KR100220172B1 - Bicyclolactam compounds, use of the same and intermediates in the production of the same - Google Patents

Abstract

Bicyclolactam compounds represented by general formula (1) are useful as the active ingredient of medicines having an excellent anxiolytic effect and a high safety with little side effects such as a hypnotic effect, a muscle relaxing effect, a sedative effect, etc. In said formula, R represents oxo or -OR<1> (wherein R<1> represents hydrogen or acyl); A represents one of the following groups (2) and (3); Q represents hydrogen or lower alkyl; l is 1 or 2, m is 0 or 1; and n is 0, 1 or 2, provided that m and n are not 0 at the same time; R<2> represents optionally substituted benzoyl.

Description

Bicyclolactam Compounds, Uses thereof and Intermediates of Manufacture

In recent years, with the rapid diversification of the social environment, the number of people suffering from anxiety is increasing, and the development of mental and physical therapy and excellent therapeutic drugs is expected.

Background Art Conventionally, benzodiazepines such as diazepam are widely used as anti-anxiety drugs. However, in this group of drugs, side effects such as sleep enhancement, muscle relaxation and sedation generally occur. In recent years, serotonin-based anti-anxiety drugs such as nuspyrone have been developed as anti-anxiety drugs having a different action structure from this benzodiazepine compound. These serotonin drugs are generally reported to reduce side effects such as sleep enhancement, muscle relaxation, and sedation compared to benzodiazepines. However, these serotonin drugs have a weak anti-anxiety effect and are due to dopamine antagonist action. There are problems such as a decrease in the amount of spontaneous momentum that is thought to occur and a serotonin syndrome that is thought to be due to the properties as a complete agonist for the setronin 1A receptor.

Compounds similar to the present invention are disclosed in WO91 / 11434, which discloses bicyclolactam compounds having brain function improvement, cerebral metabolic reactivity, protection and anti-aging dementia. Is different in the point of having or not having a substituent which directly bonds to the carbon atom on a bicyclo ring.

In addition, the compounds described in the international publication are orally administered, so a large amount of metabolites are calculated, so that the administration of non-active ingredients is not suitable for drug development, but the compound of the present invention is low in metabolites and high in safety.

SUMMARY OF THE INVENTION An object of the present invention is to provide novel bicyclolactam compounds and their intermediates, which are useful as an active ingredient of a medicament having excellent anti-anxiety action, high safety, and very low side effects such as sleep enhancement, muscle relaxation, and sedation. Is in.

The present invention relates to novel bicyclolactam compounds, their use and intermediates for their preparation. The compounds of the present invention have excellent anti-anxiety action and are useful as anti-anxiety drugs.

This invention relates to the bicyclolactam compound represented by General formula (1).

[Wherein R is an oxo group or -OR ¹ , R ¹ is a hydrogen atom or an acyl group, A is a group of formula (2) or (3), Q is a hydrogen atom or a lower alkyl group, 1 is 1 or 2, m represents 0 or 1, n represents 0, 1 or 2. Except that m and n are 0 at the same time.]

(R <^2> represents the benzoyl group which may have a substituent.

Moreover, this invention relates to the bicyclolactam compound represented by General formula (4).

(Wherein A, Q, l, m and n are as described above. R ³ represents a benzyl group which may have a substituent.)

Moreover, this invention relates to the manufacturing method of the bicyclolactam compound represented by General formula (1 ') characterized by hydrogen-substituting the bicyclolactam compound represented by General formula (4) in a suitable solvent in presence of a catalyst. .

(Wherein A, Q, l, m and n are the same as above).

Moreover, this invention relates to the manufacturing method of the bicyclolactam compound represented by General formula (1) characterized by carrying out the acylation reaction of the bicyclolactam compound represented by General formula (1 ') in a suitable solvent.

(Wherein A, Q, l, m and n are as described above. R ^1a represents an acyl group.)

Moreover, this invention is represented by General formula (1 ') characterized by making the compound represented by General formula (5), and the bicyclolactam compound represented by General formula (6) react in presence of a base in a suitable solvent. A method for producing a bicyclolactam compound.

R ² -X (5)

(Wherein R ² is as defined above. X represents a halogen atom.)

Wherein Q is the same as above.

(Wherein R ² , Q and l are the same as above).

The present invention also relates to a pharmaceutical composition comprising an effective amount of the bicyclolactam compound and a pharmaceutical carrier.

The present invention also relates to an anti-anxiety agent comprising an effective amount of the bicyclolactam compound and a pharmaceutical carrier.

Moreover, this invention also includes the method of treating the anxiety which consists of administering the effective amount of the said bicyclolactam compound to mammals including humans, and also uses the said bicyclolactam compound for manufacturing the medicine for treating anxiety.

The bicyclolactam compound represented by the general formula (1) has excellent anti-anxiety action, high safety, fewer side effects, and is useful as a medicament. Moreover, the bicyclolactam derivative represented by General formula (4) is useful as an intermediate for manufacturing compound (1).

The bicyclolactam derivative of the general formula (1) or (4) includes a stereoisomer based on a bicyclo ring, or a carbon atom and R ¹ O- or R ³ O-adduct based on the bridge of the bicyclo ring. Although geometric and optical isomers based on the combined carbon atoms exist, the present invention includes any isomers.

Although the bicyclo ring skeleton in the compound of the said General formula (1) or (4) may consider the following 14 cases by the number of 1, m, and n, all cases are included.

In the above, preferably m or n is 0, that is, in the case of (a), (b), (c), (f), (g), (h), (k) or (m), More preferably, 1 is 1, m is 0, n is 2, that is, (b) or (k).

In the present invention, when the substituent represented by R is an oxo group, the bond with the carbon atom on the bicyclolactam ring represents a double bond.

Substituent positions on the bicyclolactam ring of the substituent R [substituent -OR ³ in the compound represented by the general formula (4) of the compound represented by the general formula (1) are, for example, the bicyclolactam ring skeleton (a) The following three cases are conceived, and all cases are considered. For example, the adjacent carbon atom phase of the bicyclolactam ring bridgehead of (p) or (r) is preferable. The same applies to other bicyclolactam ring skeletons (b) to (n).

In the present invention, examples of the benzoyl group which may have a substituent represented by R ² include a benzoyl group which may have a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a cyano group, a hydroxyl group or an amino group as a substituent. It is a benzoyl group which may preferably have a halogen atom, a lower alkyl group, and a lower alkoxy group as a substituent, More preferably, it is a benzoyl group which has a lower alkoxy group. As for the number of substituents, 1-3 are preferable. In addition, the substituent of the substituent may be substituted in the ortho, meta and para positions on the phenyl ring of the benzoyl group. Examples of the benzoyl group which may have a substituent represented by R ³ include benzyl groups which may have 1 to 3 lower alkoxy groups, lower alkoxy groups, halogen atoms or trifluoromethyl groups as substituents on the phenyl ring. Is an unsubstituted benzyl group. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. It is preferably a fluorine atom. The lower alkyl group may be a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl group, and the like It can illustrate, Preferably it is a methyl or ethyl group, More preferably, it is a methyl group. As a lower alkoxy group, a C1-C6 linear or branched alkoxy group is preferable, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- Butoxy, pentyloxy, isopentyloxy, hexyloxy group, etc. can be illustrated, Preferably it is a methoxy or an ethoxy group, More preferably, it is a methoxy group.

The acyl group represented by R ¹ or R ^1a can widely represent an aliphatic acyl group and an aromatic acyl group, and examples of the aliphatic acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, pentane oil, hexane oil, C2-C6 aliphatic acyl groups, such as acryloyl, propioloyl, methacryloyl, and a crotonyl group, are mentioned, For example, an aromatic acyl group is benzoyl, 3-toluyl, 4-toluyl, 2- Methoxybenzoyl, 2,4-dimethoxybenzoyl, α-naphthylcarbonyl, β-naphthylcarbonyl group, and the like, but are preferably acetyl, benzoyl group, and more preferably an acetyl group.

Although the above-mentioned thing is mentioned as a lower alkyl group represented by Q, Preferably it is a methyl group or an ethyl group, More preferably, it is a methyl group.

As the halogen atom represented by X, the halogen atom is exemplified, preferably a chlorine atom.

Among the compounds represented by the general formula (1) or (4), the ring structure is preferably a compound in which m or n is 0 (except when m and n are 0 at the same time), and l is 1 and m is 0. , more preferably, n is 2. Moreover, in the compound represented by general formula (1), in which R is -OR <^1> , R <^1> is a hydrogen atom or an acetyl group, R <^2> is a benzoyl group which may have a lower alkoxy group, a halogen atom, or a lower alkyl group, and Q. Is a hydrogen atom, l is 1, m is 0, n is 2, more preferably, R ¹ is a hydrogen atom, R ² is a benzoyl group having a methoxy group, Q is a hydrogen atom, and l is 1 Particularly preferred are compounds where m is 0 and n is 2.

In the compound represented by the general formula (1), in the compound in which R is an oxo group, R ² is a benzoyl group which may have a lower alkoxy group or a lower alkyl group, Q is a hydrogen atom or a lower alkyl group, and l is 1, In the case where m is 0 and n is 2, a compound is more preferable, among which R ² is a benzoyl group having a methoxy group or a methyl group, Q is a hydrogen atom or a methyl group, and l is 1, m is 0 and n is 2. Particular preference is given to compounds.

In the compound represented by the general formula (4), R ² is a benzoyl group which may have a lower alkoxy group, a halogen atom or a lower alkyl group, R ³ is a benzyl group, Q is a hydrogen atom, and l is 1, m is In the case where 0 and n are 2, the compound is more preferable. Among them, R ² is a benzoyl group having a methoxy group, R ³ is a benzyl group, Q is a hydrogen atom, l is 1, m is 0, and n is 2. Compounds of are particularly preferred.

Specific examples of the compound represented by the general formula (1) or (4) include 7-benzyloxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7- Benzyloxy-2-benzoyl-2-azabicyclo [4.3.0] nonan-3-one, 7-benzyloxy-2- (4-fluorobenzoyl) -2-azabicyclo [4.3.0] nonan-3 -One, 7-benzyloxy-2- (p-toluoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-benzyloxy-2- (2,4-dimethoxybenzoyl) -2 Azabicyclo [4.3.0] nonan-3-one, 7-benzyloxy-3- (4-methoxybenzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-benzyloxy-3 -Benzoyl-3-azabicyclo [4.3.0] nonan-2-one, 7-benzyloxy-3- (4-fluorobenzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7- Benzyloxy-3- (p-toluoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-benzyloxy-3- (2,4-dimethoxybenzoyl) -3-azabicyclo [4.3 .0] nonan-2-one, 7-hydroxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-hydroxy-2-benzoyl-2- Azabicyclo [4.3.0 ] Nonan-3-one, 7-hydroxy-2- (4-fluorobenzoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-hydroxy-2- (p-toluoyl) 2-azabicyclo [4.3.0] nonan-3-one, 7-hydroxy-2- (2,4-dimethoxyzoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7- Hydroxy-3- (4-methoxy benzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-hydroxy-3-benzoyl-3-azabicyclo [4.3.0] nonan-2 -One, 7-hydrogroup-3- (4-fluorobenzoyl) -3-azabicyclo [4.3.0] nonan-2-silver, 7-hydroxy-3- (p-toluoyl) -3-azabi Cyclo [4.3.0] nonan-2-one, 7-hydroxy-3- (2,4-dimethoxybenzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-acetoxy-2 -(4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-acetoxy-2-benzoyl-2-azabicyclo [4.3.0] nonan-3-one, 7- Acetoxy-2- (4-fluorobenzyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-acetoxy-2- (p-toluoyl) -2-azabicyclo [4.3.0 ] Nonan-3-one, 7-acetoxy-2- (2,4-dimethoxybene Yl) -2-azabicyclo [4.3.0] nonan-3-one, 7-acetoxy-3- (4-methoxybenzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7- Acetoxy-3-benzoyl-3-azabicyclo [4.3.0] nonan-2-one, 7-acetoxy-3- (4-fluorobenzoyl) -3-azabicyclo [4.3.0] nonan-2- On, 7-acetoxy-3- (p-toluoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-acetoxy-3- (2,4-dimethoxybenzoyl-3-azabi Cyclo [4.3.0] nonan-2-one, 6-benzyloxy-2- (4-methoxybenzoyl) -2-azabicyclo [3.3.0] octan-3-one, 7-benzyloxy-3-benzoyl -3-azabicyclo [3.3.0] octan-2-one, 8-benzyloxy-3- (4-fluorobenzoyl) -3-azabicyclo [5.3.0] decan-2-one, 2-benzyloxy -7- (p-Toluoyl) -7-azabicyclo [4.3.0] nonan-8-one, 7-benzyl oxy-2- (2,4-dimethoxybenzoyl) -2-azabicyclo [4.4.0 ] Decane-3-one, 2-benzyloxy-8- (4-methoxybenzoyl) -8-azabicyclo [4.3.0] nonan-7-one, 7-benzyloxy-3-benzoyl-3-azabicyclo [4.4.0] decan-4-one, 8-benzyloxy -3- (4-fluorobenzoyl) -3-azabicyclo [5.4.0] undecan-4-one, 9-benzyloxy-4- (p-toluoyl) -4-azabicyclo [5.4.0] Undecane-3-one, 3- (4-methoxybenzoyl) -3-azabicyclo [5.4.0] undecane-4,8-dione, 2- (4-methoxybenzoyl) -2-azabicyclo [ 4.4.0] decane-3,7-dione, 2- (4-methylbenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (3-ethylbenzoyl) -2- Azabicyclo [4.3.0] nonan-3,7-dione, 2- (2-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3,7-dione, 2- (3-methoxybenzoyl ) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (2 , 4-dimethoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3,7-dione, 2- (2,6-dimethoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3, 7-dione, 2- (3,4-dimethoxybenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (3,5-dimethoxybenzoyl) -2-azabicyclo [ 4.3.0] nonane-3,7-dione, 2- (3,4,5-trimethoxybenzoyl) -2-azabici Rho [4.3.0] nonane-3,7-dione, 6-methyl-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 6-ethyl-2 -(4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione and the like can be exemplified.

Preferred compounds include 7-benzyloxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one and 7-benzyloxy-2-benzoyl-2-azabicyclo [4.3 .0] nonan-3-one, 7-benzyloxy-2- (4-fluorobenzoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-benzyloxy-2- (p-tolu Oil) -2-azabicyclo [4.3.0] nonan-3-one, 7-benzyloxy-2- (2,4-dimethoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-benzyloxy-3- (4-methoxybenzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-benzyloxy-3- (4-fluorobenzoyl) -3-azabicyclo [ 4.3.0] nonan-2-one, 7-benzyloxy-3- (p-toluoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-benzyloxy-3- (2, 4-dimethoxybenzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-hydroxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3- On, 7-hydroxy-2-benzoyl-2-azabicyclo [4.3.0] nonan-3-one, 7-hydroxy-2- (4-fluorobenzoyl) -2-azabicyclo [4.3.0] Nonan-3-one, 7-hydroxy- 2- (p-toluoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-hydroxy-2- (2,4-dimethoxybenzoyl) -2-azabicyclo [4.3.0] Nonan-3-one, 7-hydroxy-3- (4-methoxybenzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-hydroxy-3- (4-fluorobenzoyl) 3-azabicyclo [4.3.0] nonan-2-one, 7-hydroxy-3- (p-toluoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-acetoxy- 2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one, 2- (4-methoxybenzoyl) -2-azabicyclo [4.4.0] decane-3,7- Dione, 2- (4-methylbenzoyl) -2-azabicyclo [4.3.0] nonan-3,7-dione, 2- (2-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3 , 7-dione, 2- (3-methoxybenzoyl) -2-azabicyclo [4.3.0] nonane-3, 7-dione, 2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0 ] Nonane-3,7-dione, 2- (2,4-dimethoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3,7-dione, 2- (2,6-dimethoxybenzoyl)- 2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (3,4-dimethoxybenzo Yl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (3,5-dimethoxybenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2 -(3,4,5-trimethoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3,7-dione, 6-methyl-2- (4-methoxybenzoyl) -2-azabicyclo [ 4.3.0] nonane-3,7-dione, and the like, and more preferably 7-hydroxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one , 7-hydroxy-2-benzoyl-2-azabicyclo [4.3.0] nonan-3-one, 7-hydroxy-2- (4-fluorobenzoyl) -2-azabicyclo [4.3.0] nonane 3-one, 7-hydroxy-2- (p-toluoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-hydroxy-2- (2,4-dimethoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one, 7-hydroxy-3- (4-methoxybenzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-hydroxy -3- (4-fluorobenzoyl) -3-azabicyclo [4.3.0] nonan-2-one, 7-hydroxy-3- (p-toluoyl) -3-azabicyclo [4.3.0] nonane 2-one, 2- (4-methylbenzoyl) -2-aza Bicyclo [4.3.0] nonane-3,7-dione, 2- (3-methoxybenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (2,4-dimeth Oxybenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (3,4-dimethoxybenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (3,5-dimethoxybenzoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione, 2- (3,4,5-trimethoxybenzoyl) -2-azabicyclo [4.3 .0] Nonan-3,7-dion.

In the bicyclolactam compound in this invention, the compound whose substituent R is -OR <^1> is synthesize | combined according to following Reaction Formula, for example.

Wherein Q, R ² , R ³ , l, m and n are the same as above. R ^1a 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.)

In the above, the acyl group represented by R ^1a is exemplified above, the lower alkyl group, lower alkoxy group, and halogen atom represented by R ⁴ are exemplified above, and the halogen atom represented by X is exemplified above. do.

(Process i) Journal of Organic Chemistry (J. Org. Chem.), 42, 3764-3767 (1977), Journal of the Chemical Society, J. Chem. Soc., Chem. Commun., 24 , Compound 59B by reacting known compound A synthesized by the method described in 2759-60 (1994), Chemistry Lett., 9, 1437-40 (1985) and the like with an ethylene glycol in an appropriate solvent under an acid catalyst. Get The solvent is not particularly limited as long as it is not involved in the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene are used. Examples of the acid catalyst include sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and the like. The reaction is carried out using about 1 to 2 times the molar amount of ethylene glycol and an acid catalyst relative to compound A. The reaction temperature is preferably about 80 ° C to the boiling point temperature of the solvent, and the reaction time is 1 to 8 hours, preferably about 4 to 7 hours to complete the reaction. The compound B obtained by this reaction can be used for next reaction, isolated or not isolated.

(Step ii) Then, Compound B is reacted with a reducing agent in a suitable solvent to obtain compound trans-C in which a hydroxyl group is substituted on a trans with respect to a hydrogen atom bonded to a bridge atom a. The solvent is not particularly limited as long as it is not involved in the reaction. For example, alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as dioxane, 1,2-dimethoxyethane and tetrahydrofuran can be used. Examples of the reducing agent include lithium aluminum hydride, diisobutyl aluminum hydride, diborane, sodium borohydride and the like. The reaction is carried out using about 1 to 1.5 times the molar amount of the reducing agent relative to Compound B. The reaction temperature is -5 ° C to room temperature, preferably 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 for reaction (iii) or (v) with or without isolation.

(Step iii) Compound D is obtained by reacting compound trans-C with p-nitrobenzoic acid, triphenylphosphine and diethyl azodicarboxylic acid in a suitable solvent. The solvent is not particularly limited as long as it is not involved in the reaction. Examples thereof include ethers such as dioxane 1,2-dimethoxyethane and tetrahydrofuran, and halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane. The reaction is carried out using about 1 to 3 times the molar amount of the compound trans-C, respectively. The reaction temperature is -5 to 50 ° C, preferably 0 ° C to room temperature, and the reaction time is 1 to 15 hours, preferably 6 to 12 hours. The compound D obtained by this reaction can be used for next reaction, with or without isolation.

(Step iv) Compound D is hydrolyzed by using an anion exchange resin in a suitable solvent to obtain compound cis-C in which a hydroxyl group is substituted on the cis for a hydrogen atom bonded to the bridgehead a. The solvent is not particularly limited as long as it is not involved in the reaction. For example, alcohols such as methanol, ethanol, propanol and isopropanol can be used. Reaction is performed using about 1-10 times molar amount of anion exchange resin with respect to compound cis-D. The reaction temperature is preferably room temperature to 100 deg. C, and the reaction time is preferably about 10 to 24 hours. The compound cis-C obtained by this reaction can be used for the next reaction with or without isolation.

(Step v) Compound F is obtained by reacting compound C obtained in (ii) or (iv) with a known compound E in the presence of a base in a suitable solvent. The solvent is not particularly limited as long as it is not involved in the reaction. For example, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, dioxane and 1,2-dimeth Ethers, such as a methoxyethane and tetrahydrofuran, can be used. As the base, tertiary amines such as trimethylamine, triethylamine and pyridine, alkali metal carbonates such as potassium carbonate and sodium carbonate, hydrogenated alkali metals such as potassium hydride and sodium hydride and the like can be used. In the reaction, these bases and the compound E are used in an amount of 1 to 2 times the molar amount relative to the compound C. The reaction temperature is preferably room temperature to 100 ° C, preferably room temperature to 70 ° C, and the reaction time is 8 hours to 30 hours, preferably 20 to 28 hours. The compound F obtained by this reaction can be used for next reaction, with or without isolation.

(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 is not involved in the reaction. Examples of the solvent include alcohols such as methanol, ethanol, propanol and isopropanol, and ethers such as dioxane, 1,2-dimethoxyethane and tetrahydrofuran. As the acid, 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. Reaction temperature is 0-60 degreeC, Preferably it is about 10-70 degreeC. The reaction time is preferably about 2 to 8 hours. The compound G obtained by this reaction can be used for next reaction, with or without isolation.

(Step vii-a) The oxime of compound G is obtained by reacting compound G with hydroxylamine and sodium acetate in a suitable solvent. The solvent is not particularly limited as long as it is not involved in the reaction. Examples of the solvent include alcohols such as methanol, ethanol, propanol and isopropanol, and ethers such as dioxane, 1,2-dimethoxyethane and tetrahydrofuran. Hydroxylamine and sodium acetate are used in amounts of 1.5 to 2 times the molar amount relative to compound G. Reaction temperature is 0-50 degreeC, Preferably it is room temperature. It is preferable to make reaction time into 5 to 8 hours.

Next, the oxime of the obtained compound G is reacted with p-toluenesulfonic acid chloride in presence of a base in a suitable solvent, and the p-tosylic acid ester of compound G is obtained. Silica gel is added to this in the same solvent, and a mixture of compound Ha and compound Hb is obtained by Beckman potential reaction. The solvent is not particularly limited as long as it is not involved in the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane are used. As the base, tertiary amines such as trimethylamine, triethylamine and pyridine are used. In the reaction, about 2 to 3 times molar amount of base and p-toluenesulfonic acid chloride are used with respect to the oxime of compound G. The reaction temperature in tosylation is preferably about 0 to 10 ° C., and the reaction time is about 4 to 8 hours. Among the silica gels, the reaction temperature at the Beckman potential is good at about 10 to 30 ° C., and the reaction time is good at 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 the presence of a base in a suitable solvent. The solvent is not particularly limited as long as it is not involved in the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane are used. As the base, tertiary amines such as trimethylamine, triethylamine and pyridine are used. In the reaction, about 1 to 2 times the molar amount of Compound 5 and base are used based on the mixture. The reaction temperature is preferably about 0 to 50 ° C, preferably about 10 to 35 ° C, and the reaction time is about 12 to 36 hours, preferably about 24 to 36 hours. The mixture of compounds 4a and 4b obtained by the present invention can be separated and purified by a conventional method such as chromatography. The compound 4a or compound 4b obtained by this reaction can be used for the next reaction, with or without isolation, respectively.

(Step viii) Compound 4a or compound 4b is hydrogen substituted in the presence of a catalyst in a suitable solvent to obtain compound 1'a or 1'b. The solvent is not particularly limited as long as it is not involved in the reaction. Examples thereof include alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as dioxane, 1,2-dimethoxyethane and tetrahydrofuran and acetic acid such as ethyl acetate. Esters are used. As the catalyst, for example, palladium-carbon, platinum and the like can be used. It is preferable to use 0.5-1 weight ratio of catalysts with respect to compound 4a or compound 4b for reaction. The reaction temperature is preferably about room temperature to 50 ° C. The reaction time is about 10-20 hours.

(Step ix) Compound 1'a or 1'b is obtained in an appropriate solvent by an acylation reaction described in Japanese Patent Application Laid-Open No. 61-106593 or the like. The solvent is not particularly limited as long as it is not involved in the reaction. Examples thereof include halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, ethers such as dioxane and detrahydrofuran, and aromatic hydrocarbons such as benzene and toluene. do.

As the acylation reaction, a common acylation reaction method may be applied. For example, an acid anhydride method and an acid chloride method are applied.

The acid anhydride method is carried out by reacting compound 1'a or compound 1'b with an acid anhydride in the presence or absence of dimethylamino pyridine in a suitable solvent. As the acid anhydride, an acid anhydride corresponding to the acyl group to be introduced into R ^1a is used. Specific examples thereof include acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, and the like. In the reaction, about 1 to 3 times the amount of acid anhydride and about 0 to 3 times the amount of dimethylaminopyridine are used with respect to compound 1'a or 1'b. The reaction temperature is about 5 to 50 ° C., preferably about 10 ° C. to room temperature. The reaction time is 4 to 24 hours, preferably about 6 to 12 hours.

The acid chloride reaction is carried out by reacting the compound 1'a or 1'b with an acyl halide (R ^1a X) in the presence of a deoxidizer and in a suitable solvent. As the deoxidizer, for example, sodium bicarbonate, sodium carbonate, potassium carbonate, pyridine, triarylamine and the like can be used. The solvent shown above can be mentioned. About 1-3 times molar amount of the acyl halide is used with respect to compound 1'a or 1'b for reaction. The reaction temperature is about -30 to 100 ° C, preferably about room temperature to 80 ° C. The reaction time is 1 to 20 hours, preferably 6 to 12 hours.

Moreover, the compound whose substituent R is oxo among the bicyclolactam compounds in this invention is synthesize | combined according to the following reaction formula.

Wherein Q, R ² , l and X are as defined above.

With reference to the reaction step (vii-b), compound 1 'is obtained by reacting compound 6 and compound 5 in the presence of a base in a suitable solvent. The solvent is not particularly limited as long as it is not involved in the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene or halogenated hydrocarbons such as dichloromethane and dichloroethane are used. Examples of the base include inorganic bases such as carbonate and sodium carbonate, sodium alkoxides such as sodium methoxide and sodium ethoxide or tertiary amines such as trimethylamine, triethylamine and pyridine. About 1 to 2 times molar amount of compound 5 and a base is used with respect to compound 6. Reaction temperature is about 0-50 degreeC, Preferably it is 10-35 degreeC, and reaction time is 1 to 24 hours, Preferably it is about 6 to 12 hours.

In addition, compound 6 can be synthesized by, for example, the following A, B or C method.

According to the method of J. Org. Chem 57, 2521 (1992), Compound I obtained by ring closing 2-cyanoethyl-1,3-cyclohexanedione in a suitable solvent In the presence of palladium-carbon, reduction in hydrogen pressure yields compound 6a in which the two hydrogen atoms of the bridgehead have cisbatch. The solvent is not particularly limited as long as it is not involved in the reaction. For example, alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane, 1,2-dimethoxyethane and tetrahydrofuran are used. The reaction is carried out using about 0.1 to 1.2 times (weight ratio) of palladium-carbon relative to compound I. The hydrogen pressure is about 1 to 3 atmospheres, the reaction temperature is 0 to 50 ° C, preferably about 10 to room temperature, and the reaction time is preferably about 0 to 12 hours. The compound 6a obtained by this reaction can be used for the synthesis | combination of the compound 1 'of this invention, with or without isolation.

(B-i) Compound K is obtained by reacting well-known compound J described in Synthesis, 176 (1991), etc. with acetylene carboxylic acid methyl ester in a suitable solvent. The solvent is not particularly limited as long as it is not involved in the reaction. For example, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, dioxane and 1,2-dimethoxy Ethers, such as ethane and tetrahydrofuran, can be used. The acetylenecarboxylic acid methyl ester is used in an excessive amount, preferably 4 to 7 times the molar amount relative to the compound J. The reaction temperature is about 120 to 150 ° C., and the reaction time is preferably 6 to 18 hours. The compound K obtained by this reaction can be used for next synthesis | combination with or without isolation.

(B-ii) The compound L is obtained by reducing the obtained compound K in hydrogen solvent under the presence of palladium-carbon in a suitable solvent. The solvent is not particularly limited as long as it is not involved in the reaction. For example, alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane, 1,2-dimethoxyethane and tetrahydrofuran may be used. The reaction is carried out using about 0.1 to 0.5 times the weight of palladium-carbon relative to compound K. The hydrogen pressure is about 1 to 5 atmospheres, the reaction temperature is about 10 to 50 ° C, preferably about 15 to 30 ° C, and the reaction time is preferably about 2 to 5 hours. The compound L obtained by this reaction can be used for next synthesis | combination with or without isolation.

(B-iii) The compound M is obtained by heating the obtained compound L in a solventless. The heating temperature is about 170 to 190 ° C, and the heating time is preferably about 1 to 3 hours.

Subsequently, compound 6b is obtained by reducing compound M according to the method as described in the said A method. The compound 6b obtained by this reaction can be used for the synthesis | combination of the compound 1 'of this invention, with or without isolation.

(C-i) Compound 0 is obtained by reacting known compound N described in the Journal of Organic Chemistry (J. Org. Chem.), 31, 1489 (1966), with an excess of 25% -ammonia water or methanol-ammonia. The reaction temperature is about 15 to 30 ° C., and the reaction time is preferably about 3 to 10 hours.

(C-ii) Compound p is obtained by dehydrating and ring closing the obtained compound 0 according to the method described in Journal of Organic Chemistry (J. Org. Chem.), 35, 3499 (1970) and the like. The reaction temperature is 70 to 120 ° C, preferably about the boiling point of the solvent, and the reaction time is preferably about 2 to 6 hours.

Subsequently, compound 6c is obtained by reducing compound P according to the method described in the said A method. The compound 6c obtained by this reaction can be used for the synthesis | combination of the compound 1 'of this invention, isolated or not isolated.

The compound represented by the general formula (1) thus obtained can be isolated and purified by conventional methods such as recrystallization and column chromatography. The obtained racemate can be divided into desired optical isomers by, for example, fractionating recrystallization of a salt with an optically active acid or passing through a column packed with an optically active carrier. In addition, the individual stereoisomers can be separated and purified by conventional methods such as chromatography under fractional crystallization.

The bicyclolactam compound of the present invention can be combined with a pharmaceutical carrier to obtain a pharmaceutical composition, in particular an anti-anxiety drug.

Anti-anxiety drugs containing the compound of the present invention can be administered orally or parenterally to mammals including humans. The dosage unit form of the present invention preparation is not particularly limited, and various dosage forms may be employed depending on the purpose of prevention or treatment, and the forms may be oral, injectable, suppository, or external preparations (for example, attachments such as pops, ointments, and creams). Agent, lotion), eye drops, eye drops, and the like.

The anti-anxiety agent which uses the compound of this invention as an active ingredient is prepared as a composition which mix | blended the usual conventional pharmaceutical carrier or excipient by the method used normally, and is provided for use.

More specifically, in the form of tablets, capsules, granules, powders and the like for oral administration, as a carrier, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose Excipients such as silicic acid, water, ethanol, propanol, sweet syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, shellac, methylcellulose, ethylcellulose, potassium phosphate, Binders such as polyvinylpyrrolidone, dried starch, sodium alginate, canten powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose Disintegrating agents such as disintegrating agents, sucrose, stearic acid, cacao butter, hydrogenated oil, etc., promoting absorption of quaternary ammonium base, sodium lauryl sulfate , Moisturizers such as glycerin, starch, starch, lactose, kaolin, bentonite, adsorbents such as colloidal silicic acid, refined talc, stearates, boric acid powders, lubricants such as polyethylene glycol, white sugar, shells, citric acid, tartaric acid, etc. Etc. can be used. If necessary, tablets may be conventionally coated tablets such as dragee tablets, gelatin coated tablets, enteric coated tablets, film coated tablets, double tablets, and multilayer tablets. Can be. The capsules are mixed with various carriers exemplified above, and filled into hard gelatin capsules, soft capsules, and the like.

Liquid preparations for oral administration are aqueous or oily suspensions, solutions, syrups, elixirs, and the like, and are prepared according to a conventional method by adding a mating agent, a buffer, a stabilizing agent, a caustic agent, and the like. In this case, as the mating agent, those enumerated above may be used. Examples of the buffering agent include sodium citrate and the like, and tragant, gum arabic and gelatin as the stabilizer.

Injectables are aqueous or oily suspensions, solutions or powder fillers, lyophilizers, etc. which are dissolved in use, and when prepared, are prepared by conventional methods by adding a pH adjuster, buffer, stabilizer, tonicity agent, diluent, local anesthetic, and the like. . In this case, as a pH adjuster and a buffer, sodium citrate, sodium acetate, sodium phosphate, etc. are mentioned. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thioractic acid, and the like. Examples of the diluent include water, an aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Local anesthetics include procaine hydrochloride, lidocaine hydrochloride, and the like. When preparing suppositories, for example, polyethylene glycol, lanolin, cacao butter, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like, and surfactants such as Tuyne (registered trademark) may be used as necessary. .

When preparing in the form of an ointment (paste, cream, gel, etc.), bases, stabilizers, wetting agents, preservatives and the like which are usually used are blended as necessary. Examples of the base include liquid paraffin, white waselin, bleached beeswax, octyldodecyl alcohol, paraffin and the like. Methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, etc. are mentioned.

When preparing in the form of a patch, what is necessary is just to apply the said ointment, cream, gel, paste, etc. to a normal support body by a conventional method. As the support, a film or foam sheet made of cotton, artificial fibers, chemical fibers, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane, or the like is suitable.

Moreover, you may mix | blend a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetener, etc., and other pharmaceutical products with each said formulation as needed.

The administration method of the present invention formulation is not particularly limited, and is determined according to various types of preparations, age, sex, other conditions, symptoms of patients, and the like. For example, tablets, pills, powders, solutions, suspensions, emulsions, granules and capsules are administered orally. Suppositories are administered rectally. Injectables are administered intraarterly, alone or in admixture with common liquids, such as glucose, amino acids, etc., and again, alone, intraarterial, intramuscular, intradermal, subcutaneous or intraperitoneally as needed. Ointment is applied to the skin, oral mucosa and the like. The patch is affixed to the skin.

The dosage of the active ingredient of the present invention is appropriately selected depending on the usage, the age, sex, other conditions, and the degree of symptoms of the patient. In general, the daily dose of the active ingredient is usually 0.001 to 50 mg / kg, preferably 0.01 to 10 mg / kg. These inventive agents can be administered once or divided into 2 to 4 times a day.

The present invention will be described by reference examples and examples, but the present invention is not limited thereto.

(Reference Example 1)

Synthesis of 6-oxo-bicyclo [3.3.0] octan-2-one = ethylene = acetal (Compound B-1)

9.62 g of bicyclo [3.3.0] octane-2,6-dione, p-toluenesulfonic acid monohydrate, a known compound described in the Journal of Organic Chemistry (J. Org. Chem.), 42, 3764-3767 (1977), and the like. 0.265 g of water and 4.54 g of ethylene glycol were dissolved in 50 ml of benzene, and the mixture was refluxed for 6 hours while removing water by azeotropy. After the reaction, the reaction mixture was returned to room temperature, and 3 g of sodium bicarbonate was added thereto and left to stand for 15 minutes. The resulting precipitate was filtered off and washed with benzene. The crude oil obtained by concentrating the filtrate was purified by column chromatography on silica gel with 180 g of silica gel and hexane: ethyl acetate = 5: 1 to obtain 9.28 g (yield: 73%) of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.80 to 2.45 (m, 10H), 3.95 (s, H)

(Reference Example 2)

Synthesis of (1RS, 2RS, 5RS) -2-hydroxybicyclo [3.3.0] octane-6-one = ethylene = acetal (compound trans C-1)

9.23 g of the compound obtained in Reference Example 1 was dissolved in 70 ml of methanol, and 1.93 g of sodium borohydride was added under cooling with an ice-methanol bath. After 30 minutes, the reaction mixture was returned to room temperature and reacted again for 1 hour. Methanol was then distilled off, and 70 ml of water was added, followed by extraction twice with 10 ml of dichloromethane and 50 ml again. The resulting dichloromethane layer was washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a colorless oil. Column chromatography was performed on 150 g of silica gel and hexane: ethyl acetate = 4: 1-2: 1 to obtain 6.63 g (yield: 71%) of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.75 to 2.00 (m, 8H), 2.10 to 2.80 (m, 2H), 3.90 to 4.18 (m, 1H), 3.94 (s, 4H)

(Reference Example 3)

Synthesis of (1RS, 2RS, 5RS) -2- (4-nitrobenzoyloxy) bicyclo [3.3.0] octan-6-one = ethylene = acetal (Compound D-1)

3.68 g of the compound obtained in Reference Example 2, 6.68 g of p-nitrobenzoic acid and 10.5 g of triphenylphosphine were dissolved in 70 ml of tetrahydrofuran, and a 10 ml solution of 7.00 g of tetrahydrofuran of diethyl azodicarboxylic acid was dissolved under ice cooling. It was dripped for a minute. After stirring for 1 hour under ice-cooling, the mixture was returned to room temperature and reacted again for 16 hours. After distilling off the solvent, 50 ml of ether and 30 ml of hexane were added, and the resultant was allowed to stand in a refrigerator for 1 day. Precipitated precipitate (triphenylphosphine oxide) was filtered and washed with hexane: ether = 2: 1. The obtained filtrate was concentrated to give a yellow oily product. 90 g of silica gel, hexane and hexane: ethyl acetate = 10: 1 were purified by column chromatography to obtain 5.34 g (yield: 80%) of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ³ ) δ ppm: 1.60 to 2.20 (m, 8H), 2.45 to 2.90 (m, 2H), 3.94 (s, 4H), 5.10 to 5.33 (m, 1H), 8.24 (s, 4H)

(Reference Example 4)

Synthesis of (1RS, 2RS, 5RS) -2-hydroxybicyclo [3.3.0] octane-6-one = ethylene = acetal (compound cis-C-1)

12.85 g of the compound obtained in Reference Example 3 was dissolved in 100 ml of methanol, and 15 g of anion exchange resin Anbarite 1R400 (OH ⁻ ) (manufactured by Organo) was added and refluxed for 8 hours. Since the raw material remained, 10 g of anion exchange resin was added again, and it refluxed for 16 hours. After the reaction, the reaction mixture was reduced to room temperature, filtered through a hyflo supercell (manufactured by Nakarai Tesu Co., Ltd.), and washed with methanol.

The filtrate was concentrated and purified by column chromatography with 100 g of silica gel and hexane: ethyl acetate = 3: 1. 6.52 g (yield: 92%) of the title compound was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.20 to 2.15 (m, 8H), 2.30 to 2.80 (m, 2H), 3.80 to 4.10 (m, 1H), 3.91 (s, 4H)

(Reference Example 5)

Synthesis of (1RS, 2RS, 5RS) -2-benzyloxybicyclo [3.3.0] octan-6-one = ethylene = acetal (Compound F-1)

6.40 g of Compound E obtained in Reference Example 4 was dissolved in 40 ml of N, N-dimethylformamide, 2.08 g of 60% sodium hydride was added, and the mixture was stirred at room temperature. Hydrogen was generated and the reaction temperature rose to about 45 ° C. After 1 hour, ice-cooled and 6.3 ml of benzyl bromide was added. After 30 minutes, the mixture was reduced to room temperature and stirred for 24 hours. After 4 hours of reaction on a bath at 70 DEG C, the reaction mixture was reduced to room temperature and 80 ml of ice water was added thereto. It was extracted three times with 60 ml of ether. The ether layer was washed three times with 20 ml of water, 20 ml of saturated brine, and dried over anhydrous sodium sulfate. The oily product obtained by distilling off the solvent was purified by column chromatography with silica gel 75 g, hexane and hexane: ether = 15: 1 to obtain 6.65 g (yield: 70%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.60 to 2.10 (m, 8H), 2.40 to 2.80 (m, 2H), 3.50 to 3.80 (m, 1H), 3.90 (s, 4H), 4.92 (s, 2H) , 7.31 (s, 5H)

(Reference Example 6)

Synthesis of (1RS, 2RS, 5RS) -2-benzyloxybicyclo [3.3.0] octan-6-one (Compound G-1)

1.94 g of the compound obtained in Reference Example 5 was dissolved in 10 ml of tetrahydrofuran, 3 ml of 2N hydrochloric acid was added, and the mixture was stirred for 6 hours. After the reaction, tetrahydrofuran was distilled off from the reaction solution and extracted twice with 20 ml of ether. The ether layer was washed twice with 10 ml of saturated aqueous sodium hydrogen carbonate solution and then with 5 ml of saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 1.60 g (yield 98%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.30 to 2.40 (m, 8H), 2.60 to 3.00 (m, 2H), 3.70 to 3.90 (m, 1H), 4.51 (s, 2H), 7.33 (s, 5H)

(Reference Example 7)

Synthesis of cis-2-azabicyclo [4.4.0] decane-3,7-dione (Compound 6a)

2,3,4,5,6,7,8-heptahydro-1 (1H) -quinoline-2, a known compound described in J. Org. Chem. 57, 2522 (1992), 100 ml of methanol was added to 1.5 g of 5-dione and reduced to 0.75 g of 10% palladium-carbon under 1 atmosphere of hydrogen gas. After palladium-carbon was filtered off, the solvent was distilled off, and the residue was purified by column chromatography (silica gel, developing solvent; chloroform: ethanol = 10: 1) to obtain 0.42 g (yield 28%) of the title compound. Properties are shown in Table 1.

(Reference Example 8)

Synthesis of 3- (3-amino-2-cyclopenten-l-one-2-yl) -methyl acrylate (compound K)

0.2 g of 3-amino-2-cyclopenten-l-one and 2 ml of methyl acetylene carboxylic acid were added to 2 ml of dimethylacetamide, and the mixture was heated and stirred at 120 to 125 ° C for 19 hours. After cooling the reaction, 2 ml of ether was added, and the precipitate was filtered off and washed with ether to obtain 0.17 g (yield 46%) of the title compound.

Melting Point 278 ~ 279 ℃

Elemental analysis; Calculated as C ₉ H ₁₁ NO ₃ (analytical), C, H, N; 59.67, 6.12, 7.73 (59.34, 6.47, 8.06)

(Reference Example 9)

Synthesis of 3- (3-amino-2-cyclopenten-l-one-2-yl) -methyl propionate (Compound L)

6.0 g of the compound obtained in Reference Example 8 and 1.5 g of 10% palladium-carbon were added to 200 ml of methanol, and reacted at a hydrogen gas pressure of 2 atm for 3 hours. After the reaction, palladium-carbon was filtered off, the solvent was distilled off, and the residue was crystallized with ether to obtain 5.9 g (yield 98%) of the title compound.

Melting Point 223 ~ 224 ℃

Elemental analysis; C ₈ H ₁₁ NO ₃ .0.2 H ₂ O calculated (calculated), C, H, N; 55.61, 6.65, 8.11 (55.58, 6.69, 8.31)

(Reference Example 10)

Synthesis of 2,3,4,5,6,7-hexahydro-1 (1H) -pyridine-2,5-dione (Compound M)

2.8 g of compound L obtained in Reference Example 9 was heated and stirred at 190 to 210 ° C for 1 hour with a solvent. Isopropanol was added after the reaction, and the precipitate was filtered after cooling to obtain 1.7 g (74% yield) of the title compound.

Melting Point 247 ~ 248 ℃

Elemental analysis; Calculated as C ₈ H ₉ NO ₂ (analytical), C, H, N; 63.56, 6.00, 9.27 (63.25, 6.17, 9.30)

(Reference Example 11)

Synthesis of cis-2-azabicyclo [4.3.0] nonane-3,7-dione (Compound 6b)

3.8 g of compound N obtained in Reference Example 10 was suspended in 180 ml of methanol, and 4 g of 10% palladium-carbon was added thereto and reacted at a hydrogen gas pressure of 2 to 2.5 atm for 12 hours. After the reaction, palladium-carbon was filtered and the filtrate was concentrated and purified by column chromatography (silica gel, developing solvent; ethyl acetate: methanol = 10: 1) to obtain 3.4 g (yield 89%) of the title compound. Properties are shown in Table 1.

(Reference Example 12)

Synthesis of 2-methyl-2- (2-carbamoylethyl) -1,3-cyclopentanedione (Compound 0-1)

Known compound 2-methyl-2- (β-carbomethoxyethyl) cyclopentane-1,3-dione (Compound N) 1.6 as described in J. Org. Chem. 31, 1489 (1966) and the like. 1 ml of 25% aqueous ammonia was added to the mixture, followed by reaction at room temperature for 5 hours. After the reaction, 10 ml of THF was added, the insolubles were filtered off and recrystallized with ethanol to obtain the title compound 0.6g (yield 41%).

Melting Point 159 ~ 162 ℃

(Reference Example 13)

Synthesis of 2,3,4,4a, 5,6-hexahydro-4a-methyl-1 (lH) -pyridine-2,5-dione (Compound P-1)

4.42 g of compound 0-1 obtained in Reference Example 12 was added to 400 ml of toluene, 0.6 g of tosylic acid was added, and a dehydration apparatus was attached and heated to reflux for 3 hours. After the reaction, the solvent was distilled off and the residue was recrystallized from ethanol-chloroform to obtain 3.0 g (yield 75%) of the title compound.

Melting Point 228 ~ 230 ℃

Elemental analysis; Calculated as C ₉ H ₁₁ NO ₂ (analytic), C, H, N; 65.44, 6.71, 8.30 (65.13, 6.67, 8.30)

(Reference Example 14)

Synthesis of cis-6-methyl-2-azabicyclo [4.3.0] nonane-3,7-dione (Compound 6 c-1)

In the same manner as in Reference Example 11, the title compound was synthesized using Compound P-1 obtained in Reference Example 13 instead of Compound M. Physical properties are shown in Table 1.

TABLE 1

(Example 1)

(1RS, 6RS, 7RS) -7-benzyloxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one (compound 4a-1) and (1RS, 6RS, 7RS Synthesis of) -7-benzyloxy-3- (4-methoxybenzoyl) -3-azabicyclo [4.3.0] nonan-2-one (Compound 4b-1)

1.54 g of the compound obtained in Reference Example 6 was dissolved in 15 ml of tetrahydrofuran, 8 ml of water was added, and then 0.94 g of hydroxylamine hydrochloride and 1.84 g of sodium acetate trihydrate were added thereto. Then tetrahydrofuran was added until it became uniform, and it stirred at room temperature for 5 hours. Tetrahydrofuran was distilled off from the reaction solution, and extracted with 80 ml of ethyl acetate. The ethyl acetate layer was washed with 10 ml of water, 10 ml of saturated sodium hydrogen carbonate, and then 10 ml of saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 1.64 g of an oxime of the compound obtained in Reference Example 6 as a colorless oil.

1.60 g of the obtained oxime was dissolved in 16 ml of benzene, and 3.11 g of p-toluenesulfonic acid chloride and then 2.27 ml of triethylamine were added under ice cooling. After stirring for 4 hours under ice-cooling followed by 2 hours at room temperature, 50 ml of ether was further diluted. The solution was washed twice with 10 ml of water and 10 ml of 2N hydrochloric acid, followed by 10 ml of saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a yellow oily product. This was dissolved in 50 ml of anhydrous benzene, 43 g of silica gel (Fuji Silysia BW-300, 2N hydrochloric acid in advance, washed well with water and then dried at 230 DEG C for 16 hours) was added, and anhydrous benzene was added to the point of stirring again. It was shaken for 18 hours in a constant temperature water bath at 25 ℃. The reaction solution was poured into a column containing 20 g of silica gel and benzene as a solvent, 300 ml of benzene was flowed, and excess p-toluene sulfonic acid chloride was distilled out. Thereafter, the solvent was changed to benzene: methanol = 6: 1 to obtain an eluate. Since the obtained eluate still contained impurities, it was purified by column chromatography again with 30 g of silica gel, chloroform and chloroform: methanol = 50: 1. 1.233 g of a pale yellow oily product was obtained by drying under reduced pressure at room temperature. This product was determined by ¹ H-NMR to determine (1RS, 6RS, 7RS) -7-benzyloxy-2-azabicyclo [4.3.0] nonan-3-one and (1RS, 6RS, 7RS) -7-benzyloxy It was a mixture of about 2: 1 of 3-azabicyclo [4.3.0] nonan-2-one.

1.18 g of the obtained mixture was dissolved in 15 ml of dichloromethane, 1.31 g of p-methoxybenzoic acid chloride and 1.34 g of triethylamine were added, followed by stirring at room temperature for 36 hours. After 80 ml of ethyl acetate was added, the mixture was washed twice with 20 ml of 2N hydrochloric acid, twice with 20 ml of saturated sodium hydrogen carbonate, then with 10 ml of saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a brown oily product. This was purified by column chromatography with 30 g of silica gel and hexane: ethyl acetate = 4: 1 to 3: 1. The eluted component was the titled compound 4b-1, and 0.576 g (yield: 25%) was obtained as a yellow oil. The eluted component was the titled compound 4a-1. The solvent was distilled off and recrystallized with ethanol to obtain 1.05 g (yield: 46%). Each physical property value is shown to Tables 2-3.

(Example 2)

Compounds 4a-2 to 4a-5 and 4b-2 to 4b-4 were synthesized in the same manner as in Example 1 using various benzoic acid chloride derivatives instead of p-methoxybenzoic acid chloride. Yields and physical properties are shown in Tables 2-3.

(Example 3)

Synthesis of (1RS, 6RS, 7RS) -7-hydroxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one (Compound 1'a-1)

1.05 g of (1RS, 6RS, 7RS) -7-benzyloxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one (compound 4a-1) obtained in Example 1 The solution was dissolved in 15 ml of dioxane, 0.50 g of 10% palladium carbon (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto, followed by repeated degassing and hydrogen substitution twice with an aspirator, followed by stirring under hydrogen atmosphere (1 atm) for 16 hours. The catalyst was filtered off and washed with dioxane. The filtrate obtained was concentrated to give a colorless oily product. This was purified by column chromatography with 15 g of silica gel and chloroform. The crystals obtained after distilling off the solvent were recrystallized from ether again to obtain 0.64 g (yield: 81%) of the title compound as a colorless powder. Physical properties are shown in Table 4.

(Example 4)

Compounds 1'a-2 to 1'a-5 were synthesized in the same manner as in Example 3, using compounds 4a-2 to 4a-5 obtained in Example 2 as starting materials instead of compound 4a-1. In the same manner, compounds 1'b-2 and 1'b-3 were synthesized using compounds 4b-3 and 4b-4 obtained in Example 2 as starting materials instead of compound 4b-1. Yields and physical properties are shown in Tables 4-5.

(Example 5)

Synthesis of (1RS, 6RS, 7RS) -7-acetoxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one (Compound 1a-1)

(1RS, 6RS, 7RS) -7-hydroxy-2- (4-methoxybenzoyl) -2-azabicyclo [4.3.0] nonan-3-one (Compound 1'a-1) obtained in Example 3. 0.29 g was dissolved in 10 ml of dichloromethane, and 0.225 g of dimethylaminopyridine, followed by 0.2 g of acetic anhydride was added thereto under ice cooling, followed by reaction at room temperature for 12 hours. 20 ml of dichloromethane was added to the reaction solution, washed with 10 ml of 1N hydrochloric acid, followed by 10 ml of saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a light brown oily product. This was subjected to column chromatography purification with 20 g of silica gel and chloroform: methanol = 20: 1 to obtain 0.23 g (yield: 69%) of the titled compound 1a-1 as an oil.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.60 to 2.70 (m, 9H), 2.08 (s, 3H), 3.85 (s, 3H), 4.70 (q, 1H), 5.00 to 5.10 (m, 1H), 6.88 (d, 2H), 7.10 (d, 2H)

TABLE 2

TABLE 3

TABLE 4

TABLE 5

(Example 6)

Synthesis of cis-2- (p-toluoyl) -2-azabicyclo [4.3.0] nonane-3,7-dione (Compound 1'-2)

0.3 g of compound 6b and 0.39 g of 4-methylbenzoyl chloride obtained in Reference Example 11 were dissolved in 20 ml of dichloromethane, and 0.38 ml of triethylamine was added dropwise with ice cooling. After 12 hours of reaction at room temperature, the reaction mixture was dried with 0.1N-HCl, followed by 0.1N-NaOH solution, followed by washing with anhydrous sodium sulfate. After drying, the solvent was distilled off and the residue was recrystallized from isopropanol to obtain 0.35 g (yield 66%) of the title compound. Physical properties are shown in Table 6.

Example 7

In the same manner as in Example 6, compounds 1'-1 and 1'-3 to 1'-11 were synthesized. Physical properties are shown in Table 6. In addition, NMR analysis values of the compounds 1'-3 and 1'-4 are shown below.

Compound 1'-3

¹ H-NMR (CDCl ₃ ) δ ppm 1.80-2.90 (m, 9H), 3.75 (s, 3H), 3.94-4.20 (m, 1H), 6.70-7.04 (m, 2H), 7.22-7.48 (m, 2H)

Compound 1'-4

¹ H-NMR (CDCl ₃ ) δ ppm 1.70 to 2.80 (m, 9H), 3.80 (s, 3H), 4.84 to 5.10 (m, 1H), 6.90 to 7.35 (m, 4H)

TABLE 6

Preparation Example 1 Tablet

Compound 1 'a-1 30mg

Microcrystalline Cellulose 50mg

Hydroxypropylcellulose 20mg

Lactose 47mg

Talc 2mg

Magnesium stearate 1mg

In the above compounding ratio, 150 mg tablets per tablet were prepared according to a conventional method.

Preparation Example 2 Granules

Compound 1 'a-5 10mg

Lactose 400mg

Corn Starch 370mg

Hydroxypropylcellulose 20mg

800 mg of granules per packet were prepared according to a conventional method at the above compounding ratio.

Preparation Example 3 Capsule

Compound 1 'b-1 55mg

Lactose 50mg

Corn Starch 50mg

Microcrystalline Cellulose 94mg

Magnesium stearate 1mg

250 mg of capsules per capsule were prepared according to the conventional method at the above compounding ratio.

Preparation Example 4 Injection

Compound 1'-8 10mg

Sodium chloride 3.5mg

Distilled water for injection

2 ml per ampoule

The injection ratio was prepared according to the conventional method at the said compounding ratio.

Preparation Example 5 Syrup

Compound 1'-9 50mg

60g per tablet

5 mg of ethyl parahydroxybenzoate

5 mg of parahydroxy benzoate

Spices

Coloring amount

Purified water

A syrup was prepared according to the conventional method at the above compounding ratio.

Preparation Example 6 Suppositories

Compound 1'-10 50mg

Uthezol W-35 1400mg

(Registered trademark, mono, di and triglyceride mixtures of saturated fatty acids from lauric acid to stearic acid, manufactured by Dynamite Nobel)

The suppository was prepared according to the conventional method at the said compounding ratio.

Next, although test examples are exemplified, experiments were carried out using 2-azabicyclo [3.4.0] nonan-2-one of International Publication No. W0 91/11434 as a comparative compound.

Test Example 1 Section Conflict Test

1. Experimental Animal

In the experiment, a wister rat (a male having a weight of 140 to 160 g) was used in a range of 11 to 14 groups.

2. Drug used and administration method

Compound 1'a-1, Compound 1'a-5, Compound 1'b-1, Compound 1'-8, Compound 1'-9, Comparative Compound, Diazepam, and Buspyron were suspended in 0.5% sodium carboxymethylcellulose solution. Then, the dose of 5ml / kg was administered orally 1 hour before the start of the experiment.

3. Experiment method and result

An experimental box on a grid floor with a water supply port, referring to the method described in `` Advanced Anti-Anxiety Drugs and Antidepressant Drugs, Ueki Akigazzu, Furukawa Tatsuo Editor, Dental Medicine Publishers, 56-59, (1981) ''. The test was done using. Rats were watered for 48 hours and given to the experiment. At the first 24 hours, the rats were placed in the test box and submerged for 30 seconds to recognize the water inlets. At the time of saving water for 24 hours, the rats were put in the test box again, and electricity was supplied between the water supply port and the grid every 20 times of submersion and submerged under conditions that impart electric shock. The anti-anxiety effect was the recovery of subcutaneous behavior of the control group without the anxiety (the recovery of non-being state), the giving of the anxious electric shock (the bee state), and the administration of a solvent containing no test compound. The recovery behavior (recovery of the solvent control group) and the recovery behavior (recovery of the drug administration group) of the group that was relaxed by administration of the test compound were measured and calculated as . The results are shown in Table 7.

TABLE 7

In the above results, the compound of the present invention resolved almost 100% of anxiety at a low dose of 0.01 to 0.1 mg / kg, but the comparable compound had only 50% or less of anxiety at the same dose. Moreover, in 1.0 mg / kg administration of diazema and buspyron, anti-anxiety action was hardly confirmed. In the above, the compound of the present invention shows very excellent anti-anxiety effect.

Test Example 2 Muscle Relaxation (Suspension)

1. Test Animal and Administration Method

Compound 1'a-1, comparative compound, diazepam and buspyrone were suspended in 0.5% sodium carboxymethylcellulose solution, and male ddY mice (Group 1 5) aged 3 to 4 weeks before the start of the experiment at a dose of 10 ml / kg. Oral administration).

2. Experiment method and result

Using the method described in The Japanese Journal of Pharmacol., 49, 337-349 (1989), the front leg of the mouse was 1.2 mm in diameter and 1.30 cm in height. When the hind limb did not contact the wire within 10 seconds for three consecutive times, it was positive and evaluated as ED ₅₀ value. As a result, muscle relaxation was not confirmed even when 300 mg / kg of Compound 1'a-1 and the comparative compound were administered. Diazepam and buspyrone were 2.2 mg / kg and 427.8 mg / kg, respectively.

Test Example 3 Sedation (Voluntary Momentum)

1. Experimental Animal and Administration Method

Compound 1'a-1, comparative compound, diazepam and buspyrone were suspended in 0.5% sodium carboxymethylcellulose solution, and male ddY mice (Group 1 5) of 3 to 4 weeks before the start of the experiment at a dose of 10 ml / kg. Oral administration).

2. Experiment method and result

The test was carried out with reference to the method described in "Evaluation of drug efficacy (1), pharmacological test method" Shang ", Basic Course for Drug Development, 50-54, (1971). That is, after administration of the test compound to a mouse, a spontaneous momentum using measured 10 minutes per one of Animax MK-110 (Muromachi group Kai Co., Ltd.), momentum, and as positive when 50% or less in the control group were evaluated value ED _50. As a result, sedation was not confirmed even when the compound 1'a-1 and the comparative compound was administered 300mg / kg. Diazepam and buspyrone were 1.7 mg / kg and 149.7 mg / kg, respectively.

Test Example 4 Central Inhibition (Ethanol Enhancer)

1. Experimental method and administration method

Compound 1'a-1, comparative compound, diazepam and buspyrone were suspended in 0.5% sodium carboxymethylcellulose solution, and male ddY mice aged 3-4 weeks (1 group 6 cases) 1 hour before the start of the experiment at 10 ml / kg dose. ) Orally.

2. Experiment method and result

The test was conducted with reference to the method described in "The Japanese Journal of Pharmacol." (Japan. J. Pharmacol.), 49, 337-349 (1989). In other words, intraperitoneally administered at a dose of 20 ml / kg of 25% ethanol, more than two times more than the clove reflection loss time of the control group was positive and evaluated as ED ₅₀ value. As a result, ethanol potentiation was not confirmed even when the compound 1'a-1 and the comparative compound was administered 300mg / kg. Diazepam and buspyrone were 0.48 mg / kg and 120.1 mg / kg, respectively.

Test Example 5 Anticonvulsant Action (Pentylenetetrazole Spasm)

1. Experimental method and administration method

Compound 1'a-1, comparative compound, diazepam and buspyrone were suspended in 0.5% sodium carboxymethylcellulose solution, and male ddY mice (Group 1 6) aged 3 to 4 weeks before the start of the experiment at a dose of 10 ml / kg. Oral administration).

2. Experiment method and result

The test was carried out with reference to the method described in "Evaluation of medicinal efficacy (1), pharmacological examination method" Shang ", basics of drug development, 167-172. In other words, 150 mg / kg of pentylenetetrazole was subcutaneously administered, and the case of death without convulsions within 60 minutes was positive and evaluated at an ED value of ₅₀ . As a result, even when 300 mg / kg of Compound 1'a-1 and Comparative Compound were administered, anticonvulsant activity was not confirmed. Diazepam and buspyrone were 0.35 mg / kg and 300 mg / kg or more, respectively.

Test Example 6 Rapid Toxicity Test

Five-week-old male ddY mice were used as 6 groups. After the test compound was suspended in 0.5% carboxymethyl cellulose solution and orally administered, the number of deaths at each dose was determined by observation for 3 days. The results are shown in Table 8.

TABLE 8

In the above results, 5 of 6 cases died when the comparative compound was administered at 3000 mg / kg, but only 2 of 6 cases of the compound of the present invention were confirmed. Therefore, the compound of the present invention is lower in toxicity and higher in safety than the comparative compound.

The bicyclolactam derivative represented by the general formula (1) has excellent anti-anxiety action, less side effects such as sedation and muscle relaxation, and is low toxicity. Therefore, the drug containing the compound of the present invention is a chronic and acute anxiety disorder (or anxiety and panic neurosis), for example, panic disorder, obesity with obesity, social fear, simple fear, obsessive compulsive disorder ( Or OCD), post-traumatic stress disorder, systemic anxiety disorder, or other anxiety disorder treatment or prevention, and is also useful as a drug for the purpose of relieving anxiety of healthy people and the elderly.

In addition, the present invention is useful for treating or preventing anxiety associated with drug dependence and / or withdrawal symptoms of a drug symbol wall. That is, the present invention is useful for reducing withdrawal symptoms from alcohol dependence, nicotine dependence, cocaine dependence and benzodiazepine dependence and withdrawal symptoms from other drug dependence by reducing anxiety.

Claims (14)

Bicyclolactam compound represented by General formula (1).

[Wherein R is an oxo group or -OR ¹ , R ¹ is a hydrogen atom or an acyl group, A is a group of formula (2) or (3), Q is a hydrogen atom or a lower alkyl group, 1 is 1 or 2, m represents 0 or 1, n represents 0, 1 or 2. Except that m and n are 0 at the same time.]

(R ² represents a benzoyl group which may have a substituent.) Bicyclolactam compound represented by general formula (4).

(Wherein A, Q, l, m and n are as described above. R ³ represents a benzoyl group which may have a substituent.) The bicyclolactam compound according to claim 1 or 2, wherein m or n is zero. The bicyclolactam compound according to claim 1 or 1, wherein l is 1, m is 0, and n is 2. The benzoyl group according to claim 1, wherein R is -OR ¹ , R ¹ is a hydrogen atom or an acetyl group, R ² is a lower alkoxy group, a halogen atom or a lower alkyl group, Q is a hydrogen atom, l is 1, m is 0, n is 2. The bicyclolactam compound characterized by the above-mentioned. The bicyclolactam compound according to claim 5, wherein R is -OR ¹ , R ¹ is a hydrogen atom, R ² is a benzoyl group having a methoxy group, and Q is a hydrogen atom. 2. A compound according to claim 1, wherein R is an oxo group, R ² is a benzoyl group which may have a lower alkoxy group or a lower alkyl group, Q is a hydrogen atom or a lower alkyl group, l is 1, m is 0, n is 2 A bicyclolactam compound characterized by the above-mentioned. The bicyclolactam compound according to claim 7, wherein R ² is a benzoyl group having a methoxy group or a methyl group, and Q is a hydrogen atom or a methyl group. 3. A compound according to claim 2, wherein R ² is a benzoyl group which may have a lower alkoxy group, a halogen atom or a lower alkyl group, R ³ is a benzyl group, Q is a hydrogen atom, l is 1, m is 0, and n is 2. A bicyclolactam compound characterized by the above-mentioned. The bicyclolactam compound according to claim 9, wherein R ² is a benzoyl group having a methoxy group and R ³ is a benzyl group. A method for producing a bicyclolactam compound represented by Formula (1 '), wherein the bicyclolactam compound represented by Formula (4) is hydrogen substituted.

(Wherein A, R ³ , Q, l, m and n are the same as above).

(Wherein A, Q, l, m and n are the same as above). The manufacturing method of the bicyclolactam compound represented by General formula (1) characterized by acylating the bicyclolactam compound represented by General formula (1 ').

(Wherein A, Q, l, m and n are the same as above).

(Wherein A, Q, l, m and n are as described above. R ^1a represents an acyl group.) A process for producing a bicyclolactam compound represented by the general formula (1 '), wherein the compound represented by the general formula (5) and the bicyclolactam compound represented by the general formula (6) are reacted in the presence of a base. R ² -X (5) (Wherein R ² is as defined above. X represents a halogen atom.)

(Wherein Q and 1 are the same as above).

(Wherein R2, Q and l are the same as above). An anti-anxiety agent comprising an effective amount of the bicyclolactam compound according to claim 1 and a pharmaceutical carrier.