Substituted arylaliphatic compounds, method of preparing them an

Details Substituted arylaliphatic compounds, method of preparing them an Substituted arylaliphatic compounds, method of preparing them an

1995-11-29

1998-03-10

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546 16, 546188, 546217, 546218, 546224, C07D45302

Patent

active

057263132

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FR95/00391, Mar. 29, 1995.
The present invention relates to novel substituted arylaliphatic compounds, to a method of preparing them and to the pharmaceutical compositions in which they are present as the active principle.
More particularly, the present invention relates to a novel class of substituted arylaliphatic compounds for therapeutic use in pathological phenomena involving the tachykinin system, such as: pain (D. Regoli et al., Life Sciences, 1987, 40, 109-117), allergy and inflammation (J. E. Morlay et al., Life Sciences, 1987, 41, 527-544), circulatory insufficiency (J. Losay et al., 1977, Substance P, Von Euler, U.S. and Pernow ed., 287-293, Raven Press, New York), gastrointestinal disorders (D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50), neurological disorders and neuropsychiatric disorders (C. A. Maggi et al., J. Autonomic Pharmacol., 1993, 13, 23-93), these examples being neither limiting nor exclusive.
In recent years, numerous research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed throughout both the central nervous system and the peripheral nervous system. The tachykinin receptors have been recognized and are classified into three types: NK.sub.1, NK.sub.2, NK.sub.3. Substance P (SP) is the endogenous ligand of the NK.sub.1 receptors, neurokinin A (NK.sub.A) that of the NK.sub.2 receptors and neurokinin B (NK.sub.B) that of the NK.sub.3 receptors.
The NK.sub.1, NK.sub.2 and NK.sub.3 receptors have been identified in different species.
A recent review by C. A. Maggi et al. looks at the tachykinin receptors and their antagonists and gives an account of the pharmacological studies and the applications in human therapeutics (J. Autonomic Pharmacol., 1993, 13, 23-93).
The following non-peptide compounds may be mentioned among the antagonists specific for the NK.sub.1 receptor: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. U.S.A., 1991, 88, 10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).
For the NK.sub.2 receptor, a non-peptide selective antagonist, SR 48968, has been described in detail (Life Sciences, 1992, 50, PL101-PL106).
As far as the NK.sub.3 receptor is concerned, some non-peptide compounds have been described as having an affinity for the NK.sub.3 receptor of the rat and guinea-pig brain (FASEB J., 1993, 7 (4), A710, 4104); a peptide specificity for the NK.sub.3 receptor of the rat brain, has also been described (J. Autonomic Pharmacol., 1993, 13, 23-93).
Patent application EP-A-336230 describes peptide derivatives antagonistic towards substance P and neurokinin A which are useful for the treatment and prevention of asthma.
International patent applications WO 90/05525, WO 90/05729, WO 91/09844 and WO 91/18899 and European patent applications EP-A-0436334, EP-A-0429466 and EP-A-0430771 describe substance P antagonists.
European patent applications EP-A-0428434, EP-A-0474561, EP-A-512901, EP-A-0515240, EP-A-0559538, EP-A-591040, EP-A-0625509 and EP-A-0630887 and International patent applications WO 94/10146, WO 94/29309 and WO 94/26735 describe neurokinin receptor antagonists, all of which are characterized by the structure of the formula ##STR2## in which W is a direct bond or a methylene.
It has now been found that certain substituted arylaliphatic compounds possess valuable pharmacological properties as neurokinin receptor antagonists and are particularly useful for the treatment of any pathological condition dependent on substance P and neurokinin.
In particular, it has been found that substituted arylaliphatic compounds having the structure of formula (A) above in which W is an oxygen atom or an optionally substituted nitrogen atom possess a very high affinity for the neurokinin receptors.
Thus, according to one of its features, the present invention relates to the compounds of the formula ##STR3## in which: W.sub.1 is an oxygen atom or a group --NR--, in which R i

REFERENCES:
MacLeod et al., Journal of Medicinal Chemistry, vol. 37, No. 9, 29 Apr. 1994, 1269-1274.

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