+

WO1998031679A1 - Composes de thiophene et leur application medicinale - Google Patents

Composes de thiophene et leur application medicinale Download PDF

Info

Publication number
WO1998031679A1
WO1998031679A1 PCT/JP1998/000077 JP9800077W WO9831679A1 WO 1998031679 A1 WO1998031679 A1 WO 1998031679A1 JP 9800077 W JP9800077 W JP 9800077W WO 9831679 A1 WO9831679 A1 WO 9831679A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
tetrahydro
thiophene
methylbenzo
chlorophenyl
Prior art date
Application number
PCT/JP1998/000077
Other languages
English (en)
Japanese (ja)
Inventor
Takanobu Kuroita
Yoshifumi Togo
Masakazu Fujio
Takashi Futamura
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to AU53434/98A priority Critical patent/AU5343498A/en
Priority to JP53409998A priority patent/JP3185222B2/ja
Publication of WO1998031679A1 publication Critical patent/WO1998031679A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms

Definitions

  • Dopami emissions D 4 (hereinafter, pursuant to the approximately normal for Dopami emissions receptor subtypes described that. After D 4.) Relates to a novel Chiofue emission compounds with affinity for receptors, these Chiofen compounds Dopamine receptor blockers containing are used in the medical field as central nervous drugs, especially antipsychotics, drugs for alcohol dependence, and drugs for drug abusers.
  • the 2 5 2 5 7 No., piperidines Rajin compounds having selectivity for the D 4 receptor, Piperi Gin compound and 1, 2, 5, 6-tetrahydropyridine compound is disclosed.
  • Japanese Patent Application Laid-Open No. Hei 9-310600 discloses a benzocerenbiperazine compound having an antipsychotic effect. Compounds are disclosed.
  • GB 2 3 1 1 0 1 to 0 No., D 4 receptor that having a affinity 4 _ (Benzochiofen one 2-I le) one 1- (4 one black port benzyl) one 1, 2, 3, Tetrahydropyridine derivatives such as 6-tetrahydropyridine are disclosed.
  • Antipsychotics to schizophrenia adaptive diseases the most have a common pharmacological action of receptor blockade of dopamine which is one of the brain neurotransmitter, particularly potent D 2 receptors blocking action Is shown.
  • These drugs are effective for positive symptoms, mainly hallucinations and delusions, which are characteristic of the acute phase of schizophrenia, but they are not effective for emotional weakness, inactivity, autism, etc. It has been pointed out that it has almost no effect on the negative symptoms of cysteine.
  • Dopamine receptors have previously been identified by pharmacological techniques as being classified into two receptor subtypes based on their ligand-binding properties and their form of association with adenylate cyclase [Nature et al. Vol. 27, p. 93 (1977)]. That is, D, a receptor that activates adenylate cyclase via a promoting G protein to produce cyclic AMP, and a receptor type, and suppresses adenylate cyclase via an inhibitory G protein, resulting in cyclic cycling.
  • D 4 receptors are involved in the action site of the pathogenesis of schizophrenia or therapeutic agents. Moreover, the difference is recognized between subtypes in the brain distribution of Dopami emissions receptor, D 2 receptors for most often in the striatum, D 4 receptors in the cerebral cortex frontal lobe which governs the emotional function It is clear that it is the most abundant.
  • D 4 receptor knockout mice created by gene recombination (micelackingdo am ine D 4 receptors) Chikaraku, Anore call, cocaine, it is reported that susceptibility is enhanced to drugs, such as Metanfeta Mi emissions [cell (Cell), Vol. 90, p. 991 (1997)].
  • the present invention shows a selective and strong blocking action on D 4 receptor, characteristic hallucinations in the acute phase of schizophrenia, not only positive symptoms centering on such delusions, apathy and inaction, self is also effective against negative symptoms, such as closing, also seen when administering a conventional antipsychotic drug with D 2 receptors blocking action, extrapyramidal symptoms and endocrine abnormalities and time were the side effects is reduced
  • Another object of the present invention is to provide a highly safe antipsychotic drug which has excellent oral absorbability, bioavailability, and localization in the brain.
  • the present invention by showing a selective and strong blocking action on D 4 receptor, and to provide a alcoholic patients and drug abusers therapeutic agents.
  • a novel thiophene compound represented by the following general formula (1), an optical isomer, a pharmaceutically acceptable salt thereof or a hydrate thereof is a D 2 receptor. It began looking to have selective and strong blocking action on D 4 receptor than. Therefore, the compound of the present invention exerts an effect not only on positive symptoms such as hallucinations and delusions that are characteristic in the acute phase of schizophrenia, but also on negative symptoms such as dullness, inactivity, and autism.
  • the present invention relates to the following.
  • D is absent or represents a linear or branched alkylene chain having 1 to 8 carbon atoms
  • n 0 or an integer of 1 to 3
  • R 2 represents hydrogen or alkyl
  • R 3 represents hydrogen, halogen, alkyl, acyl, amino or nitro;
  • R 4 represents hydrogen or alkyl;
  • the bond represented by Q—T is CH, CH 2 —N, (CH 2 ) 2 —N, CH 2 — C (R 5 ) (Wherein, R 5 represents hydrogen, hydroxy, alkyl or alkoxy.) Or CH 2 C,
  • E represents an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent.
  • D represents a linear or branched alkylene chain having 1 to 5 carbon atoms
  • n 1;
  • R 2 represents hydrogen
  • R 3 represents hydrogen or alkyl
  • R 4 represents hydrogen
  • E is an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent, wherein the thiophene compound of the above (1), an optical isomer thereof, and a medicament thereof; Acceptable salts or hydrates thereof.
  • a thiophene compound of the above (1) selected from 6,6-tetrahydropyridine, an optical isomer, a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • a medicament comprising the thiophene compound of the above (1), an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • a pharmaceutical composition comprising the thiophene compound of the above (1), an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive.
  • Specific examples of each group in the general formula (1) are as follows.
  • the linear or branched alkylene chain having 1 to 8 carbon atoms in D means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexmethylene, octamethylene, methylmethylene, dimethylmethylene, 1-methylethylene Len, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, ethylmethylene, getylmethylene, 1-ethylethylene, 2-ethylethyl Tylene, 1-methyltrimethylene, 1,1-dimethyltrimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 3-methyltrimethylene, 3,3-dimethyltrimethylene, 1-ethyltrimethylene, Examples thereof include 2-ethyltrimethylene and 3-ethyltrimethylene.
  • a linear or branched alkylene chain having 2 to 5 carbon atoms is preferable, and ethylene, trimethylene or tetramethylene is particularly preferable.
  • the alkyl of R 1 represents an alkyl having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, etc. Four alkyls are preferred.
  • acyl in R 3 means alkenyl having 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isoptyryl, etc., and preferably alkanol having 2 to 4 carbon atoms.
  • the alkoxy in R 5 represents alkoxy having 1 to 8 carbon atoms such as methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, etc. Alkoxy having 1 to 4 carbon atoms is preferred.
  • halogen in R 3 examples include fluorine, chlorine, and bromine.
  • Aryl in E means phenyl, naphthyl, 4-indanyl and so on.
  • the aromatic heterocyclic group in E represents pyridyl, furyl, phenyl, pyrimidinyl and the like.
  • the aryl and the aromatic heterocyclic group in E may have a substituent, and the substituent is a halogen such as fluorine, chlorine, or bromine; a haloalkyl having 1 to 4 carbon atoms such as trifluoromethyl; Alkyl having 1 to 4 carbon atoms, such as butyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl; methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy Examples thereof include alkoxy having 1 to 8 carbon atoms such as C, pentyloxy, hexyloxy, heptyloxy, and
  • A—D— A represents methylene, and D is preferably a straight-chain or branched alkylene chain having 1 to 5 carbon atoms. In particular, — A—D— is trimethylene. Certain cases are preferred.
  • R 2 hydrogen or alkyl is preferable, and hydrogen is particularly preferable.
  • R 3 is preferably hydrogen or alkyl, and particularly preferably methyl.
  • R 4 is preferably hydrogen or alkyl, and particularly preferably hydrogen.
  • E is preferably aryl which may have a substituent.
  • the aryl in E is preferably phenyl having 1 to 2 substituents such as naphthyl or halogen, methyl, trifluoromethyl, methoxy, etc., for example, 4-chlorophenyl, 4-fluorophenyl, 3_ Trifluoromethylphenyl, 4-methylphenyl and the like.
  • substituents such as naphthyl or halogen, methyl, trifluoromethyl, methoxy, etc.
  • aromatic heterocyclic group for E phenyl, pyridyl or phenyl or pyridyl having 1 to 2 substituents such as halogen and methyl are preferable.
  • the cyclic amino group represented by NT-E includes the following embodiments (a) to (e). Among these, a group of the formula (b) or (e) in which the bond represented by Q—T is CH 2 —N or CH 2 C is preferred.
  • Pharmaceutically acceptable salts of the compound of the general formula (1) include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid) , Malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and ascorbic acid).
  • inorganic acids hydroochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • organic acids acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid
  • Malic acid tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluen
  • the compound of the general formula (1) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate, these hydrates (1Z10 hydrate, 12 water Hydrate, monohydrate, 3Z dihydrate, dihydrate, etc.) and solvates are also included in the present invention.
  • the compound of the general formula (1) has an asymmetric atom, at least two kinds of optical isomers exist. These optical isomers and their racemates are included in the present invention.
  • the compound of the general formula (1) and the compound of the present invention contained in the general formula (1) can be synthesized by a method represented by the following reaction formula.
  • Each symbol in the reaction formulas has the same meaning as described above unless otherwise specified.
  • the compound of the general formula (1-1) is converted into a solvent that does not hinder the reaction (methanol, ethanol, tetrahydrofuran, methylene chloride, chloroform, benzene, toluene, getyl ether, or any mixed solvent thereof).
  • a solvent that does not hinder the reaction methanol, ethanol, tetrahydrofuran, methylene chloride, chloroform, benzene, toluene, getyl ether, or any mixed solvent thereof.
  • the compound represented by (1-2) is obtained.
  • a solvent that does not hinder the reaction of this compound (112) such as dimethylformamide, methylene chloride, chloroform, acetonitrile, benzene, toluene, dimethylsulfoxide, or a mixture of these in any proportion
  • a base By reacting with an alkyl halide (R'-C1, R'-Br, etc.) in the presence of sodium hydride, potassium carbonate, sodium methoxide, sodium ethoxide, etc., the general formula (1-3) ) Can be obtained.
  • the compound represented by the general formula (1-2) is reacted with a solvent that does not hinder the reaction (dimethylformamide, methylene chloride, chloroform, acetonitrile, benzene, toluene, etc.) in the presence of sodium iodide, By reacting with silyl chloride at room temperature to the reflux temperature of the solvent for 1 to 8 hours, the compound represented by the general formula (1-4) can be obtained. Further, the compound of the general formula (1-4) can also be obtained by reacting the compound of the general formula (1-2) in trifluoroacetic acid with triethylsilane in the above reaction.
  • Method 2
  • the compound of the general formula (8) is obtained by hydrolysis with an aqueous solution of In a suitable solvent (such as methylene chloride, chloroform, dichloroethane, acetonitrile, benzene, toluene, xylene, or a mixed solvent of any of these), the compound of the general formula (8) is reacted at a reflux temperature of thionyl chloride and the solvent.
  • a suitable solvent such as methylene chloride, chloroform, dichloroethane, acetonitrile, benzene, toluene, xylene, or a mixed solvent of any of these
  • reaction is carried out for up to 24 hours to obtain the corresponding acid chloride compound of the compound of the general formula (8).
  • a suitable solvent nitrobenzene, methylene chloride, chloroform, dichloroethane or Mixed with any of these
  • a Lewis acid aluminum chloride, boron trifluoride, zinc chloride, iron chloride, tin chloride, etc.
  • Bases (potassium carbonate, sodium bicarbonate, triethylamine) in a solvent (methylene chloride, chloroform, acetonitrile, benzene, toluene, water or a mixture of any ratio thereof) which does not hinder the reaction of the compound of the general formula (5) , Pyridine, dimethylaminopyridine, etc.) in the presence of a haloacyl halide of the general formula (3) to give a compound of the general formula (9).
  • a solvent methylene chloride, chloroform, acetonitrile, benzene, toluene, water or a mixture of any ratio thereof
  • Lewis acid aluminum chloride, boron trifluoride, zinc chloride, etc.
  • a suitable solvent such as nitrobenzene, methylene chloride, chloroform, dichloroethane or any mixture thereof
  • iron chloride, tin chloride, etc. By reacting with iron chloride, tin chloride, etc. under cooling at room temperature or at the reflux temperature of the solvent for 1 to 24 hours, the compound of the general formula (10) can be obtained.
  • Solvents that do not interfere with the reaction of the compound of general formula (10) eg, tetrahydrofuran, methylene chloride, chloroform, benzene, toluene, getyl ether
  • the reaction can also be performed by using a suitable reducing agent (borane, lithium aluminum hydride, etc.) in a mixture of the above and reacting under ice-cooling or heating for 1 to 24 hours.
  • a compound represented by 1) is obtained.
  • Solvent Methanol, Ethanol, Ethyl Acetate, Acetic Acid, Aqueous Hydrochloric Acid, Acetonitrile, or a mixture of these in any proportion
  • a catalyst such as palladium carbon, Raney nickel or platinum oxide
  • the compound of the general formula (16) wherein R 3 is hydrogen can be obtained.
  • the thiophene compound of the general formula (1) obtained by the above method is converted into a suitable solvent such as methanol, ethanol, isopropyl alcohol, isopropyl ether, chloroform, ethyl acetate, hexane, getyl ether or a mixture thereof.
  • a suitable solvent such as methanol, ethanol, isopropyl alcohol, isopropyl ether, chloroform, ethyl acetate, hexane, getyl ether or a mixture thereof.
  • inorganic acids hydroochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • organic acids acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, quenched acid
  • Acid maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or ascorbic acid
  • a suitable solvent methanol, Ethanol, isopropyl alcohol, isopropyl ether, black hole , Shioma acetate Echiru, hexane, by recrystallized from Jefferies chill ether, water or a mixed solvent thereof and the like
  • oxalic acid hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid,
  • the compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method.
  • a conventional method such as a recrystallization method and a column chromatography method.
  • the resulting product is a racemic form, it is separated into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid or by passing through a column filled with an optically active carrier.
  • Individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These can also be obtained by using optically active starting compounds and the like.
  • Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.
  • Chiofunin compounds of the present invention is D 4 receptor blocker with a strong blocking action on D 4 receptor, schizophrenia It is a useful antipsychotic drug that is effective not only for positive symptoms such as hallucinations and delusions that are characteristic of the acute phase, but also for negative symptoms such as dullness, inactivity, and autism. Also seen in case of administration of conventional antipsychotic drug with D 2 receptors blocking action, side effects such as extrapyramidal symptoms and endocrine abnormalities are expected as antipsychotics which are alleviated. Therefore, the compound of the present invention can be used as a therapeutic drug for schizophrenia and the like. Further, the thiophene compound, its optical isomer, its pharmaceutically acceptable salt or hydrate thereof of the present invention can also be used as a therapeutic drug for alcohol-dependent patients and drug abusers. .
  • the compound of the present invention is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.).
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.
  • parenteral means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection Includes injection or infusion methods.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution.
  • acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides.
  • Suppositories for rectal administration consist of the drug and suitable nonirritating excipients, such as cocoa butter and polyethylene glycols, which are solid at normal temperatures, liquid at intestinal tract temperatures, and melt in the rectum However, it can be manufactured by mixing with a substance that releases a drug.
  • the active ingredient compound may comprise at least one additive, such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans , Pectins, tragacanth gums, gum arabic, gelatins, collagens, caseins, albumins, synthetic or semi-synthetic polymers or glycerides.
  • the active ingredient compound may comprise at least one additive, such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans , Pectins, tragacanth gums, gum arabic, gelatins, collagens, caseins, albumins, synthetic or semi-synthetic polymers or glycerides.
  • Such dosage forms may also contain, as usual, further additives, such as inert diluents, lubricants such as magnesium stearate, parabens, sorbic acid or salts thereof.
  • inert diluents such as magnesium stearate, parabens, sorbic acid or salts thereof.
  • examples include preservatives, antioxidants such as ascorbic acid, tocoprol, and cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents, and perfumes. Tablets and pills can additionally be manufactured with enteric coating.
  • Liquid preparations for oral administration include pharmaceutically acceptable emulsions, Drops, elixirs, suspensions, solutions and the like, which may contain an inert diluent commonly used in the art, such as water.
  • Dosage will depend on age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, drug combination, the extent of the condition being treated by the patient at the time, and other factors. Determined in consideration of factors.
  • the compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof can be safely used with low toxicity, and its daily dose depends on the condition and weight of the patient, the type of the compound, and the route of administration.
  • parenterally subcutaneously, intravenously, intramuscularly, or rectally, about 0.01 to 5 Omg / person, preferably 0.01 to 2 Omg Z persons It is preferably administered at about 0.01 to 150 mg / person / day, preferably 0.1 to 100 mg / day.
  • a mixed solution of 10 g of N- (4-chlorophenyl) piperazine hydrochloride and 18 g of potassium carbonate was suspended in 60 ml of (1: 1) toluene and stirred at room temperature. While dissolving 1 g of 3- (3-chloropropionyl) -1,4,5,6,7-tetrahydro-12-methylbenzo [b] thiophene in the above mixed solution 15 m1, The solution was added dropwise. After completion of the dropwise addition, the mixture was heated and stirred for 14 hours, the solvent was distilled off under reduced pressure, and water and toluene were added to the residue and stirred. The solution was extracted with toluene and dried over magnesium sulfate.
  • N- (4-monofluorophenyl) piperazine instead of N_ (4-chlorophenyl) piperazine hydrochloride in the same manner as in Example 1, 3- (4- (4-fluorophenyl) (Pirazine-1 1-yl) 1 1 1 (4,5,6,7-tetrahydro-1 2-methylbenzo [b] thiophene-3-yl) propane 1-1 I got it.
  • Example 4 In the same manner as in Example 2, the compound of Example 4 was replaced with the compound of Example 4 3- (4- (4-fluorophenyl) pidazine-1 1-yl) 1 1- (4,5, By using 6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) propane-1-one, 3- (4- (4-fluorophenyl) piperazine-1 1- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) propan-1-ol was obtained. Melting point 1 2 8 ° C
  • Example 5 In the same manner as in Example 3, the compound of Example 5 was replaced with the compound of Example 5 3- (4- (4-fluorophenyl) piperazine-1-yl) 1-1- (4,5, 6, 7 1- (4-Fluorophenyl) 1- (3-(4,5,6,7-tetrahydro) 2-tetrabenzoyl-2-methylbenzo [b] thiophen-1-yl) propane-1-ol 2-Methylbenzo [b] thiophene-3-yl) pulp) piperazine dihydrochloride was obtained. Melting point 205 ° C
  • Example 2 In the same manner as in Example 2, the compound of Example 7 was replaced with the compound of Example 1 (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-13-yl).
  • N_ (4-chlorophenyl) pidazine hydrochloride was used in place of N— (4-methylphenyl) pidazine to obtain 1 _ (4, 5, 6, 7— Tetrahydro-1-methylbenzo [b] thiophen-1-yl) -1-3- (4- (4-methylphenyl) pyrazine-1-yl) propane-1-one was obtained.
  • Example 2 the compound of Example 10 was replaced with the compound of Example 10 in place of the compound of Example 1 (4,5,6,7-tetrahydro-1-2-methylbenzo [b] thiophen-13-yl-1) 3— (4- (4-methylphenyl) piperazine-1-11) Prono, .1 1
  • 1-one 1- (4,5,6,7-tetrahydro-1-methyl-benzo [b] thiophen-13-yl) 1-3- (4- (4-methylphenyl) piperazine— 1-yl) Propane-1-ol dihydrochloride was obtained. Melting point 2 2 4 ° C Example 1 2
  • Example 11 In the same manner as in Example 3, the compound of Example 11 was replaced with the compound of Example 11 (4, 5, 6, 7-tetrahydro-2-methylbenzo [b] thiophene-3-yl).
  • 3- (4- (4-methylphenyl) piperazine-1-yl) propane-1-ol dihydrochloride 4- (3- (4,5,6,7-tetrahydro-1-yl) —Methylbenzo [b] thiophene-3-yl) propyl) -11- (4-methylphenyl) pirazine dihydrochloride was obtained. Melting point 2 2 1 ° C
  • Example 16 In the same manner as in Example 3, the compound of Example 14 was replaced with the compound of Example 1 1- (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-13-yl) 1 3— (4-(1 naphthyl) piperazine 1 1 -yl) Propane 1 by using 4-(3-(4, 5, 6, 7-tetrahydro 2- Methylbenzo [b] thiophene-3-yl) propyl) 1 1-(1 naphthyl) piperazine is obtained.
  • Example 16 Example 16
  • Example 18 In the same manner as in Example 2, the compound of Example 16 was replaced with the compound of Example 1 (4, 5, 6, 7-tetrahydro-2-methylbenzo [b] thiophen-13-yl). By using 3- (4- (3-pyridyl) piperazine-1-yl) propane-1-one, 1- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophene-1 3- (yl) -1- (4- (3-pyridyl) piperazine-1-yl) Propane-l-ol is obtained.
  • Example 18 Example 18
  • Example 19 In the same manner as in Example 2, the compound of Example 19 was replaced by the compound of Example 19 3- (4- (4-chlorophenyl) piperazine-111-yl) 1-1- (2-ethyl-1, 5,6,7—Tetrahidrobenzo [b] Thiophene-1 3-yl) Propane 1 1 1-one can be used to obtain 3 — (4- 1 (4-cloclophenyl) piperazine 1 1 1-yl) 1 1 _ (2-ethyl 4-, 5, 6, 7-tetrahydrobenzo [b] thiophen-3-yl) Propan-1-ol is obtained.
  • Example 22 In the same manner as in Example 3, the compound of Example 20 was replaced with the compound of Example 20. 3- (4- (4-chlorophenyl) pidazine-11-yl) 1-1- (2-) 1,4-, 5-, 6-, 7-tetrahydro-drobenzo [b] thiophen-1-yl) propane-1— By using ol, 1— (4-chlorophenyl) 1-41 ( 3— (2-ethyl-1,4,5,6,7-tetrahydrobenzo [b] thiophen-3-yl) propyl) piperazine is obtained.
  • Example 22 4- (4-chlorophenyl) pidazine-11-yl) 1-1- (2-) 1,4-, 5-, 6-, 7-tetrahydro-drobenzo [b] thiophen-1-yl) propane-1— By using ol, 1— (4-chlorophenyl) 1-41 ( 3— (2-ethyl-1,4,5,6,7-tetrahydro
  • Example 2 In the same manner as in Example 2, the compound of Example 22 was replaced with the compound of Example 22 (2-butyl-4,5,6,7-tetrahydrobenzene [b] thiophen-3-yl). 1) 3- (4- (4-chlorophenyl) pirazin-1-yl) propane-1-one can be used to produce 1- (2-butyl-4,5,6,7-tetrahydrobenzo). [B] Thiophene-1-yl) 3- (4- (4-chlorophenyl) piperazine-11-yl) propan-1-ol is obtained.
  • Example 2 4 4
  • Example 23 In the same manner as in Example 3, the compound of Example 23 was replaced with the compound of Example 23 1- (2-butyl-1,4,5,6,7-tetrahydrobenzo [b] thiophen-13- 1) 3- (4- (4-chlorophenyl) piperazine-1 1-yl) propane-1-ol can be used to obtain 4- (3- (2-butyl-4,5,6,7-tetra) Rahi drobenzo [b] thiophene 1- (yl) propyl) 1 1- (4-chlorophenyl) pidazine is obtained.
  • Example 25 In the same manner as in Example 2, the compound of Example 25 was replaced with the compound of Example 25 1- (2-bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-13-y in place of the compound of Example 1. 1) 3- (4- (4-chlorophenyl) pirazin-1-yl) propane-1-one can be used to give 1- (2-bromo-1,4,5,6,7-tetrahydrobenzo [ b] Thiophane 3 -yl) 1-3-(4-(4-chlorophenyl) pyridine 1 -yl) Propane 1 -ol.
  • Example 2 In the same manner as in Example 3, the compound of Example 26 was replaced with the compound of Example 26 1- (2-bromo-1,4,5,6,7-tetrahydrobenzo [b] thiophen-13- The use of 3- (4- (4-chlorophenyl) piperazine-1-yl) propane-1-1ol gives 4- (3- (2-bromo-4,5,6,7-) Tetrahidrobenzo [b] thiophene-3-yl) propyl) 1-11 (4-chlorophenyl) pidazine is obtained.
  • Example 2 In the same manner as in Example 1, the compound of the starting material synthesis example 5 was replaced with the compound of the starting material synthesis example 5 3 — (3-chloropropionyl) -14,5,6,7-tetrahydro-1,2,4- By using dimethylbenzo [b] thiophene, it is possible to obtain 3 — (4 — (4 — chloro phenyl) piperazine- 1-1 -yl) 1 1-(4, 5, 6, 7-tetrahydro- 1, 2-4 —Dimethylbenzo [b] thiophen-3-yl) propane-1-one.
  • Example 2 9 Example 2 9
  • Example 30 In the same manner as in Example 2, the compound of Example 28 was replaced with the compound of Example 28 instead of the compound of Example 1. 3- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4,5, By using 6,7-tetrahydro-1,2,4-dimethylbenzo [b] thiophen-13-yl) propan-1-one, 3- (4- (4-chlorophenyl) piperazine-1 1 —Yl) 1 1 — (4,5,6,7—tetrahydro-1,2,4-dimethylbenzo [b] thiophene 3 —yl) propane 1 1-ol is obtained.
  • Example 30 4- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4,5, By using 6,7-tetrahydro-1,2,4-dimethylbenzo [b] thiophen-13-yl) propan-1-one, 3- (4- (4-chlorophenyl) piperazine-1 1 —Yl) 1
  • Example 29 In the same manner as in Example 3, the compound of Example 29 was replaced with the compound of Example 29. 3- (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1- (4, By using 5,6,7-tetrahydro-1,2,4-dimethylbenzo [b] thiophen-1-yl) propan-1-ol, 1- (4-chlorophenyl) -14- (3— ( 4,5,6,7-tetrahydro-1,2,4-dimethylbenzo [b] thiophene
  • Example 31 In the same manner as in Example 2, the compound of Example 31 was replaced with the compound of Example 31.
  • 2- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4,5, 6,7-tetrahydro 2-methylbenzo [b] thiophene-3-yl) ethane-1-one can be used to give 2- (4- (4-chlorophenyl) piperazine-1 1- 1- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-1-yl) ethanol was obtained.
  • Example 32 In the same manner as in Example 3, the compound of Example 32 was replaced with the compound of Example 32.
  • 2- (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1 1 (4, By using 5,6,7-tetrahydro-1-methylbenzo [b] thiophen-3-yl) ethanol, it is possible to obtain 11- (4-chlorophenyl) 14- (2- (4,5,6,7-tetrahydro).
  • Draw 2-methylbenzo [b] thiophene-3-yl) ethyl) piperazine to give the 5-hydrochloride 0.1-hydrate. Melting point 2 36 ° C
  • Example 34 In the same manner as in Example 2, the compound of Example 34 was replaced with the compound of Example 34. 4- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4,5, By using 6,7-tetrahydro-2-methylbenzo [b] thiophene-3-yl) butan-1-one, it is possible to obtain 4- (4- (4-chlorophenyl) piperazine-1_yl 1- (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-3-yl) butan-1-ol was obtained.
  • Example 35 In the same manner as in Example 3, the compound of Example 35 was replaced with the compound of Example 35 instead of the compound of Example 4.
  • 1- (4-chlorophenyl) 1-4-1 (4- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-1--3-yl) butyl) Piperazine dihydrochloride was obtained. Melting point 198 ° C
  • Example 37 In the same manner as in Example 2, the compound of Example 37 was replaced with the compound of Example 37 instead of the compound of Example 1.
  • 3- (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1— (4, 5,6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) butane-1-one can be used to give 3- (4- (4-chlorophenyl) piperazine-1 — Yl) 1 1 — (4, 5, 6, 7 — tetrahydro-1- 2 — methylbenzo [b] thiof Getting Oars,
  • Example 38 In the same manner as in Example 3, the compound of Example 38 was replaced by the compound of Example 3 instead of the compound of Example 3.
  • Example 4 In the same manner as in Example 40, the compound of Example 6 was replaced with the compound of Example 6 1- (4-fluorophenyl) 1-141 (3— (4,5,6,7-tetrahydro-1 2 — Methylbenzo [b] thiophen-1-yl) propyl) piperazine dihydrochloride allows the use of 1- (4-fluorophenyl) -4-1 (3- (4,5,6,7-tetrahi Drobenzo [b] thiophen-1-yl) propyl) pidazine obtained Example 4 2
  • Example 4 In the same manner as in Example 2, the compound of Example 4 was replaced with the compound of Example 4 2 in the same manner as in Example 2.
  • Compound 3 (4- (4-chlorophenyl) 1-1,2,3,6—tetrahydropyridine1-1 — Yl) 1 1 1 (4, 5, 6, 7-tetrahydro 2-methylbenzo [b] thiophene 1 3 — yl)
  • Propane 1 _ 1 Chlorophenyl) 1,1,2,3,6 —Tetrahydropyridine_1 —1yl) 1 1 — (4,5,6,7—Tetrahydro 2 —Methylbenzo [b] thiophene 1-3 —yl) Get 1-ol propane.
  • Example 4 In the same manner as in Example 3, the compound of Example 4 was replaced with the compound of Example 4 3 in place of the compound of Example 2 3 — (4- (4-chlorophenyl) 1-1,2,3,6-tetrahydropyridine-1- 1 1) (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) propane-1 1-ol gives 4- (4-chlorophenyl) 1 1 — (3 — (4,5,6,7-tetrahydro-1-2-methylbenzo [b] thiophen-3-yl) propyl) 1 1,2,3,6 —tetrahydropyri Get the gin.
  • Example 45 In the same manner as in Example 2, the compound of Example 45 was replaced with the compound of Example 45 instead of the compound of Example 1. 3- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (5, 6-Diethyl mouth 2-methyl-14 H-cyclopentene (b) thiophene-3-yl) Propane-one is used to give 3- (4- (4-chlorophenyl) piperazine 1 1-yl) 1 1- (5,6-dihydro 2-methyl-4H-cyclopentyl [b] thiophen-3-yl) Propane-1-ol is obtained.
  • Example 4 In the same manner as in Example 3, the compound of Example 4 was replaced with the compound of Example 4 6 instead of the compound of Example 2 3 — (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1 — (5, 6-Dimethyl-l- 2-Methyl-l4H-cyclopentyl (b) thiophene-l-yl) Propane-l-ol can be used to obtain 1- (4-chlorophenyl) -l 4- (3— (5, 6-Dihydro-12-methyl-14H-cyclopenta [b] thiophen-13-yl) propyl) pidazine is obtained.
  • Example 5 the compound of Example 48 was replaced with the compound of Example 48 instead of the compound of Example 1.
  • 3- 4- (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1- (5, 6,7,8-tetrahydro 2-methyl-14H-cyclohepta [b] thiophen-13-yl)
  • propane-one 3- (4-(4-chlorophenyl)) Piperazine-1-yl) _1-1 (5,6,7,8-tetrahydro-2-methyl-4H-cyclohepta [b] thiophen-1-yl) Propane-1-yl is obtained.
  • Example 5 0
  • Formulation example 1 The compound of the present invention (0.5 part), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were mixed well, and then kneaded well with a binder made from corn starch (2 parts). The kneaded material is sieved with 16 mesh, dried in an oven at 50 ° C, and sieved with 24 mesh. The kneaded powder thus obtained, 8 parts of corn starch, 11 parts of crystalline cellulose and 9 parts of talc are mixed well, and the mixture is compressed into tablets to obtain tablets containing 0.5 mg of active ingredient per tablet.
  • D 4 receptor expression cell membrane specimen and 3 H- spiperone was 2 7 ° C, 2 hours Inkyupeto in the presence of the test compound.
  • the solution was suction-filtered with a Putman GFZB filter (trade name), and the radioactivity on the filter was measured with a liquid scintillation counter. Non-specific binding was determined in the presence of 10 / M haloperidol.
  • the 50% inhibitory concentration (IC 5 ) of the test compound was calculated by non-linear regression, and the inhibition constant (K i value) was determined.
  • the i value of Y—36074 (the compound of Example 3) was 0.50 nM.
  • Non-specific The specific binding was determined in the presence of 10 O ⁇ M (sat) -sulpiride.
  • the 50% inhibitory concentration (IC 5 ) of the test compound was calculated by non-linear regression, and the inhibition constant (K i value) was determined.
  • the Ki value of Y-36074 was 170 nM.
  • the K i value of the compound of the present invention for the D 4 receptor was 0.1 to 1 nM, but was 10 O nM or more for the D 2 receptor.
  • the onset bright compound is confirmed to have a strong affinity for D 4 receptor than D 2 receptors, the deviation was 1 or 0 0 or more times.
  • Morphine (10 mg / kg, subcutaneous) and test compound (5, 10, or 20 mg Zkg, oral) were co-administered for 5 days using 5-8 rats / group, and on day 5
  • naloxone 2.0 mgZkg, subcutaneous
  • the effects of the test compound on drug dependence can be evaluated by observing behavior such as shivering, diarrhea, and jibing, for 20 minutes, and comparing it with the control group (the group not administered the test compound).
  • K i values for the relative K i values for the D 4 receptor It shows a divergence of 100 times or more, and may be an antipsychotic drug with little influence by other central effects.
  • the compound of the present invention can be used as a therapeutic drug for schizophrenia.
  • the compounds of the present invention have excellent oral absorbability, bioavailability, and ability to enter the brain.
  • the compound of the present invention can be used as a therapeutic agent for alcohol-dependent patients and substance abusers. This application is based on patent application No. 8161 of 1997 filed in Japan, the contents of which are incorporated in full herein.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention a trait à des composés de thiophène représentés par la formule générale suivante (1) - formule dans laquelle chaque symbole est tel que défini dans le descriptif -, à leurs isomères optiques ainsi qu'à leurs sels acceptables du point de vue pharmaceutique ou à leurs hydrates. Elle concerne également des compositions médicinales renfermant, en tant qu'ingrédient actif, les composés de la formule (1), leurs isomères optiques ainsi que leurs sels acceptables du point de vue pharmaceutique ou leurs hydrates, substances auxquelles ont été adjoints des produits d'addition acceptables du point de vue pharmaceutique. Du fait de leur action bloquante puissante et sélective sur les récepteurs de D4 plutôt que sur les récepteurs de D2, ces composés se révèlent des plus utiles comme médicaments antipsychotiques, efficaces non seulement à l'encontre de symptômes positifs caractérisés par l'hallucination et le délire, en phase aiguë de la schizophrénie, mais encore à l'encontre de symptômes négatifs tels que la torpeur émotionnelle, l'aboulie et l'autisme. Ces antipsychotiques, qui s'administrent très facilement par voie orale, ont une remarquable biodisponibilité et présentent d'excellentes propriétés migratoires transcérébrales tout en ayant des effets secondaires réduits, effets découlant de l'administration des médicaments antipsychotiques existants avec un antagonisme du récepteur de D2, notamment des symptômes extrapyramidaux et la dysendocrinose. Il est également possible d'utiliser ces composés pour porter remède à la dépendance à l'égard de l'alcool ainsi qu'à l'abus des drogues.
PCT/JP1998/000077 1997-01-21 1998-01-09 Composes de thiophene et leur application medicinale WO1998031679A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU53434/98A AU5343498A (en) 1997-01-21 1998-01-09 Thiophene compounds and medicinal use thereof
JP53409998A JP3185222B2 (ja) 1997-01-21 1998-01-09 チオフェン化合物およびその医薬用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/8161 1997-01-21
JP816197 1997-01-21

Publications (1)

Publication Number Publication Date
WO1998031679A1 true WO1998031679A1 (fr) 1998-07-23

Family

ID=11685618

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/000077 WO1998031679A1 (fr) 1997-01-21 1998-01-09 Composes de thiophene et leur application medicinale

Country Status (3)

Country Link
JP (1) JP3185222B2 (fr)
AU (1) AU5343498A (fr)
WO (1) WO1998031679A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001521025A (ja) * 1997-10-27 2001-11-06 ニューロサーチ、アクティーゼルスカブ ニコチン性アセチルコリンレセプターに於けるコリン作動性リガンドとしてのヘテロアリールジアザシクロアルカン
WO2002020491A1 (fr) * 2000-09-05 2002-03-14 Merck Patent Gmbh Derives d'arylpiperazine et leur utilisation comme medicaments psychotropes

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8136354B2 (en) 2008-03-14 2012-03-20 Energy Compression Inc. Adsorption-enhanced compressed air energy storage

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0285277A (ja) * 1988-06-10 1990-03-26 Bristol Myers Co １―インドリルアルキル―４―（置換ピリジニル）ピペラジン
JPH05262759A (ja) * 1992-01-23 1993-10-12 Yoshitomi Pharmaceut Ind Ltd チオフェン化合物
JPH08325257A (ja) * 1995-05-31 1996-12-10 Adir 新規なピペラジン、ピペリジン及び１，２，５，６−テトラヒドロピリジン化合物、これらの製造方法及びこれらを含む医薬組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0285277A (ja) * 1988-06-10 1990-03-26 Bristol Myers Co １―インドリルアルキル―４―（置換ピリジニル）ピペラジン
JPH05262759A (ja) * 1992-01-23 1993-10-12 Yoshitomi Pharmaceut Ind Ltd チオフェン化合物
JPH08325257A (ja) * 1995-05-31 1996-12-10 Adir 新規なピペラジン、ピペリジン及び１，２，５，６−テトラヒドロピリジン化合物、これらの製造方法及びこれらを含む医薬組成物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001521025A (ja) * 1997-10-27 2001-11-06 ニューロサーチ、アクティーゼルスカブ ニコチン性アセチルコリンレセプターに於けるコリン作動性リガンドとしてのヘテロアリールジアザシクロアルカン
WO2002020491A1 (fr) * 2000-09-05 2002-03-14 Merck Patent Gmbh Derives d'arylpiperazine et leur utilisation comme medicaments psychotropes

Also Published As

Publication number Publication date
AU5343498A (en) 1998-08-07
JP3185222B2 (ja) 2001-07-09

Similar Documents

Publication Publication Date Title
AU679049B2 (en) Antipsychotic benzimidazole derivatives
RU2167152C2 (ru) N-замещенные азагетероциклические карбоновые кислоты или их фармацевтически приемлемые соли, способ их получения, фармацевтическая композиция на их основе и способ ингибирования нейрогенного воспаления
JPH09291034A (ja) 縮合ピリジン化合物およびその医薬としての用途
CA1340541C (fr) Derives de carboxamide, agents analgesiques
CN101302214A (zh) 芳烷基哌啶(嗪)衍生物及在治疗精神神经疾病中的应用
JPH0710853B2 (ja) チアジン（又はオキサジン）誘導体、その製法及びその合成中間体
DE69736890T2 (de) Kondensierte heterozyklische verbindungen und ihre pharmazeutische anwendung
EP1250336B1 (fr) Derives de piperidine et leur utilisation comme antagonistes du recepteur de la serotonine
CN101260075B (zh) 芳烷基哌啶衍生物及其在制备镇痛、镇静药物中的应用
JPH0735373B2 (ja) カルボン酸アミド化合物
WO1998031679A1 (fr) Composes de thiophene et leur application medicinale
NZ226681A (en) Diazepinone derivatives: preparatory processes and pharmaceutical compositions
CZ290678B6 (cs) 3-Substituované 3,4,5,7-tetrahydropyrrolo[3´,4´: 4,5]thieno[2,3-d]pyrimidinové deriváty, způsob jejich přípravy a použití
BG63206B1 (bg) Кондензирани тиазолови производни с афинитет към 5-нт рецептори
FR2558835A1 (fr) Derives d'hydantoine, leur procede de production et medicament les contenant
JP2571903B2 (ja) 新規アミノアルキルクロモン、その製造方法及びそれを含む薬学的組成物
JPH0733744A (ja) インダゾール誘導体およびその塩
JPH05247052A (ja) Ｎ−アルキルグルタールイミドの４−（４−ピペリジニル）−チエノ〔３，２−ｃ〕ピリジン誘導体
JPH0291063A (ja) 新規な６，１１‐ジヒドロ‐ジベンゾ〔ｃ，ｆ〕〔１，２，５〕チアジアゼピン‐５，５‐ジオキシド誘導体，その塩及びその製造法
Corral et al. N-Substituted 2-amino-1-(2-thienyl) ethanols as. beta.-adrenergic blocking agents
US5216178A (en) Process of reducing olefins
US5140027A (en) Aminoalkylthiodibenzoxepins and pharmaceutical use
US5656758A (en) Process for preparing analgesic compounds
US4837227A (en) Aminoalkylthiodibenzoxepins and pharmaceutical use
US5270327A (en) Analgesic compounds, their preparation, and pharmaceutical compositions containing them

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载