Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-21
2003-06-03
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S407000, C544S316000, C548S368100
Reexamination Certificate
active
06573270
ABSTRACT:
This invention relates to pyrazole 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.
Endothelin (ET) is a potent vasoconstrictor synthesised 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 most likely to be 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 could be useful in the treatment of benign prostate hypertrophy.
There is widespread localisation 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 recepotors.
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)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-0801062, WO-A-97/09318, EP-A-0852226, EP-A-0768304, WO-A-96/19459, WO-A-98/03488 and EP-A-0713875.
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.
We have unexpectedly found that pyrazoles of formulae IA and IB below have good affinity for endothelin receptors, and are selective for ET
A
over ET
B
.
According to the present invention, there are provided compounds of formulae IA and IB:
Wherein
R
1
is H, C
1-6
alkyl (optionally substituted by one or more halo, OR
4
or NR
4
R
5
groups), C
2-6
alkenyl (optionally substituted by one or more halo groups), C
2-6
alkynyl (optionally substituted by one or more halo groups), C(O)R
4
, CO
2
R
4
, CH
2
aryl
4
, CONR
4
R
5
, aryl
4
or het
1
,
R
2
is C
1-6
alkyl, cyclopropylmethyl, or CH
2
CH
2
OG where G is H, C
1-6
alkyl (optionally substituted by a C
3-6
cycloalkyl group), C(O)R
4
, CONHAr
2
or Ar
2
,
R
4
and R
5
are each independently H or C
1-6
alkyl (optionally substituted by one or more halo groups),
X is a direct link O, S, SO, SO
2
, CO or CH
2
,
R
3
is
a) a C
6-14
aromatic hydrocarbon group; or
b) an optionally benzo-fused 5- or 6-membered heterocyclic group with one to three hetero-atoms atoms in the heterocyclic ring, which hetero-atoms are independently selected from N, O and S; or
c) CH
2
CH
2
Ph, CH:CHPh; or
d) C
1-6
alkyl, optionally substituted by 1-4 substituents selected from: halo, C
1-6
alkoxy, CO
2
R
4
, OC(O)R
4
and NR
4
R
5
,
each of which groups (a), (b) and (c) is optionally substituted by up to four substituents independently selected from:
i) C
1-6
alkyl, optionally substituted by 1-4 substituents selected from: halo, OR
4
, CO
2
R
4
, OC(O)R
4
and NR
4
R
5
;
ii) C
1-6
alkoxy;
iii) CO
2
R
4
and OC(O)R
4
;
Halo;
NO
2
;
vi) CN;
NR
4
R
5
;
C
1-3
alkylenedioxy;
OH;
Alkoxy carbonyl;
Ar
1
and Ar
2
are each independently aryl
5
or het
1
aryl
4
is a phenyl or naphthyl group optionally substituted by up to three substituents independently selected from C
1-3
alkyl, CF
3
, halogen, C
1-3
alkoxy, CF
1-3
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
,
aryl
5
is a phenyl, 1,3-benzodioxyl or naphthyl group optionally substituted by up to three substituents independently selected from C
1-3
alkyl, CF
3
, halogen, C
1-3
alkoxy, OCF
3
, OH, NO
2
, CN, NR
4
R
5
, C(O)R
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
Banks Bernard Joseph
Chubb Nathan Anthony Logan
Eshelby James John
Schulz Darren John
Benson Gregg C.
Lambkin Deborah C.
Pfizer Inc.
Richardson Peter C.
Samuels Lisa A.
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