JPH0672121B2 - Indane derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to indane derivatives.

Structure of the Invention The indane derivative of the present invention is a novel compound that has not been published in the literature, and is a compound useful as an intermediate for synthesizing an indane derivative represented by the following general formula (1) as shown below.

[Wherein R ¹ is an amino group which may have a lower alkyl group, a hydroxyimino group, an alkanoylamino group having 1 to 10 carbon atoms which may have a halogen atom, a lower alkylsulfonylamino group, and a substituent on the phenyl ring. A phenylsulfonylamino group which may have a lower alkyl group, a benzoylamino group having a lower alkyl group as a substituent on the phenyl ring, and a phenyl lower alkylamino group having a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring. Show. R ² is a hydrogen atom, a lower alkyl group,
Halogen atom, nitro group, amino group, amino lower alkyl group, lower alkanoylamino group, lower alkanoylamino lower alkyl group which may have a halogen atom,
A lower alkylthio group, a 1-piperidine sulfonyl group or a lower alkenyl group is shown. R ³ represents a hydrogen atom, a lower alkyl group or a halogen atom. R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group. However, when R ¹ is a hydroxyimino group, both R ² and R ³ must not be hydrogen atoms. The indane derivative represented by the general formula (1) has an action of improving an oxygen deficiency state and symptoms associated therewith, and is a drug that improves the oxygen deficiency state and symptoms associated therewith (ie, hypoxia ( hypoxia) improver], more specifically, for example, a brain stimulant, an amnestic drug, a senile dementia drug, an agent for improving respiratory arrest and hypoxia associated with potassium cyanide poisoning, an agent for preventing arrhythmia and heart failure caused by oxygen deficiency Used effectively as etc.

Enzymes are indispensable for the living body to maintain life such as energy production and metabolism. The enzyme becomes a so-called active oxygen species such as oxygen anion radical, peroxide ion and hydroxy radical by a reaction in an energy production system, an enzymatic reaction, a reaction by ultraviolet rays, 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-mentioned reactive oxygen species, attacks biological membranes, and causes membrane disorders and inactivation of various useful enzymes [Metabolism, 15 (10) , 1978 special feature active oxygen reference]. However, in the living body, for example, superoxide distamtase (SO
D), catalase, glutathione peroxidase, and other enzymes involved in metabolic deactivation of the above reactive oxygen species are present, and vitamins having various antioxidant abilities such as α-tocopherol (vitamin E) Is present, and normal living body maintenance is performed by such actions, but for some reason there is a defect in the appropriate defense mechanism by the above enzymes, vitamins, or the ability of these defense mechanisms. It is often observed that the generation of reactive oxygen species exceeding the range and the production and accumulation of lipid peroxide occur. 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.

Conventionally, compounds having an action of removing (scavenging) active oxygen species (radicals), which are considered to be the main factor of the above-mentioned various disorders, and preventing or reducing the production / accumulation of lipid peroxides in vivo, are generally known as antioxidants. It has been reported that many preventive and therapeutic effects of the above-mentioned various diseases caused by its use are actually reported. The reported antioxidants include SOD mentioned above.
And other enzyme agents [Superoxide and Medicine, Yoshihiko Oyanagi, 1981, Kyoritsu Publishing Co., Ltd., pp. 137-141], butylhydroxytoluene (BHT) butylhydroxyanisole (BHA), α-tocopherol (vitamin E), etc. [Mino Mino, Hidetaka Tanaka, Medical Journal, 19 (12), 1983, p235
1-2359 and Toshihiko Suematsu, Ibid., 19 (5), 1983, p909.
~ 914].

The compound of the general formula (1) removes active oxygen species and also has an action of preventing or reducing in vivo production of lipid peroxide. Therefore, the compound of the present invention is used as a prophylactic and therapeutic agent for various disorders or diseases caused by excessive generation of reactive oxygen species, bioaccumulation of lipid peroxides, or deficiency of defense mechanism against, for example, anti-arteriosclerotic agents, Anti-carcinogenic agent, anti-cancer agent, anti-inflammatory agent, analgesic agent, autoimmune disease therapeutic agent, platelet aggregation inhibitor, antihypertensive agent,
It is also useful as a drug such as a hyperlipidemic agent, a retinopathy of prematurity and a preventive and therapeutic agent for cataract. Furthermore, the compound of the present invention is effective not only as the above-mentioned pharmaceuticals but also as an antioxidant of fats and oils 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, each of the groups represented by R ¹ , R ² , R ³ , R ⁴ and R ⁵ can more specifically include the following.

Examples of the lower alkyl group include 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
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as dimethylpropyl, 1-methylpentyl, 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.

As the amino group which may have a lower alkyl group,
2-methylamino, N-ethylamino, N-propylamino, N-isopropylamino, N-butylamino, N
-Tert-butylamino, N-pentylamino, N-hexylamino, N, N-dimethylamino, N, N-dipropylamino, N, N-dibutylamino, N, N-dihexylamino,
N-methyl-N-ethylamino, N-methyl-N-isopropylamino, N-methyl-N-tert-butylamino, N-methyl-N-pentylamino, N-ethyl-N
Examples thereof include an amino group which may have a linear or branched alkyl group having 1 to 6 carbon atoms such as -pentylamino and N-tert-butyl-N-ethylamino groups.

As the alkanoylamino group having 1 to 10 carbon atoms which may have a halogen atom, formylamino, acetylamino, probionylamino, butyrylamino, tert-
Butyrylamino, pentanoylamino, hexanoylamino, heptanoylamino, octanoylamino, nonanoylamino, decanoylamino, 2,2,2-trifluoroacetylamino, 2,2,2-trichloroacetylamino, 2-chloro Acetylamino, 2-bromoacetylamino, 2-fluoroacetylamino, 2-iodoacetylamino, 2,2-difluoroacetylamino, 2,2-dibromoacetylamino, 3,3,3-trifluoropropionylamino, 3, 3,3-trichloropropionylamino, 3,
-Chloropropionylamino, 2,3-dichloropropinanylamino, 4,4,4-trichlorobutyrylamino, 4-
Fluorobutyrylamino, 5-chloropentanoylamino, 3-chloro-2-methylpropionylamino, 6-
Bromohexanoylamino, 7-iodoheptanoylamino, 8-fluorooctanoylamino, 9-chlorononanoylamino, 10-bromodecanoylamino, 5,6-
Examples thereof include dibromohexanoylamino and 2,2-dichloroheptanoylamino groups.

The lower alkylsulfonylamino group has 1 to 6 carbon atoms such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino and hexylsulfonylamino groups. A linear or branched alkylsulfonylamino group can be exemplified.

The phenylsulfonylamino group which may have a lower alkyl group as a substituent on the phenyl ring includes phenylsulfonylamino, 2-, 3- or 4-methylphenylsulfonylamino, 2-, 3- or 4-ethylphenylsulfonyl. Amino, 4-propylphenylsulfonylamino, 3-isopropylphenylsulfonylamino,
2-butylphenylsulfonylamino, 4-hexylphenylsulfonylamino, 3-pentylphenylsulfonylamino, 4-tert-butylphenylsulfonylamino, 3,4-dimethylphenylsulfonylamino, 2,5-dimethylphenylsulfonylamino, 3, Examples thereof include a phenylsulfonylamino group which may have a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring such as a 4,5-trimethylphenylsulfonylamino group.

The benzoylamino group having a lower alkyl group as a substituent on the phenyl ring includes 2-, 3- or 4-methylbenzoylamino, 2-, 3- or 4-ethylbenzoylamino, 4-propylbenzoylamino, 3- Isopropylbenzoylamino, 2-butylbenzoylamino, 4
-Hexylbenzoylamino, 3-pentylbenzoylamino, 4-tert-butylbenzoylamino group and the like are exemplified by benzoylamino groups having a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring. it can.

The phenyl lower alkylamino group having a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring is 2
-, 3- or 4-hydroxybenzylamino, 2- (3-
Hydroxyphenyl) ethylamino, 1- (2-hydroxyphenyl) ethylamino, 3- (2-hydroxyphenyl) propylamino, 4- (4-hydroxyphenyl) butylamino, 1,1-dimethyl-2- (3-hydroxy) Phenyl) ethylamino, 5- (2-hydroxyphenyl) pentylamino, 6- (4-hydroxyphenyl) hexylamino, 2-methyl-3- (4-hydroxyphenyl) propylamino, 2-, 3- or 4- Methylbenzylamino, 2-, 3- or 4-ethylbenzylamino, 4-propylbenzylamino, 3-isopropylbenzylamino, 2-butylbenzylamino, 4-hexylbenzylamino, 3-pentylbenzylamino, 4
-Tert-butylbenzylamino, 2- (3-methylphenyl) ethylamino, 1- (2-ethylphenyl) ethylamino, 3- (2-propylphenyl) propylamino, 4- (4-butylphenyl) butylamino , 1,1-
Dimethyl-2- (3-hexylphenyl) ethylamino, 5- (2-pentylphenyl) pentylamino, 6
-(4-tert-butylphenyl) hexylamino, 2-
Methyl-3- (4-methylphenyl) propylamino,
2-methyl-3-hydroxybenzylamino, 3,5-di-tert-butyl-4-hydroxybenzylamino, 3-
Ethyl-5-hydroxybenzylamino, 4- (2-hydroxy-4-propylphenyl) butylamino, 6-
(2,3-Dimethyl-4-hydroxyphenyl) hexylamino, 3,5-, 3,4-, or 2,6-dihydroxybenzylamino, 3,4,5-trihydroxybenzylamino, 3,4
-, 2,5- or 2,6-dimethylbenzylamino, 3,4,5-
Examples thereof include a phenylalkylamino group having 1 to 6 carbon atoms in the alkyl moiety having a hydroxyl group or a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring such as a trimethylbenzylamino group.

Examples of the amino lower alkyl group include aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl,
4-aminobutyl, 1,1-dimethyl-2-aminoethyl, 5-aminopentyl, 6-aminohexyl, 2-methyl-3-aminopropyl group or the like having a straight or branched chain having 1 to 6 carbon atoms The aminoalkyl group which has an alkyl group can be mentioned.

As the lower alkanoylamino group, formylamino,
Examples thereof include linear or branched alkanoylamino groups having 1 to 6 carbon atoms such as acetylamino, propionylamino, butyrylamino, tert-butyrylamino, pentanoylamino and hexanoylamino groups.

Examples of the lower alkanoyl lower alkyl group which may have a halogen atom include 2,2,2-trifluoroacetylaminomethyl, 2,2,2-trichloroacetylaminomethyl, 2-chloroacetylaminomethyl and 2- (2- Bromoacetylamino) ethyl, 1- (2-fluoroacetylamino) ethyl, 3- (2-iodoacetylamino)
Propyl, 4- (2,2-difluoroacetylamino) butyl, 1,1-dimethyl-2- (2,2-dibromoacetylamino) ethyl, 5- (3,3,3-trifluoropropionylamino) pentyl, 6- (3,3,3-trichloropropionylamino) hexyl, 2-methyl-3- (3-chloropropionylamino) propyl, 2,3-dichloropropionylaminomethyl), 2- (4,4,4-trichloro) Butyrylamino) ethyl, 1- (4-fluorobutyrylamino) ethyl, 3- (5-chloropentanoylaminopropyl, 4- (3-chloro-2-methylpropionylamino) butyl, 1,1-dimethyl- 2- (6-bromohexainoylamino) ethyl, 5- (5,6-dibromohexainoylamino) pentyl group, or other straight-chain having 1 to 6 carbon atoms which may have a halogen atom Branched linear or branched alkyl group alkanoylamino substituted carbon atoms from 1 to 6 and can be exemplified.

Examples of the lower alkylthio group include methylthio, ethylthio, propylthio, isopropylthio, butylthio, te
Examples thereof include linear or branched alkylthio groups having 1 to 6 carbon atoms such as rt-butylthio, pentylthio and hexylthio groups.

Examples of the lower alkenyl group include linear, branched alkenyl groups having 2 to 10 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl groups. .

The compound of the present invention can be produced by various methods, and typical production methods thereof are shown below.

Reaction process formula-1 [In the formula, R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. The reaction of the known compound of general formula (2) with hydroxyamine (3) is
It can be carried out in the presence or absence of a basic compound in a suitable inert solvent. 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 and 1,5-
Diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU), 1,4-
Examples of such organic bases include diazabicyclo [2,2,2] octane (DABCO). The inert solvent used may be any as long as it does not adversely affect the reaction,
For example, lower alcohols such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran,
Ethers such as diethyl ether and ethylene glycol monomethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, hydrogen halides such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride,
Examples thereof include dimethylformamide, dimethyl sulfoxide, 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
℃, preferably 50 ~ 150 ℃, the general formula 1
The reaction is completed in about 10 hours.

The reduction of the compound of 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. Further, as the solvent used, for example, pardium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, etc. are used. The amount of the catalyst used is generally 0.02 to 1 with respect to the compound of the general formula (101).
It is recommended to use double the amount. The reaction temperature is generally -20 ° C to room temperature, preferably 0 ° C to room temperature, and the hydrogen pressure is usually 1 to 10
The pressure is preferably atmospheric pressure, and the reaction is generally completed in about 0.5 to 10 hours.

Reaction process formula-2 [In the formula, R ¹ , R ⁴ and R ⁵ are the same as defined above. R ² ′ and R ² ″ are the same as R ^2, with the proviso that at least one of R ² ′ and R ³ ′ represents a hydrogen atom and at least one of R ² ″ and R ³ ″ represents a halogen atom. The halogenation reaction of the compound of the general formula (103) is carried out in the presence of a usual halogenating agent, and known halogenating agents can be widely used as such a halogenating agent,
For example, halogen molecules such as bromine and chlorine, or iodine monochloride,
Sulfuryl chloride, N-bromosuccinimide, N
Examples thereof include halogenating agents such as N-halogenosuccinimide such as chlorosuccinimide. The amount of the halogenating agent to be used is usually equimolar to 10-fold molar amount, preferably equimolar to 5-fold amount, with respect to the compound of the general formula (103). 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-3 [In the formula, R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. R ⁶ is a lower alkyl group, a lower alkylsulfonyl group, a phenyl lower alkyl group having a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring, or a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring. Show. The reaction between the compound of general formula (2) and the compound of general formula (4) 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. The reaction is usually carried out at room temperature to 250 ° C, preferably about 50 to 200 ° C,
Generally, the reaction is completed in about 1 to 48 hours. General formula (4)
The amount of the compound (1) to be 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 the general formula (5) thus obtained is subjected to the following ring reaction without isolation.

Although various methods can be applied to the reduction reaction of the compound of the general formula (5), for example, a reduction method using a hydrogenation reducing agent is preferably used. Examples of the hydrogenation-reducing agent used include sodium aluminum hydride, sodium borohydride, and the like, and the amount thereof is usually at least equimolar, preferably equimolar to the compound (5).
It is in the range of 10 times mol. When lithium aluminum hydride is used as the hydrogenation reducing agent, the compounds (5) and 2
It is convenient to use a double molar amount. This reduction reaction is usually performed using a suitable solvent such as water, methanol, ethanol, lower alcohols such as isopropanol, tetrahydrofuran, ethyl ether, ethers such as diglyme, etc., and 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-4 [In the formula, R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. R ⁷ represents a phenyl lower alkyl group having a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring. The reaction between the compound of the general formula (102) and the compound of the general formula (6) is carried out under the same conditions as in the reaction between the compound of the general formula (2) and the compound of the general formula (4) in the above reaction process formula-3. To be done. Further, the reduction reaction of the compound of the general formula (7) is also performed under the same conditions as the reduction reaction of the compound of the general formula (5) of the above reaction process formula-3.

Reaction process formula-5 [In the formula, R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. R ⁸ represents an alkanoyl group having 1 to 10 carbon atoms which may have a halogen atom or a benzoylamino group having a lower alkyl group as a substituent on the phenyl ring. The reaction of the compound of the general formula (102) with 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 carboxylic acid (8) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride,
A method of reacting this with a compound (102), (b) an active ester method or an active amide method, that is, a carboxylic acid (8) such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole A method of reacting a compound (102) with an active ester such as an ester or an active amide with benzoxazoline-2-thione, and (c) a carbodiimide method, that is, a compound (102) is added to a carboxylic acid (8) such as dicyclohexyl. A method of dehydration bonding in the presence of a dehydrating agent such as carbodiimide or carbonyldiimidazole, (d) a carboxylic acid halide method, that is, a method of inducing a carboxylic acid (8) into a halo form and reacting it with a compound (102), (E) As another method, a carboxylic acid (8) is added to a dehydrating agent such as acetic anhydride. More, a carboxylic acid anhydride, a method of reacting the compound (102) thereto,
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. 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 the usual Schotten-Baumann reaction, and the compound (1) is produced by reacting it with the compound (102) without usually isolating it. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. As the basic compound used, a compound conventionally used in the Schotten-Baumann reaction is used, for example, triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 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) and other organic bases, carbonic acid Inorganic bases such as potassium, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like can be mentioned. The reaction is -20
~ 100 ℃, preferably performed at 0 ~ 50 ℃,
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 carried out at about -20 ° C to 150 ° C, preferably 10 to 50 ° 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, but
Generally, the solvent used is a solvent commonly used in the mixed acid anhydride method. Specifically, methylene chloride, chloroform, dichloroethane, and other halogenated carbons, benzene, toluene, xylene. Aromatic hydrocarbons such as, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc., esters such as methyl acetate, ethyl acetate, etc.
Examples thereof include aprotic polar solvents such as dimethylformamide, dimer sulfoxide, and hexamethylphosphoric triamide. In the method, the carboxylic acid (8), the alkylhalocarboxylic acid and the compound (102) are usually used at least in equimolar proportions. It is preferable to use 1 to 2 moles of each.

The active ester method or active amide method of the above (b) is, for example, in the case of using benzoxazoline-2-thionamide, as an example, a suitable solvent that does not affect the reaction, for example, the one used in the mixed acid anhydride method. In addition to the same solvent as 1-methyl-2-pyrrolidone, etc., 0-150 ℃,
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. When N-hydroxysuccinimide ester is used, the reaction proceeds advantageously by using a suitable base, for example, the same base as used in the carboxylic acid halide method described below.

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). This carboxylic acid halide and compound (10
The reaction with 2) 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 Schotten-Baumann reaction, sodium hydroxide,
Potassium hydroxide, sodium hydroxide, 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, other than the solvent used in the Schotten-Baumann reaction, for example, water, methanol, ethanol, propanol, butanol, 3-
Examples thereof include alcohols such as methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, acetonitrile, and the like, or a mixed solvent of two or more kinds thereof. The ratio of the compound (102) to the carboxylic acid halide used is not particularly limited and may 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 is 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. 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 triphenylphosphine or diethyl chlorophosphate and reacting the compound (102) with this 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 well by using an excessive amount of the compound (102), but if necessary, another basic compound such as triethylamine or trimethylamine may be used. , Pyridine, dimethylaniline,
N-methylmorpholine, 4-dimethylaminopyridine,
1,8-diazabicyclo [4,3,0] nonene-7 (DBN), 1,5
-Diazabicyclo [5,4,0] undecene-5 (DBU), 1,
It is also possible to use an organic base such as 4-diazabicyclo [2,2,2] octane (DABCO) or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate. The reaction is about 0 to 150 ° C, preferably about 0 to 100 ° C
At 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 ² , R ³ , R ⁴ and R ⁵ are the same as defined above. R ⁹ represents a lower alkyl group, a lower alkylsulfonyl group, a phenyl lower alkyl group having a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring, or a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring. Show. X represents a halogen atom. The reaction of the compound of general formula (102) with the compound of general formula (9) is carried out under the same reaction conditions as the reaction of the compound of general formula (102) with the carboxylic acid halide in the above-mentioned reaction process formula-5. be able to.

Reaction process formula-7 [Wherein R ¹ , R ³ , R ⁴ and R ⁵ are the same as defined above. The nitration of the compound of the general formula (109) is carried out under usual nitration reaction conditions of an aromatic compound, for example, using a nitrating agent without solvent or in a suitable inert solvent. Examples of the inert solvent include acetic acid, acetic anhydride, concentrated sulfuric acid, etc., and examples of the nitrating agent include fuming nitric acid, concentrated nitric acid, mixed acid (sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride and nitric acid), potassium nitrate, sodium nitrate, etc. Examples thereof include alkali metal nitrates and sulfuric acid. The nitrating agent may be used in an equimolar amount or more and usually in excess with respect to the raw material compound, and the reaction is advantageously carried out at 0 ° C. to room temperature for 1 to 4 hours.

The reduction of the compound of the general formula (110) is carried out by the above reaction process formula-1
Can be carried out under the same reaction conditions as the reduction of the compound of the general formula (101). Further, the reduction of the compound of the general formula (110) can also be carried out using the reducing agent shown below. Examples of the reducing agent used include iron, zinc, tin or stannous chloride and acids such as acetic acid, hydrochloric acid and sulfuric acid, or alkali metal hydroxides such as iron, ferrous sulfate, zinc or tin and sodium hydroxide. Examples thereof include sulfides such as ammonium sulfide, a mixture with aqueous ammonia, and ammonium salts such as ammonium chloride. Examples of the inert solvent used here include water, acetic acid, methanol,
Examples thereof include ethanol and dioxane. The conditions for the reduction reaction may be appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as the reducing agents, the reaction is preferably performed at about 0 ° C. to room temperature for about 0.5 to 10 hours. Is good. The amount of the reducing agent used is at least an equimolar amount, usually an equimolar to 5-fold molar amount with respect to the starting compound.

In the compound represented by the general formula (1), R ¹ is an alkanoylamino group having 1 to 10 carbon atoms which may have a halogen atom, a benzoylamino group having a lower alkyl group as a substituent on the phenyl ring, or a phenyl ring. A compound which is a phenyl lower alkylamino group having a hydroxyl group or a lower alkyl group as a substituent can be converted to a compound in which the corresponding R ¹ is an amino group by hydrolysis. Further, a compound in which R ² is a lower alkanoylamino group or a lower alkanoylamino lower alkyl group which may have a halogen atom may be converted into a compound in which the corresponding R ² is an amino group or an amino lower alkyl group by hydrolysis. it can. Here, as the hydrolysis conditions, for example, the same reaction conditions as those for the hydrolysis of the compound of the general formula (202) in the reaction formula-8 below can be adopted.

In the above reaction process formulas-1 and 3, 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-8 [In the formula, R ³ , R ⁴ and R ⁵ are the same as defined above. R ¹⁰ represents a lower alkanoylamino lower alkyl group which may have a halogen atom. R ¹¹ represents an amino 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, acids such as hydrochloric acid, sulfuric acid, boric acid, etc., metal phosphates such as sodium phosphate, boron phosphate, ferric phosphate, aluminum phosphate, etc.
Examples thereof include 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 usually the latter is equimolar or more to the former. , Preferably equimolar to 2 times the molar amount. The amount of the dehydration condensing agent to be 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 with respect 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.

For the hydrolysis of the compound of the general formula (202), conventionally known reaction conditions for hydrolysis can be widely applied. In the presence of an inorganic acid such as an acid, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkali metal carbonate such as sodium carbonate, potassium carbonate or sodium hydrogencarbonate or an inorganic alkali compound such as bicarbonate, 3-24 at 50 to 150 ° C, preferably 70 to 100 ° C, in a solvent-free or suitable solvent (for example, water or a mixed solvent of water and a lower alcohol such as methanol and ethanol).
It should be processed for about an hour.

Reaction process formula-9 [In the formula, R ³ , R ⁴ and R ⁵ are the same as defined above. R ¹² represents a lower alkanoyl group. The nitration of the compound of the general formula (201) and the reduction of the compound of the general formula (204) are carried out by nitration of the compound of the general formula (109) and reaction of the compound of the general formula (110) in the above reaction process formula-7. It can be carried out under the same reaction conditions as the reduction.
The reaction between the compound of the general formula (205) and the compound of the general formula (11) is carried out by the reaction of the general formula (105) in the above reaction process formula-5.
The reaction can be carried out under the same reaction conditions as the reaction of the compound of (4) with the compound of general formula (8).

Reaction process formula-10 [Wherein R ³ , R ⁴ , R ⁵ and X are the same as defined above. R ¹³ and R ¹⁴ represent a hydrogen atom or a lower alkyl group. The reaction between the compound of general formula (201) and the compound of general formula (12) 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-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4,3,0] nonene-5 ( Examples include organic bases such as DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU), and 1,4-diazabicyclo [2,2,2] octane (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 use ratio of the compound of the general formula (2a) and the compound of the general formula (17) 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 hours.

The reaction for obtaining the compound of the general formula (208) from the compound of the general formula (207) is generally called Claisen rearrangement. 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 to 250 ° C, preferably about 150 to 25 ° C, 1 to 20
The reaction is completed in about time.

Reaction process formula-11 [Wherein R ² , R ³ and X are the same as defined above. R ¹⁵ represents a lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group or a tetrahydropyranyl group. R ⁴ ′ and R ⁵ ′ each represent a lower alkyl group. The reaction of the compound of general formula (209) with the compound of general formula (13) is carried out in a suitable solvent in the presence of a basic compound. Examples thereof include sodium, potassium hydroxide, sodium ethylate, sodium hydride, potassium hydride, sodium amide, potassium amide, etc. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol, dioxane and diethylene glycol dimethyl ether. Ethers such as, toluene,
Examples thereof include aromatic hydrocarbons such as xylene, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and the like. The amount of the compound of general formula (13) to be used is not particularly limited and may be appropriately selected within a wide range, but is usually at least equimolar amount, preferably equimolar to 5 with respect to the compound of general formula (209). It is advisable 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.

The reaction of the compound of the general formula (14) with the compound of the general formula (15) and the reaction of the compound of the general formula (16) with the compound of the general formula (17) can be carried out by reacting the compound of the general formula (209) with the general formula It can be carried out under the same conditions as the reaction with the compound of (13).

The compound of general formula (210) is produced from the compound of general formula (18) by the method shown below. First, in the case where R ^{15 in} the compound of the general formula (18) is a phenyl lower alkyl group, a lower alkyl group or a lower alkoxy lower alkyl group, the compound is a suitable solvent such as water, methanol, ethanol or isopropanol. Lower alcohols, dioxane, ethers such as tetrahydrofuran,
In a solvent such as acetic acid or a mixed solvent thereof, palladium-
In the presence of a catalytic reduction catalyst such as carbon or palladium-black, 0
At about 100 ° C, the treatment is carried out 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. Next, when R ^{15 in} the compound of the general formula (18) is a lower alkanoyl group, tetrahydropyranyl group or benzoyl group, the compound of the general formula (210) is obtained by hydrolyzing the compound. You can This hydrolysis is carried out in the presence of an acid or basic compound in a suitable solvent. Examples of the solvent include water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane and tetrahydrofuran, and mixed solvents thereof. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and examples of the basic compound include metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide. The reaction is usually at room temperature to 150 ° C, preferably 80
The process proceeds suitably at ~ 120 ° C and is generally completed in about 1 to 15 hours.

Reaction process formula-12 [Wherein R ³ , R ⁴ , R ⁵ and X are the same as defined above. R ¹⁶ represents a lower alkyl group. The reaction between the compound of general formula (210) and the compound of general formula (19) is carried out without solvent or in the presence of a solvent. The solvent used here may be any solvent that does not affect the reaction, for example, halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, xylene, nitrobenzene, dichlorobenzene. Aromatic hydrocarbons such as General formula (1
The amount of the compound (9) used is usually at least equimolar to the compound of the general formula (201), preferably equimolar to 1.
It is recommended to use 5 times the molar amount. The reaction is usually -50 to 50 ° C,
Preferably, the reaction proceeds suitably at around 10 to 10 ° C and generally 15
The reaction is completed in about 10 minutes to 10 hours.

The reduction reaction of the compound of the general formula (211) includes iron, zinc,
A method using a metal such as tin or stannous chloride and an acid such as acetic acid, hydrochloric acid or sulfuric acid, or a method using a hydrogenation reducing agent such as lithium aluminum hydride, sodium borohydride or diborane can be adopted. When the method (1) is adopted, it is preferable that the acid is used in a large excess amount, and the metal is used in an equimolar amount with respect to the compound (211), usually in a large excess amount. This reaction is usually carried out at -50 to 150 ° C, preferably room temperature to 100 ° C, and is generally completed in about 0.5 to 10 hours. When this method is adopted, the same reaction conditions as those for the reduction of the compound of the general formula (5) in the above reaction process formula-3 can be adopted.

The reaction between the compound of general formula (212) and the compound of general formula (20) is carried out in a solvent in the presence of a dehydrohalogenating agent. As the solvent and the dehydrohalogenating agent used here, the solvent and the dehydrohalogenating agent used in the reaction of the compound of the general formula (102) in the above reaction process formula-5 with the carboxylic acid halide can be used. The reaction is usually
50 ~ 100 ℃, preferably performed at about -50 ~ 30 ℃,
Generally, the reaction is completed in about 30 minutes to 5 hours. The amount of the compound of the general formula (20) to be used is at least equimolar to the compound of the general formula (212), preferably equimolar to 1.
It is recommended to use twice the molar amount.

Reaction process formula-13 [Wherein R ³ , R ⁴ , R ⁵ and X are the same as defined above. The reaction of the compound of general formula (211) with the compound of general formula (21) is carried out without solvent or in the presence of a dehydrohalogenating agent. As the solvent and the dehydrohalogenating agent,
Any of the solvent and the dehydrohalogenating agent used in the reaction of the compound of the general formula (102) in the above reaction process formula-5 with the carboxylic acid halide can be used. Piperidine (2
1) is generally used in an amount of at least equimolar, preferably equimolar to 2 times the molar amount of the compound of the general formula (211). Further, the dehydrohalogenating agent is usually used in an amount of at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound of the general formula (211). The reaction is usually performed at -30 to 150 ° C, preferably at -20 to 100 ° C, and is generally completed in about 0.5 to 24 hours.

Reaction process formula-14 [Wherein R ³ , R ⁴ , R ⁵ and X are the same as defined above. The reaction of the compound of the formula (201) with the compound of the general formula (22) is carried out in the presence of a catalyst without solvent or in a solvent. The solvent used here may be any solvent as long as it does not affect the reaction, for example, halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride,
Examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, nitrobenzene, and dichlorobenzene, carbon disulfide, and the like. Examples of the catalyst used include aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid and other Lewis acids. The amount of the Lewis acid used may be appropriately determined, but it is usually a compound (20
The amount is about 2 to 6 times, preferably about 2 to 4 times the mol of 1). The amount of the compound (22) used is usually at least an equimolar amount, preferably an equimolar to 2 times the molar amount of the compound (201). The reaction temperature is appropriately selected, but is usually about 0 to 150 ° C., preferably 0 to 1
It is recommended that the temperature be around 00 ° C. The reaction is generally completed in about 0.5 to 10 hours.

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, recrystallization method, column chromatography, preparative thin layer chromatography and the like.

The compounds of the present invention naturally include optical isomers.

The indane derivative represented by the general formula (1) of the present invention is
An acid addition salt can be easily formed by reacting a pharmaceutically acceptable acid, and the present invention also includes this acid addition salt. In the above, examples of the acid include hydrochloric acid, sulfuric acid,
Inorganic acids such as phosphoric acid and 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 and benzoic acid can be used. .

In the general formula (1), the group represented by R ¹ is preferably an alkylamino group having 1 to 6 carbon atoms or an amino group, and particularly preferably the group is an amino group.

Of the groups represented by R ² , the group is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom or a nitro group, and particularly preferably the group is an alkyl group having 1 to 6 carbon atoms.

Among the groups represented by R ³ , preferred groups are hydrogen atom and carbon number 1
To 6 alkyl groups or halogen atoms, and particularly preferred groups are alkyl groups having 1 to 6 carbon atoms.

Among the groups represented by R ⁴ and R ⁵ , preferred groups are both a hydrogen atom or a methyl group, and particularly preferred groups are both a hydrogen atom.

The above-mentioned preferred groups wherein R ² and R ³ both have 1 to 6 carbon atoms
When the alkyl group is, the following are more preferable.

That is, when one of R ² and R ³ is an alkyl group having 1 to 6 carbon atoms and the other is an alkyl group having 2 to 6 carbon atoms (preferably a branched alkyl group having 3 to 6 carbon atoms), And R ²
And R ³ are both alkyl groups having 2 to 6 carbon atoms (preferably branched alkyl groups having 3 to 6 carbon atoms).
Of these, the most preferable one is that when one of R ² and R ³ is a methyl group and the other is an alkyl group having 2 to 6 carbon atoms (preferably a branched alkyl group having 3 to 6 carbon atoms), Also, one of R ² and R ³ is an ethyl group and the other has 2 carbon atoms.
Is an alkyl group having 6 to 6 carbon atoms (preferably a branched alkyl group having 3 to 6 carbon atoms). Preferred examples of the above-mentioned branched alkyl group having 3 to 6 carbon atoms include isopropyl, 2-methylpropyl, 1-methylpropyl, and 1,1-dimethylpropyl groups.

The compound of the general formula (1) is usually used in the form of a general pharmaceutical preparation. Formulations are commonly used fillers, fillers,
It is prepared using a diluent or excipient such as a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant. 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 ( Ointments and the like can be mentioned. In the case of molding in the form of tablets, those known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Agent, 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, Sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, sucrose, 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 tablets may be tablets coated with a usual coating, if necessary, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double-layered tablets, multi-layered tablets. In the case of molding in the form of pills, conventionally known carriers can be widely used, and examples thereof include excipients such as sucrose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc, gum arabic powder and tragacanth powder. Examples include binders such as gelatin, ethanol, and disintegrators such as laminaranthantene. 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, the solution and suspension should be used as a diluent. 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, diluents conventionally known in this field can be widely used, and examples thereof include white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone and bentonite.

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, sex and other conditions of the patient, degree of the patient and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of injections, alone or glucose,
It is administered intravenously after being mixed with a normal replenisher such as amino acid, and further, if necessary, is administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally alone. 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, age of the patient, sex and other conditions, degree of disease, etc., 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 recommended to set about 0.2 to 200 mg per kg.

Examples Production examples, reference examples, pharmacological tests and formulation examples are listed below.

Production Example 1 To 39.3 g of 4-methyl-7-hydroxy-1-indanone and 30 g of N-hydroxymethyl-α-chloroacetamide, 280 ml of concentrated sulfuric acid was added under cooling and dissolved. After standing overnight, the reaction mixture is put into ice and the precipitated crystals are collected. Recrystallization from ethanol gives 49 g of 4-methyl-6-α-chloroacetylaminomethyl-7-hydroxy-1-indanone.

Colorless needle crystals mp 166-167.5 ° C Preparation Example 2 To a solution of 4-methyl-7-hydroxy-1-indanone (25.6 g) in acetic acid (250 ml) was gradually added acetic anhydride (19.4 ml) and concentrated sulfuric acid (15.4 ml) in acetic acid (50 ml). The reaction mixture is concentrated to dryness and the residue is washed with ether to give 25.7 g of 4-methyl-6-nitro-7-hydroxy-1-indanone.

mp 154 to 157 ° C. Yellow needle crystals Production Example 3 10% Pd-C2.
6 g is added, and catalytic reduction is carried out at 0 ° C to room temperature. The catalyst was removed and the solvent was evaporated to remove 4-methyl-6-amino-7.
17.3 g of -hydroxy-1-indanone are obtained.

mp 187 to 188 ° C. (decomposition) pale yellow needle crystals Production Example 4 4-Methyl-6-α-chloroacetylaminomethyl-7
A solution of 3 g of hydroxy-1-indanone and 30 ml of concentrated hydrochloric acid in 60 ml of ethanol is heated under reflux for 8 hours. Evaporate the solvent,
The obtained residue was recrystallized from ethanol to give 4-methyl-
1-g 6-aminomethyl-7-hydroxy-1-indanone
To get

mp 300 ° C or higher Pale yellow flake NMR (DMSO) δ; 2.22 (s, 3H), 2.6 to 2.8 (m, 2H) 2.85 to 3.1 (m, 2H), 3.97 (s, 2H), 7.55 (s, 1H), 8.4 to 9.5 (br., 3H) Production Example 5 To a solution of 4-methyl-6-nitro-7-hydroxy-1-indanone (11.5 g) in acetic acid (500 ml) was added 5% Pd-C (1.5 g).
Catalytic reduction is performed at room temperature and atmospheric pressure. The catalyst is removed, the solvent is evaporated and washed with ether. Recrystallized from methanol to give 4-methyl-6-acetamide-7-hydroxy-1-
Get 6.34g of Indanone.

mp 193-198 ° C Red-orange needle crystal NMR (DMSO) δ; 2.1 (s, 3H), 2.17 (s, 3H), 2.45-2.77 (m, 2H) 2.77-3.1 (m, 2H), 7.67 (s , 1H), 9.25-10.0 (br., 2H) Production Example 6 To a solution of 36 g of 4-methyl-7-hydroxy-1-indanone and 17.6 g of potassium hydroxide in 650 ml of methanol was added 25 ml of allyl bromide, and the mixture was heated under reflux for 6 hours. . The insoluble matter is removed, and the solvent is distilled off. It is extracted with chloroform-water, the chloroform layer is separated and the solvent is distilled off. The residue is washed with ether and purified by column chromatography to 4
32 g of -methyl-7-allyloxy-1-indanone are obtained.

mp 89-92 ° C. pale yellow powdery crystal 32 g of 4-methyl-7-allyloxy-1-indanone obtained above is suspended in 100 ml of tetralin and heated under reflux for 4 hours under an argon atmosphere. The reaction solution was purified by silica gel column chromatography (eluent; n-hexane → dichloromethane: n-hexane = 1: 2) to give 4-methyl-
26.8 g of 6-allyl-7-hydroxy-1-indanone are obtained.

mp 41-45 ° C. Light brown needle crystals Production Example 7 To a solution of 4-methyl-7-hydroxy-1-indanone (10 g) and potassium hydroxide (5.3 g) in methanol (200 ml) was added crotyl bromide (8.2 ml), and the mixture was heated under reflux for 4 hours. The insoluble matter is removed, and the solvent is distilled off. After extraction with chloroform-water, the chloroform layer was washed with dilute aqueous sodium hydroxide,
After washing with water and subsequent drying over anhydrous magnesium sulfate, the solvent is distilled off. The residue is purified by silica gel column chromatography (after elution; n-hexane-dichloromethane = 1: 1) to obtain 8.72 g of 4-methyl-7-crotyloxy-1-indanone.

mp 87.5-92 ° C pale yellow needle crystal 4-methyl-7-crotyloxy-1-obtained above
Indanone (8 g) is suspended in tetralin (50 ml) and heated under reflux for 9 hours under an argon atmosphere. The reaction solution was purified by silica gel column chromatography (eluent; n-hexane → n-hexane: dichloromethane = 2: 1) and recrystallized from dichloromethane-n-hexane to give 4-methyl-6.
-(1-Methyl-2-propenyl) -1-indanone 5.
Get 44g.

mp 88-92 ° C. colorless needles Using the appropriate starting materials, the compounds shown in Table 1 below are obtained in the same manner as in Production Example 8 or 9.

Production Example 11 13.55 ml of methallyl chloride was added to a solution of 4-methyl-7-hydroxy-1-indanone (15 g) and potassium hydroxide (7.95 g) in methanol (200 ml), and the mixture was heated under reflux for 11 minutes. After removing the insoluble matter, the solvent is distilled off. The residue is purified by silica gel column chromatography (after elution; n-hexane: dichloromethane = 1: 1) to obtain 4-methyl-7-methallyloxy-1-indanone (9 g).

mp 74.2-75.2 ° C colorless powder crystal 4-methyl-7-methallyloxy-1 obtained above
-Add 8.46 g of indanone to 50 ml of tetralin and heat to reflux for 9 hours. The reaction solution was subjected to silica gel column chromatography (eluent; n-hexane: dichloromethane = 2: 1).
And then recrystallized from dichloromethane-hexane to give 4-methyl-6- (2-methyl-2-propenyl).
6.68 g of -7-hydroxy-1-indanone are obtained.

mp 62.5 to 64 ° C. colorless needle crystals Production Example 12 30 ml of 7-hydroxy-4-methyl-1-indanone was added to a solution of 90 ml of chlorosulfonic acid in 150 ml of carbon tetrachloride under ice cooling.
Add little by little. Remove the carbon tetrachloride layer, add ice water (1) to the remaining layer, and stir vigorously. The precipitated solid is washed with water to obtain 8.7 g of 7-hydroxy-6-chlorosulfonyl-4-methyl-1-indanone. This compound was a black solid, and its NMR spectrum (CDCl ₃ ) was δ; 2.3.
_{2 (s, 3H, CH 3} ), 2.78-2.90 (m, 2H, CH 2), 3.05-3.21
_{(M, 2H, CH 2)} , 7.89 (s, 1H, H), was 10.20 (s, 1H, 3H) . Stannous chloride-2 without purification
Add to a solution consisting of 31.4 g of the hydrate and 100 ml of concentrated hydrochloric acid and stir at room temperature for 4 hours. Pour the reaction solution into 500 ml of ice water,
The precipitated crystals were collected, washed with water and dried to give 7-hydroxy-6.
7.86 g of mercapto-4-methyl-1-indanone are obtained. Then, without purification, methanol 10
Suspend in 0 ml, add methyl iodide 3.9 ml and baking soda 5.1 g.
20 ml of water is added and the mixture is stirred for 1 hour at room temperature. The solvent is concentrated under reduced pressure to dryness. The residue is purified by silica gel column chromatography (eluent: chloroform) and recrystallized from ethanol to obtain 7-hydroxy-4-methyl-6-methylthio-1-indanone (1.52 g).

mp 139 ° C. colorless needle crystal Production Example 13 2 g of 7-hydroxy-4-methyl-1-indanone was added to 10 ml of dichloroethane, 2.27 g of 1-piperidinesulfonyl chloride was added, and 10 g of anhydrous aluminum chloride was added little by little and stirred at room temperature. . After heating under reflux for 8 hours, chloroform
Extract with 200 ml, wash with water and distill off the chloroform under reduced pressure.
The residue is subjected to silica gel column chromatography (eluate;
After purification with chloroform), recrystallize from ethanol to give 7
1.24 g of -hydroxy-4-methyl-6- (1-piperidinesulfonyl) -1-indanone are obtained.

mp 188 to 189 ° C. pale yellow plate-like crystal Production Example 14 4,6-Dimethyl-7-methoxymethyleneoxy-1-indanone 7.56 g of dimethylformamide 200 ml solution was added at room temperature to 60% sodium hydride 4.94 g little by little, Stir until no more hydrogen is evolved (about 1 hour). Thereafter, 14.6 g of methyl iodide was added, and the mixture was stirred at room temperature for 2 hours. After hydrochloric acid is added to the reaction mixture to make it acidic, the solvent is concentrated under reduced pressure, the resulting residue is poured into water 1 under vigorous stirring, and the mixture is extracted twice with 300 ml of ethyl acetate. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 7-methoxymethyleneoxy-2,2,4,6-tetramethyl-1-indanone 8
get g. This compound is a colorless oily substance, and the N
MR spectrum (CDCl ₃ ) is δ; 1.25 (s, 6H, CH ₃ ), 2.26
(S, 3H, CH ₃ ), 2.34 (s, 3H, CH ₃ ), 2.88 (s, 2H, CH ₂ ),
3.68 (s, 3H, OCH ₃ ), 5.26 (s, 2H, OCH ₂ −), 7.32 (s, 1
H, H). This product was dissolved in 200 ml of methanol without purification, 10 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 3 hours, and then methanol was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; n-hexane:
Purified with dichloromethane = 2: 1) and 7-hydroxy-
6.8 g of 2,2,4,6-tetramethyl-1-indanone are obtained.

mp 28-30 ° C NMR (CDCl ₃ ) δ; 9.08 (1H, s) 7.19 (1H, s) 2.84 (2H, s) 2.23 (3H, s) 2.20 (3H, s) 1.28 (6H, s) Reference example 1 28 g of hydroxylamine hydrochloride and 56 g of potassium carbonate are added to 400 ml of methanol, and the mixture is heated under reflux for 30 minutes. After allowing to cool, the supernatant is separated to prepare a hydroxylamine methanol solution. Add 7- to this hydroxylamine methanol solution.
Add 16.2 g of hydroxy-4-methyl-1-indanone and heat to reflux with stirring for 5 hours. The reaction mixture is concentrated to dryness under reduced pressure. 200 ml of ethyl acetate is added to the residue and the insoluble matter is removed. The solution was concentrated to dryness under reduced pressure, and the residue was recrystallized from methanol to give colorless needle crystals of 7-hydroxy-4.
17.6 g of -methyl-1-indanone oxime are obtained.

mp 148 to 149.5 ° C. Using the appropriate starting materials, in the same manner as in Reference Example 1, the following second
The compounds listed are obtained.

Reference Example 14 7-Hydroxy-4-methyl-1-indanone oxime
15.0 g is dissolved in 200 ml acetic acid, 1.0 g of platinum oxide catalyst is added, and catalytic reduction is carried out at room temperature under hydrogen pressure of 5 atm for 8 hours. 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 is concentrated to dryness under reduced pressure, and the residue is recrystallized from ethanol to obtain 1.30 g of 1-amino-7-hydroxy-4-methylindane hydrochloride as colorless needles.

mp 221 to 223 ° C. Using the appropriate starting materials, in the same manner as in Reference Example 14, the following third
The compounds listed are obtained.

Reference Example 30 1 g of 1-amino-7-hydroxy-4-methylindane hydrochloride was dissolved in 20 ml of water, and 5 ml of a 3N hydrochloric acid solution containing 0.85 g of iodine monochloride was added dropwise with vigorous stirring at room temperature. Two
After stirring at the same temperature for a time, the mixture is cooled with ice. The precipitated crystals are collected, converted to the hydrochloride, then washed with ether and dried.
0.70 g of yellow needle crystals of 1-amino-7-hydroxy-6-iodo-4-methylindane hydrochloride are obtained.

mp Decomposition above 200 ° C Reference example 31 1-Amino-7-hydroxyindane hydrochloride 1.0 g
Dissolve it in 60 ml and stirfuryl chloride 1.53 with stirring under ice cooling.
Drop g. After stirring at the same temperature for 3 hours, the mixture is concentrated under reduced pressure. The residue is dissolved in 50 ml of ethanol saturated with hydrochloric acid gas and then dried under reduced pressure. Recrystallization from isopropanol-ether gave colorless prism crystals of 1-amino-4,6-dichloro-7-hydroxyindane hydrochloride 0.43.

mp 238-239 ° C (decomposition) Reference Example 32 5 g of 1-amino-7-hydroxy-4-methylindane is dissolved in 30 ml of acetic acid, 1.73 ml of acetic acid solution of bromine is added thereto, and the mixture is stirred at room temperature for 1 hour. The precipitated crystals were collected and recrystallized from isopropanol to give 1-amino-6-bromo-7.
2 g of hydroxy-4-methylindane hydrobromide are obtained. The structure is determined by NMR.

mp 178 to 190 ° C (decomposition) Yellow needle crystal NMR (DMSO) δ; 2.18 (s, 3H) 1.8 to 3.35 (m, 4H) 4.75 to 5.05 (m, 1H) 7.35 (s, 1H) 7.6 to 9.2 ( bs, 3H) Reference Example 33 1-Amino-7-hydroxy-4-methylindane hydrochloride (5.75 g) was suspended in acetic acid (40 ml), and acetic anhydride (3.27 ml) was added thereto.
And a solution of concentrated nitric acid (2.59 ml) in acetic acid (10 ml) are added, and the mixture is stirred at room temperature for 6 hours. The solvent was distilled off, the residue was washed with acetone, and recrystallized from ethanol to give 1-amino-7-hydroxy-
2 g of 4-methyl-6-nitroindane hydrochloride is obtained.

mp 200 to 230 ° C (decomposition) Yellow needle crystal NMR (DMSO) δ; 2.22 (s, 3H) 2.0 to 3.45 (m, 4H) 4.7 to 5.0 (m, 1H) 7.82 (s, 1H) 8.4 to 9.7 ( br., 3H) Reference Example 34 1-Amino-4,6-dimethyl-7-hydroxyindane
1.77 g is dissolved in 100 ml of 0.2N aqueous sodium hydroxide solution, and then 1.7 g of α-chloroacetyl chloride is added with stirring under ice cooling. Then, the mixture is stirred at room temperature for 2 hours. The reaction solution is acidified with diluted hydrochloric acid and extracted with chloroform. After washing and drying, the solvent is distilled off. 2.34 g recrystallized from ethanol
2.34 g of 1-acetylamino-4,6-dimethyl-7-hydroxyindane are obtained.

mp 131-132 ° C. colorless needle-like crystals, using the appropriate starting materials, in the same manner as in Reference Example 34
The compounds listed are obtained.

Reference Example 38 1-Amino-4,6-dimethyl-7-hydroxyindane
1.72 g of methanesulfonyl chloride is added dropwise to a 100 ml chloroform solution of 1.77 g and 2 ml of triethylamine at room temperature. Then, the mixture is stirred at the same temperature for 4 hours. The reaction mixture is washed successively with diluted acid, water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over sodium sulfate. The solvent was distilled off and the residue was recrystallized from ether-n-hexane to obtain 0.58 g of 1-methanesulfonylamino-4,6-dimethyl-7-hydroxyindane.

mp 114 to 116 ° C. colorless powder, using the appropriate starting materials, in the same manner as in Reference Example 38,
The compounds listed are obtained.

Reference Example 51 4,6-Dimethyl-7-hydroxy-1-indanone 1.76 g
And a solution of 14.6 g of n-butylamine in 100 ml of ethanol 8
Heat to reflux for 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 acid, then with saturated aqueous sodium acetate.
Adjust to pH = 9. 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. 1 recrystallized from ethanol-ether
1.89 g of -n-butylamino-4,6-dimethyl-7-hydroxyindane hydrochloride is obtained.

mp 143-144 ° C. colorless needle-like crystals Using the appropriate starting materials, in the same manner as in Reference Example 51, the following 6th
The compounds listed are obtained.

Reference Example 64 A solution of 1.77 g of 1-amino-7-hydroxy-4,6-dimethyl-indane and 2.57 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 50 ml of ethanol was 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 and add sodium acetate aqueous solution to adjust the pH
And extract 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 dissolved in 50 ml of ethanol, hydrochloric acid gas saturated ethanol is added to adjust the pH to 3, and the solvent is again evaporated to dryness under reduced pressure. Recrystallized from ether-n-hexane to give 1- (3,5-di-ter
0.77 g of t-butyl-4-hydroxybenzyl) amino-4,6-dimethyl-7-hydroxyindane is obtained.

mp 154 to 155 ° C. colorless needle crystals The compounds of Reference Examples 40, 41 and 43 to 50 are obtained in the same manner as in Reference Example 64 using appropriate starting materials.

Reference Example 65 A solution of 5 g of 1-amino-4-methyl-6-α-chloroacetylaminomethyl-7-hydroxyindane and 50 ml of concentrated hydrochloric acid in 100 ml of ethanol is heated under reflux for 8 hours. Evaporate the solvent and wash with ethanol. Recrystallization from methanol-ether gave 1 g of 1-amino-4-methyl-6-aminomethyl-7-hydroxyindane dihydrochloride.

mp220 ° C (decomposition) Colorless powdery reference example 66 19.7 g of 7-hydroxy-4-methyl-6-t-butyl-1-indanone oxime is dissolved in 200 ml acetic acid, 1.0 g of platinum oxide catalyst is added, and hydrogen pressure is 5 Catalytically reduce at room temperature at atmospheric pressure for 8 hours. 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 further recrystallized from ethanol to give 1-amino- as a colorless powder.
2.2 g of 7-hydroxy-4-methyl-6-t-butyl-1-indan.hydrochloride are obtained.

mp 221 to 224 ° C (decomposition) Elemental analysis value (C ₁₄ H ₂₁ NO · HCl) C H N calculated value (%) 65.74 8.28 5.48 Measured value (%) 65.59 8.15 5.59 Reference example 67 7-hydroxy-4,6- Di-t-butyl-1-indanone oxime (23.2 g) was dissolved in 200 ml of acetic acid to prepare a platinum oxide catalyst.
1.0 g is added and catalytic reduction is carried out for 58 hours at room temperature under 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 is concentrated to dryness under reduced pressure, and then recrystallized from ethanol to obtain 18.8 g of 1-amino-7-hydroxy-4,6-di-t-butyl-1-indane-hydrochloride as colorless powder.

Elemental analysis value (C ₁₇ H ₂₇ NO · HCl) C H N calculated value (%) 68.55 9.14 4.70 Measured value (%) 68.43 9.21 4.61 mp 225 to 226.5 ° C Pharmacological test Next, the following pharmacological test using the test compound Was done.

Test compound No. 1: 4,6-dimethyl-7-hydroxy-1-indanone oxime 2: 1-amino-7-hydroxy-4-methylindane hydrochloride 3: 1-amino-7-hydroxy-4, 6-dimethylindan hydrochloride 4: 1-amino-7-hydroxy-4-methyl-6-iodoindan hydrochloride 5: 1-amino-7-hydroxy-4,6-dichloroindane hydrochloride 6: 1-methylamino -4,6-Dimethyl-7-hydroxyindane hydrochloride 7: 1-amino-2,2,4,6-tetramethyl-7-hydroxyindane hydrochloride 8: 1-amino-4-methyl-6-sec- Butyl-7-hydroxyindane hydrochloride 9: 1-amino-4-methyl-6-iso-butyl-7-hydroxyindane hydrochloride 10: 1-amino-4-methyl-6-n-propyl-7-hydroxyindane Hydrochloride 11: 1-n-butylamino-4,6-dimethyl-7-hi Droxyindane hydrochloride 12: 1-amino-4-methyl-6-bromo-7-hydroxyindane hydrobromide 13: 1-amino-4-methyl-6-nitro-7-hydroxyindane hydrochloride 14: 1- Amino-6-n-propyl-7-hydroxyindane hydrochloride 15: 1-methylamino-4-methyl-6-methylthio-7
-Hydroxyindane hydrochloride 16: 1-methylamino-4-ethyl-6- (1-methyl-
2-Propenyl) -7-hydroxyindan hydrochloride 17: 1-amino-4-ethyl-6-n-propyl-7-hydroxyindan hydrochloride 18: 1-methylamino-4-ethyl-6-methyl-7- Hydroxyindane hydrochloride 19: 1-methylamino-4-methyl-6-ethyl-7-hydroxyindane hydrochloride 20: 1-amino-4-ethyl-6-sec-butyl-7-hydroxyindane hydrochloride 21: 1 -Methylamino-4-ethyl-6-allyl-7-hydroxyindane hydrochloride (A) Anticarrageenin edema action test Using male Wistar rats weighing about 150 g, 1 group 5
The animals are fasted for 18 hours, fed for 1 hour, and then orally administered with the test compound at a concentration of 100 mg / kg. 1 hour after administration,
Inject 0.1% carrageenin 0.1ml / rat subcutaneously on the left foot heel,
The volume of the left hind limb after 3 hours is measured. The edema rate is obtained by the volume doubling rate with respect to the hindlimb volume before carrageenin treatment, and the inhibition rate is calculated from the average edema rate of the control group and the test compound administration group. The results are shown in Table 7.

(B) Anti-oxygen deficiency action The anti-oxygen deficiency action is described in Arch, int, Pharmacodyn., 233 , 137 (1
It was examined by a method similar to the test method described in 978).

ICR male mice (body weight 20 to 30 g) were used. Mouse 4
Put each in a glass desiccator and the internal pressure is 210 or 240 mm
Suction air with a vacuum pump until Hg and close the cock.
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 subcutaneously or intraperitoneally administered 15 minutes before the start of inhalation. When the patient survived for 30 minutes (210 mmHg) or 15 minutes (240 mmHg) after the start of suction, the survival time was set to 30 minutes or 15 minutes, respectively.

Table 8 shows the test results under an internal pressure of 210 mmHg, and an internal pressure of 240 mm.
The test results under Hg are shown in Table 9.

As is clear from Tables 8 and 9 above, the indane derivative of the present invention significantly prolongs the lethal time in the oxygen-deficient state, and the improving action in the oxygen-deficient state was observed.

(C) Antioxidant activity It is well known that luminol is a luminescence test in which luminescence strongly emits light with hydrogen peroxide in the presence of a hemin catalyst.
This test uses linoleic acid hydroperoxide, which is also known as a strong oxidant like hydrogen peroxide, to show how much the compound (antioxidant) to be tested suppresses the oxidation of luminol by this peroxide. The antioxidant capacity of the compound was determined by measuring the value. Control drug (antioxidant)
Vitamin E (VE) is known to reduce the blood lipid peroxide induced by, for example, alloxan in vivo based on its antioxidant ability. It is recognized that a compound having an oxidizing ability can also reduce blood lipid peroxide. The test method is as follows.

(1) Test Method Prepare a methanol solution containing the test compound in a concentration of 1 to 1 × 10 ⁻⁶ mg / ml and linoleic acid hydroperoxide in a concentration of 1.0 × 10 ⁻⁹ mol / ml (hereinafter referred to as a test liquid). . 1.25 × 10 ^-6 g of 1 × 10 ^-4 M luminol 0.1 M sodium carbonate buffer and FCS (fetal calf serum, Gibco)
Prepare 0.1 M sodium carbonate buffer containing / ml concentration.

The prepared solutions were automatically and sequentially analyzed in the order of test solution, FCS solution, and luminol solution by the flow system shown in FIG.
Inhale and mix 4 ml each, and after mixing the final luminol solution, measure the amount of luminescence with a photo counter (R649S: Hamamatsu Photonics KK) for 1 second. In FIG. 1, (1) is a photo counter, (2) is a cell, (3) is a mixer,
(4) is a test solution, (5) is a luminescent reagent (luminol solution)
(6) is the catalyst (FCS solution), (7) is the washing buffer (0.1M sodium carbonate buffer), (8) is the syringe, (9) is the drain, and (10) is the valve. Are shown respectively.

Table 10 shows the results of measuring the amount of luminescence at each concentration using the test compound shown above at a predetermined concentration. Each luminescence amount was calculated by using the luminescence amount of the test solution containing no test compound as 1 and the ratio (%) to the luminescence amount calculated according to the following formula, and indicated by the value.

Counts when no test compound is added and lipid peroxide is added B: Counts when neither test compound nor lipid peroxide is added C: Counts when both test compound and lipid peroxide are added (2) In the same test as above, 50% of 1 × 10 ^-9 mol / ml linoleic acid hydroperoxide was added to 50 μl.
The inhibition rate (that is, the concentration of each test compound that inhibits the oxidizing ability of the peroxide by 50% and the antioxidative ability IL ₅₀ ) was determined for each test compound, and the results are shown in Table 11 below.

From Tables 10 and 11 above, it can be seen that the indane derivatives of the present invention all have strong antioxidant ability. It was also found that each of the above compounds exhibits a strong activity in vivo as well as BHT and VE. From this, it is understood that the compound of the present invention is useful as a prophylactic and therapeutic agent for various diseases caused by lipid peroxide and reactive oxygen species.

(D) Effect on lethal cerebral hemorrhage by intraperitoneal administration of 50% glucose (mouse) An experiment was conducted with 30 mice per group. The compound of the present invention (0,3,
(1 and 3 mg / kg) 15 minutes after subcutaneous administration, 0.4 ml / 10 g body weight of 50% (W / Vsaline) glucose was intraperitoneally administered, and then 1.5, 3
And the survival rate of the mice was calculated at 24 hours. A two-sided test was performed by Fisher's method to determine the drug effect on the survival rate. The results are shown in Table 12.

(E) Action on post-traumatic consciousness disorder in mouse It was examined whether or not the compound of the present invention affects the consciousness disorder created by impacting the head of a mouse.

The neck skin of the mouse was grasped and the head was fixed on a 2 cm-thick Styrofoam pillow. 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, and shock was applied. The time until the development of the righting reflex (RP time) and the time until the development of spontaneous movement (SM time) were used as indices of consciousness disorder.

The test compound was negatively administered in a volume of 0.1 ml / 10 g for 15 minutes after 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 results are shown in Table 13. The number in parentheses in the table is the number of mice.

Formulation Example 1 7-Hydroxy-4-methyl-1-indanoxime 200 mg Glucose 250 mg Distilled water for injection Appropriate amount 5 ml Dissolve the compound of general formula (1) and glucose in distilled water for injection and then add to 5 ml ampoule. Inject and replace with nitrogen at 121 ° C
After sterilization under pressure for 15 minutes, an injection having the above composition is obtained.

Formulation Example 2 1-Amino-7-hydroxy-4-methylindan hydrochloride 100g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40g Constarch 30g Magnesium stearate 2g TC-5 10g (trade name, Shin-Etsu Chemical Co., Ltd.) Hydroxypropyl methylcellulose) Polyethylene glycol-6000 3 g Castor oil 40 g Methanol 40 g The compound of the general formula (1), Avicel, corn starch and magnesium stearate are taken and mixed and polished, and then tableted with a sugar coated R10 mm kine. 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 coated tablet having the above composition.

Formulation Example 3 1-Amino-4,6-dichloro-7-hydroxyindane hydrochloride 2g Purified lanolin 5g Salix beeswax 5g White petrolatum 88g Total amount 100g The compound, purified lanolin and white petrolatum are added, and the mixture is heated until it becomes liquid and then stirred until it begins to solidify to obtain an ointment having the above composition.

[Brief description of drawings]

FIG. 1 is a flow chart of an apparatus for measuring the antioxidant capacity of the compound of the general formula (1).

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display area C07C 323/22 C07D 295/22

Claims (1)

[Claims] 1. A general formula [In the formula, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ and
Each R ⁵ represents a hydrogen atom or a lower alkyl group. ^RA is-
SO ₂ X (X is a halogen atom), a lower alkylthio group, A lower alkanoylamino lower alkyl group which may have a halogen atom, an amino lower alkyl group, a nitro group,
Amino group, R ¹² NH- (R ¹² is a lower alkanoyl group) or (R ¹³ and R ¹⁴ represent a hydrogen atom or a lower alkyl group)]. Compounds represented by [In the formula, R ² represents a lower alkyl group, and R ³ ′ represents a lower alkyl group. R ⁴ 'and R ^5' represents a lower alkyl group. R ^B represents a hydrogen atom or a lower alkoxy lower alkyl group. ] An indane derivative selected from the group consisting of compounds represented by: