[go: up one dir, main page]

WO1993010089A1 - Nouveaux composes d'amide et utilisation de ces composes comme medicaments - Google Patents

Nouveaux composes d'amide et utilisation de ces composes comme medicaments Download PDF

Info

Publication number
WO1993010089A1
WO1993010089A1 PCT/JP1992/001456 JP9201456W WO9310089A1 WO 1993010089 A1 WO1993010089 A1 WO 1993010089A1 JP 9201456 W JP9201456 W JP 9201456W WO 9310089 A1 WO9310089 A1 WO 9310089A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
tetrahydroisoquinoline
butyl
dihydrobenzofuran
methoxy
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1992/001456
Other languages
English (en)
Japanese (ja)
Inventor
Shu Murakami
Hideo Tomozane
Yoshifumi Togo
Yasuto Morimoto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
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
Publication of WO1993010089A1 publication Critical patent/WO1993010089A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel amide compound, a pharmacologically acceptable salt thereof, an optical isomer thereof and a pharmaceutical use thereof, which are effective for treating psychiatric disorders and psychiatric disorders.
  • extrapyramidal symptoms acute dystonia, akashijia, Parkinson-like syndrome, and tardive dyskinesia, etc.
  • endocrine abnormalities serum pro- Elevated lactin levels
  • benzodiazepines are widely used as anxiolytics. Although these drugs have excellent anxiolytic effects, on the other hand, they also have side effects such as muscle relaxation, sedation and dependence, so they should be used with caution when treating anxiety such as psychosomatic disorders during daily activities. Problems such as cost is there. In recent years, non-benzodiazepine-structured drugs have been developed for the purpose of developing anxiolytics that selectively act on anxiety.
  • the representative compound is buspirone, which differs from conventional benzodiazepines in that it does not bind to benzodiazepine receptors, has high affinity for serotonin 1A (5-HTiJ receptor, and has 5-HT "receptors.
  • serotonin 1A 5-HTiJ receptor
  • 5-HT "receptors 5-HT serotonin 1A
  • These drugs are known to be highly safe, have no addictive properties, and have excellent features such as no abuse potential. However, these drugs still have problems to be solved, such as the time required for the onset of action.
  • the present inventors have achieved a novel amide compound having not only a D 2 receptor blocking effect but also an affinity for 5-HT 1A receptor and / or 5-HT 2 receptor in order to achieve the above object.
  • the following novel amide compounds were found to have the above-mentioned action, and the present invention was completed.
  • R 1 and R 2 are the same or different and each have a hydrogen, a lower alkyl optionally having a substituent, an aralkyl, a hydroxyl group optionally having a protecting group, and a substituent.
  • R 3 is hydrogen, alkyl, cycloalkyl cycloalkylalkyl, Ararukiru, the Amino protecting group
  • R 4 is hydrogen, lower alkyl, Ararukiru
  • R 5 are the same or different, hydrogen, lower alkyl, lower alkoxy, lower Arukeniruokishi, or R 5 oxygen atom R 6 are bonded to each other, a sulfur atom and N- R le (R 1 (1 is hydrogen, optionally substituted lower
  • R 7 , R 8 , and R 9 may be the same or different, and may have hydrogen, a substituent, or a phenyl which may have a substituent or an aralkyl which may have a substituent.
  • the present invention relates to a pharmaceutical use characterized by containing an amide compound, a pharmacologically acceptable salt thereof or an optical isomer thereof as an active ingredient.
  • preferred compounds in the present invention include the following compounds consisting of the above two groups.
  • halogen indicates fluorine, chlorine, bromine, and iodine.
  • Lower alkyl is a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, etc. .
  • Alkyl is a straight-chain or branched-chain alkyl having 7 to 15 carbon atoms in addition to the above lower alkyl, and includes heptyl, octyl, nonyl, decyl, pendecyl, tridecyl, tetradecyl, pendudecyl and the like. Show.
  • Cycloalkylalkyl is a cycloalkyl group having 3 to 7 carbon atoms (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, etc.), and a linear alkyl group having 1 to 6 carbon atoms.
  • a cycloalkyl alkyl having a branched alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, etc.), wherein cyclopropylmethyl, cyclobutylmethyl, Cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopentylethyl Shows sole, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, etc.
  • Lower alkoxy refers to straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, etc. .
  • Aralkyl is an aralkyl having an alkyl moiety having 1 to 6 carbon atoms, such as benzyl, 2-phenylphenyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, and naphthylmethyl. , 2-naphthylethyl, 3-naphthylpropyl, 4-naphthylbutyl, etc.
  • the lower alkylamino is a lower alkylamino having an alkyl portion having a straight-chain or branched alkyl having 1 to 6 carbon atoms, and may be any of mono- or di-lower-alkylamino, such as methylamino, ethylamino, propylamino, and isopropylamino. Butylamino, isopropylamino, tertiary butylamino, pentylamino, isopentylamino, hexylamino, dimethylamino, getylamino, and jib-mouth pyramino.
  • acil refers to formyl, lower alkanoyl, aroyl or heteroaroyl, and includes, for example, formyl, acetyl, propionyl, butyryl, valeryl, vivaloyl, benzoyl, naphthoyl, floyl, tenyl, nicotinol, and isonicotinoyl.
  • Acylamino means a formyl, lower alkanoyl, aroyl or heteroaroyl, etc., in which the acyl moiety is a lower alkynyl having 2 to 5 carbon atoms, which may be further substituted by phenyl.
  • Halogen, lower alkyl (as defined above), lower alkoxy (as defined above), hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl (as defined above) on the aromatic ring of Even less et election Bareru substituents may be one.
  • the lower alkyl group rubamoyl is a lower alkyl group rubamoyl having a straight-chain or branched chain alkyl having 1 to 6 carbon atoms, and may be any of mono- or di-lower-alkylamino, methylcarbamoinole, Ethyl carbamoyl, propyl carbamoyl, isopropyl carbamoyl, butyl carbamoyl, isobutyl carbamoyl, tertiary butyl carbamoyl, pentyl carbamoyl, isopentyl carb, moyl, hexyl carbamoyl, dimethyl carbamoyl, dimethyl carbamoyl, dipropyl carbamoyl, etc. .
  • a lower alkenyloxy is an alkenyl moiety having a linear or branched alkenyl group having 2 to 6 carbon atoms, and includes vinyloxy, 1-bromobenzyloxy, aryloxy, isopropyloxy, 2-butenyloxy, Shows 2-pentenyloxy, 3-hexenyloxy and the like.
  • R 5 and R s are bonded to each other to form an oxygen atom, a sulfur atom, and a 5- to 7-membered ring which may contain N—R] n.
  • a group forming a 5- to 7-membered ring together with a benzene ring is 2,3-dihydrobenzov Orchid, 2,3-dihydro-4H-1 benzopyran, 2,3-dihydro1-1,4 benzodioxane, 2,3-dihydro-4H-1,4-benzoxazine, 2,3-dihydro-4H — 3-oxo-1,4-benzoxazine, 2,3,4,5-tetrahydro-1,5-benzozozepine, 2,3,4,5-tetrahydro 4-oxo1-1,5-venzoxazepine, 2 , 3-Dihydro-4H-1,4,4-benzothiazine, 2,3-dihydro-3-oxo-1H-1,4
  • these groups forming a 5- to 7-membered ring include lower alkyl (as defined above), phenyl which may have a substituent, and aralkyl which may have a substituent (as defined above). May be substituted.
  • the substituent in the lower alkyl, lower alkoxy, phenyl or aralkyl which may have a substituent in the above definition means 1 to 3 halogens, lower alkyl (as defined above), lower alkoxy (as defined above). And aralkyl (as defined above), nitro, amino, trifluoromethyl, etc. I can do it.
  • hydroxyl-protecting groups include, for example, methoxymethyl, methylthiomethyl, Examples include toxityl, tertiary butoxydicarbonyl, benzyloxymethyl, vilanyl and acetyl groups, propionyl, butyryl, benzoyl, and phenyl groups such as phenylacetyl.
  • amino-protecting group examples include alkanols having 1 to 5 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, bivaloyl, valeryl; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Alkoxycarbonyl having 2 to 5 carbon atoms such as butoxycarbonyl, isobutoxycarbonyl, and tertiary butoxycarbonyl; and 4 carbon atoms such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl.
  • alkanols having 1 to 5 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, bivaloyl, valeryl
  • cycloalkylcarbonyls ⁇ 8 cycloalkylcarbonyls; aroyls such as benzoyl and naphthoyl (where royl is halogen, lower alkyl (as defined above), lower alkoxy (as defined above), Alkyl (as defined above), which may have a substituent such as trifluoromethyl, nitro, or amino; benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl, phenylbutoxycarbonyl Such as phenylalkoxycarbonyl (where phenylalkoxycarbonyl is a halogen, lower alkyl (as defined above), lower alkoxy (as defined above), aralkyl (as defined above), triflur on the phenyl ring Which may have a substituent such as orthomethyl, nitro, amino, etc.);
  • reaction is carried out by dicyclohexylcarbodiimide, titanium tetrachloride, phosphorus halide (trichlorophosphoric acid, oxyhydrochloric acid, etc.)
  • a condensing agent such as getyl chlorophosphite, 0-phenylene chlorophosphite, ethyl dichlorophosphite, under cooling, at room temperature or under heating.
  • the compound of the general formula ( ⁇ ) may be preliminarily reacted with phosphorus halide in an inert solvent, and then condensed with the compound of the general formula ( ⁇ ).
  • the phosphorus halide is phosphorus trichloride
  • the general formula ( ⁇ ) is phosphorus trichloride
  • reaction is carried out in an inert solvent in the presence of triethylamine, pyridine, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethyl.
  • the reaction is carried out under cooling or at room temperature in the presence of an organic base such as aniline, or in water under cooling or at room temperature in the presence of an inorganic base such as sodium hydroxide or potassium hydroxide.
  • a symmetrical acid anhydride or mixed acid anhydride alkyl carbonic acid mixed acid anhydride, alkyl phosphoric acid mixed acid anhydride, alkyl phosphorous acid mixed acid anhydride,
  • sulfuric acid mixed acid anhydride the reaction is carried out in an inert solvent in the presence of an organic base such as triethylamine, pyridine, N, N-dimethylaniline, under cooling, at room temperature, or under heating.
  • inert solvent used in each of the above condensation reactions for example, benzene, toluene, xylene, methanol, ethanol, isopropyl alcohol, ethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, hexamethylphos Holic amide, diethylene glycol, dimethylformamide and the like or a mixed solvent thereof are appropriately selected depending on the kind of the compound used in the reaction.
  • R 3 is an amino-protecting group such as a benzyloxycarbonyl group, a tertiary-butoxycarbonyl group, and a triphenylmethyl group. It can be obtained by removing the compound according to a conventional method.
  • R 3 represents a non-hydrogen atom (I) is a compound of the general formula (I)
  • R 3 is a hydrogen atom
  • the compound can be produced by reacting with a compound represented by The reaction in an inert solvent in an organic base such as triethylamine, pyridine, N, N-dimethylaniline, or an inorganic base such as sodium hydrogen carbonate, sodium carbonate, carbonated lime, sodium hydroxide, potassium hydroxide, etc. It is performed under cooling, at room temperature or under heating in the presence of a base.
  • organic base such as triethylamine, pyridine, N, N-dimethylaniline
  • an inorganic base such as sodium hydrogen carbonate, sodium carbonate, carbonated lime, sodium hydroxide, potassium hydroxide, etc. It is performed under cooling, at room temperature or under heating in the presence of a base.
  • inert solvent examples include benzene, toluene, xylene, methanol, ethanol, isopropyl alcohol, ethyl ether, dioxane, tetrahydrofuran, chlorofosolem, dichloromethane, dichloroethane, hexanemethylphosphoric amide, diethylene glycol, and dimethylformamide. Or a mixed solvent thereof.
  • the compound of the general formula [II], which is a raw material for synthesizing the compound of the present invention, can be easily produced by the following method.
  • a suitable reducing agent generally used for reduction of an amide group for example, lithium aluminum hydride, hydrogen Reduction with bis (2-methoxyethoxy) aluminum sodium, borane, ⁇ -aluminide, or the like can give the compound of the general formula ( ⁇ ).
  • the compounds of the present invention include racemates, diastereoisomers and individual optical isomers based thereon, and the present invention includes these.
  • the racemic mixture can be optically resolved by an ordinary method using an optically active acid (eg, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by utilizing its basicity. it can.
  • Diastereoisomers can be separated into enantiomers by a conventional method such as fractional crystallization.
  • the target compound (I) having a desired configuration can also be synthesized stereoselectively. .
  • the compound of the general formula (I) thus obtained is a hydrochloride, a hydrobromide, a phosphate
  • the salt may be a metal salt such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc clay, aluminum salt, etc., triethylamine, dicyclohexylamine.
  • Salts with organic bases such as N-methylmorpholine and pyridine, salts with amino acids such as lysine, histidine, ordinine and arginine, and ammonium salts can be used.
  • it can be an ester, which includes an alkyl ester (methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, tertiary butyl ester, hexyl ester, octyl ester, dodecyl ester, octadecyl ester).
  • Esters examples include aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters, triphenylmethyl esters, p-nitrobenzyl esters, ⁇ -methylbenzyl esters, etc.) or ester compounds that can be hydrolyzed in vivo Is raised.
  • aralkyl esters benzyl esters, phenethyl esters, benzhydryl esters, triphenylmethyl esters, p-nitrobenzyl esters, ⁇ -methylbenzyl esters, etc.
  • An ester residue which forms an ester compound which can be hydrolyzed in a living body is a compound which can be easily decomposed in a living body into carboxylic acid I or a salt thereof, and is dimethylaminoethyl, dimethylaminopropyl, benzyl Aminoalkyl esters such as methylaminoethyl, acetooxymethyl, bivaloyloxymethyl, 1-acetoxityl, alkanoyloxyalkyl esters such as 1-bivaloyloxycetyl, ethoxycarbonyloxymethyl, 1-ethoxy Alkoxycarbonyloxyalkyl esters such as carbonyloxyethyl, esters such as phthalidyl and dimethyloxyphthalidyl, carnomoylmethyl, carbamoylethyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl,, N-dimethylcaso Bamoyleth
  • the compound having a carboxyl group may be an amide.
  • the amide-forming residue may be amino, methylamino, or ethyl.
  • Mono or dialkylamino such as amino, propylamino, butylamino, dimethylamino, getylamino, dipropylamino, dibutylamino and the like can be mentioned.
  • D 2 dopamine 2
  • the synaptosomal fraction was separated from the striatum of 9 to 10-week-old Wistar rats, and the following was used: 120 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium chloride, 10 / M pargyline, and 0 mM sodium chloride. Suspension in 5 OmM Tris-HCl buffer (pH 7.1) containing 1% ascorbic acid was used for the experiment. Then, several concentrations of the test compound and tritiated spiperone (final concentration 0%) were added to the synabtosome suspension. 2 nM) and reacted at 37 for 20 minutes. After the reaction, the reaction solution was suction-filtered with a Whatman G FZB glass filter, and then filtered.
  • the crude synaptosome fraction was isolated from the hippocampus of Wistar rats 9 to 10 weeks old, suspended in 5 OmM Tris-HCl buffer (pH 7.4) containing 1 mM manganese chloride, and used for the experiment. Next, several concentrations of the test compound and tritiated 8-hydroxy-2-dibutyrylaminotetralin (8-OH-DPAT: final concentration of 0.2 nM) were added to the synabtosome suspension, and the mixture was incubated at 37. Allowed to react for minutes. After the reaction, the reaction The solution was filtered through a Whatman GF / B glass filter and filtered with a 50 mM Tris-HCl buffer (pH 7.7).
  • a specific serotoni 2 (5-HT 2 ) receptor binding test was carried out according to the method described in Molecular PharmacoL. 21: 301, 1981.
  • the crude synabtosome fraction was isolated from the hippocampus of 9 to 10-week-old Wistar rats, and suspended in 5 OmM Tris-HCl buffer (pH 7.7) for use in the experiment. Next, several concentrations of the test compound and tritiated ketanserin (final concentration: 0.2 nM) were added to the synaptosome suspension, and the mixture was reacted at 37 for 20 minutes. After the reaction, the reaction solution is suction-filtered with a Whatman GFZB glass filter, washed with 5 OmM Tris-monohydrochloride buffer solution (pH 7.7), and the radioactivity remaining on the filter is analyzed by liquid scintillation. It was measured by a chillon counter.
  • Nonspecific binding 10- 5 M mianserin was determined in the presence. 50 The inhibitory concentration (IC 5 ) was determined graphically, and the P and harm constants (Ki values) were determined. Table 1 shows the results. Table 1 Receptor binding capacity Ki (nM)
  • mice Male dd strain mice are used as group I three mice. 60 minutes after administration of the test compound, apomorphine hydrochloride (0.5 mg / kg) is subcutaneously administered, and immediately thereafter, the locomotor activity for 20 minutes is measured using Parimex (Columbus, USA). Performed repeatedly in each group three times, the dose to the momentum of the control group is reduced 50%, ED 5. Obtain it graphically as a value.
  • Test Example 6 Acute toxicity
  • mice When male ddY mice were used as a group of 10 mice and 30 OmgZ kg of the compound of Example 22 was intraperitoneally administered, no deaths were observed up to 5 days after administration.
  • the compounds of the present invention are useful as therapeutic agents for depressive disorders and anxiety disorders; or abnormal behaviors such as dyskinesia, senescence and cerebral vascular injury, and excitement and aggressiveness associated with alcoholic dependence, and emotions. It is useful as a drug for treating injuries, etc .; as a drug for controlling psychiatric disorders such as stomach and duodenal ulcer, or for vomiting; or as a drug for treating diarrhea and gastrointestinal complaints caused by stress and emotional tension. Is 0
  • the compound of the present invention When the compound of the present invention is used as a medicine, it is usually safe for patients in the form of tablets, powders, granules, capsules, injections, infusions, etc. by mixing with excipients, diluents, solubilizing agents, etc. Can be administered.
  • the dosage may vary depending on the patient's condition, weight, age, etc., but is usually 0.01 to 1 O mgZkg per 1 B of an adult.
  • Example 3 0.6 ml of n-nonyl bromide was used in place of n-butyl bromide to obtain (3S) -2-methoxy-5-methylthio-N-((2-nonyl 1,2,3 0.4 g of 1,4-tetrahydroisoquinoline-3-yl) methyl) benzamide was obtained.
  • Example 3 0.33 ml of benzyl chloride was used in place of n-butyl bromide to give (3S) —N — ((2-benzyl 1,2,3,4-tetrahydridoisoquinoline 1-3). 0.6 g of methyl 2-)-methoxy-5-methylthiobenzamide was obtained.
  • Example 3 2-phenylenyl bromide 0.4Sml was used instead of n-butyl bromide to obtain (3S) -2-methoxy-5-methylthio-N-((2- (2-phenylethyl) 0.4 g of 1,1,3,4-tetrahydroisoquinoline-1-yl) methyl) benzamide was obtained.
  • 2,2-Dimethyl-1-5-sulfamoyl-2,3-Dihydrobenzofuran-17 7 Add 0.7 g of rubonic acid and 0.73 ml of triethylamine to a mixture of 7 ml of dimethylformamide and 7 ml of tetrahydrofuran, and add 1-15 ° C And 0.34 ml of isobutyl carbonate was added dropwise. After stirring at the same temperature for 20 minutes, a 4 ml solution of tetrahydrofuran containing 0.50 g of (3S) -3-1-aminomethyl-2-ethyl-1,2,3,4-tetrahydroisoquinoline was added dropwise at the same temperature, and the mixture was added at the same temperature.
  • Example 15 0.61 g of 2-methoxy-5-sulfamoylbenzoic acid and 0.73 ml of triethylamine were added to a mixture of 7 ml of dimethylformamide and 7 ml of tetrahydrofuran. After cooling to C, 0.34 ml of isobutyl carbonate was added dropwise. After stirring at the same temperature for 20 minutes, a 4 ml solution of tetrahydrofuran containing 50 g of (3R) -3-aminomethyl-2-ethyl-1,2,3,4-tetrahydroisoquinoline was added dropwise at the same temperature, and the mixture was added at the same temperature. Stirred for minutes.
  • Example 21 by using 0.13 ml of n-propyl bromide in place of n-butyl bromide, (3S) -5-methylthio-N-((2-propyl 1,2,3,4-tetrahydroiso There was obtained 0.16 g of 1-3-yl) methyl-2,3-dihydrobenzofuran-7-carboxamide. Melting point 88-89 ° C
  • Example 21 by using 0.17 ml of n-pentyl bromide in place of n-butyl bromide, (3S) -5-methylthio-N-((2-pentyl 1,2,3,4-tetrahydroisoquinoline 0.13-g of 1,3- (yl) methyl) -1,2,3-dihydrobenzofuran-17-carboxamide was obtained.
  • Example 21 by using 0.27 ml of n-hexyl bromide in place of n-butyl bromide, (3S) —N — ((2-hexyl-1,2,3,4-tetrahydroisoquinoline 1-3— 0.12 g of (methyl) -1-5-methylthio-1,3 dihydrobenzozofuran-7-carboxamide was obtained.
  • Example 21 by using 0.17 ml of benzylbutamide instead of n-butyl bromide, (3S) —N — ((2-benzylyl 1,2,3,4-tetrahydroisoquinoline-13-) M)) 5-Methylthio-1,2,3-dihydrobenzofuran-17-carboxamide 0.3 g was obtained. 142-143 V
  • Example 21 by using 0.19 ml of 2-phenylethyl propyl bromide instead of n-butyl bromide, (3S) -5-methylthio-1 N — ((2- (2-phenylethyl) 1-1,2,3, 4-tetrahydroisoquinoline-3-yl) methyl) 1,2,3-dihydrobenzofuran-7-carboxamide 0,15 g I got
  • Example 20 in place of (3S) -3-aminomethyl-2-tert-butoxycarbonyl-1,3-hydroisoquinoline, (3R) -3-aminomethyl-2-tert-butoxycarbone 1
  • 3R —N — ((1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -1-5-methylthio-1
  • Example 16 2,2-dimethyl-15-methylthio-1,3-dihydrobenzofuran-17-capronic acid and (3S) -3-aminomethyl-2-ethyl-1,1,2,3,4-tetrahydro
  • isoquinoline 0.5 g of 5-methylthio-1,2,3-dihydrobenzofuran-17-capillonic acid and 0.5 g of (3 S) —3-aminomethyl-2-butyl-7-methoxy-1,2,3,4 —0.6 g of tetrahydroisoquinoline is reacted to give (3S) — N— ((2-butyl-7-methoxy-1,2,3,4-tetrahydroxyisoquinoline-3-yl) as an oil.
  • 0.2 g of methyl-5-methylthio-1,2,3-dihydrobenzofuran-17-carboxamide was obtained.
  • Example 16 2,2-dimethyl-5-methylthio-1,2,3-dihydrobenzofuran-17-carboxylic acid and (3S) -3-aminomethyl-2-ethyl-1
  • 0.5 g of 5-methylthio-2,3-dihydrobenzofuran-17-butyronic acid is added to 3-aminomethyl 2-butyl-7-chloro-1,5
  • 2,3,4-tetrahydroisoquinoline N-((2-butyl-7-chloro-1,2,3,4-tetrahydroisoquinoline-3-yl) methyl) -methyl is obtained as an oil.
  • 0.2 g of 5-methylthio 2,3-dihydrobenzofuran-17-carboxamide was obtained.
  • a tablet containing 10.0 mg of the compound of the present invention can be prepared according to the following formulation.
  • Compound of the present invention 1 0. Omg lactose 3 0. Omg corn starch 1 8.8 mg crystalline cellulose 28. Omg hydroxypropylcellulose 1. Omg talc 2. Omg magnesium stearate 0.2 mg
  • the active ingredient compound is pulverized by an atomizer into fine powder with an average particle size of 10 ⁇ or less. After mixing the compound, lactose, corn starch and crystalline cellulose in a kneading machine, add hydroxybutyl pill cellulose and knead for 20 minutes. The kneaded product is granulated through a 200-mesh sieve, dried in a hot air drier at 50 to a moisture content of 3 to 4%, passed through a 24-mesh sieve, and then talc and magnesium stearate are dried. The mixture is mixed with a rotary tablet press and compressed using a flat punch with a diameter of 6 mm.
  • R 1 and R 2 are the same or different and each have a hydrogen, a lower alkyl optionally having a substituent, an aralkyl, a hydroxyl group optionally having a protecting group, and a substituent.
  • R 3 is hydrogen, alkyl, cycloalkyl, halogen, nitro, amino, lower alkylamino, acylamino, cyano, carbamoyl, lower alkylcarba'moyl, carboxyl, alkoxycarbonyl, aralkyloxycarbonyl;
  • R 5 and R 6 are the same or different, and are hydrogen, lower alkyl, lower alkoxy, lower alkoxy, lower alkenyloxy, or R 5 and alkylalkyl, aralkyl, and amino protecting groups; mutually bonded to an oxygen atom, I Araki atoms and N- R 10 (R 1 0 is hydrogen, lower a may have a substituent Or a aralkyl which may have a substitu
  • a pharmaceutical use comprising the amide compound according to claims 1 to 5, a pharmacologically acceptable salt thereof, or an optical isomer thereof as an active ingredient.

Landscapes

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

Abstract

L'invention se rapporte à un composé d'amide représenté par la formule générale (I), à un sel pharmacologiquement acceptable de ce composé, à un isomère optique de ce composé, et à son utilisation comme médicament contenant ce composé comme ingrédient actif. Dans la formule (I), R?1, R2, R4, R5 et R6¿ représentent chacun hydrogène, alkyle inférieur, etc.; R?3, R7, R8 et R9¿ représentent chacun hydrogène, alkyle, etc.; m représente 1 etc.; n représente 1, etc.; et la chaîne A représente une chaîne de benzène, etc. Ces composés possèdent non seulement une action de blocage du récepteur D¿2? mais également une affinité pour le récepteur de sérotonine 1A(5-HT1A) et/ou pour le récepteur de sérotonine 2(5-HT2), de sorte qu'il est capable d'améliorer de façon remarquablement efficace non seulement les symptômes positifs d'un sujet schizophrène mais également ses symptômes négatifs, et qu'il peut servir comme médicament contre la schizophrénie avec des effets secondaires extrêmement réduits et comme médicament contre les maladies psychosomatiques, la névrose d'angoisse et divers troubles associés à un tel état.
PCT/JP1992/001456 1991-11-12 1992-11-09 Nouveaux composes d'amide et utilisation de ces composes comme medicaments Ceased WO1993010089A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP32530191 1991-11-12
JP3/325301 1991-11-12
JP4257158A JPH05194406A (ja) 1991-11-12 1992-09-01 新規アミド化合物
JP4/257158 1992-09-01

Publications (1)

Publication Number Publication Date
WO1993010089A1 true WO1993010089A1 (fr) 1993-05-27

Family

ID=26543080

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/001456 Ceased WO1993010089A1 (fr) 1991-11-12 1992-11-09 Nouveaux composes d'amide et utilisation de ces composes comme medicaments

Country Status (2)

Country Link
JP (1) JPH05194406A (fr)
WO (1) WO1993010089A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5580885A (en) * 1991-09-12 1996-12-03 Smithkline Beecham P.L.C. 5-HT4 receptor antagonists
US5786372A (en) * 1992-09-10 1998-07-28 Smithkline Beecham P.L.C. Heteroaryl compounds used as pharmaceuticals
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7696193B2 (en) 2002-12-20 2010-04-13 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US7728155B2 (en) 2003-10-24 2010-06-01 Wyeth Llc Dihydrobenzofuranyl alkanamines and methods for using same as cns agents
EP3565543A4 (fr) * 2017-01-06 2020-10-14 The Regents of The University of California Modulateurs du récepteur opioïde de type mu
US11352316B2 (en) 2018-04-04 2022-06-07 Epiodyne, Inc. Opioid receptor modulators and products and methods related thereto
US11634396B2 (en) 2021-04-05 2023-04-25 Epiodyne, Inc. Opioid receptor modulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS506479B1 (fr) * 1968-01-12 1975-03-14
JPS5113158B1 (fr) * 1967-06-10 1976-04-26

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5113158B1 (fr) * 1967-06-10 1976-04-26
JPS506479B1 (fr) * 1968-01-12 1975-03-14

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 70, No. 1, (1969), Abstract No. 3950r. *
CHEMICAL ABSTRACTS, Vol. 82, No. 9, (1975), Abstract No. 57733p. *
CHEMICAL ABSTRACTS, Vol. 89, No. 19, (1978), Abstract No. 163368c. *
CHEMICAL ABSTRACTS, Vol. 92, No. 13, (1980), Abstract No. 111061q. *
SCIENCE UNION ET CIE SOCIETE FRANCAISE DE RECHERCHE MEDICALE, 26 July 1975. *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5580885A (en) * 1991-09-12 1996-12-03 Smithkline Beecham P.L.C. 5-HT4 receptor antagonists
US5786372A (en) * 1992-09-10 1998-07-28 Smithkline Beecham P.L.C. Heteroaryl compounds used as pharmaceuticals
US7696193B2 (en) 2002-12-20 2010-04-13 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US7704994B2 (en) 2002-12-20 2010-04-27 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US7799773B2 (en) 2002-12-20 2010-09-21 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US8207331B2 (en) 2002-12-20 2012-06-26 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7728155B2 (en) 2003-10-24 2010-06-01 Wyeth Llc Dihydrobenzofuranyl alkanamines and methods for using same as cns agents
EP3565543A4 (fr) * 2017-01-06 2020-10-14 The Regents of The University of California Modulateurs du récepteur opioïde de type mu
US11352316B2 (en) 2018-04-04 2022-06-07 Epiodyne, Inc. Opioid receptor modulators and products and methods related thereto
US11634396B2 (en) 2021-04-05 2023-04-25 Epiodyne, Inc. Opioid receptor modulators
US12168648B2 (en) 2021-04-05 2024-12-17 Epiodyne, Inc. Opioid receptor modulators

Also Published As

Publication number Publication date
JPH05194406A (ja) 1993-08-03

Similar Documents

Publication Publication Date Title
JP5419355B2 (ja) 選択的な５ｈｔ２ａアンタゴニストとしての置換されたビスアリールおよびヘテロアリール化合物
JP2553020B2 (ja) キヌクリジン化合物およびその医薬用途
CA2398794C (fr) Pyrrolidines 1,3-disubstituees en tant qu'antagonistes du recepteur adrenergique alpha 2
WO1993011115A2 (fr) Derives de quinolone et leur utilisation comme antagonistes des recepteurs de nmda et ampa
GB2266888A (en) Tetramic acid derivatives
JP2005527463A (ja) Ｃｎｓ疾患を治療するための５−ｈｔ６受容体アフィニティーを有する３−アリールスルホニル−７−ピペラジニル−インドール、−ベンゾフランおよび−ベンゾチオフェン
JPH08508289A (ja) 抗精神病ベンゾイミダゾール誘導体
JPH05501555A (ja) ムスカリンレセプター拮抗薬
JP2008526761A (ja) 多環式ビス−アミドｍｍｐ阻害剤
CN101679273A (zh) 1位取代的四氢异喹啉化合物
JPH0710854B2 (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
JPH07500589A (ja) ベンゾジアゼピン誘導体、並びにコレシストキニン及び／又はガストリンレセプターのアンタゴニストとしての該誘導体の使用
WO1993010089A1 (fr) Nouveaux composes d'amide et utilisation de ces composes comme medicaments
WO1998009960A1 (fr) Derives de pyrimidine 2,4-bisubstitues, procede pour leur production et compositions medicales les contenant
JPH08502283A (ja) ５−ｈｔ▲下４▼レセプターアンタゴニスト用の縮合環系ｎ−アルキルピペリジニル−４−メチルカルボン酸エステル／アミド
EA005013B1 (ru) Галогензамещённые производные 4-фенил-1-пиперазина, -пиперидина и -тетрагидропиридина
PT855397E (pt) (r)-5-bromo-n-(1-etil-4-metil-hexa-hidro-1h-1,4-diazepin-6-il)-2-metoxi-6-metilamino-3-piridinocarboxamida processo para a sua preparacao e composicao farmaceutica contendo o referido composto
KR101586507B1 (ko) 아미드 유도체 및 이를 함유하는 약학적 조성물
JP6943239B2 (ja) Ｋｃｎｑ２〜５チャネル活性化剤
JPH09506885A (ja) ５ｈｔ▲下１ｄ▼（抗うつ作用）活性を有するインドール、インドリンおよびキノリン誘導体
JP2000504342A (ja) ニューロキニンアンタゴニストとしてのピペラジノ誘導体
US5620972A (en) Substituted benzene derivatives
EP0566069A1 (fr) Antagonistes du récepteur tachykinine, isoquinoléines et leur production
JPS6335573A (ja) 新規置換ピリド〔２，３−ｂ〕〔１，４〕ベンゾジアゼピン−６−オン，その製法及びその化合物を含む医薬
KR20180027050A (ko) 신규한 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 폴리(adp-리보스)폴리머라제-1(parp-1) 관련 질환의 예방 또는 치료용 약학적 조성물

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA HU KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA