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    • 专利摘要:
    The present invention relates to compounds of formula (1) below, their N-oxides, pharmaceutically acceptable addition salts and stereochemically isomers of the compounds, wherein n is from 0 to 6; p is 0 to 3; q is 0 to 3; r is 0 to 3; ROneAnd R2Are each independently hydrogen; Optionally substituted C1-6Alkyl; C1-6Alkylcarbonyl; Trihalomethylcarbonyl; ROneAnd R2Together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substituted heterocycle; Each R3And R4Is independently halo, cyano, hydroxy, trihalomethyl, trihalomethoxy, carboxyl, nitro, amino, mono- or di (C1-6Alkyl) amino, C1-6Alkylcarbonylamino, aminosulfonyl, mono- or di (C1-6Alkyl) aminosulfonyl, C1-6Alkyl, C1-6Alkyloxy, C1-6Alkylcarbonyl or C1-6Alkylcarbonyl; Each R5Is independently C1-6Alkyl, cyano or trihalomethyl; X is CR6R7, NR8, O, S, S (= O) or S (= O)2ego; Each formula (i) independently refers to a divalent aromatic heterocycle wherein the heterocycle is pyrrole, pyrazole, imidazole, triazole, furan, thiophene, isoxazole, oxazole, isothiazole, thiazole, pyridine Can be selected from the group consisting of pyridazine, pyrimidine, pyrazine and triazine; Or one of the two divalent aromatic heterocycles in the compound of formula (1) may be 1,2-benzenediyl; Aryl is optionally substituted phenyl; The present invention further relates to compositions comprising such compounds as well as to the use as therapeutic agents for the treatment and prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.
    公开号:KR19990067515A
    申请号:KR1019980703537
    申请日:1997-04-09
    公开日:1999-08-25
    发明作者:조제 이그나키오 안드레스-길；페드로 마르티네즈-지메네즈；프란시스코 자비에르 페르난데스-가데아；빅토르 카렐 시피도
    申请人:디르크 반테；얀센 파마슈티카 엔.브이.；
    IPC主号:
    专利说明:

    Isoxazolidine derivatives
    US 4,039,558 describes pyrrolidinodibenzo-azepine, -oxazepine, -tazepine and -diazepine derivatives having antihistamine, soothing and antidepressant properties. EP-A-0,421,823 describes dibenzopyrazino- or benzo-pyrido-pyrazino-azepine derivatives having anti-allergic and anti-asthmatic activity. The compounds of the present invention are distinguished from the known inventions by the presence of isoxazolidine rings and by their pharmacological properties.
    The present invention relates to tetracyclic isoxazolidine derivatives having antipsychotic, cardiovascular and gastrokinetic actions and methods for their preparation; The invention also relates to compositions containing said derivatives and to their use as pharmaceuticals.
    The present invention relates to compounds of formula (1) below, their N-oxides, pharmaceutically acceptable addition salts and stereochemically isomers of the compounds.
    In the above formula:
    n is 0, 1, 2, 3, 4, 5 or 6;
    p is 0, 1, 2 or 3;
    q is 0, 1, 2 or 3;
    r is 0, 1, 2 or 3;
    R 1 and R 2 are each independently hydrogen; C 1-6 alkyl; C 1-6 alkylcarbonyl; Trihalomethylcarbonyl; Hydroxy, C 1-6 alkyloxy, carboxyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl or is a C 1-6 alkyl substituted with aryl; R 1 and R 2 together with the nitrogen atom to which they are attached may form a morpholinyl ring or a radical of the formula:

    From here:
    R 9 , R 10 , R 11 and R 12 are each independently hydrogen, halo, trihalomethyl, or C 1-6 alkyl;
    m is 0, 1, 2 or 3;
    R 13 , R 14 , R 15 and R 16 are each independently hydrogen or C 1-6 alkyl; R 15 and R 16 can be taken together to form the divalent radical C 4-5 alkanediyl; R 17 is hydrogen; C 1-6 alkyl; C 1-6 alkylcarbonyl; Trihalomethylcarbonyl; C 1-6 alkyloxycarbonyl; Aryl; Di (aryl) methyl; Hydroxy, C 1-6 alkyloxy, carboxyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl, or is a C 1-6 alkyl substituted with aryl;
    Each R 3 is independently halo, cyano, hydroxy, trihalomethyl, trihalomethoxy, carboxyl, nitro, amino, mono- or di (C 1-6 alkyl) amino, C 1-6 alkylcar Carbonylamino, aminosulfonyl, mono- or di (C 1-6 alkyl) aminosulfonyl, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylcarbonyl or C 1-6 alkylcarbonyl ego;
    Each R 4 is independently halo, cyano, hydroxy, trihalomethyl, trihalomethoxy, carboxyl, nitro, amino, mono- or di (C 1-6 alkyl) amino, C 1-6 alkylcar Carbonylamino, aminosulfonyl, mono- or di (C 1-6 alkyl) aminosulfonyl, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylcarbonyl or C 1-6 alkyloxycar Carbonyl;
    Each R 5 is independently C 1-6 alkyl, cyano or trihalomethyl;
    X is CR 6 R 7 , NR 8 , O, S, S (= 0) or S (= 0) 2 ; Wherein R 6 and R 7 are each independently hydrogen, hydroxy, C 1-6 alkyl, trihalomethyl, C 1-6 alkyloxy or R 6 and R 7 together are methylene; Mono- or di (cyano) methylene; Formula-(CH 2 ) 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5- , -O- (CH 2 ) 2 -O- or -O- (CH 2 ) form a divalent radical of 3 -O-; With the carbon atoms to which they are attached, they may form carbonyl;
    R 8 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, arylcarbonyl, arylC 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, arylsulfonyl or arylC 1-6 alkyl Sulfonyl; bracket Are independently divalent aromatic heterocycles wherein the heterocycles are pyrrole, pyrazole, imidazole, triazole, furan, thiophene, isoxazole, oxazole, isothiazole, thiazole, pyridine, pyridazine, pyri May be selected from the group consisting of midine, pyrazine and triazine; Or one of the two divalent aromatic heterocycles in the compound of formula (1) may be 1,2-benzenediyl; Aryl is phenyl; Or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, C 1-6 alkyl and trihalomethyl.
    In the above definition, C 1-6 alkyl is a straight and branched chain having 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl To saturated hydrocarbon radicals; C 4-5 alkanediyl refers to divalent straight and branched chain saturated hydrocarbon radicals having 4-5 carbon atoms, for example 1,4-butaneidyl, 1,5-pentanediyl; Halo is generally fluoro, chloro, bromo and iodo. The term monocyanomethylene refers to a radical of the formula = CHCN, and the term dicyanomethylene refers to a radical of the formula = C (CN) 2 . The term halomethyl is meant to include mono-, di-, and trihalomethyl. Examples of halomethyl are fluoromethyl, difluoromethyl and especially trifluoromethyl. R 6 and R 7 together represent the formulas-(CH 2 ) 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5- , -O- (CH 2 ) 2 -O Or-when forming a divalent radical of -O- (CH 2 ) 3 -O-, the compound of formula (1) is a spiro compound. Heterocyclic radicals in the definition of include all divalent radicals adjacent to the heterocycle.
    Pharmaceutically acceptable addition salts as mentioned above are meant to include therapeutically active non-toxic base and acid addition salt forms which may be formed from compounds of formula (1). The acid addition salt form of the compound of formula (1), which is present in its free form as a base, may be, for example, a base form of the compound of formula (1), such as hydrochloric acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like. Inorganic acids; Or for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene It can be obtained by treatment with a suitable acid, such as organic acids such as sulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid, pamo acid and the like.
    Compounds of formula (1) containing acidic protons can be converted to their therapeutically active non-toxic base (ie metal or amine base) addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms are, for example, ammonium salts, for example alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts, for example benzatin, N-methyl-D-glucamine, hydravamine salts and the like. Salts with an organic base, and salts with amino acids such as arginine and lysine.
    Conversely, the salt form can be converted to the free form by treating with a suitable base or acid.
    In addition, the term addition salt used above includes the solvate which the compound of Formula (1) and its salt can form. Such solvates are for example hydrates, alcoholates and the like.
    N-oxides of compounds of formula (1) refer to compounds of formula (1) in which one or several nitrogen atoms are oxidized to so-called N-oxides, in particular nitrogen-N-oxidized N-oxides having R 1 and R 2 substituents It means to include.
    The term "stereochemical isomer" as used above and below defines all forms of isomers that can be formed from the compound of formula (1). The chemical designation, except as mentioned or indicated, refers to a mixture of all possible stereochemical isomers, in particular racemic mixtures, wherein the mixture includes diastereomers and enantiomers of the basic molecular structure. The stereochemical isomers of the compounds of formula (1) and mixtures of such forms are expressly intended to be included in formula (1).
    The numbering of the isoxazolidine ring-system in the compound of formula (1) is used below as defined in the Chemical Abstracts nomenclature. Compounds of formula (1) give rise to cis and trans isomers. The term relates to the position of substituents on the isoxazolidine ring and is also in accordance with Chemical Abstracts nomenclature. It is unusual for the nomenclature that the relevant substituent of carbon atom 3a is only hydrogen or R 5 . In defining the arrangements, substituents on carbon atom 3a and the best substituents on carbon atom 2 (ie,-(CH 2 ) n-NR 1 R 2 or R 5 ) are considered. If the relevant substituent on carbon atom 3a and the best substituent on carbon atom 2 are on the same side of the plane determined by the isoxazolidine ring, the arrangement is named cis, and if on the other side the arrangement is trans It is called.
    Compounds of formula (1) have at least two asymmetric centers: carbon atoms 3a and carbon atoms 2. The asymmetric center and other asymmetric centers that may be present are represented by R and S. When the monocyano methylene moiety is in the compound of formula (1), the moiety may have an E- or Z-configuration.
    Whenever the term "compound of formula (1)" is used herein, it is meant that it includes pharmaceutically acceptable acid addition salts, base addition salts and all stereoisomeric forms, and also N-oxides.
    Interesting compound has two A compound group of formula (1) wherein one of the radicals is 1,2-benzenediyl; Especially two One of the radicals is 1,2-benzenediyl and the other divalent radical This divalent pyridine, imidazole, pyrrole or thiophene radical is a group of compounds of formula (1).
    Another interesting compound is the compound group of formula (1), wherein X is CR 6 R 7 or O.
    Another interesting compound is a group of compounds of formula (1) wherein r is zero.
    Preferred compounds are groups of compounds of formula (1) wherein both R 1 and R 2 are methyl and n is 1 or 2.
    Another preferred compound is a group of compounds of formula (1) in which R 1 and R 2 together with the nitrogen atom to which they are attached form a morpholinyl ring or a radical of formula (e).
    In addition, R 1 is hydrogen or C 1-6 alkyl substituted with C 1-6 alkylcarbonyloxy, R 2 is methyl and n is 1 or 2 is a compound group of formula (1).
    Most preferred compounds are:
    2,3,3a, 8-tetrahydro-N, N-dimethylisoxazolo [2,3-a] pyrrolo [2,1-c] [1,4] benzo-diazepine-2-methanamine;
    2,3,3a, 8-tetrahydro-N, N-dimethylimidazo [2,1-c] isoxazolo [2,3-a] [1,4] -benzo-diazepine-2-methane Amines;
    2,3,3a, 7-tetrahydro-N, N-dimethylisoxazolo [2,3-a] thieno [2,3-c] [1] benz-azepine-2-methanamine;
    2,3,3a, 7-tetrahydro-N, N-dimethylisoxazolo [2,3-a] thieno [3,2-c] [1] benz-azepine-2-methanamine; Their stereochemically isomeric forms and pharmaceutically acceptable addition salts and their N-oxides.
    In general, compounds of formula (1) may be prepared by 1,3-dipolar cycloaddition of dienophiles of formula (3) and intermediates of formula (2). In intermediates 2 and 3 and in any of the other intermediates mentioned below, R 1 to R 5 , X, n, r, p, q and Is as defined above unless otherwise indicated.
    In addition, the hydrogen on the sp 2 -mixed aliphatic carbon atom in the intermediate (2) and the intermediate (3) may each be substituted with R 5 . The 1,3-dipolar cycloaddition may be optionally by mixing the reactants in a reaction-inert solvent such as, for example, toluene, 4-methyl-2-pentanone or tetrahydrofuran, or a mixture of such solvents. It can be done conveniently. Stirring and warming or pressurization can increase the reaction rate. Subsequently, the reaction of the intermediate (2) with the intermediate (3) yields the compound of formula (1) in a regioselective manner.

    In the above and below processes, the reaction product can be separated from the reaction medium and, if necessary, further purified according to generally known methods such as extraction, crystallization, polishing and chromatography.
    Compounds of formula (1) may also be converted to one another according to conversion reactions known in the art. For example,
    a) Compounds of formula (1), in which R 1 and R 2 together with the nitrogen atom to which they are attached, can be converted to the corresponding primary amine by treatment with hydrazine or aqueous alkali;
    b) The compounds of formula (1) wherein R 1 or R 2 are trifluoromethylcarbonyl can be converted into the corresponding primary or secondary amines by hydrolysis with aqueous alkalis;
    c) A compound of formula (1) wherein R 1 or R 2 is C 1-6 alkyl substituted with C 1-6 alkylcarbonyloxy, wherein R 1 or R 2 is C 1-6 alkyl substituted with hydroxy Can be hydrolyzed to the compound of (1);
    d) The compounds of formula (1) in which R 1 and R 2 are both hydrogen may be mono- or di-N-alkylated in the corresponding amine form;
    e) Compounds of formula (1) in which R 1 and R 2 are both hydrogen may be N-acylated with the corresponding amide;
    f) Compounds of formula (1) containing C 1-6 alkyloxycarbonyl groups can be hydrolyzed to the corresponding carboxylic acid.
    In addition, compounds of formula (1) wherein X is other than S may also be converted to the corresponding N-oxides according to known methods for converting trivalent nitrogen to its N-oxides. The N-oxidation reaction can generally be carried out by reacting the starting material of formula (1) with 3-phenyl-2- (phenylsulfonyl) oxaziridine or a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, alkali or alkaline earth metal peroxides such as hydrogen peroxide, such as sodium peroxide, potassium peroxide; Suitable organic peroxides are, for example, benzenecarboperoxides or halo-substituted benzenecarboperoxides such as, for example, 3-chlorobenzenecarboperoxide, such as alkanoperoxides such as acetic acid peroxide, such as tert-butyl hydroperoxide, and the like. Peroxide acids such as alkylhydroperoxides. Suitable solvents are, for example, lower alkanols such as water, for example ethanol, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.
    Intermediate of Formula (2), wherein X a is CR 6 R 7 , O, S (= O) or S (= O) 2 , which intermediate is represented by Formula (2-a) Can be prepared, for example, by oxidizing with a suitable oxidizing agent such as 2-benzenesulfonyl-3-phenyl-oxaziridine, hydrogen peroxide, tert-butylhydroxy peroxide, or metachloroperbenzoic acid.

    The oxidation is carried out in a reaction inert solvent at a temperature in the range between -20 ° C and 50 ° C, preferably between 0 ° C and room temperature. Suitable solvents are, for example, water, dichloromethane, toluene, methanol, 4-methyl-2-pentanone or mixtures of such solvents. When using an oxidant peroxide, the reaction rate is optionally controlled under a reaction-inert gas such as, for example, argon, for example Na 2 WO 4 , VO (acetylacetonate) 2 , Ti (OBu) 4 or MoO 2 (acetylacetonate). It can be augmented by using a metallic catalyst such as 2 .
    As an alternative, R 3b is the same as R 3 except for a nitro, R 4b is an intermediate of the formula (2) as R 4 other than a nitro [The intermediate is represented by the formula (2-b)] is, for water and for example Prepared by reducing the nitro group of the intermediate of formula (5) in the presence of a suitable reducing agent such as zinc or iron, and subsequently carrying out in-molecular cyclization in situ, for example in the presence of a weak acid such as ammonium chloride or acetic acid Can be. The reductive cyclization is carried out in a reaction-inert solvent, for example 1,4-dioxane. Stirring and warming can increase the reaction rate. In intermediate (5), R 3b and R 4b are as defined in intermediate of formula (2-b), and formyl and nitro substituents are both as defined in formula (1) Is present on an atom adjacent to the X radical on each of the aromatic heterocycles.

    It is believed that intermediates of formula (2) wherein X, R 3 , R 4 , p and q are defined above, are novel.
    Pure stereochemical isomers of the compounds of formula (1) can be obtained by applying methods known in the art. Diastereomers can be separated by physical methods such as selective crystallization and chromatographic techniques such as countercurrent distribution, liquid chromatography, and the like.
    Compounds of formula (1) as prepared by the processes described above are generally racemic mixtures of enantiomers, which can be separated from one another according to cleavage methods known in the art. Racemic compounds of formula (1) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric forms by reacting with a suitable chiral acid or chiral base, respectively. The diastereomeric forms are separated sequentially, for example by selection or fractionation, and the enantiomers are liberated from them by alkali or acid. Alternative methods of separating enantiomers of the compound of formula (1) include liquid chromatography using chiral stationary phases. The pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of the suitable starting materials if the reaction takes place stereospecifically. Preferably, if a particular stereoisomer is required, the compound will be synthesized by stereospecific preparation. This method may advantageously use stereoisomerically pure starting materials.
    Compounds of the invention are known as the 5-HT 2 receptors, in particular 5-HT 2A and 5-HT 2C receptors ("Serotonin (5-HT), edited by MD Ferrari and published in 1994 by Boerhaave Commission of the University of Leiden). in neurologic and psychiatric disorders "as described by D. Hoyer. Serotonin antagonism of the compounds of the present invention can be explained by their inhibitory effects in the "5-hydroxytryptophan test in rats" described in Drug Dev. Res., 13, 237-244 (1988). . In addition, the compounds of the present invention are described in the “mCPP test in mice”, Drug Dev. Res., 18, 119-144 (1989), described below, in the “constant plus irradiated plus maize test ( Elevated and Illuminated Plus Mase Test) and the "Associated Apomorphine, Tryptamine, Norepinephrine (ATN) Test in Rats", described in Arch. Int. Pharmacodyn, 227, 238-253 (1977). Pharmacological activity.
    In view of these pharmacological and physicochemical properties, the compounds of formula (1) are anxiety, depression and mild depression, bipolar disorder, sleep and sexual dysfunction, psychosis, borderline psychosis, schizophrenia, migraine, personality disorder or obsessive-compulsive disorder Treatments for the treatment and prevention of central nervous system disorders, such as phobia, panic attacks, organic mental disorders, mental disorders in children, aggression, memory and behavioral disorders in older people, addiction, obesity, macrophages and similar disorders Useful as In particular, the compounds of the present invention can be used as drugs that have the potential to control the addiction of anxiolytics, antipsychotics, antidepressants, antimigraine and drug abuse.
    The compounds of formula (1) can also be used as therapeutic agents for motility disorders. The compounds of the present invention may be advantageous for use with classical therapeutics for such disorders.
    In addition, the compound of formula (1) is damaged by the nervous system due to trauma, seizures, neurodegenerative diseases, etc .; Cardiovascular disorders such as hypertension, thrombosis, seizures, and the like; And gastrointestinal disorders such as motor dysfunction of the gastrointestinal system, and the like.
    In view of the above uses of the compounds of formula (1), the present invention also provides the treatment of warm-blooded animals suffering from such diseases, which treatments described above, in particular anxiety, psychosis, depression, migraine, and drug abuse Systemically administering a therapeutic amount of a compound of formula (1) that is effective for treating the addiction of
    The present invention therefore also relates to a compound of formula (1) as defined above for use as a medicament, in particular the compound of formula (1) is intended for the treatment of medicaments for the treatment of anxiety, psychosis, depression, migraine, and drug addiction. Can be used for manufacture.
    The skilled practitioner in the treatment of such a disease could determine the effective daily dose from the test results introduced below. A daily therapeutically effective amount will be about 0.01 mg- about 10 mg / kg body weight, more preferably about 0.05 mg- about 1 mg / kg body weight.
    To facilitate dosing, the subject compounds can be formulated in a variety of pharmaceutical forms for the purpose of dosing. In order to prepare the pharmaceutical compositions of the present invention, a therapeutically effective amount of the active compound, in particular in the form of an addition salt, is mixed with a pharmaceutically acceptable carrier to form a homogeneous mixture, wherein the carrier is preferred for administration. Depending on the type of preparation it can be taken in a wide variety of forms. These pharmaceutical compositions are preferably in single-dose form suitable for oral, rectal, transdermal or parenteral injection. For example, when preparing a composition in oral dosage form, when preparing oral liquids such as suspensions, syrups, elixirs and solutions, for example water, glycols, oils, alcohols and the like; Alternatively, when preparing powders, pills, capsules and tablets, some conventional pharmaceutical media such as solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. can be used. Because of the ease of administration, tablets and capsules are represented in the most useful form of oral dosage units, in which case solid pharmaceutical carriers are clearly used. Carriers for parenteral compositions will contain at least large amounts of sterile water, although other components may be included, for example, to aid dissolution. For example, an injectable solution may be prepared in which the carrier comprises a salt solution, a glucose solution or a mixture of salts and a glucose solution. Injectable solutions containing the compound of formula (1) may be formulated in oil for sustained action. Suitable oils for this purpose include, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures thereof, and other oils. Injectable suspensions may also be prepared in which suitable liquid carriers, suspensions and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally contains suitable wetting agents and / or penetration enhancers in combination with small amounts of suitable additives having specific properties, wherein the additives do not cause any significant toxic effects on the skin. Such additives may facilitate the administration to the skin and / or may help to prepare the desired composition. Such compositions can be administered in a variety of ways, such as for transdermal patches, as drops or as ointments. Acids or base addition salts of compounds of formula (1) are clearly more suitable for the preparation of aqueous compositions because they exhibit increased water solubility than the corresponding base or acid form.
    In order to improve the solubility and / or stability of the compound of formula (1) in the pharmaceutical composition, α-, β- or γ-cyclodextrin or derivatives thereof, in particular such as 2-hydroxypropyl-β-cyclodextrin, etc. It may be advantageous to use hydroxyalkyl substituted cyclodextrins. Co-solvents such as alcohols may also improve the solubility and / or stability of the compound of formula (1) in the pharmaceutical composition.
    It is particularly advantageous to prepare the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein and in the claims refers to a physically separable unit suitable as a single dose, each unit having a predetermined amount of activity calculated to produce the desired therapeutic effect with the required pharmaceutical carrier. Contains ingredients Examples of such dosage unit forms include tablets (including scored or coated tablets), capsules, pills, powder packets, oblates, injectable solutions or suspensions, one tablespoon of teaspoons, one tablespoon of tablets, and the like. , And separate composites each.
    The following examples illustrate the invention but do not limit the scope of the invention.
    Experiment part
    A. Preparation of Intermediate Compounds
    Example A.1
    a) Sodium hydride (60%) (0.0899 mol) is added in portions to a mixture of 2-hydroxybenzaldehyde (0.0818 mol) in N, N-dimethylformamide at room temperature under N 2 , and the mixture is placed under N 2 15 Stir for minutes. 2-Chloro-3-nitropyridine (0.0818 mol) in N, N-dimethylformamide was added and the mixture was stirred at 100 ° C. for 2 hours. The mixture was poured into an ice-water bath, extracted with diethyl ether, and the solvent was evaporated to yield 4.5 g (23%) of 2-[(3-nitro-2-pyridinyl) oxy] benzaldehyde (Intermediate 1).
    b) Zinc (0.0821 mol) was added to a suspension of intermediate (1) (0.0158 mol) in 1,4-dioxane (100 mL) and water (6.2 mL). Ammonium chloride (0.0413 mol) was added dropwise at 5-7 ° C. and the mixture was stirred at 5 ° C. for 1 hour. The precipitate was filtered off and the filtrate was evaporated. The residue (6.6 g) was treated with water, extracted with CH 2 Cl 2 and the solvent was evaporated. The product was not further purified and 3.7 g of pyrido [2,3-b] [1,4] benzoazine, 5-oxide (intermediate 2) was obtained.
    Intermediate A.2
    a) A mixture of 2-aminobenzyl alcohol (0.1218 mol), 3-thiophenecarboxaldehyde (0.1218 mol) and molecular sieve (3x) in 2-propanol (150 mL) was stirred overnight at room temperature. The crude reaction mixture was filtered, the residue was treated with CH 2 Cl 2 and the mixture was filtered again. The solvent was evaporated to afford 21.53 g (81%) of (±) -1,4-dihydro-2- (3-thienyl) -2H-3,1-benzoxazine (intermediate 3).
    b) Sodium tetrahydroborate (0.1979 mol) was added little to intermediate (3) (0.0989 mol) in ethanol (230 ml), and it stirred at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then at reflux for 90 minutes. The solvent was evaporated and the residue was treated with saturated aqueous NH 4 Cl solution and the mixture was extracted with CH 2 Cl 2 . The organic layer was separated, dried, filtered and the solvent was evaporated to yield 20.89 g (85%) of 2-[(3-thienylmethyl) amino] benzenemethanol (Intermediate 4).
    c) Tin chloride (IV) (0.2658 mol) was added dropwise to intermediate (4) (0.088 mol) in 1,2-dichloroethane (1000 mL). The reaction mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled in an ice bath. Water was added dropwise, as a result the solution was basified and then extracted with CH 2 Cl 2 . The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by flash column chromatography through silica gel (eluent: hexane / ethyl acetate 9/1 and 8/2). The desired fractions were combined and the solvent was evaporated to yield 4.76 g (27%) of 5,10-dihydro-4H-thieno [3,2-c] [1] benzazine (intermediate 5).
    d) Intermediate 5 (0.0145 mol) was dissolved in CH 2 Cl 2 (128 mL) and cooled in an ice bath. (±) -3-phenyl-2- (phenylsulfonyl) oxaziridine (0.02911 mol) was added in portions and the reaction mixture was stirred for 4 hours. The solvent was evaporated and the residue was purified by open column chromatography through silica gel (eluent: CH 2 Cl 2 / CH 3 OH 100/0 and 96/4). Pure fractions were combined and the solvent was evaporated to yield 3.64 g (82%) of 10H-thieno [3,2-c] [1] benzazine, 5-oxide (Intermediate 6).
    Intermediates of formula (2) prepared according to one of the above examples (see Example number in the column) are listed in Tables 1 and 2.
    Table 1
    Intermediate numberExample number 6 7 8 9 10A.2 A.1 A.1 A.2 A.2
    Table 2
    Intermediate numberExample NumberX 2 11A.1 A.2O CH 2
    B. Preparation of Compound of Formula (1)
    Example B.1
    A mixture of intermediate (2) (0.0174 mol) and 3-amino-1-propene (0.0261 mol) in tetrahydrofuran (60 mL) was stirred at 60 ° C. for 5 hours. The solvent was evaporated and the residue flashed through silica gel (eluent: CH 2 Cl 2 / hexane / 2-propanone 6/3/1 and CH 2 Cl 2 / hexane / CH 3 OH 6 / 3.5 / 0.5). Purification by chromatography. Pure fractions were combined and the solvent was evaporated. The residue (2.5 g) was washed with diethyl ether and further purified by HPLC (eluent: hexane / CH 2 Cl 2 / CH 3 OH 6/3/1). Pure fractions were combined and the solvent evaporated to (±) -cis-3,13b-dihydro-N, N-dimethyl-2H-isoxazolo [2,3-d] pyrido [2,3-b] [ 1,4] 1.4 g (27%) of benzoxazepine-2-methanamine (Compound 1; melting point 106.3 DEG C) was obtained.
    Example B.2
    (±) -cis-2,3,3a, 7-tetrahydro-N, N-dimethylisoxazolo [2,3-a] thieno [3,2-c] [1] benzazin-2- Methanamine ethanedioate (1: 1) (Compound 2; melting point 136.9 ° C.) was prepared by a similar method as Compound 1 in Example B.1. However, toluene was used as a solvent.
    Example B.3
    (±) -cis-2,3,3a, 8-tetrahydro-N, N-dimethylisoxazolo [2,3-a] pyrrolo [2,1-c] [1,4] -benzodiazepine-2 Methanamineamine ethanedioate (1: 1) (Compound 3; melting point 137.6 ° C.) was prepared in a similar manner to Compound 1 in Example B.1. However, a mixture of tetrahydrofuran and toluene was used as a solvent.
    Example B.4
    2- (methyl-2-propenylamino) ethanol acetate (ester) (0.0176 mol) was added to a solution of intermediate (11) (0.0160 mol) in tetrahydrofuran (110 mL) and the reaction mixture was added for 24 hours. Stir and reflux. Toluene (100 mL) was added and the mixture was stirred and refluxed for 24 h. The solvent was evaporated and the residue was passed through silica gel (eluent: CH 2 Cl 2 / (CH 3 OH / NH 3 ) 96/4) by short open column chromatography followed by HPLC (eluent: CH 2 Cl). 2 / CH 3 OH 96/4). Pure fractions were collected and the solvent evaporated to (±) -2,3,3a, 8-tetrahydro-2- (4-morpholinylmethyl) isoxazolo [3,2-a] pyrido [3,4 0.3c (10%) of -c] [2] -benzazine (Compound 9; melting point 46 ° C) was obtained.
    The compounds of formula (1) prepared according to one of the above examples (see Example number in the column) are listed in Tables 3 and 4.
    Table 3
    Compound numberExample number Physical data 2 3 4 5 6B.2 B.3 B.1 B.2 B.1 (±) -cis; Melting point 136.9 ° C .; Oxalic acid (1: 1) (±) -cis; Melting point 137.6 ° C .; Oxalic acid (1: 1) (±) -cis; Melting point 135.5 ° C .; H 2 O (1: 2). HCl (1: 2) (±) -cis; Melting point 157.8 ° C .; Oxalic acid (1: 1) melting point 112.5 ° C .; oxalic acid (1: 1) .H 2 O (1: 1) .2-propanolate (1: 1)
    Table 4
    Compound numberExample numberXR Physical data 1 7 8 9 10B.1 B.1 B.1 B.4 B.1O CH 2 CH 2 CH 2 CH 2 -N (CH 3 ) 2 -N (CH 3 ) 2 (±) -cis; melting point 106.3 ° C (±) -cis (±) -cis (±) -cis; melting point 46 ° C (±) -cis; melting point 116 ° C
    C. Pharmacological Examples
    Example C.1: "mCPP test in rats"
    At an hour of preliminary test time (T), mice were treated with test compounds with varying doses between 0.0025 mg and 40 mg / kg body weight, and 1 mg / kg of mCPP (metachlorophenylpiperazine) was injected intravenously 15 minutes before the test. did. After the preliminary test time (T), the "Open Field Test on Rats" as described in Drug Dev. Res. 18, 119-144 (1989) was treated. This was done for a mouse that used an infrared light source instead of a Kleverlux R (12V / 20W) light source. 42% of treated mice defined the active dose as the dose that exhibited mCPP induced inhibitory activity, ie mCPP-antagonism. Compounds 2, 3 and 7 were active at or below the test dose of 10 mg / kg.
    Example C.2: "Elevated and Illuminated Plus Maze Test of Constant Height in Mice"
    "Elevated and Illuminated Plus Maze Test in Rats" is described in Drug Dev. Res. 18, 119-114 (1989). In this test, the dose at which 42% of the mice found irradiated arms of maize was defined as the active dose of the test compound. Compounds 2, 4 and 5 showed activity at or below a test dose of 2.5 mg / kg.
    Example C.3; 5-HT in vitro 2A And 5-HT 2C Binding affinity for receptors
    The interaction of the compound of formula (1) with the 5-HT 2A and 5-HT 2C receptors was evaluated by radioligand binding experiments in vitro.
    In general, low concentrations of radioligand with high binding affinity for receptors are cultured in a buffer medium (0.2-5 ml) using tissue samples enriched with specific receptors (1-5 mg tissue). During incubation, the radioligand binds to the receptor. When binding equilibrium is reached, receptor binding radioactivity is separated from unbound radioactivity and the receptor binding radioactivity is counted. The interaction of test compounds with receptors is assessed by competitive binding experiments. Various concentrations of test compounds are added to the culture mixture containing tissue samples and radioligands. The binding of the radioligand will be inhibited by the test compound in proportion to its binding affinity and concentration.
    The radioligand used in the 5-HT 2A binding affinity test was 3 H-ketanserin, and the tissue used was the precortex of rats. At test concentrations of 10 −7 M, compounds 2, 3, 5, and 7 showed more than 40% of 5-HT 2A receptor inhibitory activity, while other compounds showed less than 40% of inhibitory effect.
    The radioligand used in the 5-HT 2C binding affinity test was 3 H-meshed and the tissue used was choroid choroid in pigs. At test concentrations of 10 −7 M, compounds 2, 3, 5, 6 and 7 showed more than 40% of 5-HT 2C receptor inhibitory activity, while other compounds showed less than 40% of inhibitory effect.
    D. Composition Examples
    "Active ingredient (A.I)" as used throughout these examples relates to compounds of formula (1), pharmaceutically acceptable acid addition salts, their stereochemical isomers or their N-oxides.
    Example D.1 Oral Solution
    Methyl 4-hydroxybenzoate (9 g) and propyl 4-hydroxybenzoate (1 g) were dissolved in boiling purified water (4 L). To 3 L of this solution, 2,3-dihydroxybutanedioic acid (10 g) was first dissolved, and then the active ingredient (20 g) was dissolved. The latter solution was mixed with the remainder of the former solution, to which 1,2, 3-propanetriol (12 L) and sorbitol 70% solution (3 L) were added. Sodium saccharin (40 g) was dissolved in water (500 mL) and raspberry (2 mL) and gooseberry essence (2 mL) were added. The latter solution was mixed with the former solution and 20 liters of an oral solution containing 5 mg of active ingredient per teaspoon (5 ml) were added by adding an appropriate amount of water to make a volume of 20 liters. The resulting solution was filled into a suitable container.
    Example D.2 Film-coated Tablets
    Preparation of Tablet Core
    The mixture of active ingredient (100 g), lactose (570 g) and starch (200 g) was mixed well and then wet with a solution of sodium dodecyl sulfate (5 g) and polyvinylpyrrolidone (10 g) in water (200 mL). The wet powder mixture was sieved, dried and sieved again. Then microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g) were added thereto. The whole was mixed well and compressed to give 10,000 tablets containing 10 mg of active ingredient in each tablet.
    covering
    To a solution of methylcellulose (10 g) in denatured ethanol (75 mL) was added a solution of ethylcellulose (5 g) in dichloromethane (150 mL). Then dichloromethane (75 ml) and 1,2,3-propanetriol (2.5 ml) were added thereto. Polyethylene glycol (10 g) was melted and dissolved in dichloromethane (75 mL). The latter solution was added to the former solution, and then magnesium octadecanoate (2.5 g), polyvinylpyrrolidone (5 g) and concentrated colored suspension (30 mL) were added and the whole was homogenized. The tablet cores were coated with the mixture obtained using a coating apparatus.
    Example D.3: Injectable Solution
    Methyl 4-hydroxybenzoate (1.8 g) and propyl 4-hydroxybenzoate (0.2 g) were dissolved in injectable boiling water (500 mL). After cooling to about 50 ° C., lactic acid (4 g), propylene glycol (0.05 g) and active ingredient (4 g) were added thereto while stirring. The solution was cooled to room temperature and supplemented with an appropriate amount of distilled water for injection to make 1000 ml to obtain a solution containing 4 mg / ml of the active ingredient. The solution was filtered and sterilized and placed in sterile containers.
    权利要求:
    Claims (10)
    [1" claim-type="Currently amended] A compound of formula (1) below, N-oxide, pharmaceutically acceptable addition salt or stereochemical isomer thereof.

    In the above formula:
    n is 0, 1, 2, 3, 4, 5 or 6;
    p is 0, 1, 2 or 3;
    q is 0, 1, 2 or 3;
    r is 0, 1, 2 or 3;
    R 1 and R 2 are each independently hydrogen; C 1-6 alkyl; C 1-6 alkylcarbonyl; Trihalomethylcarbonyl; Hydroxy, C 1-6 alkyloxy, carboxyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl or is a C 1-6 alkyl substituted with aryl; R 1 and R 2 together with the nitrogen atom to which they are attached may form a morpholinyl ring or a radical of the formula:

    From here:
    R 9 , R 10 , R 11 and R 12 are each independently hydrogen, halo, trihalomethyl, or C 1-6 alkyl;
    m is 0, 1, 2 or 3;
    R 13 , R 14 , R 15 and R 16 are each independently hydrogen or C 1-6 alkyl; R 15 and R 16 together may form a divalent C 4-5 alkanediyl radical; R 17 is hydrogen; C 1-6 alkyl; C 1-6 alkylcarbonyl; Trihalomethylcarbonyl; C 1-6 alkyloxycarbonyl; Aryl; Di (aryl) methyl; Hydroxy, C 1-6 alkyloxy, carboxyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl, or is a C 1-6 alkyl substituted with aryl;
    Each R 3 is independently halo, cyano, hydroxy, trihalomethyl, trihalomethoxy, carboxyl, nitro, amino, mono- or di (C 1-6 alkyl) amino, C 1-6 alkyl Carbonylamino, aminosulfonyl, mono- or di (C 1-6 alkyl) aminosulfonyl, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylcarbonyl or C 1-6 alkyloxy Carbonyl;
    Each R 4 is independently halo, cyano, hydroxy, trihalomethyl, trihalomethoxy, carboxyl, nitro, amino, mono- or di (C 1-6 alkyl) amino, C 1-6 alkyl Carbonylamino, aminosulfonyl, mono- or di (C 1-6 alkyl) aminosulfonyl, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylcarbonyl or C 1-6 alkyloxy Carbonyl;
    Each R 5 is independently C 1-6 alkyl, cyano or trihalomethyl;
    X is CR 6 R 7 , NR 8 , O, S, S (= 0) or S (= 0) 2 ; From here
    R 6 and R 7 are each independently hydrogen, hydroxy, C 1-6 alkyl, trihalomethyl, C 1-6 alkyloxy, or R 6 and R 7 together are methylene; Mono- or di (cyano) methylene; Formula-(CH 2 ) 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5- , -O- (CH 2 ) 2 -O- or -O- (CH 2 ) form a divalent radical of 3 -O-; With the carbon atoms to which they are attached, they may form carbonyl;
    R 8 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, arylcarbonyl, arylC 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, arylsulfonyl or arylC 1-6 alkyl Sulfonyl; Each Are independently divalent aromatic heterocycles, wherein the heterocycles are pyrrole, pyrazole, imidazole, triazole, furan, thiophene, isoxazole, oxazole, isothiazole, thiazole, pyridine, pyridazine, pyri May be selected from the group consisting of midine, pyrazine and triazine; One of the two divalent aromatic heterocycles in the compound of formula (1) may be 1,2-benzenediyl; Aryl is phenyl; Or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, C 1-6 alkyl and trihalomethyl.
    [2" claim-type="Currently amended] The method of claim 1, wherein One of the radicals is 1,2-benzenediyl.
    [3" claim-type="Currently amended] The compound of claim 1 or 2, wherein X is CR 6 R 7 or O. 4.
    [4" claim-type="Currently amended] 4. A compound according to any one of claims 1 to 3, wherein R 1 and R 2 are both methyl and n is 1 or 2.
    [5" claim-type="Currently amended] The method of claim 1,
    2,3,3a, 8-tetrahydro-N, N-dimethylisoxazolo [2,3-a] pyrrolo [2,1-c] [1,4] benzo-diazepine-2-methanamine;
    2,3,3a, 8-tetrahydro-N, N-dimethylimidazo [2,1-c] isoxazolo [2,3-a] [1,4] benzo-diazepine-2-methanamine ;
    2,3,3a, 7-tetrahydro-N, N-dimethylisoxazolo [2,3-a] thieno [2,3-c] [1] benz-azepine-2-methanamine;
    2,3,3a, 7-tetrahydro-N, N-dimethylisoxazolo [2,3-a] thieno [3,2-c] [1] benz-azepine-2-methanamine; A stereochemical isomer thereof, a pharmaceutically acceptable addition salt thereof, or a N-oxide thereof.
    [6" claim-type="Currently amended] A composition containing a therapeutically effective amount of a compound as claimed in any one of claims 1 to 5 as an active ingredient together with a pharmaceutically acceptable carrier.
    [7" claim-type="Currently amended] A method for preparing a composition as claimed in claim 6, characterized in that the pharmaceutically acceptable carrier is thoroughly mixed with a therapeutically effective amount of the compound as claimed in claim 1.
    [8" claim-type="Currently amended] A compound as claimed in any one of claims 1 to 5 for use as a medicament.
    [9" claim-type="Currently amended] Compound of formula (2).
    (2)
    In the above formula, , X, R 3 , R 4 , p and q are as defined in claim 1.
    [10" claim-type="Currently amended] a) reacting the dienofil of formula (3) with the intermediate of formula (2):
    b) converting a compound of formula (1) into a therapeutically active non-toxic acid addition salt by converting each other according to a conversion method known in the art, and further preferably treating the compound of formula (1) with an acid if desired. To the therapeutically active non-toxic base addition salt by treatment with a base, or conversely to the free base by treating the acid addition salt with alkali, or treating the base addition salt with an acid. To free acid; If desired, a process for the preparation of the compound as defined in claim 1 characterized in that the preparation of the stereochemical isomer or N-oxide thereof:
    In the intermediates (2) and (3), R 1 to R 5 , X, n, r, p, q and Are as defined in claim 1, and the hydrogen on the sp 2 -mixed aliphatic carbon atom may be each independently substituted by R 5 .
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    同族专利:
    公开号 | 公开日
    IL123656A|2001-09-13|
    US6156747A|2000-12-05|
    NO981077L|1998-10-12|
    HU9901875A2|1999-09-28|
    NZ329954A|1999-07-29|
    JP4299884B2|2009-07-22|
    EP0892804B1|2002-08-28|
    IL123656D0|1998-10-30|
    PL186541B1|2004-01-30|
    AT222911T|2002-09-15|
    CN1082963C|2002-04-17|
    CN1205010A|1999-01-13|
    PL326871A1|1998-10-26|
    WO1997039001A1|1997-10-23|
    HU221608B|2002-11-28|
    ZA9703122B|1998-10-12|
    AU2385297A|1997-11-07|
    HU9901875A3|2000-06-28|
    NO981077D0|1998-03-11|
    PT892804E|2003-01-31|
    MY117456A|2004-06-30|
    KR100598724B1|2006-10-25|
    DE69714980T2|2003-04-10|
    EP0892804A1|1999-01-27|
    TW514637B|2002-12-21|
    NO310077B1|2001-05-14|
    ES2182064T3|2003-03-01|
    AU716470B2|2000-02-24|
    DK892804T3|
    DK0892804T3|2002-12-02|
    DE69714980D1|2002-10-02|
    JP2000508328A|2000-07-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-04-12|Priority to EP96200991.6
    1996-04-12|Priority to EP96200991
    1997-04-09|Application filed by 디르크 반테, 얀센 파마슈티카 엔.브이.
    1997-04-09|Priority to PCT/EP1997/001830
    1999-08-25|Publication of KR19990067515A
    2006-10-25|Application granted
    2006-10-25|Publication of KR100598724B1
    优先权:
    申请号 | 申请日 | 专利标题
    EP96200991.6|1996-04-12|
    EP96200991|1996-04-12|
    PCT/EP1997/001830|WO1997039001A1|1996-04-12|1997-04-09|Isoxazolidine derivatives|
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