Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-23
2002-11-05
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S275400, C548S365700, C548S379400, C548S379700
Reexamination Certificate
active
06476060
ABSTRACT:
This application claims priority benefit under 35 U.S.C. § 119 of European patent application No. EP 00201032.0, filed Mar. 23, 2000, and Dutch patent application No. NL 1014728, filed Mar. 23, 2000, both of which are incorporated herein by reference.
The present invention relates, among many things, to a group of novel 4,5-dihydro-1H-pyrazole compounds, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.
The above mentioned 4,5-dihydro-1H-pyrazoles can be potent Cannabis-1 (CB
1
) receptor antagonists with utility for the treatment of psychiatric and neurological disorders.
Cannabinoids are present in the Indian hemp
Cannabis Sativa
L. and have been used as medicinal agents for centuries (Mechoulam, R.; Feigenbaum, J. J.
Prog. Med. Chem.
1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CB
1
and CB
2
) stimulated the search for novel cannabinoid receptor antagonists (Munro, S.; Thomas, K. L.; Abu-Shaar, M.
Nature
1993, 365, 61. Matsuda, L. A.; Bonner, T. I.
Cannabinoid Receptors
, Pertwee, R. G. Ed. 1995, 117, Academic Press, London). In addition, pharmaceutical companies became interested in the development of cannabinoid drugs for the treatment of diseases connected with disorders of the cannabinoid system. The wide distribution of CB
1
receptors in the brain, in combination with the strictly peripheral localization of the CB
2
receptor, makes the CB
1
receptor a very interesting molecular target for CNS-directed drug discovery in the areas of both psychiatric and neurological disorders (Consroe, P.
Neurobiology of Disease
1998, 5, 534. Pop, E.
Curr. Opin. In CPNS Investigational Drugs
1999, 1, 587. Greenberg, D. A.
Drug News Perspect.
1999, 12, 458). Hitherto, three types of distinct CB
1
receptor antagonists are known. Sanofi disclosed their diarylpyrazole congeners as selective CB
1
receptor antagonists. A representative example is SR-141716A, which is currently undergoing Phase II clinical development for psychotic disorders (Dutta, A. K.; Sard, H.; Ryan, W.; Razdan, R. K.; Compton, D. R.; Martin, B. R.
Med. Chem. Res.
1994, 5, 54. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S. R.; McCallion, D.; Pertwee, R.; Makriyannis, A.
J. Med. Chem.
1999, 42, 769. Nakamura-Palacios, E. M.; Moerschbaecher, J. M.; Barker, L. A.
CNS Drug Rev.
1999, 5, 43). Aminoalkylindoles have been disclosed as CB
1
receptor antagonists. A representative example is lodopravadoline (AM-630), which was introduced in 1995. AM-630 is a CB
1
receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K.; Quock, R. M.; Hosohata, Y.; Burkey, T. H.; Makriyannis, A.; Consroe, P.; Roeske, W. R.; Yamamura, H.I.
Life Sc.
1997, 61, PL115). More recently, researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CB
1
receptor antagonists (e.g., LY-320135) (Felder, C. C.; Joyce, K. E.; Briley, E. J.; Glass, M.; Mackie, K. P.; Fahey, K. J.; Cullinan, G. J.; Hunden, D. C.; Johnson, D. W.; Chaney, M. O.; Koppel, G. A.; Brownstein, M.
J. Pharmacol. Exp. Ther.
1998, 284, 291). Recently, 3-alkyl-5,5′-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M.; Govaerts, S. J.; Hermans, E.; Poupaert, J. H., Lambert, D. M.
Biorg. Med.Chem. Lett.
1999, 9, 2233). Interestingly, many CB
1
receptor antagonists have been reported to behave as inverse agonists in vitro (Landsman, R. S.; Burkey, T. H.; Consroe, P.; Roeske, W. R.; Yamamura, H. I.
Eur. J. Pharmacol.
1997, 334, R1). Recent reviews provide a nice overview of the current status in the cannabinoid research area (Mechoulam, R.; Hanus, L.; Fride, E.
Prog. Med. Chem.
1998, 35, 199. Lambert, D. M.
Curr. Med. Chem.
1999, 6, 635. Mechoulam, R.; Fride, E.; Di Marzo, V.
Eur. J. Pharmacol.
1998, 359, 1).
It has now surprisingly been found that the novel 4,5-dihydro-1H-pyrazole compounds of the formula (I), prodrugs thereof, tautomers thereof, stereoisomers thereof, and salts thereof
wherein
R represents phenyl, thienyl or pyridyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents Y, which are the same or different and are chosen from
C
1-3
-alkyl, C
1-3
-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, monoalkyl (C
1-2
)-amino, dialkyl (C
1-2
)-amino, monoalkyl (C
1-2
)-amido, dialkyl (C
1-2
)-amido, (C
1-3
)-alkyl sulfonyl, dimethylsulfamido, C
1-3
-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
or R represents naphthyl,
R
1
represents phenyl, thienyl or pyridyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents Y, which are the same or different and are chosen from
C
1-3
-alkyl, C
1-3
-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, monoalkyl (C
1-2
)-amino, dialkyl (C
1-2
)-amino, monoalkyl (C
1-2
)-amido, dialkyl (C
1-2
)-amido, (C
1-3
)-alkyl sulfonyl, dimethylsulfamido, C
1-3
-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
or R
1
represents naphthyl,
R
2
represents hydrogen, hydroxy, C
1-3
-alkoxy, acetyloxy or propionyloxy,
Aa represents one of the groups (i), (ii), (iii), (iv) or (v)
wherein
R
4
represents hydrogen, C
1-8
branched or unbranched alkyl or C
3-8
cycloalkyl; and when R
5
represents hydrogen, R
4
optionally further represents acetamido, dimethylamino, 2,2,2-trifluoroethyl, phenyl or pyridyl,
R
5
represents hydrogen, C
1-8
branched or unbranched alkyl or C
3-8
cycloalkyl,
R
6
represents hydrogen or C
1-3
unbranched alkyl,
Bb represents sulfonyl or carbonyl,
R
3
represents benzyl, phenyl, thienyl or pyridyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents Y, which are the same or different, or R
3
represents C
1-8
branched or unbranched alkyl or C
3-8
cycloalkyl, or R
3
represents naphthyl,
can be potent and/or selective antagonists of the cannabis CB
1
-receptor.
Due to the potent CB
1
antagonistic activity possible, the compounds according to the invention can be suitable for use in the treatment of one or more psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as dementia, distonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, and/or for the treatment of pain disorders and/or other CNS-diseases such as those involving cannabinoid neurotransmission, and/or in the treatment of gastrointestinal disorders and/or cardiovascular disorders. Thus, the invention further relates to methods for treating a human or animal patient in need of such treating for one or more of these disorders. A method of treating according to the invention comprises administering a compound of formula (I) in an amount efficacious for the treating.
The affinity of representative compounds of the invention for cannabinoid CB
1
receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabis CB
1
receptor is stably transfected in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.
The cannabinoid CB
1
antagonistic activity of representative compounds of the invention was determined by functional studies using CHO cells in whic
Kruse Cornelis G.
Lange Josephus H. M.
Tipker Jacobus
Tulp Martinus T. M.
Van Vliet Bernard J.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Ramsuer Robert W.
Solvay Pharmaceuticals B.V.
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