Endothelin receptor antagonists

Details Endothelin receptor antagonists Endothelin receptor antagonists

1995-06-02

2001-08-07

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S362000, C549S427000, C549S436000, C549S438000, C549S439000, C549S441000, C549S444000

Reexamination Certificate

active

06271399

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel indane and indene derivatives, pharmaceutical compositions containing these compounds and their use as endothelin receptor antagonists.
Endothelin (ET) is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists as three isoforms, ET-1, ET-2 and ET-3. [Unless otherwise stated “endothelin” shall mean any or all of the isoforms of endothelin]. Endothelin has profound effects on the cardiovascular system, and in particular, the coronary, renal and cerebral circulation. Elevated or abnormal release of endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of cardiovascular, cerebrovascular, respiratory and renal pathophysiology. Elevated levels of endothelin have been reported in plasma from patients with essential hypertension, acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis.
In vivo, endothelin has pronounced effects on blood pressure and cardiac output. An intravenous bolus injection of ET (0.1 to 3 nmol/kg) in rats causes a transient, dose-related depressor response (lasting 0.5 to 2 minutes) followed by a sustained, dose-dependent rise in arterial blood pressure which can remain elevated for 2 to 3 hours following dosing. Doses above 3 nmol/kg in a rat often prove fatal.
Endothelin appears to produce a preferential effect in the renal vascular bed. It produces a marked, long-lasting decrease in renal blood flow, accompanied by a significant decrease in GFR, urine volume, urinary sodium and potassium excretion. Endothelin produces a sustained antinatriuretic effect, despite significant elevations in atrial natriuretic peptide. Endothelin also stimulates plasma renin activity. These findings suggest that ET is involved in the regulation of renal function and is involved in a variety of renal disorders including acute renal failure, cyclosporine nephrotoxicity, radio contrast induced renal failure and chronic renal failure.
Studies have shown that in vivo, the cerebral vasculature is highly sensitive to both the vasodilator and vasoconstrictor effects of endothelin. Therefore, ET may be an important mediator of cerebral vasospasm, a frequent and often fatal consequence of subarachnoid hemorrhage.
ET also exhibits direct central nervous system effects such as severe apnea and ischemic lesions which suggests that ET may contribute to the development of cerebral infarcts and neuronal death.
ET has also been implicated in myocardial ischemia (Nichols et al.
Br. J. Pharm.
99:597-601, 1989 and Clozel and Clozel,
Circ. Res.,
65:1193-1200, 1989) coronary vasospasm (Fukuda et al.,
Eur. J. Pharm.
165:301-304, 1989 and Lüscher,
Circ,
83:701, 1991) heart failure, proliferation of vascular smooth muscle cells, (Takagi,
Biochem
&
Biophys. Res. Commun.;
168:537-543, 1990, Bobek et al.,
Am. J. Physiol.
258:408-C415, 1990) and atherosclerosis, (Nakaki et al.,
Biochem
. &
Biophys. Res. Commun.
158:880-881, 1989, and Lerman et al.,
New Eng. J. of Med.
325:997-1001, 1991). Increased levels of endothelin have been shown after coronary balloon angioplasty (Kadel et al., No. 2491
Circ.
82:627, 1990).
Further, endothelin has been found to be a potent constrictor of isolated mammalian airway tissue including human bronchus (Uchida et al.,
Eur J. of Pharm.
154:227-228 1988, LaGente,
Clin. Exp. Allergy
20:343-348, 1990; and Springall et al.,
Lancet,
337:697-701, 1991). Endothelin may play a role in the pathogenesis of interstitial pulmonary fibrosis and associated pulmonary hypertension, Glard et al., Third International Conference on Endothelin, 1993, p. 34 and ARDS (Adult Respiratory Distress Syndrome), Sanai et al., Supra, p. 112.
Endothelin has been associated with the induction of hemorrhagic and necrotic damage in the gastric mucosa (Whittle et al.,
Br. J. Pharm.
95:1011-1013, 1988); Raynaud's phenomenon, Cinniniello et al.,
Lancet
337:114-115, 1991); Crohn's Disease and ulcerative colitis, Munch et al,
Lancet
, Vol. 339, p. 381; Migraine (Edmeads, Headache, February 1991 p 127); Sepsis (Weitzberg et al.,
Circ. Shock
33:222-227, 1991; Pittet et al.,
Ann. Surg.
213:262-264, 1991), Cyclosporin-induced renal failure or hypertension (
Eur. J. Pharmacol.,
180:191-192, 1990,
Kidney Int,
37:1487-1491, 1990) and endotoxin shock and other endotoxin induced diseases (
Biochem. Biophys. Res. Commun.,
161:1220-1227, 1989,
Acta Physiol. Scand.
137:317-318, 1989) and inflammatory skin diseases, (
Clin Res.
41:451 and 484, 1993) and macular degeneration.
Endothelin has also been implicated in preclampsia of pregnancy. Clark et al.,
Am. J. Obstet. Gynecol
, March 1992, p. 962-968; Kamor et al.,
N. Eng. J. of Med
., Nov. 22, 1990, p. 1486-1487; Dekker et al.,
Eur J. Ob. and Gyn. and Rep. Bio.
40 (1991) 215-220; Schiff et al.,
Am. J. Obstet. Gynecol
. February 1992, p. 624-628; diabetes mellitus, Takahashi et al.
,Diabetologia
(1990) 33:306-310; and acute vascular rejection following kidney transplant, Watschinger et al.,
Transplantation
Vol. 52, No. 4, pp. 743-746.
Endothelin stimulates both bone resorption and anabolism and may have a role in the coupling of bone remodeling. Tatrai et al
Endocrinology
, Vol. 131, p. 603-607.
Endothelin has been reported to stimulate the transport of sperm in the uterine cavity, Casey et al.,
J. Clin. Endo and Metabolism
, Vol. 74, No. 1, p. 223-225, therefore endothelin antagonists may be useful as male contraceptives. Endothelin modulates the ovarian/menstrual cycle, Kenegsberg,
J. of Clin. Endo. and Met.
, Vol. 74, No. 1, p. 12, and may also play a role in the regulation of penile vascular tone in man, Lau et al.,
Asia Pacific J. of Pharm.,
1991, 6:287-292 and Tejada et al.,
J. Amer. Physio. Soc.
1991, H1078-H1085. Endothelin also mediates a potent contraction of human prostatic smooth muscle, Langenstroer et al.,
J. Urology
, Vol. 149, p. 495-499.
Thus, endothelin receptor antagonists would offer a unique approach toward the pharmacotherapy of hypertension, renal failure, ischemia induced renal failure, sepsis-endotoxin induced renal failure, prophylaxis and/or treatment of radio-contrast induced renal failure, acute and chronic cyclosporin induced renal failure, cerebrovascular disease, myocardial ischemia, angina, congestive heart failure, asthma, atherosclerosis, macular degeneration, Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, endotoxin shock, endotoxin induced multiple organ failure or disseminated intravascular coagulation, cyclosporin-induced renal failure and as an adjunct in angioplasty for prevention or treatment of restenosis, diabetes, preclampsia of pregnancy, bone remodeling, kidney transplant, male contraceptives, infertility and priaprism and benign prostatic hypertrophy.
SUMMARY OF THE INVENTION
This invention comprises indane and indene derivatives represented by Formula (I) and pharmaceutical compositions containing these compounds, and their use as endothelin receptor antagonists which are useful in the treatment of a variety of cardiovascular and renal diseases including but not limited to: hypertension, acute and chronic renal failure, cyclosporine induced nephrotoxicity, stroke, cerebrovascular vasospasm, myocardial ischemia, angina, heart failure, atherosclerosis, and as an adjunct in angioplasty for prevention of restenosis and benign prostatic hypertrophy.
This invention further constitutes a method for antagonizing endothelin receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are represented by structural Formula (I):
wherein:
R
1
is —X(CH
2
)
n
Ar or —X(CH
2
)
n
R
8
or
R
2
is hydrogen, Ar, C
1-4
alkyl or (c);
P
1
is —X(CH
2
)
n
R
8
;
P
2
is —X(CH
2
)
n
R
8
, or —X—R
9
—Y;
R
3
and R
5
are independently hydrogen, R
11
, OH, C
1-8
alkoxy, S(O)
q
R
11
, N(R
6
)
2
,

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