Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-02-03
2001-02-27
Davis, Zinna Northington (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S341000, C514S352000, C514S357000, C514S337000, C514S400000, C514S419000, C514S616000, C546S265000, C546S275100, C546S277400, C546S336000, C548S338100, C548S503000, C564S155000
Reexamination Certificate
active
06194437
ABSTRACT:
BACKGROUND OF THE INVENTION
Bombesin is a 14-amino acid peptide originally isolated from the skin of the European frog Bombina bombina (Anastasi A., et a.,
Experientia,
1971;27:166). It belongs to a class of peptides which share structural homology in their C-terminal decapeptide region (Dutta A. S. Small Peptides; Chemistry, Biology, and Clinical Studies, Chapter 2, pp 66-82). At present, two mammalian bombesin-like peptides have been identified (Battey J., et a.,
TINS,
1991;14:524), the decapeptide neuromedin B (NMB) and a 23-residue amino acid, gastrin-releasing peptide (GRP). Bombesin-like immunoreactivity detected in mammalian brain (Braun M., et al.,
Life. Sci.,
1978;23:2721) and GI tract (Walsh J. H., et al.,
Fed. Proc. Fed. Am. Soc. Exp. Biol.,
1979;38:2315) together with the more recent studies measuring mRNA levels in rat brain (Battey J., et al.,
TINS,
1991;14:524), point to the widespread distribution of both NMB and GRP in mammalian peripheral and central nervous systems.
NMB and GRP are believed to mediate a variety of biological actions via actin upon the corresponding bombesin receptors including their action as autocrine growth factors in human small cell lung carcinoma and other cancers (Taylor J. E., et al.,
Ann. N.Y. Acad. Sci.,
1988;547:350; Rozengurt E., Ibid., 277; Cuttitta F., et al.,
Nature,
1985;316:823; Kozacko M. F., et al.,
Proc. Natl. Acad. Sci. USA,
1996;93:2953), secretion of other neuropeptides and hormones (Ghatei M. A., et al.,
J. Clin. Endocrinol. Metab.,
1982;54:98), contraction of smooth muscle (Erspamer V., et al.,
Pure Appl. Chem.,
1973;35:463), behavioral effects (Kulkosky P. J. et al.,
Physiol. Behav.
1982;28:505; Gmerek D. E., et al.,
Peptides,
1983;4:907; Cowan A.,
Ann. N.Y. Acad. Sci.,
1988;547:204), thermoregulation (Brown M. R., et al.,
Ann. N.Y. Acad. Sci.,
1988;547:174), effects on satiety (Kirkham T. C., et al.,
Pharma. Biochem, Behav.,
1995;52:101 and Ladenheim E. E., et al.,
Eur. J. Pharmacol.,
1994;271:R7), regulation of circadian rhythms (Albers H., et al.,
J. Neurosci.,
1991;11:846), regulation of gastric acid section (Walsh J. H.,
Ann. Rev. Physiol.,
1988;50:41) and gastrointestinal motility (see Lebacq-Verheyden A., et al., in
Handbook of Experimental Pharmacology,
1990;95 (Part II) and references therein), effects on locomotor activity and nociception (Pert A., et al.,
Brain Res.,
1980;193:209), effects on memory (Flood J. F., et al.,
Brain Res.,
1988;460:314), and interaction with 5HT-containing neurones (Pinnock R. D., et al.,
Brain Res.,
1994;653:199 and Pinnock R. D., et al.,
J. Physio.,
1991;440:55).
Accordingly, compounds capable of antagonizing the effects of NMB and/or GRP at bombesin receptors will be useful in treating or preventing a variety of disorders including depression, psychoses, seasonal affective disorders, cancer, feeding disorders, gastrointestinal disorders including colitis, Crohn's disease and inflammatory bowel disease, sleeping disorders, and memory impairment.
SUMMARY OF THE INVENTION
This invention is for compounds which are bombesin receptor antagonists. The compounds have proved to be antagonists of bombesin receptors.
The compounds of the invention are those of Formula I
or a pharmaceutically acceptable salt thereof wherein
Ar is phenyl or pyridyl unsubstituted or substituted by from 1 to 3 substitutents selected from alkyl, halogen, alkoxy, nitro, amino, NH
2
CH
2
—, cyano, CF
3
, —NHCONH
2
, and CO
2
R
1
;
R
1
is hydrogen or straight, branched, or cyclic alkyl of from 1 to 7 carbon atoms;
R
8
is hydrogen or forms a ring with R
1
of from 3 to 7 carbon atoms;
R
2
is hydrogen or straight, branched, or cyclic alkyl of from 1 to 8 carbon atoms which can also contain 1 to 2 oxygen or nitrogen atoms;
R
9
is hydrogen or forms a ring of from 3 to 7 carbon atoms with R
2
which can contain an oxygen or nitrogen atom;
Ar
1
can be independently selected from Ar and can also include pyridyl-N-oxide, indolyl, imidazole, and pyridyl;
R
4
,R
5
,R
6
, and R
7
are each independently selected from hydrogen and methyl;
R
3
can be independently selected form Ar or is hydrogen, hydroxy, NMe
2
, N-methyl-pyrrole, imidazole, tetrazole, thiazole
REFERENCES:
patent: 4000297 (1976-12-01), Rovati et al.
patent: 4518587 (1985-05-01), Laruelle et al.
patent: 4639451 (1987-01-01), Katakami et al.
patent: 4965263 (1990-10-01), Nishina et al.
patent: 5200408 (1993-04-01), Bru-Maginez et al.
patent: 5340798 (1994-08-01), Nutt et al.
patent: 5346907 (1994-09-01), Kerwin, Jr. et al.
patent: 5378803 (1995-01-01), Morgan et al.
patent: 5455262 (1995-10-01), Schwartz et al.
patent: 5470834 (1995-11-01), Schwartz et al.
patent: 5472978 (1995-12-01), Baker et al.
patent: 5495047 (1996-02-01), Van Niel et al.
patent: 5594022 (1997-01-01), Horwell et al.
patent: 5610183 (1997-03-01), Owens et al.
patent: 5629347 (1997-05-01), Swain et al.
patent: 0288965 (1988-11-01), None
patent: 415413 (1991-03-01), None
patent: 0632036 (1995-01-01), None
patent: 07101929 (1993-10-01), None
patent: 9204045 (1992-03-01), None
patent: 93/01169 (1993-01-01), None
patent: 9324458 (1993-12-01), None
patent: 94/04494 (1994-03-01), None
Blommaert, J. Med. Chem, 36, pp. 2868-2877, 1993.
Sartori et al, Eur. J. Med. Chem. vol. 29, pp. 431-439, 1994.
Schogl, Chemical Abstracts, vol. 51, No. 11, Abstract 8074g, Jun. 1957.
Medenica et al., “Polypeptide Levels Increase During Acute Onset of Hepatic Porphyrias”,Cellular and Molecular Biology, vol. 41, No. 1, 1997, 9-27.
Kulkosky, “Bombesin and Ceruletide-induced Grooming and Inhibition of Ingestion in the Rat”,Ann. N.Y. Acad. Sci, vol. 525, 1988, 201-218.
Hurel et al., “Treatment of pulmonary hypertension with bombesin antagonist”,Lancet, vol. 348, 1996, 1243.
Anastasi et al., “Isolation and Structure of Bombesin and Alytesin, two Analogous Active Peptides from the Skin of the European Amphibians Bombina and Alytes”,Experiencia, vol. 27, 1971, 166-167.
Dutta, “Bombesin/Gastrin-Releasing Peptide”,Small Peptides; Chemistry, Biology, and Clinical Studies, Chapter 2, 1993, 66-82.
Battey and Wada, “Two distinct receptor subtypes for mammalian bombesin-like peptides”,TINS, vol. 14, No. 12, 1991, 524-528.
Brown et al., “Bombesin-like activity: radioimmunologic assessment in biological tissues”,Life Sciences, vol. 23, 1978, 2721-2728.
Walsh et al., “Bombesin-like peptides in mammals”,Federation Proceedings, vol. 38, 1979, 2315-2319.
Taylor et al., “Progress in the Development of Competitive Bombesin Antagonists”,Ann. N.Y. Acad. Sci., vol. 547, 1988, 150-157.
Rozengurt, “Bombesin-Induction of Cell Proliferation in 3T3 Cells”,Ann. N.Y. Acad. Sci., vol. 547, 1988, 277-292.
Cuttitta et al., “Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer”,Nature, vol. 316, 1985, 823-826.
Kozacko et al., “Bombesin antagonist prevents CO2laser-induced promotion of oral cancer”,Proc. Natl. Acad. Sci USA, vol. 93, 1996, 2953-2957.
Ghatei et al., “Bombesin: Action on Gut Hormones and Calcium in Man”,Journal of Clinical Endocrinolology and Metabolism, vol. 54, No. 5, 1982, 980-985.
Erspamer and Melchiorri, “Active polypeptides of the amphibian skin and their synthetic analogues”,Pure Appl. Chem., vol. 35, 1973, 463-494.
Kulkosky et al., “Behavioral Effects of Bombesin Administration in Rats”,Physiology&Behavior, vol. 28, 1982, 505-512.
Gmerek and Cowan, “Studies on Bombesin-Induced Grooming in Rats”,Peptides, vol. 4, 1983, 907-913.
Cowan, “Behavioral Effects of Bombesin”,Ann. N.Y. Acad. Sci., vol. 547, 1988, 204-209.
Brown et al., “Bombesin: Central Nervous System Actions to Affect the Autonomic Nervous System”,Ann. N.Y. Acad. Sci., vol. 547, 1988, 174-182.
Kirkham et al., “Meal Pattern Analysis in Rats Reveals Partial Agonist Activity of the Bombesin Receptor Antagonist BW2258U89”,Pharmacology Biochemistry and Behavior, vol. 52, No. 1, 1995, 101-106.
Ladenheim et al., “Blockade fo feeding inhibition by neuromedin B using a selective receptor antagonist”,European Journal of Pharmacology, vol. 271, 1994, R7-R9.
Albers et al., “Inter
Horwell David Christopher
Pritchard Martyn Clive
Anderson Elizabeth M.
Davis Zinna Northington
Warner-Lambert & Company
LandOfFree
Non-peptide bombesin receptor antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Non-peptide bombesin receptor antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Non-peptide bombesin receptor antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2583826