Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-27
1999-09-07
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142278, 5142358, 5142372, 514255, 514318, 514349, 544 582, 544 584, 544 586, 544 60, 544123, 544131, 544295, 544319, 544360, 546193, 5462681, 5462764, 5462791, 546297, A61K 3144, C07D21364
Patent
active
059487852
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel heterocyclic amide compounds, pharmacologically acceptable salts thereof, pharmaceutical compositions thereof and pharmaceutical use thereof. More particularly, the present invention relates to pyridone- and pyrimidoneacetamide derivatives which are useful pharmacologically, diagnostically and for the prophylaxis and treatment of diseases, and pharmacologically acceptable salts thereof. The present invention also relates to intermediates necessary for the synthesis of the above-mentioned heterocyclic amide compounds.
BACKGROUND ART
Angiotensin II shows physiological activities such as vasopression by strong contraction of blood vessel, stimulation of aldosterone secretion from adrenal cortex (aldosterone retains sodium), and the like, and is considered to be a causative substance or risk factor of diseases such as hypertension, hypercardia, myocardial infarction, arteriosclerosis, diabetic and non-diabetic renal diseases, vascular restenosis after PTCA (percutaneous transluminal coronary angioplasty) and the like.
It is known that this angiotensin II is generated by cleavage of two amino acid residues from angiotensin I, which is a peptide consisting of ten amino acids present in a living body, and that angiotensin converting enzyme (ACE) is involved in said cleavage. Thus, numerous ACE inhibitors have been developed for the prophylaxis and treatment of the above-mentioned diseases.
Meanwhile, actions of a chymase group including human heart chymase, human mast cell chymase and human cutis chymase, which is one of the subfamilies of serine protease, have been drawing attention in recent years.
It has been clarified that chymase is involved in the course of generation, which is independent from ACE, of angiotensin II in the conversion of the above-mentioned angiotensin I to angiotensin II (Okunishi et al., Jpn. J. Pharmacol. 1993, 62, p. 207 etc. and others). Also, chymase is known to use, as substrates, numerous physiologically active substances such as extracellular matrix, cytokine, substance P, VIP (vasoactive intestinal polypeptide), apoprotein B and the like, and known to be responsible for the activation of other proteases such as collagenase (Igakuno Ayumi, Miyazaki et al., 1995, 172, p. 559).
Therefore, chymase inhibitors are expected to become inhibitors of angiotensin II action, as well as agents for the prophylaxis and treatment of various diseases caused by chymase, since it inhibits generation of ACE non-dependent angiotensin II. A patent application drawn to a chymase inhibitor based on these ideas has been already filed (WO93/25574).
The above-mentioned patent application WO93/25574 in the name of PFIZER INC. discloses a series of peptide compounds which are chymase (inclusive of human heart chymase) inhibitors. However, these compounds are peptide compounds which are unsatisfactory in terms of oral absorption, and no pharmacological test data are available.
Patent applications filed by ZENECA LTD. (Japanese Patent Unexamined Publication Nos. 5-286946, 6-56785 and WO93/21210), J. Med. Chem. 1994, 37, p. 3090, J. Med. Chem. 1994, 37, p. 3303, J. Med. Chem. 1994, 37, p 3313 and others disclose or report heterocyclic compounds which are human leukocyte elastase inhibitors, and these compounds are known to selectively inhibit human leukocyte elastase.
It is therefore an object of the present invention to provide novel compounds having superior chymase inhibitory activity, pharmaceutical compositions thereof and chymase inhibitors.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies in an attempt to achieve the above-mentioned objects, and found that, by modifying or converting a part of the structure of the compound disclosed by ZENECA LTD., compounds can be obtained that inhibit chymase group, inclusive of human heart chymase, with high selectivity, without inhibiting other enzymes such as human leukocyte elastase, and exhibit superior absorption and safety, which resulted in the completion of the present invention.
Acc
REFERENCES:
Journal of Hypertension 1993, vol. 11, No. 11, Nov. 1, 1993, pp. 1155-1159 "The chymase-angiotensin system in humans".
European Heart Journal, vol. 14, No. SUPPL. I, Jan. 1, 1993, pp. 177-182 "Cardiac angiotensin II formation: the angiotensin-I converting enzyme and human chymase".
Akahoshi Fumihiko
Ashimori Atsuyuki
Eda Masahiro
Fukuyama Hajime
Imada Teruaki
Coleman Brenda
Shah Mukund J.
The Green Cross Corporation
LandOfFree
Heterocyclic amide compounds and pharmaceutical use of the same does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Heterocyclic amide compounds and pharmaceutical use of the same, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heterocyclic amide compounds and pharmaceutical use of the same will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1804696