HK1066810B - Piperazinylpyrazines compounds as antagonists of serotonin 5-ht2 receptor - Google Patents

Description

As serotonin 5-HT2Piperazinylpyrazine compounds as receptor antagonists

Technical Field

The present invention relates to a novel compound, pharmaceutical compositions comprising the compound, processes for their preparation, and the use of the compound for the preparation of a medicament which specifically acts on the central nervous system.

Background

Many central nervous system disorders are affected by the adrenergic, dopaminergic and serotonin neurotransmitter systems. For example, serotonin is implicated in a variety of diseases and disorders from the central nervous system. Numerous pharmacological and genetic experiments involving the serotonin receptor strongly suggest the presence of 5-HT in the regulation of food intake_2CThe receptor subtype (obes.1995，3，Suppl.4，449S-462S)。5-HT_2CReceptor subtypes are transcribed and expressed in hypothalamic structures involved in appetite regulation. Has been proved to be on 5-HT_2C5-HT with certain preference for receptors_2CReduced expression of common 5-HT by the receptor agonist m-chlorophenyl piperazine (mCPP)_2CFood intake in recipient mice, asWhen the compound is expressing a mutated inactive form of 5HT_2CLack of activity in mice of the receptor (Nature)1995,374, 542-546). In a recent clinical study, subjects with obesity treated with mCPP had a slight but sustained weight loss after two weeks (Psychopharmacology)1997,133, 309-312). More recently, a series of pyrrolo [3, 2, 1-ij]Quinoline derivatives were identified as having higher than p-5-HT_2AReceptor-selective 5-HT_2CReceptor agonists (Isaac m., et al., bioorg.med.chem.lett).2000,10, 919-921). The compounds are said to provide a novel method of treating obesity and epilepsy.

Other clinical studies with "serotonin" agents have also reported weight loss (see, e.g., IDrugs)1998,1, 456-470). For example, the 5-HT reuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptake inhibitor dexfenfluramine have shown weight loss in control studies. However, the currently available drugs that increase serotonin delivery appear to have only moderate and transient body weight effects in some cases.

5-HT has also been proposed_2CReceptor subtypes are implicated in CNS disorders such as depression and anxiety (exp. opin. invest. drugs)1998，7，1587-1599；IDrugs 1999，2，109-120)。

5-HT has also been proposed_2CReceptor subtypes are implicated in urinary disorders, such as urinary incontinence (IDrugs)1999，2，109-120)。

Thus, selectively act on 5-HT_2CCompounds of the receptor may have therapeutic potential for the treatment of diseases such as those mentioned above. Of course, selectivity also reduces the likelihood of side effects mediated by other serotonin receptors.

Information disclosure

US-A-3,253,989 discloses the use of mCPP as an anorectic.

EP-A1-863 136Disclosed are azetidine and pyrrolidine derivatives which are selective 5-HT derivatives having antidepressant activity_2CReceptor agonists, and may be useful in the treatment or prevention of serotonin-related disorders, including eating disorders and anxiety.

EP-A-657426 discloses ｃA method for treating 5-HT_2CTricyclic pyrrole derivatives which are active as receptors and can be used for the treatment of eating disorders.

EP-A-655440 discloses compounds having ｃA parｃA-5-HT_2C1-aminoethylindole which is active as receptor and can be used for the treatment of eating disorders.

EP-A-572863 discloses compounds having ｃA parｃA-5-HT_2CPirazinoindoles which are active as receptors and can be used for the treatment of eating disorders.

J.Med.Chem. 197821, 536-542 and US-A-4,081,542 disclose A series of piperazinylpyrazines with central serotonin-like activity.

J.Med.Chem. 198124, 93-101 discloses a series of piperazinyl quinoxalines having centromimetic serotonin activity.

WO 00/12475 discloses as 5-HT_2bAnd/or 5-HT_2CReceptor ligands, indoline derivatives particularly useful for the treatment of obesity.

WO 00/12510 discloses as 5-HT_2CReceptor agonists, particularly pyrroloindoles, pyridoindoles and azepino (azepino) indoles for the treatment of obesity.

WO 00/12482 discloses 5-HT as a selective direct activity_2CReceptor ligands, preferably 5-HT_2CReceptor agonists, indazole derivatives, particularly for use as antiobesity agents.

WO 00/12502 discloses as 5-HT_2CReceptor agonists, particularly pyrroloquinolines for use as antiobesity agents.

WO 00/35922 discloses as 5HT_2CAgonists, 2, 3, 4, 4 a-tetrahydro-1H-pyrazino [1, 2-a ] useful for the treatment of obesity]Quinoxalin-5 (6H) one.

WO 00/44737 discloses as 5-HT_2CAgonists, aminoalkylbenzofurans which can be used for the treatment of obesity.

For example, further reported as 5HT_2CThe compound of the receptor agonist is an indazolylpropylamine 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 gamma-carbolines of the type described in WO 00/77001, WO 00/77002 and WO 00/77010; benzofuranylpiperazines of the type described in WO 01/09111 and WO 01/09123; benzofurans of the type described in WO 01/09122; benzothiophenes of the type described in 01/09126; aminoalkylindazoles of the type described in WO 98/30548; indoles of the type described in WO 01/12603; indolines of the type described in WO 01/12602; pyrazino (aza) indoles of the type described in WO 00/44753 and tricyclic pyrroles or pyrazoles of the type described in WO 98/56768.

GB-B-1,457,005 discloses 1-piperazinyl-2- [2- (phenyl) vinyl ] -quinoxaline derivatives which exhibit anti-inflammatory activity.

Chem.Pharm.Bull. 199341(10)1832-1841 discloses 5-HT₃Antagonists, including 2- (4-methyl-1-piperazinyl) -4-phenoxyquinoxaline.

GB-B-1,440,722 discloses 2- (1' -piperazinyl) -quinoxaline compounds having antidepressant activity.

WO 96/11920 discloses CNS active pyridylurea derivatives.

WO 95/01976 discloses the use as 5-HT_2CIndoline derivatives which are antagonists and potentially useful in the treatment of CNS disorders.

WO 97/14689 discloses as selective 5-HT_1dAryl piperazine cyclic amine derivatives of receptor antagonists.

WO 98/42692 discloses 5-HT as human_1a、5-HT_1dAnd 5-HT_1bThe selective antagonist of the receptor consisting ofCyclic amine derived piperazines.

GB-B-1,465,946 discloses substituted pyridazinyl, pyrimidinyl and pyridinyl compounds useful as beta-blockers.

EP-A-711757 discloses [3- (4-phenyl-piperazin-1-yl) propylamino ] -pyridine, pyrimidine and benzene derivatives as alphｃA-adrenoceptor antagonists.

WO 99/03833 discloses arylpiperazine derivatives which are 5-HT₂Antagonists and 5-HT_1aReceptor agonists and are therefore useful as medicaments or prophylactics for the treatment of psychoneurosis.

WO 96/02525 discloses arylpiperazine-derived piperazine (piperazide) derivatives having 5-HT receptor antagonistic activity.

WO 99/58490 discloses that partial or total blocking of serotonin-capable 5-HT in an organism can be accomplished_2CAryl-dihydronaphthalene (dihydronaphthalene) -alkane amines of the receptor.

Object of the Invention

It is an object of the present invention to provide novel compounds.

Another object of the invention is a pharmaceutical composition comprising a compound as active ingredient for use in therapy.

Finally, an object of the present invention is a method for the treatment or prevention of diseases associated with serotonin, in particular 5-HT_2CMethods of treating a receptor-related disorder.

Summary of The Invention

The present invention provides compounds of general formula (I) and pharmaceutically acceptable salt, hydrate, geometric isomer, tautomer, optical isomer, N-oxide and prodrug forms thereof:

(I)

wherein

R₁Is hydrogen, C_1-4Alkyl radical, C_3-4-alkenyl, C_1-4-acyl group, C_1-4-alkoxycarbonyl, 2-hydroxyethyl, 2-cyanoethyl, tetrahydropyran-2-yl or a nitrogen protecting group;

R₂is hydrogen, C_1-4Alkyl, hydroxymethyl, C_1-4-alkoxymethyl or fluoromethyl;

R₃and R₄Independently of one another, hydrogen, methyl, C_1-4Alkyl, aryl, heteroaryl, wherein the aryl and heteroaryl residues may in turn be substituted at one or more positions independently of each other by: halogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4-Alkylthio radical, C_1-4-alkylsulfonyl, methylsulfonylamino, acetyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, methylamino, dimethylamino or acetylamino; or

R₃And R₄Together with the carbon atom to which they are attached form a 5 or 6 membered aromatic or heteroaromatic ring, said ring being optionally substituted at one or more positions with: halogen, methyl, methoxy, methylthio, methylsulfonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino, or acetylamino;

R₅and R₆Independently of one another are hydrogen, C₁-C₄-alkoxy-C₂-C₄-alkyl, hydroxy-C₂-C₄Alkyl radical, C₁-C₆Alkyl radical, C₂-C₆Acyl, aryl, heteroaryl, aryl-C₁-C₂-alkyl, heteroaryl-C₁-C₂Alkyl, aryl-C₁-C₂-acyl, heteroaryl-C₁-C₂-an acyl group, and wherein any aryl or heteroaryl group, alone or as part of another group, may be independently substituted at one or more positions with: c_1-4Alkyl radical, C_1-4-alkoxy, C_1-4Alkylthio radical, C_2-4-acyl group, C_1-4Alkylsulfonyl, cyano, nitro, hydroxy, C_2-3-alkenyl, C_2-3-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, dimethylamino or methylamino; or

R₅And R₆Together with the nitrogen atom to which they are bound, form a saturated heterocyclic ring having 4 to 7 ring members, which ring may contain additional heteroatoms and may be substituted by methyl, oxygen or hydroxyl;

R₇is hydrogen or a substituent selected from the group consisting of halogen, methyl, methoxy and ethoxy; and

n＝1-3。

if a compound of formula (I) contains a group that can exist in tautomeric form, the invention includes tautomeric forms of the compound and mixtures thereof.

If the compounds of formula (I) may be in the form of geometric isomers, the present invention includes these geometric isomers and mixtures thereof.

In another aspect, the invention provides a process for preparing a compound of the invention. The process comprises converting a compound of formula (II) to the just mentioned compound:

(II)

in the formula (II), R₃And R₄Independently of one another, hydrogen, methyl, C_1-4Alkyl, aryl, heteroaryl, where the aryl and heteroaryl residues may be, in turn, independently of one another in one or more positionsSubstituted with the following groups: halogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylsulfonyl, methylsulfonylamino, acetyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, methylamino, dimethylamino, or acetylamino; or

R₃And R₄Together with the carbon atom to which they are attached form a 5 or 6 membered aromatic or heteroaromatic ring, which ring may be substituted at one or more positions with: halogen, methyl, methoxy, methylthio, methylsulfonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino, or acetylamino; and

each Hal₁And Hal₂Independently a halogen.

In a further aspect, the present invention provides a compound of formula (I) as hereinbefore described for use in therapy.

In a further aspect the present invention also provides a pharmaceutical composition comprising as active ingredient a compound of formula (I) above, preferably together with a pharmaceutically acceptable carrier and other pharmacologically active agents as may be desired.

In another aspect, the invention provides a method for treating a patient suffering from a serotonin-related disease, in particular 5HT_2CA method of treating a human or animal subject suffering from a receptor-related disease, in particular eating disorders, in particular obesity, memory diseases, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunction, epilepsy and urinary disorders.

Another aspect of the present invention provides the use of a compound according to formula (I) above for the preparation of a medicament for the treatment of serotonin-related diseases, in particular 5-HT_2CUse of a medicament for the treatment of a disorder related to a receptor, in particular eating disorders, in particular obesity, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunction, epilepsy and urinary disorders.

Finally for regulating 5HT_2CMethods of receptor function are one aspect of the invention.

Detailed Description

According to the present invention, a class of compounds related to 5-HT has been developed_2CNovel compounds that bind to receptors (agonists and antagonists) and are therefore useful in the treatment of serotonin-related disorders.

First, various terms used alone or in combination in the above definitions for compounds having the general formula (I) are explained.

"heteroatom" means nitrogen, oxygen, sulfur, and also means selenium on a heteroaromatic ring.

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, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole and tetrazole.

C_1-6Alkyl, which may be linear or branched, preferably C_1-4An alkyl group. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.

C_1-4The alkoxy group may be straight or branched. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy.

C_2-4Alkenyl can be straight-chain or branched. Exemplary alkenyl groups include ethenyl, 2-propenyl, and 1-methyl-2-propenyl.

C₁-C₄-alkoxy-C₂-C₄The alkyl group may be linear or branched. Exemplary groups include 2- (methoxy) ethyl, 3-methoxy-1-propyl, 4-ethoxy-1-butyl and the like.

Exemplary aryl-C₁-C₂Acyl includes benzoyl and phenylacetyl. Exemplary heteroaryl-C₁-C₂Acyl includes nicotinoyl and 3-pyridylacetyl and the like.

C_2-4The acyl group may be saturated or unsaturated. Exemplary acyl groups include acetyl, propionyl, butyryl, isobutyryl, and crotonyl (e.g., 3-crotonyl).

Halogen includes fluorine, chlorine and bromine.

If it is stated above that the aryl and heteroaryl residues may be substituted, it applies to the aryl and heteroaryl groups themselves and to any combination of groups containing an aryl or heteroaryl residue, e.g. heteroaryl-C₁-C₂Alkyl and aryl-C₁-C₂-an acyl group.

The term "N-oxide" means that when one or more nitrogen atoms are present in a compound, the nitrogen atom is in the N-oxide form (N → O).

The term "prodrug form" means a pharmacologically acceptable derivative, such as an ester or amide, that is biotransformed in vivo to form the active drug. Reference is made to Goodman and Gilman's, The pharmaceutical basic of Therapeutics, 8th ed., McGraw-Hill, int. Ed.1992, "Biotransformation of drugs, p.13-15.

By "pharmaceutically acceptable" is meant useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic and biologically and otherwise undesirable, including in veterinary and human pharmaceutical applications.

By "pharmaceutically acceptable salt" is meant a pharmaceutically acceptable salt as defined above having the desired pharmacological activity. These 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, toluenesulfonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid, and the like.

R₁Preferably hydrogen or methyl. Most preferred is R₁Is hydrogen.

R₂Can also be used as a nitrogen protecting group, and R₁Is tert-butoxycarbonyl (t-BOC), benzyl or trityl.

R₂Preferably hydrogen or methyl (especially in position 2 of the piperazine ring).

R₃And R₄Preferably (independently) hydrogen, halogen or methyl. When R is₃And R₄When they form a ring together with the ring carbon to which they are bound, such ring is preferably benzene (to give a quinoxaline) or thiophene (to give a thieno [3, 4b ]]Pyrazine). When substituted, the ring is preferably mono-or disubstituted, preferably by halogen or methyl.

When R is₇When not hydrogen, it may occupy any available position of the phenyl ring.

group-CH₂N(R₅)(R₆) Can be bonded to the ortho-, meta-, or para-position of the benzene ring relative to the alkylenedioxy side chain, preferably to the meta-position.

N in the formula (I) is 1-3, wherein n is the number of methylene groups. n is preferably 1, with the meaning that the two oxygen atoms in formula (I) are replaced by-CH₂CH₂-the groups are spaced apart,

preferred compounds of the above general formula (I) are:

2- (1-piperazinyl) -3- {2- [3- (4-morpholinylmethyl) phenoxy ] ethoxy } pyrazine;

2- (1-piperazinyl) -3- {2- [3- (1-pyrrolidinylmethyl) phenoxy ] ethoxy } pyrazine;

2- (1-piperazinyl) -3- {2- [3- (4-methyl-1-piperazinylmethyl) phenoxy ] ethoxy } pyrazine;

2- (1-piperazinyl) -3- {2- [3- { (2-methoxyethyl) amino } methyl) phenoxy ] ethoxy } pyrazine;

2- (1-piperazinyl) -3- {2- [3- { (isopropylamino) methyl } phenoxy ] ethoxy } pyrazines and pharmacologically acceptable salts and solvates thereof.

In another aspect, the invention relates to compounds of any of the formulae herein and their uses as described herein, wherein R₂And R₆Together with the nitrogen atom to which they are bound, form a saturated heterocyclic ring having 4 to 7 ring members, and the ring may contain an additional heteroatom. Exemplary rings are azetidine, pyrrolidine, piperazine, homopiperazine, morpholine, thiomorpholine or piperidine. The saturated heterocyclic ring may be substituted with methyl, oxygen or hydroxyl.

As indicated above, the compounds of the invention are useful in the treatment (including prophylactic treatment) of a condition associated with serotonin, particularly 5-HT, in a human or animal (e.g. including companion animals)_2CReceptor-related disorders, such as eating disorders, in particular obesity; memory disorders, such as Alzheimer's disease; schizophrenia; mood disorders including, but not limited to, major depression and bipolar depression, bipolar disorders including mild and manic, Seasonal Affective Disorder (SAD); anxiety disorders including situational anxiety, generalized anxiety disorder, primary anxiety disorder (panic disorder, phobias, obsessive-compulsive disorder, and post-traumatic stress disorder), and secondary anxiety disorder (e.g., anxiety associated with substance abuse); pain; substance abuse; sexual dysfunction; epilepsy and urinary disorders, such as urinary incontinence.

The compounds of the invention in radiolabeled form are useful as diagnostic agents.

The compounds of the above general formula (I) can be prepared by the process of the present invention or by a process similar to the conventional one. The present invention relates to the preparation of compounds of any of the formulae of the present invention, said process comprising reacting any one or more of the compounds or formulae described herein, including any of the processes described herein.

For example, as shown in scheme 1, the formula (la) can be prepared by the following method(I) The compound of (1): first with the appropriate piperazine of formula (III) (wherein R₁And R₂Have the same meaning as in formula (I), and wherein R₁Compounds of formula (II) wherein Hal is halogen and R is R may be treated with a suitable nitrogen protecting group, such as trityl, benzyl or tert-butoxycarbonyl₃And R₄As defined above) to yield a compound of formula (IV). The reaction is carried out in a solvent such as acetonitrile, dioxane, Tetrahydrofuran (THF), N-butanol, N-Dimethylformamide (DMF), or in a solvent mixture such as DMF/dioxane, optionally in a base such as K₂CO₃、Na₂CO₃、Cs₂CO₃NaOH, triethylamine, pyridine, etc. at 0-200 deg.C for 1-24 hr.

The compound of formula (IV) is reacted with a diol of formula (V) wherein n has the same meaning as in formula (I) to give intermediate (VI). The reaction is carried out in a solvent such as dioxane, THF, DMF or pyridine, etc., in the presence of a base such as K-t-BuO, Na-t-BuO, NaH, etc., at 0-150 ℃ for 1-24 hours.

The intermediate (VI) is reacted with a hydroxybenzaldehyde compound of formula (VII) wherein R7 has the same meaning as in formula (I) to give the aldehyde intermediate (VIII). The reaction can be carried out in diethyl azodicarboxylate (DEAD) or 1, 1' -azobis (N, N-dimethylformamide) (cf. Tetrahedron Lett).199536, 3789-3792), preferably DEAD, and triphenylphosphine (PPh3) in a solvent such as THF or dichloromethane (Mitsunobu reaction; see org.1992，42，335-656.)

Reacting intermediate (VIII) with a suitable amine of formula (Ix) (wherein R is₅And R₆Having the same meaning as in formula (I)) together undergo a standard reductive alkylation process (as in j.199661, 3849-3862) to produce the compound (I) of the present invention.

When R1 in formula (I) is a nitrogen protecting group as defined below, it may then be subjected to standard conditions, such as those in Protective Groups in Organic Synthesis, John Wiley& Sons，1991 under conditions to obtain a compound of formula (I) wherein R₁Is hydrogen. Nitrogen protecting Groups are known in the art and include those described in t.w.greene and p.g.m.wuts, Protective Groups in organic Synthesis, 2d.ed., John Wiley and Sons (1991) and subsequent versions thereof.

Route 1

The resulting compound of formula (I) may be converted into another compound of formula (I) by methods known in the art.

The above process is carried out to obtain the compounds of the invention in free base form or as acid addition salts. The pharmaceutically acceptable acid addition salts can be obtained by: the free base is dissolved in a suitable organic solvent such as an ether or a mixture of an ether and methanol, and the solution is treated with an acid according to conventional methods for preparing acid addition salts from base compounds. Examples of acids which form acid addition salts are maleic acid, fumaric acid, succinic acid, methanesulfonic acid, acetic acid, oxalic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like.

The compounds of formula (I) may have one or more chiral carbon atoms and may thus be obtained in the form of their optical isomers, e.g. as pure enantiomers, or as mixtures of enantiomers (racemates) or as mixtures comprising diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is known in the art and may be achieved, for example, by fractional crystallisation of the salts with optically active (chiral) acids or by chromatographic separation using chiral columns.

According to the invention, the compounds of formula (I) in free base or in salt form with a physiologically acceptable acid can be formulated according to acceptable pharmaceutical methods into suitable galenic forms, such as compositions for oral, injectable, nasal spray administration and the like. Such pharmaceutical compositions according to the invention comprise both an effective amount of a compound of formula (I) and a compatible pharmaceutically acceptable carrier material, such as diluents, as known in the art. The carrier may be any organic or inorganic inert material suitable for enteral, transdermal, subcutaneous or parenteral administration, for example: water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, and the like. These compositions may also contain other pharmacologically active agents and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers and the like.

For example, the compositions according to the present invention may be prepared in solid or liquid form for oral administration, such as tablets, pills, capsules, powders, syrups, elixirs, dispersible granules, cachets, suppositories, and the like; sterile solution, suspension or emulsion forms for parenteral administration; sprays, such as nasal sprays; transdermal preparations such as patches and the like.

As mentioned above, the compounds of the invention may be used for the treatment of serotonin-related disorders, such as eating disorders, in particular obesity, memory diseases, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunction, epilepsy and urinary disorders, in humans or animals. The dose level and frequency of administration of a particular compound will vary with a variety of factors including the potency of the particular compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition being treated and the patient being treated. For example, the daily dosage may range from about 0.001mg to about 100mg per kilogram of body weight, administered singly or in multiple doses of about 0.01mg to about 25mg each. Typically, such dosages are provided orally, but parenteral administration may also be selected.

The following specific examples are to be construed as merely illustrative, and not limitative of the remainder of the specification in any way whatsoever. Without further consideration, it is believed that one skilled in the art can, using the present disclosure, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety.

Examples

General examples:

NMR spectra were recorded at 25 ℃ using a Bruker Advance DPX 400MHz spectrometer. Chemical shifts are given in ppm relative to tetramethylsilane. LC/MS data were obtained using the HP1100 hplc system coupled to MassLynx operated on a Micromass platform LC Mass Spectrometry. Details of hplc are: column, Phenomenex C18 Luna, 30X 46mm, at 40. + -. 1 ℃. Eluent gradients T0, 95% (0.1% formic acid in water) and 5% (0.1% formic acid in acetonitrile, then linear gradients to T2.5 min, 5% (0.1% formic acid in water) and 95% (0.1% formic acid in acetonitrile) were further continued under these conditions for 1 min the eluent flow rate was 2 mL/min detection was performed by UV diode array at window 210-.

Example 1

2- (1-piperazinyl) -3- {2- [3- (4-morpholinylmethyl) phenoxy ] ethoxy } pyrazine.

Step 1: 2-chloro-3- (4-tert-butoxycarbonyl-1-piperazinyl) pyrazine.

The title compound was prepared according to the procedure described in WO 00/76984. N-Boc-piperazine (11.47g, 61.5mmol), K in acetonitrile (100mL) was added at 100 deg.C₂CO₃A mixture of (8.5g, 61mmol) and 2, 3-dichloropyrazine (9.20g, 61.7mmol) was stirred for 40 h. The reaction mixture was concentrated, dissolved in toluene, washed with water and dried (MgSO)₄) And is combined withAnd (5) concentrating. The residue was purified by chromatography on silica gel using toluene/EtOAc (7: 3) as eluent to give 18.3g (100%) of the title product. HRMS m/z C₁₃H₁₉N₄O₂(M)⁺Calculated values: 298.1197, Experimental value: 298.1206.

step 2: 2- [3- (4-tert-butoxycarbonyl-1-piperazinyl) -2-pyrazinyloxy ] ethanol.

The title compound was prepared according to the procedure described in WO 00/76984. KO-t-Bu (9.92g, 103mmol) was added to a mixture of the product obtained in step 1 (18.14g, 60.7mmol) and ethylene glycol (25mL, 448mmol) in pyridine (125mL) at 85 ℃. The reaction mixture was stirred for 15 hours, then poured into ice-water and extracted with toluene. The organic phase was dried (MgSO)₄) And concentrated. The residue was purified by column chromatography on silica gel using toluene/EtOAc (1: 1) as eluent to give 16.9g (85%) of the title product. HRMS m/zC₁₅H₂₄N₄O₄(M) + calculated: 324.1798, Experimental value: 324.1784.

and step 3: 4- {3- [2- (3-Formylphenoxy) ethoxy ] -2-pyrazinyl } -1-piperazinecarboxylic acid tert-butyl ester.

A solution of the compound obtained in step 2 above (1.5g, 4.7mmol) in anhydrous tetrahydrofuran (THF; 10mL) was treated with 3-hydroxybenzaldehyde (0.74g, 6.06mmol) and triphenylphosphine (1.59g, 6.06 mmol). The solution was stirred at room temperature and then treated with diethyl azodicarboxylate in anhydrous THF (5 mL). After 1 hour, TLC showed that some 2- [3- (4-tert-butoxycarbonyl-piperazinyl) -2-pyrazinyloxy) remained]And (3) ethanol. The reaction was heated under nitrogen for 5 hours and then cooled at room temperature overnight. TLC again showed unreacted starting material. The mixture was further treated with triphenylphosphine (0.80g, 3.03mmol), diethyl azodicarboxylate (0.5mL, 3.03mmol) and 3-hydroxybenzaldehyde (0.40g, 3.03mmol) and then stirred at room temperature for an additional 3 hours (reaction completion indicated by TLC). The volatiles were removed in vacuo and the residue was purified by flash column chromatography on silica, eluting with petroleum ether/ethyl acetate (2: 1). 0.33g (16%) of the title product are obtained as a colorless oil.¹HNMR(CDCl₃)δ1.5(s，9H)；3.5(bs，8H)，4.45(m，2H)；4.75(m，2H)；7.2(d，1H)；7.45(s，1H)；7.5(m，2H)；7.6(s，1H)；7.75(s，1H)。

And 4, step 4: 4- (3- {2- [3- (4-Morpholinylmethyl) phenoxy ] ethoxy } -2-pyrazinyl) -1-piperazinecarboxylic acid tert-butyl ester

A stirred solution of the aldehyde from step 3 above (71.2mg, 0.166mmol) in 1, 2-dichloroethane (5mL) was treated with morpholine (19mg, 0.22mmol0, 3  molecular sieves and sodium triacetoxyborohydride (52mg, 0.25 mmol). the mixture was stirred at room temperature for 5 hours (TLC monitoring). the solution was filtered and the filtrate was treated with an excess of saturated aqueous sodium bicarbonate solution the ether extract was isolated and dried over magnesium sulfate. the mixture was filtered and the solvent removed in vacuo to give 54mg (65%) of the title product as a yellow oil.¹H NMR(CDCl₃)δ1.4(s，9H)；2.35(m，4H)；3.4(m，10H)；3.65(m，4H)；4.3(m，2H)；4.65(m，2H)；6.75(d，1H)；6.9(m，2H)；7.2(t，1H)；7.5(s，1H)；7.7(s，1H)。

And 5: 2- (1-piperazinyl) -3- {2- {3- (4-morpholinylmethyl) phenoxy } ethoxy } pyrazine.

The product from step 4 above (54mg, 0.11mmol) was dissolved in anhydrous ether (20mL), stirred at room temperature, and treated with hydrogen amide in ether (. about.6M; 5 mL). The resulting white suspension was stirred for 2 hours and then filtered off rapidly. The hydrochloride salt (hygroscopic) was dissolved in water and neutralized with sodium carbonate. The free base was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 13mg (29%) of the title product as a pale yellow oil. LS/MS purity of 100%.¹H NMR(CDCl₃)δ1.8(b，1H)；2.45(m，4H)；2.95(m，4H)；3.45(s，2H)；3.55(m，4H)；3.7(m，4H)；4.35(t，2H)；4.7(t，2H)；6.85(d，1H)；6.95(m，2H)；7.25(t，1H)；7.55(s，1H)；7.75(s，1H)。

The following compounds were prepared analogously from 4- {3- [2- (3-formylphenoxy) ethoxy ] -2-pyrazinyl } -1-piperazinecarboxylic acid tert-butyl ester (obtained in example 1, step 3) and the desired amine.

Example 2

2- (1-piperazinyl) -3- {2- [3- (1-pyrrolidinylmethyl) phenoxy ] ethoxy } pyrazine.

The yield was 31%. LS/MS purity 100%.¹H NMR(CDCl₃)δ1.7(m，4H)；2.45(m，4H)；2.9(m，4H)；3.4(m，4H)；3.5(s，2H)；4.3(m，2H)；4.6(m，2H)；6.7(d，1H)；6.85(m，2H)；7.15(t，1H)；7.45(s，1H)；7.7(s，1H)。

Example 3

2- (1-piperazinyl) -3- {2- [3- (4-methyl-1-piperazinylmethyl) phenoxy ] ethoxy } pyrazine.

The yield was 56%. LS/MS purity 100%.¹H NMR(CDCl₃)δ2.15(s，3H)；2.35(b，9H)；2.85(m，4H)；3.35(m，6H)；4.2(m，2H)；4.55(m，2H)；6.7(d，1H)；6.8(m，2H)；7.1(t，1H)；7.4(s，1H)；7.6(s，1H)。

Example 4

2- (1-piperazinyl) -3- {2- [3- { (2-methoxyethyl) amino } methyl) phenoxy ] ethoxy } pyrazine.

The yield was 37%. LS/MS purity 100%.¹H NMR(CDCl₃)δ2.8(t，2H)；3.05(m，6H)；3.35(s，3H)；3.6(m，6H)；3.8(s，2H)；4.35(m，2H)；4.7(m，2H)；6.8(d，1H)；6.95(d，2H)；7.25(t，1H)；7.55(s，1H)；7.8(s，1H)。

Example 5

2- (1-piperazinyl) -3- {2- [3- { (isopropylamino) methyl } phenoxy ] ethoxy } pyrazine.

The yield was 60%. LS/MS purity 100%.¹H NMR(CDCl₃)δ1.1(d，6H)；1.85(b，1H)；2.85(m，1H)；3.0(m，4H)；3.5(m，4H)；3.8(s，2H)；4.35(m，2H)；4.7(m，2H)；6.8(d，1H)；6.9(m，2H)；7.2(t，1H)；7.5(s，1H)；7.75(s，1H).

Example 6

2- (1-piperazinyl) -3- {2- [3- { (3-methoxyphenylamino) methyl } phenoxy ] ethoxy } pyrazine.

The purity of LC/MS is 100%.

Example 7

2- (1-piperazinyl) -3- {2- [3- { (2-hydroxyethylamino) methyl } phenoxy ] ethoxy } pyrazine.

The purity of LC/MS is 97%.

Preparation of pharmaceutical compositions

Example (b): preparation of tablets

Composition (I) mg/tablet

1. Active Compound 10.0

2. Cellulose, microcrystalline 57.0

3. Calcium hydrogen phosphate 15.0

4. Sodium starch glycolate 5.0

5. Silica, colloidal 0.25

6. Magnesium stearate 0.75

Active ingredient 1 was mixed with ingredients 2, 3, 4 for 10 minutes. Magnesium stearate is then added, the resulting mixture is mixed for about 5 minutes and compressed into tablets with or without coating film.

Pharmacological testing

The ability of the compounds of the present invention to bind or act on a particular 5-HT receptor subtype can be determined using in vitro and in vivo assays known in the art. The compounds prepared in the examples were tested for biological activity using different assays.

Affinity assays

Determination of 5-HT of example Compounds in Competition experiments_2CReceptor affinity, in which serial dilutions of individual compounds were monitored for displacement and stable expression of human 5-HT by the liquid Scintillation Proximity Assay (science Proximity technology)_2CMembrane-bound produced by HEK293 cell line transfected with receptor proteins³The ability to H-tag 5-HT. Nonspecific binding was defined using 5 μ M micarelin (mianserin). The results for exemplary compounds of the invention are shown in table 1 below. In general, 5HT_2CReceptor affinity value (K)_inM) in the range 1nM to 1500nM, preferably 1nM to 100 nM.

Table 1. 5-HT_2CReceptor affinity

Compound Ki (nM)

Example 118

Example 53

Efficacy assays

Stable expression of human 5-HT by mobilization of individual compounds_2CIntracellular calcium capacity in HEK293 cells transfected with receptor proteins the compounds of the examples were assayed for 5-HT using the calcium-chelating fluorescent dye FLUO-3(Sigma, St. Louis, MO, U.S. A.)_2CAgonist potency of the receptor.

In general, 5-HT (serotonin) is compared with the maximal response of 5-HT at a concentration of 1. mu.M_2CThe maximal response of agonists ranged from 15-100%.

Claims (24)

1. A compound of general formula (I) and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, N-oxides or prodrug forms thereof:

wherein

R₁Is hydrogen, C_1-4Alkyl radical, C_3-4-alkenyl, C_1-4-acyl group, C_1-4Alkoxycarbonyl, 2-hydroxyethylA 2-cyanoethyl, tetrahydropyran-2-yl or nitrogen protecting group;

R₂is hydrogen, C_1-4Alkyl, hydroxymethyl, C_1-4-alkoxymethyl or fluoromethyl;

R₃and R₄Independently of one another, hydrogen, halogen, C_1-4Alkyl, aryl, heteroaryl, wherein the aryl and heteroaryl residues may in turn be substituted at one or more positions independently of each other by: halogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4-alkylsulfonyl, methylsulfonylamino, acetyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, methylamino, dimethylamino or acetylamino; or

R₃And R₄Together with the carbon atom to which they are attached form a 5 or 6 membered aromatic or heteroaromatic ring, which groups may be substituted in one or more positions with: halogen, methyl, methoxy, methylthio, methylsulfonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino, or acetylamino;

R₅and R₆Independently of one another are hydrogen, C₁-C₄-alkoxy-C₂-C₄-alkyl, hydroxy-C₂-C₄Alkyl radical, C₁-C₆Alkyl radical, C₂-C₆Acyl, aryl, heteroaryl, aryl-C₁-C₂-alkyl, heteroaryl-C₁-C₂Alkyl, aryl-C₁-C₂-acyl, heteroaryl-C₁-C₂-an acyl group, and wherein any aryl or heteroaryl group, alone or as part of another group, may be independently substituted at one or more positions with: c_1-4Alkyl radical, C_1-4-alkoxy, C_1-4Alkylthio radical, C_2-4-acyl group, C_1-4Alkylsulfonyl, cyano, nitro, hydroxy, C_2-3-alkenyl, C_2-3-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, dimethylamino or methylamino; or

R₅And R₆Together with the nitrogen atom to which they are bound, form a saturated heterocyclic ring having 4 to 7 ring members, which ring may contain additional heteroatoms and may be substituted by methyl, oxygen or hydroxyl;

R₇is hydrogen or a substituent selected from the group consisting of halogen, methyl, methoxy and ethoxy; and

n＝1-3。

2. a compound according to claim 1, wherein R₁Is hydrogen or methyl.

3. A compound according to claim 2, wherein R₁Is hydrogen.

4. A compound according to any one of claims 1-3, wherein R₂Is hydrogen or methyl.

5. A compound according to any one of claims 1-3, wherein R₃And R₄Independently hydrogen, halogen or methyl; or wherein R is₃And R₄Together with the ring carbon to which they are bound, form a ring which is benzene for obtaining quinoxaline or for obtaining thieno [3, 4-b ]]Thiophene of pyrazine, and when the ring is substituted, they are mono-or disubstituted.

6. A compound according to claim 5, wherein R₃And R₄Are all hydrogen.

7. A compound according to any one of claims 1-3, wherein R₇Is hydrogen.

8. A compound according to claim 7, wherein R₇Is hydrogen, and the group-CH₂N(R₅)(R₆) Bonded to the meta position of the benzene ring relative to the alkylenedioxy side chain.

9. A compound according to any one of claims 1-3, wherein R₅And R₆Together with the nitrogen atom to which they are bound, form a ring selected from: azetidine, pyrrolidine, piperazine, homopiperazine, morpholine, thiomorpholine and piperidine.

10. A compound according to any one of claims 1-3, wherein n-1.

11. A compound according to claim 1 selected from

2- (1-piperazinyl) -3- {2- [3- (4-morpholinylmethyl) phenoxy ] ethoxy } pyrazine;

2- (1-piperazinyl) -3- {2- [3- (1-pyrrolidinylmethyl) phenoxy ] ethoxy } pyrazine;

2- (1-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- (1-piperazinyl) -3- {2- [3- { (isopropylamino) methyl } phenoxy ] ethoxy } pyrazines and pharmaceutically acceptable salts and solvates thereof.

12. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 11 and a pharmacologically and pharmaceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 11 for the preparation of a medicament for the prevention or treatment of a serotonin-related disease.

14. The use according to claim 13, wherein the disease is a condition associated with 5-HT_2CA receptor associated disease.

15. Use according to claim 13 or 14, wherein the disease is selected from eating disorders, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunction, epilepsy and urinary disorders.

16. Use according to claim 15, wherein the eating disorder is obesity.

17. Use of a compound according to any one of claims 1 to 11 for the preparation of a medicament for modulating 5-HT in a human or animal_2CUse of a medicament for receptor function.

18. A process for the preparation of a compound according to claim 1, which process comprises converting a compound of formula (II) to a compound according to claim 1:

wherein R is₃And R₄Independently of one another, hydrogen, halogen, C_1-4-alkyl, aryl, heteroaryl, wherein the aryl and heteroaryl residues may in turn be substituted in one or more positions independently of each other by: halogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylsulfonyl, methylsulfonylamino, acetyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, methylamino, dimethylamino, or acetylamino; or

R₃And R₄Together with the carbon atom to which they are attached form a 5 or 6 membered aromatic or heteroaromatic ring, which groups may be substituted in one or more positions with: halogen, methyl, methoxy, methylthio, methylsulfonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino, or acetylamino; and

each Hal₁And Hal₂Independently a halogen.

19. The method of claim 18, the method comprising:

reacting a compound of formula (II) with a compound of formula (III):

contacting to form a first intermediate product (IV),

wherein R is₁Hydrogen or C_1-4Alkyl radical, C_3-4-alkenyl, C_1-4-acyl group, C_1-4-alkoxycarbonyl, 2-hydroxyethyl, 2-cyanoethyl or tetrahydropyran-2-yl or a nitrogen protecting group; and

R₂is hydrogen, C_1-4Alkyl, hydroxymethyl, C_1-4An alkoxymethyl or fluoromethyl group;

reacting the first intermediate with a compound of formula (V):

contacting to form a second intermediate product (VI);

wherein n is 1-3;

reacting the second intermediate with a compound of formula (VII):

contacting to form a third intermediate product (VIII),

wherein R is₇Is hydrogen or a substituent selected from the group consisting of halogen, methyl, methoxy and ethoxy;

reacting the third intermediate with a compound of formula (IX):

contacting to form a compound of claim 1,

wherein R is₅And R₆Independently of one another are hydrogen, C₁-C₄-alkoxy-C₂-C₄-alkyl, hydroxy-C₂-C₄Alkyl radical, C₁-C₆Alkyl radical, C₂-C₆Acyl, aryl, heteroaryl, aryl-C₁-C₂-alkyl, heteroaryl-C₁-C₂Alkyl, aryl-C₁-C₂-acyl or heteroaryl-C₁-C₂-an acyl group, and wherein any aryl or heteroaryl group, alone or as part of another group, may be independently substituted at one or more positions with: c_1-4Alkyl radical, C_1-4-alkoxy, C_1-4Alkylthio radical, C_2-4-acyl group, C_1-4Alkylsulfonyl, cyano, nitro, hydroxy, C_2-3-alkenyl, C_2-3-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, dimethylamino or methylamino; or

R₅And R₆Together with the nitrogen atom to which they are bound, form a saturated heterocyclic ring having 4 to 7 ring members, which ring may contain an additional heteroatom and may be substituted by methyl, oxygen or hydroxyl.

20. The method according to claim 18, wherein R₁Is hydrogen or methyl.

21. The method according to claim 18, wherein R₂Is hydrogen or methyl.

22. The method according to claim 18, wherein R₃And R₄Are all hydrogen.

23. The method according to claim 18, wherein R₅And R₆Together with the nitrogen atom to which they are bound, form a ring selected from: azetidine, pyrrolidine, piperazine, homopiperazine, morpholine, thiomorpholine or piperidine.

24. The method according to claim 18, wherein the converting comprises reacting with a compound of formula (III):

wherein R is₁Is hydrogen or C_1-4Alkyl radical, C_3-4-alkenyl, C_1-4Acyl radical, C_1-4-alkoxycarbonyl, 2-hydroxyethyl, 2-cyanoethyl or tetrahydropyran-2-yl or a nitrogen protecting group; and

R₂is hydrogen, C_1-4Alkyl, hydroxymethyl, C_1-4-alkoxymethyl or fluoromethyl.