Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1997-09-05
1999-02-16
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562457, 562621, 560 13, 560 24, 560 43, C07C22900, C07C30300, C07C26100
Patent
active
058722815
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a sulfur or oxygen-containing amino acid derivative in which an N,N-dialkylaminophenyl group is introduced into a side chain, and which has inhibitory activity on leukotriene A.sub.4 hydrolase, and is useful as a medicine such as an agent for treating inflammatory diseases such as rheumatic diseases, psoriasis, inflammatory intestinal diseases, gout and cystic fibrosis.
BACKGROUND TECHNIQUES
Leukotriene A.sub.4 (hereinafter, abbreviated as LTA.sub.4) hydrolase, which is one of the epoxide hydrolase, is a metal-containing enzyme which requires zinc in an active center.
LTA.sub.4 hydrolase plays a catalyst-like role on biochemical conversion from LTA.sub.4 into leukotriene B.sub.4 (hereinafter, abbreviated as LTB.sub.4), which is a strong pro-inflammatory substance.
LTB.sub.4 is arachidonic acid metabolitc which is produced in 5-lipoxygenase pathway, biosynthesized in various cells including mast cell, neutrophil, monocyte, macrophage and the like, and plays a role as an important mediator in inflammation. LTB.sub.4 induces chemotaxis, coagulation and degranulation of leukocyte and accumulation of polymorphonuclear leukocyte, and accelerates blood vessel permeability and edema formation. For this reason, it was reported that particularly high level of LTB.sub.4 was detected in lesion parts in inflammatory diseases such as rheumatic diseases (J. Clin. Invest., 66, 116-117 (1980)), psoriasis (Br. J. Pharmacol., 83, 313-317 (1984)), inflammatory bowel diseases (Gastroenterology, 86, 453-460 (1984)) and gout (Lancet, 2, 1122-1124 (1982)) and in sputum in cystic fibrosis (Lancet, 342, 465-469 (1993)).
Therefore, compounds which inhibit LTA.sub.4 hydrolase arc expected to prevent production of LTB.sub.4 and manifest therapeutic effects on inflammatory diseases.
3-Oxiranyl benzoic acid and a derivative thereof were reported to have LTA.sub.4 hydrolase inhibitory activity and be useful as an agent for treating inflammatory diseases such as psoriasis, inflammatory intestinal diseases, arthritis and gout (JP-A 2-134375).
In addition, (+)-1-(3S, was reported to have LTA.sub.4 hydrolase inhibitory activity and inhibit sideration of arthritis in a collagen-induced arthritis model (J. Med. Chem., 37, 3197-3199 (1994)).
On the other hand, the structural features of the present invention is in amino acid having a sulfur or oxygen atom in which the sulfur or oxygen atom is bonded with (N,N-dialkylaminophenyl)alkyl, and an amino group is bonded to a sulfur-containing acyl group. From a viewpoint of the chemical structure, the prior art will be described below.
Compounds in which a phenyl group is introduced on a side chain of a sulfur-containing amino acid derivative was reported to be useful as a therapeutic agent for rheumatoid diseases and a hypotensive agent (JP-A 61-165362), because the compounds have rheumatoid factor's inactivating activity and angiotensin converting enzyme inhibitory activity, and also have endopeptidase 24.11 inhibitory activity (J. Med. Chem., 37, 2461-2476 (1994). However, a phenyl ring in amino acid side chain in the compounds described in these reports is not substituted and, thus, there is no description on compounds in which a substituent is introduced in a phenyl ring.
As described above, although various studies were done on sulfur-containing amino acid derivatives having a non-substituted phenyl ring on a side chain, no study has been done yet on sulfur-containing and oxygen-containing amino acid derivatives in which an N,N-dialkylamino group is introduced on its phenyl ring. Thus, a study regarding synthesis of the above compounds and a study regarding their pharmacological activities, particularly, activities on LTA.sub.4 hydrolase were very interesting themes.
DISCLOSURE OF THE INVENTION
The present inventors aimed at a phenyl ring on a side chain of an amino acid derivative, and performed synthesis of compounds represented by the N,N-dialkylamino group introduced on the phenyl ring and salts thereof (hereinafter, referred to as the
REFERENCES:
patent: 4362738 (1982-12-01), Keck et al.
patent: 5061710 (1991-10-01), Haslanger et al.
patent: 5292926 (1994-03-01), Morita et al.
Database Caplus, No. 95:61792, DE 2926471 Krueger et al., `Aminobenzoic acid derivatives for use as pharmaceuticals or intermediatee products.` abstracts, Nov. 15, 1981.
Horiuchi Masato
Kawashima Yoichi
Davis Brian J.
Geist Gary
Santen Pharmaceutical Co. Ltd.
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