Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-16
2001-05-22
Ramsuer, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S872000
Reexamination Certificate
active
06235735
ABSTRACT:
BACKGROUND OF THE INVENTION
Analgesia has historically been achieved in the central nervous system by opiates and analogs which are addictive, and peripherally by cyclooxygenase inhibitors that have gastric side effects. Substance P antagonists may induce analgesia both centrally and peripherally. In addition, substance P antagonists are inhibitory of neurogenic inflammation.
The neuropeptide receptors for substance P (neurokinin-1; NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow,
Pharmacol. Rev.,
1983, 5, 85-141). The NK-1 and NK-2 receptor subtypes are implicated in synaptic transmission (Laneuville et al.,
Life Sci.,
42: 1295-1305 (1988)).
The receptor for substance P is a member of the superfamily of G protein-coupled receptors. This superfamily is an extremely diverse group of receptors in terms of activating ligands and biological functions. In addition to the tachykinin receptors, this receptor superfamily includes the opsins, the adrenergic receptors, the muscarinic receptors, the dopamine receptors, the serotonin receptors, a thyroid-stimulating hormone receptor, a luteinizing hormone-choriogonadotropic hormone receptor, the product of the oncogene ras, the yeast mating factor receptors, a Dictyostelium cAMP receptor, and receptors for other hormones and neurotransmitters (see A. D. Hershey, et al.,
J. Biol. Chem.,
1991, 226, 4366-4373).
Substance P (also called “SP” herein) is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH
2
. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nonmenclature designates the receptors for SP, neurokinin A, and neurokinin B as NK-1, NK-2, and NK-3, respectively. More specifically, substance P is a neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence (Chang et al.,
Nature New Biol.
232, 86 (1971); D. F. Veber et al., U.S. Pat. No. 4,680,283).
Substance P is a pharmacologically-active neuropeptide that is produced in mammals and acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R. C. A. Frederickson et al.,
Science,
199, 1359 (1978); P. Oehme et al.,
Science,
208, 305 (1980)) and plays a role in sensory transmission and pain perception (T. M. Jessell,
Advan. Biochem. Psychopharmacol.
28, 189 (1981)). For example, substance P is believed to be involved in the neurotransmission of~pain sensations [Otsuka et al, “Role of Substance P 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,
8 506-510 (Dec. 1987)], specifically in the transmission of pain in migraine (see B. E. B. Sandberg et al.,
Journal of Medicinal Chemistry,
25, 1009 (1982); M. A. Moskowitz,
Trends Pharmacol. Sci.,
13, 307-311 (1992)), and in arthritis (Levine, et al.
Science
226 547-549 (1984); M. Lotz, et al,
Science,
235, 893-895 (1987)). Tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease [see Mantyh et al,
Neuroscience,
25 (3), 817-37 (1988) and D. Regoli in “Trends in Cluster Headache” Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (1987)], and emesis [
Trends Pharmacol. Sci.,
9, 334-341 (1988), F. D. Tatersall, et al.,
Eur. J. Pharmacol.,
250, R5-R6 (1993)].
It is also hypothesized that there is a neurogenic mechanism for arthritis in which substance P may play a role [Kidd et al., “A Neurogenic Mechanism for Symmetric Arthritis” in
The Lancet, Nov.
11, 1989 and Gronblad et al., “Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis” in
J. Rheumatol.
15(12) 1807-10 (1988)]. Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis [O'Byrne et al.,
Arthritis and Rheumatism,
33 1023-8 (1990)].
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 Chrohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyperreflexia is reviewed in “Tachykinin Receptors and Tachykinin Receptor Antagonists,” C. A. Maggi, R. Patacchini, P. Rovero and A. Giachetti,
J. Auton. Pharmacol,
13, 23-93 (1993); see also R. M. Snider, et al.,
Chem. Ind.,
11, 792-794 (1991). Neurokinin-1 receptor antagonists alone or in combination with bradykinin receptor antagonists may also be useful in the prevention and treatment of inflammatory conditions in the lower urinary tract, especially cystitis [Giuliani, et al.,
J. Urology,
150, 1014-1017 (1993)]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al.,
Can. J. Pharmacol. Physiol.,
66, 1361-7 (1988)], immunoregulation [Lotz, et al.,
Science,
241 1218-21 (1988), Kimball, et al.,
J. Immunol.,
141 (10) 3564-9 (1988); A. Perianin, et al.,
Biochem. Biophys. Res Commun.
161, 520 (1989)], post-operative pain and nausea [C. Bountra, et al.,
Eur. J. Pharmacol.,
249, R3-R4 (1993), F. D. Tattersall, et al.,
Neuropharmacology,
33, 259-260 (1994)], vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al.,
PNAS,
85, 3235-9 (1988)] and, possibly by arresting or slowing &bgr;-amyloid-mediated neurodegenerative changes [Yankner et al.,
Science,
250, 279-82 (1990)] in senile dementia of the Alzheimer type, Alzheimer's disease and Downs Syndrome. Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod, et. al., poster C.I.N.P. XVIIIth Congress, Jun. 28, Jul. 2, 1992], and in disorders of bladder function such as bladder detrusor hyper-reflexia [
Lancet, May
16, 1992, 1239]. Antagonists selective for the neurokinin-1 (NK-1) and/or the neurokinin-2 (NK-2) receptor may be useful in the treatment of asthmatic disease (Frossard et al.,
Life Sci.,
49, 1941-1953 (1991); Advenier, et al.,
Biochem. Biophys. Res. Comm.,
184(3), 1418-1424 (1992); P. Barnes, et al.,
Trends Pharmacol. Sci.,
11, 185-189 (1993)). Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) [Langdon et al.,
Cancer Research,
52, 4554-7 (1992)].
It has furthermore been suggested that tachykinin receptor antagonists have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina
Chambers Mark Stuart
Dorn Conrad P.
Finke Paul E.
Hale Jeffrey J
Harrison Timothy
Merck & Co. , Inc.
Ramsuer Robert
Rose David L.
Thies J. Eric
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