CA2197178C - Bicyclolactam compounds, use of the same and intermediate in the production of the same - Google Patents

Abstract

Bicyclolactam compounds represented by general formula (1) (see formula I) wherein: R is oxo or -OR1, where R1 is a hydrogen atom or an aliphatic acyl group having 2 to 6 carbon atoms, benzoyl, toluyl, methoxybenzoyl, dimethoxybenzoyl, or naphthylcarbonyl; A is a group of (2) or (3) (see formula II and III) wherein R2 is a benzoyl group or a benzoyl group substituted by a halogen atom, lower alkyl group, lower alkoxyl group, nitro group, cyano group, hydroxyl group or amino group; Q is a hydrogen atom or lower alkyl group; 1 is 1 or 2; m is 0 or 1 and n is 0, 1 or 2 (provided the case where both of m and n represent 0 simultaneously is excluded); are useful as the active ingredient of medicines having an excellent anxiolytic effect with little side effects such as hypnotic effect, a muscle relaxing effect and a sedative effect.

Description

Bicyclolactam Compounds, Use Of The Same And Intermediate In The Production Of The Same The present invention relates to novel bicyclolactam compounds, use thereof, and an intermediate for preparing the bicyclolactam compounds. The compounds have excellent anxiolytic effect and are useful as anxiolytic agents.
With rapid diversification of the social environment in recent years, an increasing number of people are suffering from anxiety, and it has been expected to develop psychosomatic therapies and excellent therapeutic agents.
Benzodiazepine compounds such as diazepam have found wide use as anxiolytics. This group of agents, however, generally have side effects such as hypnotic effect, muscle relaxant effect and sedative effect. Serotonin anxiolytic agents such as buspirone are also recently developed as anxiolytics which are different from the benzodiazepine compounds in activity mechanism. Reportedly these serotonin agents are generally lesser than the benzodiazepines in side effects such as hypnotic, muscle relaxant and sedative effects, but they are lower in anxiolytic effect and have the problems of diminishing voluntary movements presumably owing to their activity as a dopamine antagonist, and causing serotonin syndrome which appears attributable to their properties as a full agonist for serotonin lA receptor.

'~ 2~9~~7s Compounds which are similar to the bicyclolactam compounds of the present invention are disclosed in International Publication No. WO 91/11434, and are known to have a cerebral function improving effect, cerebral metabolism activating or anoxic brain damage protecting effect and effect against senile dementia. The present compounds differ from those disclosed in WO 91/11434 in that the former have a substituent directly attached to a carbon atom on the bicyclo ring.
Further, when the compounds disclosed in International Publication No. WO 91/11434 are orally administered, a lot of metabolites are produced. This causes an administration of non-effective substances and is unsuitable to develop pharmaceuticals. The present compound produces less amount of metabolites and is high in safety.
An object of the present invention is to provide novel bicyclolactam compounds and an intermediate for production of the bicyclolactam compounds. The bicyclolactam compounds have excellent anxiolytic effect, high in safety, and are useful as an effective component of medicinals which are greatly diminished in side effects such as hypnotic, muscle relaxant and sedative effects.
The present invention provides bicyclolactam compounds represented by the following formula (1) E

R. Q
( C H z)n (CH2)1 \A (1) C
( H z)m wherein R is oxo or -OR', R' is a hydrogen atom or acyl group, A is a group of (2) or (3), Q is a hydrogen atom or lower alkyl group, 1 is 1 or 2, m is 0 or 1 and n is 0, i or 2, provided the case where both of m and n represent 0 simultaneously is excluded O
(2) ~N~R2 ~N/R
(3) O
wherein R= is benzoyl group or substituted benzoyl group.
The present invention also provides a bicyclolactam compound represented by the following formula (4) ORS Q
(CH~~
2 5 (CHZ)1 /A
(CHz)m wherein A, Q, 1, m and n are as defined above, R' is benzyl group or substituted benzyl group.
X, 2197~7s The present invention further provides a process for preparing a bicyclolactam compound represented by the following formula (1'), comprising replacing Rg in the bicyclolactam compound of the formula (4) by hydrogen atom in a suitable solvent in the presence of a catalyst HO
C H Z)n (CHZ)1 \A (1') C ~) m wherein A, Q, 1, m and n are as defined above.
The present invention further provides a process for preparing a bicyclolactam compound represented by the following formula (1"), comprising acylating the bicyclolactam compound of the formula (1') in a suitable solvent Q
C ~) n C ~) m wherein A, Q, 1, m and n are as defined above, R1' is acyl group.
The present invention further provides a process for preparing a bicyclolactam compound represented by the following formula (i " '), comprising reacting a compound of the formula (5) and a bicyclolactam compound of the formula (6) in a suitable solvent in the presence of a base S
R2 - X (5) wherein R2 is as defined above, X is a halogen atom,.
O
(CHz~l ~ l C6) N
H
wherein Q and 1 are as defined above, (CH
RZ
wherein RZ, Q and 1 are as defined above.
The present invention further provides a pharmaceutical composition comprising an effective amount of the above bicyclolactam compound and a pharmaceutically acceptable carrier.
The present invention further provides an anxiolytic agent comprising an effective amount of the above bicyclolactam compound and a pharmaceutically acceptable carrier.
The present invention further includes a method of treating anxiety comprising administering an effective amount of the above bicyclolactam compound to mammals including man, and also use of the above bicyclolactam compound for the preparation of medicinals for treating anxiety.
The bicyclolactam compound of the formula (1) has an 219 7 ~ ~8 excellent anxiolytic effect, is high in safety, diminished in side effects, and useful as medicinals. Further, the bicyclolactam compound of the formula (4) is useful as an intermediate for preparing the bicyclolactam compound of the formula (1).
Existing as bicyclolactam derivatives of the formula (1) or (4) are stereoisomers due to the presence of the bicyclo ring, and also geometric isomers and optical isomers due to the presence of the carbon atom at the bridgehead position of the bicyclo ring and the carbon atom having R'0-or R'0- attached thereto. The present invention includes all of these isomers.
In view of the numbers 1, m and n, the following fourteen (14) kinds of bicycZo ring skeletons can be present in the compounds of the formula (1) or (4). The invention includes all of these cases.

. I;y}
.~"

o (a) (d) 1N N~O

'N (~) ~ (d) N
O () ~0 ~..~N ~ N
/O
(g) N (h) N' '0 O
('~ ~O G) N
N
1 (k) N
O O
(m) N
N
O
O
Preferable among these is the case wherein m or n is . , ~~r, 0, i.e. the skeleton (a) , (b) , (c) , (f) , (g) , (h) , (k) or (m) .
More preferable is the case wherein 1 is 1, m is 0, n is 2, i . a . , (b) or (k) .
In the present invention, in the case where the substituent R is oxo group, the bond between R and the carbon on the bicyclo ring shows double bond.
In case of, for example, the above bicyclolactam ring skeleton (a), the following three positions are shown where the substituent R of the compound of the formula (1) (or -OR' of the compound of the formula (4)] attaches to the bicyclolactam ring. Although the invention includes all of these cases, preferable is (p) or (r) below where R (or -OR') attaches to the vicinal carbon atom of the brigehead atom of the bicyclolactam ring. This is similar in the other bicyclolactam ring skeletons (b,) to (n) .
R
N ~ R... 0 ~N
CP) C4) R Cr) According to the invention, examples of benzoyl groups which may optionally have at least one substituent represented by R= are benzoyl groups which may optionally have, as a substituent, a halogen atom, lower alkyl group, lower alkoxyl group, vitro ~qroup, cyano group, hydroxyl group or amino group. Preferable are those which may optionally have, as a substituent, a halogen atom, lower alkyl group or lower alkoxyl group. More preferable is that which has, as a substituent, at least one lower alkoxyl group. The number of substituents is preferably 1 to 3. The substituent may be present at any of the ortho-, meta- and para-positions on the phenyl ring of the benzoyl group. Examples of benzyl groups which m°ay optionally have at least one substituent represented by R~ are benzyl groups which may optionally have on the phenyl ring, as a substituent, 1 to 3 of lower alkyl group, lower alkoxyl group, halogen atom or trifluoromethyl group.
Preferable is unsubstituted benzyl group. Examples of halogen atoms are fluorine, chlorine, bromine and iodine atom, among which fluorine atom is preferable. Examples of useful lower alkyl groups are straight-chain or branched alkyl groups having 1 to 6 ca~'bon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl group. Preferable among these is methyl or ethyl group. Methyl group is more preferable. Examples of useful lower alkoxyl groups are straight-chain or branched alkoxyl groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxy group, among which methoxy or ethoxy group is preferable. Methoxy group is more preferable.
Acyl groups represented by R' or R'' include widely an aliphatic acyl group and aromatic acyl group. Examples of aliphatic acyl groups are those having 2 to 6 carbon atoms, such as formyl,-acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, acryloyl, propioloyl, methacryloyl and crotonoyl. Examples of aromatic acyl groups are benzoyl, 3-x toluyl, 4-toluyl, 2-methoxybenzoyl, 2,4-dimethoxybenzoyl, a -naphthylcarbonyl and ~ -naphthylcarbonyl. Preferable among these is acetyl or benzoyl group. Acetyl group is more preferable.
Lower alkyl group shown by Q includes the above lower alkyl groups, among which methyl and ethyl groups are preferable. Methyl group is more preferable.
Halogen atom shown by X includes the above halogen atoms; among which chlorine atom is preferable.
10 Among the compounds of the formula (1) or (4), preferable are those having a ring structure wherein m or n is 0 [provided m and n are not 0 (zero) simultaneously), and more preferable are those wherein 1 is 1, m is 0 and n is 2. In case of the compound (1) wherein R is -OR', preferable are those wherein R' is a hydrogen atom or acetyl group, RZ is benzoyl or benzoyl having lower alkoxyl group, halogen atom or lower alkyl group, Q is a hydrogen atom, and wherein 1 is 1, m is 0 and n is 2. Especially preferable are those wherein R' is a hydrogen atom, RZ is a benzoyl having methoxy group, Q is a hydrogen atom, and wherein 1 is 1, m is 0 and n is 2.
Among the compounds of the formula (1) wherein R is oxo Qroup, preferable are those wherein R=,is a benzoyl or benzoyl having lower alkoxyl group or lower alkyl group, ø is a hydrogen atom or lower alkyl group, and wherein 1 is 1, m is 0 and n is 2. Especially preferable are those wherein R= is.
benzoyl having methoxy or methyl group, Q is a hydrogen atom or methyl group, and wherein 1 is 1, m is 0 and n is 2.
Further, in case of the compound (4), preferable are r:

2197~7s those wherein R2 is benzoyl or benzoyl having lower alkoxyl group, halogen atom or lower alkyl group, R' is benzyl group, Q is a hydrogen atom, and wherein 1 is 1, m is 0 and n is 2.
Especially preferable are those wherein RZ is a benzoyl having S methoxy group, Q is a hydrogen atom, and wherein 1 is 1, m is 0 and n is 2.
Examples of the compound of the above formula (1) or (4) are 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.Ojnonan-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.Ojnonan-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.Ojnonan-2-one, 7-benzyloxy-3-(2,4-dimethoxybenzoyl)-3-azabicyclo[4.3.Ojnonan-2-one, 7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.Ojnonan-3-one, 7-hydroxy-2-benzoyl-2-azabicyclo[4.3.Ojnonan-3-one, 7-hydroxy-2-(4-fluorobenzoyl)-2-azabicyclo[4.3.0jnonan-3-one, 7-hydroxy-2-(p-toluoylj-2-azabicyclo[4.3.Ojnonan-3-one, 7-hydroxy-2-(2,4-dimethoxybenzoyl)-2-azabicyclo[4.3.Ojnonan-3-one, 7-hydroxy-3-(4-methoxybenzoyl)-3-azabicyclo[4.3.Ojnonan-2-one, 7-hydroxy-3-benzoyl-3-azabicyclo[4.3.Ojnonan-2-one, 7-hydroxy-3-(4-fluorobenzoyl)-3-azabicyclo[4.3.Ojnonan-2-one, 7-hydroxy-3- (p-toluoyl) -3-azabicyclo [4 . 3. Oj 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-fluorobenzoyl)-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-dimethoxybenzoyl)-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-one, 7-acetoxy-3-(p-toluoyl)-3-azabicyclo[4.3.0)nonan-2-one, 7-acetoxy-3-(2,4-dimethoxybenzoyl)-3-azabicyclo[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-benzyloxy-2-[2,4-dimethoxybenzoyl)-2-azabicyclo[4.4.0]decan-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]undecan-3-one, 3-(4-methoxybenzoyl)-3-azabicyclo[5.4.0]undecan-4,8-dione, 2-(4-methoxybenzoyl)-2-azabicyclo[4.4.0]decan-3,7-dione, 2-(4-methybenzoyl)-2-azabicyclo[4.3.0]nonan-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]nonan-3,7-dione, 2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-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]nonan-3,7-dione, 2-(3,5-dimethoxybenzoyl)-2-azabicyclo[4.3.0)nonan-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]nonan-3,7-dione and 6-ethyl-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione.
Preferable examples are 7-benzyloxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.OJnonan-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-benvyloxy-2- (p-toluoyl) -2-azabicyclo [4.3~.Oj nonan-3-one, 7-benzyloxy-2-(2,4-dimethoxybenzoyl)-2-azabicyslo[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-one, 7-hydroxy-2-benzoyl-2-azabicyclo[4.3.Ojnonan-3-one, 7-hydroxy-2-(4-fluorobenzoyl)-2-azabicyclo[4.3.Ojnonan-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.OJnonan-2-one, 7-hydroxy-3-(p-toluoyl)-3-azabicyclo[4.3.Ojnonan-2-one, 7-acetoxy-2-(4-methoxybenzoyl)-Z-azabicyclo[4.3.0)nonan-3-one, x ,.~., 2-(4-methoxybenzoyl)-2-azabicyclo[4.4.Ojdecan-3,7-dione, 2-(4-methylbenzoyl)-2-azabicyclo[4.3.Ojnonan-3,7-dione, 2-(2-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione, 2-(3-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione, 2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione, 2-(2,4-dimethoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione, 2-(2,6-dimethoxybenzoyl)-2-azabicyclo[4.3.Ojnonan-3,7-dione, 2-(3,4-dimethoxybenzoyl)-2-azabicyclo(4.3.0]nonan-3,7-dione, 2-(3,5-dimethoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione, 2-(3,4,5-trimethoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione and 6-methyl-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione.
More preferable examples are 7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3-one;
7-hydroxy-2-benzoyl-2-azablcyclo[4.3.0jnonan-3-one, 7-hydroxy-2-(4-fluorobenzoyl)-2-azabicyclo[4.3.0jnonan-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.Ojnonan-2-one, 2-(4-methylbenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione, 2- (3-methoxybenzoyl) -2-azabicyclo [4.3.Oj nonan-3, 7-dione, 2-(2,4-dimethoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione, 2-(3,4-dimethoxybenzoyl)-2-azabicyclo[4..3.Ojnonan-3,7-dione, 2-(3,5-dimethoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione and 2-(3,4,5-trimethoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3,7-dione.

The bicyclolactam compound of the present invention wherein R is -OR' can be prepared, for example, by the following reaction process Q (CH2)° \ Q (CNZ)n O
(CHZ)( ~0 ---~. (CH2)I
(CHZ)rn (CH2)m ~0 Compound A Compound B
OCOPh-p-NOZ
O)-\ Q (CI-12)n O \ Q (CHZ)n O
~ a iii (CHI b ---~- (CN2)1 (CH2)m 0 (CH2)m O
Compound traps-C Compound D
R'- X
Compound E
OH Q (CH~n O R3- x 0 \ Q {CH2)n O
iv ~ a v -----~. (CH2)l b '-~ (CHZ)l (CIf~rn O (CH~m O
Compound cis-C Compound F
s OR Q (CHZ)n vi (CH~t ~O
(CH~m Compound G

OR3 Q ((~~n O ORS Q (CH n ~'HH
C o m p o a n d G v~~ a -~ (C ~I ~ t (~ i NH
(CH~m (CH~m 0 Compound Ha ~ Compound Hb vii-b R2 - X
Compound 5 O \ Q (CH~n O
/ Q
(CH~)I ~ ORS z (CHZ)t\ h / R
(CH~m N~ Rz %
+ (CHI
Compound 4a l.l, (C ~)m C) Compound 4b viii viii O
OH Q (C!-(fin (CH~1 (CH~mN~Rz OH Q (CH~n ~Rz 'N
Compound 1' a (CHI
H
(C ~m 0 Compound 1' b ix ix R''O~ Q (CH>)~ O
(~~l N (Z
(CH~m ~ R, s R~b~ <CHy / R s y Compound 1" a (~>)!
(CH~m O
Compound 1" b wherein Q, R', R', l, m and n are as defined above, R'' is acyl group, R' is a hydrogen atom, lower alkyl group, lower alkoxyl group, halogen atom or trifluoromethyl group, X is a halogen atom.
In the above, acyl group represented by R'' includes same acyl groups as above, lower alkyl group, lower alkoxyl group and halogen atom represented by R' includes same ones as above, and halogen atom shown by X includes same ones as above.
(Step i ) A known compound A obtained by the method disclosed in J. Org. Chem., 42, 3764-y 3767 (1977), J. Chem.
Soc., Chem. Commun., 24, 2759 60 (1994) or Chem. Lett., _9, 1437 40 (1985) is reacted with ethylene glycol in a suitable solvent in the presence of an acid catalyst to obtain a compound B. The solvent to be used is not particularly limited insofar as it does not participate in the reaction; it is, for example, an aromatic hydrocarbon such as benzene, toluene or xylene. Examples of useful acid catalysts are sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and the like. The reaction is conducted using ethylene glycol and the acid catalyst each in an amount of about 1 to about 2 moles per mole of the compound A. The reaction temperature is 80 °C to a temperature around the boiling point of the solvent. For the completion of the reaction, the reaction time is 1 to 8 hours, preferable about 4 to about 7 hours. The.compound B obtained by the invention can be,used for the subseQuent reaction, as isolated or without being isolated.
(Step ii) Next, the compound B is reacted with a 219 7 ~ 78 reducing agent in a suitable solvent to obtain a compound traps-C Which has a hydroxyl group in the traps-position to hydrogen atom attached to a bridgehead atom a. The solvent to be used is not limited specifically insofar as it does not participate in the reaction. Examples of such solvents are methanol, ethanol, propanol, isopropanol and like alcohols, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers.
Examples of useful reducing agents are lithium aluminum hydride, diisobutyl aluminum hydride, diborane, sodium boron hydride and the like. The reaction is conducted using the reducing agent in about 1 to about 1.5 moles per mole of the compound B. The reaction temperature is -5 °C to room temperature, preferably about 0 to about 10 'C . The reaction time is preferably about 1 to about 3 hour-s_ The compound traps-C resulting from the reaction can be used for the subsequent reaction (Step m ) or (Step v ) , as isolated or without being isolated.
(Step in ) The compound traps-C is reacted with p-nitrobenzoic acid, triphenylphosphine and diethyl azodicarboxylate in a suitable solvent to obtain a compound D.
The solvent to be used is not limited specifically insofar as it does not participate in the reaction. Examples of such solvents are dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers, chloroform, dichloromethane, dichloroethane and like hydrocarbon halides. The reaction is conducted using the latter three reactants each in about 1. to about 3 moles per mole of the compound traps-C. The reaction temperature is -5 to 50 'C , preferably about 0 'C to around room temperature.
X

The reaction times is 1 to 15 hours, preferably about 6 to about 12 hours. The compound D resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(Step iv ) The compound D is hydrolyzed in a suitable solvent with use of an anion exchange resin to obtain a compound cis-C which has a hydroxyl group in the cis-position to hydrogen atom attached to a bridgehead atom a. The solvent to be used is not limited specifically insofar as it will not participate in the reaction. Examples of such solvents are methanol, ethanol, propanol, isopropanol and like alcohols.
The reaction is conducted using the anion exchange resin in about 1 to about 10 moles per mole of the compound D. The reaction temperature is room temperature to 100 'C , and the reaction time is about 10 to about 24 hours. The compound cis-C resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(Step v ) The compound C obtained in (Step ii ) or (Step iv) is reacted with a known compound E in a suitable solvent in the presence of a base to obtain'a compopund F. The solvent to be used is not limited specifically insofar as it does not participate in the reaction. Examples of such solvents- are N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and like aprotic polar solvents, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers. Examples of useful bases are trimethylamine, triethylamine, pyridine and like tertiary amines, potassium carbonate, sodium carbcsnate and like alkali metal~carbonate, and potassium hydride, sodium hydride and like alkali metal hydrides. For the reaction, the base and compound E are used each in about 1 to about 2 moles per mole of the compound C. The reaction temperature is room temperature to 100 °~ , preferably room temperature to about 70 °C . The reaction time is 8 to 30 hours, preferably about 20 to about 28 hours. The compound F resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(Step vi) The compound F is subjected to a ketal removing reaction in a suitable solvent with use of an acid to obtain a compound G. The solvent is not limited specifically insofar as it does not participate in the reaction. Examples of solvents are alcohols such as methanol, ethanol, propanol and isopropanol, and ethers such as dioxane, 1~2-dimethoxyethane and tetrahydrofuran. Examples of useful acids are acetic acid, trifluoroacetic acid, oxalic acid and like organic acids, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and like inorganic acids. The reaction temperature is 0 to 60 'C , preferably about 10 to about 70 °C .
The reaction time is about 2 to about 8 hours. The compound G
resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(Step va - a) The compound G is reacted with hydroxylamine and sodium acetate in a suitable solvent to obtain an oxime of the compound G. The solvent is not limited specifically insofar as it does not participarte in the reaction. Examples of useful solvents are methanol, ethanol, propanol, isopropanol and like alcohols, dioxane, 1,2-219 1?8 dimethoxyethane, tetrahydrofuran and like ethers.
Hydroxylamine and sodium acetate are used each in about 1.5 to 2 moles per mole of the compound G. The reaction temperature is 0 to 50 ~ , preferably room temperature. The reaction time is preferably 5 to 8 hours.
Subsequently, the resulting oxime of the compound G
is reacted with p-toluenesulfonyl chloride in a suitable solvent in the presence of a base to obtain a p-tosylic acid ester of the compound G. Silica gel is added to the ester in the same solvent, followed by a Beckmann rearrangement reaction to obtain a mixture of compound Ha and compound Hb.
The solvent to be used is not limited specifically insofar as it does not participate in the reaction. Examples of such solvents are benzene, toluene, xylene and like aromatic hydrocarbons, chloroform, dichloromethane, dichloroethane and like hydrocarbon halides. Examples of useful bases are trimethylamine, triethylamine, pyridine and like tertiary amines. For the reaction, the base and p-toluenesulfonic chloride are used each in 2 to 3 moles per mole of the oxime of~the compound G. The reaction temperature for tosylation is about 0 to 10 'C , and the reaction time is about 4 to about 8 hours. The 8eckmann rearrangement reaction in silica gel is conducted at a temperature of about 10 to about 30 'C for about 12 to about 24 hours.
(Step ~a -b) The resulting mixture of compound Ha and compound Hb is reacted With a compound 5 in a suitable solvent in the presence of a base to obtain a compound 4a and compound 4b. The solvent is not limited specifically insofar as it does X

X19? 178 not participate in the reaction. Examples of useful solvents are benzene, toluene, xylene and like aromatic hydrocarbons, chloroform, dichloromethane, dichloroethane and like hydrocarbon halides. Examples of useful bases are tertiary amines such as trimethylamine, triethylamine and pyridine. For the reaction, compound 5 and the base are used each in about 1 to about 2 moles per mole of the mixture. The reaction temperature is about 0 to about 50 'C , preferably about 10 9C
to about 35 °C . The reaction time is 12 to 36 hours, preferably about 24 to about 36 hours. The mixture of compound 4a or compound 4b resulting from the reaction can be isolated and purified by a usual method such as chromatography and the like. The compound 4a or compound 4b resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(Step " ) The compound 4a or compound 4b is hydrogenated in a suitable solvent in the presence of a catalyst to obtain a compound 1'a or 1'b. The solvent is not limited specifically insofar as it does not participate in the reaction. Examples of useful solvents are methanol, ethanol, propanol, isopropanol and like alcohols, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers, and methyl acetate, ethyl acetate and like acetic acid esters. As a catalyst is used for example palladium-charcoal and platinum.
For the reaction, the catalyst is used preferably in the ratio of 0.5 to 1 by weight based on the compound 4a or 4b. The reaction temperature is preferably around room temperature to about 50 'C . The reaction time is about 10 to about 20 hours.

(Step ix) The compound 1'a or compound 1'b is acylated in a suitable solvent by the method disclosed for example in JP-A-106,593/1986 to obtain a compound 1"a or 1 " b. The solvent is not limited specifically insofar as it does not participate in the reaction. Examples of useful solvents are dichloromethane, dichloroethane, chloroform and like hydrocarbon halides, dioxane, tetrahydrofuran and like ethers, benzene, toluene and like aromatic hydrocarbons.
Usual acylation method is employed, and for example acid anhydride method and acid chloride method are applicable.
In acid anhydride method, the compound 1'a or compound 1'b is reacted with acid anhydride in a suitable solvent in the pr-~sence or absence of dimethylaminopyridine.
As acid anhydride is used those having acyl group which should be introduced to R''. Examples thereof are acetic anhydride, propionic anhydride, butyric anhydride and benzoic anhydrude.
For the reaction, acid anhydride is used in about 1 to about 3 moles and dimethylaminopyridine is used in 0 to about 3 moles each per mole of the compound 1'a or compound 1'b. The reaction temperature is about 5 to about 50 °C , preferably .about 10 'C to around room temperature. The reaction time is 4 to 24 hours, preferably about 6 to about 12 hours.
In acid chloride method, the compound 1'a or compound 1'b is reacted with acyl halide (R''X) in a suitable solvent in the presence a dehydrohalogenation agent. Examples of dehydrohalogenation agents are sodium hydrogen carbonate, sodium carbonate, potassium carbonate, pyridine and triethylamine. The solvent includes those mentioned above. For x the reaction, acyl halide is used in about 1 to about 3 moles per mole of the compound 1'a or compound 1'b. The reaction temperature is about -30 to about 100 ~ , preferably around room temperature to 80 °C . The reaction time is 1 to 20 hours, preferably about 6 to about 12 hours.
Further, the bicyclolactam compound of the present invention wherein R is oxo group can be prepared, for example, by the following reaction process.
( C H 2 + R 2 - X ---.-j ( C H ;

C ompound 6 C ompound 5 C ompound 1 ' ' ' wherein Q, RZ, 1 and X are as defined above.
According to the above reaction step (vn -b), the compound 6 is reacted with the compound 5 in a suitable solvent in the presence of a base to obtain a compound 1" '.
The solvent.is not limited specifically insofar as it does not participate in the reaction. Examples of such solvents are benzene, toluene, xylene and like aromatic hydrocarbons, dichloromethane, dichloroethane and like.hydrocarbon halides.
Examples of useful bases are potassium carbonate, sodium carbonate and like inorganic base's, sodium methoxide, sodium ethoxide and like sodium alkoxides, trimethylamine, triethylamine, pyridine and like tertiary amines. For the reaction, the compound 5 and the base are used each in 1 to 2 moles per mole of the compound 6. The reaction temperature is 219" 178 about 0 to 50 °C , preferably 10 to 35 °C , and the reaction time is 1 to 24 hours, preferably about 6 to about 12 hours.
The compound 6 can be prepared by the following A, B
or C process.

5 A process:
A

~o H H H
Compound I Compound 6 a The compound I is obtained by cyclizing 2-cyanoethyl-1,3-cyclohexanedione according to the method di-sclosed in J.. Org. Chem., 57, 2521 (1992). The compound I is 15 reduced in a suitable solvent with hpdrogen in the presence of palladium-charcoal to obtain the compound 6a wherein two hydrogen atoms on both of the bridgehead carbons have cis configuration. The solvent is not limited specifically insofar as it does not participate in the reaction. Examples of useful 20 solvents are methanol, ethanol, isopropanol and like alcohols, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers.
For the reaction, palladium-charcoal is used in~the ratio of 0.1 to 1.2 by weight based on the compound I. The. hydrogen pressure is about 1 to 3 atom. The reaction temperature is 0 25 to 50 'C , preferably 10 1C to around room temperature. The reaction time is preferably about 6 to about l2 hours. The resulting compound 6a can be used for the subsequent reaction for obtaining the present compound 1" ', as isolated or ~19717g without being isolated.
B process:
0 '~C O ZMe O C O ZMe 0 C 0 ZMe ~ 1 C ompound J C ompound K C ompound L
O Q H
-~ ---H HH
Compound M Compound 6 b (Step B-i ) A known compound J disclosed for example in Synthesis-, 176 (1991) is reacted in a suitable solvent with methyl ester of acetylenecarboxylic acid to obtain a compound K. The solvent is not limited specifically insofar as it does not participate in the reaction. Examples of useful solvents are N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and like aprotic polar solvents, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers. Methyl ester of acetylenecarboxylic acid is used~in an excess amount, preferably about 4 to 7 moles per mole of the compound J. The reaction temperature is preferably about 120 to 150 °~ , and the reaction time is preferably about 6 to about 18 hours. The resulting compound K can be used for the subsequent reaction, as isolated or without being isolated.
(Step B-ii) The resulting compound K is reduced in a suitable solvent with hydrogen in the presence of palladium-charcoal to 219 7 1~7g obtain the compound L. The solvent is not limited specifically insofar as it does not participate in the reaction. Examples of useful solvents are methanol, ethanol, isopropanol and like alcohols, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers. For the reaction, palladium-charcoal is used in the ratio of 0.1 to 0.5 by weight based on the compound K. The hydrogen pressure is about 1 to 5 atom. The reaction temperature is 10 to 50 'C , preferably 15 to 30 °C . The reaction time is preferably about 2 to about 5 hours. The resulting compound L can be used for the subsequent reaction, as isolated or without being isolated.
(Step B-m ) The resulting compound L is heated without solvent to obtain a compound M. The heating is conducted at a temperature of ,about 170 to about 190 °~ and for abort 1 to about 3 hours.
Consequently, the compound.M is reduced according to the method mentioned in the above A process to obtain a compound 6b. The resulting compound 6b can be used for the subsequent reaction for obtaining the present compound 1 " ', as isolated or without being isolated.

2197 ~7g C process:
O Q O

~C02CH3 ---~ ~ ~CONH2 C ompound N C ompound O

ii \\
--- j i <'~0 H H H
Compound P Compound 6 c (Step C-i ) To a known compound N discolsed for example in J.
Org. Chem., 31, 1489 (1966) is added an excess amount of 25 -aqueous ammonia solution or methanol-ammonia for reaction, ~5 thereby a compound 0 is obtained. The reaction temperature is preferably about 15 to about 30 °IC . The reaction time is preferably about 3 to about 10 hours.
(Step C-a ) The resulting compound 0 is ring-colsed with dehydration according to the method disclosed for example in 20 J. Org. Chem., 35, 3499 (1970) to obtain a compound P. The reaction temperature is about 70 to about 120 'C , preferably around a boiling temperature of solvent. The reaction time is preferably about 2 to about 6 hours.
Consequently, the compound P is reduced according to the method mentioned in the above A process to obtain a compound 6c. The resulting compound 6c can be used for the subsequent reaction for obtaining the present compound 1 " ', as isolated or without being isolated.
x The compound of the formula (1) thus obtained can be isolated and purified by a usual method such as recrystallization or column chromatography. The racemic compound obtained can be divided into the desired optical isomers, for example, by fractional recrystallization for the separation of salts from optically active acids or by passing a column packed with an optically active carrier. The stereoisomers can be individually separated off and purified by a usual method such as fractional crystallization or chromatography.
The present bicyclolactam compound is added to a pharmaceutical carrier to afford a pharmaceutical composition, particularly an anxiolytic agent.
The.anxiolytic agent having incorporated the present compound therein as an effective component can be given orally or parenterally to mammals including man. The pharmaceutical preparations of the present invention are not limited specifically in the unit form of administration but can be in various forms in conformity with preventive or therapeutic purposes. These forms of preparations include, for example, oral preparations, injections, suppositories, external preparations (such as poultices and like plasters, ointments, creams and lotions),. eye drops, nasal drops or sprays, etc.
The anxiolytic agent having incorporated the present compound therein as an effective component is prepared and used in the form of a composition having a desired conventional pharmaceutical carrier or excipient incorporated therein by a usual method.

Stated more specifically, examples of carriers for use in formulating the agent as tablets, encapsulated preparations, granules, powders, etc. for oral administration are excipients such as lactose, sucrose, sodium chloride, S glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, propanol, syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, shellac, methyl cellulose, ethyl 10 cellulose, potassium phosphate and polyvinylpyrrolidone, disintegrators such as dried starch, sodium alginate, agar powder, laminaria powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sarbitan fatty acid esters, sodium laurylsulfate, stearic acid monoglyceride, starch and lactose, 15 disintegration suppressants such as sucrose, stearic acid, cacao butter and hydrogenated oils, absorption promotors such as quaternary ammonium bases and sodium laurylsulfate, humectants such as glycerin and starch, absorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, 20 glazing agents such as purified talc, stearic acid salts, boric acid powder and polyethylene glycol, corrigents such as sucrose, bitter orange peel, citric acid and tartaric acid, etc. When required, the tablets can be those having a usual coating, such as sugar-coated tablets, gelatin-coated tablets, 25 enteric-coated tablets, film-coated tablets, double-layer tablets and multi-layer tablets. The encapsulated preparation is made by mixing the present compound with carriers such as those exemplified above and filling the mixture into hard A

gelatin capsules or soft capsules.
Liquid preparations for oral administration include aqueous or oily suspensions, solutions, syrups and elixirs, and are prepared in the usual manner by adding a corrigent, buffer, stabilizer, flavoring agent, to the present compound.
In this case, examples of useful corrigents are those exemplified above, useful buffers include sodium citrate, and useful stabilizers include tragacanth, gum arabic and gelatin, etc.
Injections are aqueous or oily suspensions and solutions, or powdery fillers and freeze-dried preparations which are dissolved when to be used. Injections are prepared in the usual manner by adding to the present compound a pH
adjusting- agent, buffer, stabilizer, isotonic agent, di:luent, local anesthetic, etc. Examples of pH adjusting agent. and buffers for use in this case are sodium citrate, sodium acetate, sodium phosphate and the like. Examples of useful stabilizers are sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc. Examples of useful diluents are water, aqueous solution of lactic acid, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, etc.
Examples of useful stabilizers are sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc. Examples of useful local anesthetics are procaine hydrochloride, lidocaine hydrochloride, etc.
In preparing suppositories, use can be made of carriers such as polyethylene glycol, lanolin, cacao fat, 2197 ~ 7g esters of higher alcohols, gelatin, semisynthetic glyceride, etc., and.when required, surfactants such as Tween (trademark) .
Ointments (pastes, creams, gels, etc.) are prepared by admixing with the present compound a base, stabilizer, lubricant, preservative, etc. which are usually used. Examples of bases are fluid paraffin, white petrolatam, bleached beeswax, octyldodecyl alcohol, paraffin and the like. Examples of useful preservatives are methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and the like.
Plasters are prepared by applying the ointment, cream, gel, .paste or the like to a usual support in the conventional manner. Examples of suitabie supports are woven or nonwoven fabrics of cot..ton, staple fiber or chemical fiber, films of flexible polyvinyl chloride, polyethylene, polyurethane or the like, and foamed sheets of such material.
When required, the foregoing preparations may have further incorporated therein a coloring agent, preservative, perfume, flavoring, sweetener and the like, and other medicinals.
The method of administering the pharmaceutical preparation of the invention is not limited specifically but determined according to the form of preparation, age, sex and other conditions of the patient and degree of symptom of the patient. For example, tablets, pellets, powders, solutions, suspensions, emulsions, granules and capsules are given orally. Suppositories are introduced into the rectum.
Injections are intravenously given singly or as mixed with a usual auxiliary solution such as glucose or amino acid solution. Further when required, they are singly administered intra-arterially, intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Ointments are applied to the skin, mucous membrane of the oral cavity, etc. Plasters are applied to the skin.
The dosage of the effective component of the preparation of the invention can be suitably determined according to the mode of administration, age, sex and other conditions of the patient and degree, of the symptom. Generally the effective component is administered at a daily dose usually of 0.001 to 50 mg/kg body weight, preferably 0.01 to 10 mg/~k~ body weight. The present preparation can be given once or in about 2 to about~four divided d~ses per day.
BEST MODE OF CARRYING OUT THE >iN'VENTION
The present invention will be described below with reference to reference examples and examples. However, the invention is not limited by these examples.
Reference Example 1 Preparation of 6-oxo-bicyclo[3.3.0]octan-2-one=ethylene=acetal (Compound B-1) A 9.62 g quantity of bicyclo[3.3.OJoctan-2,6-dione which is known as disclosed for example in J. Org. Chem., _42, 3764 3767 (1977), 0.265 g of p-t.oluenesulfonic acid monohydrate and 4.54 g of ethylene glycol were dissolved fn 50 ml of benzene, and the mixture was refluxed for reaction for 6 hours while removing water as an azeotropic mixture. After the reaction, the mixture was cooled to room temperature and xJ;

219 7 w78 allowed to stand for 15 minutes with addition of 3 g of sodium hydrogencarbonate. The resulting precipitate was.filtered off and washed with benzene. The filtrate was concentrated to obtain a brown oily product, which was purified by column chromatography using 180 g of silica gel and hexane-ethyl acetate (5:1) to obtain 9.28 g of Compound mentioned above in the form of a colorless oily substance (yield: 73 ~ ).
' H-NMR (CDCls ) a ppm . 1 . 80~- 2. 45 (m, 10H) , 3. 95 (s, 4H) Reference Example 2 Preparation of (1RS, 2SR, 5RS)-2-hydroxybicyclo-[3.3.Ojoctan-6-one=ethylene=acetal (Compound trans-C-1) A 9.23 g quantity of Compound obtained in Reference Example 1 was dissolved in 70 ml of methanol; and 1.93 g of sodium boron hydride was added to the solution while cooling the solution in an ice-_methanol bath. The m~.xuture was returned to room temperature 30 minutes later,. followed by further reaction for 1 hour. The methanol was thereafter distilled off, 70 ml of water was added to the residue, and the mixture was subjected to extraction with 100 ml of dichloromethane and 50 ml of dichloromethane twice. The dichloromethane layer obtained was washed with 50 ml of saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate and distilled for the removal of solvent, giving a colorless oily product. The product was purified by column chromatography using 150 g of silica gel and hexane-ethyl acetate (4:1 to 2:1) to obtain 6.63 g of Compound mentioned above in the form of a colorless oily substance (yield: 71 ~.

' H-NMR (CDCls ) a ppm . 1 . 75~- 2. 00 (m, 8H) , 2. 10~ 2. 80 (m, 2H) , 3. 90~ 4. 18 (m, 1H) , 3.94 (s, 4Hj Reference Example 3 Preparation of (1RS, 2RS, SRS)-2-(4-nitrobenzoyl-5 oxy)bicyclo-[3.3.0)octan-6-one=ethylene=acetal (Compound D-1) A 3.68 g quantity of 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 solution of 7.00 g of diethyl azodicarboxylate in 10 ml 10 of tetrahydrofuran was added dropwise to the solution with ice cooling over a period of 10 minutes. The mixture was stirred with ice cooling for 1 hour, then returned to room temperature and further reacted for 16 hours. The solvent was distilled off from the reaction mixtur-e, 50 ml of ether and 30 ml of 15 hexane were added to the residue, and the resulting mixture was aTIowed to stand in a refrigerator for. 1 day. The resulting precipitate (triphenylphosphine oxide) was filtered off and washed with hexane-ether (2:1). The filtrate obtained was concentrated to obtain a yellow oily product. The product 20 was purified by column chromatography using 90 g of silica gel, hexane and hexane-ethyl acetate (10:1), giving 5.34 g of Compound mentioned above in the form of a light yellow oily substance (yield: 80 94 ) .
' H-NMR (CDCls ) d ppm . 1 . 60~ 2 . 20 (m, 8H) , 2. 45~ 2 . 90 (m, 2H) , 25 3.94 (s, 4H) , 5. 10~ 5.23 (m, 1H) , 8.24 (s, 4H) Reference Example 4 Preparation of (1RS, 2RS, 5RS)-2-hydroxybicyclo-[3.3.0)octan-6-one=ethylene=acetal (Compound cis-C-1) of 70 °C for 4 hours. The mixture was returned to room temperature, and 80 ml of ice water was added thereto. The resulting mixture was subjected to extraction with 60 ml of ether three times. The ethereal layer was washed with 20 ml of water three times and with 20 ml of saturated aqueous solution of sodium chloride and thereafter dried over anhydrous sodium sulfate. Removal of the solvent from the layer gave an oily product, which was then purified by column chromatography using 75 g of silica gel and hexane and hexane-ether (15:1), whereby 6.65 g of Compound mentioned above was obtained as an oily substance (yield: 70 j ).
' H-NMR (CDC1~ ) a ppm . 1 . 60~- 2 . 10 (m, 8H) , 2 . 40~ 2 . 80 (m, 2H) , 3.. 50~- 3.80 (m, 1H) , 3.90 (s, 4H) , 4.92 (s,, 2H) , 7.31 (s, 5H) Reference Example 6 15_ Preparation of (1RS, 2RS, 5RS)-2-benzyloxybicyclo-[3.3.0}-octan-6-one (Compound G-1) A 1.94 g quantity of Compound obtained in Reference Example 5 was dissolved in 10 ml of tetrahydrofuran, and the solution was stirred for 6 hours with 3 ml of 2N hydrochloric acid added thereto. The tetrahydrofuran was distilled off from the resulting reaction mixture, followed by extraction with 20 ml of ether twice. The ethereal layer was washed with 10 ml of saturated aqueous solution of sodium hydrogencarbonate twice and then with 5 ml of saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Removal of the solvent from the layer give 1.60 g of Compound mentioned above as an oily substance (yield: 98 ~ ), ' H-NMR (CDC1~ ) a ppm . 1 . 30~ Z . 40 (m, 8N) , 2 . 60~- 3 . 00 (m, 2H) , x 38 '297 X78 3. 70~ 3. 90 (m, 1H) , 4. 51 (s, 2H) , 7.33 (s, 5H) Reference Example 7 Preparation of cis-2-azabicyclo[4.4.0]decan-3,7-dione (Compound 6a) Methanol (100 ml) was added to 1.5 g of 2,3,4,5,6,7,8-heptahydro-1(1H)-quinoline-2,5-dione which was known as disclosed for example in J. Org. Chem., _57, 2522 (1992). The mixture was subjected to reduction in the hydrogen stream (1 atm.) in the presence of 0.75 g of 10 ~ palladium-carbon. The palladium-carbon was filtered off and the solvent was removed. The residue was purified for isolation by column chromatography (silica gel, developer; chloroform . ethanol=
10 . 1 ) to obtain 0. 42 g of Compound mentioned above(yield:
28 96 ) . Table i shows analytical data.
Reference Examp7.e 8 Preparation of methyl 3-(3-amino-2-cyclopenten-1-one-2-yl)-acrylate (Compound K) To 2 ml of dimethylacetamide were added 0.2 g of 3-amino-2-cyclopenten-1-one and 2 ml of methyl acetylenecarbonate. The mixture was heated with stirring at 120 to 125 'C for 19 hours. After cooled, 2 ml of ether was added and the precipitates were filtered. and washed with ether to obtain 0. 17 g of Compound mentioned above (yield: 46 $~ ) .
m. p. 278- 279 'G
Elementary analysis; C, H~ , NOs Calcd. C 59.67 H 6.12 N 7.73 Found C 59.34 H 6.47 N 8.06 Reference Example 9 3g Preparation of methyl 3-(3-amino-2-cyclopenten-1-one-2-yl) -propionate (Compound L) To 200 ml of methanol were added 6.0 g of Compound K
obtained in Reference Example 8 and 1.5 g of 10 % palladium-s charcoal. The mixture was reacted at room temperature in the hydrogen stream (2 atm.) for 3 hours. After reaction, the palladium-carbon was filtered off and the solvent was removed.
The residue was crystallized from ether to obtain 5.9 g of Compound mentioned above (yield: 98 m. p. 223-- 224 °C
Elementary analysis; Ca H, ~ NOs ~ 0. 2 HZ 0 Calcd. C 55.61 H 6.65 N 8.11 Found C 55.58 H 6.69 N 8.31 Reference Example 10 Preparation of 2,3,4,5,6,7-hexahydro-1(1H)-pyrindin-2 , 5-dione (Com.pound Nf) A 2.8 g quantity of Compound L obtained in Reference Example 9 was heated with stirring without solvent at an oil bath temperature of 190 to 210 9C for one hour. After reaction, when hot, isopropanol was added. After cooling, the precipitates were filtered to obtain 1.7 g of Compound mentioned above (yield: 74 ~ ) .
m. p. 247- 248 °C
Elementary analysis; C, H, NOZ
Calcd. C 63.56 H 6.00 N 9.27 Found C 63.25 H 6.17 N 9.30 Reference Example 11 Preparation of cis-2-azabicyclo[4.3.OJnonan-3,7-dione (Compound 6b) In 180 ml of methanol was suspended 3.8 g of Compound N obtained in Reference Example 10 and thereto was added 4 g of 10 % palladium-charcoal. The mixture was reacted S in the hydrogen stream (2 to 2.5 atm.) for 12 hours. After reaction, the palladium-charcoal was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, developer; ethyl acetate .
methanol= 10 . 1) to obtain 3.4 g.of Compound mentioned above (yield: 89 % ). Table 1 shows analytical data.
Reference Example 12 Preparation of 2-methyl-2-(2-carbamoylethyl)-1,3-cyclopentanedione (Compound 0-1) A 1 ml quantity of 25 9S .aqueous ammonia solution was added to 1.6 g of 2-methyl.-2.-(~ -carbomethoxyethyl)-cyclopentan-1,3-dione which was known and disclosed for example in J. Org. Chem., 31, 1489 (1966). The mixture was reacted at room temperature for 5 hours. After reaction, 10 ml of tetrahydrofuran (THF) was added. The insolubles were filtered and recrystallized from ethanol to obtain 0.6 g of Compound mentioned above (yield: 41 90).
m.p. 159- 162 1C
Reference Example 13 Preparation of 2,3,4,4a,5,6-hexahydro-4a-methyl-1(1H)-pyrindin-2,5-dione (Compound P-1) To 400 ml of toluene was added 4.42 g of Compound 0-1 obtained in Reference Example 12, and thereto was added 0.6 g of tosyl acid. The mixture was heated with stirring for ~19717g 3 hours with dehydration device attached. After reaction, the solvent was removed and the residue was recrystallized from ethanol-chloroform to obtain 3.0 g of Compound mentioned above (yield: 75 % ) .
m.p. 228~- 230 °C
Elementary analysis; C9 H~ , NOZ
Calcd. C 65.44 H 6.71 N 8.30 Found C 65.13 H 6.67 N~8.30 Reference Example 14 Preparation of cis-6-methyl-2-azabicyclo[4.3.Oj-nonan-3,7-dione (Compound 6c-1) Compound mentioned above was prepared in the same manner aj in Reference Example 11 except that Compound P-1 obtained,in Reference Example 13 was used in place of Compound M. Table 1 shows analytical data.

Table 1 ( C H ; ( C ompound 6 ) elem. anal.

CompdQ 1 yield m.p. formula calcd.(found) ~MS

No (3'6 ) ('C ) C H N +
.

(M
) 64.65 7.84 8.38 6a H 2 28 177- 178 C9 H~ s NO

(64.65 7.37 8.34) CB H, 1 60. 59 7. 37 8. 83 6b H 1 ? 1 140 142 NOZ ~

0. 3HZ 0 (60. 41 7. 08 8.
88) 64.65 7.84 8.38 6c-1 CH9 1 77 129- 131 C9 H~ $
NO

(64.41 7.58 8.32) Example 1 Preparation of (1RS, 6RS, 7RS)-7-benzyloxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3-one (Compound 4a-1) and (1RS, 6RS, 7RS)-7-benzyloxy-3-(4-methoxybenzoyl)-3-azabicyclo [4.3.0) nonan-2-.one (Compound 4b-1) A 1.54 g quantity of Compound obtained in Reference Example 6 was dissolved in 15 ml of tetrah.ydrofuran, followed by addition of 8 ml of water and thereafter by addition of 0.94 g of hydroxylamine hydrochloride and 1.84 g of sodium acetate trihydrate. Tetrahydrofuran was subsequently added to obtain a homogeneous mixture, which was then stirred at room temperature for 5 hours. The tetrahydrofuran was distilled off from the reaction mixture, followed by extraction with 80 ml 43 ~ ~.~
of ethyl acetate. The ethyl acetate layer was washed with 10 ml of water, with 10 ml of saturated sodium hydrogencarbonate solution and subsequently with 10 ml of saturated aqueous solution of sodium chloride, and thereafter dried over S anhydrous sodium sulfate. Distillation of the layer for the removal of the solvent gave 1.64 g of oxime of Compound of Reference Example 6 as a colorless oily substance.
A 1.60 g of the oxime obtained was dissolved in 16 ml of benzene, followed by addition of 3.11 g of p-toluenesulfonyl chloride and then by addition of 2.27 ml of triethylamine with ice cooling. The mixture was stirred for 4 hours with ice cooling and subsequently for 2 hours at room temperature, and thereafter diluted with 50 ml of ether. The resulting solution was washed with 10 ml of water, with 10 ml of 2N hydrochloric acid twice .and subsequently with 10 ml of saturated aqueous solution of sodium chloride, and thereafter dried over anhydrous sodium sulfate. Removal of the solvent from the solution gave a yellow oily product. The product was dissolved in 50 ml of anhydrous benzene, followed by addition of 43 g of silica gel (Fuji Silysia, BW-300 as washed with 2N
HC1 and then thoroughly with water, and dried at 230 ~ for 16 hours) and further by addition of anhydrous benzene in an amount of permitting stirring of the resulting mixture. The mixture was shaken on a water bath having a constant temperature of 25 °C for 18 hours. The reaction mixture was poured into a column packed with 20 g of silica gel, and 300 ml of benzene was passed through the column to cause an excess of p-toluenesulfonyl chloride to flow out. The solvent was ~'r f thereafter changed for benzene-methanol (6:1) to obtain an eluate. The eluate still contained impurities and was therefore purified by column chromatography again using 30 g of silica gel, and chloroform and chloroform-methanol (50:1).
The product was dried in a vacuum at room temperature to obtain 1.233 g of a light yellow oily substance. 'Ii-NMR
analysis revealed that the product was a mixture of (1RS, 6RS, 7RS)-7-benzyloxy-2-azabicyclo[4.3.0)nonan-3-one and (1RS, 6RS, 7RS)-7-benzyloxy-3-azabicyclo[4.3.0]nonan-2-one approximately in the ratio of 2:i.
The mixture (1.18 g) obtained was dissolved in 15 ml of dichloromethane, 1.31 g of p-methoxybenzoyl chloride and i.34 g of triethylamine were added-to the solution, and the mixture was stirred at room temps-rature for 36 hours. With addition of 80 ml of ethyl acetate, the reaction mixture was washed with 20 ml of 2N hydrochloric acid twice, with 20 ml of saturated solution of sodium hydrogencarbonate twice and then with 10 ml of saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Removal of the solvent gave a brown oily product, which was then purified by column. chromatography using 30 g of silica gel and hexane-ethyl acetate (4:1 to 3:1]. The component eluted first was Compound 4b-1 mentioned above and obtained in an amount of 0.576 g as a yellow oily substance (yield: 25 ~ ). The component eluted thereafter was Compound 4a-1 mentioned above.
The fraction was distilled for the removal of the solvent and recrystallized from ethanol,. giving 1.05 g of the compound (yield: 46 9S). Tables 2 to 3 show analytical data.

l Example 2 Compounds 4a-2 to 4a-5 and Compounds 4b-2 to 4b-4 were prepared in the same manner as in Example 1 except that various benzoic chloride derivatives were used in place of p-5 methoxybenzoic chloride. Tables 2 to 3 show analytical data.
Example 3 Preparation of (1RS, 6RS, 7RS)-7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one (Compound 1'a-1) 10 A 1.05 g quantity of (1RS, 6RS, 7RS)-7-benzyloxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.Ojnonan-3-one (Compound 4a-1) obtained in Example 1 was dissolved in 15 ml of dioxane, 0.50 g of 10 % palladium-charcoal (product of Wako Junyaku Co., Ltd.) was added to the solution, and the air in the 15 reactor was removed by an aspirator and replaced by hydrogen repeatedly twice. The mixture was thereafter stirred in the hydrogen atmosphere (1 atm.) for 16 hours. The catalyst was filtered off and washed with dioxane. The resulting filtrate was concentrated to obtain a colorless oily product, which was 20 then purified by column chromatography using 15 g of silica gel and chloroform. Removal of the solvent from the product afforded crystals, which were further recrystallized from ether, giving 0.64 g of Compound mentioned above in the form of a colorless powder (yield: 81 94j. Table 4 shows analytical 25 data.
Example 4 Compounds 1'a-2 to 1'a-5 were prepared in the same manner as in Example 3 except that Compounds 4a-Z to 4a-5 x 2197 y7s obtained in Example 2 were used as a starting material in place of Compound 4a-1. Similarly, Compounds 1'b-2 and 1'b-3 were prepared in the same manner as in Example 3 except that Compounds 4b-3 and 4b-4 obtained in Example 2 were used as a starting material in place of Compound 4b-1. Tables 4 to 5 show yield and analytical data.
Example 5 Preparation of (1RS, 6RS, 7RS)-7-acetoxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one (Compound 1~" a-1) A 0.29 g quantity of (1RS, 6RS, 7RS)-7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3-one (Compound 1'a-1) obtained in Example 3 was dissolved in 10 ml of dichloromethane. With ice cooling, thereto were added 0.225 g of dimethylaminopyridine and then 0.2 g of acetic anhydride.
The mixture was reacted at room temperature for 12 hours and then thereto was added 20 ml of dichloromethane. The reaction mixture was washed with 10 ml of 1N hydrochloric acid and then with 10 ml of saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Removal of the solvent gave a light brown oily product, which was then purified by column chromatography using 20 g of silica gel and chloroform-methanol (20: 1) to obtain 0.23 g of Compound 1 "a-1 as an oily substance (yield: 69 9~ ) .
' H-NMR (CDC1, ) 8 ppm: 1 . 60~ 2. 70 (m; 9H) , 2.08 (s, 3H) , 3.85 (s, 3H) , 4.70 (q, 1H) , 5.00 5. 10 (m, 1H) , 6.88 (d, 2H) , 7. i0 (d, 2H]

,~

Table 2 PhCHZp H
N~0 H
~0 CR 5)n Compd. (R5 ) n yield m. p. ' H-NMR (CDC1~ ) No . (~ ) (C ) ( 8 ppm) 4a-1 4-OCHS 46 108 . 5 1 . 30~ 2 . 70 (m, 10H) , 3 . 70~
4 . 00 (m, 1H) , ~- 3. 83 (s, 3H) , 4. 54 (s, 2H) , 109. 5 6. 8? (d, 2H) , 7. 34 (s, 5H) , 7 . 58 (d, 2H) .
.
.

4a-2 H 26 oil 1 . 50~ 2 . 31 (m, 6H) , 2 . 40~ 2 . 57 (m, 3H).,.

3. 89 (m, 1H) , 4. 52 (m, 2H) , _..._._..__.__.._.__.____.____._..__...__..._._...__....__...._...._.__._.._.__ ._..____.._._4_ 55_(q,.lH)__c....~_.26.".:~__.58,_(m_,._1_OH)_.:._...._....

_.
4a-3 4-F 27 of 1 1 . 10~ 2 . 25 (m, 6H) , 2 . 25~
2 . 75 (m, 3H) , 3 . 70~ 3 . 95 (m, 1H) , 4 . 55 (dd, 2H) , ._............_._................._.._...__..._.._....._..._...................
.._....__.__.4_ : ~ ~. ~ q .1 H ). ._...6 :.9 ~ ~ ~.:. ~ ~ _(m ,. 9 H ) . ,_...._......___ 4a-4 4-CHs 28 97~ 98 1 .00~- 2. 30 (m, 6H) , 2. 36 (s, 3H) , 2 . 30~ 2 . 70 (m, 3H) , 3 . 70~
4 . 00 (m, 1H) , 4 . 54 (dd, 2H) , 4. 69 (q,1H) , .......__.._..__..._....__._......_........_.__._._...____._._..__.._..._._._._ .__._._...___~. : ~ ~_".. ~ :.6 ~_ ~!~ . -9 H )...._.__._.__.___.__...__._...___.._......._.......

4a-5 2, 4- (OCHa ) = 20 oil 1 . 42~ 2 .06 (m, 5H) , 2 . 25~ 2 . 50 (m, 4H) , 3 . 73 (s, 3H) , 3 . 79 (s, 3H) , 3. 86 (m, 1H) , 4. 50 (d, 1H) , 4.53 (d, 1H)-, 4.58 (q, 1H) , 6. 50 (d, 1H) , 6. 54 (dd, 1H) , 7. 28 (m, 1H) , 7. 32 (d, 1H) , 7.
35 (m, 4H) 48 219 7 1 7g Table 3 PhCHzp ~N O

(R')m-IT
U
Compd (RS ) n yield m. p. ' H-NMR (CDCla ) No . (% ) (C ) ( d ppm) 4b-1 4-OCHs 25 oil 1 .303.30 (m, 10H) , 3.604. 10 (m, 1H) , 3.83 (s,3H) , 4.52 (s,2H) , 6. 86 (d, 2H) , _7. 33 (s, 5H) ,_ 7. _54 (d, 2H) ..
.
..
..

4b-2 4-F 14 128 1 . 20~ 2 . 30 (m, 6H) , 2 . 40~ 2 . 80 (m, 1H) , ~ 2.903.30 (m, 1H) , 3.403.65 (m, 1H) , 130 3.653.85 (m, 1H) , 3.954.25 (m, 1H) , 4 . 52 (dd, 2H) , 6 .

~ 7. 70 (m, 9H) ' _ 4b-3 4-CH$ 14 oil __ _ _ _ _____ 1 . 20~ 2 . 30 (m , 6H) , . 2.. 36'(s, 3H) , ..' 2 . 40~ 2 . 80 (m, 1H) , 2 . 90~
3 . 30 (m, 1H) , 3.403.65 (m, 1H) , 3.653.85 (m, 1H) , 3 . 95~ 4. 25 (m, 1H) , 4. 52 (dd, 2H) , ...._.._..._..........._..._..__...._........__................................
......._.~ ~ ~ ~". ~:.:_'.~. (~._ 9 H ).........._.___...___........_.___ ........_....._ 4b-4 2, 4- (OCH' j = 17 oil 1 . 44~ 2. 52 (m, 7H) , 3 .02 (m, 1H) , 3. 48 (m, 1H) , 3 . 69 (s, 3H) , 3.71 (m, 1H) , 3.79 (s,3H) .

4.07 (m, 1Hj , 4.48 (d; 1Hj , 4. 50 (d, 1H) , 6. 49 (d, 1H) , ' 6. 52 (dd, 1Hj , 7. 22 (d,1Hj , 7. 28 (m, 1Hj , 7 . 32N 7. 38 (m, 4Hj x Table 4 HO
~ N O
H
~0 (R 5)n Compd (R5 ) n yield m. p. ' H-NMR (CDC19 ) No. (% ) (C ) ( 8 ppm) 1 ' 4-OCH9 81 120 1 . 20~ 2 . 70 (m, 10H) , 3 .
a-1 84 (s , 3H) , 3. 90~ 4 . 30 (m, 1H) , 4. 20 (q, 1H) , 121 6 . 88 (d, 2H) , 7. 59 (d, 2H) 1 ' H 37 137 . 1 . 36~ 2 . 29 (m, 7H) , 2. 45 a-2 5 (t , 2H) , 3.96 (q, 1H) , 4.56 (q, 1H) , 139 4. 86 (d, 1H) , 7. 41 (m, 2H) , 7 . 48~ 7 . 56 (m, 3H) 1 ' 4-F 39 1 10 1 . 20~ 2 . 80 (m, 9H) , a-3 3. 90~ 4 . 25 (m, 1H) , 4. 73 (q, 1H) , ._.._.._...._.._........_____..._._.....___.-......._......__......__ ~
~ ~m . 4 H ) ~ 6 x :

"

:

. .............
. .
. .
..... ._ ..
.
.
...._-..._.._..._....____...__.....__...._.

1 ' 4-CHs 27 131 1 . Z0~ 2 . 70 (m, 9H) , 2 .
a-4 37 (s , 3H) , ~- 4.00 4. 25 (m, 1H) , 4. 71 (q, 1H) , .__......_..._-..___..._._.._..._..._..____.__..______________133 7 . 10~
7 . 60 (m, 4H) 1 ' a-5 2, 4- (OCH' ) = 56 1 14 1 . 28~ 2 . 27 (m, 7H) , 2. 39 (t, 3H) , ~- 3. 73 (s, 3H) , 3. 80 (s, 3H) , 1 15. 5 3.93 (m, 1H) , 4. 59 (q, 1H) , 4. 84 (d, 1H) , 6. 49 (d, 1H) , 6. 54 (dd, 1H) , 7. 31 (d, 1H) 219717s Table 5 HO H

(R 5)n Compd (R5 ) n yield m. p. ' H-NMR (CDCls ) No. (% ) (~ ) ( 8 ppm) 1 ' b-1 4-OCHg 72 108 1 . 50~ 1 . 70 (m, 2H) , 1 . 90~ 2 . 40 (m, 7H) , ~- 3.003. 15 (m, 1H) , 3.503.65 (m, 1H) , 109 3 .80 (s, 3H) , 3. 90~ 4. 10 (m, 1H) , __........_.__._.._____._..._......._______..__._._._.._......._...._.__._._...
. 6 ._ 9 ~ _~ a._~ 2 H ) , 7 . 5 5 ( d , 2 H ) 1 ' b-2 4-F 30 oil 1 . 20~ 2 . 55 (m, 7H) , 2 . 9~5~ 3 . 30 (m, 1 H) , 3 . 40~ 3 . 80 (m, 2H) , 3 . 90~ 4 . 30 (m, 2H) , 6 . 90~ 7 . 70 (m, 4H) 1 ' b-3 4-CHs 28 104 1 . 30~ 2 . 60 (m, 7H) , 2 . 37 (s , 3H) , ~- 2 . 90~ 3 . 30 (m, 1H) , 3 . 30~ 3 . 80 (m, 1H) , 106 3 . 90~ 4 . 30 (m, 2H) , 7 . 10~ 7 . 65 (m, 4H) Example 6 Preparation of cis-2-(p-toluoyl)-2-azabicyclo-[4. 3.0] nonan-3, 7-dione (Compound 1 " '-2) In 20 ml of dichloromethane were dissolved 0.3 g of Compound 6b obtained in Example 11 and 0.39 g of 4-methylbenzoyl chloride. Thereto was added dropwise 0.38 ml of triethylamine with ice cooling. The mixture was reacted at room temperature for 12 hours. The reaction mixture was washed "~ X197178 with 0.1N hydrochloric acid, with 0.1N aqueous solution of NaOH and then with water, and dried over anhydrous sodium sulfate. After dried, the solvent was removed and the residue was recrystallized to obtain 0.35 g of Compound mentioned above (yield: 66 °/a). Table 6 shows analytical data.
Example 7 Compound 1 " ' -1 , and Compounds 1 " ' -3 to 1 " ' -1 1 were prepared in the same manner as in Example 6. Table 6 shows analytical data. Analytical data of NMR of Compounds 1 " '-3 and 1 " ' -4 were shown below.
Compound 1 " ' -3 ' H-NMR (CDC13 ) 8 ppm 1 . 80--- 2. 90 {m, 9H) , 3. 75 (s, 3H) , 3 . 94~- 4. 20 (m, 1H) , 6.70-r 7.04 (m, 2H) , 7.22 7. 48 (m, 2H) ~ 5 Compound 1 " ' -4 ' H-NMR (CDC13 ) 8 ppm 1 .70~ 2.80 (m, 9H) , 3.80 (s, 3H) , 4.84- 5. 10 (m, 1H) , 6.90-~- 7.35 (m, 4H) '~ 2197~~8 Table 6 ( C H ~ ( C ompound 1 " ' ) (R 5)n Compound No. Q 1 (RS ) n yield (%
) m.p. ( C
) 1"'-1 H 2 4-OCHa 83 169 171 1 ' ' ' -2 H 1 4-CHa 66 148- 149 1 " ' -3 H 1 2-OCHa 85 oil 1 "'-4 H 1 3-OCHa 89 oil 1~~~-5 H 1 4-OCHa 49 115 117 1,_6 H 1 2,4-(OCHa)z 74 153 154 1"'-7 H 1 2,6-~OCHa)z 68 144-r 145 1 " ' -8 H 1 3, 4- (OCHa ) 56 123- 125 z 1~~~-9 H 1 3,5-(OCHa)z 81 135 136 1"'-10 H 1 3,4,5-(OCHa)e 79 150 151 1 "'-1 1 CHa 1 4-OCHa 62 111 113 Preparation Example 1 Tablet Compound 1'a-1 30 mg Microcrystalline cellulose 50 mg Hydroxypropyl cellulose 20 mg Lactose 47 mg Talc 2 mg Magnesium stearate 1 mg By the usual method, the above ingredients in the proportions given were made into tablets each weighing 150 mg.

Preparation Example 2 Granule Compound 1'a-5 10 mg Lactose 400 mg Corn starch 370 mg Hydroxypropylmethyl cellulose 20 mg The above ingredients in the proportions g iven were made into a granular preparation by the usual method in an amount of 800 mg per wrapper.

Preparation Example 3 Capsule Compound 1'b-1 55 mg Lactose 50 mg Corn starch 50 mg Microcrystalline cellulose 94 mg Magnesium stearate 1 mg By the usual method, the above ingredients in the proportions given were made into a granular preparation in an amount of 250 mg in each capsule.

Preparation Example 4 Injection Compound 1" '-8 10 mg Sodium chloride 3.5 mg Distilled water for injections, suitable amount The above ingredients in the proportions gi ven were made into an injection by the usual method.

Preparation Example 5 Syrup Compound 1" '-9 50 mg Purified sucrose 60 g "' 2197~~s Ethyl para-hydroxybenzoate Smg Butyl para-hydroxybenzoate 5mg Perfume suitable amount Coloring agent suitable amount Purified water suitable amount The above ingredients in the proportions given were made into a syrup by the usual method.
Preparation Example 6 Suppositories Compound 1" '-10 50 mg Witepsol W-35 1400 mg (Trademark, a mixture of mono-, di- and triglyceride of saturated fatty acids from lauric acid to stearic acid, Dynamite Nobel Co., Ltd.) By the usual method, the above ingredients in the proportions given were made into suppositories.
Test examples are shown below in which 2-azabicyclo[3.4.0]nonane-2-one disclosed in International Public Disclosure No. WO 91/11434 was used as a comparison compound.
Test Example 1 Anticonflict Test 1. Expermental animals Wistar rats (males weighing 140 to 160 g) were used for experiment in groups of 11 to 14.
2. Test agents and administration method Compound 1'a-1, 1'a-5, i'b-1, 1"'-8, 1"'-9, the above comparison compound, diazepam or buspirone was suspended in a 0.5 9~ sodium carboxymethyl cellulose solution, and the X

suspension was orally given to the animal in a volume of 5 ml/kg one hour before the start of experiment.
3. Experimental method and result With reference to a method described in "Process in 5 Anxiolytics and Antidepressants," edited by Showa Ueki and Tatsuo Furukawa, Ishiyaku Shuppansha, 56~ 59 (1981), the agents were tested using experimental boxes having a grid floor and a metal drinking tube in the floor. No water was supplied to the rats for 48 hours before the experiment. Upon 10 lapse of first 24 hours, each group of rats were placed into the experimental box, permitted access to water for 30 seconds and caused to recognize the metal drinking tube. Upon lapse of further 24 hours with access to water prevented, the rats were placed into the box again and permitted access to water on 15 condition that an electric current was passed between the metal drinking tube and the grid to give an electroshock for every 20 times of water drinking behavior to measure the frequency of water drinking behavior for 3 minutes. Anxiolytic effect was evaluated as relieving rate of anxiety as 20 calculated by the following equation.
Relieving rate of anxiety = (C-B) / (A-B) x 100 A: Frequency of water drinking behavior of a control group without an electroshock and no anxiety (frequency under no punishment) 25 B: Frequency of water drinking behavior of a group with an electroshock and anxiety (under punishment) and having been administerd a solvent containing no test compound (frequency under solvent-control group) C: Frequency of water drinking behavior of a group having been administered a test compound and relieved anxiety (frequency under test compound-administered group) Table 7 Anticonflict Test Test compound Dose Relieving rate of (mg/kg) anxiety (% ) Compound 1'a-1 0.01 g3 0. 1 86 1.0 76 Compound 1'a-5 0.01 g9 Compound 1'b-1 0.01 gp Compound 1"'-8 0.01 g6 Compound 1" '-9 0.01 g6 Comparison 0.01 43 Compound 0.1 44 1.0 46 Diazepam 1.0 -3 Buspirone 1.0 From the above, the present compound decreased anxiety almost nearly 100 $S at low doses of 0.01 to 0.1 mg/kg. Contrary, the comparison compound decreased anxiety up to 50 ~ at the same dose. Diazepam and buspirone were found almost ineffective even at a dose of 1.0 mg/kg. Accordingly, the present compound exhibits extremely excellent anxiolytic effect.
Test Example 2 X

2197 ~7g Muscle Relaxant Effect (Traction Method) 1. Experimental animals and administration method Compound 1'a-1, the comparison compound, diazepam or buspirone was suspended in a 0.5 ~ sodium carboxymethyl cellulose solution, and the suspension was orally administered to 3- to 4-week-old male ddY mice (in groups of 5) in a volume of 10 ml/kg one hour before the start of experiment.
2. Experimental method and result With reference to a method described in Japan. J.
Pharmacol., 49. 337-349(1989), the foreleg of the mouse was hung on a horizontal wire, having a diameter of 1.2 mm and fixed at a level of 30 cm, three times consecutively. If the hind leg did not touch the wire within 10 seconds each time, the result was interpreted as positive. Thus, EDbo was determined for evaluation. Consequently, Compound 1'a-:1 and the comparison compound exhibited no muscle relaxant effect even when given at a dose of 300 mg/kg. Diazepam and buspirone were 2.2 mg/kg and 427.8 mg/kg, respectively, in EDbe-Test Example 3 Sedative Effect (Spontaneous locomotor activity) 1. Experimental animals and administration method Compound 1'a-1, the comparison compound, diazepam'or buspirone was suspended in a 0.5 96 sodium carboxymethyl cellulose solution, and the suspension was orally administered to 3- to 4-week-old male ddY mice (in groups of 5) in a volume of 10 ml/kg one hour before the start of experiment.
2. Experimental method and result The test was conducted with reference to a method i ...~

~19717g described in "Evaluation of Medicinal Efficacies (1), Pharmacological Test Method (I ), Basic Lectures on Development of Pharmaceuticals," 50~-54(1971). More specifically, the group of mice were given the test drug and thereafter measured the amount of spontaneous locomotor activity for 10 minutes per mouse using Animex MK-110TM
(Muromachi Kikai Co., Ltd.). When the amount of activity was up to 50 % of the control group, the result was interpreted as positive to determine EDso for evaluation. Consequently, Compound 1'a-1 and the comparison compound exhibited no sedative effect even at a dose of 300 mg/kg. Diazepam and buspirone were 1.7 mg/kg and 149.7 mg/kg, respectively, in the above value.
Test Example 4 Effect on central nervous system depressant (Ethanol enhancing method) 1. Experimental method and administration method Compound 1'a-1, the comparison compound, diazepam or buspirone was suspended in a 0.5 % sodium carboxymethyl cellulose solution, and the suspension was orally administered to 3- to 4-week-old male ddY mice (in groups of 6) in a volume of 10 ml/kg one hour before the start of experiment.
2. Experimental method and result The test was conducted with reference to a method described in Japan. J. Pharmacol., 49, 337-r 349(1989). More specifically, the group of mice were intraperitoneally given 25 % ethanol at a dose of 20 ml/kg and checked for the time interval between loss and recovery of the righting reflex.

When the time measurement was in excess of twice the measurement of the control group, the result was interpreted as positive to determine EDSO for evaluation. Consequently, Compound 1'a-1 and the comparison compound produced no ethanol enhancing effect even at a dose of 300 mg/kg. Diazepam and buspirone were 0.48 mg/kg and 120.1 mg/kg, respectively, in the value.
Test Example 5 Anticonvulsant Effect (Pentylenetetrazol-induced Convulsion Method) 1. Experimental method and administration method Compound 1'a-1, the comparison compound, diazepam or buspirone was suspended in a 0.5 % sodium carboxyme~hyl cellulose solution, aad the suspension was orally administered to 3- to 4-week-old male ddY mice (in groups of 6) 1n a volume of 10 ml/kg one hour before the start of experiment.
2. Experimental method and result The test was conducted with reference to a method described in "Evaluation of Medicinal Efficacies (1), Pharmacological Test Method (I ), Basic Lectures on Development of Pharmaceuticals," 1b7-r 172 (1971) .
More specifically, pentylenetetrazol was subcutaneously administered to the mouse at a dose of 150 mg/kg, and when the mouse did not die due to onset of convulsion within 60 minutes, the result was interpreted as positive to determine ED6o for evaluation. Consequently, Compound 1'a-1 and the comparison compound exhibited no anticonvulsant effect even at a dose of 300 mg/kg. Diazepam and buspirone were 0.35 mg/kg x.

and at least 300 mg/kg, respectively, in the value.
Test Example 6 Acute Toxicity Test Five-week-old male ddY mice were used in groups of 6. The mice were orally given the test compound as suspended in a 0.5 % sodium carboxymethyl cellulose solution and thereafter observed for 3 days to measure the number of deaths at each of doses. Table 8 shows the result.
Table 8 Acute Toxicity Test Test compound Dose Number of Number of (mg/kg) animal death Compound 1'a-1 2000 6 0 Compound 1'a-1 3000 6 2 Comprn. compnd 2000 6 1 Comprn. compnd 3000 6 5 From the above, although 5 mice died among 6 mice at a dose of 3000 mg/kg in the comparison compound, only two mice ' died among 6 mice in the present compound. Accordingly, the present compound is low in toxicity and high in safety compared with the comparison compound.
INDUSTRIAL APPLICABILITY
The bicyclolactam derivative represented by the formula (i) has an excellent anxiolytic effect, is reduced in side effects such as sedative and muscle relaxant effects and is low in toxicity. Accordingly, the agent comprising the xJ
J

present compound as an effective component is useful for treating or preventing chronic or acute anxiety disorders (or anxiety and fear neuroses), such as panic disorder accompanied or not accompanied by agoraphobia, social phobia or simple phobia, obsessive-compulsive disorder (neurosis), stress disorder resulting from injury and systemic anxiety disorder, and other anxiety disorders, and also for relieving healthy persons and the aged of anxiety.
Additionally, the present invention is useful for treating or preventing the anxiety attendant on withdrawal symptoms due to drug dependance and/or drug addiction. Thus, the present invention is useful for allaying withdrawal symptoms due to alcohol dependence, nicotine dependence, cocaine dependence and benzodiazepine dependence and ~5 withdrawal symptoms due to other drug dependence.

X

Claims (18)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A bicyclolactam compound represented by the formula (1) wherein:
R is oxo or -OR1, where R1 is a hydrogen atom or an aliphatic acyl group having 2 to 6 carbon atoms, benzoyl, toluyl, methoxybenzoyl, dimethoxybenzoyl, or naphthylcarbonyl;
A is a group of (2) or (3) wherein R2 is a benzoyl group or a benzoyl group substituted by a halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, hydroxyl group or amino group;

Q is a hydrogen atom or lower alkyl group;
l is 1 or 2;
m is 0 or 1; and n is 0, 1 or 2;
provided the case where both of m and n represent 0 simultaneously is excluded.

2. A bicyclolactam compound represented by the formula (4) wherein A, Q, l, m and n are as defined in claim 1; and R3 is a benzyl group or a benzyl group substituted by a lower alkyl group, a lower alkoxyl group, a halogen atom or a trifluoromethyl group.

3. A bicyclolactam compound as defined in claim 1 or 2, wherein m or n is 0.

4. A bicyclolactam compound as defined in claim 1 or 2, wherein 1 is 1, m is 0 and n is 2.

5. A bicyclolactam compound as defined in claim 1, wherein:
R is -OR1, where R1 is a hydrogen atom or an acetyl group;
R2 is a benzoyl group or a benzoyl group substituted by a lower alkoxyl group, a halogen atom or a lower alkyl group;

Q is a hydrogen atom; and l is 1, m is 0 and n is 2.

6. A bicyclolactam compound as defined in claim 5, wherein:
R is -OR1, where R1 is a hydrogen atom;
R2 is a benzoyl group substituted by a methoxy group; and Q is a hydrogen atom.

7. A bicyclolactam compound as defined in claim 1, wherein:
R is an oxo group;
R2 is a benzoyl group or a benzoyl group substituted by a lower alkoxyl group or a lower alkyl group;
Q is a hydrogen atom or a lower alkyl group; and l is 1, m is 0 and n is 2.

8. A bicyclolactam compound as defined in claim 7, wherein:
R2 is a benzoyl group substituted by a methoxy or methyl group; and Q is a hydrogen atom or a methyl group.

9. A bicyclolactam compound as defined in claim 2, wherein:
R2 is a benzoyl group or a benzoyl group substituted by a lower alkoxyl group, a halogen atom or a lower alkyl group;

R3 is benzyl group;
Q is a hydrogen atom; and 1 is l, m is 0 and n is 2.

10. A bicyclolactam compound as defined in claim 9, wherein:
R2 is a benzoyl group substituted by a methoxy group; and R3 is benzyl group.

11. A process for preparing a bicyclolactam compound represented by the formula (1') wherein A, Q, l, m and n are as defined in any one of claims 1 and 3 to 7;
comprising hydrogenating, in a suitable solvent and in the presence of a catalyst, a bicyclolactam compound of the formula (4) wherein A, R3, Q, l, m and n are as defined in claim 2, 9 or 10.

12. A process as defined in claim 11, wherein the solvent is an alcohol, an ether or an acetic acid ester, and the catalyst is a palladium-charcoal catalyst or platinum.

13. A process for preparing a bicyclolactam compound represented by the formula (1'') wherein A, Q, l, m and n are as defined in any one of claims 1 and 3 to 7, R1a is an acyl group;
comprising acylating, in a suitable solvent, a bicyclolactam compound of the formula (1') wherein A, Q, l, m and n are as defined in any one of claims 1 and 3 to 7.

14. A process for preparing a bicyclolactam compound represented by the formula (1''') wherein R2, Q and l are as defined in any one of claims 1 and 3 to 7;
comprising reacting, in the presence of a base, a compound of the formula (5) R2 - X (5) wherein R2 is as defined in any one of claims 1 and 3 to 7, and X is a halogen atom, and a bicyclolactam compound of the formula (6) wherein Q and l are as defined in any one of claims 1 and 3 to 7.

15. A pharmaceutical composition comprising a pharmaceutically-effective amount of the bicyclolactam compound of any one of claims 1 and 3 to 7, and a pharmaceutically-acceptable carrier therefor.

16. An anxiolytic agent comprising an anxiolytically-effective amount of the bicyclolactam compound of any one of claims 1 and 3 to 7, and a pharmaceutically-acceptable carrier therefor.

17. Use of the bicyclolactam compound of any one of claims 1 and 3 to 7, in the preparation of medicinal preparations useful for treating anxiety.

18. Use of an anxiolytically-effective amount of the bicyclolactam compound of any one of claims 1 and 3 to 7, for alleviating anxiety in mammals.