JPH0665177A - 2,3-dihydro-1h-indene derivative - Google Patents

Abstract

PURPOSE:To obtain a new derivative useful as a synthetic intermediate for medicine such as an improver for anoxia and antioxidant. CONSTITUTION:A derivative of formula I [R<1> and R<2> are H or lower alkyl; R<3> is lower alkyl; RA is CH2-C(R<9>)=CHR<8> or R<11> (R<8> is H or lower alkyl; R<9> is phenyl or cycloalkyl; R<11> is pyridinium lower alkanoylamino lower alkyl or piperidyl lower alkanoylamino lower alkyl)] or its salt such as 2,3-dihydro-7- hydroxy-4-methyl-6(1-phenyl-2-propenyl)-1H-inden-1-onoxime. The compound of formula I, for example, is obtained by reacting a compound of formula II with hydroxylamine in an inert solvent such as methanol in the presence of a basic compound such as sodium hydroxide or pyridine preferably at 50-150 deg.C for 1-10 hours and further reduced in a solvent in the presence of a catalyst such as palladium preferably at 0 deg.C to about room temperature under 1-10 atmospheric pressure hydrogen pressure for 0.5-10 hours.

Description

Detailed Description of the Invention

[0001]

This invention relates to 2,3-dihydro-1.
It relates to H-indene derivatives.

[0002]

DISCLOSURE OF THE INVENTION The 2,3-dihydro-1H-indene derivative of the present invention is a novel compound not described in the literature and represented by the following general formulas (A) and (B).

[0003]

[Chemical 3]

[In the formula, R ¹ and R ² represent a hydrogen atom or a lower alkyl group. R ³ represents a lower alkyl group. R ^A is a group ^{_{-CH 2 -C (R 9) =}} CHR 8 or R ^11. Here, R ⁸ represents a hydrogen atom or a lower alkyl group, and R ⁹ represents a phenyl group or a cycloalkyl group. R ¹¹ represents a pyridinium lower alkanoylamino lower alkyl group or a piperidinyl lower alkanoylamino lower alkyl group. ]

[0005]

[Chemical 4]

[Wherein R ¹ , R ² and R ³ are the same as defined above.
R ⁴ represents a phenyl lower alkyl group, a cycloalkyl lower alkyl group, a piperidinyl lower alkanoylamino lower alkyl group, a pyridinium lower alkanoylamino lower alkyl group or a lower alkyl group. R ^B is a group = NR
¹³ or the group -N = CH-R ¹³ is shown. Here, R ¹³ is C ₇
To C ₁₀ lower alkyl groups are shown. The compounds (A) and (B) of the present invention are useful as intermediates for 2,3-dihydro-1H-indene derivatives represented by the following general formula (1), as shown below.

General formula (1), which is the final end product of the compound of the present invention, is a novel compound not described in the literature and represented by the following general formula.

[0008]

[Chemical 5]

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above. R ⁵ represents a hydroxyimino group, a C ₇ -C ₁₀ alkylamino group or a group —NHR ⁶ . Here, R ⁶ is a hydrogen atom, a halogen-substituted lower alkanoyl group or a group -AB
Indicates. A represents a lower alkylene group which may have a hydroxy group, a group -CO-D- or a group -D-CO- (D is a lower alkylene group), and B is a 5- or 6-membered saturated or unsaturated heterocycle. Indicates a group. The heterocyclic group is selected from a lower alkyl group, an oxo group, a carboxy group, a lower alkoxycarbonyl group, a pyridyl group or a substituent on the phenyl ring as a substituent selected from a halogen atom, a lower alkyl group, a lower alkoxy group and a nitro group. It may have a phenyl group which may have 1 to 3 groups. However, when R ⁵ represents a hydroxyimino group or is a group —NHR ⁶ and R ⁶ represents a hydrogen atom or a halogen-substituted lower alkanoyl group, R ⁴ must not be a lower alkyl group. ]
The compound represented by the general formula (1) has an action of improving oxygen deficiency and symptoms associated therewith, and is a drug that improves oxygen deficiency and symptoms associated therewith (ie, hypoxia (hypoxia)). As an improving agent, more specifically, for example, a brain stimulant, an amnestic drug, a senile dementia drug, a respiratory arrest and hypoxia improving drug associated with potassium cyanide poisoning, an arrhythmia due to oxygen deficiency and a heart failure preventive drug, etc. Used effectively.

Regarding 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 causes generation of alkoxy radicals and hydroxy radicals like the above-mentioned active oxygen species, attacks biological membranes, and causes membrane damage and deactivation of various useful enzymes [Metabolism, 15 (10)]. , 1978 Special Feature Active Oxygen Reference]. However, in vivo, there are enzymes involved in metabolic deactivation of the above-mentioned reactive oxygen species such as superoxide dismutase (SOD), catalase, glutathione peroxidase, and α-tocopherol (vitamin E) and the like. There are various kinds of vitamins with antioxidative ability, etc., and normal living body maintenance is done by these actions, but for some reason there is a deficiency in the appropriate defense mechanism by the above enzymes, vitamins, etc. It is often observed that reactive oxygen species are generated or lipid peroxide is produced or accumulated, which occurs or exceeds the ability of the defense mechanism. When such a defense mechanism deficiency occurs, a serious disorder accompanying a chain reaction progression of the peroxidation reaction, for example, various diseases caused by platelet aggregation, inflammation, liver injury, arteriosclerosis, hemolysis, aging or senile dementia, retina Diseases, lung disorders, heart and lung disorders due to certain drugs, ischemic vascular diseases, and the like.

Compounds having the action of removing (scavenging) active oxygen species (radicals), which have been conventionally considered to be the main factor of the above-mentioned various disorders, and preventing or reducing the production and accumulation of lipid peroxide in the living body, are generally Called an oxidizer,
In fact, many reports have been made on the preventive and therapeutic effects of the above-mentioned various diseases caused by its use. As the reported antioxidants, enzyme agents such as SOD described above [Superoxide and Medicine, Yoshihiko Oyanagi, 1981, Kyoritsu Publishing, 1
37-141] and butylhydroxytoluene (BH
T) Butylhydroxyanisole (BHA), α-tocopherol (vitamin E), etc. [Mino Makoto, Tanaka Hidetaka, Pharmaceutical Journal, 19 (12), 1983, p2351-
2359 and Toshihiko Suematsu, Ibid., 19 (5), 1983.
, P909-914].

The compound of the general formula (1) also has the action of removing active oxygen species and preventing or reducing the production of lipid peroxide in the living body. Therefore, the compound of the general formula (1) is used as a prophylactic and therapeutic agent for various disorders or diseases caused by excessive generation of reactive oxygen species, bioaccumulation of lipid peroxide, or lack of defense mechanism against the above, for example, Anti-arteriosclerosis agent, carcinogenesis preventive agent, carcinostatic agent, anti-inflammatory agent, analgesic agent, autoimmune disease treatment agent, platelet aggregation inhibitor, antihypertensive agent, hyperlipidemic agent, retinopathy of prematurity and cataract prevention and treatment agent, etc. It is also useful as a medicine. Further, the compound of the general formula (1) is not limited to the above-mentioned pharmaceuticals,
For example, it is also effectively used as an antioxidant of oils and fats contained in processed foods and the like. The compound also has excellent anti-inflammatory action, antihypertensive action, gastric acid secretion inhibitory action and immunomodulating action, and is useful as, for example, an anti-inflammatory agent, an antihypertensive agent and the like.

In the present specification, R ¹ , R ² , R ³ and R
More specific examples of the groups represented by ⁴ and R ⁵ are as follows.

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-methyl Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as pentyl, 1,1-dimethylbutyl and 1-ethylbutyl groups.

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

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

As the cycloalkyl lower alkyl group,
Cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclohexylethyl, 1-cyclohexylethyl, 1-cyclohexylpropyl, 3-cyclopentylpropyl, 2-cyclopentylethyl, 4-cyclo Butyl butyl, 5-cycloheptyl pentyl, 6-cyclooctyl hexyl, 1,1
-Dimethyl-2-cyclopropylethyl, 2-methyl-
3 carbon atoms, which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as 3-cyclopentylpropyl group
The cycloalkylalkyl group of 8 can be illustrated.

Examples of the halogen-substituted lower alkanoyl group include 2,2,2-trifluoroacetyl and 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,
Examples thereof include linear or branched alkanoyl groups having 1 to 6 carbon atoms and having a halogen atom, such as 6-bromohexanoyl and 5,6-dibromohexanoyl groups.

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-
Hydroxy groups such as 2-methyltrimethylene, 1-hydroxy-2,2-dimethyltrimethylene, 1-methyl-2-hydroxytrimethylene, 2-hydroxytetramethylene, 3-hydroxypentamethylene and 4-hydroxyhexamethylene. Examples of the linear or branched alkylene group having 1 to 6 carbon atoms that may have

As the lower alkylene group, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,
2-dimethyltrimethylene, 1-methyltrimethylene,
Examples thereof include linear or branched alkylene groups having 1 to 6 carbon atoms such as methylmethylene, ethylmethylene, tetramethylene, pentamethylene and hexamethylene groups.

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

The lower alkoxycarbonyl group has 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups.
The straight chain or branched chain alkoxycarbonyl group can be exemplified.

The lower alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert.
Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms such as butoxy, pentyloxy and hexyloxy groups.

The phenyl group which may have 1 to 3 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group and a nitro group on the phenyl ring as a substituent includes phenyl, 2-chlorophenyl and 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, 2,6-dichlorophenyl Enyl, 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, 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,
A halogen atom as a substituent and a straight chain having 1 to 6 carbon atoms as a substituent on a phenyl ring such as 2,4-dinitrophenyl, 3-methyl-4-chlorophenyl, 2-chloro-6-methylphenyl, and 2-methoxy-3-chlorophenyl group. Or, a phenyl group which may have 1 to 3 groups selected from a branched chain alkyl group, a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms and a nitro group can be exemplified.

As a substituent, a lower alkyl group, an oxo group,
Carboxy group, lower alkoxycarbonyl group, pyridyl group or phenyl group having a phenyl group which may have 1 to 3 groups selected from halogen atom, lower alkyl group, lower alkoxy group and nitro group on the ring As the optionally saturated 5- or 6-membered saturated or unsaturated heterocyclic 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, 2-oxo-1-pyrrolidinyl, 2-carboxy-1-pyrrolidinyl, 3-carboxy-1-pyrrolidinyl, 4-carboxy-1-pyrrolidinyl, 2-methoxycarbonyl-1 -Pyrrolidinyl, 2-ethoxycarbonyl-1-pyrrolidinyl, 3-propoxycarbonyl-
1-pyrrolidinyl, 4-butoxycarbonyl-1-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)
As a substituent such as -1-piperazinyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, an oxo group, a carboxy group,
A halogen atom as a substituent on a straight-chain or branched-chain alkoxycarbonyl group having 1 to 6 carbon atoms, a pyridyl group or a phenyl ring, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, Examples include 5- or 6-membered saturated or unsaturated heterocyclic groups which may have 1 to 3 groups selected from linear or branched alkoxy groups and nitro groups and which may have a phenyl group. .

Examples of the piperidinyl lower alkanoylamino lower alkyl group include piperidinylacetylaminomethyl, (3-piperidinylpropionyl) aminomethyl,
(4-piperidinylbutyryl) aminomethyl, (5-piperidinylpentanoyl) aminomethyl, (6-piperidinylhexanoyl) aminomethyl, 2- (piperidinylacetylamino) 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) propyl group and other alkanoylamino groups are straight-chain or branched alkanoylamino groups having 2 to 6 carbon atoms, and the alkyl portion has carbon atoms of 2 to 6 carbon atoms. The piperidinyl alkanoylaminoalkyl group which is a linear or branched alkyl group of 1-6 can be illustrated.

The C ₇ -C ₁₀ alkylamino group includes
Examples thereof include linear or branched alkylamino groups such as heptylamino, octylamino, nonylamino and decylamino groups.

Examples of the pyridinium lower alkanoylamino lower alkyl group include pyridinium acetylaminomethyl, (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- (pyridiniumacetylamino) propyl group and other alkanoylamino groups are linear or branched alkanoylamino groups having 2 to 6 carbon atoms, and the alkyl portion has 1 to 1 carbon atoms. Examples thereof include a pyridinium alkanoylaminoalkyl group which is a straight chain or branched chain alkyl group of 6.

The compound of the general formula (1) can be produced by various methods, and typical production methods are shown below.

Reaction process formula-1

[0031]

[Chemical 6]

[Wherein R ¹ , R ² , R ³ and R ⁴ 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 inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, piperidine, pyridine, triethylamine, 1,5-diazabicyclo [4,3,0]. Nonene-5 (DBN), 1,8-diazabicyclo [5,4,4]
Examples thereof include organic bases such as 0] undecene-7 (DBU) and 1,4-diazabicyclo [2,2,2] octane (DABCO). The inert solvent used may be any as long as it does not adversely influence the reaction, for example, lower alcohols such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, diethyl ether, ethers such as ethylene glycol monomethyl ether. , Benzene, toluene, xylene and other aromatic hydrocarbons, dichloromethane, dichloroethane,
Examples thereof include hydrogen halides such as chloroform and carbon tetrachloride, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like. The amount of hydroxylamine (3) used is usually at least equimolar, preferably equimolar to 5 times the molar amount of the compound of general formula (2). The reaction temperature is usually room temperature to 200.
C., preferably 50 to 150.degree. C., and the reaction is generally completed in about 1 to 10 hours.

The reduction of the compound of the general formula (101) 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, 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 catalyst is generally used in an amount of 0.02 to 1 times the amount of the compound of the general formula (101). The reaction temperature is usually −20 ° C. to room temperature, preferably 0 ° C. to room temperature, and the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 10 hours.

When R ⁴ is a phenyl lower alkyl group or a pyridinium lower alkanoylamino lower alkyl group, R ⁴ is a cyclohexyl lower alkyl group or a piperidinium lower alkyl group under the conditions of the reduction. A compound of general formula (102), which is a group, may be produced.

Reaction process formula-2

[0036]

[Chemical 7]

[Wherein R ¹ , R ² , R ³ , R ⁴ , B and D
Is the same as above. X ¹ represents a halogen atom, X represents a hydrogen atom or a halogen atom, and A ′ represents a lower alkylene group. The reaction of the compound of general formula (102) with the compound of general formula (4) is carried out in the presence of a dehydrohalogenating agent in a suitable inert solvent. As the inert solvent used here,
Halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran and diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, dimethylformamide, dimethyl sulfoxide, hexa Methylphosphoric triamide, acetonitrile, acetone, acetic acid,
Examples include polar solvents such as 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 (DB
U), 1,4-diazabicyclo [2,2,2] octane (DABCO), organic bases such as sodium acetate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide and the like. An inorganic base is mentioned. The amount of the compound (4) used with respect to the compound (102) is usually at least equimolar, preferably equimolar to 2 times the molar amount. The reaction is usually performed at about -20 to 100 ° C, preferably 0 to 50 ° C, and the reaction time is about 5 minutes to 5 hours. Thus, the compound (103) is obtained.

When X is a halogen atom in compound (103), compound (5) is added to compound (103).
Can be reacted to induce compound (104). The reaction between compound (103) and compound (5) is carried out in the presence of a dehydrohalogenating agent in a suitable inert solvent. Examples of the inert solvent used here include methanol, ethanol, propanol, butanol, and 3
-Methoxy-1-butanol, ethyl cellosolve, alcohols such as methyl cellosolve, tetrahydrofuran,
Ethers such as diethyl ether, aromatic hydrocarbons such as benzene, toluene, xylene, aprotic polar solvents such as acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, methylene chloride, dichloroethane, chloroform, etc. Examples thereof include halogenated hydrocarbons, esters such as methyl acetate and ethyl acetate, and mixed solvents thereof.
The dehydrohalogenating agent used is a usual basic compound 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, sodium carbonate,
Examples thereof include inorganic bases such as 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. The amount of the compound (5) used with respect to the compound (103) is usually at least equimolar, preferably equimolar to 3 times the molar amount. still,
The compound (5) can be used also as a dehalogenating agent by using an excess amount. The reaction is usually about 0 to 120 ° C,
It is preferably carried out at room temperature to 100 ° C, and generally 0.5
It will be completed in about 10 hours. Thus, the compound (10
4) is obtained.

Compound (104) is reduced to give compound (10
Although various methods can be applied to the reaction for obtaining 5), for example, a reduction method using a hydrogenation 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. Is the range. This reduction reaction is usually carried out using a suitable solvent such as water, lower alcohols such as 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 performed at about 170 ° C. for about 10 minutes to about 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

[0041]

[Chemical 8]

[Wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ ,
A'and B are the same as above. The reaction between the compound (102) and the compound (6) can be performed under the same reaction conditions as the reaction between the compound (102) and the compound (4).

Reaction process formula-4

[0044]

[Chemical 9]

[Wherein R ¹ , R ² , R ³ , R ⁴ , A'and B are the same as defined above. Z is the base

[0046]

[Chemical 10]

Alternatively, the group X ¹ CH ₂ CH (OH)-is shown.
However _{-CH 2 CH (OH) CH 2} A'- of carbon atoms does not exceed six. ] Compound (102) and compound (7)
The reaction with is carried out without solvent or in a suitable solvent in the presence of a basic compound. As the solvent used here,
For example, dioxane, tetrahydrofuran, ethers such as ethylene glycol diethyl ether, benzene, toluene, aromatic hydrocarbons such as xylene, methanol,
Examples thereof include alcohols such as ethanol and isopropanol, and aprotic polar solvents such as acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Examples of the basic compound used include inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and sodium amide, triethylamine, tripropylamine, pyridine, quinoline, DB.
Organic bases such as N, DBU, DABCO and the like can be mentioned.
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 about 0 to 200 ° C,
It is preferably carried out at 50 to 100 ° C, and generally 1 to 1
It will be finished in about 2 hours.

Reaction process formula-5

[0049]

[Chemical 11]

[In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as defined above. R ⁷ represents a halogen-substituted lower alkanoyl group. The reaction of the compound of the general formula (102) with the compound of the general formula (8) is achieved by subjecting it to an ordinary amide bond forming reaction. In this case, an activated compound may be used as the carboxylic acid (8). 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 the compound (102) with the mixed acid anhydride.
(B) Active ester method or active amide method, that is, carboxylic acid (8) is converted to, for example, p-nitrophenyl ester, N.
-Hydroxysuccinimide ester, an active ester such as 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione,
This is reacted with compound (102), (c) carbodiimide method, that is, carboxylic acid (8) is reacted with compound (1).
02) is dehydrated and bound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole, (di) carboxylic acid halide method, that is, a carboxylic acid (8) is converted into a halide, and the compound (102) is added thereto. And (e) as another method, the carboxylic acid (8) is converted to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and the compound (102) is reacted with the carboxylic acid (8). For example, a method of reacting the compound (102) with an ester with a lower alcohol under high pressure and high temperature can be mentioned. 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 employed.

Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include, for example, methyl chloroformate,
Examples include methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. The mixed acid anhydride is obtained by the usual Schottuten-Baumann reaction, and the compound (1) is produced by reacting it with the compound (102) without usually isolating it. SHIOTTEN-
The Baumann reaction is usually performed in the presence of a basic compound.
As the basic compound used, a compound commonly used in the Schottuten-Baumann reaction is used, for example, triethylamine, trimethylamine, pyridine, dimethylaniline,
N-methylmorpholine, 4-dimethylaminopyridine,
Examples thereof include organic bases such as DBN, DBU and DABCO, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. The reaction is -20 to 1
It is carried out at about 00 ° C, preferably 0 to 50 ° C,
The reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the compound (102) is about -20 ° C to 150 ° C, preferably 10-5.
It is carried out at 0 ° C. for about 5 minutes to 10 hours, preferably about 5 minutes to 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. , Halogenated carbons such as chloroform, dichloroethane, benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, aprotons such as dimethylformamide, dimer sulfoxide and hexamethylphosphoric triamide. Examples thereof include polar solvents. Carboxylic acid (8), alkylhalocarboxylic acid and compound (102) in the method
The use ratio is usually at least equimolar, but it is preferable to use the alkylhalocarboxylic acid and the compound (102) in an amount of 1 to 2 times the molar amount of the carboxylic acid (8).

In the active ester method or active amide method of (b) above, for example, when benzoxazoline-2-thionamide is used, a suitable solvent which does not affect the reaction, such as the mixed acid anhydride method is used. 1-methyl-2-pyrrolidone or the like in addition to the same solvent as that used in
0.5 to 150 ° C, preferably 10 to 100 ° C.
It is carried out by reacting for 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. Also N
-When using hydroxysuccinimide ester,
The reaction proceeds advantageously using a suitable base, for example, a base similar to that used in the carboxylic acid halide method described below.

In the carboxylic acid halide method (c) above, the carboxylic acid (8) is reacted with a halogenating agent to obtain a carboxylic acid halide, and the carboxylic acid halide is isolated and purified, or without isolation and purification. , The compound (10
It is carried out by reacting 2). The reaction between the carboxylic acid halide and the compound (102) is carried out in the presence of a dehydrohalogenating agent in a suitable solvent. A basic compound is usually used as a dehydrohalogenating agent, and in addition to the basic compound used in the Schottuten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, sodium methylate. , And alkali metal alcoholates such as 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 Schoutten-Baumann reaction, alcohols such as water, methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, pyridine, acetone, acetonitrile. Etc. or those two
Examples include mixed solvents of one or more kinds. 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-fold molar relative to the former. The reaction temperature is usually about -30 to 180 ° C, preferably about 0 to 15
At 0 ° C, 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 the latter. When the reaction is carried out in (1), the latter is usually used in at least an equimolar amount, preferably 2 to 4 times the molar amount of the former. The reaction temperature and reaction time are not particularly limited, but usually room temperature to about 100 ° C., preferably 50 to 80.
It is carried out at 30 ° C. for about 30 minutes to 6 hours.

The method of activating the carboxylic acid (8) with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate 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, dimethyl sulfoxide and hexamethylphosphoric triamide. Since the compound (102) itself acts as a basic compound in the reaction, the reaction proceeds favorably by using it in an amount more than the theoretical amount, but if necessary, other basic compound,
For example, organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, and sodium hydrogencarbonate can be used. It can also be used. The reaction is about 0 to 150 ° C., preferably about 0.
It is achieved by carrying out at -100 ° C for about 1-30 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

[0056]

[Chemical 12]

[Wherein R ¹ , R ² , R ³ , R ⁴ , B, D and X ¹ are the same as defined above. ] The reaction of the compound (102) with the compound (9) is carried out by reacting the compound (102) with the compound (4).
The reaction can be performed under the same reaction conditions as in the above reaction.

In the above-mentioned 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

[0060]

[Chemical 13]

[Wherein R ¹ , R ² , R ³ and X ¹ are the same as defined above. R ⁸ represents a hydrogen atom or a lower alkyl group, and R ⁹ represents a phenyl group or a cycloalkyl 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 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, alcoholates such as sodium ethylate, triethylamine, pyridine, N, N-
Organic bases such as dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO and the like can be mentioned. The reaction can be carried out without solvent or in the presence of a solvent, and as the solvent, any inert one which does not adversely influence the reaction can be used. For example, water, alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol. , Dimethyl ether,
Ethers such as tetrahydrofuran, dioxane, monoglyme and diglyme, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, N, N-dimethylformamide, Examples include aprotic polar solvents such as 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 use ratio of the compound of the general formula (201) and the compound of the general formula (8) in the above method is not particularly limited and is appropriately selected from a wide range, but usually the latter is equimolar to 5 to the former. It is desirable to use a double molar amount, preferably an equimolar to double molar amount. The reaction temperature is also not particularly limited, but is usually room temperature to 200 ° C, preferably 50 to 150 ° C. The reaction time is usually 1 to 30 hours, preferably 1 to 15
It's time.

From the compound of the general formula (202), the compound of the general formula (2
The reaction for obtaining the compound of 03) is generally called Claisen rearrangement, and can be converted to the compound (203) by heating the compound (202) in a suitable solvent, for example. Examples of the solvent used include high boiling point solvents such as dimethylformamide and tetralin.
The heating temperature is usually 100 to 250 ° C., preferably about 150 to 250 ° C., and the reaction is completed in about 1 to 20 hours.

Reaction process formula-8

[0064]

[Chemical 14]

[In the formula, R ¹ , R ² and R ³ are the same as defined above.
R ¹⁰ represents a lower alkanoylamino lower alkyl group having a halogen atom. R ¹¹ represents a pyridinium lower alkanoylamino lower alkyl group or a piperidinyl lower alkanoylamino lower alkyl group. ] General formula (20
The reaction of the compound of 1) with the compound of the 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 such as hydrochloric acid, sulfuric acid, boric acid,
Examples thereof include metal phosphates such as sodium phosphate, boron phosphate, ferric phosphate, and aluminum phosphate, activated alumina, sodium bisulfate, Raney-Nickel 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 the latter is usually equimolar or more to the former. , Preferably equimolar to 2 times the 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 generally proceeds suitably at -30 to 50 ° C, preferably 0 ° C to around room temperature, and generally 1 to 30.
The reaction ends in about time.

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) include novel compounds and are produced, for example, according to the method shown in the following reaction process scheme.

Reaction process formula-9

[0069]

[Chemical 15]

[Wherein X, X ¹ , X ² , A ', D and B are the same as defined above. The reaction between the compound (11) and the compound (5) and the reaction between the compound (4) 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 scheme.

Reaction process formula-10

[0073]

[Chemical 16]

[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.
Examples of the basic compound used here include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, metallic sodium and metallic potassium, piperidine and pyridine. , Triethylamine, D
Examples thereof include organic bases such as BN, DBU, DABCO and the like. 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. Compound (12)
The amount used of 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

[0076]

[Chemical 17]

[In the formula, R ¹ , R ² , R ³ , R ⁴ and X ¹ are the same as defined above. R ¹² is a C ₇ -C ₁₀ alkyl group or group-
A "B (A" is a lower alkylene group which may have a hydroxy group, and B is the same as defined above). ] Compound (1
02) and the compound (13) are reacted with each other by the above-mentioned compound (10
It can be carried out under the same reaction conditions as the reaction of 2) with the compound (4).

Reaction process formula-12

[0079]

[Chemical 18]

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above. R ¹³ represents a C _{7 to} C ₁₀ lower alkyl group. The reaction between the compound of general formula (2) and 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. Examples of the solvent used here include alcohols such as methanol, ethanol and isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, aprotic polar solvents such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone. Etc. 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 generally the reaction is completed in about 1 to 48 hours.
The amount of the compound of the general formula (14) used is not particularly limited, but it is usually at least equimolar to the compound of the general formula (2), preferably a large excess amount. 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.

Although various methods can be applied to the reduction reaction of the compound of the general formula (111), for example, a reduction method using a hydrogenation reducing agent is preferably used. Examples of the hydrogenation-reducing agent used include lithium aluminum hydride, sodium borohydride, and ciborane, and the amount thereof is usually at least equimolar, preferably equimolar to 10 times the amount of the compound (111). It is in the molar range. When lithium aluminum hydride is used as the hydrogenation reducing agent, it is convenient to use the compound (111) in a 2-fold molar amount. This reduction reaction is usually carried out using a suitable solvent such as water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, ethyl ether and diglyme and the like, and usually about -60.
It is carried out at -50 ° C, preferably -30 ° C 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-13

[0083]

[Chemical 19]

[In the formula, R ¹ , R ² , R ³ , R ⁴ and R ¹³ are the same as defined above. ] The compound of the general formula (2) and the general formula (15)
The reaction of the compound of (1) is carried out under the same conditions as the reaction of the compound of the general formula (2) of the above-mentioned reaction process formula-12 and the compound of the general formula (111). Further, the reduction reaction of the compound of the general formula (16) can also be carried out by the general formula (11
It is carried out under the same conditions as in the reduction reaction of the compound of 1).

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

The compound of the general formula (1) naturally includes optical isomers.

The indane derivative represented by the general formula (1) 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, etc. Can be used.

The compound of the general formula (1) 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, and injections ( Liquids, suspensions and the like), ointments and the like. In the case of molding in the form of tablets, those known in this field can be widely used as carriers, for example, shaping of lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Agents, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, Disintegrators such as sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc., disintegration inhibitors such as white sugar, stearin, cocoa butter, hydrogenated oil, etc. Ammonium bases, absorption enhancers such as sodium lauryl sulfate, glycerin, a humectant such as starch,
Examples thereof include adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, refined talc, stearates, boric acid powders, and lubricants such as polyethylene glycol. In addition, tablets are tablets with a normal coating, if necessary,
For example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, or a double-layered tablet or a multi-layered tablet can be used. In the case of molding in the form of pills, conventionally known ones 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. Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. 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. When forming into paste, cream and gel form,
As the diluent, those conventionally known in this field can be widely used, for example, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone,
Examples include bentonite.

General formula (1) to be contained in a pharmaceutical preparation
The amount of the compound is not particularly limited and may be appropriately selected within a wide range, but 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 it is administered according to various preparation forms, patient's age, sex and other conditions, patient's degree and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. Further, in the case of an injection, it is administered alone or mixed with a normal replacement fluid such as glucose and amino acid, and then intravenously administered.
It is administered subcutaneously or intraperitoneally. In the case of suppositories, it will be administered rectally.

The dose of the above-mentioned pharmaceutical preparation is appropriately selected depending on the usage, the age and sex of the patient, other conditions, the degree of disease and the like, but the amount of the compound of the general formula (1) which is an active ingredient is usually the body weight per day. It is preferable that the amount is about 0.2 to 200 mg per kg.

[0092]

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

Reference Example 1 2,3-dihydro-7-hydroxy-4-methyl-1H
-Inden-1-one 196 g, potassium hydroxide 80 g
After heating and refluxing a mixture of and 2.5 L of methanol for 30 minutes, the mixture is cooled to room temperature and 250 g of cinnamyl bromide is added dropwise with vigorous stirring. After stirring at the same temperature for 8 hours,
The precipitated crystals are collected by filtration, washed with cold methanol and dried. Recrystallization from ethanol gives 126 g of 7-cinnamyloxy-2,3-dihydro-4-methyl-1H-inden-1-one.

Mp 110-111 ° C., colorless needles.

Reference Example 2 7-Cinnamyloxy-2,3-dihydro-4-methyl-1H-inden-1-one 7 g and tetralen 40 ml
Are heated to reflux for 3 hours in a nitrogen stream. After completion of the reaction, the mixture is cooled to room temperature and purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 10: 1). Recrystallized from ethanol, 2.64 g of 2,
3-dihydro-7-hydroxy-4-methyl-6- (1
-Phenyl-2-propenyl) -1H-indene-1-
Get on

Mp 131 to 131.5 ° C., colorless scaly crystals.

Reference Example 3 17.2 g of 7-hydroxy-4,6-dimethyl-1-indanone oxime was dissolved in 200 ml of acetic acid, 1.0 g of platinum oxide catalyst was added, and the hydrogen pressure was 5 atm at room temperature for 8 hours. Contact reduction. After filtering off the catalyst, the filtrate 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 into the residue to be saturated. Concentrate the solvent to dryness under reduced pressure,
The residue was recrystallized from isopropanol to give colorless needle crystals 1
-Amino-2,3-dihydro-7-hydroxy-4,6
-3.40 g of dimethyl-1H-indene hydrochloride is obtained.

Mp 229-230 ° C. (decomposition) Using the appropriate starting materials, the following compound is obtained in the same manner as in Example 3.

1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-sec-butyl-1H-indene hydrochloride mp 177.5-179 ° C (methanol-ether), colorless powder 1- Amino-2,3-dihydro-7-hydroxy-2,
2,4,6-Tetramethyl-1H-indene hydrochloride mp 231-233 ° C (ethyl acetate), colorless needle crystals.

Reference Example 4 1-Amino-4,6-dimethyl-7-hydroxy-2,
To a solution of 3-dihydro-1H-indene (17.7 g) and triethylamine (15.2 g) in chloroform (200 ml) was added dropwise chloroacetyl chloride (13.56 g) under ice-cooling and stirring. After completion of dropping, the mixture is stirred at 25 ° C. for 3 hours. After completion of the reaction, the reaction mixture was washed with 100 ml of 1N hydrochloric acid aqueous solution,
Then, wash with 100 ml of water three times. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. Recrystallize from ethanol to give 21 g of 1-chloroacetylamino-2,
3-dihydro-4,6-dimethyl-7-hydroxy-1
Get H-indene.

Mp 131-132 ° C., colorless needles.

The compounds shown in Table 1 below are obtained in the same manner as in Reference Example 4 using appropriate starting materials.

[0103]

[Table 1]

Reference Example 8 (3-Methoxyphenyl) piperazine (2.00 g) was dissolved in chloroform (20 ml) to prepare triethylamine (1.40 ml).
Then, at 0 ° C, chloroacetyl chloride 0.9 was added.
2 ml was added little by little, and after completion of dropping, the mixture was further stirred at the same temperature for 30 minutes. 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 obtain 3.2 g of oily 1-chloroacetyl-4- (3-methoxyphenyl) piperazine.

Reference Example 9 To a mixture of 1.50 g of 4- (3-chlorophenyl) piperazine and 0.31 g of sodium hydride was added epichlorohydrin 2.4 ml at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, 100 ml of ethyl acetate was added for extraction, the extract was washed with water (100 ml x 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.
To give 4- (3-chlorophenyl) -1- (2,3-epoxypropyl) piperazine as an oil.

Example 1 2,3-Dihydro-7-hydroxy-4-methyl-6-
(1-phenyl-2-propenyl) -1H-indene-
A solution of 120 g of 1-one, 45 g of hydroxylamine hydrochloride and 200 ml of pyridine in 1200 ml of ethanol is heated under reflux for 4 hours. After completion of the reaction, the mixture is concentrated under reduced pressure to dryness, the residue is dissolved in 2 L of ethyl acetate, washed 3 times with 1 L of water, and then dried again under reduced pressure. Recrystallize from ethyl acetate-n-hexane to give 90 g of 2,3-dihydro-7-hydroxy-4-.
Methyl-6- (1-phenyl-2-propenyl) -1H
-Inden-1-one oxime is obtained.

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 2 below are obtained.

[0109]

[Table 2]

Example 4 2,3-Dihydro-7-hydroxy-4-methyl-6-
(1-phenyl-2-propenyl) -1H-indene oxime (2.93 g) and platinum oxide (0.293 g) were added to acetic acid (20).
Resuspend in 0 ml and reduce at room temperature and hydrogen pressure of 3 atm for 8 hours. After completion of hydrogenation, the catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure. The residue was dissolved in 100 ml of ethanol, and the pH was adjusted to about 1 by adding ethanol saturated with chlorine gas, dried under reduced pressure to dryness again, and recrystallized from ethanol-ether to give 0.8.
8 g of 1-amino-2,3-dihydro-7-hydroxy-4-methyl-6- (1-phenylpropyl) -1H-
Obtain indene hydrochloride.

Mp 187.5-189.5 ° C., colorless powder.

Example 5 2,3-Dihydro-7-hydroxy-4-methyl-6-
(1-phenyl-2-propenyl) -1H-indene oxime (2.93 g) and platinum oxide (0.293 g) were added to acetic acid (20).
Suspend in 0 ml and reduce at room temperature and hydrogen pressure of 7 atm for 8 hours. After completion of hydrogenation, the catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure. The residue was dissolved in 100 ml of ethanol, pH of the solution was adjusted to about 1 by adding ethanol saturated with chlorine gas, dried again under reduced pressure to dryness, and recrystallized from ether-n-hexane to obtain 1.
0 g of 1-amino-2,3-dihydro-7-hydroxy-4-methyl-6- (1-cyclohexylpropyl)-
1H-indene hydrochloride is obtained.

Mp 184-185.5 ° C., colorless powder.

Example 6 1-Amino-2,3-dihydro-7-hydroxy-4-
13.56 g of chloroacetyl chloride was added dropwise to a solution of 31.8 g of methyl-6- (1-phenylpropyl) -1H-indene hydrochloride and 15.2 g of triethylamine in 200 ml of chloroform under stirring with ice cooling. 2 after the dropping
Stir at 5 ° C. for 3 hours. After the reaction was completed, the reaction mixture was adjusted to 1N.
Washing with 100 ml of aqueous hydrochloric acid, followed by washing with 100 ml of water three times. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. Recrystallize from ether-n-hexane to give 14.7 g of 1-chloroacetylamino-2,3-
Dihydro-4-methyl-6- (1-phenylpropyl)
-7-Hydroxy-1H-indene is obtained.

Mp 172-174 ° C., colorless powder.

Example 7 In the same manner as in Example 6, using the appropriate starting materials, the following compound is obtained.

1-chloroacetylamino-2,3-dihydro-4-methyl-6- (1-cyclohexylpropyl) -7-hydroxy-1H-indene mp 131-132 ° C. (recrystallized from n-hexane),
Colorless powder.

Example 8 6.64 g of 1-chloroacetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene was dissolved in 100 ml of acetonitrile and stirred to give 4 -(3-Chlorophenyl) piperazine 9.27
g and heat to reflux for 2 hours. After cooling with ice, the precipitated excess 4- (3-chlorophenyl) piperazine hydrochloride was filtered off, the filtrate was concentrated under reduced pressure, and recrystallized from ethanol.
8.10 g of 1- [4- (3-chlorophenyl) -1-
Piperazinyl] acetylamino-2,3-dihydro-7
-Hydroxy-2,2,4,6-tetramethyl-1H-
Get inden.

Mp 125-126 ° C., colorless powder.

In the same manner as in Example 8, using the appropriate starting materials, the compounds shown in Table 3 below were obtained.

[0121]

[Table 3]

[0122]

[Table 4]

[0123]

[Table 5]

[0124]

[Table 6]

Example 24 3.63 g of 2-pyrrolidone was added to dimethylformamide 40.
Dissolve in 60 ml of 60% sodium hydride 1.71
g in small portions and stir for 30 minutes. To this suspension, 4.00 g of 1-chloroacetyl-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene is added, and the mixture is stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture is poured into 100 ml of ice water and extracted 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), recrystallized from ethanol, and 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 25 1.07 g of 4-methylpiperazine, 1-chloroacetylamino-2,3-dihydro-7-hydroxy-2,2
1.50 g of 4,6-tetramethyl-1H-indene and 24 ml of acetonitrile are heated under reflux for 2 hours. The reaction mixture is ice-cooled, the precipitated crystals are filtered off, and the filtrate 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 189-190 ° C., colorless needles.

In the same manner as in Example 25, using the appropriate starting materials, the compounds shown in Table 4 below were obtained.

[0130]

[Table 7]

[0131]

[Table 8]

Example 34 1-Amino-2,3-dihydro-2,2,4,6-tetramethyl-7-hydroxy-1H-indene hydrochloride 2.
3.0 g of 1-chloroacetyl-4- (3-methoxyphenyl) piperazine is added to a solution of 50 g, 4.33 ml of triethylamine and 30 ml of acetonitrile, and the mixture is heated under reflux for 10 hours. After completion of the reaction, the solvent is distilled off, the obtained 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;
Purify with ethyl acetate: n-hexane = 1: 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 35 In a manner similar to Example 34, using the appropriate starting materials, the following compound is obtained.

1- (2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene-1
-Yl) aminoacetyl-4- (3-chlorophenyl)
Piperazine mp 144.0-145.5 ° C (recrystallized from ethanol), colorless powder.

Example 36 1- [4- (3-Chlorophenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene 5. While stirring, 4.3 g of lithium aluminum hydride was added little by little to a solution of 00 g of diglyme in 100 ml, followed by heating 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 filtrate 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, 2.3 g of 1- {2- [4-
(3-Chlorophenyl) -1-piperazinyl] ethylamino} -2,3-dihydro-7-hydroxy-2,2
4,6-Tetramethyl-1H-indene fumarate is obtained.

Mp 144-146 ° C., colorless powder.

Example 37 In a manner similar to Example 36, using the appropriate starting materials, the following compound is obtained.

1- {2- [4- (3-methoxyphenyl) -1-piperazinyl] ethylamino} -2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H- Indene fumarate mp 122-125 ° C (recrystallized from ethanol), colorless powder.

Example 38 1-Amino-2,3-dihydro-7-hydroxy-2,
2,4,6-Tetramethyl-1H-indene hydrochloride 2
A solution of 2.65 g and 15.2 g of triethylamine in 200 ml of chloroform was stirred under ice-cooling under stirring with [4- (3-chlorophenyl) -1-piperazinyl] acetyl chloride 3
2.76 g is added dropwise. After completion of dropping, the mixture is stirred at 25 ° C. for 3 hours. After the reaction was completed, the reaction mixture was mixed with 1N-hydrochloric acid aqueous solution 1
Wash with 00 ml, followed by 3 washes with 100 ml of water. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.
Recrystallized from ethanol to give 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 125-126 ° C., colorless powder.

In the same manner as in Example 38, using the appropriate starting materials, the compounds of Examples 9 to 23 are obtained.

Example 39 To a 100 ml chloroform solution of 1.77 g of 1-amino-4,6-dimethyl-7-hydroxyindane and 2 ml of triethylamine, 2.23 g of octyl chloride was added dropwise at room temperature. Then, the mixture is stirred at the same temperature for 4 hours. The reaction mixture was diluted with dilute hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution,
It is washed with water and saturated saline in this order and then dried over sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol, and hydrochloric acid gas-saturated ethanol was added to this to give the hydrochloride, followed by recrystallization from acetonitrile to give 1-octylamino-
4,6-Dimethyl-7-hydroxyindane hydrochloride 0.
49 g are obtained.

Mp 120-121 ° C., colorless needle crystals.

Example 40 Using the appropriate starting materials and in the same manner as in Example 39, the compounds of Examples 36 and 37, the following compound and the compound of Example 47 described later are obtained.

1-decylamino-4,6-dimethyl-7
-Hydroxyindane hydrochloride mp 124-126 ° C (recrystallized from acetonitrile), colorless needle crystals.

EXAMPLE 41 1.76 g of 4,6-dimethyl-7-hydroxy-1-indanone and 25.8 g of n-octylamine 100
The ml ethanol solution is heated to reflux for 8 hours. After cooling to room temperature, 1 g of sodium borohydride was added, and further 1
Stir for hours. The reaction mixture was concentrated to dryness, and water was added to the residue.
Add 0 ml to dissolve. Acidify with concentrated hydrochloric acid and then adjust the pH to about 9 with saturated aqueous sodium acetate. 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 made with ethanol saturated with hydrochloric acid gas. Recrystallization from acetonitrile gives 1.40 g of 1-n-octyl-4,6-dimethyl-7-hydroxyindane hydrochloride.

Mp 120-121 ° C., colorless needle crystals.

Example 42 The following compound was obtained in the same manner as in Example 41 using appropriate starting materials.

1-decylamino-4,6-dimethyl-7
-Hydroxyindane hydrochloride mp 124-126 ° C (recrystallized from acetonitrile), colorless needle crystals.

Example 43 A solution of 1.77 g of 1-amino-7-hydroxy-4,6-dimethyl-indane and 1.56 g of octylaldehyde in 50 ml of ethanol is stirred for 2 hours at room temperature. Then, a sodium borohydride solution is added little by little to the reaction solution under ice cooling. After stirring at room temperature for 2 hours, the reaction solution is acidified with hydrochloric acid and the solvent is evaporated to dryness under reduced pressure. Add 100 ml of water to the residue,
The pH is adjusted to about 8 by adding an aqueous solution of sodium acetate and extracted with 100 ml of ethyl acetate. After washing with water, it is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is ethanol 5
Dissolve in 0 ml, add hydrochloric acid gas saturated ethanol,
Is adjusted to about 3 and the solvent is again evaporated to dryness under reduced pressure. Recrystallization from acetonitrile gives 0.56 g of 1-octylamino-4,6-dimethyl-7-hydroxyindane hydrochloride.

Mp 120-121 ° C., colorless needle crystals.

Example 44 The compound of the above-mentioned Example 42 is obtained in the same manner as in Example 43 by using appropriate starting materials.

Example 45 6-Chloroacetylaminomethyl-2,3-dihydro-
200 g of 7-hydroxy-4-methyl-1H-inden-1-one, 77.9 g of hydroxyamine hydrochloride, 300 ml of pyridine and 1800 ml of ethanol 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, and the mixture is vigorously stirred, cooled and crystallized. The crystals were collected by filtration, washed with water, and recrystallized from water to give 167 g of (2,3-dihydro-7-hydroxy-1-hydroxyimino-4-methyl-1H-inden-6-yl) methylaminocarbonylmethylpyridinium. Get chloride.

Mp 279 ° C. (decomposition), colorless scaly crystals.

Example 46 (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 catalytically reduced at a hydrogen pressure of 3 atm and room temperature for 8 hours. After completion of the reaction, the catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure. The obtained residue was dissolved in 100 ml of methanol, and a hydrochloric acid gas-saturated methanol solution was added under ice-cooling to adjust the pH to 1, then dried under reduced pressure again and recrystallized from ethanol-ether.
4.8 g of 1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-piperidinylacetylaminomethyl-1H-indene dihydrochloride are obtained.

Mp 146 ° C. (decomposition), colorless powder.

Example 47 0.21 g of 4- (3-chlorophenyl) -1- (2,3-epoxypropyl) piperazine was added to 1-amino-2,3
A solution of 0.21 g of dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene hydrochloride in 10 ml of ethanol was added, and the mixture was heated under reflux for 5 hours. After the reaction,
The solvent is concentrated under reduced pressure, the residue obtained is made alkaline with 10% aqueous sodium hydrogen carbonate solution and extracted with 100 ml of methylene chloride. The extract was washed with water (100 ml x 3 times) and 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) to give 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), 6.90-6.70 (m, 4H), 4.60-
3.70 (br., 2H), 4.20 (s, 1H), 3.9
0 (m, 1H), 3.20 (t, 6H), 2.90 ~
2.30 (m, 8H), 2.18 (s, 3H), 2.8
0 (s, 3H), 1.20 (s, 2H), 0.85
(S, 3H).

(A) Anti-oxygen deficiency action The anti-oxygen deficiency action is described in Arch.int.Pharmacodyn., 233 ,
It investigated by the method similar to the test method described in 137 (1978).

ICR male mice (weight 20 to 30 g)
Was used. Four mice each are placed in a glass desiccator and air is sucked with a vacuum pump until the internal pressure reaches 210 or 240 mmHg, and the cock is closed. The time from the actuation of the vacuum pump to the respiratory arrest of each mouse was measured and used 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 10
The percentage of survival time when the test compound was administered was defined as 0, and the results are shown in Table 5.

[0162]

[Equation 1]

(B) Effect on Post-Injury Consciousness of Mouse Head Injury Whether or not the compound of the general formula (1) had an influence on the consciousness disorder produced by impacting the head of a mouse was examined.

The neck skin of the mouse was grasped and the head was fixed on a foamed polystyrene pillow having a thickness of 2 cm. An acrylic cylinder rod (20 g) was placed along an acrylic tube and dropped from the height of 30 cm onto the crown of the mouse 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 indices of consciousness disorder.

The test compound was adjusted to 0. 15 minutes before the impact.
It was administered orally or intraperitoneally in a volume of 1 ml / 10 g. 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.

When the RR time or SM time of the control mouse is 100, the RR time or S of the test compound-administered mouse is set.
The percentage of M time is shown and the results are shown in Table 6.

[0167]

[Equation 2]

Test compound 1. 1- [4- (3-chlorophenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene 1. 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) -1
H-indene hydrochloride 5. 1- [4- (3-chlorophenyl) -1-piperazinyl] acetylamino-2,3-dihydro-7-hydroxy-4,6-dimethyl-1H-indene hydrochloride 6. 7. 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

[0169]

[Table 9]

[0170]

[Table 10]

Formulation Example 1 1- [3- {4- (3-chlorophenyl) -1-piperazinyl} propionyl] amino-7-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1H -Indene 200mg Glucose 250mg Distilled water for injection Appropriate amount 5ml Dissolve the compound of general formula (1) and glucose in distilled water for injection and then inject it into an ampoule of 5ml.
The composition is sterilized by autoclaving at 15 ° C. for 15 minutes to obtain an injection of the above composition.

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.) 40 g Konstarch 30 g Magnesium stearate 2 g TC-5 10 g (trade name, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethylcellulose) Polyethylene glycol-6000 3 g Castor oil 40 g Methanol 40g Compound of the general formula (1), Avicel, corn starch and magnesium stearate are taken and mixed and polished.
Tablet with the key. The obtained tablets are coated with a film coating agent consisting of TC-5, polyethylene glycol-6000, castor oil and methanol to produce a film coating 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 2 g Purified lanolin 5 g Sarah beeswax 5 g White petrolatum 88 g Total amount 100 g Sarah beeswax is heated to form a liquid, and then the compound of the general formula (1), purified lanolin and white petrolatum are added and added until a liquid is formed. After warming, the mixture is stirred until it begins to solidify to obtain an ointment of the above composition.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] August 9, 1991

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0083

[Correction method] Change

[Correction content]

[0083]

[Chemical 19]

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0098

[Correction method] Change

[Correction content]

Mp 229 to 230 ° C. (decomposition) Using the appropriate starting materials, the following compound was obtained in the same manner as in Reference Example 3.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0130

[Correction method] Change

[Correction content]

[0130]

[Table 7]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication C07C 49/733 7457-4H 233/23 7106-4H 251/20 9160-4H C07D 207/16 8314- 4C 213/04 233/61 103 295/14 AZ C09K 15/24 15/30 // C07C 251/44 9160-4H

Claims (2)

[Claims] 1. A general formula: [In the formula, R ¹ and R ² represent a hydrogen atom or a lower alkyl group. R ³ represents a lower alkyl group. R ^A is a group -CH ₂ -
C (R ⁹ ) = CHR ⁸ or R ¹¹ is shown. Here, R ⁸ represents a hydrogen atom or a lower alkyl group, and R ⁹ represents a phenyl group or a cycloalkyl group. R ¹¹ represents a pyridinium lower alkanoylamino lower alkyl group or a piperidinyl lower alkanoylamino lower alkyl group. ] The 2,3-dihydro-1H-indene derivative represented by these or its salt. 2. A general formula: [In the formula, R ¹ and R ² represent a hydrogen atom or a lower alkyl group. R ³ represents a lower alkyl group. R ⁴ represents a phenyl lower alkyl group, a cycloalkyl lower alkyl group, a piperidinyl lower alkanoylamino lower alkyl group, a pyridinium lower alkanoylamino lower alkyl group or a lower alkyl group. R ^B is a group = N-R ¹³ or a group -N = CH
-R ¹³ is shown. Here, R ¹³ represents a C _{7 to} C ₁₀ lower alkyl group. ] 2,3-dihydro-1H- represented by
Indene derivative or its salt.