Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-08
2002-10-15
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252120, C514S253010
Reexamination Certificate
active
06465467
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament which particularly acts on the central nervous system.
BACKGROUND OF THE INVENTION
Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. A number of pharmacological and genetic experiments involving receptors for serotonin strongly implicate the 5-HT
2c
receptor subtype in the regulation of food intake (Obes. Res. 1995, 3, Suppl. 4, 449S-462S). The 5-HT
2c
receptor subtype is transcribed and expressed in hypothalamic structures associated with appetite regulation. It has been demonstrated that the non-specific 5-HT
2c
receptor agonist m-chlorophenylpiperazine (mCPP), which has some preference for the 5-HT
2c
receptor, causes weight loss in mice that express the normal 5-HT
2c
receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT
2c
receptor (Nature 1995, 374, 542-546). In a recent clinical study, a slight but sustained reduction in body weight was obtained after 2 weeks of treatment with mCPP in obese subjects (Psychopharmacology 1997, 133, 309-312). Weight reduction has also been reported from clinical studies with other “serotonergic” agents (see e.g. IDrugs 1998, 1, 456-470). For example, the 5-HT reuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptake inhibitor dexfenfluramine have exhibited weight reduction in controlled studies. However, currently available drugs that increase serotonergic transmission appear to have only a moderate and, in some cases, transient effects on the body weight.
The 5-HT
2c
receptor subtype has also been suggested to be involved in CNS disorders such as depression and anxiety (Exp. Opin. Invest. Drugs 1998, 7, 1587-1599; IDrugs, 1999, 2, 109-120).
The 5-HT
2c
receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (IDrugs, 1999, 2, 109-120).
Compounds which have a selective effect on the 5-HT
2c
receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above. Of course, selectivity also reduces the potential for adverse effects mediated by other serotonin receptors.
INFORMATION DISCLOSURE
U.S. Pat. No. 3,253,989 discloses the use of mCPP as an anorectic agent.
EP-A1-863 136 discloses azetidine and pyrrolidine derivatives which are selective 5-HT
2c
receptor agonists having antidepressant activity and which can be used for treating or preventing serotonin-related diseases, including eating disorders and anxiety.
EP-A-657 426 discloses tricyclic pyrrole derivatives having activity on the 5-HT
2c
receptor and which inter alia may be used for treating eating disorders.
EP-A-655 440 discloses 1-aminoethylindoles having activity on the 5-HT
2c
receptor and which may be used for treating eating disorders.
EP-A-572 863 discloses pyrazinoindoles having activity on the 5-HT
2c
receptor and which may be used for treating eating disorders.
J. Med. Chem. 1978, 21, 536-542 and U.S. Pat. No. 4,081,542 disclose a series of piperazinylpyrazines having central serotonin-mimetic activity.
J. Med. Chem. 1981, 24, 93-101 discloses a series of piperazinylquinoxalines with central serotoninmimetic activity.
WO 00/12475 discloses indoline derivatives as 5-HT
2b
and/or 5-HT
2c
receptor ligands, especially for the treatment of obesity.
WO 00/12510 discloses pyrroloindoles, pyridoindoles and azepinoindoles as 5-HT
2c
receptor agonists, particluarly for the treatment of obesity.
WO 00/12482 discloses indazole derivatives as selective, directly active 5-HT
2c
receptor ligands, preferably 5-HT
2c
receptor agonists, particularly for use as anti-obesity agents.
WO 00/12502 discloses pyrroloquinolines as 5-HT
2c
receptor agonists, particularly for use as anti-obesity agents.
WO 00/12475 discloses indoline derivatives as 5-HT
2b
and/or 5-HT
2c
receptor ligands, especially for the treatment of obesity.
GB-B-1,457,005 discloses 1-piperazinyl-2-[2-(phenyl)ethenyl]-quinoxaline derivatives which exhibit anti-inflammatory activity.
Chem. Pharm. Bull. 1993, 41(10) 1832-1841 discloses 5-HT
3
antagonists including 2-(4-methyl-1-piperazinyl)-4-phenoxyquinoxaline.
GB-B-1,440,722 discloses 2-(1′-piperazinyl)-quinoxaline compounds having pharmaceutical activity against depression.
WO 96/11920 discloses CNS-active pyridinylurea derivatives.
WO 95/01976 discloses indoline derivatives active as 5-HT
2c
antagonists and of potential use in the treatment of CNS disorders.
WO 97/14689 discloses aryl-piperazine cyclic amine derivatives which are selective 5-HT
1d
receptor antagonists.
WO 98/42692 discloses piperazines derived from cyclic amines which are selective antagonists of human 5-HT
1a
, 5-HT
1d
and 5-HT
1b
receptors.
GB-B-1,465,946 discloses substituted pyridazinyl, pyrimidinyl and pyridyl compounds which are active as P-receptor blocking agents.
EP-A-711757 discloses [3-(4-phenyl-piperazin-1-yl)propylamino]-pyridine, pyrimidine and benzene derivatives as &agr;-adrenoceptor antagonists.
WO 99/03833 discloses aryl-piperazine derivatives which are 5-HT
2
antagonists and 5-HT
1a
receptor agonists and therefore are useful as remedies or preventives for psychoneurosis.
WO 96/02525 discloses aryl-piperazine-derived piperazide derivatives having 5-HT receptor antagonistic activity.
WO 99/58490 discloses aryl-hydronaphthalen-alkanamines which may effectuate partial or complete blockage of serotonergic 5-HT
2c
receptors in an organism.
SUMMARY OF THE INVENTION
According to the present invention, a class of novel compounds have been developed which bind to the
5
-HT
2c
receptor (agonists and antagonists) and which therefore may be used for the treatment of serotonin-related disorders.
In one aspect, the invention provides novel compounds of the general formula (I):
wherein
Ar is aryl or heteroaryl which may be independently substituted in one or more positions by C
1-6
-alkyl, C
1-6
-alkoxy, C
1-6
-alkylthio, C
1-6
-acyl, C
1-6
-alkylsulphonyl, cyano, nitro, hydroxy, C
2-6
-alkenyl, C
2-6
-alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, halogen, —N(R
2
)(R
3
), aryl, aryloxy, arylthio, aryl-C
1-4
-alkyl, aryl-C
2-4
-alkenyl, aryl-C
2-4
-alkynyl, heterocyclyl, heterocyclyloxy, heterocyclylthio or heterocyclyl-C
1-4
-alkyl, wherein any aryl and heterocyclyl residues as substituents or part of substituents on aryl or heteroaryl in turn may be substituted in one or more positions independently of each other by halogen, C
1-6
-alkyl, C
1-6
-alkoxy, C
1-6
-alkylthio, C
1-6
-acyl, C
1-6
-alkylsulphonyl, nitro, trifluoromethyl, trifluoromethylthio, cyano, hydroxy, amino, C
1-6
-alkylamino, di(C
1-6
-alkyl)amino or C
1-6
-acylamino;
A is (i) —O—, —S—, —SO
2
—or —NH—; (ii) a C
1-4
-alkyl-substituted nitrogen atom, or (iii) a C
1-8
-alkylene chain or a heteroalkylene chain having 2 to 8 chain atoms, which optionally contains one or more unsaturations, wherein C
1-8
-alkylene and heteroalkylene may be independently substituted in one or more positions by C
1-4
-alkyl or oxo, and wherein two juxtaposed or spaced chain atoms in C
1-8
-alkylene or heteroalkylene optionally are joined through an alkylene bridge having 1 to 5 chain carbon atoms or a heteroalkylene bridge having 2 to 5 chain atoms, or two spaced chain atoms in C
1-8
-alkylene or heteroalkylene optionally are joined through a bridging bond, to form a saturated or partially or fully unsaturated carbocyclic or heterocyclic ring having 3 to 8 ring members;
B is —C(R
4
)(R
5
)—, —OC(R
4
)(R
5
)—, —N(R
6
)C(R
4
)(R
5
)—, —N(R
6
)—, —O—, —S—or —SO
2
—;
R is C
3-8
-cycloalkyl, aryl or heteroaryl, each of which may
Jönsson Mattias
Nilsson Björn
Nilsson Jonas
Pelcman Benjamin
Ringberg Erik
Biovitrum AB
Fish & Richardson PC
Patel Sudhaker B.
Raymond Richard L.
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