CN1065245C - Substituted tetracyclic oxazepine and thiazepine derivatives having affinity for 5-HT2 receptors - Google Patents

Substituted tetracyclic oxazepine and thiazepine derivatives having affinity for 5-HT2 receptors Download PDF

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CN1065245C
CN1065245C CN95195988A CN95195988A CN1065245C CN 1065245 C CN1065245 C CN 1065245C CN 95195988 A CN95195988 A CN 95195988A CN 95195988 A CN95195988 A CN 95195988A CN 1065245 C CN1065245 C CN 1065245C
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hydrogen
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CN1162314A (en
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F·J·弗南狄兹·盖狄尔
V·K·西彼多
J·I·安德鲁斯吉尔
T·F·米尔特
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Janssen Pharmaceutica NV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention relates to the compounds of formula(I), the pharmaceutically acceptable salts and stereoisomeric forms thereof, and also the N-oxide forms thereof, wherein: R<1> and R<2> each independently are hydrogen; C1-6alkyl; C1-6alkylcarbonyl; trihalomethylcarbonyl; C1-6alkyl substituted with hydroxy, C1-6alkyloxy, carboxyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl or aryl; or R<1> and R<2> taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substituted heterocycle; R<3> to R<10> each independently are hydrogen, halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, amino, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonylamino, aminosulfonyl, mono- or di(C1-6alkyl)-aminosulfonyl, C1-6alkyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl; R<11> is hydrogen, C1-6alkyl, or trifluoromethyl; R<12> is hydrogen, C1-6alkyl, cyano, or trifluoromethyl; n is zero to 6; and X is O, S, S(=O) or S(=O)2. The compounds of formula(I)may be used as therapeutic agents in the treatment or the prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.

Description

Substituted tetracyclic oxygen azepine and sulphur azepine derivatives to 5-HT2 acceptor tool affinity
The present invention relates to have antipsychotic, the cardiovascular and active substituted tetracyclic oxygen of gastric motility azepine _ and sulphur azepine _ derivative and their preparation; The invention still further relates to the composition that comprises them, and they are as the application of medicine.
The compound of similar structures is existing the description in United States Patent (USP) 4039558, this patent disclosure pyridine alkane and dibenzo-azepine _ ,-oxygen azepine _ ,-sulphur azepine _ and-diaza _ derivative, they have antihistamine, calm and antidepressant characteristic.European patent-A-0421823 described tool antiallergic property and the active similar dibenzo pyrazine of anti-asthma also-or benzo-pyrido-pyrazine also-azepine _ derivative.The compounds of this invention and they different are in there being different oxazolidine ring, and their pharmacological characteristics.
The present invention relates to formula I Compound, its pharmaceutically acceptable acid or base addition salt and stereochemistry heterogeneous forms and its N-oxide form, wherein: R 1And R 2Be hydrogen independently of one another; C 1-6Alkyl; C 1-6Alkyl-carbonyl; The trihalogenmethyl carbonyl; Use hydroxyl, C 1-6Alkoxyl group, carboxyl, C 1-6Alkyl carbonyl oxy, C 1-6The C that alkoxy carbonyl or aryl replace 1-6Alkyl; Or R 1And R 2The nitrogen-atoms that is connected with them can form the group of morpholine basic ring or following formula together:
Figure 9519598800061
Wherein:
R 13, R 14, R 15And R 16Be hydrogen independently of one another, halogen, trifluoromethyl, or C 1-6
Alkyl;
M is 1,2 or 3;
R 17, R 18, R 19And R 20Be hydrogen or C independently of one another 1-6Alkyl; Or
R 19And R 20Can form divalent radical C together 4-5Alkane 2 basis:
R 21Be hydrogen; C 1-6Alkyl; C 1-6Alkyl-carbonyl; The trihalogenmethyl carbonyl; C 1-6Alkane
Oxygen base carbonyl; Aryl; Two (aryl) methyl; Use hydroxyl, C 1-6Alkoxyl group, carboxyl,
C 1-6Alkyl carbonyl oxy, C 1-6The C that alkoxy carbonyl or aryl replace 1-6Alkyl; R 3, R 4, R 5, R 6, R 7, R 8, R 9And R 10Be hydrogen independently of one another, halogen, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, amino, single-or two (C 1-6Alkyl) amino, C 1-6Alkyl-carbonyl-amino, amino-sulfonyl, single-or two (C 1-6Alkyl)-and amino-sulfonyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkyl-carbonyl, C 1-6Alkoxy carbonyl; R 11Be hydrogen, C 1-6Alkyl or trifluoromethyl; R 12Be hydrogen, C 1-6Alkyl, cyano group or trifluoromethyl; N is 0,1,2,3,4,5, or 6; X is O, S, S (=O) or S (=O) 2Aryl is a phenyl; Or to be selected from halogen, hydroxyl, C 1-6The phenyl that 1,2 or 3 substituting group of alkyl and trifluoromethyl replaces.
In above-mentioned definition, C 1-6Alkyl refers to have the straight chain and the branched saturated hydrocarbon group of 1-6 carbon atom, for example, and methyl, ethyl, propyl group, butyl, 1-methyl-propyl, 1,1-dimethyl ethyl, amyl group, hexyl; C 4-5Alkane 2 basis refers to have the divalence direct sum branched saturated hydrocarbon group of 4-5 carbon atom, and for example 1,4-fourth two bases, 1,5-penta 2 bases; Halogen is a fluorine, chlorine, the common name of bromine and iodine.
Pharmaceutically-acceptable acid addition mentioned above means activated non-toxicity acid salt on the therapeutics that the compound that comprises formula I can form.Can obtain described salt by compound with the formula I of suitable acid treatment alkali formula.Acid that these are suitable such as mineral acid, for example, haloid acid example hydrochloric acid or Hydrogen bromide, sulfuric acid, nitric acid, acid such as phosphoric acid; Or organic acid, acetate for example, oxyacetic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, propanedioic acid, Succinic Acid, maleic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids, the cyclohexyl thionamic acid, Whitfield's ointment, right-aminosallcylic acid, pamoic acid etc.
The compound that contains the formula I of acid proton also can be by being converted into activated non-toxic metal or amine additive salt form on its therapeutics with suitable organic or inorganic alkaline purification.Suitable base salt form comprises, for example, ammonium salt, basic metal and alkaline earth salt, as lithium, sodium, potassium, magnesium, calcium salt etc., the salt that forms with organic bases, for example, benzyl, N-methyl D-glycosamine, the salt of breathing out amine salt and forming with amino acid such as arginine, Methionin.
On the contrary, described salt form can be by being converted into free form with suitable alkali or acid treatment.
Above the term additive salt of Shi Yonging also comprises the solvate that formula I compound and salt thereof can form.This solvate is, for example, and hydrate, alcoholate etc.
The N-oxide form of the compound of formula I represent to comprise those wherein one or more nitrogen-atoms be oxidized to the compound of the formula I of so-called N-oxide compound, particularly those wherein have R 1And R 2Substituent nitrogen is by the N-oxide compound of N-oxidation.
Preamble and the term " stereochemistry heterogeneous forms " that hereinafter uses refer to all possible isomeric form that the compound of formula I can exist.Unless mention in addition or point out that the chemical name of compound refers to the mixture of all possible stereochemistry heterogeneous forms, particularly racemic mixture, described mixture comprises all diastereomers and the enantiomorph of basic molecular structure.The stereochemistry heterogeneous forms of the compound of formula I and the mixture of these isomeric form obviously will be included in the formula I.
The numbering of the Fourth Ring loop systems that exists in the compound of formula I defines as " chemical abstracts " nomenclature, is shown in the formula (I ').
Figure 9519598800081
There is " cis " and " trans " isomer in the compound of formula I.Described term refer to substituting group on different oxazolidine ring the position and in " chemical abstracts " nomenclature unanimity.The special feature of this nomenclature is, as the carbon atom 3b of the part of loop systems, is not considered to the relevant substituting group of carbon atom 3a.When determining configuration, the substituting group of consideration on carbon atom 3a (promptly, " Z ") and at the substituting group (i.e. " T " or " Y ") that has override power on the carbon atom 2 when having substituting group that override weighs on " Z " and the carbon atom 2 when being positioned at homonymy by the definite mean level of the sea of different oxazolidine ring, this configuration promptly is named as " cis ", otherwise this configuration is named as " trans ".
The compound of formula I has at least 2 asymmetric centers, promptly has substituent R 11Carbon atom 3a and have a substituent R 12Carbon atom 2.Described asymmetric center and any asymmetric center that other may exist are represented with descriptor R and S.
When using below, the compound of term formula I always represents also to comprise pharmaceutically-acceptable acid addition, base addition salt and all stereoisomeric forms in any ratio, and N-oxide form.
The concrete group of formula I compound is wherein to use one or more following qualification person: a) R 1And R 2Be hydrogen independently of one another, C 1-6Alkyl, the trihalogenmethyl carbonyl is by carboxyl or C 1-6The C that alkoxy carbonyl replaces 1-6Alkyl, or R 1And R 2The nitrogen-atoms that is connected with them forms a morpholine basic ring or formula (b) together, (c), (d), group (e); B) R 15And R 16Be hydrogen; C) R 17And R 18For hydrogen and m are 1 or 2; D) R 19And R 20Form a divalence C together 4-5The alkane 2 basis group; E) R 21Be hydrogen, C 1-6Alkyl, two (aryl) methyl, C 1-6Alkoxy carbonyl, the trihalogenmethyl carbonyl is used hydroxyl, carboxyl, C 1-6The C that alkoxy carbonyl replaces 1-6Alkyl; F) R 3, R 4, R 5, R 6Be hydrogen independently of one another, halogen, trifluoromethyl, C 1-6Alkoxy carbonyl, C 1-6Alkyl amino sulfonyl, carboxyl; G) R 7, R 8, R 9, R 10Be hydrogen independently of one another, halogen, trifluoromethyl, C 1-6Alkoxy carbonyl, C 1-6Alkyl amino sulfonyl, carboxyl; H) R 11And R 12Be hydrogen; I) X is O, S or S (=O).
Significant compound is the compound or the subgroup of those formula I as defined above, wherein R 3, R 5, R 6, R 7, R 10, R 11And R 12Be hydrogen; Particularly, R 4, R 8And R 9Be selected from C independently of one another 1-6Alkoxy carbonyl and carboxyl, preferred R 4, R 8And R 9Be selected from hydrogen independently of one another, halogen, trifluoromethyl and C 1-6Alkyl amino sulfonyl.
Compound or subgroup that same significant compound is those formula I as defined above, wherein n be 1,2 or 3 and X be O.
Compound or subgroup that further significant compound is a formula I as defined above, wherein n be 1 and X be S or S (=O).
More significant compound is R wherein in those significant compounds 1And R 2Be selected from hydrogen independently of one another, methyl is with carboxyl or C 1-6The C that alkoxy carbonyl replaces 1-6Alkyl; Or R 1And R 2The nitrogen-atoms that is connected with them forms a morpholine basic ring or a formula (b) together, (c) or group (e).
Preferred compound is the compound of those formula I, and wherein X is O; N is 1,2 or 3; R 1And R 2All be methyl, or form wherein R with the nitrogen-atoms that they connected 15And R 16Be the group of the formula (b) of hydrogen, or R wherein 21Be hydrogen, C 1-6The group of the formula of alkyl or trifluoromethyl carbonyl (e); R 4And R 9Be selected from hydrogen independently of one another, halogen, trifluoromethyl, C 1-6Alkyl amino sulfonyl; R 3, R 5To R 8And R 10To R 12Be hydrogen.
Most preferred is:
Suitable-2-((dimethylamino) methyl)-3,3a-dihydro-N-methyl-2H-dibenzo [b, f] isoxazole also [2,3-d]-[1,4] oxygen azepine _-the 11-sulphonamide;
Suitable-11-chloro-3,3a-dihydro-2-(1-piperazinyl methyl)-2H-dibenzo [b, f] isoxazole also [2,3-d]-[1,4] oxygen azepine _;
Suitable-2-[[3,3a-dihydro-11-(trifluoromethyl)-2H-dibenzo [b, f] isoxazole also [2,3-d] [1,4] oxygen azepine _-the 2-yl] methyl isophthalic acid H-isoindole-1,3-(2H)-diketone; With
Suitable-11-chloro-3,3a-dihydro-N, N-dimethyl-2H-dibenzo [b, f] isoxazole also [2,3-d] [1,4] oxygen azepine _-the 2-propionic acid amide;
Its stereochemistry heterogeneous forms and pharmaceutically-acceptable acid addition, and their N-oxide form.
Ironically, the compound of formula I is easy to synthesize.Usually, the intermediate product that they can be by formula II prepares with 1,3 dipole cycloaddition of the dienophile of formula III.In intermediate product (II) and any following intermediate product of (III) neutralization, unless otherwise indicated, R 1To R 12, X and n are as defined above.Described 1,3-dipole cycloaddition can be easily finished by being in or be not in the reaction-inert solvent mixed reactant, and the example of these reaction-inert solvents has for example aromatic solvent such as toluene; Ether, as tetrahydrofuran (THF), or the mixture of these solvents.Stir and elevated temperature, or pressure boost, speed of response can be improved.Intermediate product (II) is a regioselective reaction with the reaction of intermediate product (III) in practice, produces the compound of formula I.
In this and following preparation, reaction product can from reaction solvent, separate and, if necessary, as extracting, crystallization is ground and chromatography is further purified according to methodology well known in the art.
The compound of formula I also can transform mutually according to the known method for transformation in field.For example, a) R wherein 1And R 2Form the formula of the group of formula (b) with the nitrogen-atoms that they connected
(I) compound can be converted into corresponding primary amine by handling with hydrazine or alkali aqueous solution; B) R wherein 1And R 2Be the compound of the formula I of trifluoromethyl carbonyl, can be by molten with alkali
The liquid hydrolysis is converted into corresponding one-level or secondary amine; C) R wherein 1Or R 2For using C 1-6The C that alkyl carbonyl oxy replaces 1-6The formula I compound hydrolyzable of alkyl is R wherein 1Or R 2Be the C that replaces with hydroxyl 1-6The formula I compound of alkyl; D) R wherein 1And R 2The compound that is the formula I of hydrogen can be single-or two-N-alkyl turn to corresponding amine form; E) R wherein 1And R 2But the compound N-acidylate that is the formula I of hydrogen is a corresponding amide; F) contain C 1-6The compound hydrolyzable of the formula I of alkoxycarbonyl groups is a corresponding carboxylic acid.
Wherein X is not that the compound of the formula I of S can adopt conversion trivalent nitrogen well known in the art to be converted into corresponding N-oxide form for the step of its N-oxide form.Described N-oxidizing reaction usually can be by making formula I initial substance and 3-phenyl-2-(benzene sulfonyl) oxaza propane or carry out with suitable organic or inorganic peroxide reactions.Suitable inorganic peroxide comprises, as hydrogen peroxide, and basic metal or alkaline earth metal peroxide, as sodium peroxide, Potassium peroxide; Suitable organo-peroxide can comprise peroxy acid such as peroxybenzoic acid or halo peroxybenzoic acid, as 3-chlorine peroxybenzoic acid, and the peroxide bond alkanoic acid, as peracetic acid, alkyl peroxide such as tertbutyl peroxide.Appropriate solvent is, for example, water, low-level chain triacontanol, as ethanol etc., hydrocarbon, as toluene, ketone, as 2-butanone, halohydrocarbon is as the mixture of methylene dichloride and these solvents.
By formula (the wherein X of the representative of II-a) is O, S (=O) or S (=O) 2The intermediate product of formula II, can be by with suitable oxygenant such as 2-benzene sulfonyl-3-phenyl-chlorine ethylenimine, hydrogen peroxide, tert-butyl hydroxyl peroxide (t-butgl hydroxyperoxide), or metachloroperbenzoic acid oxidation and preparing.
Described oxidation in reaction-inert solvent between-20 ℃ of-50 ℃ of temperature, preferably at 0 ℃ to carrying out between room temperature.Appropriate solvent is, for example, water, hydrochloric ether is as chloroform; Aromatic hydrocarbon; As toluene; Alcohols is as methyl alcohol; Ketone is as 4-methyl-2 pentanone; Or the mixture of these solvents.When using peroxide oxidant, speed of response can be by using metal catalyst such as Na 2WO 4, VO (methyl ethyl diketone) 2, Ti (OBu) 4, or MoO 2(methyl ethyl diketone) 2Improve, can randomly in the presence of rare gas element such as argon gas, react.
In addition, formula (the wherein R of representative of II-b) 11Be hydrogen and R 3To R 10As defined above but be not that the intermediate product of the formula II of nitro can be prepared as follows: there is water in the nitryl group of the intermediate product of formula (V) and is suitably reducing under reductive agent such as zinc or the iron situation; And carry out the original position intramolecular cyclization existing under weak acid such as ammonium chloride or the acetate situation subsequently.Described reductive cyclization reaction-inert solvent as (1, carry out under the 4-diox exists.Stirring and elevated temperature can improve speed of response.In intermediate product (V), R 3To R 10Suc as formula (intermediate product of II-b) defines.
Figure 9519598800121
Can adopt method well known in the art to obtain the pure stereochemistry heterogeneous forms of the compound of formula I, diastereomer can be by physical method such as selective crystallization and chromatographic technique, is separated as adverse current distribution liquid phase chromatography etc.
The compound of Zhi Bei formula I is generally the racemic mixture of enantiomorph as stated above, and they can adopt the known technology of taking apart in field separated from each other.The racemic mixture of enough alkalescence or tart formula I can be respectively by with suitable chirality acid, or chirality alkali reaction and be converted into corresponding diastereomer salt form.Described diastereomer salt form subsequently separately by selective freezing for example or fractional crystallization, and with alkali or acid from wherein discharging enantiomorph.Other method of the enantiomorph of the compound of separation formula I comprises the liquid phase chromatography of using the chirality stationary phase.Described pure stereochemistry heterogeneous forms also can derive from the corresponding pure stereochemistry heterogeneous forms of suitable initial substance, and precondition is that the reaction solid takes place specifically.Specific if desired steric isomer is preferably by the synthetic described compound of stereospecific preparation method.These methods will advantageously adopt initial substance pure on the enantiomerism.
The pharmacological activity of The compounds of this invention is by following one or Multitest explanation; External 5-HT 2Receptor binding assays; " rat APOMORPHINE, tryptamines, the norepinephrine Combined Trials " described in the international pharmacodynamics document (Arch.Int.Pharmacodyn) 227,238-253 (1997); " rat mCPP test "; " rat that improve with reinforcement maze test illumination " (Elevated and Illuminated Plus Maze Test onRats).Latter two test all is described below.In addition, compound of the present invention shows significant pharmacological activity in " tail hanging test " (Tair Suspension Test) and pharmaceutical progress and research (Drug Dev.Res.) 18 among " the LSD medicine is differentiated test " (the LSDDrug Discrimination Test) that describes among the 119-144 (1989).The significant characteristic of another of the compound of formula I is that they suppress amphetamine inductive stereotyped action behavior in the rat.
In view of these pharmacological characteristics, the compound of formula I is in treatment or prevent useful as therapeutics in the following central nervous system disease.These diseases are as anxiety, and are depressed and slight depressed, the bipolarity mental disorder, sleep and sexual dysfunction, psychosis, marginal psychosis, schizophrenia, migraine, personality disorder or compulsive insanity, social phobia or panic attack, organic mental disorders, children ' s spirit obstacle, aggressive behaviour, memory of elderly person obstacle and purpose obstacle, habituation, obesity, Bulimia nerovsa and similar illness.Particularly, The compounds of this invention can be used as anxiolytic, and thymoleptic and conduct have the medicine to the addicted ability of abuse resistant drugs.
The compound of formula I also can be used as therapeutical agent in treatment of dyskinesias.These diseases are united use with The compounds of this invention and classic treatment agent may be favourable.
Compound of the present invention also can be used as therapeutical agent and is used for the treatment of and prevents by wound apoplexy, the nervous system damage that neurodegenerative disease etc. cause; Cardiovascular disorder such as hypertension, thrombosis, apoplexy etc.; Gastrointestinal illness such as gastro-intestinal system motor dysfunction etc.Compound of the present invention also can be used as anticonvulsant drug.
In view of the such use of the compound of formula I, thereby the present invention also provides a kind of method for the treatment of the warm-blooded animal that suffers from these diseases, and described method comprises the compound that systemic administration is treated the formula I of the effective therapeutic dose of above-mentioned disease.
Therefore the present invention also relates to compound by defined formula I above as a kind of medicine, in particular as the medicine of the above-mentioned disease of treatment.
The professional who treats these diseases can determine effective every day of therapeutic dose from test-results given below.Effectively every day, therapeutic dose should be about 0.001mg/kg to about 10mg/kg body weight, and more preferably from about 0.005mg/kg is to about 1mg/kg body weight.
For being easy to medication, this compound can fill a prescription for various medicament forms for using.For preparing pharmaceutical composition of the present invention, with the specific compound of treatment significant quantity, can select the additive salt form, mix closely with pharmaceutically acceptable carrier as activeconstituents, can take various ways according to the desirable dosage form of medication.These pharmaceutical compositions are preferably made suitable oral, per rectum, and through skin, or the unit dosage form of parenteral injecting drug use.For example, in the preparation of compositions of oral dosage form, can adopt any common drug matrix.Such as, for oral liquid such as suspension, syrup, elixir and solution can make water, glycol, oil, alcohols etc.; For pulvis, pill, capsule and tablet can use solid carrier such as starch, sucrose, kaolin, lubricant, tackiness agent, disintegrating agent etc.Owing to be easy to medication, tablet and capsule are represented the oral dosage unit form of most convenient, obviously adopt solid pharmaceutical carriers in this case.To the parenteral composition, carrier comprises aqua sterilisa usually, and major part is an aqua sterilisa at least, though other composition, such as increase solubleness person, in also can being included in.Injectable solution can be prepared as wherein that carrier comprises salt brine solution, the mixture of glucose solution or salt solution and glucose solution.The Injectable solution that comprises the compound of formula I can be prepared in oil to provide long-acting.The oil that is fit to this purpose is, for example, and peanut oil, sesame oil, oleum gossypii seminis, Semen Maydis oil, soya-bean oil, the synthetic glyceride of longer chain fatty acid and these and other oily mixture.Also injectable suspensions can be prepared, suitable liquid vehicle, suspension agent etc. can be adopted in this case.Be fit in the composition of skin medication, optional penetration enhancers and/or the suitable wetting agent of whether comprising of carrier, whether can choose wantonly and be used in combination with the suitable additives of any character in a small amount, these additives do not cause any significant deleterious effect on skin.But described additive facilitation is to the medication of skin and/or can help to prepare desired composition.These compositions can be used in many ways, for example, and as the transdermal plaster, as spray (spot-on) or as ointment.The acid of the compound of formula I or base addition salt are because they are than corresponding alkali or the increase of sour form water-soluble.Thereby obviously be more suitable for preparing waterborne compositions.
Be solvability and/or the stability of compound in pharmaceutical composition of increase formula I, use α-, β-, the cyclodextrin that γ-Huan Hujing or their derivative, particularly hydroxyalkyl replace, as, 2-hydroxyl-propyl group-beta-cyclodextrin can be beneficial to.In addition, cosolvent such as alcohols can improve solvability and/or the stability of compound in pharmaceutical composition of formula I.
It evenly is particularly advantageous to be easy to medication and to make dosage that aforementioned pharmaceutical composition is mixed with dosage unit form.The dosage unit form that uses in this specification sheets and claims refers to be suitable as the physics discrete units of dosage unit, and per unit contains the activeconstituents of the predetermined amount of the platform therapeutic effect that can produce expectation as calculated, and needed pharmaceutical carrier.The example of this dosage form is tablet (including the tablet of cut or dressing), capsule, pill, powder bag, wafer capsule, injectable solvent or suspension, one, a table spoon etc. and its isolating polyad.
Routine embodiment is intended to illustrate and does not limit the scope of the invention down.Experimental section A. prepares intermediate product
Below, " EtOAc " refers to ethyl acetate, and " DMF " refers to dimethyl formamide and " RT " refers to room temperature.Embodiment 1a) with the mixture stirring of 1-(2-propenyl) piperazine (6.6g) in the ethanol (100ml) and 2-ethyl propenoate (11.3ml) and refluxed 1 hour 30 minutes, evaporating solvent produces 9.6g (80%) 4-(2-propenyl)-1-piperazine-ethyl propionate (intermediate product 1).B) with the intermediate product 1 (7.5g) of hydrochloric acid soln (35%) in (20ml), the mixture of acetate (20ml) and water (10ml) stirs also and refluxed 4 hours.Mixture being iced but on ice bath and add NaOH (50%) makes mixture pH value be about 6 and evaporating solvent.Residue is handled with EtOAc, leaches throw out and evaporates filtered solution.The oily residue is dissolved in toluene and evaporating solvent.Residue is by the short column chromatography (elutriant: CH of purifying on silica gel of opening 2Cl 2/ (CH 3OH/NH 3) 8/2).Collect pure fraction and evaporation, produce 5.3g (81%) 4-(2-propenyl)-1-piperazine propionic acid (intermediate product 2).
Embodiment 2
With 2-hydroxy benzaldehyde (16.7g) and Al among the DMF 2O 3The mixture of/KF (65.5g) is at N 2Be heated to 120 ℃ and add 4-bromo-1-fluoro-2-oil of mirbane (30g) among the DMF under the gas.This mixture stirred 3 hours at 120 ℃.Leach throw out and permeate is evaporated.Residue is by opening the column chromatography (elutriant 1: hexane/CH of purifying on silica gel 2Cl 2/ AcOEt, 8/1/1; Elutriant 2:CH 2Cl 2/ 2-acetone, 9/1), collect pure fraction, produce 26g (59%) 2-(4-bromo-2-nitro-phenoxy phenyl aldehyde (intermediate product 3).Similarly, preparation 5-chloro-2-(2-nitro-phenoxy) phenyl aldehyde (intermediate product 4).
Embodiment 3a) with 1,4-two chloro-2-oil of mirbane (31.6g) add 2 in the methyl alcohol (820ml), in the mixture of 2 '-dithio, two phenyl aldehydes (41g) and potassiumphosphate (41.3g), and with the reaction mixture stirring with refluxed 2 hours.Add more 1,4-two chloro-2-oil of mirbane (31.6g) also stir reaction mixture and refluxed 2 hours.Add entry and with mixture CH 2Cl 2Extract.On silica gel, purify by opening column chromatography with isolating organic layer evaporation and with residue (elutriant: hexane/EtOAc, 97.5/2.5).Collect pure fraction and evaporating solvent, produce 37g (84%) 2-((4-chloro-2-oil of mirbane) sulfo-) phenyl aldehyde (intermediate product 5).Similarly, preparation 2-((2-nitro-4-(trifluoromethyl) phenyl) sulfo-) phenyl aldehyde (intermediate product 6).B) mistake-vitriolate of tartar (35.6g) mixture in (120ml) in water is dropwise added in the mixture of the intermediate product 5 (8.5g) in the refrigerative methyl alcohol (120ml) on ice-water bath and with mixture stirring at room 7 hours.Evaporating solvent adds entry and throw out is leached.Residue is by the flash chromatography (elutriant: CH of purifying on silica gel 2Cl 2/ CH 3OH, 98/2).Collect pure fraction and evaporation, produce 4.8g (51%) 2-((4-chloro-2-oil of mirbane) sulfinyl)-phenyl aldehyde (intermediate product 7).
Embodiment 4a) at N 2Under the gas with the LiAlH in the tetrahydrofuran (THF) (100ml) 4(1M) dropwise add 1,3-chloro-dibenzo (b in the 4-diox (400ml), f) (1,4) oxygen azepine _-11 (10H)-ketone (12.3g) is (according to India's The Chemicals (Indian J.Chem.) 1974,12 (3), prepare described in the 227-35) in, mixture is stirred, refluxed 1 hour 30 minutes, cooling also dropwise adds entry.Extract organic layer Na with the mixture acidifying and with EtOAc 2SO 4Drying is filtered and evaporation.Residue is purified on silica gel by opening column chromatography, (elutriant: CH 2Cl 2).Collect pure fraction and evaporation, produce 9.74g (84%) 3-chloro-10,11-dihydro-dibenzo [b, f]-[1,4] oxygen azepine _ (intermediate product 8).B) will also this mixture at room temperature be stirred 1 hour in the mixture of 3-phenyl-2-(benzene sulfonyl) oxaza propane (3.64g) adding intermediate product 8 (15.4g) and trichloromethane (700ml).Evaporating solvent and with residue by opening the column chromatography (elutriant: CH of on silica gel, purifying 2Cl 2).Collect pure fraction and evaporation, produce 8.6g (34%) 3-chlorodiphenyl also (b, f) (1,4) oxygen azepine _, 10-oxide compound (intermediate product 9).
Embodiment 5
1, the mixture in 4-diox (200ml) and the water (15ml) is in stirring at room with intermediate product 3 (10g) and zinc (10.3g).The temperature that is lower than 25 ℃ dropwise add in the entry (17ml) ammonium chloride (4.3g) and with mixture stirring at room 1 hour.Throw out is leached and filtered solution is evaporated.Residue is with water treatment and use CH 2Cl 2/ CH 3OH, 9/1 extracts.Dry organic layer filters and evaporation.Residue is by opening column chromatography (the elutriant 1:CH that purifies on silica gel 2Cl 2/ hexane/EtOAc, 5/4/1; Elutriant 2:CH 2Cl 2/ 2-acetone, 9/1).Collect pure fraction and evaporation, generation 2.2g (24%) 8-bromine dibenzo (b, f) (1,4) oxygen azepine _, 10-oxide compound (intermediate product 10).Similarly, be prepared as follows intermediate product: table 1
Figure 9519598800171
Intermediate product number X ?R 4 ?R 9
?10 ?11 ?12 ?13 ?14 ?15 ?16 ?17 ?O ?O ?O ?O ?O ?O ?S ?S=O ?Br ?H ?Cl CF 3CO-O-CH 3?H ?CF 3?Cl ?H ?Cl ?H ?H ?H ?H ?H ?H
B. the preparation of the compound of formula I
Embodiment 6
With intermediate product 15 (2.6g) and N, the N-dimethyl-2-propylene-mixture of 1-amine (29ml) in toluene (40ml) stirred 2 hours at 80 ℃.Evaporating solvent and with residue by the column chromatography (elutriant: hexane/CH of on silica gel, purifying 2Cl 2/ CH 3OH, 3.5/6/0.5).Collect pure fraction and evaporation.Residue in room temperature at C 2H 5Be converted into oxalate (1: 1) among the OH, produce 1g (63%) (±)-3,3a-dihydro-N, N-dimethyl-2H-dibenzo (b, f) isoxazole also (2,3-d) (1,4)-oxygen azepine _-2-formicester oxalate (1: 1); Fusing point: 179.6 ℃ (compound 1).
Embodiment 7
According to embodiment 6 in identical step, but use tetrahydrofuran (THF) as solvent, also prepared (±)-suitable-11-chloro-3,3a-dihydro-N, N-dimethyl-2H-dibenzo [b, f] isoxazole-[2,3-d] [1,4] oxygen azepine _-2-methylamine oxalate (1: 1); Fusing point, 154.4 ℃ (compound 2).
Embodiment 8
Will be according to method preparation (±)-suitable-1-((11-chloro-3 of embodiment 7,3a-dihydro-2H-dibenzo [b, f] isoxazole also [2,3-d] [1,4]-oxygen azepine _-the 2-yl) methyl)-salt of wormwood (4.2g) in 4-(trifluoroacetyl) piperazine (7.1g) and the methyl alcohol (300ml) and the mixture of water (43ml) be stirring at room 2 hours.Evaporating solvent.CH is used in the residue water treatment 2Cl 2Extraction is also evaporated isolated organic layer.Residue (5.1g) is by the flash chromatography (elutriant: CH of purifying on silica gel 2Cl 2/ CH 3OH 9/1,8/2 to 7/3), collect pure fraction and evaporation.In room temperature in C 2H 5Among the OH residue (4.2g) is converted into oxalate (2: 3), produces 3.9g (47%) (±)-suitable-11-chloro-3, and 3a-dihydro-2-(1-piperazinyl methyl)-2H-dibenzo [b, f] isoxazole is [2,3-d] [1,4] oxygen azepine _ oxalate (2: 3) also; Fusing point＞250.0 ℃ (compound 3).
Embodiment 9
With (±)-methyl-suitable-2-((dimethylamino) methyl)-3 in the ethanol (60ml) according to the preparation of the method for embodiment 7,3a-dihydro-2H-dibenzo [b, f] isoxazole also [2,3-d] [1,4]-the oxygen azepine _-11-carboxylate adipic acid salt (1: 1) (1.53g) dropwise adds sodium hydroxide (0.3g) mixture in the entry (7.5ml), and mixture stirred and refluxed 2 hours.Evaporating solvent and residue is acidified to the pH value with HCl (4N) is 3.6 in a vacuum.Throw out is leached, use P 2O 5Dry and by the short column chromatography (elutriant: CH of on silicagel column, purifying 2Cl 2/ CH 3OH/NH 3) 7/3).Collect pure fraction and evaporation, and with residue CH 2Cl 2/ C 2H 5OH/H 2O 25ml/5ml/5ml handles.Throw out leached and dry, produces 0.5g (38%) (±)-suitable-2-((dimethylamino) methyl)-3,3a-dihydro-2H-dibenzo [b, f] isoxazole also [2,3-d] oxygen azepine _-11-carboxylic acid semihydrate; Fusing point: 229.8 ℃ (compound 4).
Embodiment 10
(±)-suitable-2-((3 that will prepare according to the method for embodiment 7,3a-dihydro-11-(trifluoromethyl)-2H-dibenzo [b, f] isoxazole also [2,3-d] [1,4] the oxygen azepine _-the 2-yl) methyl)-hydrazine hydrate (0.28ml) in 1H-isoindole-1,3 (2H)-diketone (2.53g) and the ethanol (30ml) stirred 5 hours at 80 ℃.Leach throw out and filtered solution is evaporated.Oily residue (3.3g) is by the flash chromatography (elutriant: CH of purifying on silica gel 2Cl 2/ CH 3OH 9.5/0.5).Collect pure fraction and evaporation., and with oily residue (0.7g) at room temperature at C 2H 5Be converted into oxalate (1: 1) among the OH, produce 0.8g (35%) (±)-suitable-3,3a-dihydro-11-(trifluoromethyl)-2H-dibenzo [b, f]-isoxazole also [2,3-d] [1,4] oxygen azepine _-2-methylamine oxalate (1: 1); Fusing point: 250 ℃ (compound 5).
Table 2-5 lists the compound with the method preparation that is similar to one of the foregoing description.Table 2
Figure 9519598800191
Compound number The experiment number n ?X ?R 1 ?R 2 ?R 4 ?R 8 ?R 9 Physical data (fusing point ℃)
?1 ?2 ?4 ?5 ?6 ?7 ?8 ?9 ?10 ?11 ?12 ?13 ?14 ?15 ?16 ?17 ?18 ?19 ?20 ?21 ?22 ?23 ?24 ?6 ?7 ?9 ?10 ?9 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?1 ?1 ?1 ?1 ?1 ?1 ?2 ?3 ?6 ?1 ?1 ?1 ?1 ?2 ?1 ?1 ?2 ?1 ?1 ?1 ?1 ?1 ?1 ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?S ?S ?S ?SO ?O ?O ?O ?CH 3?CH 3?CH 3?H ?H ?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3 ?CH 3?CH 3?CH 3?H ?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 2-COOH ?CH 2COOCH 3(CH 2) 2COOH ?H ?Cl ?COOH ?CF 3?CF 3?F ?Cl ?Cl ?Cl ?H ?H ?Br ?CF 3?CF 3?COOCH 3?SO 2NHCH 3?H ?Cl ?CF 3?Cl ?Cl ?C1 ?Cl ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?Cl ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?Cl ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ±-suitable/(COOH) 2/ 179.6 ±-suitable/(COOH) 2/ 154.4 ±-suitable/1/2H 2O/229.8 ±-suitable/(COOH) 2/ 250.0 ±-suitable/(COOH) 2±-suitable/(COOH) 2/ 181.3 ±-suitable/(COOH) 2/ 186.9 ±-suitable/(COOH) 2/ 164.3 ±-suitable/72.5 ±-suitable/(COOH) 2/ 181.5 ±-suitable/(COOH) 2/ 163.9 ±-suitable/(COOH) 2/ 152.6 ±-suitable/(COOH) 2/ 177.8 ±-suitable/(COOH) 2/ 197.1 ±-suitable/(COOH) 2/ 152.4 ±-suitable/(COOH) 2/ 78.2 ±-suitable/105.8 ±-suitable/113.0 ±-(suitable+anti-)/107.4 ±-(suitable+anti-)/144.7 ±-suitable/H 2O/86.2 ±-suitable/(COOH) 2/ 148.1 ±-suitable/1/2H 2O/57.3
Compound number The experiment number n ?X ?R 1 ?R 2 ?R 4 ?R 8 ?R 9 Physical data (fusing point ℃)
25 26 27 28 29 30 31 32 33 34 35 ?7 ?7 ?7 ?7 ?7 ?9 ?7 ?7 ?7 ?7 ?7 ?1 ?1 ?1 ?1 ?1 ?1 ?1 ?1 ?1 ?1 ?1 ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3?CH 3 (CH 2)COOC 2H 5(CH 2) 3COOH (CH 2) 3COOC 2H 5(CH 2) 4COOH (CH 2) 4COOC 2H 5(CH 2) 2COOH (CH 2) 2COOC 2H 5(CH 2) 4COOH (CH 2) 4COOC 2H 5(CH 2) 4COOH ?CO-CF 3 ?Cl ?Cl ?Cl ?Cl ?Cl ?H ?H ?H ?H ?CF 3?CF 3 ?H ?H ?H ?H ?H ?Cl ?Cl ?Cl ?Cl ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ±-suitable/3/2 fumaric acid/147.3 ±-suitable/(COOH) 2/ 157.2 ±-suitable/(COOH) 2/ 149.8 ±-suitable/(COOH) 2/ 170.1 ±-suitable/(COOH) 2/ 155.4 ±-suitable/159.5 ±-suitable ±-suitable/(COOH) 2/ 148.4 ±-suitable/(COOH) 2/ 132.5 ±-suitable/(COOH) 2±-suitable
Table 3
Figure 9519598800202
Compound number The experiment number R 4 ?R 19 Physical data (fusing point ℃)
?36 ?37 ?38 ?39 ?40 ?41 ?42 ?43 ?44 ?45 ?46 ?47 ?8 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?a ?Cl ?Cl ?Cl ?Cl ?Cl ?Cl ?Cl ?a ?a ?a ?F ?CF 3 ?H ?CH 3(CH 2) 2-OH ?CO-CH 3?CO-O+C 4H 9?CO-CF 3(CH 2) 2-COOH (CH 2) 2-COOC 2H 53-chloro-phenyl-diphenyl methyl two (4-fluorophenyl) methyl CH 3CH 3 ±-suitable/3/2 (COOH) 2/＞250.0 ±-suitable/2 (COOH) 2/ 189.4 ±-suitable/2 (COOH) 2/＞250.0 ±-suitable/1/2H 2O/46.8 ±-suitable/124.7 ±-suitable/110.9 ±-suitable/H 2O/59.2 ±-suitable/3/2 (COOH) 2/ 266.6 ±-suitable/154.5 ±-suitable/198.4 ±-suitable/107.2 ±-suitable/2 (COOH) 2/ 186.2 ±-suitable/2 (COOH) 2
Table 4
Compound number The experiment number ?n ?X ?R 4 ?Q Physical data (fusing point ℃)
?48 ?49 ?50 ?51 ?52 ?53 ?54 ?7 ?7 ?7 ?7 ?7 ?7 ?7 ?1 ?1 ?1 ?1 ?2 ?3 ?1 ?O ?O ?O ?O ?O ?O ?S ?CF 3?CF 3?Cl ?CF 3?CF 3?CF 3?CF 3 7.9-dioxy-8-azaspiro [4.5] last of the ten Heavenly stems-8-base 1-pyrrolidinyl 4-morpholinyl 1.3-dihydro-1.3-dioxy-2H-iso-indoles-2-base 1.3-dihydro-1.3-dioxy-2H-iso-indoles-2-base 1.3-dihydro-1.3-dioxy-2H-iso-indoles-2-base 1.3-dihydro-1.3-dioxy-2H-iso-indoles-2-base ±-suitable/149.7 ... ±-suitable/(COOH) 2/ 174.1 ±-suitable/(COOH) 2/＞250.0 ±-suitable/165.6 ±-suitable/113.9 ±-suitable/112.2 ±-(suitable+anti-)/135.9
C. pharmacological examples embodiment 11: " rat mCPP test "
Rat is handled with the dosage of 0.0025mg/kg-40mg/kg body weight with test compound, and the trial test time T is 5-480 minute, tests preceding 15 minutes intravenous injection 1mg/kg mCPP (a chlorobenzene piperazine).After the trial test time T is gone over, the rat of handling is accepted as drug research and progress (Dmg Dev, Res) 18, " test of rat barnyard " described in the 119-144 (1989) (Open Field Test on Rats), but use infrared light sources to replace Kleverlux _(12V/20W) light source.40% is tried the dosage that rat demonstrates the inhibition (being the mCPP antagonistic action) to the effect of mCPP inductive is defined as active dose.The field of activity of test compound is measured the ratio of LAD (lowest activity dosage) by HAD (high reactivity dosage).Sequence number 9 and 11 compound have 4 or higher ratio (HAD is to LAD).Sequence number 2,3,5-7,10,13,14,16,18-21,26,28,33,38,44,48,50 and 52 compound is demonstrated the mCPP antagonistic action at least a by amount of reagent.Embodiment 12: " to the reinforcement maze test of raising and the illumination of rat "
" to the reinforcement maze test of raising and the illumination of rat " sees pharmaceutical progress and research (Drug.Dev.Res.) 18 for details, 119-144 (1989).The active dose of test compound is defined as the dosage that 40% tested rat detects the illuminated branch road in labyrinth in described mensuration.Field of activity according to embodiment 11 in similarly method measure.Sequence number 3,8,17,19,21,40,51,53 and 54 compound has 4 or higher ratio (HAD is to LAD).Sequence number 1,2,4-6,9-13,16,18,22,26-30,32,33,36,39,41,43,44,46,47,49,50 and 52 compound shows active in one or more tested rat at least one dosage.D. composition embodiment
" activeconstituents " that uses in all these embodiment (A.I.) all relates to compound, its pharmaceutically-acceptable acid addition, stereochemistry heterogeneous forms or its N-oxide form of formula (I).
Embodiment 13: oral drops
500 gram A.I. (activeconstituents) are dissolved in 0.5L 2 hydroxy propanoic acid and 1.5L polyoxyethylene glycol at 60-80 ℃.After being cooled to 30-40 ℃, add the 35L polyoxyethylene glycol and mixture is fully stirred.Add 1750 in 2.5L pure water gram soluble saccharin solution then, and under agitation add 2.5L cocoa aromatic flvouring and an amount of polyoxyethylene glycol to volume is 50L, produce the oral drops solution that contains the 10mg/ml activeconstituents.The solution that is produced is packed in the proper container.
Embodiment 14: oral liquid
9 gram 4-hydroxyl methyl-formiates and 1 gram 4-nipasol are dissolved in the 4L ebullient pure water.The 10 gram 2,3 dihydroxybutanedioic acids of dissolving earlier also dissolve the 20g activeconstituents subsequently in this solution of 3L.The remainder of back one solution and last solution is merged, and to wherein adding 12L 1,2,3-glycerol and 3L sorbyl alcohol 70% solution.Be dissolved in the 40g soluble saccharin in the 0.5L water and add 2ml and cover plate essence and 2ml dayberry essence.Back one solution and the former merge, and adding water to volume is 20L, contains the oral liquid of every (5ml) 5mg activeconstituents with generation.The solution that produces is packed in the proper container.Embodiment 15: the preparation of film-coated tablet tablet core
With 100 gram activeconstituentss, 570 gram lactose and 200 gram starch thorough mixing, and be used in the solution wetted that the gram sodium lauryl sulphate of 5 in about 200ml water and 10 restrains polyvinylpyrrolidones subsequently.Wet-milling powder mixture is sieved, dry and after sieve.Add 100 gram Microcrystalline Celluloses and 15 gram hydrogenant vegetables oil then.With whole mixture thorough mixing and be pressed into tablet, obtain 10,000, every contains the 10mg activeconstituents.Dressing
Add in the 10 gram methocel solutions in the 75ml Denatured alcohol and be dissolved in the gram of 5 in 150ml methylene dichloride ethyl cellulose solution.Add 75ml methylene dichloride and 2.5ml1 then, 2, the 3-glycerol.10 gram polyoxyethylene glycol are melted and be dissolved in the 75ml methylene dichloride.Will back one solution add in the last solution and add 2.5 gram Magnesium Stearates subsequently, 5 gram polyvinylpyrrolidones and 30ml concentrate pigment suspension, and with whole mixture uniform mixing.In a coating device, the tablet core is used the mixture dressing of acquisition like this.
Embodiment 16: Injectable solution
1.8 gram 4-methyl hydroxybenzoates and 0.2 gram 4-nipasol are dissolved in about 0.5L ebullient water for injection.In stirring, add 4 gram lactic acid after being cooled to about 50 ℃, 0.05 gram propylene, two pure and mild 4 gram activeconstituentss.This solution is cooled to room temperature and is supplemented to 1L with water for injection, produce the solution that contains the 4mg/ml activeconstituents.This solution is with in the filtration method sterilization and the sterilising vessel of packing into.

Claims (8)

1. the compound of formula I, its pharmaceutically acceptable acid or base addition salt and stereochemistry heterogeneous forms, and N-oxide form,
Figure 9519598800021
Wherein, R 1And R 2Be hydrogen, C independently of one another 1-6Alkyl, C 1-6Alkyl-carbonyl, trihalomethyl group carbonyl, usefulness hydroxyl, C 1-6Alkoxyl group, carboxyl, C 1-6Alkyl carbonyl oxy, C 1-6The C that carbalkoxy or aryl replace 1-6Alkyl, or R 1And R 2Can form the group of a morpholine basic ring or following formula with the nitrogen-atoms that they connected,
Figure 9519598800022
Wherein: R 13, R 14, R 15And R 16Be hydrogen, halogen, trifluoromethyl or C independently of one another 1-6Alkyl; M is 1,2 or 3; R 17, R 18, R 19And R 20Be hydrogen or C independently of one another 1-6Alkyl; Or R 19And R 20Lump together and to form a divalent radical C 4-5Alkane 2 basis; R 21Be hydrogen, C 1-6Alkyl, C 1-6Alkyl-carbonyl, trihalomethyl group carbonyl, C 1-6Carbalkoxy, aryl, two (aryl) methyl, usefulness hydroxyl, C 1-6Alkoxyl group, carboxyl, C 1-6Alkyl carbonyl oxy, C 1-6The C that carbalkoxy or aryl replace 1-6Alkyl; R 3, R 4, R 5, R 6, R 7, R 8, R 9And R 10Be hydrogen, halogen, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, amino, list-or two (C independently of one another 1-6Alkyl) amino, C 1-6Alkyl-carbonyl-amino, amino-sulfonyl, list-or two (C 1-6Alkyl)-amino-sulfonyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkyl-carbonyl, C 1-6Alkoxy carbonyl; R 11Be hydrogen, C 1-6Alkyl or trifluoromethyl; R 12Be hydrogen, C 1-6Alkyl, cyano group or trifluoromethyl; N is 0,1,2,3,4,5 or 6; X be O, S, S (=O) or S (=O) 2Aryl is a phenyl; Or with being selected from halogen, hydroxyl, C 1-6The phenyl that 1,2 or 3 substituting group of alkyl and trifluoromethyl replaces.
2. according to the compound of claim 1, R wherein 3, R 5, R 6, R 7, R 10, R 11And R 12Be hydrogen.
3. according to the compound of claim 2, wherein n is 1,2 or 3.
4. according to the compound of claim 3, R wherein 1And R 2Be selected from hydrogen, methyl independently of one another, with carboxyl or C 1-6The C that carbalkoxy replaces 1-6Alkyl; Or R 1And R 2Form a morpholine basic ring or formula (b), (c) or group (e) with the nitrogen-atoms that they connected.
5. according to the compound of claim 1, wherein this compound is
Suitable-the 2-[(dimethylamino) methyl]-3,3a-dihydro-N-methyl-2H
-dibenzo [b, f] isoxazole also [2,3-d] [1,4] oxygen azepine _-the 11-sulphonyl
Amine;
Suitable-11-chloro-3,3a-dihydro-2-(1-piperazinyl methyl)-2H-hexichol
And [b, f] isoxazole also [2,3-d]-[1,4] oxygen azepine _;
Suitable-2-[[3,3a-dihydro-11-(trifluoromethyl)-2H-dibenzo [b, f]
Isoxazole also [2,3-d] [1,4] oxygen azepine _-the 2-yl] methyl-the 1H-isoindole-
1,3-(2H)-diketone;
Suitable-11-chloro-3,3a-dihydro-N, N-dimethyl-2H-dibenzo [b, f]
Isoxazole also [2,3-d] [1,4] oxygen azepine _-the 2-propionic acid amide;
Its stereochemistry heterogeneous forms, pharmaceutically-acceptable acid addition and N-oxide form.
6. composition, it comprises pharmaceutically acceptable carrier and as any one compound in the claim 1 to 5 of significant quantity on the therapeutics of activeconstituents.
7. the application that any one compound is used to prepare medicine in the claim 1 to 5.
8. prepare the method for the compound of claim 1, it is characterized in that: a) dienophile of formula III and the intermediate product of formula II are reacted: Wherein in intermediate product (II) and (III), R 1To R 12, X and n be according to definition in the claim 1; B) according to method for transformation well known in the art, the compound of formula I is transformed mutually, and if desired, further the compound of formula I is gone up activated non-toxicity acid salt by be converted into treatment with acid treatment, or by be converted into upward activated non-toxic bases additive salt of treatment with alkaline purification, or conversely, be free alkali, or be free acid by transforming the base addition salt form with acid treatment by transforming the acid salt form with alkaline purification; And, if necessary, prepare its form of three-dimensional chemical isomer or N-oxide form.
CN95195988A 1994-11-02 1995-10-25 Substituted tetracyclic oxazepine and thiazepine derivatives having affinity for 5-HT2 receptors Expired - Fee Related CN1065245C (en)

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