
;
B is (CH
2
)
m
, NH or O;
W is aryl, substituted aryl, heteroaryl or substituted heteroaryl;
R
2
is —N(H)YR
3
or —YN(H)R
3
wherein Y is H or carbonyl;
R
3
is H, alkyl, substituted alkyl, aryl or substituted aryl;
m is 1-3;
n is 1-5; and
p is 0 or 1.
The compounds of the present invention are vasopressin receptor antagonists useful as aquaretics and, in general, in disease states of vascular resistance.
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.
An example of the invention is a method of treating congestive heart failure 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.
Another example of the invention is a method of inhibiting the onset of a condition of vascular resistance in the subject, which comprises administering to the subject a prophylactically effective dose of the pharmaceutical composition of a compound of Formula I.
Further exemplifying the invention is the method of treating congestive heart failure, wherein the therapeutically effective amount of the compound is about 1 to about 30 mg/kg/day.
Still further exemplifying the invention is the method of inhibiting the onset of congestive heart failure, wherein the prophylactically effective amount of the compound is about 1 to about 30 mg/kg/day.
An additional illustration 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 and ischemia, stroke, thrombosis, or water retention 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. Preferably, the therapeutically effective amount of the compound administered for treating any of these conditions is about 1 to about 30 mg/kg/day.
Also included in the invention is the use of any of the compounds described above for the preparation of a medicament for treating a condition selected from inner ear disorders, 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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides nonpeptide substituted benzothiazepine compounds which are useful as antagonists of vasopressin. More particularly, the compounds of Formula I inhibit the binding of vasopressin to V-1 and V-2 receptors, and are therefore useful in treating conditions with increased vascular resistance. Examples of conditions with increased vascular resistance include, but are not limited to, congestive heart failure, edema, water retaining states, and the like. More particularly, the present invention is directed to compounds of Formula I:
wherein
R
1
is selected from —COOH, formyl, o-mesylate, —SO
2
OH, alkoxysulfonyl, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, —NR
4
R
5
, —OH, cyano, N-morpholino, alkoxy, aralkoxy, alkylcarbamoyl, substituted alkylcarbamoyl, alkoxycarbonyl, substituted alkoxycarbonyl, —NHCOR
6
and —CONR
7
R
8
, wherein
R
4
, R
5
, R
6
, R
7
, and R
8
are independently selected from the group consisting of H, alkyl, and aryl;
A is S, SO or SO
2
;
X is CH
2
or carbonyl;
Z is CH
2
, SO
2
or carbonyl, with the proviso that X is not CH
2
when Z is CH
2
;
B is (CH
2
)
m
, NH or O;
W is aryl, substituted aryl, heteroaryl or substituted heteroaryl;
R
2
is —N(H)YR
3
or —YN(H)R
3
wherein Y is H or carbonyl;
R
3
is H, alkyl, substituted alkyl, aryl or substituted aryl;
m is 1-3;
n is 1-5; and
p is 0 or 1.
The nonpeptide substituted benzodiazepine compounds of the present invention are vasopressin receptor antagonists, in a preferred embodiment, the compounds are orally active. As demonstrated by the results of the pharmacological studies described hereinafter, the compounds show the ability to block vasopressin binding to recombinant V-1 and V-2, and therefore are useful as therapeutics in or prophylactics against the conditions of hypertension, congestive heart failure/cardiac insuffi
Chen Robert H. K.
Urbanski Maud J.
Kifle Bruck
Ortho-McNeil Pharmaceutical , Inc.
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