Substituted pyrazin-2-yl-sulphonamide (-3-pyridyl) compounds...

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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C514S255060, C514S227800, C514S235500, C514S235800, C544S060000, C544S111000, C544S360000, C544S405000

Reexamination Certificate

active

06258817

ABSTRACT:

The present invention relates to novel heterocyclic compounds and, more particularly, to novel
N
-heterocyclyl sulphonamides, and pharmaceutically-acceptable salts thereof, which possess endothelin receptor antagonist activity. These compounds are of value whenever such antagonist activity is desired, such as for research tools within pharmacological, diagnostic and related studies or in the treatment of diseases or medical conditions including, but not limited to, hypertension, pulmonary hypertension, cardiac or cerebral circulatory disease and renal disease, in warm-blooded animals (including man), in which elevated or abnormal levels of endothelin play a significant causative role. The invention also relates to pharmaceutical compositions of the novel compounds (and their salts) for use in treating said diseases or medical conditions, and to processes for the manufacture of the novel compounds. The invention further relates to the use of the novel compounds in treating one or more of the said diseases or medical conditions. A method of treating one or more of the said diseases or medical conditions using said compounds is also provided.
The endothelins are a family of endogenous 21 amino acid peptides comprising three isoforms, endothelin-1, endothelin-2 and endothelin-3. The endothelins are formed by cleavage of the Trp
21
-Val
22
bond of their corresponding proendothelins by a putative endothelin converting enzyme. The endothelins are among the most potent vasoconstrictors known and have a characteristic long duration of action. They exhibit a wide range of other activities including cell proliferation and mitogenesis, extravasation and chemotaxis, and also interact with a number of other vasoactive agents. They also have direct effects on the heart. Thus the biological profile of the endothelins is consistent with a pathophysiological role in the cardiovascular system. The endothelins also have actions on other physiological systems including the airways, gastro-intestinal tract, reproductive system, kidney, liver, central nervous system, neuro-endocrine system and the blood.
The endothelins are released from a range of tissue and cell sources including vascular endothelium, vascular smooth muscle, kidney, liver, uterus, airways, intestine and leukocytes. Release can be stimulated by hypoxia, shear stress, physical injury and a wide range of hormones and cytokines. Elevated endothelin levels have been found in a number of disease states in man including hypertension, pulmonary hypertension, pre-eclampsia, congestive heart failure, myocardial infarction, angina pectoris, acute and chronic renal failure, ischaemic stroke, subarachnoid haemorrhage, atherosclerosis, hypercholesterolaemia, cardiogenic and endotoxic shock, diabetes mellitus, Raynaud's disease, scleroderma, systemic sclerosis, Buerger's disease, rheumatoid arthritis, asthma, bronchitis, acute respiratory failure, liver cirrhosis, Crohn's disease, ulcerative colitis, certain cancers and after surgery.
In European patent applications, publication nos. 558258 and 569193, and in International patent application, publication no. WO 94/27979, are described certain N-(isozaxolyl)sulphonamides and in European patent application, publication no. 640596 are described certain N-(pyridazinyl)sulphonamides, which are referred to as endothelin receptor antagonists.
Although a number of endothelin receptor antagonists are known, there is a continuing need for alternative antagonists. The present invention is based in part on this need and on our discovery of the unexpected antagonism of the endothelin receptor by certain
N
-heterocyclyl sulphonamides.
According to one aspect of the invention there is provided a compound of the formula I (set our hereinafter, together with the other chemical formulae identified by Roman numerals) wherein one of A
1
, A
2
, A
3
and A
4
is nitrogen and the remainder of A
1
, A
2
, A
3
and A are CH; Ar is a phenyl group which is unsubstituted or bears 1, 2 or 3 substituents independently selected from (1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-6C)alkyl,
N
-[(1-4C)alkyl]amino(1-6C)alkyl,
N
,
N
-[di(1-4C)alkyl]amino(1-6C)alkyl, carboxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylcarbonyloxy(1-6C)alkyl, carbamoyl(1-6C)alkyl,
N
-(1-6C)alkylcarbamoyl(1-6C)alkyl, di-
N
-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N
-(1-6C)alkylcarbamoyloxy(1-6C)alkyl, carboxy(1-6C)alkoxy, carboxy(1-6C)alkylthio, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxycarbonyl(1-6C)alkylthio, carbamoyl(1-6C)alkoxy, (1-6C)alkylcarbamoyl(1-6C)alkoxy, di(1-6C)alkylcarbamoyl(1-6C)alkoxy, carbamoyl(1-6C)alkylthio, (1-6C)alkylcarbamoyl(1-6C)alkylthio, di(1-6C)alkylcarbamoyl(1-6C)alkylthio, (2-6C)alkenyl, carboxy(2-6C)alkenyl, (2-6C)alkynyl, carboxy(2-6C)alkynyl, halogeno(2-6C)alkyl, trifluoromethyl, trichloromethyl, tribromomethyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihalogeno(1-6C)alkoxy, trihalogeno(1-6C)alkoxy, (2-6C)alkenyloxy(1-6C)alkyl, (2-6C)alkenyloxy, (1-4C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy(1-6C)alkyl, carboxy(1-6C)alkoxy(1-6C)alkyl, hydroxy(1-6C)alkoxy(1-6C)alkyl, (1-4C)alkylthio(1-6C)alkyl, (1-4C)alkylsulphinyl(1-6C)alkyl, (1-4C)alkylsulphonyl(1-6C)alkyl, (1-4C)alkylenedioxy, (3-6C)cycloalkyl, (3-8C)cycloalkyl(1-6C)alkyl, phenyl, phenyl(1-6C)alkyl, phenoxy, phenyl(1-6C)alkoxy, pyridyl(1-6C)alkoxy(1-6C)alkyl, halogeno, hydroxy, mercapto, cyano, nitro, carboxy, (1-6C)alkoxycarbonyl, (2-6C)alkenyloxycarbonyl, phenyloxycarbonyl, phenyl(1-6C)alkoxycarbonyl, (1-6C)alkanoyl, benzoyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, (1-6C)alkanoylamino, trifluoroacetyl, trifluoroacetamido,
N
-[(1-4C)alkyl]trifluoroacetamido, benzamido,
N
-[(1-4C)alkyl]benzamido, carbamoyl, (1-4C)alkylcarbamoyl, di-(1-4C)alkylcarbamoyl, phenylcarbamoyl, sulphamoyl,
N
-(1-4C)alkylsulphamoyl,
N
,
N
-di(1-4C)alkylsulphamoyl,
N
-phenylsulphamoyl, (1-6C)alkanesulphonamido, benzenesulphonamido, ureido, 3-(1-6C)alkylureido, 3-phenylureido, thioureido, 3-(1-6C)alkylthioureido, 3-phenylthioureido, a five membered heterocyclyl group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulphur, a six membered heterocyclyl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, and a group —NRaRb in which Ra and Rb are independently selected from hydrogen, (1-6C)alkyl, phenyl(1-4C)alkyl and (1-6C)alkyl bearing a carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkylcarbamoyl or di(1-6C)alkylcarbamoyl group, or the group —NRaRb taken together complete a 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 1-piperidinyl, 2-oxo-1-piperidinyl, morpholino or thiamorpholino ring;
B
1
is an optional substituent on a carbon atom of A
1
, A
2
, A
3
or A
4
selected from (1-4C)alkyl, halogeno and (1-4C)alkoxy; m is zero, 1, 2 or 3; the ring containing W, X, Y and Z and bearing substituent R
1
is selected from:
(a) a ring in which W is nitrogen; X is CH; Y is nitrogen; and Z is CRy in which Ry is hydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy or trifluoromethoxy; and substituent R
1
is hydrogen, halogeno, (1-4C)alkyl, methoxy, ethoxy, trifluoromethyl or ethynyl;
(b) a ring in which W is CRz in which Rz is hydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy or trifluoromethoxy; X is nitrogen; Y is nitrogen; and Z is CH; and substituent R
1
is halogeno, (1-4C)alkyl, methoxy, ethoxy, trifluoromethyl or ethynyl; and
(c) a ring in which W and X are both nitrogen; Y is CH; and Z is CRx in which Rx is hydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy or trifluoromethoxy; and substituent R
1
is halogeno, (1-4C)alkyl, methoxy, ethoxy, trifluoromethyl or ethynyl; and wherein any of said phenyl or benzene or heterocyclyl moieties of a substituent on Ar may be unsubstituted or bear one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano, carboxy and trifluoromethyl; or an
N
-oxide thereof; or a pharmaceutically-acceptable salt thereof.
According to a

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