Pyridazine endothelin antagonists

Details Pyridazine endothelin antagonists Pyridazine endothelin antagonists

2001-09-12

2003-12-30

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S238000

Reexamination Certificate

active

06670362

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pyridazine derivatives useful in the treatment of a variety of conditions mediated by endothelin and to pharmaceutical formulations containing such compounds useful for the treatment of human and non-human mammals.
BACKGROUND
Endothelin (ET) is a potent vasoconstrictor synthesized and released by endothelial cells. There are three distinct isoforms of ET: ET-1, ET-2 and ET-3, all being 21-amino acid peptides and herein the term ‘endothelin’ refers to any or all of the isoforms. Two receptor subtypes, ET
A
and ET
B
have been pharmacologically defined (see for example H. Arai et al.,
Nature,
348, 730, 1990) and further subtypes have recently been reported. Stimulation of ET
A
promotes vasoconstriction and stimulation of ET
B
receptors causes either vasodilation or vasoconstriction. The main effects of ET are observed in the cardiovascular system, particularly in the coronary, renal, cerebral and mesenteric circulation, and the effects of endothelin are often long-lasting. Stimulation of ET receptors also mediate further biological responses in cardiovascular and non-cardiovascular tissues such as cell proliferation and matrix formation.
Increased circulating levels of endothelin have been observed in patients who have undergone percutaneous transluminal coronary angioplasty (PTCA) (A. Tahara et al.,
Metab. Clin. Exp.,
1991, 40,1235) and ET-1 has been found to induce neointimal formation in rats after balloon angioplasty (S. Douglas et al.,
J. Cardiovasc. Pharm.,
1993, 22 (Suppl 8), 371). The same workers have found that an endothelin antagonist, SB-209670, causes a 50% reduction in neointimal formation relative to control animals (S. Douglas et al.,
Circ. Res.,
1994, 75). Antagonists of the endothelin receptor may thus be useful in preventing restenosis post PTCA. The ET
A/B
receptor antagonist Bosentan reportedly decreased blood pressure in hypertensive patients (H. Krum et al.,
New Eng. J. Med.,
1998, 338, 784-790). Antagonists of ET
B
receptors such as BQ-788 have been demonstrated to increase peripheral resistance in man (
Hypertension,
1999, 33, 581-585). Thus ET
A
-selective receptor antagonists are of benefit in hypertension.
Endothelin-1 is produced in the human prostate gland and endothelin receptors have been identified in this tissue (Y. Saita et al.,
Eur. J. Pharmacol.,
1988, 349,123-128). Since endothelin is a contractile and proliferative agent, endothelin antagonists are useful in the treatment of benign prostate hypertrophy.
There is widespread localization of endothelin and its receptors in the central nervous system and cerebrovascular system (R. K. Nikolov et al.,
Drugs of Today,
1992, 28(5), 303) with ET being implicated in cerebral vasospasm, cerebral infarcts, septic shock, myocardial infarction and neuronal death.
Elevated levels of endothelin have also been observed in patients with: recurrent airway obstruction (
Pulm. Pharm. Ther.,
1998, 11: 231-235); asthma (
Am. J. Resp. Crit. Care Med.,
1995, 151:1034-1039); acute renal failure (K. Tomita, et al.,
Med. Philos.,
1994, 13(1), 64-66); chronic renal failure (F. Stockenhuber et al.,
Clin. Sci.
(Lond.), 1992, 82, 255); ischemic Heart Disease (M. Yasuda,
Am. Heart J.,
1990, 119, 801); stable or unstable angina (J. T. Stewart,
Br. Heart J.,
1991, 66, 7); pulmonary hypertension (D. J. Stewart et al.,
Ann. Internal Medicine,
1991, 114, 464); congestive heart failure (R. J. Rodeheffer et al.,
Am. J. Hypertension,
1991, 4, 9A); preeclampsia (B. A. Clark et al.,
Am. J. Obstet. Gynecol.,
1992, 166, 962); diabetes (A. Collier et al.,
Diabetes Care,
1992, 15 (8), 1038); Crohn's disease (S. H. Murch et al.,
Lancet,
1992, 339, 381); and atherosclerosis (A. Lerman et al.,
New Eng. J. Med.,
1991, 325, 997).
In every case the disease state associated with the physiologically elevated levels of endothelin is potentially treatable with a substance which decreases the effect of endothelin, such as an endothelin receptor antagonist, or a compound which binds endothelin such that it reduces the effective concentration thereof at the endothelin receptors.
Compounds that antagonise the ET
A
receptor to a greater extent than the ET
B
receptor are preferred as ET
A
receptors are predominantly present in vascular smooth muscles. Blockade of ET
B
receptor activation may reverse endothelial dependent vasodilation which is beneficial in hypertension. ET may also mediate regeneration of damaged tissue via the ET
B
receptor, such as proximal tubule cells in the kidney. Thus blockade of ET
B
receptors, e.g. with a non-selective ET antagonist could inhibit tissue repair. ET
B
receptors are also involved in the clearance of ET from the systemic circulation. Increased levels of ET are generally considered detrimental. Rises in circulating levels have been observed with non-selective ET antagonists. Treatment with selective ET
A
receptor antagonists are not likely to induce such rises in circulating levels.
There are a number of publications relating to N-(pyrimidin-4-yl) sulfonamide derivatives having endothelin binding/antagonist activity, for example EP-A-0743307, EP-A-0658548, EP-A-0633259, EP-A-0882719, WO-A-96/20177, EP-A-0801062, WO-A-97/09318, EP-A-0852226, EP-A-0768304, WO-A-96/19459, WO-A-98/03488, EP-A-0601386, EP-A-0510526 and EP-A-0713875.
Various N-4-pyrimidinyl sulfonamide derivatives possessing endothelin antagonist activity are described in JP-A-09059160, JP-A-10194972 and JP-A-10226649.
International Patent Application publication number WO-A-96/19455 discloses phenyl and pyridin-4-yl sulfonamides as endothelin antagonists.
SUMMARY OF THE INVENTION
According to the present invention, there are provided compounds of formula (I)
wherein
R
1
is (CR
7
R
8
)
n
—(C
3
-C
8
)cycloalkyl, (CR
7
R
8
)
n
—heterocycle, (CR
7
R
8
)
n
-(benzofused heterocycle), (CR
7
R
8
)
n
-aryl, NR
9
R
10
, (CR
7
R
8
)
n
-heteroaryl, and (CR
7
R
8
)
n
-(benzofused heteroaryl), where R
7
and R
8
are each independently H or (C
1
-C
6
)alkyl, R
9
and R
10
are each independently H or (C
1
-C
6
)alkyl optionally substituted by aryl, heterocycle, benzofused heterocycle, heteroaryl, benzofused heteroaryl, or (C
3
-C
8
)cycloalkyl, and n is 2, 3, 4, 5, or 6;
R
2
is (a) phenyl optionally fused with a heterocycle, benzofused heterocycle, heteroaryl, or benzofused heteroaryl, (b) naphthyl optionally fused with a heterocycle, benzofused heterocycle, heteroaryl, or benzofused heteroaryl, or (c) heteroaryl or benzofused heteroaryl, where groups (a), (b) and (c) are optionally substituted by (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, halo, unsubstituted heterocycle, unsubstituted benzofused heterocycle, unsubstituted heteroaryl, unsubstituted benzofused heteroaryl, phenyl, naphthyl, CO
2
R
11
, OC(O)R
11
, CONR
11
R
12
, or S(O)
p
R
11
, where p is 0, 1, or 2, and R
11
and R
12
are each independently H or (C
1
-C
6
)alkyl;
R
3
is (e) (C
1
-C
6
)alkyl, (f) (C
2
-C
6
)alkenyl, (g) (C
2
-C
6
)alkynyl, or (h) (C
3
-C
8
)cycloalkyl, where groups (e), (f), (g) and (h) are optionally substituted by OR
11
, halo, NHC(O)(C
1
-C
6
)alkyl, O-heterocycle, O-(benzofused heterocycle), O-heteroaryl, O-(benzofused heteroaryl), OC(O)NH-heterocycle, OC(O)NH-(benzofused heterocycle), OC(O)NH-heteroaryl, OC(O)NH-(benzofused heteroaryl), NH
2
, NHC(O)O-heteroaryl, NHC(O)O-(benzofused heteroaryl), NHC(O)NH-heteroaryl, or NHC(O)NH-(benzofused heteroaryl);
X is O, NH, a direct link, or S(O)
p
, where p is 0, 1 or 2;
Y is O, NH, or S(O)
p
, where p is 0, 1 or 2; and
R
4
, R
5
and R
6
are each independently selected from the group consisting of H, halo, heterocycle, benzofused heterocycle, heteroaryl, benzofused heteroaryl, aryl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkyl optionally substituted by halo, OR
9
or NH
2
, and S(O)
p
R
9
, where p is 0, 1 or 2;
a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, a solvate or the compound, salt or prodrug, or a polymorph of the compound, salt, prodrug, or solvate. Processes for making compounds of formula (I) and key

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