Spiro-substituted azacyclic derivatives and their use as therape

Details Spiro-substituted azacyclic derivatives and their use as therape Spiro-substituted azacyclic derivatives and their use as therape

1997-01-07

1998-09-22

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546 17, A61K 31445, C07D40104

Patent

active

058114319

DESCRIPTION:

BRIEF SUMMARY
This application is 371 of PCT/GB95/08167 which is now published as WO 96/05203 on Feb. 22, 1995.
This invention relates to a class of spiro-substituted azacyclic compounds, which are useful as tachykinin antagonists. More particularly, the compounds of the invention comprise an azacyclic ring system spiro-substituted by an indolyl moiety and a substituted serine derived moiety.
The tachykinins are a group of naturally occurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in peripheral nervous and circulatory systems.
At present, there are three known mammalian tachykinins referred to as substance P, neurokinin A (NKA, substance K, neuromedin L) and neurokinin B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides (1985) 6(suppl. 3), 237-242). The current nomenclature designates the three tachykinin receptors mediating the biological actions of substance P, NKA and NKB as the NK.sub.1, NK.sub.2 and NK.sub.3 receptors, respectively.
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyper-reflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists", C. A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton. Pharmacol. (1993) 13, 23-93.
For instance, substance P is believed inter alia to be involved in the as a Sensory 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 (1987) 8, 506-510!, specifically in the transmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem, 547-549!. Tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract such as inflammatory bowel disease "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Eur. J. Pharmacol., (1993) 250, R.sup.5 -R.sup.6 !. It is also hypothesised that there is a neurogenic mechanism for arthritis in which Symmetrical Arthritis" in The Lancet, 11 Nov. 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 arthritis and osteoarthritis, and fibrositis areas where tachykinin antagonists are believed to be useful are allergic al, J. Immunol. (1988) 141(10), 3564-9! vasodilation, bronchospasm, reflex and, possibly by arresting or slowing .beta.-amyloid-mediated 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 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 eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alc

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