Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-19
2004-06-29
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235800, C544S120000, C544S357000
Reexamination Certificate
active
06756377
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 5-HT
2c
receptor agonist m-chlorophenylpiperazine (mCPP), which has some preference for the 5-HT
2c
receptor, reduces food intake 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). Recently, a series of pyrrolo[3,2,1-ij]quinoline derivatives was identified to be 5-HT
2C
receptor agonists having selectivity over the 5-HT
2A
receptor (Isaac M., et al., Bioorg. Med. Chem. Lett. 2000, 10, 919-921). The compounds are said to offer a novel approach to the treatment of obesity and epilepsy.
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 dexfenflurarnine 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 l-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 00/35922 discloses 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)ones as 5HT
2c
agonists, which may be used for the treatment of obesity.
WO 00/44737 discloses aminoalkylbenzofurans as 5-HT
2c
agonists, which may be used for the treatment of obesity.
Further compounds reported to be 5HT
2c
receptor agonists are, for example, indazolylpropylamines of the type described in WO 00/12481; indazoles of the type described in WO 00/17170; piperazinylpyrazines of the type described in WO 00/76984; heterocycle fused &ggr;-carbolines of the type described in WO 00/77001, WO 00/77002 and WO 00/77010; benzofurylpiperazines of the type described in WO 01/09111 and WO 01/09123; benzofurans of the type described in WO 01/09122; benzothiophenes of the type described in 01/09126; aminoalkylindazoles of the type described in WO 98/30548; indoles of the type described in WO 01/12603; indolines of the type described in WO 01/12602; pyrazino(aza)indoles of the type described in WO 00/44753 and tricyclic pyrroles or pyrazoles of the type described in WO 98/56768.
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 arylpiperazine 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 &bgr;-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 arylpiperazine 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 arylpiperazine-derived piperazide derivatives having 5-HT receptor antagonistic activity.
WO 99/58490 disloses aryl-hydronaphthalen-alkane amines which may effectuate partial or complete blockage of serotonergic 5-HT
2c
receptors in an organism.
OBJECT OF THE INVENTION
It is an object of the present invention to provide new compounds.
Another object of the invention is a pharmaceutical composition comprising compounds for use in therapy as an active ingredient.
Finally, an object of the invention is a method of treatment or prophylaxis of a serotonin related disease, especially a disease related to the 5-HT
2c
receptor.
SUMMARY OF THE INVENTION
According to the invention novel compounds of the general formula (I) are provided:
wherein
R
1
is hydrogen, C
1
-C
4
-alkyl, C
3-4
-alkenyl, C
1-4
-acyl, C
1-4
-alkoxycarbonyl, 2-hydroxyethyl, 2-cyanoethyl, tetrahydropyran-2-yl, or a nitrogen protecting group;
R
2
is hydrogen, C
1-4
-alkyl, hydoxymethyl, C
1-4
-alkoxymethyl, or fluoromethyl;
R
3
and R
4
independently of each other are hydrogen, halogen, methyl, C
1-4
-alkyl, aryl, heteroaryl wherein aryl and heteroaryl residues in turn may be substituted in one or more positions independently of each other by ha
Nilsson Björn M.
Scobie Martin
Biovitrum AB
Fish & Richardson P.C.
Raymond Richard L.
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