Isoxazole-sulfonamide endothelin antagonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C548S244000, C514S380000, C544S315000

Reexamination Certificate

active

06387915

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to isoxazole 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 humans 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
. 40, 1235, 1991) and ET-1 has been found to induce neointimal formation in rats after balloon angioplasty (S. Douglas et al.,
J.Cardiovasc. Pharm
., 22 (Suppl 8), 371, 1993). 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
, 75, 1994). 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
, 28(5), 303, 1992) 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.), 82, 255, 1992);
ischaemic Heart Disease (M. Yasuda,
Am. Heart J
., 119, 801, 1990);
stable or unstable angina (J. T. Stewart,
Br. Heart J
., 66, 7 1991);
pulmonary hypertension (D. J. Stewart et al.,
Ann. Internal Medicine
, 114, 464, 1991);
congestive heart failure (R. J. Rodeheffer et al.,
Am. J Hypertension
, 4, 9A, 1991);
preeclampsia (B. A. Clark et al.,
Am. J. Obstet. Gynecol
., 166, 962, 1992);
diabetes (A. Collier et al.,
Diabetes Care
, 15 (8), 1038, 1992);
Crohn's disease (S. H. Murch et al.,
Lancet
, 339, 381, 1992); and
atherosclerosis (A. Lerman et al.,
New Eng. J. Med
., 325, 997, 1991).
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 antagonize 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 is not likely to induce such rises in circulating levels.
There are a number of publications relating to N-(pyrimidin-4-yl)sulphonamide 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-15 0801062, WO-A-97/09318, EP-A-0852226, EP-A-0768304, WO-A-96/19459, WO-A-98/03488, WO-A-98/57938, WO-A-99/36408, WO-A-01/17976 and EP-A-0713875.
Various N-4-pyrimidinyl sulphonamide derivatives possessing endothelin antagonist activity are described in EP-A-0882719, JP-A-09059160, JP-A-1 0194972 and JP-A-1 0226649.
International Patent Application publication number WO-A-96/19455 discloses phenyl and pyridin-4-yl sulphonamides as endothelin antagonists.
International Patent Application publication number WO-A-97/11942 discloses various (4-arylthioisoxazol-3-yl)sulphonamides, with an aldehyde moiety linked to the 5-position of the isoxazole ring, as selective ET
B
receptor selective antagonists.
SUMMARY OF THE INVENTION
We have unexpectedly found that isoxazoles of formula (I) below have good affinity for endothelin receptors, and are selective for ET
A
over ET
B
.
wherein
R
1
is
a) a phenyl group,
b) a 5- or 6-membered heterocyclic group containing one to three heteroatoms each independently selected from the group consisting of N, O and S, said heterocyclic group being optionally fused to a benzo group,
c) CHR
6
CHR
7
Ph, or
d) CR
6
═CR
7
Ph,
 where groups (a) (b) and (c) are optionally each independently substituted with one to three substituents selected from the group consisting of halo, C
1-6
alkyl optionally substituted by OH, halogen, NR
4
R
5
, OCOR
4
, CO
2
R
4
, CN, O(C
1-6
alkyl optionally substituted by one or more halogens), and CO
2
R
4
, where R
4
and R
5
are each independently H or C
1-6
alkyl optionally substituted by one or more halo, and R
6
and R
7
are each independently H or C
1-3
alkyl;
R
2
is aryl
1
or het
1
; and
R
3
is H, C
1-6
alkyl, C(O)R
4
, CONHaryl
1
, CONHhet
1
, aryl
1
and het
1
;
where aryl
1
is a phenyl or a naphthyl group, said phenyl and said naphthyl groups being optionally substituted with one to three substituents each independently selected from the group consisting of C
1-3
alkyl, CF
3
, halo, C
1-3
alkoxy, OCF
3
, OH, NO
2
, CN, NR
4
R
5
, COR
4
, CO
2
R
4
, CONR
4
R
5
, S(O)
p
(C
1-3
alkyl), CH
2
NR
4
COR
5
, COCF
3
, CH
2
OH, S(O)
p
CF
3
, C(═NH)NH
2
, C
2-3
alkynyl, C
2-3
alkenyl, phenyl and het
2
,
het
1
is a 5- to 7-membered fully saturated, partially unsaturated, or fully unsaturated heterocyclic group containing one to three hetero-atoms each independently selected from the group consisting N, O and S, said heterocyclic group being optionally fused to a benzo group and optionally substituted with one to three substituents each independently selected from the group consisting of C
1-3
alkyl, CF
3
, halo, C
1-3
alkoxy, CF
3
O, OH, NO
2
, CN, NR
4
R
5
, COR
4
, CO
2
R
4
, CONR
4
R
5
, S(O)
p
(C
1-3
alkyl), CH
2
NR
4
R
5
, NR
4
COR
5
, COCF
3
, CH
2
OH, S(O)
p
CF
3
, C(═NH)NH
2
, C
2-3
alkynyl, C
2-3
alkenyl, phenyl and het
2
,

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