Aromatic compounds, compositions containing them and their use i

Details Aromatic compounds, compositions containing them and their use i Aromatic compounds, compositions containing them and their use i

1995-08-21

1997-10-07

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514415, 548495, 548496, 548506, 548507, A61K 31405, C07D20910, C07D20914

Patent

active

056748892

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of PCT/EN94/00438, filed Feb. 15, 1994.
This invention relates to a class of heterocyclic compounds, which are useful as tachykinin receptor antagonists.
The tachykinins are a group of naturally-occurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in the peripheral nervous and circulatory systems. The structures of three known mammalian tachykinins are as follows:
Substance P:
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2
Neurokinin A:
His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH.sub.2
Neurokinin B:
Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH.sub.2
Substance P is believed inter alia to be involved in the neurotransmission Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS (December 1987) 8 506-510!, specifically in the transmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem, 547-549!. These peptides have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract such as inflammatory bowel in "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific al., Eur. J. Pharmacol., (1993) 250, R5-R6!. It is also hypothesised that there is a neurogenic mechanism for arthritis in which substance P may in The Lancet, 11 November 1989 and Gronblad et al "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10!. Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid (1990) 33 1023-8!. Other disease areas where tachykinin antagonists are Science (1988) 241 1218-21 and Kimball et al, J. Immunol. (1988) 141 (10) 3564-9!, vasodilation, bronchospasm, reflex or neuronal control of the al, Science (1990) 250, 279-82!, in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.
Tachykinin antagonists may also be useful in the treatment of small cell Cancer Research (1992) 52, 4554-7!.
Substance P may also play a role in demyelinating diseases such as multiple poster presented at C.I.N.P. XVIIIth Congress, 28th Jun 2nd Jul., 1992! and in disorders of bladder function such as bladder detrusor hyper-reflexia (Lancet, 16th May, 1992, 1239).
It has furthermore been suggested that tachykinins have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythmatosis (European patent specification no. 0 436 334), ophthalmic disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (European patent specification no. 0 394 989).
In view of their metabolic instability, peptide derivatives are likely to be of limited utility as therapeutic agents. It is for this reason that non-peptide tachykinin receptor antagonists are sought.
In essence, this invention provides a class of potent non-peptide tachykinin receptor antagonists. By virtue of their non-peptide nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
The present invention provides a compound of formula (I), or a salt or prodrug thereof: ##STR2## wherein Q.sup.1 represents a phenyl group substituted by one or more halo, optionally substituted naphthyl, optionally substituted indolyl, optionally subst

REFERENCES:
patent: 5328927 (1994-07-01), Lewis et al.
patent: 5472978 (1995-12-01), Baker et al.
Vaught JF. Life Science. 43 (18) 1419-1431. 1988.

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