NZ523216A

NZ523216A - New combination of serotonin agonist (5HT2) and antagonist (5HT6) as pharmaceutical formulation

Info

Publication number: NZ523216A
Application number: NZ523216A
Authority: NZ
Inventors: Sukhwinder Jossan; Bjorn M Nilsson; Kjell S Sakariassen; Jan Svartengren
Original assignee: Biovitrum Ab
Priority date: 2000-07-21
Filing date: 2001-07-19
Publication date: 2005-05-27
Also published as: ZA200210234B; IL154057A0; AU8273401A; BR0112661A; KR100845450B1; EA006604B1; CN1443162A; AU2001282734B2; KR20030036599A; HUP0301346A2; CA2411192A1; HK1057536A1; MXPA03000548A; SE0002754D0; HUP0301346A3; EA200300183A1; JP2004504376A; PL360309A1; NO20030304L; NO20030304D0

Abstract

A pharmaceutical composition comprising an effective amount of a combination of a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist, or a salt, enantiomer or prodrug form of the said agonist and/or antagonist, and optionally a pharmaceutically acceptable carrier is disclosed.

Description

<div class="application article clearfix" id="description"> WO 02/08178 523216 pct/se01/01651 NEW COMBINATION OF SEROTONIN AGONIST (5HT2) AND ANTAGONIST (5HT6)AS PHARMACEUTICAL FORMULATION TECHNICAL FIELD 5 The present invention relates to the prophylaxis or treatment of a 5-HT2C and a 5-HTs receptor-related disease. In addition, the invention provides a pharmaceutical composition containing a 5-HT2C receptor agonist and a 5-HTg receptor antagonist for therapeutic use. 10 BACKGROUND ART Serotonin (5-hydroxytryptamine or 5-HT) is a key neurotransmitter of the peripheral 15 and central nervous system (PNS and CNS) and has been implicated in a variety of sensory, motor and behavioral functions such as regulation of eating, sleeping, body temperature, blood pressure, emotions and cognition. At least 14 distinct serotonin receptor subtypes are expressed in the mammalian PNS and CNS and have been fonnally classified; see Glennon, et al., Neiirosci. Biobehav. Rev. 1990,14, 35-37; and 20 D. Hoyer, et al., Pharmacol. Rev. 1994, 46, 157-203. Serotoninergic agonists and antagonists have been suggested for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, drug abuse and addiction, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-25 induced vomiting. The 5-HT2 subfamily of receptors is composed of three subtypes, the 5-HT2A> 5-HT2B and 5-HT2c receptors. Serotonin 5-HT2C receptors are expressed in many brain regions and have been implicated in the regulation of food intake (Dourish, C.T. Obes. Res. 1995, 3, Suppl. 4, 449S-462S; Bickerdike, M.J., et al. Diabetes, Obes. Metab. 30 1999,1, 207-214). It has been demonstrated that the non-specific 5-HT2C receptor agonist m-chlorophenylpiperazine (m-CPP), which has some preference for the 5-HT2C receptor, reduces food intake in mice that express the normal 5-HT2C receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT2C receptor (Tecott, L.H., et al. Nature 1995, 374, 542-546). 1 WO 02/08178 PCT/SEO1/01651 Moreover, it has been reported that m-CPP and the azepinoindole U-22394A, the latter recently identified to be a 5-HT2c receptor agonist (unpublished observation), reduce body weight in humans following two and nine weeks of treatment, respectively (Walsh, A. E. S., Psychopharmacology 1994,116,120-122; Sargent, P.A., et al. 5 Ps)>chopharmacology 1997,133, 309-312 and Gallant, D.M., et al. Curr. Tlier. Res. 1967, 9, 579-581). Recently, a series of pyrrolo[3,2,l-y]quinoline derivatives was identified to be 5-HT2C receptor agonists having selectivity over the 5-HT2A receptor (Isaac M., et al., Bioorg. Med. Chem. Lett. 2000,10, 919-921). The compounds are said to offer a novel 10 approach to the treatment of obesity and epilepsy. The 5-HT2C receptor subtype has also been suggested to be involved in CNS disorders, such as depression and anxiety (Jenck, F., et al. Expert Opin. Invest. Drugs 1998, 7, 1587-1599; Leysen, D.C.M. IDrugs 1999,2, 109-120). The 5-HT2c receptor subtype has further been suggested to be involved in urinary disorders such as urinary 15 incontinence (Leysen, D.C.M. IDrugs 1999, 2, 109-120). Also the 5-HTg receptor (identified in 1993 - Monsma et al., Mot Pharmacol. 1993, 43, 320-327 and Ruat, M. et al. Biochem. Biophys. Res. Commun. 1993,193, 269-276) has been implicated in the regulation of food intake and CNS disorders. Thus, for example, Bentley, J. C., et al., Br. J. Pharmacol. 1999,126, 66P 20 describes food intake reduction in rats by the administration of a 5-HT5 antagonist. Also, several antidepressants and atypical antipsychotics display high affinity for the 5-HT6 receptor which have suggested the involvement of the 5-HTe receptor in schizophrenia (Roth et al. J. Pharmacol. Exp. Ther. 1994,268, 1403-1410; Sleight et al. Expert Opin. Ther. Patents 1998, 8,1217-1224; Bourson et al. Br. J. Pharm. 1998,125, 25 1562-1566; Boess et al. Mol. Pharmacol. 1998, 54, 577-583; Sleight et al. Br. J. Pharmacol. 1998,124, 556-562). In addition, the 5-HTg receptor has been linked to generalized stress and anxiety states (Yoshioka et al. Life Sci. 1998,17/18,1473-1477). 30 SUMMARY OF THE INVENTION According to the present invention it has now unexpectedly been found that the combined administration of a 5-HT2c receptor agonist and a 5-HTg receptor antagonist 2 wo 02/08178 pct/seo1/01651 reduces food intake by more than the administration of either agonist or antagonist alone. Such combined administration of a 5-HT2C receptor agonist and a 5-HTg receptor antagonist may offer therapeutic advantages as compared to treatment with either agonist or antagonist alone. One aspect of the present invention therefore provides a pharmaceutical composition comprising an effective amount of a combination of a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist, or a salt, enantiomer or prodrug form of the said agonist and/or antagonist, and optionally a pharmaceutically acceptable carrier, wherein the 5-HT2c receptor agonist is selected from the group comprising: a) a compound of the general formula (I): -A R (I) wherein Ar is aryl or heteroaryl which may be independently substituted in one or more positions by Ci.g-alkyi, Ci.^-alkoxy, Ci.6"alMthio, C^-acyl, Ci_6-alkylsulphonyl, cyano, nitro, hydroxy, C2_6"a^kenyl, C2_6-alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, halogen, -N(R2)(R.3), aryl, aryloxy, arylthio, aryl-Ci_4-alkyl, aryl-C2-4-alkenyl, aryl-C2-4-alkynyl, heterocyclyl, heterocyclyloxy, heterocyclylthio or heterocyclyl-C j .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, Ci.g-alkyl, Cj.g-alkoxy, Cj^-alkylthio, Cj^-acyl, C\.g-alkylsulphonyl, nitro, trifluoromethyl, trifluoromethylthio, cyano, hydroxy, amino, Ci_6-alkylamino, di(Ci_g-alkyl)amino or Ci.g-acylamino; A is (i) -0-, -S-, -SO2- or -NH-; (ii) a C^-alkyl-substituted nitrogen atom, or (iii) a C} .g-alkylene chain or a heteroalkylene chain having 2 to 8 chain atoms, which optionally contains one or more unsaturations, wherein .g-alkylene and heteroalkylene may be independently substituted in one or more positions by Cj.4-alkyl or oxo, and wherein two juxtaposed or spaced chain atoms in C] .g-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 Cg-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; INTELLECTUAL PilG OP iV.Z ""2 MAR wo 00/76984 3a pct/se00/01017 B is -C(R4)(R5)-, -OC(R4)(R5)-, -N(R6)C(R4)(R5)-, -N(R6>, -0-, -S- or -SO2-; R is C3_g-cycloalkyl, aryl or heteroaryl, each of which may be substituted in one or more positions independently of each other by Cj.g-alkyl, C1 .g-alkoxy, 5 fluoro-C|_g-alkoxy, 2,2,2-trifluoroethoxy, C3_5-alkynyloxy, C3_5-alkenyloxy, dimethylamino-C \ .g-alkoxy, methylamino-C \ .g-alkoxy, Ci[_^-alkylthio, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethylthio, difluoromethoxy, difluoromethylthio, trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano, trifluoromethylsulphonyloxy, C j.5-alkylsulphonamido, C2_6-alkenyl, C2-6-alkynyl, 10 Cj.g-acyl, C1 .g-alkylcarbonyl-C]_6-alkyl, Cj^-alkylsulphonyl, C1 .g-alkylsulphonyloxy, C1 .g-alkoxy-C j .g-alkyl, C \ .g-alkoxycarbonyl, C ] .g-alkoxycarbonyl-C \ .g-alkyl, C1 .g-acyloxy-C 1 .g-alkyl, hydroxy-C \ .g-alkyl, hydroxy-C] .g-alkoxy, C1.5-alkoxy-C j .g-alkoxy, C \ .g-alkoxy-C 1 .g-alkylthio, hydroxy-Ci_6-alkylthio, heteroaryl-Cj.5-alkylthio, aryl-Cj.g-alkylthio, Cj.g-alkoxy-15 C^.g-alkylamino, N-(C 1 .g-alkoxy-C j.g-alkyO-N-methylamino, C3_6-cycloalkyl-Cj.g-alkoxy, aryl-Cj.g-alkoxy, heterocyclyl-C 1 .g-alkoxy, C3_g-cycloalkyl, C3 .g-cycloalkyloxy, aryl, aryloxy, arylthio, arylsulphonyl, aryl-Cj.g-acyl, aryl-C alkyl, aryl-C2_6-alkenyl, aryl-C2_6-alkynyl, heterocyclyl-C \ .g-alkyl, heterocyclyl-C2-g-alkenyl, heterocyclyl-C2-6-alkynyl, heterocyclyl, heterocyclyloxy, heterocyclylthio, 20 heterocyclylsulphonyl, heterocyclylamino, heterocyclyl-C 1 -6-acyl, -N(R2)(R3), -CON(R7)(Rg) or, when R is optionally substituted C3_g-cycloalkyl, oxo, wherein any cycloalkyl, aryl and heterocyclyl residues as substituents on C3_g-cycloalkyl, aryl or heteroaryl or as part of substituents on C3_g-cycloalkyl, aryl or heteroaryl in turn may be substituted in one or more positions independently of each other by Cj. 4-alkyl, Cj_4~ 25 alkoxy, methanesulphonamido, C^-alkylthio, Cj.4-alkylsulphonyl, Cj^-acyl, heterocyclyl, heterocyclyloxy, heterocyclylthio, aryloxy, arylthio, fluoromethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano, N(R2)(R3) or, for C3.g-cycloalkyl and partially or fully saturated heterocyclyl, oxo or hydroxy; 30 Rj is (i) a saturated or unsaturated azacyclic or aminoazacyclic ring, or a saturated diazacyclic or aminodiazacyclic ring, which has 4 to 7 ring members, or a saturated aminoazabicyclic, azabicyclic or diazabicyclic ring which has 7 to 10 ring ^ if lLxC UJmL Jr'Hi« Y OH" OF l\j.Z 7 ti<n wnc 1 Firtit iuw wo 00/76984 3b pct/seq0/01017 members, which mono- or bicyclic rings may be mono- or disubstituted in one or more positions independently of each other by, preferably bound to a carbon atom, Cj.4-alkyl, Cj.5-alkoxy, fluoromethyl, trifluoromethyl, difluoromethyl, oxo, hydroxymethyl or methoxymethyl or -N(Rg)2, or, preferably bound to a ring nitrogen atom, hydroxy, 2-hydroxyethyl or 2-cyanoethyl, or, bound to a ring nitrogen atom, Cj.g-acyl, C}_4-alkoxycarbonyl or tetrahydropyran-2-yl, and wherein a saturated azacyclic ring may contain a further heteroatom selected from oxygen and sulphur; or (ii) a group -[C(R4)(R5)]xN(R2a)(R3a); R2 and R3 independently of each other are hydrogen, C^.g-alkyl, Ci.g-acyl, -CON(R7)(Rg), aryl, heterocyclyl, aryl-C 1 .g-alkyl, heterocyclyl-C j.g-alkyl, aryl-Cj.g-acyl or heterocyclyl-C6-acyl, wherein any aryl and heterocyclyl residues in turn may be substituted in one or more positions independently of each other by halogen, C1.4-alkyl, Cj_4-alkoxy, C[_4-alkylthio, C].4-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or -N(R2)(R3); or R2 and R3 together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members and optionally containing a further heteroatom, which ring may be substituted by Cj.g-alkyl, Cj.g-alkoxy, oxo or hydroxy; R2a and R3a independently of each other are hydrogen, methyl or ethyl, or R2a and R3a together with the nitrogen atom to which they are bound form a pyrrolidine, piperazine or morpholine ring; R4 and R5 independently of each other, and independently on each substituted carbon atom, are hydrogen or C^g-alkyl; Rg is hydrogen or C ] .5-alkyl; R7 and Rg independently of each other are hydrogen, C j.g-alkyl, aryl, heteroaryl, aryl-C \ .4-alkyl or heteroaryl-C j .4-alkyl, wherein aryl and heteroaryl residues in turn may be substituted in one or more positions independently of each other by halogen, Ci_6-alkyl, Cj.g-alkoxy, Cj.g-alkylthio, C\.g-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or -N(R2)(R3); or R7 and Rg together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members and optionally containing a further heteroatom; n is 0 or 1, and wo 00/76984 3c pct/se00/01017 x is 2, 3 or 4; with the proviso that (i) when -A-R is phenoxy or phenylthio, then Ar is other than quinoxalinyl or pyridyl, and (ii) when A is ethenylene, then Ar is other than quinoxalinyl; 5 and pharmaceutical^ acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof; b) a compound of the general formula (II): 10 R2 Y R1 ^ wherein (i) X and. Y represent both nitrogen and Z represents CH, forming a pyrazine derivative, or 15 (ii) X and Z represent both CH and Y represents nitrogen, forming a pyridine derivative, or (iii) X represents C-CF3, Z represents CH, and Y represents nitrogen, forming a 4-trifluoromethylpyridine derivative, or /■ (iv) Y and Z represent both nitrogen and X represents CH, forming a pyrimidine derivative, and wherein Rj and R2 are each, independently, selected from a group A consisting of 20 R3 /N *CH3 N H3C^N ;% ;Rd ;25 ;or from a group B, consisting of aryl-Ci-Cg-alkyl, aryl-C 1 -Cg-alltoxy, heteroaryl-Ci-C6-alkoxy, aryloxy-C2-C6-alkoxy, heteroaryloxy-C2-C<5-alkoxy, 1-indanyloxy, 2-indanyloxy, aryloxy, heteroaryloxy, arylthio, heteroarylthio, Cs-Ce-cycloalkylthio, Cs-Cg-alkoxy, Cs-Cg-alkylthio, C3-C6-alkynyloxy, C3-C6-alkenyloxy, fluoro-C2~C4~ alkoxy, C^Ca-cycloalkyloxy, C3-C8-cycloalkyl-Ci-C4-alkoxy, halogen, aryl-Ci-C4-alkylthio, heteroaryl-Ci-C4-alkylthio, aryl-Ci-C4-alkylamino, heteroaryl-Ci-C4-alkylamino, heteroaryl and aryl; ;with the proviso that; ;(i) Ri and R2 are different and are not both selected from group A or group B at he ;OF fti.Z ;ft f i'Y 0i ;WO 02/40456 ;3d ;PCT/SE01/02569 ;same time; ;(ii) when formula (I) is a pyrazine derivative Ri or R2 are other than phenylthio, phenylmethylthio, phenyl or phenyl substituted by halogen; ;(iii) Rj in formula (I) is halogen, only when (I) is a pyrazine derivative and when R2 5 simultaneously is 2-methylpiperazin-1 -yl, 2-ethylpiperazin-1 -yl, or trans-2,5- ;dimethylpiperazin-1 -yl; ;(iv) when formula (I) is a pyrazine derivative and Ri is 4-piperidinyloxy, R2 is other than 3-pyridinyhnethoxy, 4-quinoHnylmethoxy and 3-(4-pyridinyl)propoxy; ;(v) when both X and Z are CH and Y is N in formula (I), forming a pyridine ;10 derivative, and Rj is 1-piperazinyl or 4-methylpiperazin-1 -yl, then R2 is other than 2-phenylethyl, benzyloxy, benzylamino, phenylthio, phenoxy, substituted phenoxy, G^-Cg-cycloalkyloxy and Cs-Cs-cycloalkylmethoxy; ;(vi) when X is CH and Z and Y both are nitrogen in formula (I), forming a ;. pyrimidine derivative, and R2 is 1-piperazinyl, then Rj is other than phenoxy, phenyl 15 or phenyl substituted by bromo, and Cs-Cg alkoxy; and when R2 is 4-methylpiperazin-l-yl or ;4-(2-hydroxyethyl)piperazin-l-yl, then Rj is other than 5-nitro-2-furyl; ;(vii) when X is CH and Z and Y both are nitrogen in formula (I), forming a pyrimidine derivative, and Ri is 1-piperazinyl, then R2 is other than C5-C8 alkoxy; ;20 and where R3 is H or Ci_4-alkyl, allyl, 2-hydroxyethyl, 2-cyanoethyl, or a nitrogen protecting group, or a prodrug moiety such as an acyl- or an alkoxycarbonyl group forming a cleavable amide or carbamate linkage; ;R4 is hydrogen, or Cm alkyl; ;and wherein any aryl or heteroaryl residue, alone or as part of another group, in Ri or 25 R2 may be independently substituted in one or more positions, by C \ .4-alkyl, C^_4-alkoxy, Ci_4-alkylthio, C2-4-acyl, C \ _4-alkylsulphonyl, cyano, nitro, hydroxy, C2-g-alkenyl, C2_6-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, -N(R5)(Rg), aryl, aryloxy, arylthio, aryl-C^.4-alkyl, aryl-C2-4-alkenyl, aryl-C2_4-alkynyl, heteroaryl, heteroaryloxy, heteroarylthio or heteroaryl-Ci_4-alkyl, aryl-Cj. 30 4-alkoxy, aryloxy-Cj.4-alkyl, dimethylamino-C2-4-alkoxy; and ;«. * •'«!v L,,.. 0>- i\!.Z ~ tm m —EEpEf VED wo 02/40456 pct/se01/02569 10 15 20 25 wherein any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in Rj or R2 in turn may be substituted in one or more postions, independently of each other by Cj. 4-alkyl, C 1.4-alkoxy, halogen, trifluoromethyl, cyano, hydroxy or dimethylamino; and R5 and Rg independently of each other are hydrogen, methyl or ethyl, or together with the nitrogen atom to which they are bound form a pyrrolidine, piperazine, morpholine, thiomorpholine or a piperidine ring; and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, //-oxides and prodrug forms thereof ; and c) a compound of the general formula (III): Rc (III) wherein Ri is hydrogen, C4.4 alkyl, C3_4~alkenyl, Ci_4-acyl, C\_4-alkoxycarbonyl, 2-hydroxyelhyl, 2-cyanoethyl, tetrahydropyran-2-yl, or a nitrogen protecting group; R2 is hydrogen, Cj.4-alkyl, hydroxymethyl, CM-alkoxymethyl, or fluoromethyl; R3 and R4 independently of each other are hydrogen, methyl, Ci_4-alkyl, aryl, heteroaryl wherein aryl and heteroaryl residues in turn maybe substituted in one or more positions independently of each other by halogen, Ci_4-alkyl, Ci_4-alkoxy, Ci_4~alkylthio, Cj_4-alkylsulphonyl, methanesulphonamido, acetyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, methylamino, dimethylamino, or acetamido; or R3 and R4 together with the carbon atoms to which they are bound form a 5-or 6-membered aromatic or heteroaromatic ring, which may be substituted in one or more positions by halogen, methyl, methoxy, methylthio, meihylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino or acetamido; Of1 ~2 MA HZ -:F,i'V 0j IV F WO 02/40457 3f PCT/SE01/02570 R5 and Rg independently of each other are hydrogen, Ci-C4-alkoxy-C2-C4-alkyl, hydroxy-C2~C4-alkyl, Ci-C6-alkyl, C2-C6-acyl, aryl, heteroaryl, aryl-Ci-C2-alkyl, heteroaryl-Ci-C2-alkyl, aryl-Ci-C2-acyl, heteroaryl-Ci-C2-acyl, and wherein any aryl or heteroaryl, alone or as part of another group, may be independently substituted in one or more positions by Ci_4-alkyl, Ci_4-allcoxy, Ci-4-alkylthio, C2_4-acyl, C \ .4-alkylsulphonyl, cyano, nitro, hydroxy, C2_3-alkenyl, C2-3-aIkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, dimethylamino, or methylamino; or R5 and Rq together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members which ring may contain an additional heteroatom and which maybe substituted by methyl, oxo, or hydroxy; R7 is hydrogen or a substituent selected from halogen, methyl, methoxy, and ethoxy; and n = 1 — 3; and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, TV-oxides or prodrug forms thereof; and the 5-HT receptor antagonist is selected from the group comprising: a) a 9-arylsulfone of the general formula (IV): where R3 is: (1)-H, (2) C,-C4 alkyl, (3) Co-C4-<|> where the -<j> substituent is optionally substituted with 1 or 2 (a) -F, -CI, -Br, -I, (b) -O-r3-1 where R3.| is: -H, C1-c4 alkyl, •4. (c) -cf3, (IV) 3g 15 (d) -CO-nr3.2r.3-3 where r3.2 and r3-3 are -H and C1-c4 alkyl, and where r3. 2 and r3.3 are taken with the attached nitrogen atom to form a ring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl, (e) -NH-so2-r3-4 where R3^ is -H and C1-c4 alkyl, (f) -nr3.2r3-3 where R3.2 and r3.3 are as defined above, 20 (g) -NR3_4-CO-R3.4 where r3-4 is as defined above, (h) -so2-nr3.2r3-3 where R3.2 and R3.3 are as defined above, (D -C=N, (j) -no2, where Rn is: 25 (1) -H, (2) CrC4 alkyl, (3) C0-C4-<|> where the -<)> substituent is optionally substituted with 1 or 2 (a) -F, -CI, -Br, -I, (b) -O-Rn-i where Rn-i is 30 -h, C1-C4 alkyl, -<(>, (c) -CF3, (d) -CO-NRn-2Rn-3 where Rn-2 and Rn-3 are -H and C1-c4 alkyl, and where 5 R3.2 and R3.1 are taken with the attached nitrogen atom to form a ring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl, (e) -NH-S02-RN-4 where RN_4 is -H and C1-C4 alkyl, (f) -NRn-2Rn-3 where Rn-2 and Rn-3 are as defined above, (g) -NRn-4-CO-Rn-4 where Rn-4 is as defined above, 10 (h) -S02-NRN-2Rn-3 where Rn-2 and Rn-3 are as defined above, (D -C=N, 0)-no2, where Rx is: (1)-H 15 (2) -F, -CI, -Br, -I, (3) -O-Rx-i where Rx-i is: -H, C1-c4 alkyl, ■4. 20 (4) -CF3, (5) -CO-NRx-2Rx-3 where Rx-2 and Rx-3 are as defined above, (6) -NH-S02-Rx^ where Rx-4 is as defined above, a. -ehiV Uf OF H2 R E C ivsn 3h (7) -NRx-2Rx-3 where Rx-2 and Rx-3 are as defined above, (8) -NRx-4-CO-Rx.4 where Rx-4 is as defined above, 25 (9) -SC>2-NRx-2Rx-3 where RX-2 and Rx.3 are as defined above, (10) -CNN, (11) -N02; where R9 is: (I)-H, 30 (2) ~F, -CI, (3) C,-C4 alkyl, (4) C,-C3 alkoxy, (5) -cf3, (6) Co-C4-<(> where the -<|» substituent is optionally substituted with 1 or 2 (a) -F, -CI, -Br, -I, (b) -O-R9.1 where R9.1 is: -H, C1-c4 alkyl, -<t>, (c) -CF3, (d) -CO-nr9.2r9-3 where R9.2 and r9.3 are -H and C1-c4 alkyl, and where r9.2 and r9.3 are taken with the attached nitrogen atom to form a ring selected from the group consisting of 1-pyirolidiny1, 1-piperazinyl and 1-morpholinyl, (e) -NH-SO1-r9-4 where r9-4 is -H and C1-c4 alkyl, (0 -nr9.2r9-3 where r9.2 and r9.3 are as defined above, (g) —nr9.4-CO-r9.4 where r9-4 is as defined above, (h) -so2-nr9.2r9-3 where R9.2 and r9.3 are as defined above, (D -ON, 0) -no2 (7) -or9.1 where r9.1 is as defined above, (8) -CO-nr9-2r9.3 where r9-2 and r9.3 are as defined above, (9) -nr9.2r9-3 where R9-2 and r9-3 are as defined above, (10) ~NH-S02-R9.4 where R9.4 is as defined above, (II) -NH-co2-r9-2 where r9.2 is as defined above and pharmaceutical^ acceptable salts thereof,; and 3i b) a compound of the general formula (V): (V) wherein Ar is (1) phenyl, (2) naphthyl, (3) a 5- to 10-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, or (4) -R9-phenyl; wherein each of phenyl, naphthyl, and heterocyclic ring is independently optionally substituted with halogen, C)_6 alkyl, CF3, hydroxyl, Ci_6 alkoxyl, OCF3, COCF3, CN, NO2, phenyloxy, phenyl, Ci_6 alkylsulfonyl, C2-6 alkenyl, -NR7R8, C1-6 alkylcarboxyl, formyl, -Ci.g alkyl-NH-CO-phenyl, -Ci_e alkyl-CO-NH-phenyl, -NH-CO-Ci-e alkyl, -CO-NR?R8, or SR7; wherein each ofR7 and R8 is independently H or CVe alkyl; and R9 is Ci_6 alkyl or C2.6 alkenyl, each of which being optionally substituted with phenyl or phenyloxy; R2 is H, phenyl, I, or Cm alkyl; R3 is H or 3-(l-azabicyclo[2.2.2]oct-2~en)yl; R4 is H. or a heterocyclic ring selected from the group consisting of: wherein R6 is H, C1-6 alkyl, or benzyl; and 3j R5 is H, hydroxy, C1-3 alkoxy, F, N02j CF3, OCF3, or a heterocyclic ring selected from the group consisting of: or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, with the proviso that when is alkyl, is not H. Also described is a method of preventing or treating a disease, in particular obesity, related to the 5-HT2C receptor and the 5-HTg receptor, comprising administering to a human or animal subject in need thereof a 5-HT2c receptor agonist and a 5-HT6 receptor antagonist (simultaneously or sequentially) in sufficient amounts to provide a therapeutic effect. Still another aspect of the invention provides the use of a 5-HT2C receptor agonist and a 5-HTg receptor antagonist for the manufacture of a medicament for the treatment of a disease related to the 5-HT2C receptor and the 5-HT6 receptor, wherein the 5-HT2C receptor agonist and the 5-HT6 receptor antagonist are as defined above. Also described is a process for preparing a pharmaceutical composition, wherein a 5-HT2C receptor agonist and a 5-HT^ receptor antagonist in a combined therapeutic amount are intimately mixed with a pharmaceutically acceptable carrier. Yet another aspect of the invention provides a product containing a 5-HT2c receptor agonist and a 5-HT6 receptor antagonist as a combined preparation for simultaneous, separate or sequential use in therapy of a disease, in particular obesity, related to the 5-HT2C receptor and 5-HT6 receptor, wherein the 5-HT2c receptor agonist and the 5-HT6 receptor antagonist are as defined above. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the effect on food intake in ob/ob mice following combined administration with a 5-HT2C receptor agonist (PNU-183933F; 50 mg/kg po) and a 5-HTg receptor antagonist (PNU-186053A; 50 mg/kg sc), as well as the effect of eadti:,Ui: agonist and antagonist alone. j WO 02/08178 PCT/SEO1/01651 Figure 2 shows the effect on food intake in ob/ob mice following combined administration of a 5-HT2C receptor agonist (BVT.2938F; 5 mg/kg sc) and a 5-HT6 receptor antagonist (BVT.5182C; 3 mg/kg sc), as well as the effect of each agonist and antagonist alone. 5 DETAILED DESCRIPTION OF THE INVENTION As mentioned above, the present invention is based on the unexpected finding that 10 combined administration of a 5-HT2c receptor agonist and a 5-HTg receptor antagonist reduces food intake more than either agonist or antagonist alone. Such combined administration of a 5-HT2C receptor agonist and a 5-HTg receptor antagonist may also offer several benefits, for instance in the treatment of obesity, as compared to treatment with either agonist or antagonist alone. 15 Firstly, the combined administration requires lower doses of each compound to yield similar or improved reduction of food intake than mono-therapy. Secondly, the lower doses required by the combined administration may reduce the risk of adverse events. Thirdly, the lower doses required by the combined administration may reduce 20 the risk of tolerance development and abuse liability. Fourthly, therapy based on two targets may increase the individual therapeutic efficacy relative to therapy based on one target. The risk of non-responsive efficacy (non-responders) may be reduced as well. The beneficial effects of the combined administration of this invention is useful 25 not only for the modulation of eating behavior, and for treating over-weight and obesity, but may also be useful for the treatment of CNS disorders such as, depression, mania, schizophreniform disorders, anxiety, memory disorders (such as Alzheimer's disease) migraine headache, drug addiction, convulsive disorders, personality disorders, posttraumatic stress syndrome, and sleep disorders as well as for treatment of urinary 30 incontinence (or more generally overactive bladder), sexual dysfunctions, gastrointestinal disorders and glaucoma. The term "5-HT2C receptor agonist" as used herein refers to a compound that causes activation of the serotonin 5-HT2c receptor. The 5-HT2q receptor agonist 4 WO 02/08178 PCT/SEO1/01651 preferably has an affinity constant, Kj, of less than 50 nM, preferably less than 20 nM, and an in vitro intrinsic activity, measured as intracellular Ca2+ levels, greater than 20%, preferably greater than 50%, relative to 5-HT (1 The term "5-HT6 receptor antagonist" as used herein refers to a compound that causes blockade of the serotonin 5-HT6 receptor mediated responses. The 5-HT5 receptor antagonist preferably has an affinity constant, Kj, of less than 50 nM, preferably less than 20 nM, and an in vitro intrinsic activity, measured as intracellular cAMP levels, less than 50%, preferably less than 20%, relative to 5-HT (1 jlM). In vitro assays that may be used for determining the affinity and the intrinsic activity, respectively, of 5-HT2C receptor agonists and 5-HTg receptor antagonists are known in the art and are also given in the Experimental Part below, as are assays for determining affinity to 5-HT2j\ and 5-HT2b receptors. Generally, the 5-HT2C receptor agonists and 5-HTg receptor antagonists should be sufficiently selective not to cause any substantial adverse side effects. The terms "selective" and "substantial" in this context are, however, to be interpreted broadly, the meanings thereof being readily apparent to the skilled person. The 5-HT2c receptor agonist preferably has a selectivity for the 5-HT2C receptor of at least 5, preferably at least 10 and more preferably at least 20, relative to the 5-HT2A, 5-HT2b and 5-HTg receptors, respectively (measured as the affinity ratios 5-HT2A/5-HT2C, 5-HT2B/5-HT2C and 5-HT6/5-HT2C). The 5-HTg receptor antagonist preferably has a selectivity for the 5-HTg receptor of at least 5, preferably at least 10 and more preferably at least 20, relative to the 5-HT2A, 5-HT2B and 5-HT2C receptors, respectively (measured as the affinity ratios 5-HT2A/5-HT6, 5-HT2B/5-HT6 and 5-HT2C/5-HT6). Relevant tests to determine whether a compound is a selective 5-HT2c receptor agonist or a selective 5-HTg receptor antagonist are known in the art, and are, as mentioned above, also outlined in the Experimental Part below. Compounds known to be 5-HT2C receptor agonists are, for example, azetidine and pyrrolidine derivatives of the type described in EP-A-0863136; tricyclic pyrrole derivatives of the type described in EP-A-0657426; 1-aminoethylindoles of the type described in EP-A-0655440; pyrazinoindoles of the type described in EP-A-0572863; piperazinylpyrazines of the type described in US 4,081,542; indoline derivatives of the type described in WO 00/12475; pyrroloindoles, pyridoindoles and azepinoindoles of WO 02/08178 PCT/SE01/01651 the type described in WO 00/12510; indazole derivatives of the type described in WO 00/12482; pyrroloquinolines of the type described in WO 00/12502; 2,3,4,4a-tetrahydro-1 H-pyrazino[ 1,2-a]quinoxalin-5(6#)ones of the type described in WO 00/35922; indazolylpropylamines of the type described in WO 00/12481; indazoles of 5 the type described in WO 00/17170; piperazinylpyrazines of the type described in WO 00/76984, WO 02/40456 and WO 02/40457; . heterocycle fused y-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 10 01/09122; benzothiophenes of the type described in 01/09126; pyridinylpiperazines of the type described in EP 370560; pyrroloquinolines of the type described in Bioorg. Med. Chem. Lett. 2000,10,919-921; 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 15 00/44753; tricyclic pyrroles or pyrazoles of the type described in WO 98/56768. Currently preferable 5-HT2c receptor agonists are of the arylpiperazine and piperazinylpyrazine compound classes, in particular compounds disclosed in WO 00/76984, WO 02/40456 and WO 02/40457. 20 Compounds known to be 5-HT6 receptor antagonists are, for example, piperazinylbenzenesulfonamides of the type described in WO 99/37623; sulfonylbenzene derivatives of the type described in EP-A-0930302; sulfonamide derivatives of the type described in WO 99/02502; sulfonamide derivatives of the type described in WO 99/42465; sulfonamide derivatives of the type described in WO 25 98/27081; carboxamide derivatives of the type described in WO 98/27058; sulfonamide derivatives of the type described in EP-A-0815861; pyrrolidonomethylindole derivatives of the type described in WO 99/47516; bicyclic piperidine and piperazine derivatives of the type described in WO 99/65906; pyrazolopyrimidine and pyrazolotriazine derivatives of the type described in EP-A-0941994; arylsulfone-30 substituted hexahydroazepinoindoles of the type described in WO 01/05793; oxazinocarbazoles of the type described in WO 01/09142; aminoalkoxycarbazoles of the type described in WO 01/17963; diphenylsulfones of the type described in the international patent application PCT/US00/30177, filed on June 20,2000; and INTELLECTUAL PROPERTY OFFICE Of i\i.z -1 APR 2005 RECEi V E D WO 02/08178 PCT/SE01/01651 arylsulfonylindoles of the type described in the WO 02/32863. Currently preferable 5-HTg receptor antagonists include the.azepinoindole compound class, such as the class of arylsulfone-substituted hexahydroazepinoindoles 5 compounds disclosed in WO 01/05793. Other preferred 5-HTg receptor antagonists include the arylsulfonylindole compound class, such as the compound class described in WO 02/32863. The 5-HT2c receptor agonists and the 5-HTg receptor antagonists may be the compounds as such or where appropriate the pharmaceutically acceptable salts (acid or 10 base addition salts) thereof or stereochemical^ isomeric forms thereof (including optical isomers, such as enantiomers and racemates). The pharmaceutically acceptable addition salts as mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form. Compounds which have basic properties can be 15 converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid; and organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic 20 acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino 25 acids, such as, e.g. arginine and lysine. The term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like. The 5-HT2c receptor agonists and the 5-HT6 receptor antagonists may also be prodrugs or forms that may release the active ingredient in question after metabolic 30 tranformation in vivo. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985. 7 WO 02/08178 PCT/SE01/01651 The 5-HT2c receptor agonists and the 5-HTg receptor antagonists may be formulated into various pharmaceutical forms for administrative purposes, either in the same pharmaceutical dosage form, such as in the same tablet, or in separate pharmaceutical dosage forms. In the latter case, however, it may be advantageous to put 5 the 5-HT2C receptor agonist unit dosage form and the 5-HTg receptor antagonist unit dosage form in the same package, for example in the same blister. The 5-HT2c receptor agonists and the 5-HTg receptor antagonists, in the form of free bases or salt, can be brought into suitable galenic forms, such as compositions for oral use, for injection, for nasal spray administration or the like, in accordance with 10 accepted pharmaceutical procedures. Such pharmaceutical compositions according to the invention comprise an effective amount of a 5-BT2C receptor agonist and a 5-HTg receptor antagonist in association with compatible pharmaceutically acceptable carrier materials, or diluents, as are well known in the art. The carriers may be any inert material, organic or inorganic, suitable for oral, enteral, rectal, percutaneous, 15 subcutaneous or parenteral administration, such as: water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such compositions may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, and 20 the like. The compositions according to the invention can e.g. be made up in solid or liquid form for oral administration, such as tablets, pills, capsules, powders, syrups, elixirs, dispersable granules, cachets, suppositories and the like, in the form of sterile solutions, suspensions or emulsions for parenteral administration, sprays, e.g. a nasal 25 spray, transdermal preparations, e.g. patches, and the like. The dose level of each of the specific 5-HT2c receptor agonist and 5-HTg receptor antagonist, and the frequency of dosage of the specific combination will vary depending on a variety of factors including the potency of each specific compound employed, the metabolic stability and length of action of that compound, the patient's 30 age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated). The daily dosage may, for example, range from about 0.001 mg to about 150 mg per kilo of body weight, preferably from about 0.01 mg to about 100 mg per kilo of body weight, 8 WO 02/08178 PCT/SE01/01651 especially from about 0.1 to about 50 mgper kilo of body weight of each of the 5-HT2C receptor agonist and of the 5-HTg receptor antagonist, administered singly or multiply in doses, e.g. dosages of from about 0.01 mg to about 1 g each. Usually, such a combined dosage is given orally but e.g. parenteral or rectal administration may also be 5 chosen. An exemplary tablet combination formulation may be in the form of either (A) two separate tablets, i.e. one tablet containing 10 mg, 20 mg or 50 mg of a 5-HT2c receptor agonist, and one tablet containing 10 mg, 20 mg or 50 mg of a 5-HTg receptor antagonist; or (B) a combined tablet containing 10 mg, 20 mg or 50 mg of a 5-HT2C receptor agonist and 10 mg, 20 mg or 50 mg of a 5-HTg receptor antagonist. 10 The invention will now be illustrated further by the following non-limiting Experimental Section. EXPERIMENTAL SECTION 15 A. Preparation of test compounds The free base of the 5-HT2c receptor agonist (2R)-methyl-l-{3-[2-(3-pyridinyloxy) ethoxy]-2-pyrazinyl}piperazine, fumarate ("PNU-183933F") was prepared as described in WO 00/76984. The free base was converted to its fumarate salt, m.p. 126-129°C. MS 20 m/z 315 (M)+. Anal. (C16H21N5O2 ■ C4H4O4) C, H, N. The 5-HT6 receptor antagonist 6-methyl-9-(phenylsulfonyl)-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole, hydrochloride ("PNU-186053A") was prepared as described in WO 01/05793. 25 The 5-HT2C receptor agonist (2R)-l-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, fumarate ("BVT.2938F") was prepared as described in WO 00/76984. 30 The 5-HT6 receptor antagonist l-(phenylsulfonyl)-4-(l-piperazinyl)-lH-indole, hydrochloride ("BVT.5182C") was prepared as described in Swedish patent application No. 0003810-9, filed on October 20, 2000. Briefly, BVT.5182C was prepared according 9 WO 02/08178 PCT/SEO1/01651 the general procedure depicted in Scheme 1, below, starting from commercially available 4-piperazinoindole (compound 1) that undergoes steps (a) to (c) to afford 1-(phenylsulfonyl)-4-(l-piperazinyl)-l#-indole, hydrochloride (yield 80%). HPLC purity >95%; JH NMR (DMSO-^6) 8 9.64 (br s, 2 H), 8.00-7.85 (m, 3 H), 7.79 (d, J= 3>.ll 5 Hz, 1 H), 7.70-7.65 (m, 1 H), 7.63-7.60 (m, 3 H), 7.27-7.22 (m, 1 H), 6.95 (d, J= 3.76 Hz, 1 H), 6.81-6.77 (m, 1 H), 3.30-3.20 (m, 4 H); 13C NMR (DMSO-c?6) 5 144.79, 137.02, 135.22, 134.62,129.82, 126.85, 125.63,125.54,123.49, 111.15, 107.87, 107.76, 47.81,42.86; MS (posES-FIA) m!z 342 (M+H). Scheme 1 h 0 N CO \ H 1 10 Step (a): BOC protection of the piperazine N4 nitrogen 4-Piperazinoindole (leq), DMAP (0.1 eq) and Et3N (4 eq) were dissolved in DMF. (boq2o (1.1 eq) was added and the reaction mixture was stirred at room temperature (12 h). DMF was evaporated and the residue was purified by chromatography on silica gel using a mixture of chloroform, methanol and ammonia as 15 eluent. HPLC: 100 % purity. MS m/z 302.2 (M+H). Step (b): Preparation of intermediate 3 The intermediate 2 (1.0 eq) was dissolved in DMF and NaH (1.3 eq) was added and the suspension was stirred for 0.5 h under nitrogen atmosphere. Benzenesulfonyl 20 chloride (1.2 eq) was added and the reaction was stirred overnight at room temperature. The volatiles were evaporated. The residue was dissolved in DCM, washed with a saturated solution of NaHC03, dried (MgS04), filtered and concentrated to give an oily residue that was purified by chromatography on silica gel using a mixture of hexane and ethylacetate (7:3) as eluent to give tert butyl 4-[ 1 -(benzenesulfonyl)-l£T-indol-4-yl)]-1 - 10 WO 02/08178 PCT/SE01/01651 piperazinecarboxylate (3). HPLC 100 %. NMR (]H and 13C) and MS analyses support the stated structure. Step (c): Removal of the BOC protecting group 5 The BOC group on intermediate 3 was removed by dissolving the compound in methanol followed by addition of ether saturated with HC1 gas. The HC1 salt (4) was filtered and dried. B. Preparation of a pharmaceutical composition 10 Tablet Ingredients me/tablet 1. 5-HT2c receptor agonist 10.0 2. 5-HTg receptor antagonist 10.0 3. Cellulose, microcrystalline 57.0 4. Calcium hydrogen phosphate 15.0 5. Sodium starch glycolate 5.0 6. Silicon dioxide, colloidal 0.25 7. Magnesium stearate 0.75 20 The active ingredients 1 and 2 are mixed with ingredients 3,4, 5 and 6 for about 10 minutes. The magnesium stearate (7) is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating. 25 C. Receptor affinity and efficacy assays 5-HT2C receptor affinity assay 5-HT2C receptor affinity is determined in competition experiments, where the ability of a compound in serial dilution to displace 3H-labeled 5-HT, bound to 30 membranes prepared from a transfected HEK293 cell line stably expressing the human 5-HT2C receptor protein, is monitored by Scintillation Proximity Assay (SPA) technology. Non-specific binding is defined using 5 |iM mianserin. ll WO 02/08178 PCT/SEO1/01651 5-HT2A receptor affinity assay 5-HT2A receptor affinity is determined in competition experiments, where the ability of a compound in serial dilution to displace 3H-labeled ketanserin or lysergic acid diethylamide (LSD), bound to membranes prepared from a transfected CHO cell 5 line stably expressing the human 5-HT2A receptor protein, is monitored by measuring the radioactivity of filtered membrane homogenates on glass fiber filters in a scintillation counter. Non-specific binding is defined using 5 jiM mianserin. 5-HT2B receptor affinity assay 10 5-HT2B receptor affinity is determined in competition experiments, where the ability of a compound in serial dilution to displace ^H-labeled 5-HT, bound to membranes prepared from a transfected CHO cell line stably expressing the human 5-HT2B receptor protein, is monitored by Scintillation Proximity Assay (SPA) technology. Non-specific binding is defined using 5 |iM mianserin. 15 5-HT2C receptor efficacy assay The agonist efficacy at the 5-HT2c receptor is determined by the ability of a compound to mobilise intracellular calcium in transfected HEK293 cells, stably expressing the human 5-HT2c receptor protein, using the calcium-chelating fluorescent 20 dye FLUO-3 (Sigma, St. Louis, MO, U.S.A.). Relative efficacy (%) is measured relative to that of serotonin at 1 juJVt. 5-HT6 receptor affinity assay The radioligand binding assay uses [3H]-lysergic acid diethylamide (LSD). The 25 assay is carried out in 96-well sample plates by the addition of 11 pJ of the test compound at the appropriate dilution (the assay employs 11 serial concentrations of samples run in duplicate), 11 (il of radioligand, and 178 [xl of a washed mixture of WGA-coated SPA beads and membranes in binding buffer prepared from HEK293-cells containing cloned human 5-HTg receptor. The plates are shaken for about 5 30 minutes and then incubated at room temperature for 1 hour. The plates are then loaded into counting cassettes and counted in a scintillation counter. The specifically bound cpm obtained are fit to a one-site binding model using GraphPad Prism ver. 2.0. 12 WO 02/08178 PCT/SE01/01651 Estimated IC50 values are converted to Kj (affinity constant) values using the Cheng-Prusoff equation (Cheng, Y. C. et al., Biochem. Pharmacol. 1973,22, 3099-3108). 5-HT6 receptor efficacy assay 5 The antagonist potency at the 5-HT6 receptor is determined by the ability of a compound to antagonize the increase in cAMP induced by 5-HT in HEK293 cells, stably expressing the human 5-HTg receptor protein, using a cAMP SPA direct screening assay system (RPA559, Amersham Pharmacia Biotech, Uppsala, Sweden). 10 D- Food intake test Test compounds 5-HT2C receptor agonists (2i?)~methyl-l~{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, fumarate ("PNU-183933F") and (2J?)-l-(3-{2-[(2-ethoxy-3-15 pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, fumarate ("BVT.2938F") were dissolved in saline (0.9% NaCl) and diluted in the same vehicle to the appropriate concentration. 5-HTg receptor antagonists 6-methyl-9-(phenylsulfonyl)-l,2,3,4,5,6-hexahydroazepino[4,5-&]indole, hydrochloride ("PNU-186053A") and 1-20 (phenylsulfonyl)-4-( 1 -piperazinyl)- liJ-indole, hydrochloride (5-HTg receptor antagonist ("BVT.5182C") were dissolved and diluted in 25% cyclodextrin. Fresh solutions were prepared on the day of treatment. Animals 25 Male mice 8-9 weeks old (C57BL/6JBom~Lepob (ob/ob), Bomholtsgaard, Denmark) with an average body weight of 45 g were used. The animals were housed singly in cages at 23±1°C, 40-60% humidity and had free access to water and standard laboratory chow. The 12/12 h light/dark cycle was set to lights off at 5 p.m. The animals were conditioned for at least one week before start of study. During 30 experimental sessions, the animals obtained special chow (BioServ, Frenchtown, NJ, USA dust-free precision pellets weighing 20 mg each). 13 WO 02/08178 PCT/SE01/01651 Experimental section At the start of the study the animals were transferred to special cages "operant test cages" (Habitest Modular Animal Behavior Test System; Colbourn Instr, Allentown, PA, USA). These cages consist of a feeder trough with sensors for 5 measurement of food intake, an optic lickometer for registration of water intake and an infrared-based monitor for recording overall general motor activity. The monitors are coupled to a computer, which controls and monitor events continuously. Food pellets were weighed to the amount needed for one whole study and water bottles were filled with fresh tap water and weighed. The animals were conditioned to their new 10 environment for three days to establish baseline values. The animals were weighed at 3 p.m. at the start and at the end of the study. The compounds were administered between 4.20 and 5.00 p.m. before dark onset. Three groups of animals received (i) 5-HTg antagonist in 25% cyclodextrin; (ii) 5-HT2c agonist in saline; and (iii) the combination 5-HT2C agonist/5-HTg antagonist, respectively. When combined, 5-HTg antagonist or 15 saline was administered 30 min before administration of the 5-HT2c agonist or 25% cyclodextrin. A fourth group received respectively vehicle administered in the same way. The study ended on the fifth day. Weighing was performed with a computer-assisted Mettler-Toledo PR5002/PR802 balance. 20 Evaluation of results Each dose group consisted of 12-16 animals. Data were corrected for food spillage based on the weighed spillage during 22 hours and assumed to be proportional over time. Calculations were performed for the data before and after treatment. The values were expressed as % of basal food intake (mean ± SEM) for the difference 25 between food intake before treatment and 3 h (5 pm - 8 pm), 6 h (5 pm - 11 pm), 12 h (5 pm - 5 am), 21 h (5 pm - 2 pm). The results shown in Fig. 1 indicate that combined treatment with the 5-HTg receptor antagonist "PNU-186053A" (50 mg/kg subcutaneously) and the 5-HT2C receptor agonist "PNU-183933F" (50 mg/kg per orally) decreased food consumption 30 significantly more than the compounds given alone. Correspondingly, the results shown in Fig. 2 indicate that combined treatment with the 5-HT2C receptor agonist "BVT.2938F" (5 mg/kg subcutaneously) and the 5-HTg receptor antagonist "BVT.5182C" (3 mg/kg subcutaneously) decreased food consumption, at 12 and 21 14 WO 02/08178 PCT/SEO1/01651 hours following administration, significantly more than the compounds given alone. Thus, it is apparent that combined therapy with a 5-HT2C receptor agonist and a 5-HTg receptor antagonist reduces food intake more efficiently as compared to treatment with either agonist or antagonist alone. 15 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 16 WHAT WE CLAIM IS: 1. A pharmaceutical composition comprising an effective amount of a combination of a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist, or a salt, enantiomer or prodrug form of the said agonist and/or antagonist, and optionally a pharmaceutically acceptable carrier, wherein the 5-HT2C receptor agonist is selected from the group comprising: a) a compound of the general formula (I): -A R (I) \(B)n—R, wherein Ar is aryl or heteroaryl which may be independently substituted in one or more positions by C^g-alkyl, C^.g-alkoxy, Cj.g-alkylthio, Cj.g-acyl, C j.g-alkylsulphonyl, cyano, nitro, hydroxy, C2-6-alkenyl, C2-6-alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, halogen, -N(R2)(R.3), aryl, aryloxy, arylthio, aryl-Cj.4-alkyl, aryl-C2-4-alkenyl, aryl-C2_4-alkynyl, heterocyclyl, heterocyclyloxy, heterocyclylthio or heterocyclyl-C^.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, Cj.g-alkyl, Cj.^-alkoxy, Cj.g-alkylthio, Cj.g-acyl, Cj.g-alkylsulphonyl, nitro, trifluoromethyl, trifluoromethylthio, cyano, hydroxy, amino, Cj.g-alkylamino, di(Cj_6-alkyl)amino or Cj^-acylamino; A is (i) -0-, -S-, -SO2- or -NH-; (ii) a Ci_4-alkyl-substituted nitrogen atom, or (iii) a C}_g-alkylene chain or a heteroalkylene chain having 2 to 8 chain atoms, which optionally contains one or more unsaturations, wherein Cj.g-alkylene and heteroalkylene may be independently substituted in one or more positions by C^.4-alkyl or oxo, and wherein two juxtaposed or spaced chain atoms in C] .g-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 ; n atoms in C1 .g-alkylene or heteroalkylene optionally are joined through a bridging bo|id, to form a saturated or partially or folly unsaturated carbocyclic or heterocyclic ring having 3 to 8 ring members; p wo 00/76984 pct/se00/01017 17 B is -C(R4)(R5K -OC(R4)(R5)-, -N(R6)C(R4)(R5)-, -N(R6>, -0-, -S- or -S02-; R is C3_g-cycloalkyl, aryl or heteroaryl, each of which may be substituted in one or more positions independently of each other by Cj.g-alkyl, Cj.g-alkoxy, fluoro-Ci_6-alkoxy, 2,2,2-trifluoroethoxy, C3_5-alkynyloxy, C3_5-alkenyloxy, dimethylamino-C\.^-alkoxy, methylamino-C\.g-alkoxy, Ci.^-alkylthio, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethylthio, difluoromethoxy, difluoromethylthio, trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano, trifluoromethylsulphonyloxy, C \_5-alkylsulphonamido, C2_6-alkenyl, C2-6~alkynyl, Ci.6-acyl, C j.g-alkylcarbonyl-C j.^-alkyl, Ci.g-alkylsulphonyl, C i .g-alkylsulphonyloxy, C i .g-alkoxy-Cj .g-alkyl, C \ .^-alkoxycarbonyl, C j .g-alkoxycarbonyl-C \ .g-alkyl, C j .g-acvloxy-C j .g-alkyl, hydroxy-C j .g-alkyl, hydroxy-C j .g-alkoxy, C i .g-alkoxy-C j .g-alkoxy, C \ .g-alkoxy-C j .g-alkylthio, hydroxy-Ci-6-alkylthio, heteroaryl-Ci.^-alkylthio, aryl-C^.g-alkylthio, C^g-alkoxy-C i .g-alkylamino, N-(C i .g-alkoxy-C \ _6-alkyl)-N-methylamino, Cj.g-cycloalkyl-Cj_g-alkoxy, aryl-Cj.g-alkoxy, heterocyclyl-Cj-g-alkoxy, Cg.g-cycloalkyl, C3_g-cycloalkyloxy, aryl, aryloxy, arylthio, arylsulphonyl, aryl-C^.g-acyl, aryl-Cj.g-alkyl, aryl-C2_6-alkenyl, aryl-C2-6-alkynyl, heterocyclyl-C \ .g-alkyl, heterocyclyl-C2-6" alkenyl, heterocyclyl-C2-6-alkynyl, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylsulphonyl, heterocyclylamino, heterocyclyl-C \ .g-acyl, -N(R2)(R3), -CON(R7)(Rg) or, when R is optionally substituted C3_g-cycloalkyl, oxo, wherein any cycloalkyl, aryl and heterocyclyl residues as substituents on C3_g-cycloalkyl, aryl or heteroaryl or as part of substituents on C3_g-cycloalkyl, aryl or heteroaryl in turn may be substituted in one or more positions independently of each other by Cj. 4-alkyl, C1.4-alkoxy, methanesulphonamido, Ci_4-alkylthio, C \ .4-alkylsulphonyl, Cj^j-acyl, heterocyclyl, heterocyclyloxy, heterocyclylthio, aryloxy, arylthio, fluoromethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano, N(R2)(R3) or, for C3_g-cycloalkyl and partially or fully saturated heterocyclyl, oxo or hydroxy; R] is (i) a saturated or unsaturated azacyclic or aminoazacyclic ring, or a saturated diazacyclic or aminodiazacyclic ring, which has 4 to 7 ring members, or a saturated aminoazabicyclic, azabicyclic or diazabicyclic ring which has 7 to 10 ring wo 00/76984 18 pct/se00/01017 members, which mono- or bicyclic rings may be mono- or disubstituted in one or more positions independently of each other by, preferably bound to a carbon atom, Cj.4-alkyl, Cj.g-alkoxy, fluoromethyl, trifluoromethyl, difluoromethyl, oxo, hydroxymethyl or methoxymethyl or -N(Rg)2, or, preferably bound to a ring nitrogen atom, hydroxy, 2-hydroxyethyl or 2-cyanoethyl, or, bound to a ring nitrogen atom, Cj.g-acyl, C1.4-alkoxycarbony 1 or tetrahydropyran-2-yl, and wherein a saturated azacyclic ring may contain a further heteroatom selected from oxygen and sulphur; or (ii) a group -[C(R4)(R5)]xN(R2a)(R3a); R2 and R3 independently of each other are hydrogen, Cj.g-alkyl, Cj.g-acyl, -CON(R7)(Rg), aryl, heterocyclyl, aryl-Ci.g-alkyI, heterocyclyl-C\.g-alkyl, aryl-Cj.g-acyl or heterocyclyl-C j _g-acyl, wherein any aryl and heterocyclyl residues in turn may be substituted in one or more positions independently of each other by halogen, C]_4-alkyl, Ci_4-alkoxy, C^_4-alkylthio, C j _4-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or -N(R2)(R3); or R2 and R3 together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members and optionally containing a further heteroatom, which ring may be substituted by Cj.g-alkyl, Cj.g-alkoxy, oxo or hydroxy; R2a and R3a independently of each other are hydrogen, methyl or ethyl, or R2a and R3a together with the nitrogen atom to which they are bound form a pyrrolidine, piperazine or morpholine ring; R4 and R5 independently of each other, and independently on each substituted carbon atom, are hydrogen or Cj.g-alkyl; Rg is hydrogen or C \ .g-alkyl; R7 and Rg independently of each other are hydrogen, Cj. g-alkyl, aryl, heteroaryl, aryl-Cj^4-alkyl or heteroaryl-C],4-alkyl, wherein aryl and heteroaryl residues in turn may be substituted in one or more positions independently of each other by halogen, Cj.g-alkyl, C^.g-alkoxy, Cj.g-alkylthio, Ci_g-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or -N(R2)(R3); or R7 and Rg together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members and optionally containing a further heteroatom; nisOorl,and wo 00/76984 19 pct/se00/01017 x is 2,3 or 4; with the proviso that (i) when -A-R is phenoxy or phenylthio, then Ar is other than quinoxalinyl or pyridyl, and (ii) when A is ethenylene, then Ar is other than quinoxalinyl; and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof; b) a compound of the general formula (II): (i) X and Y represent both nitrogen and Z represents CH, forming a pyrazine derivative, or (ii) X and Z represent both CH and Y represents nitrogen, forming a pyridine derivative, or (iii) X represents C-CF3, Z represents CH, and Y represents nitrogen, forming a 4-trifluoromethylpyridine derivative, or (iv) Y and Z represent both nitrogen and X represents CH, forming a pyrimidine derivative, and wherein Ri and R2 are each, independently, selected from a group A consisting of or from a group B, consisting of aryl-Ci-C6~alkyl, aryl-Ci-C6-alkoxy, heteroaryl-Cr C6-alkoxy, aryloxy-C2-Q-alkoxy, heteroaryloxy-C2-C6-alkoxy, 1-indanyloxy, 2-indanyloxy, aryloxy, heteroaryloxy, arylthio, heteroarylthio, Cs-Ce-cycloalkylthio, Cs-Cg-alkoxy, Cs-Cg-alkylthio, C3-C6-alkynyloxy, C3-Ce-alkenyloxy, fluoro-C2-C4-alkoxy, C4-C8-cycloalkyloxy, C3-C8-cycloalkyl-Ci-C4-alkoxy, halogen, aryl-Ci-C4-alkylthio, heteroaryl-Ci-C4-alkylthio, aryl-C 1 -C4-alkylamino, heteroaryl-Ci-C4-alkylamino, heteroaryl and aryl; with the proviso that; (i) Ri and R2 are different and are not both selected from group A or group B at (II) wherein wo 02/40456 20 pct/se01/02569 same time; (ii) when formula (I) is a pyrazine derivative Rj or R2 are other than phenylthio, phenylmethylthio, phenyl or phenyl substituted by halogen; (iii) Rj in formula (1) is halogen, only when (I) is a pyrazine derivative and when R2 5 simultaneously is 2-methylpiperazin-l-yl, 2-ethylpiperazm-l-yl, or trans-2,5- dimethylpiperazin-1 -yl; (iv) when formula (I) is a pyrazine derivative and Ri is 4-piperidinyloxy, R2 is other than 3-pyridinyhnethoxy, 4-quinolinylmethoxy and 3-(4-pyridinyl)propoxy; (v) when both X and Z are CH and Y is N in formula (I), forming a pyridine 10 derivative, and Rj is 1-piperazinyl or 4-methylpiperazin-l-yl, then R2 is other than 2-phenylethyl, benzyloxy, benzylamino, phenylthio, phenoxy, substituted phenoxy, C^Cg-cycloalkyloxy and Cs-Cs-cycloalkylmethoxy; (vi) when X is CH and Z and Y both are nitrogen in formula (I), forming a . pyrimidine derivative, and R2 is 1-piperazinyl, then Ri is other than phenoxy, phenyl 15 or phenyl substituted by bromo, and C5-C8 alkoxy; and when R2 is 4-methylpiperazin-l-yl or 4-(2-hydroxyethyl)piperazin-l-yl, then Ri is other than 5-nitro~2-furyl; (vii) when X is CH and Z and Y both are nitrogen in formula (I), forming a pyrimidine derivative, and Ri is 1-piperazinyl, then R2 is other than Cs-Cg alkoxy; 20 and where R3 is H or C 1.4-alkyl, allyl, 2-hydroxyethyl, 2-cyanoethyl, or a nitrogen protecting group, or a prodrug moiety such as an acyl- or an alkoxycarbonyl group forming a cleavable amide or carbamate linkage; R4 is hydrogen, or Cm alkyl; and wherein any aryl or heteroaryl residue, alone or as part of another group, in Ri or 25 R2 may be independently substituted in one or more positions, by Cj.4-alkyl, C1.4-alkoxy, C^4-alkylthio, C2-4-acyl, C^ _4-alkylsulphonyl, cyano, nitro, hydroxy, C2-g-alkenyl, C2_6-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, -N(R5)(Rg), aryl, aryloxy, arylthio, aryl-C 1.4-alkyl, aryl-C2-4-alkenyl> aryl-C2-4-alkynyl, heteroaryl, heteroaryloxy, heteroarylthio or heteroaryl-Ci_4-alkyl, aryl-Cj_ 30 4-alkoxy, aryloxy-C 1 _4-alkyl, dimethylamino-C2_4-alkoxy; and P'Sllc wo 02/40456 21 pct/se01/02569 wherein any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in Ri or R2 in turn may be substituted in one or more postions, independently of each other by Cj. 4-alkyl, Ci_4-alkoxy, halogen, trifluoromethyl, cyano, hydroxy or dimethylamino; and R5 and Rg independently of each other are hydrogen, methyl or ethyl, or together with the nitrogen atom to which they are bound form a pyrrolidine, piperazine, morpholine, thiomojpholine or a piperidine ring; and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof,; and c) a compound of the general formula (III): Ri is hydrogen, Ci_4 alkyl, C3_4~alkenyl, Cj^-acyl, C\_4-alkoxycarbonyl, 2-hydroxyethyl, 2-cyanoethyl, tetrahydropyran-2-yl, or a nitrogen protecting group; R2 is hydrogen, Ci ..4-alkyl, hydroxymethyl, Ci-4-alkoxymethyl, or fluoromethyl; R3 and R4 independently of each other are hydrogen, methyl, Ci_4-alkyl, aryl, heteroaryl wherein aryl and heteroaryl residues in turn may be substituted in one or more positions independently of each other by halogen, Ci_4-alkyl, Ci_4-alkoxy, Ci_4-alkylthio, Cj^-alkylsulphonyl, methanesulphonamido, acetyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, methylamino, dimethylamino, or acetamido; or R3 and R4 together with the carbon atoms to which they are bound form a 5-or 6-membered aromatic or heteroaromatic ring, which may be substituted in one or ; more positions by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, ! cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino or acetamido; (III) wherein WO 02/40457 22 PCT/SE01/02570 R5 and Rg independently of each other are hydrogen, Ci-C4-alkoxy-C2-C4-alkyl, hydroxy~C2-Cralkyl, Ci-C6-alkyl, C2-C6-acyl, aryl, heteroaryl, aryl-Ci-C2-alkyl, heteroaiyl-Ci-C2-alkyl, aryl-Ci-C2-acyl, heteroaryl-Ci-C2-acyl, and wherein any aryl or heteroaryl, alone or as part of another group, may be independently substituted in one or more positions by C^.4-alkyl, Ci_4-alkoxy, Ci-4~alkylthio, C2-4-acyl, C\.4-alkylsulphonyl, cyano, nitro, hydroxy, C2_3-alkenyl, C2-3-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, dimethylamino, or methylamino; or R5 and Rg together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members which ring may contain an additional heteroatom and which maybe substituted by methyl, oxo, or hydroxy; R7is hydrogen or a substituent selected from halogen, methyl, methoxy, and ethoxy; and and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, iV-oxides or prodrug forms thereof; and the 5-HT receptor antagonist is selected from the group comprising: a) a 9-arylsulfone of the general formula (IV): (1)-H, (2) C,-C4 alkyl, (3) C0-C4-41 where the -<j> substituent is optionally substituted with 1 or 2 (a) -F, -CI, -Br, -I, (b) -O-r3-1 where R.vi is: n= 1 —3; (IV) where R3 is: -H, C1-c4 alkyl, -<)>, (c) -CF3> 23 15 (d) -CO-nr3.2r.3-3 where r3.2 and r3.3 are -h and C1-c4 alkyl, and where r3. 2 and r3.3 are taken with the attached nitrogen atom to form a ring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl, (e) -nh-so2-r3-4 where r3-4 is -h and C,-C4 alkyl, (f) -nr3-2r3-3 where r3.2 and r3.3 are as defined above, 20 (g) -nr3-4-CO-r3.4 where r3-4 is as defined above, (h) -so2-nr3.2r3-3 where r3-2 and r3.3 are as defined above, (d-on, (j) -no2, where Rn is: 25 (1) -H, (2) C1-c4 alkyl, (3) Co-C4-<t> where the -<)> substituent is optionally substituted with 1 or 2 (a) -F, -CI,-Br, -I, (b) -O-Rn-i where Rn-i is 30 -h, C1-c4 alkyl, -<t>, (c) -CF3, (d) -CO-NRn-2Rn-3 where Rn-2 and Rn-3 are -H and C1-c4 alkyl, and where 5 R3-2 and r3.3 are taken with the attached nitrogen atom to form a ring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl, (e) -NH-S02-RN-4 where Rn-4 is -H and C1-C4 alkyl, (f) -NRn.2Rn-3 where Rn-2 and Rn-3 are as defined above, (g) -NRn^-CO-Rn-4 where Rn-4 is as defined above, 10 (h) -SO2-NRN-2RN-3 where Rn-2 and Rn_3 are as defined above, (D -CeN, 0) -no2, where Rx is: (1)-H 15 (2) -F, -CI, -Br, -I, (3) -O-Rx-i where Rx-i is: -H, C,-C4 alkyl, 20 (4) -cf3, (5) -CO-NRx-2Rx-3 where Rx-2 and Rx-3 are as defined above, (6) -NH-S02-Rx-t where Rx^t is as defined above, j 'tLU 24 (7) -NRx-2Rx-3 where RX-2 and Rx-3 are as defined above, (8) -NRx-4-CO-Rx.4 where Rx-4 is as defined above, 25 (9) -SC>2-NRx-2Rx-3 where Rx-2 and Rx-3 are as defined above, (10) -C=N, (11)-N02; where R9 is: (D-H, 30 (2) -F, -CI, (3) C,-C4 alkyl, (4) C1-c3 alkoxy, (5) -cf3, (6) Co-CH) where the -<)» substituent is optionally substituted with 1 or 2 (a) -F, -CI, -Br, -I, (b) -O-r9.1 where r9.1 is: -H, C1-c4 alkyl, -, (c) -CFj, (d) -CO-nr9-2r9-3 where r9.2 and r9-3 are -H and C1-c4 alkyl, and where r9-2 and r9.3 are taken with the attached nitrogen atom to form a ring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl, (e) -NH-SO2-R9-4 where R9-4 is -H and C1-C4 alkyl, (f) -nr9.2r9-3 where r9.2 and r9.3 are as defined above, (g) —NR9JI-CO-R9-4 where R9-4 is as defined above, (h) -so2-nr9.2r9-3 where r9.2 and r9.3 are as defined above, (D -ON, (j) -no2 (7) -or9.1 where R9.1 is as defined above, (8) -CO-nr9.2r9.3 where r9-2 and r9.3 are as defined above, (9) -nr9.2r9-3 where R9.2 and r9-3 are as defined above, (10) -NH-so2-r9-4 where R9^ is as defined above, (11) -NH-co2-r9-2 where R9.2 is as defined above and pharmaceutically acceptable salts thereof; and 25 b) a compound of the general formula (V): R R" R' ,2 \ Ar (V) wherein Ar is (1) phenyl, (2) naphthyl, (3) a 5- to 10-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, or (4) -R9-phenyl; wherein each of phenyl, naphthyl, and heterocyclic ring is independently optionally substituted with halogen, Ci_6 alky!, CF3, hydroxyl, Ci-e alkoxyl, OCF3, COCF3, CN, NO2, phenyloxy, phenyl, Ci-6 alkylsulfonyl, C2-6 alkenyl, -NR7R8, Cue alkylcarboxyl, formyl, -Ci.g alkyl-NH-CO-phenyl, -C]_6 alkyl-CO-NH-phenyl, -NH-CO-Ci-s alkyl, -CO-NR7R8, or SR7; wherein each of R7 and R8 is independently H or C-t-e alkyl; and R9 is Ci-6 alkyl or C2-6 alkenyl, each of which being optionally substituted with phenyl or phenyloxy; R2 is H, phenyl, I, or Cu alkyl; R3 is H or 3-(L-azabicyclo[2.2.2]oct-2-en)yl; R4 is H or a heterocyclic ring selected from the group consisting of: wherein R6 is H, Cmj alkyl, or benzyl; and 26 Rs is H, hydroxy, C1-3 alkoxy, F, no2, cf3, OCF3, or a heterocyclic ring selected from the group consisting of: or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, with the proviso that when is alkyl, is not H. The pharmaceutical composition according to claim 1 wherein the 5-HT2C receptor agonist is (2R)-methyl-l-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, wherein the 5-HT2C receptor agonist is (2R)-l-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 3, wherein the 5-HT6 receptor antagonist is 6-methyl-9-(phenylsulfonyl)-l,2,3,4,5,6-hexahydroazepino[4,5]indole, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 3, wherein the 5-HT6 receptor antagonist is l-(phenylsulfonyl)-4-(l-piperazinyl)-lH-indole, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 5, wherein the 5-HT2C receptor agonist has a selectivity for the 5-HT2C receptor of at least about 10, relative to the 5-HT2A receptor, the 5-HT2B receptor, and the 5-HTg receptor, respectively. The pharmaceutical composition according to any one of claims 1 to 5, wherein the 5-HT2C receptor agonist has a selectivity for the 5-HT2c receptor of at least about 20, relative to the 5-HT2A receptor, the 5-HT2B receptor, and the 5-HT6 receptor, respectively. The pharmaceutical composition according to any one of claims 1 to 7, whdrein receptor antagonist has a selectivity for the 5-HT6 receptor of at least about 10, rektive .to., n ^ I'iAh £' the 5-HT2A receptor, the 5-HT2B receptor, and the 5-HT2C receptor, respectively. 27 9. The pharmaceutical composition according to any one of claims 1 to 7 wherein the 5-HT6 receptor antagonist has a selectivity for the 5-HT6 receptor of at least about 20, relative to the 5-HT2A receptor, the 5-HT2B receptor, and the 5-HT2C receptor, respectively. 10. A process for preparing a pharmaceutical composition according to any one of claims 1 to 9, wherein a 5-HTac receptor agonist and a 5-HT6 receptor antagonist in a combined therapeutic amount are intimately mixed with a pharmaceutically acceptable carrier. 11. A product containing a 5-HT2C receptor agonist and a 5-HT(, receptor antagonist, as a combined preparation for simultaneous, separate or sequential use in therapy of a disease related to the 5-HT2C receptor and the 5-HT6 receptor, wherein the 5-HT2C receptor agonist and the 5-HT6 receptor antagonist are as defined in claim 1. 12. The product according to claim 11, wherein the 5-HT2C receptor agonist is (2R)-methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, or a pharmaceutically acceptable salt thereof. 13. The product according to claim 11, wherein the 5-HT2C receptor agonist is (2R)-l-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, or a pharmaceutically acceptable salt thereof. 14. The product according to any one of claims 11 to 13, wherein the 5-HT6 receptor antagonist is 6-methyl-9-(phenylsulfonyl)-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole, or a pharmaceutically acceptable salt thereof. 15. The product according to any one of claims 11 to 13, wherein the 5-HT6 receptor antagonist is l-(phenylsulfonyl)-4-(l-piperazinyl)-lH-indole, or a pharmaceutically acceptable salt thereof. 16. The product according to any one of claims 11 to 15, wherein the disease is selected from eating disorders, CNS disorders, urinary incontinence and glaucoma. 17. The product according to claim 16, wherein the disease is over-weight or obesity. OF 18. 19. 20. 21. 22. 23. 24. 25. 26, 27 28 28 Use of a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist, or a salt, enantiomer or prodrug form of the said agonst and/or agonist, wherein the 5-HT2C receptor agonist and the 5-HT6 receptor antagonist are as defined in claim 1, for the manufacture of a medicament for the treatment of a disease related to the 5-HT2C receptor and the 5-HT6 receptor. The use according to claim 18, wherein the 5-HT2C receptor agonist is (2R)-methyl-l-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, or a pharmaceutically acceptable salt thereof. The use according to claim 18 wherein the 5-HT2C receptor agonist is (2R)-l-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, or a pharmaceutically acceptable salt thereof. The use according to any one of claims 18 to 20, wherein the 5-HT6 receptor antagonist is 6-methyl-9-(phenylsulfonyl)-l,2,3,4,5,6-hexahydroazepino[4,5]indole, or a pharmaceutically acceptable salt thereof. The use according to any one of claims 18 to 20, wherein the 5-HT6 receptor antagonist is 1-(phenylsulfonyl)-4-(l-piperazinyl)-lH-indole, or a pharmaceutically acceptable salt thereof. The use according to any one of claims 18 to 22, wherein the disease is selected from eating disorders, CNS disorders, urinary incontinence and glaucoma. The use according to claim 23, wherein the disease is over-weight or obesity. A pharmaceutical composition as claimed in claim 1 substantially as herein described with reference to any example thereof. A process as claimed in claim 10 substantially as herein described with reference to any example thereof. A product as claimed in claim 11 substantially as herein described with reference to any example thereof. A use as claimed in claim 18 substantially as herein described with reference to any example thereof. </div>