Tricyclic benzodiazepines as vasopressin receptor antagonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C540S497000, C540S559000

Reexamination Certificate

active

06713475

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel tricyclic 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 nonapeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through membrane-bound V-1 and 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, nonapeptide 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 the V-1 receptor in the vasculature, vasopressin V-1 antagonists have reduced blood pressure as a potential treatment for hypertension. 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 general formulas (I) and (II):
wherein m is an integer from 0 to 1 such that “HET” in the compound of formula (II) is a stable five- or six-membered monocyclic aromatic ring system composed of carbon atoms and one heteroatom, wherein the heteroatom is selected from N, O or S which may occupy any position in the ring whereby the resulting ring system is stable; for example, thiophene, furan, pyrrole or pyridine;
A is selected from —C(O)—, SO
2
or CH
2
, preferably, A is —C(O)—;
Y is selected from CH
2
or CH as part of an olefin;
X is selected from CH
2
, CH as part of an olefin, NR
3
, S or O;
with the proviso that if Y is CH as part of an olefin, then X is CH as part of an olefin;
Z is selected from N or CH;
R
1
is one to two substituents independently selected from hydrogen, alkyl, alkoxy, halogen, aminoalkyl, oxo or nitro;
Ar is selected from naphthyl, wherein naphthyl is optionally substituted with from one to four (or one to three) substituents independently selected from C
1
-C
8
alkyl, C
1
-C
8
alkoxy, fluorinated C
1
-C
8
alkyl (preferably trifluoromethyl), fluorinated C
1
-C
8
alkoxy (preferably trifluoromethoxy), halogen, cyano, hydroxy, amino, nitro, C
1
-C
4
alkylamino (preferably —NH—C
1
-C
4
alkyl) or C
1
-C
4
dialkylamino (preferably —N—(C
1
-C
4
alkyl)
2
, wherein the alkyl groups on the amino may be the same or different); or phenyl, wherein phenyl is optionally substituted with from one to four (or one to three) substituents independently selected from C
1
-C
8
alkyl, C
1
-C
8
alkoxy, fluorinated C
1
-C
8
alkyl, fluorinated C
1
-C
8
alkoxy, C
1
-C
8
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, C
1
-C
4
alkyl, C
1
-C
6
alkylthio or hydroxyl), C
1
-C
8
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, C
1
-C
4
alkyl, C
1
-C
6
alkylthio or hydroxyl), halogen, cyano, hydroxy, amino, nitro, C
1
-C
8
alkylamino, C
1
-C
4
dialkylamino (wherein the alkyl groups on the amino may be the same or different), (halo)
1-3
(C
1
-C
8
)alkylthio, C
1
-C
8
alkylsulfonyl, C
1
-C
8
alkylthio, C
1
-C
8
alkylsulfinyl, heteroaryl (optionally substituted with one to two substituents independently selected from C
1
-C
8
alkyl) or phenyl (optionally substituted with from one to two substituents 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, C
1
-C
4
dialkylamino (wherein the alkyl groups on the amino may be the same or different), C
1
-C
4
alkylsulfonyl, C
1
-C
4
alkylthio, or C
1
-C
4
alkylsulfinyl);
R
2
is selected from NR
4
COAr, NR
4
CO-heteroaryl, NR
4
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, SCH
2
—Ar or NR
4
CH
2
Ar;
preferably, R
2
is selected from NR
4
COAr, NR
4
CO-heteroaryl, NR
4
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 or CH═CCl-heteroaryl; more preferably, R
2
is NR
4
COAr; most preferably, R
2
is NHCOAr;
R
3
is selected from hydrogen, acyl, alkyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl;
R
4
is selected from hydrogen or C
1
-C
4
alkyl; preferably, R
4
is hydrogen or methyl; most preferably, R
4
is hydrogen; and
R
5
is selected from hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, chlorine, fluorine, hydroxy, dialkylamino (wherein the alkyl groups on the amino may be the same or different), trifluoromethyl or trifluoromethoxy;
and pharmaceutically acceptable salts thereof.
The compounds of the present invention are vasopressin receptor antagonists useful as aquaretics and, in general, for treating cardiovascular disease.
In one embodiment of the present invention is a compound of the formula (III):
wherein
Y is selected from CH
2
or CH as part of an olefin;
X is selected from CH
2
, CH as part of an olefin, NR
3
, S or O;
with the proviso that if Y is CH as part of an olefin, then X is CH as part of an olefin;
R
1
is one to two substituents independently selected from hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, amino C
1
-C
4
alkyl, oxo or nitro;
R
2
is NHCOAr;
R
3
is selected from hydrogen, acyl, alkyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl; and
R
5
is selected from hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, chlorine, fluorine, hydroxy, dialkylamino (wherein the alkyl groups on the amino may be the same or different), trifluoromethyl or trifluoromethoxy;
all other variables are as defined previously; and pharmaceutically acceptable salts thereof.
In a class of the invention is a compound wherein
Y is selected from CH
2
or CH as part of an olefin;
X is selected from CH
2
, CH as part of an olefin, S or O;
with the proviso that if Y is CH

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