Title of Invention

PIPERAZINYLPYRAZINES COMPOUNDS AS ANTAGONISTS OF SEROTONIN 5-HT2 RECEPTOR

Abstract The invention relates to compounds of general formula (I), wherein R1, R2 and R3 are as described in the specification, which compounds are ligands to the serotonin 5-HY <sub>2c</sub> receptor.
Full Text

PIPERAZINYLPYRAZINES COMPOUNDS AS ANTAGONISTS OF SEROTONIN 5.HT2 RECEPTOR.
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-HT2c receptor subtype in the regulation of food intake (Obes. Res, 1995. 3, Suppl. 4,449S-462S). The 5-HT2c receptor subtype is transcribed and expressed in hypothalamic structures associated with appetite regulation. It has been demonstrated that the 5-HT2c receptor agonist 7n-chlorophenyIpiperazine (mCPP), 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 (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 m obese subjects (Psychopharmacology 1997,133,309-312). Recently, a series of pyrrolo[3,2,l-/y]quinolines derivatives was identified to be 5-HT2C receptor agonists having selectivity over the 5-HT2A receptor (Isaac M., et al., Borg. 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., Drugs 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-HT2c 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; I Drugs 1999,2,109-120).
The 5-HT2c receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (E)rugs 1999,2,109-120).
Compounds which have a selective effect on the 5-HT2c 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
US-A-3,253,989 discloses the use of mCPP as an anorectic agent.
EP-Al-863 136 discloses astatine and pyrrolidine derivatives which are selective 5-HT2c 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-HT2c receptor and which inter alia may be used for treating eating disorders.
EP-A-655 440 discloses 1-aminoethylindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
EP-A-572 863 discloses pyrazinoindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
J. Med Chem. 1978,21,536-542 and US-A-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-HT2b and/or 5-HT2c receptor ligand, especially for the treatment of obesity.
WO 00/12510 discloses pyrroloindoles, pyridoindoles and azepinoindoles as 5-HT2c receptor agonists, particularly for the treatment of obesity.

woo 00/12482 discloses indazole derivatives as selective, directly active 5-HT2c receptor ligands, preferably 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/12502 discloses pyrroloquinolines as 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/35922 discloses 2,3,4,4a-tetrahydro-li7-pyrazino[l,2-a]quinoxalin-5(6H)ones as 5HT2c agonists, which may be used for the treatment of obesity.
WO 00/44737 discloses aminoalkylbenzofurans as 5-HT2c agonists, which may be used for the treatment of obesity.
Further compounds reported to be 5HT2c 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 y-carbonizes 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; Benz furans 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 tiie type described in WO 01/12603; indoline of the type described in WO 01/12602; pyra2ino(a2a)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 l-piperazinyl-2-[2-(phenyl)ethenyl]"quinoxaline derivatives which exhibit anti-inflammatory activity.
Chem. Pharm. Bull. 1993.41(10) 1832-1841 discloses 5-HT3 antagonists including 2-(4-methyM-piperazinyl)-4-phenoxyquinoxaline,
GB-B-1,440,722 discloses 2-(r-pipera2inyl)-quinoxaline compounds having pharmaceutical activity against depression.
WO 96/11920 discloses CNS-active pyridinylurea derivatives. WO 95/01976 discloses indoline derivatives active as 5-HT2c antagonists and of potential use in the treatment of CNS disorders.
WO 97/14689 discloses arylpiperazine cyclic amine derivatives, which are selective S-Thud receptor antagonists.

wo 98/42692 discloses piperazines derived form cyclic amines, which are selective antagonists of human 5-HTia, 5-HTi(j and S-Hut, receptors.
GB-B-1,465,946 discloses substituted pyridazinyl, pyrimidinyl and pyridyl compounds which are active as p-receptor blockage agents.
EP-A-711757 discloses [3-(4-phenyl-pipera2in-l-yl)propylamino]-pyridine, pyrimidine and benzene derivatives as a-adrenoceptor antagonists.
WO 99/03833 discloses aiylpiperazine derivatives, which are 5-HT2 antagonists and S-Hits 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 discloses aryl-hydronaphthalen-alkane amines which may effectuate partial or complete blockage of serotonergic 5-HT2c 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 computed 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 tiie 5-HT2c receptor.
Summary of the Invention According to the invention novel compounds of the general formula (Q are provided:





R3 and R4 together with the carbon atoms to which they are bound form a 5-or 6-membered aromatic orheteroaromatic ring, which may be substituted in one or more positions by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethyl thio, amino, methylamino, dimethylamino or acetamide; and
each of Hall and Hal2, independently, is halogen.
In further another aspect, the invention provides the compounds according to fondle (T) above for use in therapy.
Still another aspect of the invention provides a pharmaceutical composition comprising a compound according to formula (I) above as the active ingredient, preferably together with pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents.
In yet another aspect, the invention provides a method for the treatment of a human or animal subject suffering from a serotonin-related disease, particularly 5-HT2C receptor-related, especially eating disorders, particularly obesity; memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy and urinary disorders.
Another aspect of the invention provides the use of the compounds according to fondle (I) above for the manufacture of a medicament for the treatment of a serotonin-related disease, particularly 5-HT2c receptor-related, especially eating disorders, particularity obesity; memory disorders; schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy and urinary disorders.
Finally a method for modulating 5HT2c receptor function is an aspect of the invention.
Detailed Description of the Invention According to the present invention, a class of novel compounds has been developed which bind to the 5-HT2c receptor (agonists and antagonists) and which therefore may be used for the treatment of serotonin-related disorders.
First, the various times used, separately and in combinations, in the above definition of the compounds having the general funnels (T) will be explained.

By "heteroatom" is meant nitrogen, oxygen, sulphur, and in heteroaromatic rings, also selenium.
The term "aryl" includes phenyl, 1-naphthyl and 2-naphthyl.
The term "heteroaryl" includes five- and six-membered heteroaromatic rings such as pyrrole, imidazole, thiophene, furan, selenophene, thiazole, isothiazole, thiadiazolyl, oxazole, isoxazole, oxadiazole, pyridine, pyrazines, pyrimidine, pyridazine, pyrazoles, triazole and tetrazolyl.
, which may be straight or branched, is preferably alkyl. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, -butyl, to-/-butyl, pentyl, isopentyl, hexyl, and isO hexyl.
Ci_4-alkoxy may be straight or branched. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy -butoxy and butoxy.
C2^"alkenyl may be straight or branched. Exemplary alkenyl groups include vinyl, 2-propenyl and l-methyl-2-propenyl.
Ci-C4-alkoxy-C2-C4-alkyl may be straight or branched. Exemplary groups include 2-(methoxy)ethyl, 3-methoxy-1-propyl, 4-ethoxy-l-butyl and the like.
Exemplary aiyl-Ci-C2-acyl include benzoyl and phenylacetyl. Exemplary heteroaiyl-Ci-C2-acyl include nicotine and 3-pyridinylacetyl and the like.
C2-4-acyl may be saturated or unsaturated. Exemplary acyl groups include acetyl, propynyl, butyryl, isobutyryl, and butenyl (e.g. 3-butenoyI).
Halogen includes fluorine, chlorine and bromine.
Where it is stated above that aryl and heteroaryl residues maybe substituted, this applies to aryl and heteroaryl as well as to any combined groiqjs
containing aryl or heteroaryl residues, such as heteroaryl- Ci-C2-alkyi and aryl-
C2-acyl
The term "A -oxides" means that one or more nitrogen atoms, when present in a compound, are in -oxide form (N->0),
The term "prodrug forms" means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman's, The Pharmacological

basis of Therapeutics, 8* ed,, McGraw-fill, Int. Ed. 1992, "Biotransformation of Dmgs, p. 13-15.
"Pharmaceutically acceptable" means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" mean salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, toluenesulphonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid, and the like.
Ri is preferably hydrogen or methyl. Most preferably Rj is hydrogen.
Ri may also serve as a nitrogen protecting group, and then Ri is r-butoxycarbonyl (t-BOQ, benzyl, or trityl.
R2 is preferably hydrogen or methyl (especially in the 2-position of the
piperazine ring).
R3 and R4 are preferably (independently) hydrogen, halogen or methyl. When R3 and R4 form a ring together with the ring carbons to which they are bound, such a ring is preferably benzene (to give quinoxaline) or thiophene (to give thieno[3,4-bjpyrazine). When substituted, the rings are preferably mono- or disubstituted, preferably by halogen or methyl.
When R7 is other than hydrogen it may occiqjy any available position of the
phenyl ring.
The group -CH2N(R5)(R6) may be attached to the ortho-, meta-, or iH para position, relative to the alkylenedioxy side-chain, of the phenyl ring, preferably the meta position.
n in formula (I) is 1-3 where n is the number of methylene groups, n is preferably 1, having the meaning that the two oxygen atoms in formula (I) are spaced between a -CH2CH2- group;

Preferred compounds of the general formula (I) above are: 2-(l-Piperazinyl)-3-{2-[3-(4-moipholinyhnethyl)phenoxy]ethoxy}pyra2ine; 2-(l -Pipera2inyl)-3- {2-[3-(l -pyrrolidinyhnethyl)phenoxy]ethoxy}pyra2ine; 2-(l-Pipera2inyl)-3-{2-[3-(4-methyl-l-pipera2inylmethyl)phenoxy]ethoxy}pyrazine; 2"(1-Pipera2inyl)-3-{2-[3-{(2-
methoxyethyl)amino}methyI)phenoxy]ethoxy}pyrazine; 2-(l-Piperazinyl)-3-{2-[3-{(isopropylamino)methyl}phenoxy]ethoxy}pyrazine, and their pharmacologically acceptable salts and solvates.
In another aspect, this invention relates to compounds of any of the formulae herein and their use as delineated herein, wherein R5 and R together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members, and which may contain an additional heteroatoms. Exemplary rings are acetonide, pyrrolidine, piperazine, homopiperazine, morpholine, thiomorpholinyl, or piperidine. The saturated heterocycie ring may be substituted by methyl, 0x0, or
hydroxy.
As mentioned above, the compounds of the present invention are useful for the treatment (including prophylactic treatment) of serotonin-related disorders, especially
5-HT2C receptor-related, in a human being or in an animal (including e.g. pets), such as eating disorders, especially obesity^, memory disorders, such as Alzheimer’s disease; schizophrenia; mood disorders, including, but not restricted to, major depression and bipolar depression, including both mild and manic bipolar disorder, seasonal affective disorder (SAD); anxiety disorders, including situational anxiety, genera Used anxiety disorder, primary anxiety disorders (panic disorders, phobias, obsessive-compulsive disorders, and post-traumatic stress disorders), and secondary anxiety disorders (for example anxiety associated with substance abuse); pain; substance abuse; sexual dysfunctions; epilepsy and urinary disorders, such as urinary incontinence.
The compounds of the present invention in radiolabeled form, maybe used as a diagnostic agent
The compounds of the general formula (T) above maybe prepared by a method of this invention, or by, in analogy with, a conventional method. This

invention relates to methods of making compounds of any formulae herein comprising reacting any one or more of the compounds or formulae delineated herein including any processes delineated herein.
For example, as shown in Scheme 1, a cowpox of formula (I) maybe
prepared by first treating a compound of formula (II), wherein Hal is halogen and R3
and R4 axe as defined above, with an appropriate piperazine of formula (EI), wherein
R] and R2 have the same meaning as m formula (I) and where Ri may be a suitable nitrogen protecting group, such as trityl, ben2yl or /err-butoxycarbonyl, to provide a compound of formula (IV). The reaction is carried out in a solvent, such as, acetonitrile, dioxane, tetrahydrofliran (THF), n-butanol, TV^AT-dimethylformamide (DMF), or in a mixture of solvents such as DMF/dioxane, optionally in the presence of a base, such as K2CO3, Na2C03, CS2CO3, NaOH, triethylamine, pyridine, or the
like, at 0-200 ""C for 1-24 hours.
The compound of formula (IV) is reacted with a diol of formula (V), wherein n has the same meaning as in formula (I), to provide intermediate (VI). The reaction is earned out in a solvent, such as, dioxane, THF, DMF or pyridine, and the like, in the presence of a base such as K-r-BuO, Na-r-BuO, NaH, or tiie like, at 0-150 °C for 1-24 hoaxers.
Interaiediate (VI) is reacted with a hydroxy benzaldehyde compound of
formula (VII), wherein R7 has the same meaning as in formula (T), to provide the aldehyde intermediate (VIII). The reaction may be carried out in the presence of diethyl azodicarboxylate (DEAD) or l,r-azobis( dimethylformamide) (cf. Tetrahedron Lett, 1995,36,3789-3792), preferably DEAD, and triphenylphosphine (PPhs) in a solvent such as THF or dichloromethane (Mitsimobu reaction; see: Org.
React. 1992,42, 335-656.).
Subjecting intermediate (VIII) to a standard reductive alkylating procedure (such as described in J. Org. Chem, 1996.61,3849-3862), with an q) propriate amine of frail (DQ, wherein R5 and R^ have the same meaning as in formula (I), results in a compound of this invention Q),
When Ri in formula (I) is a nitrogen protecting group as defined below, the subsequent JV-deprotection may be performed under standard conditions, suds as



addition salts from base compounds. Examples of addition salt forming acids are maleic acid, fumaric acid, succinic acid, methanesulfonic acid, acetic acid, oxalic acid, benzoic acid, hydrochloric acid, sulphuric acid, phosphoric acid, and the like.
The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g., as a pure enantiomer, or as a mixture of enantiomers (racemates) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
In accordance with the present invention, the compounds of formula (T), in the form of free bases or salts with physiologically acceptable acids, can be brought into suitable galena forms, such as compositions for oral use, for injection, for nasal spray administration or the like, in accordance with accepted pharmaceutical procedures. Such pharmaceutical compositions according to the invention comprise an effective amount of the compounds of formula (I) 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 enteral, percutaneous, subcutaneous or parenteral administration, such as: water, gelatin, gum arabiciun, 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 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, dispersible granules, cachets, suppositories and the like, in the form of sterile solutions, suspensions or emulsions for parenteral administration, sprays, e.g. a nasal spray, transiently preparations, e.g. patches, and the like.
As mentioned above, the compounds of the invention may be used for the treatment of serotonin-related disorders in a human being or an animal, such as eating disorders, particularly obesity, memory disorders, schizophrenia, mood districts,

anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy and urinary disorders. The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that cowpox, the patient's 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, and the patient undergoing theory. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its finest extent All populations cited herein are hereby incorporated by reference in their entirety.
EXAMPLES
General:
NMR spectra were recorded on a Bruker Advance DPX 400 MHz spectrometer at 25 **C. Chemical shifts are given in ppm relative to tetramethylsilane. LC/MS data were obtained using an HP 1100 hplc system coupled to a Micromass platform LC mass spectrometer running MassLynx. Details of the hplc are: Coleman, Phenomenex CIS Luna, 30 x 46 mm at 40 ± 1 °C. Eluant gradient T= 0,95% (0.1% formic acid in water) and 5% (0.1% formic acid in acetonitrile, then a linear gradient to T= 2.5 min, 5% (0.1% formic acid in water) and 95% (0.1% formic acid in acetonitrile), then a further 1 min at these conditions. Eluent flow rate was 2 mL/min. Detection was by UV diode array at window 210-400 nm. Alternate 4-ve and -ve ion APCI mass spectra were collected throughout the 3.5 min, scanning between 100 and 650 mass units. High resolution MS were obtained on a Micromass LCT spectrometer. Developing solvents for TLC on sihca were di-isopropyl ether or ethyl acetate/light petroleum mixtures.

EXAMPLE 1 2-(l-Piperazinyl)-3-{2-[3-(4-raorpholinyImethyl)phenoxy]ethoxy}pyramid.
Step 1: 2-Chloro-3"(4 -butoxycarbonyH"piperazinyl)pyrazine. The title compound was prepared according to the procedure described in WO 00/76984. A mixture of 7\/'-BoC"piperazine (11.47 g, 61.5 mmol), K2CO3 (S;5 g, 61 mmol) and 2,3-dichloropyrazine (9.20 g, 61.7 mmol) in acetonitrile (100 mL) was stirred at 100
°C for 40 h. The reaction mixture was concentrated, dissolved in toluene, washed
with water, dried (MgS04), and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (7:3) as eluent to give 18.3 g (100%) of the title product. HRMS miss called for C13H19N4O2 (M)"^ 298.1197, found 298.1206.
Step 2: 2-[3-(4-/e/^-Butoxycarbonyl-l-piperazmyI)-2-pyrazinyloxy] ethanoL The
title compound was prepared according to the procedure described in WO 00/76984. KO-^Bu (9.92 g, 103 mmol) was added to a mixture of the product obtained in step 1 (18.14 g, 60.7 mmol) and ethylene glycol (25 mL, 448 mmol) in pyridine (125 mL) at
85 ^'C. The reaction mixture was stirred for 15 h and then poured into ice-water and extracted with toluene. The organic phase was dried (MgS04) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 16.9 g (85%) of the title product HRMS for C15H24N4O4 (M)-" 324.1798, found 324.1784.
Step 3: tert’butyl 4-{3-[2-(3-formylphenoxy)ethoxy]-2-pyrazinyl}-l-piperazine carboxylate.
A solution of the compound obtained in step 2 above (1.5 g, 4.7 mmol) in dry tetrahydrofliran (THF; 10 mL) was treated with 3-hydroxybenzaldehyde (0.74 g, 6.06 mmol) and triphenylphosphine (1.59 g, 6,06 mmol). This solution was stirred at room temperature then treated with diethyl azodicarboxylate (0.96 mL, 6.06 mmol) in dry THF (5 mL). After 1 hr, TLC indicated some remaining 2-[3-(4-re?t-butoxycarbonyl-l-pipera2inyl)-2-pyrazinyloxy]ethanol The reaction was heated at reflux under

nitrogen for 5 h, then left to cool to room temperature overnight. TLC again showed unreacted starter. The mixture was treated with further triphenylphosphine (0.80 g, 3.03 mmol), diethyl azodicarboxylate (0.5 mL, 3.03 mmol) and S-hydroxybenzal-dehyde (0.40 g, 3.03 mmol), then stirred at RT for a further 3 hrs (reaction complete by TLC). The volatiles were removed in vacuo and the residue was purified by flash column on silica gel, eluting with petroleum ether/ethyl acetate (2:1). This furnished 0.33 g (16%) of the title product as a colourless oil. ^H NMR (CDCI3) 5 1.5 (s, 9H); 3.5 (bs, 8H), 4.45 (m, 2H); 4.75 (m, 2H); 7.2 (d, IH); 7.45 (s, IH); 7.5 (m, 2H); 7.6 (s, IH); 7.75 (s, IH).
Step 4: teri-Bntyl 4-(3-{2-[3-(4-morphoUnylmethyI)phenoxy ethoxy}-2-pyrazinyl)-l-piperazine carboxylate.
A stirred solution of the aldehyde from step 3 above (71.2 mg, 0.166 mmol) in 1 dichloroethane (5 mL) was treated with morpholine (19 mg, 0.22 mmol), 3A molecular sieves and sodium triacetoxyborohydride (52 mg, 0.25 mmol). The mixture was stirred at room temperature for 5 h (TLC monitoring). The solution was filtered and the filtrate was treated with an excess of saturated aqueous sodium bicarbonate. The ether extracts were separated and dried over magnesium sulfate. The mixture was filtered and solvent was removed in vacuo to give 54 mg (65%) of
the title product as a yellow oil. Pure by NMR. ^H NMR (CDCI3) 5 1.4 (s, 9H); 2,35 (m, 4H); 3.4 (m, lOH); 3.65 (m, 4H); 4.3 (m, 2H); 4.65 (m, 2H); 6.75 (d, IH); 6,9 (m, 2H); 7.2 (t, IH); 7.5 (s, IH); 7.7 (s, IH).
Step 5:2-(l-Pipera2inyI)-3-{2-I3-(4-raorphoIinyImethyl)phenoxy]ethoxy}pyramid,
The product from step 4 above (54 mg, 0,11 mmol) was dissolved in dry ether (20 mL), stirred at room temperature and treated with hydrogen chloride in ether (-€ M; 5 mL), The resulting white suspension was stirred for 2 h, then quickly filtered off. The hydrochloride salt (hygroscopic), was dissolved in water and neutralized with sodium carbonate. The free base was extracted into dichloromethane. The organic layers were dried magnesium sulfat, filtered, and concentrated in vacuo to finish 13 mg (29%) of the title product as a pale yellow oil. LS/MS purity 100%. ^H NMR (CDas) 5 1.8 (b, IH); 2.45 (m, 4H); 2,95 (m, 4H); 3.45 (s, 2H); 3.55 (m, 4H); 3.7





Affinity assay
The 5-HT2c receptor affinity of compounds in the Examples was determined in competition experiments, where the ability of each compound in serial dilution to displace ^H-labelled 5-HT, bound to membranes prepared from a transfected HEK293 cell line stably expressing the human 5-HT2c receptor protein, was monitored by Scintillation Proximity Assay technology. Non-specific binding was defined using 5 pM mainspring. Results obtained for exemplary compounds of the invention are illustrated in Table 1 below. Typically, the 5HT2c receptor affinity values (Ki, nM) were in the range of 1 nM to 1500 nM, preferably 1 nM to 100 nM.





CLAIMS
1. A compound of the general formula (T);

wherein
Ri is hydrogen, alkyl, -alkenyl, C1-4-acyl, C1-4-alkoxycaibonyl, 2-hydroxyethyl, 2-cyanoethyl, tetrahydropyran-2-yi, or a nitrogen protecting glory;
R2 is hydrogen, C1-4-alkyl, hydroxymethyl, C1-4-alkoxymethyl, or
fluoromethyl;
R3 and R4 independently of each other are hydrogen, methyl C1-4-alkyl, aryl, heteroaryl wherein aryl and heteroaryl residues in turn may be substituted in one or more positions independently of each other by halogen, C1-4-alkyl, alkoxy, C1-4-alkylthio, C1-4-alkylsulphonyl, methanesulphonamido, acetyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, triiluoromethylthio, amino, methylamino, dimethylamino, or acetamide; 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;

R5 and R5 independently of each other are hydrogen, C1-4-alkoxy-C2-C4-
alkyl, hydroxy-C2-C4-alkyl, Ci-Cg-alkyl, C2-C6-acyl, aryl, heteroaryl, aryl-C1-4-
alkyl, heteroaryl-C1-4"alkyl, aryl-CrC2-acyl, heteroaryl-C1-4-acyl, and wherein any aryl or heteroaryl, alone or as part of another group, may be independently substituted in one or more positions by C1-4-alkyl, alkoxy, Ci-4-alkylthio, C2-4-'acyl, alkylsulphonyl, cyano, nitro, hydroxy, C2-3-alkenyl, C2-3-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, dimethylamino, or methylamino; or
R5 and R together with the nitrogen atom to which they are bound form a saturated heterocycc ring having 4-7 ring members which ring may contain an additional heteroatom and which may be substituted by methyl, 0x0, or hydroxy;
R7 is hydrogen or a substituent selected from halogen, methyl, methoxy, and
ethoxy; and
n=l-3; and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, TV-oxides or prodrug forms thereof
2. The compound according to claim 1, wherein Ri is hydrogen or methyl
3. The compound according to claim 2, wherein Ri is hydrogen.
4. The compound according to any one of claims 1 to 3, wherein R2 is hydrogen or methyl.
5. The compound according to any one of claims 1 to 4, wherein R3 and
R4 independently are hydrogen, halogen or methyl; or wherein R3 and R4 form a ring together with the ring carbons to which they are bound and the ring is benzene, to give quinoxaline, or thiophene, to give thieno[3,4-b]pyrazine, and when the rings are substituted, they are mono- or disubstituted.

6. The compound according to claim 5, wherein R3 and R4 both are hydrogen.
7. The compound according to any one of claims 1 to 6, wherein R7 is hydrogen.
8. The compound according to claim 7, wherein R7 is hydrogen and the group
-CH2N(R5)(R6) is attached to the /n^/a-position, relative to the alkylenedioxy side-chain, of the phenyl ring.
9. The compound according to any one of claims 1 to 8, wherein R5 and R6 together with the nitrogen atom to which they are boom form a ring selected from astatine, pyrrolidine, piperazine, homopiperazine, morpholine, thiomorpholinyl, and piperidine.
10. The compound according to any one of claims 1 to 9, wherein n = 1.
11. The compound according to claim 1, selected from
2-(l -Pipera2inyl)-3- {2-[3-(4-morpholinylmeth>1)phenoxy]ethoxy}pyrazine;
2-(l-Piperazinyl)-3-{2-[3-(l-pyrrolidinylmethyl)phenoxy]ethoxy}pyrazine;
2-(l -Piperazinyl)-3- {2-[3-(4-methyl-1 -piperazinylmethyl)phenoxy]ethoxy}pyrazine;
2-( 1 -Piperazinyl)-3- {2-[3- {(2-
methoxyethyl)amino}methyl)phenoxy]ethoxy}pyrazine;and
2-(l -Piperazinyl)-3- {2-[3- {(isopropylamino)methyl}phenoxy]ethoxy}pyrazine and
their pharmacologically acceptable salts and solvates.
12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.

13. A method for the prophylaxis or treatment of a serotonin-related disease in a human being or in an animal, which method comprises administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 11.
14. The method according to claim 13 wherein said disease is a 5-HT2C receptor-related disease.
15. The method according to claim 13 or 14 wherein said disease is selected from eating disorders, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy and urinary disorders,
16. The method according to claim 15 wherein the eating disorder is obesity.
17. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the prophylaxis or treatment of a serotonin-related disease.
18. The use according to claim 17 wherein said disease is a 5-HT2c receptor-related disease.
19. The use according to claim 17 or 18 wherein said disease is selected from eating disorders, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy and luminary disorders,

20. The use according to claim 19 wherein flie eating disorder is obesity.
21. A method for modulating 5-HT2c receptor functions in a human being or animal, comprising administering to a subject in need thereof an effective amount )f a compound according to any one of claims 1 to 11.





25. The method according to claim 22, wherein Rs is hydrogen or methyl.
26. The method according to claim 22, wherein R3 and R4 both are
hydrogen.
27. The method according to claim 22, wherein R5 and R6 together with
the nitrogen atom to which they are bound form a ring selected from astatine, pyrrolidine, piperazine, homopiperazine, morphine, thiomorpholinyl or piperidine.
28. The method according to claim 22, wherein the converting includes a
reaction with a compound of formula QJJ):


A compound substantially as herein described and exemplified.
A pharmaceutical composition substantially as herein described and exemplified.


Documents:

759-chenp-2003-abstract.pdf

759-chenp-2003-assignement.pdf

759-chenp-2003-claims filed.pdf

759-chenp-2003-claims granted.pdf

759-chenp-2003-correspondnece-others.pdf

759-chenp-2003-correspondnece-po.pdf

759-chenp-2003-description(complete) filed.pdf

759-chenp-2003-description(complete) granted.pdf

759-chenp-2003-form 1.pdf

759-chenp-2003-form 26.pdf

759-chenp-2003-form 3.pdf

759-chenp-2003-form 5.pdf

759-chenp-2003-other documents.pdf

759-chenp-2003-pct.pdf


Patent Number 209648
Indian Patent Application Number 759/CHENP/2003
PG Journal Number 50/2007
Publication Date 14-Dec-2007
Grant Date 05-Sep-2007
Date of Filing 19-May-2003
Name of Patentee M/S.. BIOVITRUM AB
Applicant Address SE-112 76 Stockholm
Inventors:
# Inventor's Name Inventor's Address
1 NILSSON, Bjorn M Djaknegatan 15:650, SE 754 23 Uppsala
2 SCOBIE, Martin Murargatan 27, S-754 37 Uppsala
PCT International Classification Number C07D 241/20
PCT International Application Number PCT/SE2001/002570
PCT International Filing date 2001-11-20
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0004244-0 2000-11-20 Sweden
2 60/253,702 2000-11-28 Sweden