Sulfur-containing amino acid derivatives

Details Sulfur-containing amino acid derivatives Sulfur-containing amino acid derivatives

1999-03-01

2000-04-04

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514522, 514523, 514524, 514575, 558414, 560 13, 560 41, 562443, 562444, 562449, 562450, 562621, A61K 31275, C07C25533, C07C30973, C07C22906

Patent

active

060462353

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel sulfur-containing amino acid derivatives which have inhibitory effects on leukotriene A.sub.4 hydrolase and are useful as medicines such as therapeutic agents for inflammatory diseases such as rheumatic diseases, psoriasis, inflammatory bowel diseases, gout and cystic fibrosis.


BACKGROUND ART

Leukotriene A.sub.4 (hereinafter referred to as LTA.sub.4) hydrolase, which is one of epoxide hydrolases, is a metal-containing enzyme which requires zinc in its active center.
LTA.sub.4 hydrolase plays a catalyst-like role on biochemical conversion from LTA.sub.4 into leukotriene B.sub.4 (hereinafter referred to as LTB.sub.4), which is a strong pro-inflammatory substance.
LTB.sub.4 is an arachidonic acid metabolite which is produced in 5-lipoxygenase pathway, is biosynthesized in various cells including mast cell, neutrophil, monocyte, macrophage, etc., and plays a role as an important mediator in inflammation. LTB.sub.4 induces chemotaxis, aggregation and degranulation of leukocyte and accumulation of polymorphonuclear leukocyte, and accelerates blood-vessel permeability and edema formation. For this reason, it was reported that a particularly high level of LTB.sub.4 is detected at lesion sites in inflammatory diseases such as rheumatic diseases (J. Clin. Invest., 66 1166-1170 (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)).
Accordingly, compounds which inhibit LTA.sub.4 hydrolase are expected to prevent production of LTB.sub.4 and exhibit therapeutic effects on inflammatory diseases.
It was reported that 3-oxiranylbenzoic acid and derivatives thereof have inhibitory effects on LTA.sub.4 hydrolase and are useful as therapeutic agents for inflammatory diseases such as psoriasis, inflammatory bowel diseases, arthritis and gout (Japanese Laid-open Patent Publication No. 134375/1990).
It was also reported that (+)-1-(3S, 4R)-[3-(4-phenylbenzyl)-4-hydroxychroman-7-yl]cyclopentanecarboxylic acid had an inhibitory effect on LTA.sub.4 hydrolase and inhibited the onset of arthritis in a collagen-induced arthritis model (J. Med. Chem., 37, 3197-3199 (1994)).
On the other hand, structural features of the present compounds represented by the general formula [I] are that a sulfur atom of sulfur-containing amino acids such as cysteine is bonded to a substituted phenylalkyl group and an N-terminal is bonded to a sulfur-containing branched lower alkanoyl group. Prior art publications are described hereinafter from the standpoint of chemical structure. ##STR2##
The following two kinds of known compounds have similar chemical structures to those of the present compounds; compounds of which R.sup.3 is a hydrogen atom and compounds of which R.sup.4 is a benzyl group in the general formula [I]. It was reported that diastereomers of the former compounds have inhibitory effects on ACE (Chem. Pharm. Bull., 35, 2382-2387 (1987)) and optically active substances of the former compounds have inhibitory effects on ACE and inhibitory effects on endopeptidase 24.11 (J. Med. Chem., 37, 2461-2476 (1994)). It was reported that the latter compounds are useful as therapeutic agents for rheumatoid diseases and antihypertensives since they have inhibitory effects on ACE and inactivating effects on rheumatoid factors (Japanese Laid-open Patent Publication No. 165362/1986), they have inhibitory effects on endopeptidase 24.11 and are useful for treatment of hypertension (Japanese Laid-open Patent Publication No. 39855/1988), and they enhance natriuretic effects of endogenous ANF and are useful for treatment of hypertension and congestive heart failure (Japanese Laid-open Patent Publication No. 503799/1990).
However, no inhibitory effect on LTA.sub.4 hydrolase is described in the reports.
As mentioned above, various studies were carried out, focusing attention on the inhibitory effects on ACE, the inhibitory effects on e

REFERENCES:
patent: 4749688 (1988-06-01), Haslanger et al.
patent: 5061710 (1991-10-01), Haslanger et al.
patent: 5292926 (1994-03-01), Morita et al.
L. Klichstein et al, "Lipoxygenation of Arachidonic Acid as a Source of Polymorphonuclear Leukocyte Chemotactic Factors in Synovial Fluid and Tissue in Rheumatoid Arthritis and Spondyloarthritis", J. Clin. Invest., vol. 66, pp. 1166-1170, Nov. 1980.
S.D. Brain et al, "Leukotriene B.sub.4 -like material in scale of psoriatic skin lesions", Br. J. Pharmac., vol. 83, pp. 313-317, 1984.
P. Sharon et al, "Enhanced Synthesis of Leukotriene B.sub.4 by Colonic Mucosa in Inflammatory Bowel Disease", Gastroenterology, vol. 86, No. 3, pp. 453-460, 1994.
S.A. Rae et al, "Leukotriene B.sub.4, An Inflammatory Mediator in Gout", The Lancet, vol. 2, pp. 1122-1123, Nov. 20, 1982.
R. Lawrence et al, Eicosapentaenoic acid in cystic fibrosis: evidence of a pathogenetic role for leukotriene B.sub.4, The Lancet, vol. 342, pp. 465-469, Aug. 21, 1993.
K. Koch et al, "(+)-1-(3S,4R)-[3-(4-Phenylbenzyl)-4-hydroxychroman-7-yl]cyclopentane Carboxylic Acid, a Highly Potent, Selective Leukotriene B.sub.4 Antagonist with Oral Activity in the Murine Collagen-Induced Arthritis Model", J. Med. Chem., vol. 37, No. 20, pp. 3197-3199, Sep. 30, 1994.
T. Komori et al, "Sulfur-Containing Acylamino Acids. I. Synthesis and Angiotensin I Converting Enzyme-Inhibitory Activities of Sulfur-Containing N-Mercaptoalkanoyl Amino Acid", Chem. Pharm. Bull., vol. 35, No. 6, pp. 2382-2387, 1987.
B. Neustadt et al, "Mercaptoacyl Amino Acid Inhibitors of Atriopeptidase. 1. Structure-Activity Relationship Studies of Methionine and S-Alkylcysteine Derivatives", J. Med. Chem., vol. 37, No. 15, pp. 2461-2476, 1994.

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