JPH0822816B2 - Hypoxia improver and antioxidant - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to 2,3-dihydro-1H-inde derivatives.

DISCLOSURE OF THE INVENTION The 2,3-dihydro-1H-inde derivative of the present invention is a novel compound which has not been described in the literature and is represented by the following general formula.

[Wherein R ¹ and R ^{2 each} have a hydrogen atom, a lower alkyl group, a halogen atom as a substituent on the phenyl ring, a phenyl group which may have a lower alkyl group, or a halogen atom on the cycloalkyl ring. Optionally, a cycloalkyl, a cycloalkyl lower alkyl group, a hydroxyl group, a phenyl lower alkoxy group or a phenyl lower alkyl group optionally having a halogen atom, a lower alkylenedioxy group or a lower alkoxy group on the phenyl ring. R ³ represents a halogen atom or a lower alkyl group. R ⁴ is a hydrogen atom, a halogen atom, a phenyl lower alkyl group, a cycloalkyl lower alkyl group,
Piperidinyl lower alkanoylamino lower alkyl group,
A piperidinium lower alkanoylamino lower alkyl group or a lower alkyl group is shown. R ⁵ is a hydroxyimino group,
An alkyl amino group or a group -NHR ⁸ of C ⁷ -C ^10. Wherein R ⁸ represents a hydrogen atom, a halogen-substituted lower alkanoyl group, lower alkylamino-lower alkyl group, a phenyl lower alkyl group or a group -A-B. A represents a lower alkylene group which may have a hydroxy group, a group -CO- (D) l- or a group -D-CO- (D represents a lower alkylene group, l represents an integer of 0 or 1), B represents a 5- or 6-membered saturated or unsaturated heterocyclic group. The heterocyclic group may have a lower alkyl group which may have a hydroxy group as a substituent, an oxo group, a carboxy group, a lower alkoxycarbonyl group, a pyridyl group, a phthalimido group, a pyrrolidinylcarbonyl lower alkyl group, and a phenyl ring. Halogen atom as a substituent,
A lower alkyl group which may have a halogen atom, a lower alkoxy group and a phenyl group which may have 1 to 3 groups selected from a nitro group, a phenyl lower alkyl group or a lower alkoxy group as a substituent on the phenyl ring. It may have a benzoyl group which may have a group. R ⁶ represents a hydrogen atom or a phenyl group. R ⁷ represents a hydrogen atom or a lower alkyl group. Provided that R ⁵ represents a hydroxyimino group or a group —NHR ⁸ and R ⁸ represents a hydrogen atom or a halogen-substituted lower alkanoyl group, R ⁶ and R ⁷ both represent a hydrogen atom, and R ¹ and R ² are When each represents a hydrogen atom or a lower alkyl group, R ⁴ must not be a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, an amino group or a lower alkanoylamino group. The compound of the present invention represented by the above general formula (1) has an action of improving an oxygen-deficient state and symptoms associated therewith, and is a drug that improves the oxygen-deficient state and symptoms associated therewith (that is, hypoxia). (Hypoxia improving agent), more specifically, for example, brain stimulant, amnestic drug, senile dementia drug, respiratory arrest and hypoxia improving drug associated with potassium cyanide poisoning, arrhythmia and heart failure due to oxygen deficiency It is effectively used as a preventive drug.

The compound of the present invention includes, as the above-mentioned cerebral activator, for example, cerebrovascular disorder (cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, hypertensive encephalopathy), encephalitis, brain tumor, head trauma, psychosis, metabolic disorder, drug poisoning,
It is useful for improving consciousness disorder caused by physical disorders and for treating or ameliorating after-effects, decreased attention, movement, speech disorders, and mental retardation caused by the above diseases.

In addition, the compound of the present invention has low toxicity and few side effects.

For the living body, oxygen is indispensable for maintaining life such as energy production and metabolism. The oxygen becomes so-called active oxygen species such as oxygen anion radicals, peroxide ions and hydroxy radicals by the reaction in the energy production system, the enzymatic reaction, the reaction by ultraviolet rays, the radiation and the like. While the reactive oxygen species are useful for living organisms such as oxygenase and bactericidal action of leukocytes, they are abundant in living organisms, such as oleic acid, linoleic acid, linolenic acid, and arachidonic acid, which form phospholipids in biological membranes. It promotes the peroxidation of fatty acids and forms lipid peroxides. This lipid peroxide induces the generation of alkoxy radicals and hydroxy radicals similarly to the above reactive oxygen species, attacks biological membranes, and causes membrane damage and deactivation of various effective enzymes (metabolism, 15 (10) , 1978 special feature active oxygen reference). However, in vivo, for example, superoxide dismutase (SO
D), enzymes such as catalase, glutathione peroxidase, etc. which are involved in metabolic inactivation of the above-mentioned reactive oxygen species, and various antioxidant vitamins such as α-tocopherol (vitamin E), etc. Exists, and the normal functioning of the body is normally maintained by the action of the above, but the deficiency of the appropriate defense mechanism by the above enzymes, vitamins, etc. occurs for some reason, or the capacity of the defense mechanism. It is often recognized that the generation of reactive oxygen species exceeding the limit and the production and accumulation of lipid peroxide occur. When such a defense mechanism deficiency occurs, various disorders due to chain reaction progression of peroxidation reaction such as various diseases due to platelet aggregation, inflammation, liver damage, arteriosclerosis, hemolysis, aging or senile dementia, retina Diseases, lung disorders, heart and lung disorders due to certain drugs, ischemic vascular diseases, and the like.

Conventionally, compounds having an action of removing (scavenging) reactive oxygen species (radicals), which are considered to be the main causes of the above-mentioned various disorders, and preventing or reducing the production and accumulation of lipid peroxide in vivo, are generally used as antioxidants. It has been reported that many of the effects of preventing and treating the above-mentioned diseases by its use have been reported. The reported antioxidants include the SO described above.
Enzymes such as D (Superoxide and Medicine, Yoshihiko Oyanagi, 1981, Kyoritsu Publishing Co., Ltd., pp.137-141), butylhydroxytoluene (BHT) butylhydroxyanisole (BHA), α-tocopherol (vitamin E) Et al. [Mino Mino, Hidetaka Tanaka, Pharmaceutical Journal, 19 (12), 1983, p2
351-2359 and Toshihiko Suematsu, Ibid., 19 (5), 1983, p90.
9-914].

The compound of the present invention has an effect of removing reactive oxygen species and preventing or reducing the production of lipid peroxide in vivo. Accordingly, the compound of the present invention can be used as an agent for preventing and treating various disorders or diseases caused by excessive generation of the above-mentioned reactive oxygen species, accumulation of lipid peroxide in a living body, or deficiency of a defense mechanism against the above, such as an anti-arteriosclerotic agent. , Cancer prevention agents, anti-inflammatory agents, analgesics, autoimmune disease treatment agents, platelet aggregation inhibitors, antihypertensive agents, antihyperlipidemic agents,
It is also useful as a medicine for preventing and treating retinopathy of prematurity and cataract.

In the present specification, each group represented by R ^{1 to} R ⁸ can more specifically include the following.

As the lower alkyl group, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl,
Hexyl, 1-methylpropyl, 2-methylpropyl,
1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 2,3-dimethylpropyl, 1-methylpentyl, 1,1
-C 1 to C 1 such as dimethylbutyl and 1-ethylbutyl
6 straight chain or branched chain alkyl groups can be exemplified.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, and 2-methyl A phenylalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as a -3-phenylpropyl group can be exemplified.

Examples of the cycloalkyl lower alkyl group include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclohexylethyl,
Cyclohexylethyl, 1-cyclohexylpropyl,
3-cyclopentylpropyl, 2-cyclopentylethyl, 4-cyclobutylbutyl, 5-cycloheptylpentyl, 6-cyclooctylhexyl, 1,1-dimethyl-
Examples thereof include a cycloalkylalkyl group having 3 to 8 carbon atoms, which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as 2-cyclopropylethyl and 2-methyl-3-cyclopentylpropyl group. .

The halogen-substituted lower alkanoyl group includes 2,2,2-
Trifluoroacetyl, 2,2,2-trichloroacetyl,
2-chloroacetyl, 2-bromoacetyl, 2-fluoroacetyl, 2-iodoacetyl, 2,2-difluoroacetyl, 2,2-dibromoacetyl, 3,3,3-trifluoropropionyl, 3,3,3- Trichloropropionyl, 3-
Chloropropionyl, 2,3-dichloropropionyl, 4,
4,4-trichlorobutyryl, 4-fluorobutyryl, 5
-Chloropentanoyl, 3-chloro-2-methylpropionyl, 6-bromohexanoyl, 5,6-dibromohexanoyl group or the like having a straight or branched alkanoyl group having 1 to 6 carbon atoms having a halogen atom. It can be illustrated.

As the alkylene group which may have a hydroxy group, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, Hexamethylene, 1-hydroxymethylene, 1-hydroxyethylene, 2-hydroxytrimethylene, 1-hydroxy-2-methyltrimethylene, 1-hydroxy-2,2-dimethyltrimethylene, 1-methyl-2-hydroxytrimethylene Examples thereof include linear or branched alkylene groups having 1 to 6 carbon atoms which may have a hydroxy group such as 2-hydroxytetramethylene, 3-hydroxypentamethylene and 4-hydroxyhexamethylene groups.

Examples of the lower alkylene group include methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene. Examples thereof include straight-chain or branched-chain alkylene groups of Formulas 1 to 6.

Examples of the 5- or 6-membered saturated or unsaturated heterocyclic group include piperazinyl, morpholino, thiomorpholino, piperidinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, thienyl, furyl and pyranyl groups. it can.

Lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Isopropoxycarbonyl, butoxycarbonyl, tert
Examples thereof include linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms such as butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups.

Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.
And 6 straight-chain or branched-chain alkoxy groups.

As a phenyl group which may have 1 to 3 groups selected from a halogen atom, a lower alkyl group which may have a halogen atom, a lower alkoxy group and a nitro group as a substituent on the phenyl ring, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-
Fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 3,5-dichlorophenyl, 2,2. 6-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl, 3,4,5-trichlorophenyl, 2-trifluoromethylphenyl, 3- Trichloromethylphenyl, 4-chloromethylphenyl, 2-dibromomethylphenyl, 3
-(2,2,2-trifluoroethyl) phenyl, 4- (1,2
-Dichloroethyl) phenyl, 2- (5-chloropentyl) phenyl, 3- (6-bromohexyl) phenyl,
4- (5,6-dibromohexyl) phenyl, 2-iodomethylphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-
Ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3- Methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3
-Ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-hexyloxyphenyl, 3,
4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,
4,5-trimethoxyphenyl, 2,5-dimethoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3-methyl-
1 to 4 halogen atoms or halogen atoms as substituents on the phenyl ring such as 4-chlorophenyl, 2-chloro-6-methylphenyl and 2-methoxy-3-chlorophenyl group
1 to 3 groups selected from a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms and a nitro group which may have 3 Examples thereof include a phenyl group that may have.

A lower alkyl group which may have a hydroxy group as a substituent, an oxo group, a carboxy group, a lower alkoxycarbonyl group, a pyridyl group, a phthalimido group, a pyrrolidinylcarbonyl lower alkyl group, a halogen atom as a substituent on the phenyl ring. , A phenyl group which may have 1 to 3 groups selected from a lower alkyl group optionally having a halogen atom, a lower alkoxy group and a nitro group, a phenyl lower alkyl group or a lower group as a substituent on the phenyl ring. As the 5- or 6-membered saturated or unsaturated heterocyclic group which may have an benzoyl group which may have an alkoxy group, 4-methyl-1-piperazinyl, 4-butyl-1
-Piperazinyl, 4-ethyl-1-piperazinyl, 4-
Hexyl-1-piperazinyl, 3-ethyl-1-morpholino, 2-propyl-1-thiomorpholino, 4-methyl-1-piperidinyl, 3-ethyl-1-pyrrolidinyl,
5-methylimidazolyl, 3-methylpyridyl, 4-ethylpyridyl, 3-methylpyrazolyl, 5-methylisothiazolyl, 5-ethylisoxazolyl, 3-methyl-
2-pyrazinyl, 4-pentyl-2-pyrimidinyl, 5
-Propylthienyl, 5-methylfuryl, 4-hexylpyranyl, 4- (hydroxymethyl) -1-piperazinyl, 4- (1-hydroxyethyl) -1-piperazinyl, 4- (6-hydroxyhexyl) -1-piperazinyl, 2- (3-hydroxypropyl) -1-thiomorpholino, 3- (2-hydroxyethyl) -1-morpholino, 4- (hydroxymethyl) -1-piperidinyl, 3
-(2-hydroxyethyl) -1-pyrrolidinyl, 5-
(Hydroxymethyl) imidazolyl, 3- (hydroxymethyl) pyridyl, 4- (1-hydroxyethyl) pyridyl, 3- (hydroxymethyl) pyrazolyl, 5- (hydroxymethyl) isothiazolyl, 5- (2-hydroxyethyl) isoxazolyl, 3-hydroxymethyl-2
-Pyrazinyl, 4- (5-hydroxypentyl) -2-
Pyrimidinyl, 5- (3-hydroxypropyl) thienyl, 5-hydroxymethylfuryl, 4- (6-hydroxyhexyl) pyranyl, 2-oxo-1-pyrrolidinyl, 2-carboxy-1-pyrrolidinyl, 3-carboxy-1pyrrolidinyl , 4-carboxy-1-pyrrolidinyl, 2-methoxycarbonyl-1-pyrrolidinyl, 2-
Ethoxycarbonyl-1-pyrrolidinyl, 3-propoxycarbonyl-1-pyrrolidinyl, 4-butoxycarbonyl-11-pyrrolidinyl, 2-hexyloxycarbonyl-1-pyrrolidinyl, 3-pentyloxycarbonyl-1-pyrrolidinyl, 4- (2- Pyridyl) -1-piperazinyl, 4-phenyl-1-piperazinyl, 4- (2
-Chlorophenyl) -1-piperazinyl, 4- (3,5-
Dichlorophenyl) -1-piperazinyl, 4- (2,3-
Dichlorophenyl) -1-piperazinyl, 4- (2-methoxyphenyl) -1-piperazinyl, 4- (4-nitrophenyl) -1-piperazinyl, 4- (2,3-dimethylphenyl) -1-piperazinyl , 4- (2,4,5-trimethyl) -1-piperazinyl, 4- (3-methoxyphenyl) -1-piperazinyl, 4- (3-methylphenyl) -1-piperazinyl, 4- (4-bromophenyl)
-1-Piperazinyl, 4- (3-fluorophenyl)-
1-piperazinyl, 4- (2-iodophenyl) -1-
Piperazinyl, 4- (2-butoxyphenyl) -1-piperazinyl, 4- (3-pentyloxyphenyl) -1
-Piperazinyl, 4- (4-hexyloxyphenyl)
-1-piperazinyl, 4- (3,4,5-trimethoxyphenyl) -1-piperazinyl, 4- (3-ethylphenyl) -1-piperazinyl, 4- (4-propylphenyl) -1-piperazinyl, 4- (3-pentylphenyl) -1-piperazinyl, 4- (4-hexylphenyl) -1-piperazinyl, 4- (3-butylphenyl)
-1-piperazinyl, 4-benzyl-1-piperazinyl, 4- (2-phenylethyl) -1-piperazinyl,
4- (3-phenylpropyl) -1-piperazinyl, 4
-(4-phenylbutyl) -1-piperazinyl, 4-
(1,1-Dimethyl-2-phenylethyl) -1-piperazinyl, 4- (5-phenylpentyl) -1-piperazinyl, 4- (6-phenylhexyl) -1-piperazinyl, 4- (2-methyl-3) -Phenylpropyl) -1-
Piperazinyl, 4-benzoyl-1-piperazinyl, 4
-(2-Methoxybenzoyl) -1-piperazinyl, 4
-(3-Methoxybenzoyl) -1-piperazinyl, 4
-(4-Methoxybenzoyl) -1-piperazinyl, 4
-(2-Ethoxybenzoyl) -1-piperazinyl, 4
-(4-isopropoxybenzoyl) -1-piperazinyl, 4- (4-hexyloxybenzoyl) -1-piperazinyl, 4- (3,4-dimethoxybenzoyl) -1-
Piperazinyl, 4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl, 4- (pyrrolidinylcarbonylmethyl) -1-piperazinyl, 4- [2- (pyrrolidinylcarbonyl) ethyl] -1- Piperazinyl, 4-
[1- (pyrrolidinylcarbonyl) ethyl] -1-piperazinyl, 4- [4- (pyrrolidinylcarbonyl) butyl] -1-piperazinyl, 4- [6- (pyrrolidinylcarbonyl) hexyl] -1- Piperazinyl, 4-phthalimido-1-piperazinyl, 4-phthalimido-1-piperidinyl, 4- (2-trifluoromethylphenyl)
-1-piperazinyl, 4- (3-trichloromethylphenyl) -1-piperazinyl, 4- (4-chloromethylphenyl) -1-piperazinyl, 4- [3- (2,2,2-trifluoroethyl) ) Phenyl] -1-piperazinyl, 4
-[4- (1,2-Dichloroethyl) phenyl] -1-piperazinyl, 4- [2- (5-chloropentyl) phenyl] -1-piperazinyl, 4- [3- (6-bromohexyl) phenyl] -1-piperazinyl, 4- [4- (5,
6-dibromohexyl) phenyl] -1-piperazinyl, 4- (2-iodomethylphenyl) -1-piperazinyl group and the like, which may have a hydroxy group as a substituent, a straight chain having 1 to 6 carbon atoms or On a branched-chain alkyl group, oxo group, carboxy group, linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, pyridyl group, phthalimido group, pyrrolidinylcarbonyl C ₁ -C ₆ alkyl group, on a phenyl ring As a substituent, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, and nitro. A phenyl group which may have 1 to 3 groups selected from the group, a phenyl C ₁ -C ₆ alkyl group or ₁ to 3 having a C ₁ -C ₆ alkoxy group as a substituent on the phenyl ring Good benzoyl group And a 5- or 6-membered saturated or unsaturated heterocyclic group which may have

Examples of the piperidinyl lower alkanoylamino lower alkyl group include piperidinyl acetylaminomethyl and (3-
Piperidinylpropionyl) aminomethyl, (4-piperidinylbutyryl) aminomethyl, (5-piperidinylpentanoyl) aminomethyl, (-piperidinylhexanoyl) aminomethyl, 2- (piperidinylacetyl) Amino) ethyl, 1-[(3-piperidinylpropionyl) amino] ethyl, 3-[(4-piperidinylbutyryl) amino] -propyl, 4-[(5-piperidinylpentanoyl) amino] Butyl, 1,1-dimethyl-2-
[(6-piperidinylhexanoyl) amino] ethyl,
5- (piperidinylacetylamino) pentyl, 6-
[(3-Piperidinylpropionyl) amino] hexyl, 2-methyl-3- (piperidinylacetylamino)
The number of carbon atoms in the alkanoylamino group such as propyl is 2
~ 6 straight or branched chain alkanoylamino group,
An example is a piperidinylalkanoylaminoalkyl group, which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety.

The alkylamino group of C ₇ -C _10, heptyl amino, octyl amino, nonylamino, a straight-chain or branched-chain alkyl amino groups such as decylamino group can be exemplified.

Examples of the pyridinium lower alkanoylamino lower alkyl group include pyridinium acetylaminomethyl and (3-
Pyridinium propionyl) aminomethyl, (4-pyridinium butyryl) aminomethyl, (5-pyridinium pentanoyl) aminomethyl, (6-pyridinium hexanoyl) aminomethyl, 2- (pyridinium acetylamino) ethyl, 1-[(3 -Pyridinium propionyl) amino] ethyl, 3-[(4-pyridinium butyryl) amino] propyl, 4-[(5-pyridinium pentanoyl) amino] butyl, 1,1-dimethyl-2-
[(6-pyridinium hexanoyl) amino] ethyl,
5- (pyridinium acetylamino) pentyl, 6-
[(3-Pyridinium propionyl) amino] hexyl, 2-methyl-3- (pyridinium acetylamino)
The number of carbon atoms in the alkanoylamino group such as propyl is 2
~ 6 straight or branched chain alkanoylamino group,
A pyridinium alkanoylaminoalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl portion can be exemplified.

Examples of the phenyl group which may have a halogen atom or a lower alkyl group on the phenyl ring as a substituent include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl and 3-fluorophenyl. , 4-fluorophenyl, 2-bromophenyl,
3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl,
3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4
-Dichlorophenyl, 3,4-difluorophenyl, 3,5-
Dibromophenyl, 3,4,5-trichlorophenyl, 2-
Methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-
Ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 3,4,5-trimethylphenyl, 3-methyl-
Having 1 to 3 groups selected from a halogen atom and a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring such as 4-chlorophenyl and 2-chloro-6-methylphenyl group. And a phenyl group having

Examples of the cycloalkyl group which may have a halogen atom on the cycloalkyl ring include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-chlorocyclopropyl, 1
-Bromocyclobutyl, 2-chlorocyclobutyl, 1-
Chlorocyclopentyl, 2-bromocyclopentyl, 1
-Chlorocyclohexyl, 2-bromocyclohexyl,
3-fluorocyclohexyl, 1-chlorocycloheptyl, 2-bromocycloheptyl, 3-fluorocycloheptyl, 2-iodocycloheptyl, 1-chlorocyclooctyl, 2-bromocyclooctyl, 3-fluorocyclooctyl, 4-iodo Cyclooctyl, 1,2-dichlorocyclopentyl, 2,3-dibromocyclohexyl,
It has 1 to 3 halogen atoms on the cycloalkyl ring such as 2,4-dichlorocycloheptyl, 3,4-dibromocyclooctyl, 2,3,4-trichlorocyclohexyl and 2-bromo-4,4-dichlorocyclohexyl. Examples of the optionally substituted cycloalkyl group having 3 to 8 carbon atoms can be given.

As the phenyl lower alkoxy group, benzyloxy, 2-phenylethoxy, 1-phenylmethoxy, 3
-Phenylpropoxy, 4-phenylbutoxy, 1,1-
Dimethyl-2-phenylethoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 2-methyl-
Examples thereof include a phenylalkoxy group which is a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety such as a 3-phenylpropoxy group.

Examples of the phenyl lower alkyl group which may have a halogen atom, a lower alkoxy group or a lower alkylenedioxy group on the phenyl ring include (2-chlorophenyl) methyl, 2- (3 -Chlorophenyl) ethyl, 1- (4-chlorophenyl) ethyl, 3- (2-fluorophenyl) propyl, 4-
(3-Bromophenyl) butyl, 1,1-dimethyl-2-
(4-iodophenyl) ethyl, 5- (3,5-dichlorophenyl) pentyl, 6- (3,4-difluorophenyl) hexyl, 2-methyl-3- (3,4,5-trichlorophenyl) Propyl, (2,6-dibromophenyl) methyl, (2-methoxyphenyl) methyl, 2- (3-ethoxyphenyl) ethyl, 1- (4-isopropoxyphenyl) ethyl, 3- (4- Hexyloxyphenyl) propyl, 4- (3,4-dimethoxyphenyl) butyl, 1,1
-Dimethyl-2- (2.5-dimethoxyphenyl) ethyl, 5- (3,4,5-trimethoxyphenyl) pentyl,
6- (3-pentyloxyphenyl) hexyl, 2-methyl-3- (2-n-butyloxyphenyl) propyl, 3,4-methylenedioxybenzyl, 2- (2,3-methylenedioxyphenyl) Enyl) ethyl, 1- (3,4-ethylenedioxyphenyl) ethyl, 3- (2,3-trimethylenedioxyphenyl) propyl, 4- (3,4-tetramethylenedioxyphenyl) butyl , 1,1-dimethyl-2-
(3,4-methylenedioxyphenyl) ethyl, 5- (2,3
-Methylenedioxyphenyl) pentyl, 6- (3,4-
1 to 3 halogen atoms, a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, or a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms on a phenyl ring such as ethylenedioxyphenyl) hexyl group. Examples thereof include a phenylalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety which may have one dioxy group.

Lower alkylamino As a lower alkyl group, methylaminomethyl, 2- (ethylamino) ethyl, 1- (propylamino) ethyl, 3- (n-butylamino) propyl, 4- (pentylamino) butyl, 5- ( Hexylamino) pentyl, 6- (dimethylamino) hexyl,
2-methyl-3- (diethylamino) propyl, 1,1-
Dimethyl-2- (diisopropylamino) ethyl, 3-
(Dihexylamino) propyl, 4- (methyl, ethylamino) butyl, 5- (methyl, pentylamino) pentyl, 6- (ethyl, propylamino) hexyl, 2-
Methyl-3- (methyl, hexylamino) propyl, 1,
A straight chain or branched chain having 1 to 6 carbon atoms such as a 1-dimethyl-2- (dimethylamino) ethyl group and a straight chain or branched chain having 1 to 2 carbon atoms and an amino group having 1 to 2 alkyl groups An alkyl group can be illustrated.

Examples of the lower alkyl group which may have a hydroxy group include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 3 in addition to the above lower alkyl group.
It may have a hydroxy group such as -hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl, and 1,1-dimethyl-2-hydroxyethyl group. Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms.

The lower alkyl group which may have a halogen atom, in addition to the above lower alkyl group, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl,
Fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloroethyl, 1,2-dichloroethyl, 3,3,3-trichloropropyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 6-bromohexyl, 5,6-dibromohexyl,
A straight chain or branched chain alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms such as 2,2-dichloropentyl group can be exemplified.

The benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring includes benzoyl and 2-
Methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 4-hexyloxybenzoyl,
Carbon number of 1 as a substituent on a phenyl ring such as 3,4-dimethoxybenzoyl, 3,4-diethoxybenzoyl, 3,4,5-trimethoxybenzoyl and 2,5-dimethoxybenzoyl group
The benzoyl group which may have a linear or branched alkoxy group of 6 to 6 can be illustrated.

Examples of the lower alkylenedioxy group include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms such as methylenedioxy, ethylenedioxy, trimethylenedioxy and tetramethylenedioxy groups.

Cycloalkyl lower alkyl groups include cyclopropylmethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 1,1-dimethyl-2-cycloheptylethyl, 5-cymaroctyl. Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms, which is substituted with a cycloalkyl group having 3 to 8 carbon atoms such as pentyl, 6-cyclohexylhexyl, and 2-methyl-3-cyclohexylpropyl group.

As the pyrrolidinylcarbonyl lower alkyl group, pyrrolidinylcarbonylmethyl, 2-pyrrolidinylcarbonylethyl, 1-pyrrolidinylcarbonylethyl, 3-
Pyrrolidinylcarbonylpropyl, 4-pyrrolidinylcarbonylbutyl, 1,1-dimethyl-2-pyrrolidinylcarbonylethyl, 5-pyrrolidinylcarbonylpentyl, 6-pyrrolidinylcarbonylhexyl, 2-methyl-3- Examples thereof include pyrrolidinylcarbonylalkyl groups such as pyrrolidinylcarbonylpropyl groups, which are linear or branched alkyl groups having 1 to 6 carbon atoms in the alkyl moiety.

The compound of the present invention can be produced by various methods,
The typical production method is shown below.

Reaction process formula-1 [In the formula, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined above. The reaction of the compound of general formula (2) with hydroxylamine (3) can be carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of the basic compound used at this time include sodium hydroxide, potassium hydroxide, sodium carbonate, inorganic basic compounds such as potassium carbonate, piperidine, pyridine, triethylamine,
1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8
-Diazabicyclo [5,4,0] undecene-7 (DBU), 1,
An organic base such as 4-diazabicyclo [2,2,2] octane (DABCO) can be exemplified. As the inert solvent used,
Any one may be used as long as it does not adversely affect the reaction, for example, lower alcohols such as methanol, ethanol and isopropanol, dioxane, tetrahydrofuran, diethyl ether, ethers such as ethylene glycol monomethyl ether, benzene, toluene and xylene. Aromatic hydrocarbons, dichloromethane, dichloroethane, chloroform, hydrogen halides such as carbon tetrachloride, dimethylformamide, dimethyl sulfoxide,
Hexamethylphosphoric triamide and the like can be mentioned. The amount of hydroxylamine (3) used is usually at least an equimolar amount, preferably an equimolar amount to the compound of the general formula (2).
It is preferable to use a 5-fold molar amount. The reaction temperature is usually room temperature to
200 ° C, preferably 50-150 ° C, generally 1
The reaction is completed in about 10 hours.

The reduction of the compound of the general formula (101) is carried out by the following reaction process formula-
The conditions for the reduction reaction of the compound of the general formula (104) of 2 can also be used, but preferably, it can be carried out by catalytic hydrogenation in the presence of a catalyst in a suitable solvent. Examples of the solvent used include water, acetic acid, alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran and diethyl ether, ethyl acetate and methyl acetate. And the like, aprotic polar solvents such as dimethylformamide, mixed solvents thereof, and the like. As the solvent used, for example, palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney-Nitzkel, etc. are used. The amount of the catalyst used is generally 0.02 with respect to the compound of the general formula (101).
It is preferable to use about 1 time. Reaction temperature is usually -20 ℃
The temperature is preferably around 100 ° C., preferably 0 ° C. to 70 ° C., and the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 2 hours.

Further, in the case of the compound of the general formula (101) in which R ¹ , R ² or R ⁴ is a phenyl group, a phenyl lower alkyl group or a pyridinium lower alkanoylamino lower alkyl group, R ¹ , R ² Alternatively, a compound of the general formula (102) in which R ⁴ is a cyclohexyl group, a cyclohexyl lower alkyl group or a piperidinium lower alkyl group may be produced. Also, the halogen atom of R ³ or R ⁴ is reduced to the corresponding
R ³ or R ⁴ may be a hydrogen atom.

Reaction process formula-2 IN FORMULA, R < ¹ >, R < ² >, R < ³ >, R < ⁴ >, R < ⁶ >, R <^7> , B AND D ARE THE SAME AS THE ABOVE-MENTIONED. X ¹ represents a halogen atom, X represents a hydrogen atom or a halogen atom, and A ′ represents a lower alkylene group. The reaction between the compound of the general formula (102) and the compound of the general formula (4) is carried out in a suitable inert solvent in the presence of a dehydrohalogenating agent. Examples of the inert solvent used herein include halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran and diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, methyl acetate, and ethyl acetate. And polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetonitrile, acetone, acetic acid, pyridine, and water. Examples of the dehydrohalogenating agent used include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, 1,5-diazabicyclo (4,3 , 0) Nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU), 1,4-diazabicyclo [2,2,2] octane (DABCO), sodium acetate, etc. Examples thereof include organic bases, inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium hydroxide, and sodium hydroxide. Compound (10
The amount of the compound (4) used with respect to 2) is usually at least equimolar, preferably equimolar to 2 times the molar amount. The reaction is usually about -20 to 150 ° C, preferably 0.
It is carried out at -100 ° C, and the reaction time is about 5 minutes to 7 hours. Thus, the compound (103) is obtained.

When X is a halogen atom in compound (103), compound (103) can be reacted with compound (5) to give compound (104). The reaction between compound (103) and compound (5) is carried out in a suitable inert solvent in the presence of a dehydrohalogenating agent. Examples of the inert solvent used here include methanol, ethanol,
Alcohols such as propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve and methyl cellosolve, ethers such as tetrahydrofuran and diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, acetone, acetonitrile and dimethylformamide. Aprotic polar solvents such as dimethylsulfoxide and hexamethylphosphoric triamide, halogenated hydrocarbons such as methylene chloride, dichloroethane and chloroform, esters such as methyl acetate and ethyl acetate, and mixed solvents thereof. . Examples of the dehydrohalogenating agent used include common basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, DBN, DBU. ,
DABCO, organic base such as sodium acetate, potassium carbonate,
Inorganic bases such as sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride and sodium amide, and alkali metal alcoholates such as sodium methylate and sodium ethylate. . Compound (10
The amount of the compound (5) used with respect to 3) is usually at least equimolar, preferably equimolar to 3 times the molar amount. Incidentally, the compound (5) can also be used as a dehalogenating agent by using an excess amount. The reaction is usually 0
~ 120 ° C, preferably room temperature to 100 ° C, and generally completed in 0.5 to 10 hours. Thus the compound (1
04) is acquired.

In the above reaction, the compound May be obtained. The compound of the general formula (120) and the compound of the general formula (104) can be easily separated by an ordinary separation means.

Various methods can be applied to the reaction for reducing the compound (104) to obtain the compound (105).
The reducing condition of the compound (101) in the above can also be used, but a reducing method using a hydrogenating / reducing agent is preferably used. Examples of the hydrogenation reducing agent used include lithium aluminum hydride, sodium borohydride, diborane and the like, and the amount thereof is usually at least equimolar to the compound (104), preferably equimolar to 10-fold molar. The range is. This reduction reaction is usually carried out using a suitable solvent, for example, lower alcohols such as water, methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, ethyl ether and diglyme, acetic acid and the like, usually about 0 to 200 ° C., preferably 0. It is carried out at ~ 170 ° C for about 10 minutes to 10 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as ethyl ether, tetrahydrofuran or diglyme.

Reaction process formula-3 IN FORMULA, R < ¹ >, R < ² >, R < ³ >, R < ⁴ >, R < ⁶ >, R < ⁷ >, X < ¹ >, A'and B are the same as the above. The reaction between the compound (102) and the compound (6) can be carried out under the same reaction conditions as the reaction between the compound (102) and the compound (4).

Reaction process formula-4 [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , A ′ and B are the same as defined above. Z is Indicates.

However The number of carbon atoms in the product does not exceed 6. ) The reaction between the compound (102) and the compound (7) is carried out in the presence of a basic compound in the absence of a solvent or a suitable solvent.
As the solvent used here, for example, dioxane, tetrahydrofuran, ethers such as ethylene glycol diethyl ether, benzene, toluene, aromatic hydrocarbons such as xylene, methanol, ethanol, alcohols such as isopropanol, acetone, acetonitrile, Examples thereof include aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Examples of the basic compound used include potassium carbonate, sodium carbonate, potassium hydroxide,
Examples thereof include inorganic bases such as sodium hydroxide, sodium hydrogen carbonate and sodium amide, and organic bases such as triethylamine, tripropylamine, pyridine, quinoline, DBN, DBU and DABCO. The amount of the compound (7) used with respect to the compound (102) is usually at least equimolar, preferably equimolar to 5 times the molar amount. The reaction is usually performed at about 0 to 200 ° C, preferably 50 to 100 ° C,
Generally, it is completed in about 1 to 12 hours.

Reaction process formula-5 [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are the same as defined above. R ⁹ represents a halogen-substituted lower alkanoyl group. The reaction between the compound of the general formula (102) and the compound of the general formula (8) can be achieved by subjecting to an ordinary amide bond formation reaction. In this case, the albonic acid (8) may use an activated compound. The conditions for the amide bond formation reaction can be applied as the amide bond formation reaction. For example, (a) a mixed acid anhydride method, that is, a method of reacting a carboxylic acid (8) with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with a compound (102), (b) an active ester method or an activity The amide method, that is, the carboxylic acid (8) is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione, A method of reacting this with a compound (102), (c) a carbodiimide method, that is, a method of dehydrating the compound (102) to the carboxylic acid (8) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole, ( D) Carboxylic acid halide method, that is, carboxylic acid (8) is converted to a halide. A method of reacting this with compound (102), and (e) as another method, a method of converting carboxylic acid (8) into a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and reacting compound (102) with this. ,
Examples thereof include a method of reacting the compound (102) with an ester of a carboxylic acid (8) and a lower alcohol, for example, under high pressure and high temperature. Further, a method in which the carboxylic acid (8) is activated with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate and the compound (102) is reacted therewith can also be adopted.

Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. The mixed acid anhydride is obtained by a usual Schottuten-Baumann reaction, and the compound (1) is produced by reacting the mixed acid anhydride with the compound (102) without isolation. The Diyotten-Baumann reaction is usually carried out in the presence of a basic compound. As the basic compound used, a compound conventionally used in the Schoutten-Baumann reaction is used, for example, triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DA.
Examples thereof include organic bases such as BCO, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. The reaction is about −20 to 100 ° C., preferably 0 to 5
The reaction time is about 5 minutes to 10 hours,
It is preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the compound (102) is -20 ° C to 150 ° C, preferably 10 to 50 ° C for 5 minutes to 10 hours, preferably 5 minutes to
It takes about 5 hours. The mixed acid anhydride method does not need to use a solvent in particular, but it is generally carried out in a solvent. The solvent used can be any solvent commonly used in the mixed acid anhydride method, specifically, methylene chloride. , Chloroform,
Halogenated carbons such as dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, dimethylformamide, diester Examples include aprotic polar solvents such as mer sulfoxide and hexamethylphosphoric triamide. The carboxylic acid (8), the alkylhalocarboxylic acid and the compound (102) used in the method are usually used at least in equimolar proportions.
The alkylhalocarboxylic acid and the compound (102) are preferably used in 1 to 2 moles per mol of the carboxylic acid (8).

In the active ester method or the active amide method (b), for example, in the case where benzoxazoline-2-thioneamide is used, a suitable solvent that does not affect the reaction, for example, the method used in the mixed acid anhydride method Using 1-methyl-2-pyrrolidone and the like in addition to the same solvent as
The reaction is preferably carried out at 10 to 100 ° C for 0.5 to 75 hours. In this case, the compound (102) and the benzoxazoline-2-thionamide are used in such a ratio that the latter is usually at least equimolar to the former, preferably equimolar to 2-fold molar. When an N-hydroxysuccinimide ester is used, the reaction proceeds advantageously when an appropriate base, for example, the same base as that used in the carboxylic acid halide method described below is used.

The carboxylic acid halide method of the above (c) comprises reacting the carboxylic acid (8) with a halogenating agent to obtain a carboxylic acid halide, which is isolated and purified, or without isolation and purification. It is carried out by reacting compound (102). The carboxylic acid halide and the compound (10
The reaction with 2) is carried out in the presence of a dehydrohalogenating agent in a suitable solvent. Basic compounds are usually used as the dehydrohalogenating agent, and in addition to the basic compounds used in the above-mentioned Schottten-Baumann reaction, sodium hydroxide,
Potassium hydroxide, sodium hydride, potassium hydride,
Examples thereof include alkali metal alcoholates such as silver carbonate, sodium methylate and sodium ethylate. The compound (102) can also be used in excess as a dehydrohalogenating agent. As the solvent, in addition to the solvent used in the Schoutsten-Baumann reaction, for example, water, methanol, ethanol, propanol, butanol, 3-
Examples include alcohols such as methoxy-1-butanol, ethylcellosolve, and methylcellosolve, pyridine, acetone, acetonitrile, and the like, or a mixed solvent of two or more thereof. The ratio of the compound (102) to the carboxylic acid halide used is not particularly limited and can be selected within a wide range. Usually, the latter is used at least equimolar, preferably equimolar to 2 times the molar amount of the former. The reaction temperature is usually about -30 to 180 ° C, preferably about 0 to 150 ° C, and the reaction is generally completed in 5 minutes to 30 hours. The carboxylic acid halide used is produced by reacting the carboxylic acid halide (8) with a halogenating agent in the absence or presence of a solvent. As the solvent, any solvent which does not adversely influence the reaction can be used, for example, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride, dioxane and tetrahydrofuran. , Ethers such as diethyl ether, dimethylformamide, dimethylsulfoxide, and the like. As the halogenating agent, an ordinary halogenating agent capable of converting a hydroxyl group of a carboxy group into a halogen can be used, and examples thereof include thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide and the like. . The use ratio of the carboxylic acid (8) and the halogenating agent is not particularly limited and may be appropriately selected. However, when the reaction is carried out in the absence of a solvent, the latter is usually used in a large excess amount in the solvent, and When the reaction is carried out in, the latter is usually at least equimolar to the former, preferably 2
~ 4 times the molar amount is used. The reaction temperature and reaction time are not particularly limited, but usually room temperature to about 100 ° C, preferably 5
It is carried out at 0 to 80 ° C for about 30 minutes to 6 hours.

The method of activating the carboxylic acid (8) with a phosphorus compound such as tolphenyl phosphine or diethyl chlorophosphate and reacting it with the compound (102) is carried out in a suitable solvent. Any solvent can be used as long as it does not affect the reaction. Specifically, halogenated carbons such as methylene chloride, chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Compound (102) in the reaction
Since the compound itself acts as a basic compound, the reaction proceeds well by using it in excess of the theoretical amount. , N-methylmorpholine, 4-dimethylaminopyridine, organic bases such as DBN, DBU and DABCO, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate can also be used. The reaction is about 0-15
It is achieved by carrying out at 0 ° C., preferably about 0 to 100 ° C. for about 1 to 30 hours. The proportions of the phosphorus compound and the carboxylic acid (8) used with respect to the compound (102) are usually at least equimolar amounts, preferably 1 to 3 times the molar amounts.

Reaction process formula-6 [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , B, D, l and X ¹ are the same as defined above. The reaction between the compound (102) and the compound (9) can be carried out under the same reaction conditions as the reaction between the compound (102) and the compound (4).

In the above reaction process formula-1, the compound of the general formula (2) used as a starting material includes a novel compound and is produced, for example, according to the method shown below.

Reaction process formula-7 [In the formula, R ¹ , R ² , R ³ , R ⁶ and X ¹ are the same as defined above. R ¹⁰ , R ¹¹ ,
R ²³ and R ²⁴ each represent a hydrogen atom, a lower alkyl group, a phenyl group or a cycloalkyl group. The reaction between the compound of general formula (201) and the compound of general formula (10) is carried out in the presence of a basic compound. A wide variety of known basic compounds can be used, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and silver carbonate, and alkali metals such as sodium and potassium. , Sodium methylate, sodium ethylate and other alcoholates, triethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, organic bases such as DBN, DBU and DABCO. The reaction can be carried out without solvent or in the presence of a solvent, and any inert solvent which does not adversely influence the reaction can be used as the solvent. For example, water, alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol. , Dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and other ethers, acetone, methyl ethyl ketone and other ketones, benzene, toluene, xylene and other aromatic hydrocarbons, methyl acetate, ethyl acetate and other esters, N, N- Examples thereof include aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, and mixed solvents thereof. Further, it is advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide. The general formula (20
The ratio of the compound of 1) to the compound of general formula (8) used is not particularly limited and is appropriately selected from a wide range, but the latter is usually equimolar to 5 times by mole, preferably equimolar to the former. It is desirable to use it in a molar amount to 2 times the molar amount. The reaction temperature is also not particularly limited, but is usually room temperature to 200 ° C, preferably 50 to 150 ° C. Reaction time is usually 1-3
It is 0 hours, preferably 1 to 15 hours.

The reaction for obtaining the compound of the general formula (203) from the compound of the general formula (202) is generally called Claisen rearrangement. For example, by heating the compound (202) in a suitable solvent, I can guide you. Examples of the solvent used include high boiling point solvents such as dimethylformamide and tetralin. The heating temperature is usually
100-250 ℃, preferably about 150-250 ℃, 1-20
The reaction is completed in about an hour.

Reaction process formula-8 IN FORMULA, R < ¹ >, R < ² >, R < ³ >, R < ⁶ > AND R < ⁷ > ARE THE SAME AS THE ABOVE-MENTIONED. R ¹² represents a lower alkanoylamino lower alkyl group having a halogen atom. R ¹³ represents a pyridinium lower alkanoylamino lower alkyl group or a piperidinyl lower alkanoylamino lower alkyl group. The reaction of the compound of general formula (201) with the compound of general formula (10) is carried out in the presence of a dehydration condensing agent without solvent or in a suitable solvent. Examples of the dehydration condensation agent used include condensed phosphoric acids such as polyphosphoric acid, phosphoric acids such as orthophosphoric acid, pyrophosphoric acid, and metaphosphoric acid, phosphorous acids such as orthophosphoric acid, and anhydrous phosphorus such as phosphorus pentoxide. Acids, hydrochloric acid, sulfuric acid, acids such as boric acid, sodium phosphate, boron phosphate, ferric phosphate, metal phosphates such as aluminum phosphate,
Examples thereof include activated alumina, sodium bisulfate, Raney-Nitzkel and the like. Examples of the solvent used include dimethylformamide and tetralin. The ratio of the compound of the general formula (201) to the compound of the general formula (10) is not particularly limited and can be appropriately selected within a wide range, but usually the latter is equimolar or more to the former. However, it is preferable to use an equimolar to 2-fold molar amount. The amount of the dehydration condensing agent used is not particularly limited and may be appropriately selected from a wide range, but it is usually a catalytic amount or more, preferably a large excess amount relative to the compound of the general formula (201). The reaction normally proceeds suitably at -30 to 50 ° C, preferably 0 ° C to around room temperature, and generally the reaction is completed in about 1 to 30 hours.

The reaction of compound (204) with pyridine or piperidine can be carried out under the same reaction conditions as the reaction of compound (102) with compound (4).

The compound of the general formula (6) and the compound of the general formula (9) are
It includes a novel compound and is produced, for example, according to the method shown in the following reaction scheme.

Reaction process formula-9 [Wherein X, X ¹ , X ² , A ', D and B are the same as defined above. ] Reaction of Compound (11) with Compound (5) and Compound (4)
The reaction between the compound (5) and the compound (5) can be carried out under the same reaction conditions as the reaction between the compound (102) and the compound (4).

The compound of the general formula (7) includes a novel compound and is produced, for example, according to the method shown in the following reaction process scheme.

Reaction process formula-10 [Wherein X ¹ , A ′, Z and B are the same as defined above. The reaction between compound (12) and compound (5) is carried out in the presence of a basic compound in the absence of solvent or a suitable solvent. As the basic compound used here, sodium hydroxide,
Inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, metallic sodium and metallic potassium,
Piperidine, pyridine, triethylamine, DBN, DBU,
Examples include organic bases such as DABCO. Examples of the solvent used include ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile, water and the like. In addition, compound (12) may be used as a solvent. The amount of the compound (12) used is usually a large excess amount, preferably 5 to 10 times the molar amount of the compound (5). The reaction is usually performed at 0 to 150 ° C., preferably 50 to 100 ° C., and generally completed in about 1 to 12 hours.

Reaction process formula-11 [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and X ¹ are the same as defined above. The cyclization reaction of the compound of the general formula (206) is carried out in the presence of an acid,
It is carried out without solvent or in a solvent. As the acid used here, for example, aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid and the like can be used. Examples of the solvent used here include aromatic hydrocarbons such as carbon disulfide, nitrobenzene and chlorobenzene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloroethane and tetrachloroethane. The amount of the Lewis acid used may be appropriately determined, but is usually at least equimolar, preferably equimolar to 6-fold molar with respect to the compound of the general formula (206). The reaction is usually room temperature to 200 ° C., preferably 50 to 180.
The process proceeds suitably at around 0 ° C and is generally completed in about 10 minutes to 7 hours.

Reaction process formula-12 [Wherein R ¹ , R ³ , R ⁴ and R ⁶ are the same as defined above. The cyclization reaction of the compound of the general formula (208) is
It is carried out under the same conditions as the cyclization reaction of the compound of 06).

Reaction process formula-13 [In the formula, R ¹ , R ³ , R ⁴ , R ⁶ and R ⁷ are the same as defined above. ] The cyclization reaction of the compound of the general formula (211) is carried out in the presence of an acid,
It is carried out in a suitable solvent. Examples of the acid used here include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, alkanoic acids such as acetic acid and trifluoroacetic acid, and organic acids such as p-toluenesulfonic acid. Examples of the solvent used here include alcohols such as methanol, ethanol and isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, dichloroethane, and the like.
Halogenated hydrocarbons such as chloroform and carbon tetrachloride,
Diethyl ether, tetrahydrofuran, dioxane,
Examples thereof include ethers such as diclime and monoglyme, polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction is
Usually, the reaction proceeds suitably at about 0 to 150 ° C, preferably at about 0 to 100 ° C, and the reaction is completed in about 30 minutes to 24 hours.

The reaction for converting the compound of the general formula (212) to the compound of the general formula (210) is carried out in a suitable solvent, for example, lower alcohols such as water, methanol, ethanol and isopropanol, ethers such as dioxane and tetrahydrofuran, solvents such as acetic acid. Or, in these mixed solvents, in the presence of a catalytic reduction catalyst such as palladium-carbon, palladium-black, etc., at about 0 to 100 ° C., at a hydrogen pressure of 1 to 10 atm for about 0.5 to 3 hours, or In a mixture of an acid such as hydrobromic acid or hydrochloric acid and a solvent such as water, methanol, ethanol or isopropanol,
The compound of the general formula (210) can be obtained by heating at 30 to 150 ° C, preferably 50 to 120 ° C. Further, the compound of the general formula (210) can also be obtained by hydrolyzing the compound (212). This hydrolysis is carried out in the presence of an acid or basic compound in a suitable solvent. Examples of the solvent include water, methanol, ethanol,
Lower alcohols such as isopropanol, dioxane,
Ethers such as tetrahydrofuran, polar solvents such as acetonitrile, mixed solvents thereof, and the like can be mentioned. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, Lewis acids such as aluminum chloride, iodides such as sodium iodide and potassium iodide, and mixtures of the above Lewis acids and iodides, and the like. Examples of the compound include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. The reaction normally proceeds at room temperature to 150 ° C., preferably room temperature to 100 ° C., and is generally completed in about 0.5 to 15 hours.

Reaction process formula-14 [Wherein R ³ , R ⁴ , R ⁶ and X ¹ are the same as defined above. R ¹⁶ represents a lower alkyl group. R ¹⁷ and R ¹⁸ are each a lower alkyl group,
A cycloalkyl group or a phenyl lower alkyl group which may have a halogen atom or a lower alkyl group on the phenyl ring is shown. The reaction between the compound of general formula (207) and the compound of general formula (16) is carried out in the presence of a basic compound in a suitable solvent. Examples of the basic compound used here include sodium hydroxide, potassium hydroxide, sodium ethylate, sodium hydride, potassium hydride, sodium amide, potassium amide and the like. Examples of the solvent include alcohols such as methanol, ethanol, and isopropanol, dioxane, ethers such as diethylene glycol dimethyl ether, toluene, aromatic hydrocarbons such as xylene, dimethylhelmamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. Can be mentioned. The amount of the compound of the general formula (16) used is not particularly limited and may be appropriately selected within a wide range, but is usually at least an equimolar amount, preferably an equimolar amount to 5 with respect to the compound of the general formula (207). It is better to use a double molar amount. The reaction is usually performed at about 0 to 70 ° C., preferably 0 ° C. to about room temperature, and the reaction is generally completed in about 0.5 to 12 hours.

Reaction of a compound of general formula (213) with a compound of general formula (17), in which R ¹ and R ² are both hydrogen atoms, and general formula (214)
The reaction of the compound of formula (18) with the compound of general formula (18) can be carried out under the same conditions as the reaction of the compound of general formula (207) with the compound of general formula (16).

The compound of general formula (216) is produced from the compound of general formula (215) in the same manner as the reaction for obtaining compound (210) from compound (212).

Reaction process formula −15 [In the formula, R ³ , R ⁴ , R ⁶ , R ⁷ and R ¹⁷ are the same as defined above. R ¹⁹ represents a phenyl lower alkyl group which may have a halogen atom or a lower alkyl group on the phenyl ring. The reaction of the compound of general formula (217) with the compound of general formula (19) is carried out in the presence of a basic compound in the absence of a solvent or a suitable solvent. As the solvent used here, any solvent that does not affect the reaction can be used, for example, water, alcohols such as methanol, ethanol and isopropanol, aromatic carbonization such as benzene, toluene and xylene. Hydrogen, ethers such as diethyl ether, tetrahydrofuran, dioxane, diglyme, monoglyme, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. It can be illustrated. Examples of the basic compound used include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and sodium hydride, and metals such as sodium ethylate and sodium methylate. Alcoholates, 1,5-diazabicyclo [4,3,0] nonene-5,1,8-diazabicyclo [5,4,0] undecene-
Examples of such organic bases include 7,1,4-diazabicyclo [2,2,2] octane and triethylamine. The amount of the compound of the general formula (19) used is usually at least equimolar, preferably equimolar to 2 times the molar amount of the compound of the general formula (217). The amount of the basic compound to be used is usually at least equimolar, preferably equimolar to 5 times the molar amount of the compound of the general formula (217). The reaction usually proceeds at 0 to 150 ° C., preferably room temperature to around 100 ° C., and generally the reaction is completed in about 0.5 to 8 hours.

The reduction reaction of the compound of general formula (218) can be carried out under the same conditions as the reduction of the compound of general formula (101) in the above reaction process formula-1.

The reaction between the compound of general formula (219) and the compound of general formula (17) is carried out under the same conditions except the reaction and the reaction temperature of the compound of general formula (213) and the compound of general formula (17). . The reaction temperature is usually 0 to 90 ° C, preferably 0 to 60 ° C.

Reaction process formula-16 [Wherein R ¹ , R ² , R ⁶ and R ⁷ are the same as defined above. ] R ³ ′ and R ³ ″ are the same as R ^3. R ⁴ ′ and R ⁴ ″ are the same as R ⁴ .
However, at least one of R ⁴ ′ and R ³ ′ represents a hydrogen atom, and at least one of R ⁴ ″ and R ³ ″ represents a halogen atom.

The halogenation reaction of the compound of the general formula (221) is carried out under the same conditions as the halogenation reaction of the compound of the general formula (115) in the reaction reaction step formula-20 described later.

The general formula (211), which is the starting material of the above reaction process formula-13
The compound (1) is produced, for example, by the method of the following reaction scheme-18.

Reaction process formula -17 [In the formula, R ¹ , R ³ and R ⁴ are the same as defined above. R ⁶ 'represents a phenyl group. The reaction of the compound of the general formula (223) and the compound of the general formula (20) is carried out under the same conditions as the reaction of the compound of the general formula (217) and the compound of the general formula (19) in the above reaction process formula-15. Done below.

The method for converting the compound of general formula (223) to the compound of general formula (225) is (R ²⁵ and R ²⁶ each represent a lower alkyl group.) And a method of reacting with formaldehyde [Mannich reaction (Ma
nnich Reaction)], Can be conducted by a method of reacting with.

The method of is the compound of the general formula (223), the general formula (21)
It is carried out by reacting the compound of 1) with formaldehyde in the presence of an acid in a suitable solvent. As the solvent used here, any one can be used as long as it is usually used in a Mannich reaction, for example, water,
Examples thereof include alcohols such as methanol, ethanol and isopropanol, alkanoic acids such as acetic acid and propionic acid, acid anhydrides such as acetic anhydride, polar solvents such as acetone and dimethylformamide, and mixed solvents thereof. Examples of the acid used include mineral acids such as hydrochloric acid and hydrobromic acid, and organic acids such as acetic acid. As formaldehyde, 20
Aqueous solutions containing 量 40% by weight formaldehyde, trimers, polypolymers (paraformaldehyde) and the like are usually used.

The amount of the compound of the general formula (21) used is represented by the general formula (22
It is usually used in an amount of at least equimolar, preferably equimolar to 2 times the molar amount of the compound of 3). The amount of formaldehyde used is at least equimolar to the compound of the general formula (223), and usually a large excess amount is used. The reaction is usually performed at 0 to 200 ° C, preferably at room temperature to 150 ° C.
The reaction proceeds suitably in the vicinity, and the reaction is completed in about 0.5 to 10 hours.

Is carried out in the presence of an acid, in a suitable solvent or in the absence of a solvent. Examples of the acid used here include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and organic acids such as acetic acid and acetic anhydride, but acetic anhydride is preferred. As the solvent used here, any of the solvents used in the above method can be used.
The amount of the compound (22) used is usually at least equimolar, preferably equimolar to 5 with respect to the compound of the general formula (223).
It is better to use twice the molar amount. The reaction is usually performed at 0 to 150 ° C.
Preferably, the reaction is completed at about room temperature to about 100 ° C. for about 0.5 to 5 hours.

Reaction process formula-18 [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and X ¹ are the same as defined above. R ¹⁴ is
Alkyl C ₇ -C _10, a lower alkenyl group, a lower alkylamino-lower alkyl group, phenyl-lower alkyl group, or a group -A "B (A" lower alkylene group which may have a hydroxy group, B is the The same). The reaction between the compound (102) and the compound (13) can be carried out under the same reaction conditions as the reaction between the compound (102) and the compound (4).

Reaction process formula −19 [Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above. R ¹⁵ represents a lower alkenyl group, a lower alkylamino lower alkyl group, a phenyl lower alkyl group or a C _{7 to} C ₁₀ lower alkyl group. The reaction of the compound of general formula (2) with the compound of general formula (14) is carried out in the absence or presence of a dehydrating agent in a solvent-free or suitable solvent. As the solvent used here, for example, alcohols such as methanol, ethanol, isopropanol, benzene, toluene, aromatic hydrocarbons such as xylene, dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, Examples include aprotic polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and mixed solvents thereof. Examples of the dehydrating agent include desiccants used for dehydrating ordinary solvents such as molecular sieves, mineral acids such as hydrochloric acid, sulfuric acid and boron trifluoride, and organic acids such as p-toluenesulfonic acid. it can. The reaction is usually carried out at room temperature to 250 ° C, preferably about 50 to 200 ° C, and the reaction is generally completed in about 1 to 48 hours. The amount of the compound of general formula (14) to be used is not particularly limited, but it is usually at least an equimolar amount, preferably an equimolar to large excess amount based on the compound of the general formula (2).
The amount of the dehydrating agent used is usually a large excess in the case of the desiccant, and a catalytic amount in the case of using the acid. The compound of general formula (111) thus obtained is subjected to the next reduction reaction without isolation.

Various methods can be applied to the reduction reaction of the compound of the general formula (111), for example, the reduction reaction conditions of the compound of the general formula (101) can be used, but a reduction method using a hydrogenation reducing agent is preferable. Used for. Examples of the hydrogenation reducing agent used include lithium aluminum hydride, sodium borohydride, and ciborane, and the amount thereof is usually at least equimolar to the compound (111),
The preferred range is equimolar to 10-fold molar. When lithium aluminum hydride is used as the hydrogenation reducing agent, it is convenient to use the compound (111) in a two-fold molar amount. This reduction reaction is usually carried out using a suitable solvent such as water, methanol, ethanol, lower alcohols such as isopropanol, tetrahydrofuran, ethyl ether, ethers such as diglyme, etc., usually about -60 to 50 ° C, preferably -30. It is carried out at a temperature of from ℃ to room temperature for about 10 minutes to 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, an anhydrous solvent such as ethyl ether, tetrahydrofuran or diglyme is preferably used.

Reaction process formula −20 [Wherein R ¹ , R ² , R ⁵ , R ⁶ and R ⁷ are the same as defined above. R ³ ′, R ⁴ ′, R
³ ″ and R ⁴ ″ are the same as described later. The halogenation reaction of the compound of the general formula (113) is carried out in the presence of a usual halogenating agent. As the halogenating agent used in such a reaction, a wide variety of known ones can be used. And halogenating agents such as halogenosuccinimide. The halogenating agent is usually used in an equimolar amount with respect to the compound of the general formula (113). Examples of the solvent used in the reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, acetic acid, propionic acid, water and the like. In the reaction, the reaction temperature is usually 0 ° C to the boiling point of the reaction solvent, preferably 0 to 40 ° C, and the reaction is usually completed in about 1 to 10 hours.

Reaction process formula-21 [In the formula, R ¹ , R ³ , R ⁴ , R ⁶ , R ⁷ and R ¹⁵ are the same as defined above. The reaction of the compound of general formula (212) with the compound of general formula (14) is carried out in a solvent, preferably in the presence of a dehydrating agent.
As the solvent used here, for example, methanol,
Alcohols such as ethanol and isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, dimethylformamide,
Examples include aprotic polar solvents such as dimethylacetamide and N-methylpyrrolidone, and mixed solvents thereof. Examples of the dehydrating agent include desiccants used for dehydrating ordinary solvents such as molecular sieve, mineral acids such as hydrochloric acid, sulfuric acid and boron trifluoride, and organic acids such as p-toluenesulfonic acid. it can. The reaction is usually performed at 0 to 150 ° C.
The reaction is preferably completed at room temperature to around 100 ° C., generally in about 1 to 48 hours. The amount of the compound of general formula (14) to be used is not particularly limited, but it is usually at least an equimolar amount, preferably an equimolar to 2-fold molar amount with respect to the compound of the general formula (212). The amount of the dehydrating agent to be used is usually a large excess amount in the case of the desiccant, and is preferably a catalytic amount in the case of using the acid.

The reduction reaction of the compound represented by the general formula (226) is
It can be carried out under the same conditions as the reduction reaction of the compound of 01).

In the compound of the general formula (225), when R ¹⁵ is a phenyl lower alkyl group, the compound of the general formula (225) (Wherein RA is a phenyl lower alkyl group) (11
6) may be obtained. This compound and the general formula (115)
The compound can be easily separated by a conventional separation means.

The target compound obtained in each step thus obtained can be easily isolated and purified by a usual separation means. Examples of the separating means include solvent extraction method, dilution method, recrystallization method, column chromatography, and preparative thin layer chromatography.

The compounds of the present invention naturally include optical isomers.

The indane derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting a pharmaceutically acceptable acid, and the present invention also includes this acid addition salt. In the above, as the acid, for example, hydrochloric acid,
Inorganic acids such as sulfuric acid, phosphoric acid, hydrobromic acid, organic acids such as acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, methanesulfonic acid, benzoic acid Can be used.

The compound of the present invention is usually used in the form of a general pharmaceutical preparation. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions,
Granules, capsules, suppositories, injections (solutions, suspensions, etc.), ointments and the like can be mentioned. When molding into a tablet form, a wide variety of carriers known in the art can be used as carriers, such as lactose, sucrose, sodium chloride, glucose,
Excipients such as urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl Binders such as pyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, white sugar , Stearin,
Decay inhibitor for cocoa butter, hydrogenated oil, quaternary ammonium base, absorption promoter for sodium lauryl sulfate, humectant for glycerin, starch, adsorption of starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Examples thereof include agents, purified talc, stearates, boric acid powders, and lubricants such as polyethylene glycol. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet or a multi-layer tablet. In molding in the form of pills, conventionally known carriers can be widely used, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, Examples thereof include a binder such as gelatin and ethanol, a disintegrating agent such as laminaranthantene, and the like. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into the form of these solutions, emulsions and suspensions, they are used as diluents. All those customary in the field can be used, for example water, ethyl alcohol,
Examples thereof include propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent,
A buffering agent, a soothing agent, etc. may be added. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation. In the case of molding into a paste, cream or gel form, it is possible to widely use conventionally known diluents in this field, for example, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like. .

The amount of the compound of the general formula (1) to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight in the pharmaceutical preparation.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and is administered according to various preparation forms, age and sex of the patient, other conditions, degree of the patient and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

The dose of the above-mentioned pharmaceutical preparation is appropriately selected depending on the usage, the age of the patient, the sex and other conditions, the degree of disease, etc. It is recommended to use about 0.2-200 mg.

Examples Reference examples, examples, pharmacological tests and formulation examples are listed below.

Reference Example 1 2,3-dihydro-7-hydroxy-4-methyl-1H-
A mixture of 196 g of inden-1-one, 80 g of potassium hydroxide and 2.5 l of methanol was heated under reflux for 3 minutes, cooled to room temperature, and 250 g of cinnamyl bromide was added dropwise with vigorous stirring. After stirring for 8 hours at the same temperature, the precipitated crystals are collected, washed with cold methanol and dried. Recrystallized from ethanol to give 126 g of 7-cinnamyloxy-2,3-dihydro-4
-Methyl-1H-inden-1-one is obtained.

mp 110 to 111 ° C. colorless needle crystal Reference Example 2 7 g of 7-cinnamyloxy-2,3-dihydro-4-methyl-1H-inden-1-one and 40 ml of tetralen are heated under reflux for 3 hours in a nitrogen stream. After completion of the reaction, the mixture was cooled to room temperature and subjected to silica gel column chromatography (eluent; n
-Hexane: ethyl acetate = 10: 1). Recrystallization from ethanol gives 2.64 g of 2,3-dihydro-7-hydroxy-4-methyl-6- (1-phenyl-2-propenyl) -1H-inden-1-one.

Colorless scale-like crystal Reference Example 3 76.2-Hydroxy-4,6-dimethyl-1-indanone oxime 16.2 g was dissolved in 200 ml acetic acid to prepare a platinum oxide catalyst 1.0 g.
Is added and catalytic reduction is carried out at room temperature for 8 hours under a hydrogen pressure of 5 atm.
After removing the catalyst, the liquid is concentrated to dryness under reduced pressure. 200 ml of ethanol is added to the residue to dissolve it, and hydrochloric acid gas is blown in to saturate the residue. The solvent was concentrated to dryness under reduced pressure, and the residue was recrystallized from isopropanol to give colorless needle crystals of 1-amino-2,3.
3.40 g of dihydro-7-hydroxy-4,6-dimethyl-1H-indene hydrochloride are obtained.

mp 222-230 ° C. (decomposition) The following compounds are obtained in the same manner as in Example 3 using appropriate starting materials.

1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-sec-butyl-1H-indene hydrochloride mp 117.5-179 ° C (methanol-ether) colorless powder 1-amino-2,3- Dihydro-7-hydroxy-2,2,4,6
-Tetramethyl-1H-indene hydrochloride mp 231-233 ° C (ethanol) colorless needle crystal Reference Example 4 1-Amino-4,6-dimethyl-7-hydroxy-2,3-
Dihydro-1H-indene 17.7 g and triethylamine 15.
13.56 g of chloroacetyl chloride was added dropwise to a solution of 2 g of chloroform in 200 ml under ice cooling. After completion of dropping, the mixture is stirred at 25 ° C for 3 hours. After the completion of the reaction, the reaction mixture is washed with 100 ml of 1N-hydrochloric acid aqueous solution, and then with 100 ml of water three times.
After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. Recrystallisation from ethanol gives 21 g of 1-chloroacetylamino-2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-indene.

mp 131-132 ° C. Colorless Needle Crystals In the same manner as in Reference Example 4 using the appropriate starting materials, the compounds shown in Table 1 below are obtained.

Reference Example 8 (3-Methoxyphenyl) piperazine (2.00 g) was dissolved in chloroform (20 ml), triethylamine (1.40 ml) was added, and chloroacetyl chloride (0.92 ml) was added little by little at 0 ° C, and the mixture was further stirred at the same temperature for 30 minutes after the addition. To do. After completion of the reaction, the reaction mixture is washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give an oily substance, 1-chloroacetyl-4- (3-methoxyphenyl) piperazine.
3.2g is obtained.

Reference Example 9 To a mixture of 1.50 g of 4- (3-chlorophenyl) piperazine and 0.31 g of sodium hydride, 2.4 ml of epichlorohydrin was added at 0 ° C, and then the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, 100 ml of ethyl acetate is added for extraction, the extract is washed with water (100 ml × 5 times), and dried over anhydrous magnesium sulfate. The solvent was concentrated, and the obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 1) to give 1.66 g of 4- (3-chlorophenyl) -1- ( 2,3-Epoxypropyl) piperazine is obtained as an oil.

Reference Example 10 2,4-Dimethylphenyl cinnamate 10g was melted at 80 ℃, under stirring, 7.93g of finely ground aluminum chloride was added,
After stirring for 0 minutes at the same temperature, 100 g of ice is added to the reaction solution, and the mixture is extracted with 200 ml of methylene chloride. After washing the extract with water and drying,
Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: n-hexane = 1: 1) and recrystallized from ethanol to give 2.89 g of 2,3-dihydro-7-hydroxy-3-phenyl-. 1H-Inden-
Get 1-on.

Light yellow powder mp 137-138 ° C Reference Example 11 4,6-Dimethyl-2- (2-phenylacetyl) phenol 212.6 g was dissolved in N, N, N ', N'-tetramethyldiaminomethane 350 ml, Under ice-cooling stirring, 350 ml of acetic anhydride is added dropwise. After stirring at room temperature for 2 hours, the reaction solution is poured into 1 kg of ice and stirred vigorously. The precipitated crystals are collected, washed with water, dried and recrystallized from ethanol to obtain 186 g of 2,4-dimethyl-6- (2-phenylacryloyl) phenol.

Colorless needle crystals mp 83-84 ° C Reference Example 12 2,4-Dimethyl-6- in 15 ml of concentrated sulfuric acid under stirring with ice cooling.
3.0 g of (2-phenylacryloyl) phenol was added little by little, and the mixture was stirred at room temperature for 1 hour. The reaction mixture is poured into 100 g of ice and extracted with 200 ml of methylene chloride. The extract is washed with water and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was recrystallized from ethanol to give 2.11 g.
2,3-dihydro-4,6-dimethyl-2-phenyl-7-
Hydroxy-1H-inden-1-one is obtained.

mp 90.5 to 91 ° C colorless prism NMR (CDCl ₃ ) δ: 9.03 (s, 1H) 7.42 to 7.08 (m, 6H) 3.92 (dd, 1H, J = 8.4Hz, 3.6Hz) 3.52 (dd) , 1H, J = 16.8Hz, 8.4Hz) 3.02 (dd, 1H, J = 16.8Hz, 3.6Hz) 2.23 (s, 6H) Using the appropriate starting materials under the same conditions as in Reference Example 12, The compounds in Table 2 are obtained.

Reference Example 19 2'-methoxy-5'-methylpropiophenone 140 g
And a solution of 83.4 g of benzaldehyde in 1.5 l of ethanol,
With stirring, 154 ml of 20% aqueous sodium hydroxide solution is added.
After stirring overnight at room temperature, 10% hydrochloric acid is added to acidify and benzene extraction is performed. After washing with water and a saturated saline solution in this order, and drying, 212 g of 2'-methoxy-5'-methyl-2-benzylidenepropionenone is obtained.

Yellow oil NMR (CDCl ₃ ) δ: 2.20 (s, 3H) 2.30 (s, 3H) 3.37 (s, 3H) 6.81 (d, 2H, J = 7Hz) 7.00 to 7.60 (m, 8H) Reference Example 20 2 1 kg of trifluoroacetic acid was added to 210 g of'-methoxy-5'-methyl-2-benzylidenepropiophenone, and the mixture was heated under reflux for 10 hours with stirring. After completion of the reaction, concentrate and extract with methylene chloride. Saturated sodium bicarbonate, water,
Wash with saturated saline solution in this order and dry. After concentration, it was recrystallized from benzene to give a mixture of cis and trans cis- and trans-positions of the indene skeleton (hereinafter cis-trans mixture means this) 2,3-dihydro-2,4-dimethyl-3. 40 g of -phenyl-7-methoxy-1H-inden-1-one are obtained.

Cis NMR (CDCl ₃ ) δ: 0.81 (d, 3H, J = 7Hz) 1.95 (s, 3H) 3.00 (dq, 1H, J = 7Hz) 3.95 (s, 3H) 4.57 (d, 1H, J = 7Hz) ) 6.70 to 7.47 (m, 7H) Trans NMR (CDCl ₃ ) δ: 1.34 (d, 3H, J = 7Hz) 1.84 (s, 3H) 2.50 (dq, 1H, J = 4Hz, J = 7Hz) 3.90 to 4.70 (m, 7H) 6.70 to 7.47 (m, 7H) Reference Example 21 2,3-dihydro-2,4-dimethyl-3-phenyl-7-
A solution of 19.6 g of methoxy-1H-inden-1-one, 11.5 g of sodium iodide and 10.3 g of aluminum chloride in 200 ml of acetonitrile is stirred at room temperature for 2 hours. After the reaction,
The reaction solution is poured into water and extracted with dichloromethane.
After passing through Celite once, it is washed with an aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After drying, it is concentrated and the resulting residue is purified by silica gel column chromatography.
Recrystallization from n-hexane gives 1, 3 g of a cis / trans mixture of 2,3-dihydro-2,4-dimethyl-3-phenyl-7-hydroxy-1H-inden-1-one.

Colorless prism cis cis NMR (CDCl ₃ ) δ: 0.81 (d, 3H, J = 7Hz) 1.89 (s, 3H) 3.08 (dq, 1H, J = 7Hz) 4.61 (d, 1H, J = 7Hz) 6.57 ~7.47 (m, 7H) 8.94 ( s, 1H) trans form _{NMR (CDCl 3) δ: 1.37} (d, 3H, J = 7Hz) 1.80 (s, 3H) 2.58 (dq, 1H, J = 4Hz, J = 7Hz) 3.98 (d, 1H, J = 7Hz) Reference Example 22 2,3-dihydro-2,4-dimethyl-3-phenyl-7-
Acetone 2 of 19.0 g of hydroxy-1H-inden-1-one, 13.98 g of crotyl bromide and 5.47 g of potassium hydroxide
The 00 ml solution is heated to reflux with stirring. The reaction mixture is concentrated, extracted with ethyl acetate, washed with water and saturated brine, and dried. After concentrating the solvent, recrystallize with methanol to
11.8 g of 2,3-dihydro-2,4-dimethyl-3-phenyl-7-crotyloxy-1H-inden-1-one are obtained as a mixture of trans.

Colorless rod mp 138.5-139.5 ° C. cis NMR (CDCl ₃ ) δ: 0.78 (d, 3H, J = 7Hz) 1.66-1.78 (m, 3H) 1.93 (s, 3H) 2.98 (dq, 1H, J = 7Hz) ) 4.70 to 4.83 (m, 2H) 5.56 to 6.20 (m, 2H) 6.67 to 7.43 (m, 7H) Trans NMR (CDCl ₃ ) δ: 1.67 (d, 3H, J = 7Hz) 1.66 to 1.78 (m, 3H) 1.82 (s, 3H) 2.48 (dq, 1H, J = 4Hz, J = 7Hz) 4.53 to 4.67 (m, 2H) 5.56 to 6.20 (m, 2H) 6.67 to 7.43 (m, 7H) Reference example 23 2 , 3-Dihydro-2,4-dimethyl-3-phenyl-4-
Methyl-7-crotyloxy-1H-inden-1-one
11 g of tetralin is added to 55 ml, and the mixture is heated under reflux with stirring for 6 hours. After completion of the reaction, tetralin is concentrated and the resulting residue is purified by silica gel column chromatography.
As a mixture of cis and trans, 2,3-dihydro-2,4-
Dimethyl-3-phenyl-6- (1-buten-3-yl) -7-hydroxy-1H-inden-1-one 11.2 g
Get.

Yellow oily cis NMR (CDCl ₃ ) δ: 0.80 (d, 3H, J = 7Hz) 1.36 (d, 3H, J = 8Hz) 1.87 (s, 3H) 3.10 (dq, 3H, J = 7Hz) 3.70 to 4.06 (M, 1H) 4.57 (d, 1H, J = 7Hz) 4.93 to 5.23 (m, 2H) 5.80 to 6.26 (m, 1H) 6.66 to 7.43 (m, 6H) 9.23 (s, 1H) Trans NMR (CDCl) ₃ ) δ: 1.34 (d, 3H, J = 7Hz) 1.36 (d, 3H, J = 8Hz) 1.80 (s, 3H) 2.58 (dq, 1H, J = 4Hz, 7Hz) 3.94 (d, 1H, J = 4Hz) 3.70 to 4.06 (m, 1H) 4.93 to 5.23 (m, 2H) 5.80 to 6.26 (m, 1H) 6.66 to 7.43 (m, 6H) 9.33 (s, 1H) Reference Example 24 2,3-dihydro-4 , 6-Dimethyl-7-hydroxy-1H
-Inden-1-one 10g to dimethylformamide 200ml
Dissolve in, add 5.45 g of 60% sodium hydride little by little, and stir at room temperature for 30 minutes. p-anisaldehyde 6.91 ml
And further stirred at room temperature for 1 hour. The reaction mixture is poured into 500 ml of ice water, acidified with hydrochloric acid, and the precipitated crystals are collected. After washing with water and n-hexane, it is dried. Recrystallization from ethanol gives 16.09 g of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2- (4-methoxybenzylidene) -1H-inden-1-one.

Yellow needles mp 192-193 ° C Reference Example 25 2,3-dihydro-4,6-dimethyl-7-hydroxy-2
-(4-Methoxybenzylidene) -1H-indene-1-
16.09 g of ON was dissolved in a mixed solvent of 150 ml of ethyl acetate and 100 ml of acetic acid, and catalytic reduction was carried out in the presence of 1.5 g of palladium black at room temperature and 3 atm hydrogen pressure. The catalyst was removed, the liquid was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 9: 1), and then colorless oily 2,3-dihydro -4,6-Dimethyl-7-
8.5 g of hydroxy-2- (4-methoxybenzyl) -1H-inden-1-one are obtained.

NMR (CDCl ₃ ) δ: 2.12 (s, 3H) 2.18 (s, 3H) 2.40 to 3.40 (m, 5H) 3.76 (s, 3H) 6.81 (d, 2H, J = 8Hz) 7.09 (s, 1H) 7.11 (D, 2H, J = 8 Hz) 9.03 (s, 1H) Reference Example 26 In the same manner as in Reference Example 25, the following compounds were obtained using appropriate starting materials.

2,3-dihydro-4,6-dimethyl-7-hydroxy-2-
Benzyl-1H-inden-1-one colorless prism mp 107-108 ° C (recrystallized from ethanol) NMR (CDCl ₃ ) δ: 2.11 (s, 3H) 2.19 (s, 3H) 2.40-3.50 (m, 5H) 7.13 (s, 1H) 7.25 (m, 5H) 9.04 (s, 1H) 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-
(4-chlorobenzyl) -1H-inden-1-one colorless prism mp 108-109 ° C (recrystallized from n-hexane) NMR (CDCl ₃ ) δ: 2.12 (s, 3H) 2.19 (s, 3H) 2.20 ~ 3.40 (m, 5H) 7.09 (s, 1H) 7.10-7.40 (m, 4H) 8.70-9.30 (broad s, 1H) 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-
(3,4-Methylenedioxybenzyl) -1H-indene-
1-one colorless prism mp 108-109 ° C (recrystallized from ethanol) NMR (CDCl ₃ ) δ: 2.17 (s, 3H) 2.21 (s, 3H) 2.40-3.40 (m, 5H) 5.90 (s, 2H) 6.71 (m, 3H) 7.13 (s, 1H) 9.04 (s, 1H) Reference Example 27 In the same manner as in Reference Example 24, using the appropriate starting materials, the following compounds are obtained.

2,3-dihydro-4,6-dimethyl-7-hydroxy-2-
Benzylidene-1H-inden-1-one Light yellow prism mp 161-162 ° C (recrystallized from ethanol) NMR (CDCl ₃ ) δ: 2.18 (s, 3H) 2.22 (s, 3H) 3.71 (s, 2H) 7.08 (S, 1H) 7.30 to 7.70 (m, 5H) 9.23 (s, 1H) 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-
(4-chloro-benzylidene)-1H-inden-1-one light yellow needles mp 184-185 ° C. (recrystallized from _{ethanol) NMR (CDCl 3) δ:} 2.19 (s, 3H) 2.23 (s, 3H) 3.69 (S, 2H) 7.10 (s, 1H) 7.30 to 7.60 (m, 4H) 9.20 (s, 1H) 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-
(3,4-methylenedioxyphenyl benzylidene)-1H-inden-1-one light yellow needles mp two hundred forty-three to two hundred forty-four ° C. (recrystallized from _{ethanol) NMR (DMSO-d 6)} δ: 2.18 (s, 3H) 2.30 (S, 3H) 3.90 (s, 2H) 6.10 (s, 2H) 7.02 (d, 1H, J = 9Hz) 7.25 (s, 1H) 7.28 (d, 1H, J = 2Hz) 7.36 (dd, 1H) , J = 9 Hz, 2 Hz) Reference Example 28 2,3-dihydro-4,6-dimethyl-7-hydroxy-2
-Benzyl-1H-inden-1-one (28.3 g) was dissolved in dimethylformamide (350 ml), 60% sodium hydride (5.2 g) was added at 55-60 ° C, and after stirring for 40 minutes, methyl iodide (8 m) was added.
Add l and heat at the same temperature for 1 hour. Subsequently, 60% sodium hydride (5.2 g) is added, the mixture is stirred at the same temperature for 40 minutes, methyl iodide (8 ml) is added, and the mixture is heated at the same temperature for 1 hour and 10 minutes. Further, 5.2 g of 60% sodium hydride is added, the mixture is stirred at the same temperature for 55 minutes, 8 ml of methyl iodide is added, and the mixture is heated at the same temperature for 3 hours and 20 minutes. Dimethylformamide was distilled off under reduced pressure,
The obtained residue is extracted with ethyl acetate and washed with water and saturated brine in this order. The solvent was distilled off under reduced pressure, and the obtained residue was
After purification by silica gel column chromatography (eluent: n-hexane-ethyl acetate), 23.0 g of 2,3-dihydreo-2,4,6-trimethyl-7-methoxy-2-benzyl-1H-indene- Get 1-on.

NMR (CDCl ₃ ) δ: 1.25 (s, 3H) 2.14 (s, 3H) 2.21 (s, 3H) 2.30 to 3.20 (m, 4H) 3.91 (s, 3H) 7.15 (m, 5H) 7.23 (s, 1H) ) Reference Example 29 2,3-dihydro-2,4,6-trimethyl-7-methoxy-
2-Benzyl-1H-inden-1-one (23.0 g) and sodium iodide (25.8 g) are dissolved in acetonitrile (90 ml), aluminum chloride (22.9 g) is added at room temperature, and the mixture is stirred for 1 hr. The solvent is distilled off under reduced pressure, and the obtained residue is extracted with ethyl acetate. Wash with saturated saline, an aqueous solution of sodium thiosulfate, and saturated saline in this order to remove the insoluble matter. The solvent was distilled off, and the obtained residue was recrystallized from n-hexane to give 19.7
g of 2,3-dihydro-2,4,6-trimethyl-7-hydroxy-2-benzyl-1H-indene is obtained.

Colorless prism mp.86-87 ° C NMR (CDCl ₃ ) δ: 1.22 (s, 3H) 2.08 (s, 3H) 2.15 (s, 3H) 2.30-3.20 (m, 4H) 7.02 (s, 1H) 7.08- 7.40 (m, 5H) 9.03 (s, 1H) Reference Example 30 4,6-Dimethyl-7-hydroxy-2-phenyl-1
5.0 g of indanone are dissolved in 10 ml of diethyl ether and 10 ml of dichloromethane, and gradually added dropwise to a mixture of 2.55 ml of benzylamine 10 ml of diethyl ether and 8 g of Molecular Sieves 5A. After stirring for 2 days at room temperature, pass through with Celite. Celite is washed with dichloromethane and ethanol, and the washing solution and the above solution are combined and concentrated. Recrystallize from dichloromethane-ethanol to give 3.83
g of 4,6-dimethyl-7-hydroxy-1-benzylamino-2-phenyl-3H-indene is obtained.

Orange needle crystals mp. 214-215 ° C Example 1 2,3-Dihydro-7-hydroxy-4-methyl-6-
(1-phenyl-2-propenyl) -1H-indene-1
A solution of 120 g of -one, 45 g of hydroxylamine hydrochloride and 200 ml of pyridine in 1200 ml of ethanol is heated under reflux for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to dryness, and the residue was diluted with ethyl acetate (2 L).
Dissolve in water, wash 3 times with water 1, and dry again under reduced pressure.
Recrystallized from ethyl acetate-n-hexane to give 90 g of 2,3-
This gives dihydro-7-hydroxy-4-methyl-6- (1-phenyl-2-propenyl) -1H-inden-1-one oxime.

mp 146 ° C. (decomposition) pale yellow scaly crystals In the same manner as in Example 1, using the appropriate starting materials, the compounds shown in Table 3 below are obtained.

Example 22 2,3-Dihydro-7-hydroxy-4-methyl-6-
2.93 g of (1-phenyl-2-propenyl) -1H-indene oxime and 0.293 g of platinum oxide are suspended in 200 ml of acetic acid and reduced at room temperature and a hydrogen pressure of 3 atm for 8 hours. After completion of hydrogenation, the catalyst is removed and the liquid is concentrated to dryness under reduced pressure. The residue was dissolved in 100 ml of ethanol, hydrochloric acid gas-saturated ethanol was added to adjust pH to 1, re-dried under reduced pressure and recrystallized from ethanol-ether to give 0.88 g of 1-amino-2,3-dihydro-7-. Hydroxy-4-methyl-6- (1-phenylpropyl) -1H-indene hydrochloride is obtained.

mp 187.5-189.5 ° C. colorless powder Example 23 2,3-dihydro-7-hydroxy-4-methyl-6-
2.93 g of (1-phenyl-2-propenyl) -1H-indene oxime and 0.293 g of platinum oxide are suspended in 200 ml of acetic acid and reduced at room temperature and a hydrogen pressure of 7 atm for 8 hours. After completion of hydrogenation, the catalyst is removed and the liquid is concentrated to dryness under reduced pressure. The residue was dissolved in 100 ml of ethanol, ethanol saturated with hydrochloric acid gas was added to adjust pH to 1, and the mixture was again dried under reduced pressure to dryness with ether-n-
Recrystallization from hexane gives 1.0 g of 1-amino-2,3-dihydro-7-hydroxy-4-methyl-6- (1-cyclohexylpropyl) -1H-indene hydrochloride.

mp 184-185.5 ° C. colorless powder Example 24 2,3-dihydro-4,6-dimethyl-2-phenyl-7-
Hydroxy-1H-inden-1-one oxime (4.79 g) was dissolved in glacial acetic acid (88 ml), and platinum oxide (0.71 g) was added to the solution.
Perform catalytic reduction under atmospheric hydrogen pressure for about 18 hours. After removing the catalyst, the solution is concentrated under reduced pressure. 100 ml of water is added to the obtained residue, neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with 300 ml of chloroform. The insoluble matter was removed, washed with water and ether, and then recrystallized from ethanol to give 1-amino-2 in which the 1-position and 2-position of the indene skeleton are trans.
-Cyclohexyl-2,3-dihydro-4,6-dimethyl-7
2.50 g of hydroxy-1H-indene acetate are obtained.

Pale yellow powder mp.170~172 ℃ _{(decomposition) NMR (DMSO-d 6)} δ: 6.74 (s, 1H) 4.47 (d, 1H, J = 6Hz) 2.80~2.45 (m, 2H) 2.09 (s, 6H) 1.85 (s, 3H) 1.97 to 0.83 (m, 12H) After the above insoluble matter is removed, the liquid is washed with water and dried over magnesium sulfate. The residue obtained after concentration of chloroform under reduced pressure was recrystallized from ethanol to give 1-amino-2-cyclohexyl-2, which has cis at the 1- and 2-positions of the indene skeleton.
1.40 g of 3-dihydro-4,6-dimethyl-7-hydroxy-1H-indene are obtained.

Colorless needle crystals mp.125-126 ° C NMR (CDCl ₃ ) δ: 6.77 (s, 1H) 4.30 (d, 1H, J = 7.5Hz) 3.03 to 2.70 (m, 1H) 2.87 (dd, 1H, J = 15Hz, 7.5Hz) 2.42 (dd, 1H, J = 15Hz, 3Hz) 2.18 (s, 3H) 2.12 (s, 3H) 1.07 to 1.97 (m, 11H) Example 25 2,3-dihydro- 4,6-Dimethyl-7-hydroxy-2
3.00 g of -phenyl-1H-inden-1-one oxime is dissolved in 55 ml of glacial acetic acid, and catalytically reduced in the presence of 0.3 g of platinum oxide at 4 atm hydrogen pressure and room temperature. When the theoretical amount of hydrogen has been absorbed, the reaction is stopped, the catalyst is removed, and the liquid is concentrated. The obtained residue is dissolved in water, adjusted to pH≈8 with an aqueous sodium hydrogen carbonate solution, and then extracted with 200 ml of chloroform. The extract is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. Recrystallize from ethanol to give 0.24 g of 1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-2.
-Phenyl-1H-indene is obtained.

Colorless needle crystals mp.135-136 ° C NMR (CDCl ₃ ) δ: 7.30-7.13 (m, 3H) 7.03-6.87 (m, 2H) 6.80 (s, 1H) 4.89 (d, 1H, J = 7.5Hz) 3.68 (d-d-d, 1H, J = 7.55Hz, 7.5HZ, 3.0HZ) 3.25 (d-d, 1H, J = 16.5Hz, 7.5Hz) 2.95 (d-d, 1H, J = 16.5Hz, 3.0 Hz) 2.18 (s, 6H) In the same manner as in Examples 22 to 25, using the appropriate starting materials, the compounds shown in Table 4 below are obtained.

1) NMR (CDCl ₃ ) δ: 7.26 to 7.00 (m, 5H) 6.78 (s, 1H) 4.40 (s, 1H) 4.0 (br., 2H) 3.30 (d, 1H, J = 17Hz) 2.86 (d, 1H, J = 17Hz) 2.15 ( s, 6H) 1.59 (s, 3H) 2) NMR (DMSO-d 6) δ: 7.35 (d, 2H, J = 8.5Hz) 7.14 (d, 2H, J = 8.5Hz ) 6.77 (s, 1H) 4.74 (d, 1H, J = 6Hz) 3.85 ~ 3.60 (m, 1H) 3.20 ~ 2.95 (m, 2H) 2.15 (s, 3H) 2.10 (s, 3H) 3) NMR (CDCl ₃ ) δ: 7.20 (d, 2H, J = 8.5Hz) 6.88 (d, 2H, J = 8.5Hz) 6.83 (s, 1H) 4.90 (d, 1H, J = 7Hz) 3.75 to 3.50 (m, 1H) 3.24 (d-d, 1H, J = 15Hz, 7Hz) 3.95 (d-d, 1H, J = 15Hz, 3Hz) 2.19 (s, 6H) 4) NMR (CDCl 3 -DMSO-d 6) δ: 7.05 ( s, 4H) 6.80 (s, 1H) 6.60 (s, 1H) 4.78 (d, 1H, J = 7.5Hz) 3.65 (m, 1H) 3.15 ~ 2.90 (m, 2H) 2.25 (s, 3H) 2.12 (s , 6H) 5) NMR (DMSO-d ₆ ) δ: 2.17 (s, 6H) 2.40 (s, 3H ) 2.91 (dd, 1H, J = 15Hz, 6Hz) 3.60 (dd, 1H, J = 15Hz, 12Hz) 3.80 ~ 4.17 (m, 1H) 4.80 ~ 5.10 (m, 1H) 6.95 (s, 1H) ) 7.10 to 7.30 (m, 3H) 7.43 to 8.00 (m, 3H) 9.10 (br., 1H) 6) NMR (DMSO-d ₆ ) δ: 2.01 (s, 3H) 2.06 (s, 3H) 2.30 to 3.20 (M, 5H) 4.21 (m, 1H) 6.46 (s, 1H) 6.73 (s, 1H) 6.87 (d, 2H, J = 8Hz) 7.13 (d, 2H, J = 8Hz) 7) NMR (CDCl ₃ ) δ: 7.40 to 7.18 (m, 3H) 7.10 to 6.90 (m, 3H) 4.90 (d, 1H, J = 7.5Hz) 3.84 to 3.60 (m, 1H) 3.50 to 3.10 (m, 2H) 2.20 (s, 3H) ) 8) NMR (CDCl ₃ ) δ: 7.25 to 7.10 (m, 3H) 6.92 (m, 2H) 6.80 (s, 1H) 4.88 (d, 1H, J = 7.5Hz) 3.68 (t-d, 1H, J = 7.0Hz, 3Hz) 3.25 (dd, 1H, J = 15Hz, 7.5Hz) 2.95 (dd, 1H, J = 15Hz, 3Hz) 2.80 to 2.35 (m, 2H) 1.20 (t, 3H) 9 _{) NMR (CDCl 3 -DMSO-d} 6) δ: 8.60~7.70 (br. 4H) 6.83 (s, 1H) 4.73 (d, 1H, J = 6Hz) 3.50 ~ 3.20 (m, 1H) 2.85 ~ 2.60 (m, 2H) 2.18 (s, 3H) 2.12 (s, 3H) 2.20 ~ 0.80 ( m, 10H) 10) NMR (CDCl ₃ ) δ: 2.18 (s, 6H) 2.95 (dd, 1H, J = 15Hz, 3Hz) 3.25 (dd, 1H, J = 16.5Hz, 7.5Hz) 3.68 (D-d-d, 1H, J = 7.5Hz, 7.5Hz, 3.0Hz) 4.89 (d, 1H, J = 7.5Hz) 6.80 to 7.03 (m, 2H) 7.13 to 7.30 (m, 3H) 11) NMR (CDCl ₃ -DMSO-d ₆ ) δ: 7.40 to 7.15 (m, 5H) 6.83 (s, 1H) 6.68 (s, 2H) 4.85 (d, 1H, J = 7.5Hz) 3.90 to 3.60 (m, 1H) 3.25~3.10 (m, 2H) 2.18 ( s, 6H) 12) NMR (DMSO-d 6) δ: 2.06 (s, 3H) 2.11 (s, 3H) 2.30~3.30 (m, 5H) 4.70 (m, 1H ) 6.50 (s, 1H) 6.79 (s, 1H) 7.20 ~ 7.40 (m, 5H) 7.00 ~ 8.20 (br., 6H) 13) NMR (CDCl ₃ ) δ: 2.20 (s, 3H) 2.99 (dd, 1H) , J = 16.5Hz, 3Hz) 3.23 (dd, 1H, J = 16.5Hz, 7.5Hz) 3.7 0 (ddd, 1H, J = 7.5Hz, 7.5Hz, 3Hz) 4.91 (d, 1H, J = 7.5Hz) 6.89 (d, 1H, J = 6Hz) 6.93 (d, 1H, J = 6.0Hz) 7.20 ( s, 4H) 14) NMR (DMSO-d ₆ ) δ: 2.20 (s, 3H) 3.03 (dd, 1H, J = 15Hz, 7.5Hz) 3.27 to 4.03 (m, 2H) 4.67 to 4.93 (br.m, 1H) 6.90 (ABq, 2H, J = 22.5Hz, 8.5Hz) 7.23 to 7.63 (m, 5H) 7.67 to 8.03 (brm, 3H) 9.77 to 10.07 (brm, 1H) 15) NMR (DMSO-d ₆ ) δ : 2.02 (s, 3H) 2.10 (s, 3H) 2.15 ~ 3.15 (m, 5H) 4.35 (m, 1H) 6.50 (s, 2H) 6.82 (s, 1H) 7.20 ~ 7.50 (m, 4H) 8.20 ~ 10.00 (Br., 5H) 16) NMR (DMSO-d ₆ ) δ: 2.01 (s, 3H) 2.10 (s, 3H) 2.20 to 3.20 (m, 5H) 4.65 (s, 1H) 5.97 (s, 2H) 6.45 (S, 1H) 6.50 to 7.00 (m, 4H) 7.90 to 9.00 (br., 4H) 17) NMR (DMSO-d ₆ ) δ: 0.98 (s, 3H) 0.50 to 2.00 (m, 13H) 2.09 (s , 3H) 2.15 (s, 3H) 2.55 (d, 1H, J = 15Hz) 3.94 (d, 1H, J = 15 Hz) 4.23 (s, 1H) 6.90 (s, 1H) 8.20-9.50 (br., 4H) Example 46 1-Amino-2,3-dihydro-7-hydroxy-4-
Methyl-6- (1-phenylpropyl) -1H-indene hydrochloride 31.8 g and triethylamine 15.2 g chloroform
Chloroacetyl chloride 13.
56 g is dropped. After completion of dropping, the mixture is stirred at 25 ° C for 3 hours.
After the completion of the reaction, the reaction mixture is washed with 100 ml of 1N-hydrochloric acid aqueous solution, and then with 100 ml of water three times. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. Ether-n
Recrystallization from hexane gives 14.7 g of 1-chloroacetylamino-2,3-dihydro-4-methyl-6- (1-phenylpropyl) -7-hydroxy-1H-indene.

mp 172-174 ° C colorless powder In the same manner as in Example 46, using the appropriate starting materials, the compounds shown in Table 5 below are obtained.

Example 51 1-chloroacetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene 6.64 g
Was dissolved in 100 ml of acetonitrile, and 4- (3-
9.27 g of chlorophenyl) piperazine is added, and the mixture is refluxed with heating for 2 hours. After ice-cooling, the precipitated excess 4- (3-chlorophenyl) piperazine hydrochloride was removed, and the solution was concentrated under reduced pressure and recrystallized from ethanol to give 8.10 g of 1- [4-
(3-Chlorophenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene is obtained.

mp 125-126 ° C. colorless powder In the same manner as in Example 51, using the appropriate starting materials, the compounds shown in Table 6 below are obtained.

Example 104 3.63 g of 2-pyrrolidone is dissolved in 40 ml of dimethylformamide, 1.71 g of 60% sodium hydride is added little by little, and the mixture is stirred for 30 minutes. In this suspension, 1-chloroacetylamino-2,3-dihydro-7-hydroxy-2,
Add 4.00 g of 2,4,6-tetramethyl-1H-indene and stir at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was cooled to 100 m with ice water.
Pour into l and extract with 200 ml of methylene chloride. The extract is washed with water and dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 2) and recrystallized from ethanol to give 2.27 g of 2,3-dihydro-7-hydroxy-1. -(2-Pyrrolidone-1-yl) acetylamino-2,2,4,6-tetramethyl-1H-indene is obtained.

mp 165-168 ° C. colorless needles Example 105 4-methylpiperazine 1.07 g, 1-chloroacetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene 1.50g and acetonitrile 24m
Heat 1 to reflux for 2 hours. The reaction mixture is ice-cooled, the precipitated crystals are removed, and the liquid is concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 2) and recrystallized from ethanol to give 1.20 g of 2,3-dihydro-7-hydroxy-1-.
(4-Methyl-1-piperazinyl) acetylamino-2,
2,4,6-Tetramethyl-1H-indene is obtained.

mp 189 to 190 ° C. colorless needles In the same manner as in Example 105, using the appropriate starting materials, the compounds shown in Table 7 below are obtained.

Example 114 1-amino-2,3-dihydro-2,2,4,6-tetramethyl-7-hydroxy-1H-indene hydrochloride 2.50 g, triethylamine 4.33 ml and acetonitrile 30 ml solution, 1-
Chloroacetyl-4- (3-methoxyphenyl) piperazine (3.0 g) is added, and the mixture is heated under reflux for 10 hours. After completion of the reaction, the solvent is distilled off, the resulting residue is dissolved in 200 ml of chloroform, washed with water and dried over anhydrous magnesium sulfate. The solvent was again evaporated to dryness under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 1).
Purify in 2). Recrystallized from ethanol to give 0.90 g of 1- (2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-inden-1-yl) aminoacetyl-
4- (3-Methoxyphenyl) piperazine is obtained.

mp 164.5-166.0 ° C. colorless scaly crystals Example 115 In the same manner as in Example 114, the following compounds are obtained using appropriate starting materials.

1- (2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-inden-1-yl) aminoacetyl-
4- (3-chlorophenyl) piperazine mp 144.0-145.5 ° C (recrystallized from ethanol) colorless powder Example 116 1- [4- (3-chlorophenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7 To a solution of 5.00 g of -hydroxy-2,2,4,6-tetramethyl-1H-indene in 100 ml of diglyme, 4.3 g of lithium aluminum hydride was added little by little with stirring, and then the mixture was heated under reflux for 3 hours.
After completion of the reaction, the reaction mixture is cooled with ice, and ice water is added to the reaction mixture to decompose excess lithium aluminum hydride.
After filtration, the liquid is extracted with 200 ml of methylene chloride. The extract is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is dissolved in 50 ml of ethanol, an ethanol solution containing 1.31 g of fumaric acid is added, and the mixture is concentrated to dryness under reduced pressure. Recrystallized from ethanol to give 2.3 g of 1
-{2- [4- (3-chlorophenyl) -1-piperazinyl] ethylamino} -2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indenefumarate .

mp 144-146 ° C. colorless powder Example 117 In the same manner as in Example 116, the following compounds are obtained using appropriate starting materials.

1- {2- [4- (3-methoxyphenyl) -1-piperazinyl] ethylamino} -2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indenefumaric acid Salt mp 122-125 ° C. (recrystallized from ethanol) Colorless powder Example 118 1-amino-2,3-dihydro-7-hydroxy-2,2,
To a solution of 4,6-tetramethyl-1H-indene hydrochloride (22.65 g) and triethylamine (15.2 g) in chloroform (200 ml), [4- (3-chlorophenyl) -1-piperazinyl] acetyl chloride (32.76 g) was added dropwise under ice-cooling and stirring. After completion of dropping, the mixture is stirred at 25 ° C for 3 hours. After the reaction is completed, the reaction mixture is
Wash with 100 ml of 1N-hydrochloric acid aqueous solution, and then wash with 100 ml of water three times. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. Recrystallization from ethanol gave 17.6 g of 1- [4- (3-chlorophenyl) -1-piperazinyl] acetylamino} -2,3-dihydro-2,2,4,6.
-Tetramethyl-7-hydroxy-1H-indene is obtained.

mp 125 to 126 ° C. colorless powder In the same manner as in Example 118, using the appropriate starting materials, the compounds of Examples 52 to 113 are obtained.

Example 119 1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-indane 1.77 g and triethylamine 2 ml
2.23 g of octyl chloride is added dropwise to 100 ml of chloroform solution at room temperature. Then, the mixture is stirred at the same temperature for 4 hours. The reaction mixture is washed with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, and dried over sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol, hydrochloric acid gas saturated ethanol was added to this to give the hydrochloride, and then recrystallized from acetonitrile to give 2,3-dihydro-1-
Octylamino-4,6-dimethyl-7-hydroxy-1H
-0.49 g of indan hydrochloride is obtained.

mp 120-121 ° C. colorless needles Example 120 Using the appropriate starting materials, the compounds of Examples 116 and 117, and the compounds of Examples 122 to 124 below and Example 127 below are obtained in the same manner as in Example 119. .

Example 121 2,3-Dihydro-4,6-dimethyl-7-hydroxy-1H
-Inden-1-one 1.76 g and n-octylamine 25.
8 g of 100 ml ethanol solution is heated under reflux for 8 hours. After cooling to room temperature, 1 g of sodium borohydride was added, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture is concentrated to dryness, and 100 ml of water is added to the residue to dissolve it. Acidify with concentrated hydrochloric acid, and then adjust to pH≈9 with saturated aqueous sodium acetate solution. The obtained precipitate is extracted with ethyl acetate, washed with water and dried. The solvent is distilled off, the obtained residue is dissolved in 100 ml of ethanol, and the hydrochloride is obtained by adding hydrochloric acid gas saturated ethanol. Recrystallization from acetonitrile gives 2.40 g of 2,3-dihydro-1-n-octylamino-4,6-dimethyl-7-hydroxy-1H-indene hydrochloride.

mp 120-121 ° C. colorless needles Example 122 Using appropriate starting materials, the following compounds in Table 8 are obtained in the same manner as in Example 121.

Example 125 6-Chloroacetylaminomethyl-2,3-dihydro-
7-Hydroxy-4-methyl-1H-inden-1-one
200 g, hydroxyamine hydrochloride 77.9 g, pyridine 300 ml and ethanol 1800 ml are heated under reflux for 3 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, 2 l of water is added to the residue, the mixture is vigorously stirred, cooled and crystallized. After taking the crystals and washing them with water,
Recrystallization from water gives 167 g of (2,3-dihydro-7-hydroxy-1-hydroxyimino-4-methyl-1H-inden-6-yl) methylaminocarbonylmethylpyridinium chloride.

mp 279 ° C. (decomposition) colorless scale crystals Example 126 (2,3-dihydro-7-hydroxy-1-hydroxyimino-4-methyl-1H-inden-6-yl) methylaminocarbonylmethylpyridinium chloride 10 g,
200 ml of acetic acid and 1.0 g of platinum oxide are added at a hydrogen pressure of 3 atm at room temperature for 8
Perform time catalytic reduction. After the reaction, remove with a catalyst,
The solution is concentrated under reduced pressure to dryness. The residue obtained is methanol 10
It was dissolved in 0 ml, and under cooling with ice, a hydrochloric acid gas saturated methanol solution was added to adjust the pH to 1, then dried under reduced pressure again to dryness, and recrystallized from ethanol-ether to give 4.8 g of 1-amino-2. , 3-Dihydro-7-hydroxy-4-methyl-6-
Piperidinyl acetylaminomethyl-1H-indene dihydrochloride is obtained.

mp 146 ° C. (decomposition) colorless powder Example 127 0.21 g of 4- (3-chlorophenyl) -1- (2,3-epoxypropyl) piperazine was added to 1-amino-2,3-dihydro-7-hydroxy-2, A solution of 0.21 g of 4,6-tetramethyl-1H-indene hydrochloride in 10 ml of ethanol is added, and the mixture is heated under reflux for 5 hours. After completion of the reaction, the solvent is concentrated under reduced pressure, the resulting residue is made alkaline with a 10% aqueous sodium hydrogen carbonate solution and extracted with 100 ml of methylene chloride. The extract is washed with water (100 ml x 3 times) and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1),
0.21 g of 1- {3- [4- (3-chlorophenyl) -1
-Piperazinyl] -2-hydroxypropylamino}-
2,3-Dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene is obtained.

NMR (CDCl ₃ ) δ; 7.14 (t, 1H), 6.90 to 6.70 (m, 4H) 4.60 to 3.70 (br., 2H) 4.20 (s, 1H) 3.90 (m, 1H) 3.20 (t, 6H) 2.90 ~ 2.30 (m, 8H) 2.18 (s, 3H) 2.80 (s, 3H) 1.20 (s, 2H) 0.85 (s, 3H) Example 128 4,6-Dimethyl-7-hydroxy-1-benzylamino-2 -Phenyl-3H-indene 2.60 g, 10% Pd-C0.26
g and 50 ml of acetic acid are catalytically reduced at 4 atm hydrogen pressure and room temperature. After completion of the reaction, the catalyst is removed and the product is washed with ethanol. The washing solution and the solution were combined and concentrated, and the obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 5) to give 0.67 g of 1-amino-2-phenyl- 2-Benzyloxy-4,6-dimethyl-2,3-dihydro-7-hydroxy-1H-indene (A) and 0.37 g of 1-amino-2-phenyl-2-hydroxy-4,6-dimethyl-2. There is obtained 3,3-dihydro-7-hydroxy-1H-indene (B).

(A); Light yellow prismatic crystal mp.166 to 167 ° C (recrystallized from ethanol) (B); Colorless needle crystal mp.151 to 153 ° C (recrystallized from ethanol) Example 129 1-chloroacetylamino- 2,3-Dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene 7.04 g
Is dissolved in 200 ml of acetonitrile and triethylamine 10 m
Add 5.0 g of L, m-methoxyphenylpiperazine and heat to reflux for 2 hours. Concentrate to dryness under reduced pressure and add 100 ml of water to the residue.
Was added, and the pH was adjusted to ≈ 8 with saturated aqueous sodium hydrogen carbonate, and the ethyl acetate was 500m.
Extract with l. The extract is washed with water, concentrated to dryness under reduced pressure, added with ethanol and boiled. The poorly soluble portion of ethanol was removed and recrystallized from ethanol to give 3.90 g of 2,3-dihydro-
7-hydroxy-1- [4- (3-methoxyphenyl)
-1-Piperazinyl] carbonylamino-2,2,4,6-tetramethyl-1H-indene is obtained.

mP.206-208 ° C colorless powder NMR (CDCl ₃ -DMSO-d ₆ ) δ: 1.10 (s, 3H) 1.23 (s, 3H) 2.10 (s, 3H) 2.15 (s, 3H) 2.46 (d, 1H , J = 15Hz) 2.92 (d, 1H, J = 15Hz) 3.05 ~ 3.30 (m, 4H) 3.50 ~ 3.65 (m, 4H) 3.76 (s, 3H) 4.64 (d, 1H, J = 7.5Hz) 6.25 ~ 6.60 (m, 3H) 6.74 (s, 1H) 7.14 (t, 1H, J = 9Hz) 7.50 (m, 1H) Concentrate the above ethanol extract under reduced pressure and add ethanol solution of fumarate to pH ≈ 4 After adjusting to ~ 5, under reduced pressure,
The mixture was concentrated to dryness, and the obtained residue was recrystallized from ethanol to give 5.2 g of 2,3-dihydro-7-hydroxy-1- [4
-(3-Methoxyphenyl) -1-piperazinyl] acetylamino-2,2,4,6-tetramethyl-1H-indene fumarate is obtained.

Mp.167～169 ° C. Colorless powdery _{NMR (CDCl 3 -DMSO-d 6} ) δ: 1.13 (s, 3H) 1.26 (s, 3H) 2.10 (s, 3H) 2.18 (s, 3H) 2.48~2.92 (m , 6H) 3.10 to 3.34 (m, 6H) 3.78 (s, 3H) 4.68 (d, 1H, J = 7.5Hz) 6.30 to 6.60 (m, 3H) 6.74 (s, 2H) 6.80 (s, 1H) 7.15 ( t, 1H, J = 9Hz) 8.08 (d, 1H, J = 7.5Hz) 8.70 to 10.0 (br., 3H) Example 130 In the same manner as in Example 51, the obtained crude crystals were dissolved by heating in ethanol. The mixture was allowed to cool at room temperature and the precipitated crystals were collected to give 1- [4- (3-methoxyphenyl) -1- as colorless prism crystals.
Piperazinyl] acetylamino-2,3-dihydro-7-
Hydroxy-2,2,4,6-tetramethyl-1H-indene is obtained.

mp 143-143.5 ° C NMR (CDCl ₃ ) δ; 1.13 (s, 1H) 1.25 (s, 3H) 2.11 (s, 3H) 2.20 (s, 3H) 2.40-9.93 (m, 6H) 3.00-3.33 (m, 6H) 3.80 (s, 3H) 4.70 (d, 1H, J = 7.5Hz) 6.33 to 6.60 (m, 3H) 6.82 (s, 1H) 7.17 (t, 1H, J = 9Hz) 8.0 (br d, 1H, J = 7.5 Hz) 8.8 (brs, 1H) The NMR spectrum of this compound is shown in FIG.

Example 131 1- [4- (3-Methoxyphenyl) -1-piperazinyl] acetylamino-2,3 obtained in Example 130 above
-Dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene was heated and dissolved in ethanol saturated with hydrogen chloride, allowed to cool to room temperature, water was added until it became cloudy, and the mixture was left with stirring. , Precipitated crystals were collected and 1- [4- (3-methoxyphenyl) -1-piperazinyl] acetylamino-
The hydrochloride salt of 2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene is obtained.

Colorless fine needles mp 187 ℃ Shrink, 192-194 ℃ (decomposition) NMR (CDCl ₃ ) δ: 1.13 (s, 3H) 1.25 (s, 3H) 2.12 (s, 3H) 2.20 (s, 3H) 2.43 ~ 2.93 (m, 6H) 3.10 to 3.30 (m, 6H) 3.80 (s, 3H) 4.70 (d, 1H, J = 7.5Hz) 6.33 to 6.60 (m, 3H) 6.82 (s, 1H) 7.17 (t, 1H) , J = 9 Hz) 8.30 (br d, 1H, J = 7.5 Hz) 8.80 (s, 1H) The NMR spectrum of this compound is shown in FIG.

(A) Anti-oxygen deficiency action The anti-oxygen deficiency action is described in Arch.int.Pharmacodyn., 233 , 137.
(1978).

ICR male mice (weight 20-30 g) were used. Place 4 mice at a time in a glass desiccator and the internal pressure is 210 or 240.
Vacuum the air until it reaches mmHg and close the cock. The time from the activation of the vacuum pump to the cessation of respiration of each mouse was measured and defined as the survival time. The test compound was orally or intraperitoneally administered 15 minutes before the start of inhalation. The survival time of control mice was set to 100 and the percentage of the survival time when the test compound was administered was shown. The results are shown in Table 9.

(B) Effect on post-traumatic consciousness disorder in mouse head It was examined whether or not the compound of the present invention has an influence on the consciousness disorder created by impacting the mouse head.

The neck skin of the mouse was grasped and the head was fixed on a 2 cm-thick Styrofoam pillow. Acrylic column bar (20g)
Was placed on an acrylic tube and dropped from the height of 30 cm to the top of the mouse's head to give an impact. The time until the development of the righting reflex (RR time) and the time until the development of spontaneous movement (SM time) were used as indicators of consciousness disorder.

The test compound was orally or intraperitoneally administered in a volume of 0.1 ml / 10 g 15 minutes before the impact. As a control, the same amount of physiological saline was administered. After the experiment, head autopsy of all mice was performed, and those with brain contusion were excluded from the determination.

The RR time or SMN time of control mice was set to 100, and the percentage of the RR time or SM time of the test compound-administered mice was shown. The results are shown in Table 10.

Test compound 1. 1- [4- (3-chlorophenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene 2.1 -[4- (3-Methoxyphenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-4-methyl-6- (1-methylpropyl) -1H-
Indene dihydrochloride 3. 1- [4- (3,5-dichlorophenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-4-methyl-6- (1-methylpropyl ) -1H
-Indene 4.1- [4- (3-chlorophenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-4-methyl-6- (1-methylpropyl) -1H-indene / hydrochloric acid Salt 5. 1- [4- (3-chlorophenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-4,6-dimethyl-1H-indene hydrochloride 6.1- [4- (3-Methoxyphenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene 7.2,3-dihydro-7-hydroxy -4-methyl-1
-(4-Methyl-1-piperazinyl] acetylamino-
6- (1-Methylpropyl) -1H-indene 8. 1-Amino-2-phenyl-4,6-dimethyl-7-
Hydroxy-2,3-dihydro-1H-indene 9. 1-amino-2- (2-methylphenyl) -4,6-
Dimethyl-7-hydroxy-2,3-dihydro-1H-indene 10.1-Amino-2- (4-chlorophenyl) -4,6-
Dimethyl-7-hydroxy-2,3-dihydro-1H-indene 11. 1- [4- (3-chlorophenyl) -1-piperazinyl] acetylamino-4-methyl-6- (1-phenylpropyl) -7 -Hydroxy-2,3-dihydro-1H
-Indene 12.1- [4- (3-methoxyphenyl) -1-piperazinyl] acetylamino-2-cyclohexyl-4,6
-Dimethyl-7-hydroxy-2,3-dihydro-1H-indene 13.1- [4- (3-methoxyphenyl) -1-piperazinyl] amide-2,2,4,6-tetramethyl-7- Hydroxy-2,3-dihydro-1H-indene 14. 1-Amino-4-methyl-6- (1-dichlorohexylpropyl) -7-hydroxy-2,3-dihydro-1H
-Indene 15.1- (4-Methyl-1-piperazinyl) acetylamino-2,2,4,6-tetramethyl-7-hydroxy-2,3
-Dihydro-1H-indene 16.1-amino-4-methyl-2-phenyl-4,6-dimethyl-7-methoxy-2,3-dihydro-1H-indene 17.1- {2- [4- ( 3-chlorophenyl) -1-
Piperazinyl] ethylamino} -2,2,4,6-tetramethyl-7-hydroxy-2,3-dihydro-1H-indene 18.1- (2,3-dihydro-7-hydroxy-2,2,4 , 6
-Tetramethyl-1H-inden-1-yl) aminoacetyl-4- (3-chlorophenyl) piperazyl 19. 1- (pyrrolidinylacetylamino) -7-hydroxy-2,2,4,6-tetramethyl- 2,3-dihydro-1H-
Indene 20.1- (piperidinylacetylamino) -7-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1H-
Indene 21.2,3-dihydro-1-amino-2-phenyl-2-
Hydroxy-4,6-dimethyl-7-hydroxy-1H-indene 22.2,3-dihydro-1- [2- (dimethylamino) ethylamino] -2-phenyl-4,6-dimethyl-7-hydroxy- 1H-indene 23.2,3-dihydro-1-benzylamino-2-phenyl-4,6-dimethyl-7-hydroxy-1H-indene 24.2,3-dihydro-1-amino-2-phenyl-4 , 6
-Dimethyl-7-hydroxy-1H-indene 25.2,3-dihydro-1-amino-3-phenyl-4,6
-Dimethyl-7-hydroxy-1H-indene 26.2,3-dihydro-1- [4- (3-methoxyphenyl) -1-piperazinyl] acetylamino-2,2,4-trimethyl-7-hydroxy- 1H-indene 27.2,3-dihydro-1- [4- (4-methoxyphenyl) -1-piperazinyl] acetylamino-2,2,4,6-
Tetramethyl-7-hydroxy-1H-indene 28.2,3-dihydro-1- [4- (4-methoxybenzoyl) -1-piperazinyl] acetylamino-2,2,4,6
-Tetramethyl-7-hydroxy-1H-indene 29.2,3-dihydro-1- [4- (3-methoxyphenyl) -1-piperazinyl] acetylamino-2,2,4,6-
Tetramethyl-7-methoxy-1H-indene 30.2,3-dihydro-1- [4- (2-hydroxyethyl) -1-piperazinyl] acetylamino-2,2,4,6-
Tetramethyl-7-hydroxy-1H-indene 31.2,3-dihydro-1- [4- (2,4,6-trimethylphenyl) -1-piperazinyl] acetylamino-2,2,
4,6-Tetramethyl-7-hydroxy-1H-indene 32.2,3-dihydro-2- (2-chlorohexyl) -1
-Amino-4,6-dimethyl-7-hydroxy-1H-indene 33.2,3-dihydro-1-amino-2-phenyl-4-
Chloro-6-methyl-7-hydroxy-1H-indene 34.2,3-dihydro-1- [4- (3-chlorophenyl) -1-piperazinyl] acetylamino-2- (2-
Methylphenyl) -4,6-dimethyl-7-hydroxy-1
H-indene 35.2,3-dihydro-1-amino-2-benzyl-4,6
-Dimethyl-7-hydroxy-1H-indene 36.2,3-dihydro-1-amino-2- (4-methoxybenzyl) -4,6-dimethyl-7-hydroxy-1H-indene 37.2,3- Dihydro-2,2,4,6-tetramethyl-1-
(4-Pyrrolidinylcarbonylmethyl-1-piperazinyl) acetylamino-7-hydroxy-1H-indene 38.2,3-dihydro-2,4,6-trimethyl-2-phenyl-1- [4- (3 -Methoxyphenyl) -1-piperazinyl] acetylamino-7-methoxy-1H-indene 39.2,3-dihydro-2,2,4,6-tetramethyl-1-
[4- (2-ethoxyphenyl) -1-piperazinyl]
Acetylamino-7-hydroxy-1H-indene 40.2,3-dihydro-2,2,4,6-tetramethyl-1-
[4- (2,5-Dichlorophenyl) -1-piperazinyl] acetylamino-7-hydroxy-1H-indene 41.2,3-dihydro-2,2,4,6-tetramethyl-1-
[4- (3-fluorophenyl) -1-piperazinyl]
Acetylamino-7-hydroxy-1H-indene 42. 2,3-dihydro-2,2,4,6-tetramethyl-1-
[4- (3,4-Dimethoxyphenyl) -1-piperazinyl] acetylamino-7-hydroxy-1H-indene 43.2,3-dihydro-2- (4-chlorobenzyl) -1
-Amino-4,6-dimethyl-7-hydroxy-1H-indene 44.2,3-dihydro-2- (cyclohexylmethyl)-
2,4,6-Trimethyl-7-hydroxy-1-amino-1H
-Indene 45.2,3-dihydro-1-amino-2-phenyl-4-
Methyl-6-bromo-7-hydroxy-1H-indene 46. 1- [4- (3-methoxyphenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-2,2,4 , 6-Tetramethyl-1H-indene fumarate 47. 1- [4- (3-methoxyphenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6 -Tetramethyl-1H-indene hydrochloride Formulation Example 1 1- [3- {4- (3-chlorophenyl) -1-piperazinyl} propionyl] amino-7-hydroxy-2,2,
4,6-Tetramethyl-2,3-dihydro-1H-indene 200 m
g Glucose 250 mg Distilled water for injection Appropriate amount 5 ml Dissolve the compound of the present invention and glucose in distilled water for injection, pour into an ampoule of 5 ml, replace with nitrogen, and sterilize under pressure at 121 ° C for 15 minutes. An injection having the above composition is obtained.

Formulation Example 2 1- (2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-inden-1-yl) -aminoacetyl-4- (3-methoxyphenyl) piperazine 100 g Avicel (trade name, manufactured by Asahi Kasei Co., Ltd.) 40g Constarch 30g Magnesium stearate 2g TC-5 10g (trade name, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethylcellulose) Polyethylene glycol-6000 3g Castor oil 40g Methanol 40g Present invention Take the compound of Avicel, corn starch and magnesium stearate, mix and polish, and tablet with a sugar coated R 10 mm kine. The resulting tablets are coated with a film coating agent consisting of TC-5, polyethylene glycol-6000, castor oil and methanol to produce a film coated tablet having the above composition.

Formulation Example 3 1- {2- [4- (3-methoxyphenyl) -1-piperazinyl] ethylamino} -2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H- Indene 2g Purified lanolin 5g White beeswax 5g White petrolatum 88g Total 100g White beeswax is heated to form a liquid, then the compound of the present invention, purified lanolin and white petrolatum are added, and after heating until a liquid, solidification begins Stir to obtain an ointment of the above composition.

[Brief description of drawings]

FIG. 1 is an NMR spectrum diagram of the compound obtained in Example 53, FIG. 2 is an NMR spectrum diagram of the compound obtained in Example 130, and FIG. 3 is an NMR spectrum diagram of the compound obtained in Example 131. It is a spectrum figure.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/495 31/535 31/54 C07D 207/16 213/04 233/61 103 295/14 A 317/58 401/04 235

Claims (5)

[Claims] 1. A general formula [Wherein R ¹ and R ^{2 each} have a hydrogen atom, a lower alkyl group, a halogen atom as a substituent on the phenyl ring, a phenyl group which may have a lower alkyl group, or a halogen atom on the cycloalkyl ring. Optionally, a cycloalkyl, a cycloalkyl lower alkyl group, a hydroxyl group, a phenyl lower alkoxy group or a phenyl lower alkyl group optionally having a halogen atom, a lower alkylenedioxy group or a lower alkoxy group on the phenyl ring. R ³ represents a halogen atom or a lower alkyl group. R ⁴ is a hydrogen atom, a halogen atom, a phenyl lower alkyl group, a cycloalkyl lower alkyl group,
Piperidinyl lower alkanoylamino lower alkyl group,
A pyridinium lower alkanoylamino lower alkyl group or a lower alkyl group is shown. Wherein R ⁸ is a group -A-B. A represents a lower alkylene group which may have a hydroxy group, a group -CO- (D) l- or a group -D-CO- (D is a lower alkylene group, l represents an integer of 0 or 1),
B represents a 5- or 6-membered saturated or unsaturated heterocyclic group. The heterocyclic group may have a lower alkyl group which may have a hydroxy group as a substituent, an oxo group, a carboxy group, a lower alkoxycarbonyl group, a pyridyl group, a phthalimido group,
A pyrrolidinyl carbonyl lower alkyl group, a halogen atom as a substituent on the phenyl ring, a lower alkyl group which may have a halogen atom, a lower alkoxy group and 1 to 3 groups selected from a nitro group It may have a phenyl group, a phenyl lower alkyl group, or a benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring. R ⁶ represents a hydrogen atom or a phenyl group. R ⁷ represents a hydrogen atom or a lower alkyl group. ] A hypoxia-improving agent and an antioxidant comprising a 2,3-dihydro-1H-indene derivative represented by the following or a salt thereof as an active ingredient. 2. An agent for improving hypoxia, which comprises the 2,3-dihydro-1H-indene derivative according to claim 1 or a salt thereof as an active ingredient. 3. An antioxidant containing the 2,3-dihydro-1H-indene derivative or the salt thereof according to claim 1 as an active ingredient. 4. A 2,3-dihydro-1H-indene derivative or a salt thereof is 1- [4- (3-methoxyphenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-2. The hypoxia-improving agent according to claim 2, which is 2,2,4,6-tetramethyl-1H-indene or a salt thereof. 5. A 2,3-dihydro-1H-indene derivative or a salt thereof is 1- [4- (3-methoxyphenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-2. The antioxidant according to claim 3, which is 2,2,4,6-tetramethyl-1H-indene or a salt thereof.