Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-09-30
1999-01-19
Shah, Mukund
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514256, 514297, 544238, 544255, 544336, A01N 4358, C07D23900, C07D40100, C07D24100
Patent
active
058614010
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel nitrogen derivatives 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.sup.21 -Val.sup.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 are described certain N-(isoxazolyl)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 out hereinafter, together with the other chemical formulae indentified by Roman numerals) wherein and are independently selected from hydrogen, (1-6C)alkyl, halogeno(1-6C)alkyl, (1-6C)alkoxy, dihalogeno(1-6C)alkoxy, trihalogeno(1-6C)alkoxy, (2-6C)alkenyloxy, (1-4C)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)alk
REFERENCES:
patent: 5270313 (1993-12-01), Burri et al.
patent: 5292740 (1994-03-01), Burri et al.
patent: 5302718 (1994-04-01), Agback et al.
patent: 5420129 (1995-05-01), Breu et al.
patent: 5464853 (1995-11-01), Chan et al.
patent: 5514691 (1996-05-01), Chan et al.
patent: 5668137 (1997-09-01), Phillips et al.
R.D. Desai et al., "Studies in Sulphonamides: Part II. Preparation of N.sup.1 -Heterocyclic Substituted Sulphonamides from Alpha-naphthylamine and Evaluation of their Antibacterial Properties", Jour. Indian Chem. Soc., pp. 115-118, vol. 46, No. 2, 1969.
R.D. Desai et al., "Studies in Sulphonamides: Part IV. Some N.sup.6 -Heterocyclic Sulphonamides from 2-Naphthylamine as possible Antibacterial Agents", J. Indian Chem. Soc., pp. 411-414, vol. 46, No. 5, 1969.
P. Mamalis et al., "142. Some Heterocyclic N-Oxides", J. Chem. Soc., pp. 703-705, 1950.
Chemical Abstracts, vol. 84, No. 15, 1976, 84:100672y.
Chemical Abstracts, vol. 100, No. 15, 1984, 100:131420t.
Chemical Abstracts, vol. 106, No. 17, 1987, 106:133792p (corresponds to JP61257960).
Himel et al., "Fluorescent Analogs of Insecticides and Synergists. Synthesis and Reactions of Active-Site-Directed Fluorescent Probes", Journal Agr. Food Chem., vol. 19, No. 6, 1971, pp. 1175-1180.
Shigehara et al., "Preparation of Pyridine Derivatives and their Salts as Phospholipase A.sub.2 Inhibitors", Chemical Abstracts, vol. 122, No. 25, 1995, 122:314455g.
STN Printout identifying compounds disclosed in PCT 90-009787 and Japan 61-257960.
The Discovery of Sulfonamide Endothelin Antagonists and the Development of the Orally Active ET.sub.A Antagonist 5-(Dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesul fonamide, Journal of Medicinal Chemistry, Feb. 4, 1994, vol. 37, No. 3, pp. 329-331.
Identification of a New Class of ET.sub.A Selective Endothelin Antagonists by Pharmacophore Directed Screening, Biochemical and Biophysical Research Communications, May 30, 1994, vol. 201, No. 1, pp. 228-234.
Pharmacological Characterization of Bosentan, a New Potent Orally Active Nonpeptide Endothelin Receptor Antagonist, Journal Pharmacol. Exp. Therap., 1994, 270, 228-235.
Pages copied from a book of abstracts provided in an International Business Communications Conference entitled "Endothelin Inhibitors--Advances in Therapeutic Application and Development", Philadelphia, PA, Jun. 9-10, 1994, 33 pages.
Ngo Tamthom T.
Shah Mukund
Zeneca Limited
LandOfFree
N-heterocyclyl sulphonamide derivatives and their use as endothe does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with N-heterocyclyl sulphonamide derivatives and their use as endothe, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N-heterocyclyl sulphonamide derivatives and their use as endothe will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1246850