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WO1996041796A1 - Composes de bicyclolactame, leur emploi et compose intermediaire dans leur production - Google Patents

Composes de bicyclolactame, leur emploi et compose intermediaire dans leur production Download PDF

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Publication number
WO1996041796A1
WO1996041796A1 PCT/JP1996/001565 JP9601565W WO9641796A1 WO 1996041796 A1 WO1996041796 A1 WO 1996041796A1 JP 9601565 W JP9601565 W JP 9601565W WO 9641796 A1 WO9641796 A1 WO 9641796A1
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WO
WIPO (PCT)
Prior art keywords
compound
group
azabicyclo
bicyclolactam
reaction
Prior art date
Application number
PCT/JP1996/001565
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English (en)
Japanese (ja)
Inventor
Kazuo Ogawa
Ichiro Yamawaki
Manabu Kaneda
Takashi Arima
Original Assignee
Taiho Pharmaceutical Company, 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 Taiho Pharmaceutical Company, Ltd. filed Critical Taiho Pharmaceutical Company, Ltd.
Priority to DK96916350T priority Critical patent/DK0790237T3/da
Priority to AU59118/96A priority patent/AU697656B2/en
Priority to EP96916350A priority patent/EP0790237B1/fr
Priority to CA002197178A priority patent/CA2197178C/fr
Priority to AT96916350T priority patent/ATE224369T1/de
Priority to KR1019970700925A priority patent/KR100220172B1/ko
Priority to DE69623747T priority patent/DE69623747T2/de
Publication of WO1996041796A1 publication Critical patent/WO1996041796A1/fr
Priority to US10/041,555 priority patent/US6500819B2/en

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Classifications

    • 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
    • C07D209/52—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 condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered

Definitions

  • the present invention relates to novel bicyclolactam compounds, uses thereof, and intermediates for producing them.
  • the compound of the present invention has an excellent anxiolytic effect and is useful as an anxiolytic.
  • benzodiazepine compounds such as diazebam have been widely used as anxiolytics.
  • this group of drugs generally has side effects such as a sleep enhancing action, a muscle relaxing action, and a sedative action.
  • serotonin anxiolytics such as buspirone have been developed as anxiolytics having a different mechanism of action from the benzodiazepine compound.
  • serotonin drugs generally have reduced side effects such as sleep-enhancing action, muscle relaxation action, and sedative action as compared with benzodiazepine drugs, but they have weak anxiolytic effects, and There are problems such as a decrease in spontaneous locomotor activity thought to be caused by dopamine's enzymatic gonist action and a serotonin syndrome considered to be caused by its properties as a fluagonist for serotonin 1A receptor.
  • International Publication No. WO 91/114434 discloses a bicyclolactam compound having a cerebral function improving action, a brain metabolic activation / protection action, and an antisenile dementia action. However, they differ from the compounds of the present invention in that they have a substituent directly bonded to a carbon atom on the bicyclic ring.
  • An object of the present invention is to provide a novel bicyclolactam useful as an active ingredient of a medicine having an excellent anxiolytic effect, high safety, and very few side effects such as a sleep-enhancing action, a muscle relaxing action, and a sedative action.
  • the present invention relates to a bicyclolactam compound represented by the general formula (1).
  • R is Okiso group or one OR 1
  • R 1 is a hydrogen atom or a Ashiru group
  • A is a group of formula (2) or (3)
  • Q is a hydrogen atom or a lower alkyl group Yes
  • R 2 represents a benzoyl group which may have a substituent.
  • the present invention also relates to a bicyclolactam compound represented by the general formula (4) (
  • R 3 represents a benzyl group which may have a substituent.
  • the present invention also provides a process for producing a bicyclic lactam compound represented by the general formula (II), wherein the bicyclolactam compound represented by the general formula (4) is hydrogen-substituted in a suitable solvent in the presence of a catalyst. According to the law.
  • the present invention relates to a process for producing a bicyclolactam compound represented by the general formula (1 "), which comprises performing an acylation reaction of the bicyclolactam compound represented by the general formula ( ⁇ ) in a suitable solvent. .
  • the present invention provides a compound represented by the general formula (5) and a compound represented by the general formula (6).
  • the present invention relates to a process for producing a bicyclolactam compound represented by the general formula (1 "'), which comprises reacting a bicyclolactam compound in a suitable solvent in the presence of a base.
  • R 2 — X (5) (In the formula, R 2 is the same as above. X represents a halogen atom.)
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the above bicyclolactam compound and a pharmaceutical carrier.
  • the present invention relates to an anxiolytic drug comprising an effective amount of the above bicyclolactam compound and a pharmaceutical carrier.
  • the present invention also provides a method for treating anxiety comprising administering an effective amount of the above bicyclolactam compound to mammals including humans, and a method for producing a medicament for treating anxiety. Including use.
  • the bicyclolactam compound represented by the general formula (1) has an excellent anxiolytic effect, is highly safe, has few side effects, and is useful as a medicine. Further, the bicyclolactam derivative represented by the general formula (4) is useful as an intermediate for producing the compound (1).
  • the bicyclo lactam compound of the general formula (1) or (4), stereoisomer that is based on the bicyclo ring, and more bicyclo bridgehead position carbon atoms and R i O-or R 3 0- rings are bound carbon
  • the following 14 cases may be considered for the bicyclo ring skeleton in the compound of the above general formula (1) or (4) depending on the number of 1, m and n, but all cases are included.
  • m or n is 0, that is, (a), (b), (c), (f), (g), (h), (k) or (m). More preferably, 1 is 1, m is 0, and n is 2, that is, (b) or (k).
  • the substitution position on the bicyclolactam ring of the substituent R of the compound represented by the general formula (1) [the substituent 10 R 3 in the compound represented by the general formula (4)] is, for example, the bicyclolactam ring.
  • the following three types of bases can be considered if represented by the skeleton (a), and include all cases, but preferably on the carbon atom next to the bridgehead atom of the bicyclolactam ring such as (p) or (r) below .
  • L Te as good Benzoiru group optionally having a substituent represented by R 2, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, Shiano group, a hydroxyl group or an Amino group
  • a benzoyl group which may have a substituent preferably a benzoyl group which may have a halogen atom, a lower alkyl group or a lower alkoxy group as a substituent, and more preferably a benzoyl group having a lower alkoxy group; Group.
  • the number of substituents is one to three.
  • the substituent may be substituted at any of the ortho, meta and para positions on the phenyl ring of the benzoyl group.
  • the benzyl group which may have a substituent represented by R 3 has 1 to 3 lower alkyl groups, lower alkoxy groups, halogen atoms or trifluoromethyl groups as substituents on the phenyl ring.
  • the halogen atom include fluorine, chlorine, bromine, and iodine, and a fluorine atom is preferable.
  • As a lower alkyl group A linear or branched alkyl group having 1 to 6 carbon atoms is preferable.
  • a methyl or ethyl group is preferable, and a methyl group is more preferable.
  • the lower alkoxy group a linear or branched alkoxy group having 1 to 6 carbon atoms is preferable.
  • methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- Examples include butoxy, pentyloxy, isopentyloxy and hexyloxy groups, preferably methoxy or ethoxyquin groups, and more preferably methoxy groups.
  • the Ashiru group represented by R 1 or R 1 11, can be shown aliphatic Ashiru group, an aromatic Ashiru group widely, aliphatic Ashiru group such as formyl, Asechiru, propionyl, butyryl, isobutyryl, Pentanoiru, Examples thereof include aliphatic acyl groups having 2 to 6 carbon atoms such as hexanoyl, acryloyl, propioyl, methacryloyl, and crotonyl groups. Examples of the aromatic acyl group include benzoyl, 3-tolyl, 4-tolyl, and 2-methyl.
  • Examples include toxicbenzoyl, 2,4-dimethoxybenzoyl, ⁇ -naphthylcarbonyl, and ⁇ -naphthylcarbonyl group, and are preferably acetyl and benzoyl groups, and more preferably acetyl group.
  • the lower alkyl group represented by Q includes those described above, but is preferably a methyl group or an ethyl group, and more preferably a methyl group.
  • halogen atom represented by X examples include the above-described halogen atoms, and are preferably chlorine atoms.
  • a compound in which m or n is 0 (except when m and n are simultaneously 0) is preferable as the ring structure, and 1 is 1, Compounds in which m is 0 and n is 2 are more preferred.
  • R of the represented reduction Gobutsu in the - in the compounds of OR 1 is used, the number R 1 is a hydrogen atom or an Asechiru group, R 2 is a lower alkoxy group, a halogen atom or a lower alkyl group
  • R 1 is a hydrogen atom or an Asechiru group
  • R 2 is a lower alkoxy group, a halogen atom or a lower alkyl group
  • a benzoyl group which may be a compound wherein Q is a hydrogen atom, 1 is 1, m is 0, and n is 2 is more preferable, and among them, R 1 is a hydrogen atom, R 2 Has a methoxy group
  • Particularly preferred are the compounds wherein the group, Q is a hydrogen atom, 1 force, m is 0, and n is 2.
  • R 2 is a benzoyl group optionally having a lower alkoxy group or a lower alkyl group
  • Q is a hydrogen atom. or a lower alkyl group
  • 1 is more preferably 1
  • m is a compound which is the case of 0, n is 2, among them, Benzoiru group that have a R 2 turtles butoxy group or a methyl group
  • Q is a hydrogen atom Or a compound which is a methyl group and 1 is 1, m is 0, and n is 2 is particularly preferable.
  • R 2 is a lower alkoxy group, a benzoyl group optionally having a halogen atom or a lower alkyl group
  • R 3 is a benzyl group
  • Q is a hydrogen atom.
  • Compounds in which 1 is 1, m is 0, and n is 2 are more preferred.
  • R 2 is a benzoyl group having a methoxy group
  • R 3 is a benzyl group
  • Q is a hydrogen atom.
  • compounds where 1 is 1, m is 0, and n is 2 are particularly preferred.
  • Specific examples of the compound represented by the above general formula (1) or (4) include 7-benzyloxy-2- (4-methoxybenzoyl) -12-azabicyclo [4.3.0] nonan-3-one, —Benzyloxy 2—Benzoyl 2—Azabicyclo [4.3.0] Nonane-3-one, 7—Benzyloxy 2— (4-Fluorobenzoyl) 1-2—Azabicyclo [4.3.0] Nonane 3-one, 7—Benzylquin One 2- (p-toluoyl) one 2-azabicyclo [4.3.0] nonane-3-one, one benzyloxy one two- (2,4-dimethoxybenzoyl) one two-azabicyclo
  • Preferred compounds include 7-benzyloxy-2- (4-methoxybenzoyl) -12-azabicyclo [4.3.0] nonan-3-one and 7-benzyloxy 2-benzoyl 2-azabicyclo [4.3.0] nonane 3-one, 7-benzyloxy 2-(4-fluorobenzoyl) 1-2-azabicyclo [4.3.0] nonane 3-one, 7-benzyloxy 2- ( ⁇ -toluoyl) 1-2-azabicyclo [4.3.0] nonane-3-one, 7-benzyloxy 2- (2,4-dimethoxybenzoyl) 1-2-azabicyclo [4.3.0] nonane 3-one, 7-benzyloxy 1 3- (4-methoxybenzoyl) 1-3-azabicyclo [4.3.0] nonan 2-one, 7-benzyloxy 3— (4-fluorobenzoyl) 1-3 3-azabicyclo [4.3 .0] Nonane 1-one, 7-benzyloxy 3-
  • Compound is a substituent R Gar OR 1 of the bottle black lactam compound in the present invention can be synthesized for example by the following reaction scheme.
  • R la is an acyl group
  • R 4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a trifluoromethyl group.
  • X represents a halogen atom.
  • examples of the acyl group represented by R la include those described above.
  • examples of the lower alkyl group, lower alkoxy group and halogen atom represented by R 4 include those described above, and are represented by X.
  • examples of the halogen atom include those described above.
  • the compound B is obtained by reacting with ethylene glycol in an appropriate solvent in the presence of an acid catalyst to obtain a compound B.
  • the solvent is not particularly limited as long as it does not take part in the reaction.
  • the acid catalyst include sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc.
  • the reaction is performed by reacting compound A with ethylene glycol and an acid catalyst.
  • the reaction is carried out at a temperature of about 80 ° C to about the boiling point of the solvent, and the reaction time is about 1 to 8 hours, preferably about 4 to 7 hours.
  • the compound B obtained by the present invention can be isolated or can be used for the next reaction without isolation.
  • Step ii Next, compound B is reacted with a reducing agent in a suitable solvent to obtain compound trans-C in which a hydroxyl group is substituted at the trans position with respect to the hydrogen atom bonded to bridgehead atom a.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • alcohols such as methanol, ethanol, propanol, and isopropanol
  • ethers such as dioxane, 1,2-dimethoxetane, and tetrahydrofuran can be used.
  • the reducing agent include lithium aluminum hydride, dibutyl aluminum hydride, diborane, sodium borohydride and the like.
  • the reaction is carried out using a reducing agent in an amount of about 1 to 1.5 times the molar amount of compound C.
  • the reaction temperature is preferably 15 ° C. to room temperature, preferably about 0 to 10 ° C., and the reaction time is preferably about 1 to 3 hours.
  • the compound trans-C obtained by this reaction can be used in the reaction (iii) or (V) without isolation or without isolation.
  • Step iii) Compound D is obtained by reacting compound trans-C with p-ditrobenzoic acid, triphenylphosphine and acetyldicarboxylate in a suitable solvent.
  • the solvent is not particularly limited as long as it does not participate in the reaction, and for example, ethers such as dioxane, 1,2-dimethoxetane and tetrahydrofuran, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane can be used. .
  • the reaction is carried out using about 1 to 3 moles of the compound trans-C.
  • the reaction temperature is 15 to 50 ° C., preferably about 0 ° C. to room temperature, and the reaction time is 1 to 15 hours, preferably about 6 to 12 hours.
  • the compound D obtained by this reaction can be isolated or used without isolation for the next reaction.
  • Step iv Compound D is hydrolyzed in an appropriate solvent by using an anion exchange resin to obtain compound cis-C in which a hydroxyl group is substituted at the cis position with respect to the hydrogen atom bonded to bridgehead atom a.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • alcohols such as methanol, ethanol, propanol and isopropanol can be used.
  • the reaction is carried out using an anion exchange resin in an amount of about 1 to 10 moles per mole of the compound cis-C.
  • the reaction temperature is preferably from room temperature to 100 ° C., and the reaction time is preferably from about 10 to 24 hours.
  • the compound cis-C obtained by this reaction can be isolated or used for the next reaction without isolation.
  • Step V Compound F is obtained by reacting compound C obtained in step (ii) or (iv) with known compound E in a suitable solvent in the presence of a base.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and acetonitrile, dioxane, 1,2 — Ethers such as dimethoxetane and tetrahydrofuran can be used.
  • Bases include tertiary amines such as trimethylamine, triethylamine and pyridin; alkali metal carbonates such as potassium carbonate and sodium carbonate; Alkali metal hydrides such as potassium hydride and sodium hydride can be used.
  • the base and the compound E are used in an amount of about 1 to 2 times the molar amount of the compound C.
  • the reaction temperature is from room temperature to 100 ° C, preferably from room temperature to about 70 ° C, and the reaction time is preferably from 8 hours to 30 hours, preferably from about 20 to 28 hours. Good.
  • the compound F obtained by this reaction can be isolated or used without isolation for the next reaction.
  • Step vi Compound F is deketalized with an acid in a suitable solvent to obtain compound G.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • alcohols such as methanol, ethanol, propanol, and isopropanol
  • ethers such as dioxane, 1,2-dimethoxetane, and tetrahydrofuran can be used.
  • Organic acids such as acetic acid, trifluoroacetic acid, and oxalic acid, and inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, and nitric acid are used as the acid.
  • the reaction temperature is 0 to 60, preferably about 10 to 70 ° C.
  • the reaction time is preferably about 2 to 8 hours.
  • the compound G obtained by this reaction can be isolated or used without isolation for the next reaction.
  • Step vii-a Compound G is reacted with hydroxylamine and sodium acetate in an appropriate solvent to obtain an oxime form of Compound G.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • alcohols such as methanol, ethanol, propanol and isopropanol
  • ethers such as dioxane, 1,2-dimethoxetane and tetrahydrofuran can be used.
  • Hydroxylamine and sodium acetate are used in an amount of about 1.5 to 2 times the molar amount of Compound G.
  • the reaction temperature is 0 to 50 ° C, preferably room temperature.
  • the reaction time is preferably 5 to 8 hours.
  • the resulting compound in a suitable solvent to Okishimu of G, the presence of a base, p- Torr reacted with toluenesulfonic acid Kurori de, c which in the same solvent to obtain p- tosylate ester of Compound G Sili-force gel is added, and a mixture of compound Ha and compound Hb is obtained by Beckmann rearrangement reaction.
  • the solvent is not particularly limited as long as it does not participate in the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as mouth form, dichloromethane and dichloroethane are used.
  • Tertiary amines such as trimethylamine, triethylamine and pyridine are used as the base.
  • a base and p-toluenesulfonic acid chloride are used in a molar amount of about 2 to 3 times the amount of the oxime form of compound G.
  • the reaction temperature in tosylation is preferably about 0 to 10 ° C, and the reaction time is preferably about 4 to 8 hours.
  • the reaction temperature of the Beckmann rearrangement in silica gel is preferably about 10 to 30 ° C, and the reaction time is preferably about 12 to 24 hours.
  • Step vii-b Compound 4a and compound 4b are obtained by reacting the obtained mixture of compounds Ha and Hb with compound 5 in a suitable solvent in the presence of a base.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • examples include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane. .
  • Tertiary amines such as trimethylamine, triethylamine and pyridine are used as the base.
  • compound 5 and a base are used in an amount of about 1 to 2 moles per mole of the mixture.
  • the reaction temperature is, 0 to [delta] 0 ° C, preferably about well to be about 1 0 to 3 5 D C, reaction time 1 2
  • the mixture of 4a and 4b can be separated and purified by a conventional method such as chromatography.
  • Compound 4a or compound 4b obtained by this reaction can be used in the next reaction without isolation or isolation.
  • Step viii Compound 4a or 4b is subjected to hydrogen replacement in an appropriate solvent in the presence of a catalyst to obtain compound ⁇ a or ⁇ b.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • examples include alcohols such as methanol, ethanol, propanol and isopropanol, dioxane, ethers such as 1,2-dimethyloxetane and tetrahydrofuran, methyl acetate, ethyl acetate and the like. Acetates are used.
  • the catalyst for example, palladium-carbon, platinum and the like can be used.
  • Step ix Compound 1'a or compound 1'b is subjected to an acylation reaction described in JP-A-6-161093, etc., in a suitable solvent to give compound l "a or compound l" Obtain b.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • examples include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ethers such as dioxane and tetrahydrofuran, and aromatics such as benzene and toluene. Hydrocarbons and the like are used.
  • acylation reaction a usual acylation reaction method can be applied, and for example, an acid anhydride method and an acid chloride method can be applied.
  • the acid anhydride method is carried out by reacting compound ⁇ a or compound ⁇ b with an acid anhydride in a suitable solvent in the presence or absence of dimethylaminopyridine.
  • the acid anhydride use the acid anhydride corresponding to the acyl group to be introduced. Specific examples thereof include acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride and the like.
  • the reaction uses about 1 to 3 times the amount of an acid anhydride and about 0 to 3 times the molar amount of dimethylaminopyridine with respect to the compound ⁇ a or ⁇ b.
  • the reaction temperature is about 5 to 50 ° C, preferably about 10 to room temperature.
  • the reaction time is about 4 to 24 hours, preferably about 6 to 12 hours.
  • the acid chloride reaction is carried out by reacting compound ⁇ a or 1′b with acyl halide (R 1 SX) in the presence of a deoxidizing agent in a suitable solvent.
  • a deoxidizing agent for example, sodium hydrogencarbonate, sodium carbonate, lium carbonate, pyridine, triethylamine and the like can be used.
  • the solvent include those described above.
  • the reaction uses about 1 to 3 times the molar amount of acyl halide based on compound ⁇ a or ⁇ b.
  • the reaction temperature is about 130 to 100 ° C, preferably room temperature to about 80 ° C.
  • the reaction time is 1 to 20 hours, preferably 6 to 12 hours.
  • compound 6 and compound 5 are reacted in a suitable solvent in the presence of a base to give compound ⁇ ′′.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • aromatic hydrocarbons such as benzene, toluene and xylene and halogenated hydrocarbons such as dichloromethane and dichloroethane are used.
  • Potassium carbonate as base inorganic bases such as sodium carbonate, Na Toriumume Tokishido, sodium ethoxide command like the Na Bok potassium alkoxide or preparative Rimechiruamin, Toryechiruamin, c reactions tertiary Amin such as pyridine is used relative to Compound 6
  • the compound 5 and the base are used in a molar amount of about 1 to 2 times.
  • the reaction temperature is about 0 to 50 ° C, preferably 10 to 35 ° C, and the reaction time is 1 to 24 hours, preferably about 6 to 12 hours.
  • the compound 6 c A method which can be TaiNaru by example, the following A, B or Method C
  • Compound I obtained by cyclizing 2-cyanoethyl-1,3-cyclohexanedione according to the method described in Journal of Organic Chemistry (Org. Chem) 57, 2521 (1992). Is reduced in a suitable solvent in the presence of palladium carbon under hydrogen pressure, so that the two hydrogen atoms at the bridgehead are Compound 6a having a cis configuration is obtained.
  • the solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include alcohols such as methanol, ethanol, and isopropanol, and ethers such as dioxane, 1,2-dimethoxetane, and tetrahydrofuran.
  • the reaction is performed using palladium monocarbon in an amount of about 0 :! to 1.2 times (by weight) the compound I.
  • the hydrogen pressure is about 1 to 3 atm
  • the reaction temperature is 0 to 50 ° C, preferably about 10 to room temperature
  • the reaction time is preferably about 6 to 12 hours.
  • the compound 6a obtained by this reaction can be isolated or used without isolation for the synthesis of the compound of the present invention.
  • Compound K can be obtained by reacting a known compound J described in Synthesis, 176 (1991) with acetylene carboxylic acid methyl ester in a suitable solvent.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and acetonitrile; dioxane; Ethers such as 2-dimethoxetane and tetrahydrofuran can be used.
  • Methyl acetylene carboxylate is used in an excess amount, preferably about 4 to 7 times the molar amount of the compound:!.
  • the reaction temperature is about 120 to 150 ° C, and the reaction time is 6 to 18 hours. Is good. Compound K obtained by this reaction can be isolated or used for the next synthesis without isolation.
  • (B-ii) Compound L obtained by reducing the obtained compound K in a suitable solvent in the presence of palladium on carbon under hydrogen pressure.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • alcohols such as methanol, ethanol, and isopropanol
  • ethers such as dioxane, 1,2-dimethoxetane, and tetrahydrofuran can be used.
  • the reaction is carried out using about 0.1 to 0.5 times the weight of palladium monocarbon with respect to compound K.
  • the hydrogen pressure is about 1 to 5 atm
  • the reaction temperature is about 10 to 50 ° C, preferably about 15 to 30 ° C
  • the reaction time is preferably about 2 to 5 hours.
  • the compound L obtained by this reaction can be isolated or used for the next synthesis without isolation.
  • Compound M is obtained by heating the obtained compound L without solvent.
  • the heating temperature is preferably about 170 to 190 ° C, and the heating time is preferably about 1 to 3 hours.
  • the compound M is reduced according to the method described in the above-mentioned Method A to obtain the compound 6b.
  • the compound 6b obtained by this reaction can be isolated or used without isolation for synthesizing the compound of the present invention.
  • Compound P Compound 6 c (C-i) 25% -ammonia water or methanol in a known compound N described in Journal of Organic Chemistry (J. Org. Chem.), 31, 149 (1966), etc.
  • Compound 0 is obtained by adding excess ammonia and reacting.
  • the reaction temperature is preferably about 15 to 30 ° C, and the reaction time is preferably about 3 to 10 hours.
  • the compound represented by the general formula (1) thus obtained can be isolated and purified by a conventional method such as a recrystallization method or column chromatography.
  • the obtained racemate can be separated into desired optical isomers by, for example, fractional recrystallization of a salt with an optically active acid or passing through a column packed with an optically active carrier.
  • the individual stereoisomers can be separated and purified by a conventional method such as fractional crystallization or chromatography.
  • a pharmaceutical composition in particular, an anxiolytic can be obtained.
  • the anxiolytic comprising the compound of the present invention as an active ingredient can be orally or parenterally administered to mammals including humans.
  • the dosage unit form of the preparation of the present invention is not particularly limited, and various dosage forms can be adopted depending on the purpose of prevention or treatment. Examples of the dosage form include oral preparations, injections, suppositories, and external preparations (for example, cataplasms). Patch, ointment, cream, mouth lotion, etc.), eye drops, nasal drops and the like.
  • the anxiolytic drug containing the compound of the present invention as an active ingredient is prepared as a composition prepared by using a commonly used pharmaceutical carrier or excipient by a method usually used, and provided for use. More specifically, in the form of tablets, capsules, granules, powders, and the like for oral administration, carriers such as lactose, sucrose, sodium chloride, butyl sugar, urea, starch, and calcium carbonate are used as carriers.
  • Excipients such as kaolin, microcrystalline cellulose, gay acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, Binders such as shellac, methylcellulose, ethylcellulose, calcium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, powdered agar, powdered laminaran, powdered sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, Disintegrators such as sodium uryl sulfate, monoglyceride stearate, starch, and lactose; disintegrators such as sucrose, stearic acid, cocoa butter, and hydrogenated oil; quaternary ammonium salt groups; and promotion of absorption of sodium lauryl sulfate Agents, humectants such as glycerin and starch, adsorbents
  • the tablets may be tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets and the like.
  • Capsules are prepared by mixing with the various carriers described above and filling them in hard gelatin capsules, soft capsules, or the like.
  • Liquid preparations for oral administration are aqueous or oily suspensions, solutions, syrups, elixirs and the like, and are prepared in a conventional manner by adding a flavoring agent, a buffer, a stabilizer, a flavoring agent and the like.
  • the flavoring agent may be any of those described above.
  • the buffering agent include sodium citrate
  • examples of the stabilizing agent include tragacanth, gum arabic, and gelatin.
  • the injection may be an aqueous or oily suspension, a solution or a powder filler which can be dissolved at the time of use, a freeze-dried agent, etc., and when adjusted, a pH adjuster, a buffer, a stabilizer, a tonicity agent , Diluents, local anesthetics, etc. are added and prepared in a conventional manner.
  • a pH adjuster a buffer, a stabilizer, a tonicity agent , Diluents, local anesthetics, etc.
  • the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • diluent examples include water, aqueous lactic acid, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • stabilizer examples include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • Local anesthetics include procaine hydrochloride, lidocaine hydrochloride, and the like.
  • carriers include, for example, polyethylene glycol, lanolin, cocoa butter, esters of higher alcohols, gelatin, semi-synthetic glyceride, and, if necessary, a surfactant such as Tween (registered trademark). Etc. can be used.
  • ointment When adjusting to the form of an ointment (paste, cream, gel, etc.), commonly used bases, stabilizers, wetting agents, preservatives, etc. are added as necessary.
  • the base include liquid paraffin, white petrolatum, beeswax, octyldodecyl alcohol, paraffin and the like.
  • preservatives include methyl paraoxybenzoate, ethyl ethyl paraoxybenzoate, pulpyl paraoxybenzoate and the like.
  • the above-mentioned ointment, cream, gel, paste or the like may be applied to a usual support in a conventional manner.
  • a woven or non-woven fabric made of cotton, staple, or chemical fiber, a non-woven fabric, a film of soft vinyl chloride, polyethylene, polyurethane, or the like, or a foam sheet is suitable.
  • a coloring agent a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be added to each of the above preparations as necessary.
  • the administration method of the preparation of the present invention is not particularly limited, and is determined according to various preparation forms, age, sex and other conditions of the patient, degree of symptoms of the patient, and the like. For example, tablets, pills, powders, solutions, suspensions, emulsions, granules, and capsules are administered orally. Suppositories are given rectally.
  • the injection is administered intra-arterially, alone or as a mixture with a normal replenisher such as glucose or amino acid, and further administered alone if necessary, intra-arterially, intramuscularly, intradermally, subcutaneously or intraperitoneally. Ointments are applied to the skin, oral mucosa and the like.
  • the patch is applied to the skin Is done.
  • the dose of the active ingredient of the preparation of the present invention can be appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the symptoms, and the like. Generally, the dose of the active ingredient is usually 0.001 to 50 mg / kg, preferably 0.01 to 1 OmgZkg. These preparations of the present invention can be administered once or in 2 to 4 divided doses.
  • the ether layer was washed three times with 20 ml of water and 20 ml of saturated saline, and then dried over anhydrous sodium sulfate.
  • the ethyl acetate layer was washed with 1 Oml of water, 10 ml of saturated sodium bicarbonate, and then with 1 Oml of saturated saline, and then dried over anhydrous sodium sulfate.
  • the solvent was distilled off, and 1.64 g of the oxime form of the compound obtained in Reference Example 6 was obtained as a colorless oil.
  • 1.6 g of the obtained oxime compound was dissolved in 16 ml of benzene, and under ice cooling, 3.1 lg of p-toluenesulfonic acid chloride and then 2.27 ml of triethylamine were added.
  • reaction mixture was diluted with additional 5 ml of ether.
  • the solution was washed twice with 10 ml of water and 10 ml of 2N hydrochloric acid, then with 10 ml of saturated saline, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off to obtain a yellow oil. This was dissolved in 50 ml of anhydrous benzene, and 43 g of silica gel (Fuji Silicia BW-300, previously washed with 2N hydrochloric acid, then thoroughly washed with water, and dried at 230 ° C for 16 hours) was added. Added.
  • Capsules of 25 Omg per capsule were prepared at the above mixing ratio according to a conventional method.
  • an L injection was prepared according to a conventional method.
  • purified water A syrup was prepared at the above mixing ratio according to a conventional method.
  • Suppositories were prepared at the above mixing ratios according to a conventional method.
  • Wistar rats male weighing 140 to 1608 were used in the experiment in the range of 11 to 14 per group.
  • the anti-anxiety effect is an electric shock that does not cause anxiety
  • the number of watering behaviors in the control group (number of times in non-punishment), the electric shock to give anxiety (punishment), and the number of watering behaviors in the group to which a solvent containing no test compound was administered (solution)
  • the number of water control behaviors (the number of vehicle control groups) and the number of water intake behaviors (the number of drug administration groups) in the group whose anxiolysis was alleviated by the administration of the test compound were measured, and calculated as the anxiety remission rate by the following formula. Table 7 shows the results.
  • Buspirone 1 • 0 2 Based on the above results, the compound of the present invention reduced anxiety by nearly 100% at a low dose of 0.01 to 0.1 mg / kg, but the comparative compound reduced anxiety by 50% or less at the same dose. Stayed. For jazebam and buspirone, l.OmgZkg Almost no anxiolytic effect was observed. As described above, the compound of the present invention shows a very excellent anxiolytic effect.
  • Test example 2 Muscle relaxation (suspension method)
  • Compound ⁇ a-1 a comparative compound, diazebam and buspirone were suspended in 0.5% sodium carboxymethylcellulose solution, and 3 to 4 weeks old male ddY mouse (1 Group 5 subjects) orally.
  • the mouse's forelimb is 1.2 ⁇ in diameter and 30 cm in height. subjected to the Hori zone null wire, hind limbs within 10 seconds three consecutive times as a positive to be touching the wire, it was evaluated by the ED 50 value.
  • Compound ⁇ a-1 and the comparative compound were each administered at a dose of 300 mgZkg, no muscle relaxing action was observed.
  • Dizeno, benzilone, and buspirone were 2.2 mg / kg and 427.8 mg / kg, respectively.
  • Compound ⁇ a-1 the comparative compound, diazebam and buspirone were suspended in 0.5% sodium carboxymethylcellulose solution, and 3 to 4 weeks old male d dY mouse (1 Group 5 subjects) orally.
  • Compound a-1 the comparative compound, diazebam and buspirone were suspended in 0.5% sodium carboxymethylcellulose solution, and 3 to 4 weeks old male ddY mouse (1 hour before starting the experiment at a volume of 10 ml / kg) was administered orally to 6 patients in the group).
  • mice Five-week-old male ddY mice were used as 6 mice per group. Test compound suspended in 0.5% sodium carboxymethylcellulose solution and orally administered for 3 days The number of deaths at each dose was determined by observation. C showing the results in Table 8
  • the compound of the present invention has lower toxicity and higher safety than the comparative compound.
  • the bicyclolactam derivative represented by the general formula (1) has excellent anxiolytic action, has few side effects such as sedative action and muscle relaxant action, and has low toxicity. Therefore, drugs containing the compound of the present invention as an active ingredient are useful for chronic and acute anxiety disorders (or anxiety and fear neurosis), for example, agoraphobia, social fear, panic disorder with or without simple fear, obsessive-compulsive disorder. (Or obsessive-compulsive disorder), treatment or prevention of post-traumatic stress disorder, general anxiety disorder, and other anxiety disorders, and is also useful as a drug for relieving anxiety in healthy and elderly people.
  • anxiety disorders or anxiety and fear neurosis
  • agoraphobia social fear
  • obsessive-compulsive disorder Or obsessive-compulsive disorder
  • treatment or prevention of post-traumatic stress disorder, general anxiety disorder, and other anxiety disorders is also useful as a drug for relieving anxiety in healthy and elderly people.
  • the present invention is useful for treating or preventing anxiety associated with withdrawal symptoms of drug dependence and drug addiction. That is, the present invention is useful for reducing withdrawal symptoms from alcohol dependence, nicotine dependence, cocaine dependence and benzodiazepine dependence, and from other drug dependence by reducing anxiety.

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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
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  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyrrole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Les composés de bicyclolactame représentés par la formule générale (1) sont utiles comme ingrédient actif de médicaments ayant un excellent effet anxiolytique et une sécurité élevée avec peu d'effets secondaires tels qu'un effet hypnotique, de relaxation musculaire, sédatif, etc. Dans cette formule, R représente oxo ou -OR1 (R1 représente hydrogène ou acyle); A représente l'un des groupes suivants (2) et (3); Q représente hydrogène ou un alkyle inférieur; l vaut 1 ou 2, m vaut 0 ou 1, et n vaut 0, 1 ou 2 mais m et n ne valent pas 0 en même temps; R2 est du benzoyle éventuellement substitué.
PCT/JP1996/001565 1994-03-28 1996-06-07 Composes de bicyclolactame, leur emploi et compose intermediaire dans leur production WO1996041796A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
DK96916350T DK0790237T3 (da) 1995-06-12 1996-06-07 Bicyclolactamforbindelser, deres anvendelse og mellemprodukter til deres fremstilling
AU59118/96A AU697656B2 (en) 1995-06-12 1996-06-07 Bicyclolactam compounds, use thereof and intermediates for preparing thereof
EP96916350A EP0790237B1 (fr) 1994-03-28 1996-06-07 Composes de bicyclolactame, leur emploi et compose intermediaire dans leur production
CA002197178A CA2197178C (fr) 1995-06-12 1996-06-07 Composes de type bicyclolactame; leur emploi et intermediaire pour leur preparation
AT96916350T ATE224369T1 (de) 1995-06-12 1996-06-07 Bicyclolactam verbindungen deren verwendung und zwischenprodukte zu deren herstellung
KR1019970700925A KR100220172B1 (ko) 1995-06-12 1996-06-07 비시클로락탐 화합물, 그 용도 및 그 제조중간체
DE69623747T DE69623747T2 (de) 1995-06-12 1996-06-07 Bicyclolactam verbindungen deren verwendung und zwischenprodukte zu deren herstellung
US10/041,555 US6500819B2 (en) 1994-03-28 2002-01-10 Bicyclolactam compounds, use thereof and intermediates for preparing thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP17032995 1995-06-12
JP7/170329 1995-06-12
JP7/274654 1995-09-27
JP27465495A JP3161948B2 (ja) 1995-06-12 1995-09-27 ビシクロラクタム化合物

Related Child Applications (1)

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JP (1) JP3161948B2 (fr)
KR (1) KR100220172B1 (fr)
AT (1) ATE224369T1 (fr)
AU (1) AU697656B2 (fr)
CA (1) CA2197178C (fr)
DE (1) DE69623747T2 (fr)
DK (1) DK0790237T3 (fr)
ES (1) ES2183956T3 (fr)
PT (1) PT790237E (fr)
WO (1) WO1996041796A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011434A1 (fr) * 1990-02-02 1991-08-08 Taiho Pharmaceutical Company, Limited Derive de bicyclolactame
WO1995026187A1 (fr) * 1994-03-28 1995-10-05 Taiho Pharmaceutical Company, Ltd. Agent anxiolytique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011434A1 (fr) * 1990-02-02 1991-08-08 Taiho Pharmaceutical Company, Limited Derive de bicyclolactame
WO1995026187A1 (fr) * 1994-03-28 1995-10-05 Taiho Pharmaceutical Company, Ltd. Agent anxiolytique

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AU697656B2 (en) 1998-10-15
DE69623747T2 (de) 2003-05-22
DE69623747D1 (de) 2002-10-24
JP3161948B2 (ja) 2001-04-25
CA2197178C (fr) 2001-05-01
DK0790237T3 (da) 2002-10-14
PT790237E (pt) 2003-02-28
ATE224369T1 (de) 2002-10-15
KR100220172B1 (ko) 1999-09-01
JPH0959251A (ja) 1997-03-04
AU5911896A (en) 1997-01-09
KR970704686A (ko) 1997-09-06
ES2183956T3 (es) 2003-04-01
CA2197178A1 (fr) 1996-12-27

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