JPH03128340A - Indane derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<3> is H, alkyl or halogen; R<4> and R<5> are H or alkyl; RA is SO2X (X is halogen), SH, alkylthio, NO2, group shown by formula II (R<13> and R<14> are H or alkyl), etc.], group shown by formula III (R2 is H, alkyl, halogen, NO2, NH2, etc.; R<4>' and R<5>' are alkyl; R<8>is H, alkyl, benzoyl, etc.), group shown by formula IV (R<15> are alkyl, benzoyl, tetrahydropyranyl, etc.) or group shown by formula V [A is C=N-R<6> (R<6> is alkyl, alkylsulfonyl, etc.) or CH-N=CH-R<7> (R<7> is phenylalkyl)]. EXAMPLE:7-Hydroxy-6-chlorosulfonyl-4-methyl-1-indanone. USE:A synthetic intermediate for a compound for improving an oxygen insufficient state or symptoms following the state. PREPARATION:For example, 7-hydroxy-4-methyl-indanone is reacted with chlorosulfonic acid to give the example compound.

Description

[Detailed description of the invention] 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 described in any literature, and is a compound useful as an intermediate for synthesizing an indane derivative represented by the following general formula (1), as shown below.

3 [In the formula, R1 is an amino group that may have a lower alkyl group, a hydroxyimino group, an alkanoylamino group having 1 to 10 carbon atoms that may have a halogen atom, a lower alkylsulfonylamino group, or a substituent on the phenyl ring. A phenylsulfonylamino group that may have a lower alkyl group as a substituent, a benzoylamino group that has a lower alkyl group as a substituent on the phenyl ring, and a phenyl lower alkylamino group that has a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring. show.

R2 is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, an amino group, an amino lower alkyl group, a lower alkanoylamino group, a lower alkanoylamino lower alkyl group that may have a halogen atom, a lower alkylthio group, 1-piperidinesulfonyl group or lower alkenyl group. R3 represents a hydrogen atom, a lower alkyl group or a halogen atom. R4 and R5 each represent a hydrogen atom or a lower alkyl group. However, when R1 is a hydroxyimino group, both R2 and R3 must not be hydrogen atoms. ] The indane derivative represented by the above general formula (1) has the effect of improving the oxygen-deficient state and the symptoms associated therewith, and is used as a drug for improving the oxygen-deficient state and the symptoms associated therewith [i.e., hypoxia ( hB+oIia) improving agent], more specifically, for example, a brain stimulant, an amnesia drug, a senile dementia drug,
It is effectively used as a drug to improve respiratory arrest and hypoxia associated with potassium cyanide poisoning, and to prevent arrhythmia and heart failure caused by lack of oxygen.

For living organisms, enzymes are essential for maintaining life, such as energy production and metabolism. The enzyme becomes so-called active oxygen species such as oxygen anion radicals, peroxide ions, and hydroxyl radicals through reactions in energy production systems, enzyme reactions, ultraviolet rays, radiation, and the like. While these reactive oxygen species are useful for living organisms, such as oxygenating enzymes and bactericidal effects on white blood cells, they are also useful for living organisms, such as oleic acid, linoleic acid, lylunic acid, etc., which are abundant in living organisms.
Promotes peroxidation of unsaturated fatty acids such as arachidonic acid that form phospholipids in biological membranes, forming lipid peroxides. This lipid peroxide causes generation of alkoxy radicals and hydroxyl radicals like the above-mentioned active oxygen species, attacks biological membranes, and causes membrane damage and deactivation of various useful enzymes [Metabolism, 15 (10) -2゜Refer to 1978 Special Feature on Active Oxygen]. However, there are enzymes involved in the metabolic deactivation of the above-mentioned reactive oxygen species, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, and enzymes such as α-tocopherol (vitamin E), etc. There are various vitamins and other substances that have antioxidant abilities, and the action of these substances normally maintains normal living organisms, but for some reason, the appropriate defense mechanisms such as the enzymes and vitamins mentioned above are deficient. It is often observed that the generation of reactive oxygen species and the production and accumulation of lipid peroxides occur in a manner that exceeds the capacity of these defense mechanisms.

When a deficiency in such a defense mechanism occurs, the peroxidation reaction progresses in a chain reaction, leading to serious disorders such as various diseases caused by platelet aggregation, inflammation, liver damage, arteriosclerosis, hemolysis, aging and senile dementia, and retina. symptoms, lung damage, heart and lung damage caused by certain drugs, and ischemic vascular disease.

Compounds that scavenge active oxygen species (radicals), which have traditionally been thought to be the main cause of the various disorders listed above, and prevent or reduce the production and accumulation of lipid peroxides in living organisms are generally referred to as antioxidants. In fact, there have been many reports on the preventive and therapeutic effects of the above-mentioned diseases through its use.

Reported antioxidants include enzyme agents such as the above-mentioned SOD [Superoxide and Medicine, written by Yoshihiko Oyanagi, 1]
981, Kyoritsu Shuppansha, pp. 137-141], butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), α-tocopherol (vitamin E), etc. [Makoto Mino, Hidetaka Tanaka, Pharmaceutical Journal, 19 (12)
, 1983.

p2351-2359 and Toshihiko Suematsu, same magazine, 19 (
5), 1983, p.909-914).

The compound of general formula (1) also has the effect of removing active oxygen species and preventing or reducing the production of lipid peroxide in the body. Therefore, the compounds of the present invention can be used as preventive and therapeutic agents for various disorders and diseases caused by the excessive generation of active oxygen species, the accumulation of lipid peroxides in the body, or the deficiency of defense mechanisms against these, for example, as antiarteriosclerotic agents. Also useful as medicines such as cancer prevention agents, anticancer agents, anti-inflammatory agents, analgesics, autoimmune disease treatment agents, platelet aggregation inhibitors, antihypertensive agents, hyperlipidemia agents, and agents for preventing and treating retinopathy of prematurity and cataracts. It is. Furthermore, the compounds of the present invention are effective not only as the above-mentioned pharmaceuticals, but also as antioxidants for oils and fats contained in processed foods and the like.

The compound also has excellent anti-inflammatory action, antihypertensive action, gastric acid secretion suppressing action, and immunomodulating action, and is useful as, for example, an anti-inflammatory agent, an antihypertensive agent, and the like.

In this specification, each group represented by R1, R2, R3, R4 and R5 can be more specifically exemplified by the following groups.

Lower alkyl groups include methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, pentyl,
hexyl, l-methylpropyl, 2-methylpropyl,
1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 2,3-dimethylpropyl, 1-methylpentyl, 1.1-dimethylbutyl, 1-ethylbutyl group, etc. Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms.

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

As amine groups that may have lower alkyl groups,
N-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-
dibutylamino, N-methyl-N-ethylamino, N-
Methyl-N-isopropylamino, N-methyl-N-f
erf-butylamino, N-methyl-N-pentylamino, N-ethyl-N-pentylamino, N-tert-
Examples include amino groups that may have a linear or branched alkyl group having 1 to 6 carbon atoms, such as a butyl-N-ethylamino group.

Examples of the alkanoylamino group having 1 to 10 carbon atoms that may have a halogen atom include formylamino, acetylamino, propionylamino, butyrylamino, 1e
rt-butyrylamino, pentanoylamino, hexanoylamino, heptanoylamino, octanoylamino, nonanoylamino, decanoylamino, 2,2,2-
Trifluoroacetylamino, 2,2.2-trichloroacetylamino, 2-chloroacetylamino, 2-bromoacetylamino, 2-fluoroacetylamino, 2-
iodoacetylamino, 2,2-difluoroacetylamino, 2,2-dibromoacetylamino, 3,3.3-
Trifluoropropionylamino, 3,3.3-trichloropropionylamino, 3-chloropropionylamino, 2,3-dichloropropionylamino, 4.4.4
-) Chlorobutyrylamino, 4-fluorobutyrylamino, 5-chloropentanoylamino, 3-chloro-2
-Methylpropionylamino, 6-bromohexanoylamino, 7-iodoheptanoylamino, 8-fluorooctanoylamino, 9-chlorononanoylamino, 1
Examples include 0-bromodecanoylamino, 5,6-dibromohexanoylamino, and 2,2-dichloroheptanoylamino groups.

Examples of lower alkylsulfonylamino groups include those having 1 to 6 carbon atoms, such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, and hexylsulfonylamino groups. Examples include straight-chain or branched alkylsulfonylamino groups.

Examples of the phenylsulfonylamino group that may have a lower alkyl group as a substituent on the phenyl ring include phenylsulfonylamino, 2-3- or 4-methylphenylsulfonylamino, 2-3- or 4-ethylphenylsulfonylamino, 4-propylphenylsulfonylamine, 3-isopropylphenylsulfonylamine, 2-
Butylphenylsulfonylamino, 4-hexylphenylsulfonylamino, 3-pentylphenylsulfonylamino, 4-tert-butylphenylsulfonylamino, 3,4-dimethylphenylsulfonylamino, 2,
5-dimethylphenylsulfonylamino, 3,4.5-
Examples include phenylsulfonylamino groups that may have a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring, such as 4-lymethylphenylsulfonylamino groups.

Examples of the benzoylamino group having a lower alkyl group as a substituent on the phenyl ring include 2-3- or 4-methylbenzoylamino, 2-. 3- or 4-ethylbenzoylamino, 4-propylbenzoylamino, 3-isopropylbenzoylamino, 2-butylbenzoylamino,
A benzoylamino group having a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring such as 4-hexylbenzoylamino, 3-pentylbenzoylamino, 4-tert-butylbenzoylamino group, etc. I can give an example.

The phenyl lower alkylamino group having a hydroxyl group or lower alkyl group as a substituent on the phenyl ring includes 2-
3- or 4-hydroxybenzylamino, 2- (3-
Hydroxyphenyl)ethylamino, 1-(2-hydroxyphenyl)ethylamino, 3-(2-hydroxyphenyl)propylamino, 4-(4-hydroxyphenyl)butylamino, ↓, 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, 2-23- or 4-ethylbenzylamino, 4-propylbenzylamino, 3-isopropylbenzylamino, 2-butylbenzylamino, 4-hexylbenzylamino, 3-pentylbenzylamino , 4+er+-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, 3,5-13
．． 4-1 or 2,6-cyhydroxybenzylamino, 3
．． 4.5-1 hydroxybenzylamino, 3.4-2
．． 5- or 2,6-dimethylbenzylamino, 3,4.
Examples of phenylalkylamino groups in which the alkyl moiety has 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 5-trimethylbenzylamino group can.

Examples of the amine lower alkyl group include aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl,
Straight-chain or branched carbon atoms having 1 to 6 carbon atoms such as 4-aminobutyl, 1,1-dimethyl-2-aminoethyl, 5-aminopentyl, 6-aminohexyl, 2-methyl-3-aminopropyl, etc. An aminoalkyl group having an alkyl group can be mentioned.

Examples of lower alkanoylamino groups include formylamino,
Examples include straight-chain or branched alkanoylamino groups having 1 to 6 carbon atoms, such as acetylamino, propionylamino, butyrylamino, tert-butyrylamino, pentanoylamino, and hexanoylamino groups.

Examples of lower alkanoyl lower alkyl groups that may have a halogen atom include 2.2.2-1-lifluoroacetylaminomethyl, 2,2.2-trichloroacetylaminomethyl, 2-chloroacetylaminomethyl, 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
,3,3-1lichloropropionylamino)hexyl,
2-methyl-3-(3-chloropropionylamino)propyl, 2,3-dichloropropionylaminomethyl,
2-(4,4゜4-trichlorobutyrylamino)ethyl, 1-(4-fluorobutyrylamino)ethyl, 3(
5-chloropentanoylaminopropyl, 4-(3-chloro-2-methylpropionylamino)butyl, 1,1
-dimethyl-2-(6-bromohexanoylamino)ethyl, 5-(5,6-dibromohexanoylamino)
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms substituted with straight chain or branched alkanoylamino having 1 to 6 carbon atoms, which may have a halogen atom such as a pentyl group.

Lower alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio,! c.
Examples include straight-chain or branched alkylthio groups having 1 to 6 carbon atoms such as rt-butylthio, pentylthio, and hexylthio groups.

Examples of lower alkenyl groups include linear or 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. can.

The compound of the present invention can be manufactured by various methods, and typical manufacturing methods are shown below.

Reaction Scheme-1 3 3 (2) (101) 3 (102) [In the formula, R2, R3, R4 and R5 are the same as above. ] The reaction between the known compound of general formula (2) and hydroxylamine (3) can be carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of basic compounds used in this case include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, piperidine, pyridine, triethylamine, and 1°5-diazabicyclo(4,3,O). Nonen-5 (
DBN), 1,8-diazabicyclo (5,4゜O) Lounsen-7 (DBU), 1,4-diazabicyclo [
Examples include organic bases such as 2,2,2) octane (DABCO). Any inert solvent may be used as long as it does not adversely affect the reaction, such as lower alcohols such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, diethyl ether, ethylene glycol monomethyl ether, etc. ethers, aromatic hydrocarbons such as benzene, toluene, xylene, hydrogen halides such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. . The amount of hydroxylamine (3) to be 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°C, and generally 1 to 1
The reaction is completed in about 0 hours.

Reduction of the compound of general formula (101) can be carried out by catalytic hydrogenation in a suitable solvent in the presence of a catalyst. Examples of solvents used include water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether, ethyl acetate, Examples include esters such as methyl acetate, aprotic polar solvents such as dimethylformamide, and the like. Examples of the solvent used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. The amount of catalyst used is generally 0.0 per compound of general formula (101).
It is best to use about 2 to 1 times the amount. The reaction temperature is usually -20
℃ to around room temperature, preferably O0C to around room temperature, and the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally carried out at a temperature of 0.
It will be completed in about 5 to 10 hours.

Reaction scheme-2 R3/ R3z
(103) (104) [
In the formula, R1, R4 and R5 are the same as above.

R2/ and R2' are the same as R2. However, R2/ and R3/
shall represent a hydrogen atom, and at least one of R2'' and R3' shall represent a halogen atom.] The halogenation reaction of the compound of general formula (103) is carried out using a conventional halogenating agent. A wide variety of known halogenating agents can be used as the halogenating agent used in such a reaction, such as halogen molecules such as bromine and chlorine, iodine chloride, sulfuryl chloride, N-bromosuccinimide, N- Examples include halogenating agents such as N-halogenosuccinimide such as chlorosuccinimide.The amount of the halogenating agent used is usually based on the general formula (103
) is preferably used in an amount of about 10 to 10 times the molar amount of the compound (equal to 5 times the molar amount). The solvent used in the reaction is, for example, dichloromethane, dichloroethane,
Halogenated hydrocarbons such as chloroform and carbon tetrachloride,
Examples include acetic acid, propionic acid, water, and the like. In this 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 formula-3 (2) (5) 3 (105) [In the formula, R2, R3, R4 and R5 are the same as above.

R6 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 that may have a lower alkyl group as a substituent on the phenyl ring. . ] The reaction between the compound of general formula (2) and the compound of general formula (4) is carried out without a solvent or in a suitable solvent, in the absence or presence of a dehydrating agent. Examples of solvents used here include alcohols such as methanol, ethanol, and isopropanol, aromatic hydrocarbons such as benzene, toluene, and xylene, and aprotic solvents such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. Examples include polar solvents. Examples of dehydrating agents include desiccants used for dehydrating ordinary solvents such as molecular sieves, hydrochloric acid,
Examples include mineral acids such as sulfuric acid and boron trifluoride, and organic acids such as p-h luenesulfonic acid. The reaction is usually carried out at room temperature to 250°C, preferably about 50 to 200°C, and is generally completed in about 1 to 48 hours. The amount of the compound of general formula (4) to be used is not particularly limited, but it is usually used in at least an equimolar amount, preferably in large excess, relative to the compound of general formula (2).

The amount of the dehydrating agent to be used is usually a large excess in the case of a desiccant, and a catalytic amount in the case of an acid. The compound of general formula (5) thus obtained is subjected to the next reduction reaction without being isolated.

Although various methods can be applied to the reduction reaction of the compound of 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 siborane, etc., and the amount used is usually at least equimolar, preferably equimolar to compound (5).
The range is 10 times the mole. When lithium aluminum hydride is used as the hydrogenation reducing agent, it is convenient to use it in twice the molar amount of compound (5). This reduction reaction is
Usually a suitable solvent such as water, methanol, ethanol,
Using lower alcohols such as isopropanol, ethers such as tetrahydrofuran, ethylnityl, diglyme, etc., the temperature is usually -60 to 50°C, preferably -306°C.
~ It is carried out at room temperature for about 10 minutes to about 5 hours. Note that 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, diglyme, or the like.

Reaction formula-4 7 3 3 (102) (7) 3 (106) [In the formula, R2, R3, R4 and R5 are the same as above.

R7 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 general formula (102) and the compound of general formula (6) is carried out under the same conditions as the reaction between the compound of general formula (2) and the compound of general formula (4) in reaction scheme-3 above. It will be held in Further, the reduction reaction of the compound of general formula (7) is also carried out under the same conditions as the reduction reaction of the compound of general formula (5) in the reaction scheme-3.

Reaction formula-5 (102) (107) [In the formula, R2, R3, R4 and R5 are the same as above.

R8 has 1 to 10 carbon atoms, which may have a halogen atom
represents an alkanoyl group or a benzoylamino group having a lower alkyl group as a substituent on the phenyl ring. ] The reaction between the compound of general formula (102) and the compound of general formula (8) is achieved by subjecting them to a usual amide bond-forming reaction. In this case, an activated compound may be used as the alponic acid (8). The conditions for the amide bond forming reaction can be applied to the amide bond forming reaction. For example, (a) mixed acid anhydride method, that is, reacting the carboxylic acid (8) with an alkylhalocarboxylic acid to form a mixed acid anhydride;
A method of reacting compound (102) with this, (b) active ester method or active amide method, that is, carboxylic acid (8
) is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione, and the compound (102) is reacted with this. (c) Carbodiimide method, i.e., a method of dehydrating compound (102) to carboxylic acid (8) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) Carboxylic acid halide method That is, carboxylic acid (8) is induced into a halide form, and compound (102) is added to this.
(e) Other methods include converting carboxylic acid (8) to carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and reacting this with compound (102); For example, a method may be used in which compound (102) is reacted with an ester with a lower alcohol under high pressure and high temperature. Alternatively, a method may be adopted in which carboxylic acid (8) is activated with a phosphorus compound such as triphenylphosphine or diethyl chlorophosphate, and compound (102) is reacted therewith.

Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromate, ethyl chloroformate, ethyl bromate, and isobutyl chloroformate.

The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and is usually converted into compound (102) without isolation.
Compound (1) is produced by reacting with. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compounds used are those commonly used in the Schotten-Baumann reaction, such as 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), organic bases such as 1,4-diazabicyclo(2,2,2)octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate. It will be done. The reaction is carried out at about -20 DEG to 100 DEG C., preferably 0 DEG to 50 DEG C., and 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 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. . Although the mixed acid anhydride method does not require the use of a particular solvent, it is generally carried out in a solvent, and any solvent commonly used in the mixed acid anhydride method can be used, specifically methylene chloride. , halogenated carbons such as chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, dimethyl formamide,
Examples include aprotic polar solvents such as dimer sulfoxide and hexamethylphosphoric triamide. The ratio of carboxylic acid (8), alkylhalocarboxylic acid, and compound (102) used in this method is usually at least the same molar amount; It is preferable to use 1 to 2 times the mole of each.

For example, in the case of using benzoxazoline-2-thionamide, the activated ester method or activated amide method in (b) above can be carried out using an appropriate solvent that does not affect the reaction, such as the one used in the mixed acid anhydride method described above. Using a similar solvent such as 1-methyl-2-pyrrolidone, 0 to 150°C,
Preferably at 10 to 100°C, 0. This is carried out by reacting for 5 to 75 hours. In this case, the compound (1
02) and benzoxazoline-2-thionamide, the latter is usually at least equimolar to the former;
Preferably, the amount is equimolar to twice the molar amount. When N-hydroxysuccinimide ester is used, the reaction proceeds advantageously when a suitable base is used, for example, a base similar to that used in the carboxylic acid halide method described below.

The carboxylic acid halide method (c) above uses carboxylic acid (8
) is reacted with a halogenating agent to form a carboxylic acid halide, and this carboxylic acid halide is isolated and purified, or is reacted with compound (102) without being isolated and purified. This carboxylic acid halide and compound (102
) is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. Basic compounds are usually used as dehydrohalogenation agents, and in addition to the basic compounds used in the Schotten-Baumann reaction mentioned above, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, sodium methylate, etc. , alkali metal alcoholades such as sodium ethylate, and the like. Note that the compound (102) can also be used as a dehydrohalogenating agent by using an excess amount. In addition to the solvent used in the Schotten-Baumann reaction, examples of the solvent include water, methanol, ethanol, propatool, butanol, and
Alcohols such as methoxy-1-butanol, ethyl seltul, methyl cellosolve, pyridine, acetone,
Examples include acetonitrile and a mixed solvent of two or more thereof. The ratio of compound (102) and carboxylic acid halide to be used is not particularly limited and can be selected within a wide range, but the latter is usually used in an amount of at least equimolar to the former, preferably equimolar to twice the molar amount. The reaction temperature is usually -30 to 1
The reaction is generally completed in 5 minutes to 30 hours at about 80°C, preferably about 0 to 150°C.

The carboxylic acid halide used is produced by reacting the carboxylic acid halide (8) with a halogenating agent without a solvent or in a solvent. Any solvent can be used as long as it does not adversely affect the reaction, such as 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, dimethyl sulfoxide, and the like. As the halogenating agent, a normal halogenating agent that can convert the hydroxyl group of a carboxy group into a halogen can be used, such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, etc. .

The ratio of the carboxylic acid (8) and the halogenating agent to be used is not particularly limited and is selected appropriately, but when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former, or in the solvent. When the reaction is carried out, 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 also not particularly limited, but are usually carried out at room temperature to about 100°C, preferably 50 to 80°C, for about 30 minutes to 6 hours.

The method of activating carboxylic acid (8) with a phosphorus compound such as triphenylphosphine or diethyl chlorophosphate and reacting it with 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, and aromatic hydrocarbons such as benzene, toluene, and xylene. , ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. In this reaction, the compound (102
) itself acts as a basic compound, so if it is used in excess of the theoretical amount, the reaction will proceed well, but
If necessary, other basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicyclo[4°3,O]nonene-7
(DBN), 1,5-diazabicyclo(5,4,03
undecene-5 (DBU) 1,4-diazabicyclo[2
,2,2]octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc. can also be used. The reaction is accomplished at about 0 to 150°C, preferably about 0 to 100°C, for about 1 to 30 hours. Compound (1
The ratio of the phosphorus compound and carboxylic acid (8) to 02) is usually at least about equimolar amounts, preferably 1 to 3 times the molar amount.

Reaction formula-6 (102) (108) [In the formula, R2, R3, R4 and R5 are the same as above.

R9 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 that may have a lower alkyl group as a substituent on the phenyl ring. . X represents a halogen atom. ] The reaction between the compound of general formula (102) and the compound of general formula (9) is carried out under the same reaction conditions as the reaction of the compound of general formula (102) and carboxylic acid halide in reaction scheme-5 above. be able to.

Reaction Scheme 7% Formula %) (110) ) [In the formula, RI, R3, R4 and R5 are the same as above. ] The nitration of the compound of general formula 109) is carried out under the usual nitration reaction conditions for aromatic compounds, for example, using a nitration agent without a solvent or in a suitable inert solvent. Examples of inert solvents include acetic acid, acetic anhydride, and concentrated sulfuric acid. Examples of nitrating agents include fuming nitric acid, concentrated nitric acid, and mixed acids (
Examples include sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride and nitric acid), alkali metal nitrates such as potassium nitrate and sodium nitrate, and sulfuric acid. The amount of the nitrating agent used may be an equimolar or more excess amount relative to the starting compound, and the reaction is preferably carried out at O0C to around room temperature for 1 to 4 hours.

The reduction of the compound of general formula (1,10) can be carried out under the same reaction conditions as the reduction of the compound of general formula (101,) in the above reaction scheme-1.

Further, the reduction of the compound of general formula (110) can also be carried out using the reducing agent shown below. Reducing agents used include, for example, iron, zinc, tin or stannous chloride and acids such as acetic acid, hydrochloric acid or sulfuric acid, or iron, ferrous sulfate, zinc or tin and alkali metal hydroxides such as sodium hydroxide. , sulfides such as ammonium sulfide, aqueous ammonia, and mixtures with ammonium salts such as ammonium chloride. Examples of the inert solvent used here include water, acetic acid, methanol, 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 reducing agents, the conditions are preferably O0C to around room temperature, 0. It is preferable to carry out the reaction for about 5 to 10 hours. The amount of the reducing agent used is small (equimolar amount, usually equimolar to 5 times the molar amount of the raw material compound).

In the compound of the above general formula (1), R1 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 benzoylamino group having a lower alkyl group as a substituent on the 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 by hydrolysis into a corresponding compound where R1 is an amino group. Further, a compound in which R2 is a lower alkanoylamino group or a lower alkanoylamino lower alkyl group that may have a halogen atom can be converted by hydrolysis into a compound in which the corresponding R2 is an amino group or an amino lower alkyl group. Here, as conditions for hydrolysis, for example, the general formula (202
) can be employed.

In the above reaction schemes 1 and 3, the compound of general formula (2) used as a starting material includes a new compound, and is produced, for example, according to the method shown below.

Reaction Scheme-8 R3 3 (201) (202) 3 (203) [In the formula, R3, R4 and R5 are the same as above. RIO represents a lower alkanoylamino lower alkyl group that may have a halogen atom. R1+ represents an amino lower alkyl group. ] The reaction between the compound of general formula (201) and the compound of general formula (10) is carried out in the presence of a dehydration condensation agent without a solvent or in an appropriate solvent. The dehydration condensation agent used is
For example, condensed phosphoric acids such as polyphosphoric acid, phosphoric acids such as orthophosphoric acid, pyrophosphoric acid, metaphosphoric acid, phosphorous acids such as strained layer phosphoric acid, phosphoric anhydrides such as phosphorus pentoxide, hydrochloric acid, sulfuric acid, boric acid, etc. acids, sodium phosphate, boron phosphate,
Examples include metal phosphates such as ferric phosphate and aluminum phosphate, activated alumina, sodium bisulfate, and Raney nickel. Examples of the solvent used include dimethylformamide and tetralin. Compound of general formula (201) and general formula (10)
There is no particular limit to the ratio of the compound to be used, and it can be appropriately selected within a wide range, but it is generally recommended to use the latter in an equimolar amount or more, preferably in equimolar to twice the molar amount of the former. good. The amount of the dehydration condensation agent used is not particularly limited and can be appropriately selected from a wide range.
It is generally advisable to use a catalytic amount or more, preferably a large excess amount, relative to the compound 1).

The reaction normally proceeds suitably at -30 to 50°C, preferably from O0C to around room temperature, and is generally completed in about 1 to 30 hours.

For the hydrolysis of the compound of general formula (202), a wide range of conventionally known hydrolysis reaction conditions can be applied. In the presence of inorganic acids such as acids, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and inorganic alkali compounds such as alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate, No solvent or a suitable solvent (for example, water or a mixed solvent of water and a lower alcohol such as methanol or ethanol)
medium, at 50 to 150°C, preferably 70 to 100°C,
The treatment may be carried out for about 3 to 24 hours.

Reaction Scheme-9 3 3 (201) (204) 3 3 (205) (206) [In the formula, R3, R4 and R5 are the same as above. RI2 represents a lower alkanoyl group. ] Nitration of the compound of general formula (201) and general formula (20
The reduction of the compound of 4) is the nitration of the compound of the general formula (109) in the above reaction scheme-7, and the reduction of the compound of the general formula (109), respectively.
It can be carried out under the same reaction conditions as for the reduction of the compound in 110). Moreover, the compound of the general formula (205) and the general formula (
The reaction with the compound of formula (11) can be carried out under the same reaction conditions as the reaction between the compound of general formula (102) and the compound of general formula (8) in Reaction Scheme-5 above.

Reaction formula-10 (201) (204) 3 (208> [R3 in the formula 4 R5 and X are the same as above.

R+3 and R+4 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 range of known basic compounds can be used, including inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, and alkali metals such as sodium and potassium. , sodium methylate, sodium ethylate, alcoholade, triethylamine, pyridine, N, N
-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicycloC4,3
,0] nonene-5 (DBN), 1,8-diazabicyclo[5,4,01 undecene-7 (DBU), 1.4-
Diazabicyclo[2゜2.2]octane (DABCO)
Organic bases such as The reaction can be carried out without a solvent or in the presence of a solvent, and all inert solvents that do not adversely affect the reaction can be used, such as water, alcohols such as methanol, ethanol, propatool, butanol, and ethylene glycol. ethers such as dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, ketones such as acetone, methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, xylene, esters such as methyl acetate, ethyl acetate, N, N -Aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc., and mixed solvents thereof can be mentioned. It is also advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide. The usage ratio of the compound of general formula (2a) and the compound of general formula (17) in the above method is not particularly limited and is appropriately selected from a wide range, but usually the latter is used in an equimolar proportion of -5 to the former. It is desirable to use twice the molar amount, preferably equimolar to twice the molar amount. The reaction temperature is also not particularly limited, but is usually carried out at room temperature to 200°C, preferably 50 to 150°C. The reaction time is usually 1 to 30 hours, preferably 1 to 30 hours.
It is 15 hours.

The reaction to obtain the compound of general formula (208) from the compound of general formula (207) is generally called Claisen rearrangement, and for example, by heating compound (207) in an appropriate solvent, compound (208) is obtained. can lead. 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 150 to 250°C.
℃, and the reaction is completed in about 1 to 20 hours.

Reaction formula-1 1 3 3 (209) (14) 3 3 (16) (18) 3 (210) [In the formula R2 R3 and X are the same as above.

R"5 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. R41 and R5'
each represents a lower alkyl group. ] The reaction between the compound of general formula (209) and the compound of general formula (13) is carried out in a suitable solvent in the presence of a basic compound. Examples of the basic compound used here include sodium hydroxide, potassium hydroxide, sodium ethylate, sodium hydride, potassium hydride, sodium amide, potassium amide, and the like. Examples of solvents include alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. can be mentioned. 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 it is usually at least an equimolar amount, preferably an equimolar amount of -5 to the compound of general formula (209). It is better to use twice the molar amount. The reaction is usually carried out at a temperature of about 0 to 70°C.
Preferably it is carried out at around 0°C to room temperature, and generally 0.5
The reaction is completed in about 12 hours.

The reaction between the compound of general formula (14) and the compound of general formula (↓5) and the reaction between the compound of general formula (16) and the compound of general formula (17) are the same as those of general formula (209) and general formula (↓5). The reaction can be carried out under the same conditions as the reaction with the compound of formula (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 of a compound of general formula (18) in which RI5 is a phenyl lower alkyl group, a lower alkyl group, or a lower alkoxy lower alkyl group, the compound is dissolved in a suitable solvent such as water, methanol, ethanol, isopropanol, etc. in lower alcohols such as dioxane 1, ethers such as tetrahydrofuran, solvents such as acetic acid, or mixed solvents thereof, in the presence of a catalytic reduction catalyst such as palladium-carbon or palladium-black, at around 0 to 100 °C. , hydrogen pressure 1
~10 atm for about 0.5~3 hours, or in a mixture of an acid such as hydrobromic acid or hydrochloric acid and a solvent such as water, methanol, ethanol, isopropanol, etc.
C., preferably 50 to 120.degree. C., a compound of general formula (210) can be obtained. Next, in the case of a compound of general formula (18) in which RIS is a lower alkanoyl group, tetrahydropyranyl group, or benzoyl group, the compound of general formula (210) can be obtained by hydrolyzing the compound. can. This hydrolysis is carried out in a suitable solvent in the presence of an acid or basic compound. 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 acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and examples of basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. The reaction is usually carried out at room temperature to 150°C, preferably at 8°C.
It proceeds suitably at 0 to 120°C and generally takes about 1 to 15 hours to complete.

Reaction scheme -1,2 3 3 (201) (211) R3R3 (212) (213) [In the formula, R3, R4, R5 and X are the same as above.

R16 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 a solvent or in the presence of a solvent. The solvent used here may be any solvent as long as it does not affect the reaction, but examples include chloroform, dichloromethane, halogenated hydrocarbons such as carbon tetrachloride, benzene, toluene, xylene, nitrobenzene, dichlorobenzene. Examples include aromatic hydrocarbons such as. The amount of the compound of general formula (19) to be used is usually
The amount is preferably at least equimolar, preferably equimolar - 1.5 times the molar amount of the compound i). The reaction is usually −
The reaction proceeds suitably at 50-50°C, preferably around 10-10°C, and is generally completed in about 15 minutes to 10 hours.

The reduction reaction of the compound of general formula (211) can be carried out using: ■ a method using a metal such as iron, zinc, tin, or tin chloride and an acid such as acetic acid, hydrochloric acid, or sulfuric acid, or ■ lithium aluminum hydride.
A method using a hydrogenation reducing agent such as sodium borohydride or diborane can be employed. When method
) is preferably used in at least an equimolar amount, usually in large excess. This reaction is usually carried out at -50 to 150'C, preferably around room temperature to 100'C, and is generally 0.5
Leave in the room for about 10 hours. In addition, when method (2) is employed, the same reaction conditions as for the reduction of the compound of general formula (5) in the above reaction scheme-3 can be employed.

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 dehydrohalogenation agent used here, the general formula (102
) The solvent and dehydrohalogenating agent used in the reaction of the compound and the carboxylic acid halide can be used. The reaction is
The reaction is usually carried out at about 50 to 1,00°C, preferably about -50 to 30°C, and the reaction is generally completed in about 30 minutes to 5 hours. The amount of the compound of general formula (20) to be used is:
At least equimolar to the compound of general formula (212),
Preferably, the amount is equimolar to L twice the molar amount.

Reaction Scheme 13 %Formula %) [In the formula, R3, R4, R5 and X are the same as above. ] The reaction between the compound of general formula (211) and the compound of general formula (21) is carried out without a solvent or in a solvent in the presence of a dehydrohalogenating agent. As a solvent and a dehydrohalogenating agent,
Any of the solvents and dehydrohalogenating agents used in the reaction of the compound of general formula (102) and the carboxylic acid halide in Reaction Scheme-5 above can be used. piperidine (
21) is usually used in an amount of at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (211). 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 general formula (211). The reaction is usually -30~
It is carried out at 150°C, preferably about -20 to 100°C, and generally at a temperature of 0. It will be completed in about 5 to 24 hours.

Reaction Scheme-14 (201) (214) [In the formula, R3, R4, R5 and X are the same as above. ] The reaction between the compound of general formula 201) and the compound of general formula (22) is carried out without a solvent or in a solvent in the presence of a catalyst. The solvent used here may be any solvent as long as it does not affect the reaction, but examples include chloroform, dichloromethane, halogenated hydrocarbons such as carbon tetrachloride, benzene, toluene, xylene, nitrobenzene, dichlorobenzene. Examples include aromatic hydrocarbons such as, carbon disulfide, etc. Examples of the catalyst used include Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, and concentrated sulfuric acid. The amount of Lewis acid to be used may be determined appropriately, but usually the amount of the compound (201
), the amount is about 2 to 6 times, preferably about 2 to 4 times, by mole. The amount of compound (22) to be used is usually at least an equimolar amount relative to compound (201),
Preferably, the amount is equimolar to twice the molar amount. The reaction temperature is
Although it is selected as appropriate, it is usually about 0 to 150°C, preferably about 0 to 100°C. The reaction is generally 0
．． It will be completed in about 5 to 10 hours.

The target products obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

Note that the compounds of the present invention naturally include optical isomers.

The indane derivative represented by the general formula (1) of the present invention is
It can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid, and the present invention also includes this acid addition salt. In the above, examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid,
Organic acids such as citric acid, malonic acid, methanesulfonic acid, benzoic acid, etc. can be used.

Among the groups represented by R+ in the above general formula (1), a preferable group is an alkylamino group having 1 to 6 carbon atoms or an amino group, and an especially preferable group is an amino group.

Among the groups represented by R2, preferred are a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom, or a nitro group, and a particularly preferred group is an alkyl group having 1 to 6 carbon atoms.

Among the groups represented by R3, preferred are a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a halogen atom, and a particularly preferred group is an alkyl group having 1 to 6 carbon atoms.

Among the groups represented by R4 and R5, preferred groups are both a hydrogen atom or a methyl group, and particularly preferred groups are both a hydrogen atom.

The above preferred group in which both R2 and R3 have 1 carbon number
-6 alkyl groups, the following are more preferred.

That is, when one of R2 and R3 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 This is the case when both R2 and R3 are an alkyl group having 2 to 6 carbon atoms (preferably a branched alkyl group having 3 to 6 carbon atoms). Among these, the most preferred is the case where one of R2 and R3 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), and R2 and One of R3 is an ethyl 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). The number of carbon atoms mentioned above is 3
-6 branched alkyl groups are preferably isopropyl, 2-methylpropyl, 1-methylpropyl, 1,
Examples include 1-dimethylpropyl group.

The compound of general formula (1) is usually used in the form of a pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, solutions, suspensions,
Examples include emulsions, granules, capsules, heavy doses, injections (solutions, suspensions, etc.), ointments, and the like. When forming tablets, a wide variety of carriers known in this field can be used, including excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid. agent, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., quaternary Absorption enhancers such as ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose,
Examples include adsorbents such as kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming into an emulsion, a wide variety of conventionally known carriers can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, powdered tragacanth, and gelatin. , a binder such as ethanol, and a disintegrant such as laminaran agar. When molding into the form of heavy punishment, a wide variety of conventionally known carriers can be used, such as polyethylene glycol,
Examples include cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when forming these solutions, emulsions, and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, including water, ethyl alcohol, 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 may be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You can. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. When forming into a paste, cream or gel form, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like.

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

There are no particular restrictions on the method of administering the above pharmaceutical preparations, and the administration method is determined depending on the various preparation forms, age, sex and other conditions of the patient, and the severity of the patient. For example, tablets, emulsions, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of injections, it may be used alone or with glucose,
It is administered intravenously in a mixture with a normal replacement fluid such as an amino acid, and if necessary, it is administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. In cases of severe punishment, it is administered rectally.

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

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

Production example 1 4-methyl-7-hydroxy-1-indanone 39.3
g and N-hydroxymethyl-α-chloroacetamide 3
While cooling, add 280 z/ml of concentrated sulfuric acid to 0 g and dissolve. - After standing overnight, the reaction mixture was poured into water and the precipitated crystals were collected in a furnace. Recrystallization from ethanol yields 49 g of 4-methyl-6-α-chloroacetylaminomethyl-7-hydroxy-1-indanone.

Colorless needle crystals mp 166-167.5°C Production example 2 4-methyl-7-hydroxy-1-indanone 25.6
g of acetic acid 250 zll solution, acetic anhydride 1.9.4xl
and 50xl of acetic acid with 15.4yA' of concentrated sulfuric acid! Add the solution gradually. The reaction mixture was concentrated to dryness, and the residue was washed with ether to give 4-methyl-6-nitro-7-hydroxy-1.
- Obtain 25.7 g of indanone.

mp 154-157°C Yellow needle crystal production example 3 A solution of 26 g of 4-methyl-6-nidolph-hydroxy-1-indanone in dimethylformamide 5011
%Pd-C2.6g is added and catalytic reduction is carried out at normal pressure O<0>C to room temperature. The catalyst was eliminated and the solvent was distilled off to give 4-methyl-6-ami2-hydroxy-1-indanone17.
Obtain 3g.

mp 187-188°C (decomposition) Pale yellow needle crystal production example 4 4-methyl-6-α-chloroacetylaminomethyl-7
-Hydroxy-1-indanone 3g and concentrated hydrochloric acid 301/
60yrl of ethanol! The solution is heated to reflux for 8 hours.

The solvent was distilled off, and the resulting residue was recrystallized from ethanol to give 4-methyl-6-amitsumethyl-dihydroxy-t.
- Obtain 1 g of indanone.

mp 300°C or higher Light brown needle crystal NMR (DMSO) δ; 2.22 (s, 3H), 2.6-2.8 (m, 2H) 2.85-3.1 (m, 2H), 3 .97 (s, 2H), 7.55 (s, LH), 8.4-9.5 (br,, 3H) Production Example 5 4-Methyl-6-nidolph-hydroxy-1-indanone 11. ．． 5% Pd in 5g of 500rIl acetic acid solution
-C1.5g is added and catalytic reduction is carried out at room temperature and normal pressure. Eliminate the catalyst, distill off the solvent and wash with ether. Recrystallization from methanol yields 6.34 g of 4-methyl-6-acetamido-7-hydroxy-1-indanone.

mp 193-198°C Red-orange needle 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, N(), 9.25~10.0 (br,, 2H) Production Example 6 36 g of 4-methyl-7-hydroxy-1-indanone and water Add allyl bromide 251111 to a solution of 17.6 g of potassium oxide in 650 zl of methanol and heat under reflux for 6 hours. Eliminate insoluble matter and distill off the solvent. Extract with chloroform-water, separate the chloroform layer and remove the solvent. The residue was washed with ether and purified by column chromatography to give 4-methyl-7-allyloxy-1
- Obtain 32 g of indanone.

mp 89-92°C Light brown needle crystal production example 7 4-methyl-7-allyloxy-1-indanone 32 g
was suspended in Tetralin 100z/ under an argon atmosphere.
Heat to reflux for 4 hours. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane-dichloromethane: n-hexane = 1 = 2) to obtain 4-methyl-
6-allyl-7-hydroxy-1-indanone 26.8
get g.

mp 41-45°C Light brown needle crystals Production Example 8 8.2*l of crotyl bromide was added to a methanol 200zA' solution of 10g of 4-methyl-7-hydroxy-1-indanone and 5.3g of potassium hydroxide, Heat to reflux for 4 hours. Insoluble matter is eliminated and the solvent is distilled off. After extraction with chloroform and water, the chloroform layer was washed with diluted sodium hydroxide solution, water, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: n-hexane-dichloromethane=1=1) to obtain 8.72 g of 4-methyl-7-crotyloxy-1-indanone.

mp87.5-92°C Pale yellow needle crystals Production Example 9 4-Methyl-7-crotyloxy-1-indanone 8g
was suspended in Tetralin 5011, and under an argon atmosphere, 9
Heat to reflux for an hour. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane→n-hexane:dichloromethane=2:1), and then recrystallized from dichloromethane-〇-hexane to obtain 4-methyl-6-(1
-Methyl-2-propenyl)-1-indanone 5.44
get g.

mp 88-92°C Colorless needle crystals Compounds listed in Table 1 below are obtained in the same manner as in Production Example 8 or 9 using appropriate starting materials.

Table Production Example 14 15 g of 4-methyl-7-hydroxy-1-indanone and 7.95 g of potassium hydroxide in methanol 200zA'
Add methallyl chloride 13.55111 to the solution,
Heat to reflux for 1 hour. After eliminating insoluble matter, the solvent is distilled off. The residue was purified by silica gel column chromatography (eluent; n-hexane:dichloromethane = 1:1) to obtain 4-methyl-7-methallyloxy-1-indanone 9.
get g.

mp 74.2-75.2°C Colorless powder crystal production example 15 4-methyl-7-methallyloxy-1-indanone 8
．． 46g of Tetralin 5. Add Oxl and heat to reflux for 9 hours. The reaction solution was subjected to silica gel column chromatography (eluent; n-hexane: dichloromethane = 2:
1) and further recrystallized from dichloromethane-hexane to obtain 6.68 g of 4-methyl-6-(2-methyl-2-propenyl)-7-hydroxy-1-indanone.

mp62.5-64℃ Colorless needle crystal production example 16 Chloro/1<carbon tetrachloride of sulfonic acid 9011 1'50r
7-hydroxy-4-methyl-1 to the ll solution under water cooling.
- Add 30 g of indanone little by little. Remove the carbon tetrachloride layer, add ice water from Step 11 to the remaining layer, and stir vigorously. The precipitated solid was collected in a furnace and washed with water to obtain 8.7 g of 7-hydroxy-6-chlorosulfonyl-4-methyl-1-indanone. This product was added without purification to a solution consisting of 31.4 g of stannous chloride dihydrate and 100 yA' of concentrated hydrochloric acid, and stirred at room temperature for 4 hours. Pour the reaction solution into 500xl of ice water.
The precipitated crystals are collected in a furnace, washed with water, and dried to form a 7-
7.86 g of hydroxy-6-mercapto 4-methyl-1-indanone are obtained. This product was then suspended in 100 liters of methanol without purification, and 3.9 d! of methyl iodide was added to it. and a solution of 5.1 g of sodium bicarbonate in water 201/solution, and stirred for 1 hour at room temperature.

The solvent is concentrated to dryness under reduced pressure. After purifying the residue by silica gel column chromatography (eluent: chloroform),
Recrystallization from ethanol yields 1.52 g of 7-hydroxy-4-methyl-6-methylthio-1-indanone.

mp 139°C Colorless needle crystal production example 1゜7 2.27 g of 1-piperidinesulfonyl chloride was added to a solution of 2 g of dihydroxy-4-methyl-1-indanone in 1011 dichloroethane, and 10 g of anhydrous aluminum chloride was added little by little at room temperature. Stir. After heating under reflux for 8 hours, the mixture was extracted with chloroform 20011, washed with water, and then chloroform was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography (eluent;
After purification with chloroform), recrystallized from ethanol to obtain 7
1.24 g of -hydroxy-4-methyl-6-(1-piperidinesulfonyl)-1-indanone are obtained.

mp 188-189°C Pale yellow plate crystals Production Example 18 4.6-dimethyl-7-methoxymethyleneoxy-1-
Indanone 7.56g dimethylformamide 200y
4.94 g of 60% sodium hydride is added little by little to the solution at room temperature, and the mixture is stirred until no hydrogen is generated (about 1 hour). Thereafter, 14.6 g of methyl iodide was added, and the mixture was further stirred at room temperature for 2 hours. After adding hydrochloric acid to the reaction mixture to make it acidic, the solvent was concentrated under reduced pressure, and the resulting residue was mixed with water II! under vigorous stirring. Pour into the solution and extract twice with 300 r/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-medoxymethyleneoxy 2.2,4
, 8 g of 6-tetramethyl-l-indanone are obtained. This product was dissolved in methanol 20011 without purification, concentrated hydrochloric acid 1011 was added, and after stirring at 50°C for 3 hours, methanol was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:dichloromethane = 2:1) to obtain 7-hydroxy-2,
6.8 g of 2.4.6-tetramethyl-1-indanone are obtained.

mp 28-30°C NMR (CDC13) δ; 9.08 (IH, s) 7.19 (LH, 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
g to 400 zl of methanol and heated under reflux for 30 minutes. After cooling, the supernatant is collected and a hydroxylamine methanol solution is prepared. 1.6.2 g of 7-hydroxy-4-methyl-1-indanone is added to this hydroxylamine methanol solution, and the mixture is heated under reflux for 5 hours while stirring. The reaction mixture is concentrated to dryness under reduced pressure. Add 2 ethyl acetate to the residue
Add 002A' to eliminate insoluble matter. The furnace solution was concentrated to dryness under reduced pressure, and the residue was recrystallized from methanol to obtain 17.6 g of 7-hydroxy-4-methyl-1-indanone oxime in the form of colorless needles.

mp 148-149.5℃ Using appropriate starting materials, the following 2.
The compounds listed in the table are obtained.

Reference Example 14 15.0 g of 7-hydroxy-4-methyl-1-indanone oxime is dissolved in 200zA' acetic acid, 1.0 g of platinum oxide catalyst is added, and catalytic reduction is carried out at room temperature under a hydrogen pressure of 5 atm for 8 hours. After the catalyst is separated from the furnace, the furnace liquid is concentrated to dryness under reduced pressure. Add 200 zf of ethanol to the residue to dissolve it, and saturated it by blowing in hydrochloric acid gas. Concentrate the solvent to dryness under reduced pressure,
The residue was recrystallized from ethanol to give colorless needle-like crystals of 1-amino-7-hydroxy-4-methylindane hydrochloride 3.3
Obtain 0g.

mp 221-223°C Compounds listed in Table 3 below are obtained in the same manner as in Reference Example 14 using appropriate starting materials.

Reference Example 30 1 g of 1-amino-7-hydroxy-4-methylindane hydrochloride was dissolved in water 20111, stirred vigorously at room temperature, and then 3N hydrochloric acid solution 5 containing 0.85 g of iodine monochloride was prepared.
Drip zl. After stirring at the same temperature for 2 hours, cool on ice. The precipitated crystals are collected in a furnace and converted into a hydrochloride, then washed with ether and dried. 1-Amino-7-hydroxy-6-iodo-4-methylindane hydrochloride in yellow needles 0.70
get g.

mp Decomposition at 200° C. or higher Reference Example 31 1.0 g of 1-amino-7-hydroxyindan hydrochloride is dissolved in 60 zll of acetic acid, and 1.53 g of sulfuryl chloride is added dropwise with stirring while cooling with water. After stirring at the same temperature for 3 hours, the mixture was concentrated under reduced pressure. The residue was saturated with hydrochloric acid gas in ethanol 5
Ozl! After dissolving in, drying under reduced pressure. Recrystallized from isopropanol-ether to obtain colorless prism product 1-
0.43 of amino-4°6-dichloro-7-hydroxyindan hydrochloride is obtained.

mp 238-239°C (decomposition) Reference example 32 I-amino-7-hydroxy-4-methylindane 5 g
was dissolved in 30 ytll of acetic acid, and 1.73 zl of bromine was added to this.
Add acetic acid solution and stir at room temperature for 1 hour. The precipitated crystals were collected and recrystallized from isopropanol to give 1-amino-
2 g of 6-promo-7-hydroxy-4-methylindane hydrobromide are obtained. The structure is determined by NMR.

mp 178-190°C (decomposition) Yellow needle crystal NMR (DMSO) δ; :2. 18 (s, 3H) L, 8-3. 35 (m, 4H) 4, 75~5
．． 05 (m, IH)7, 35 (s,
LH) 7.6-9.2 (b, s, 3H) Reference Example 33 5.75 g of 1-amino-7-hydroxy-4-methylindane hydrochloride was suspended in acetic acid 4011, and acetic anhydride 3. 27zA' and concentrated nitric acid 2.59ytll acetic acid 1
Add 011 solution and stir at room temperature for 6 hours.

The solvent was distilled off, the residue was washed with acetone, and then recrystallized from ethanol to obtain 2 g of 1-amino-7-hydroxy-4-methyl-6-nitroindane hydrochloride.

mp 200-230°C (decomposition) Yellow needle NMR (DMSO) δ; 2.22 (s, 3H) 2.0-3.45 (m, 4H) 4, 7-5. 0 (m, IT()7.82 (
s, IH) 8, 4-9. 7 (br,, 3H) Reference example 3
4 1.77 g of 1-amino-4,6-dimethyl-7-hydroxyindan was added to 100 g of 0.2N aqueous sodium hydroxide solution.
zA', and then add 1.7 g of α-chloroacetyl chloride while stirring while cooling with water.

Then stir at room temperature for 2 hours. The reaction solution was made acidic with dilute hydrochloric acid and extracted with chloroform. After washing and drying, the solvent is distilled off. Recrystallize from ethanol to obtain 2.34g of 1
2.34 g of -acetylamino-4,6-dimethyl-7-hydroxyindan are obtained.

mp 131-132°C Colorless needle crystals Compounds listed in Table 4 below are obtained in the same manner as in Reference Example 34 using appropriate starting materials.

Reference Example 38 1.77 g of 1-amino-4,6-dimethyl-7-hydroxyindan and 100z of triethylamine 27A'
72 g of methanesulfonyl chloride was added dropwise to the chloroform solution at room temperature. Thereafter, the mixture was stirred at the same temperature for 4 hours. The reaction mixture was washed successively with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated brine, and then 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-hydroxyindan.

mp 114-116°C Compounds listed in Table 5 below are obtained in the same manner as in Reference Example 38 using appropriate starting materials in the form of colorless powder.

Reference example 51 4,6-dimethyl-7-hydroxy-1-indanone 1
．． 100z/76g and 14.6g of n-butylamine
Heat the ethanol solution to reflux for 8 hours. After cooling to room temperature, 1 g of sodium borohydride is added, and the mixture is further stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness, and the residue was diluted with 100% water.
Add z/ and dissolve. Acidify with concentrated hydrochloric acid, then adjust to pH=9 with saturated aqueous sodium acetate solution. The obtained precipitate is extracted with ethyl acetate, washed with water, and dried. The solvent was distilled off, the resulting residue was dissolved in 100 yIl of ethanol, and the solution was converted into a hydrochloride with ethanol saturated with hydrochloric acid gas. Recrystallization from ethanol-ether yields 1.89 g of 1-n-butylamino-4,6-dimethyl-7-hydroxyindan hydrochloride.

mp 143-144°C Colorless needle crystals Compounds listed in Table 6 below are obtained in the same manner as in Reference Example 51 using appropriate starting materials.

Reference Example 64 1.77 g of 1-amino-7-hydroxy-4,6-dimethyl-indan and 3,5-di-tert-butyl-
A solution of 2.57 g of 4-hydroxybenzaldehyde in 50xl of ethanol is stirred for 2 hours at room temperature. Thereafter, sodium borohydride solution is added little by little to the reaction solution while cooling with water. After stirring at room temperature for 2 hours, the reaction solution was acidified with hydrochloric acid,
The solvent is dried under reduced pressure. Add 100 ml of water to the residue, add an aqueous sodium acetate solution to adjust the pH to 8, and add 1 ml of ethyl acetate.
Extract at 00yA'. After washing with water, it is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Dilute the residue with 50% ethanol
11 and add hydrochloric acid gas saturated ethanol to adjust the pH.
= 3, and dry the solvent under reduced pressure again. ether-n
- recrystallized from hexane to give 1-(3,5-di-tert)
-butyl-4-hydroxybenzyl)amino-4,6-
0.77 g of dimethyl-7-hydroxyindan is obtained.

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

Reference Example 65 5 g of 1-amino-4-methyl-6-α-chloroacetylaminomethyl-7-hydroxyindan and 50 g of concentrated hydrochloric acid
A 1/1 ethanol solution at 100 rA' is heated under reflux for 8 hours. The solvent is distilled off and washed with ethanol. Recrystallized from methanol-ether to give 1-amino-4-methyl-6
-amitsumethyl-dihydroxyindan dihydrochloride 1
get g.

mp 220°C (decomposition) Colorless powder reference example 66 19.7 g of 7-hydroxy 4-methyl-6-t-butyl-1-indanone oxime was dissolved in 200 r/acetic acid, and 1.0 g of platinum oxide catalyst was added. , catalytic reduction at room temperature for 8 hours under a hydrogen pressure of 5 atm. After the catalyst is separated from the furnace, the furnace liquid is concentrated to dryness under reduced pressure.

200zA of ethanol in the residue! Add and dissolve, then blow in hydrochloric acid gas to saturate. The solvent was concentrated to dryness under reduced pressure, and recrystallized from ethanol to obtain 1-amino-
2.2 g of 7-hydroxy-4-methyl-6-t-butyl-1-indane hydrochloride are obtained.

mp 221-224°C (decomposition) Elemental analysis value (C14H21N O・HCl')C)i
N Calculated value (%) 65,74 8.28 5.48 Actual value (%) 65.59 8.15 5.59 Reference example 67 7-hydroxy 4,6-di-t-butyl-1-indanone oxime Dissolve 23.2g in 200n7 acetic acid,
1.0 g of platinum oxide catalyst was added, and catalytic reduction was carried out at room temperature for 8 hours under a hydrogen pressure of 5 atm. After the catalyst is separated from the furnace, the furnace liquid is concentrated to dryness under reduced pressure. Add 200% ethanol to the residue. Add vl to dissolve, and saturated by blowing in hydrochloric acid gas. The solvent was concentrated to dryness under reduced pressure and further recrystallized from ethanol to obtain 18.8 g of 1-amino-7-hydroxy-4,6-di-t-butyl-1-indane hydrochloride as a colorless powder.

Elemental analysis value (Ct□H27NO-HCoCHN Calculated value (%) 68.55 9.14 4.70 Actual value (%) 68.43 9.21 4.61mp
225-226.5°C Pharmacological Test Next, the following pharmacological test was conducted using the test compound.

Test compound N.

1: 4.6-dimethyl-7-hydroxy-1-indanone oxime 2: 1-amino-7-hydroxy-4-methylindane hydrochloride 3: 1-amino-7-hydroxy-4,6-dimethylindane hydrochloride 4:1-amino-7-hydroxy-4-methyl-6-iodoindan hydrochloride 5:1-amino-7-hydroxy-4,6-dichloroindan hydrochloride 6:1-methylamino-4,6-simethyl- 7-Hydroxyindane hydrochloride 7:1-amino-2,2,4,6-tetramethyl=7-
Hydroxyindane hydrochloride 8: 1-amino-4-methyl-(3-see-butyl-
7-Hydroxyindane hydrochloride 9:1-amino-4-methyl-5-iso-butyl-7
-Hydroxyindane hydrochloride 10:1-amino-4-methyl-6-n-propyl-7
-Hydroxyindane hydrochloride 11:1-n-butylamino-4,6-cymethyl-7-
Hydroxyindane hydrochloride 12:1-amino-4-methyl-6-bromohydroxyindane hydrobromide 13:1-amino-4-methyl-6-nitro-dihydroxyindane hydrochloride 14:1-amino -6-n-propyl-7-hydroxyindane hydrochloride 15:1-methylamino-4-methyl-6-methylthio-twohydroxyindane hydrochloride 16:1-methylamino-4-ethyl-6-(1-methyl -2-propenyl)
-7-hydroxyindan hydrochloride 17:1-amino-4-ethyl-6-n-propyl-7
-Hydroxyindane hydrochloride 18:1-methylamino-4-ethyl-6-methyl-7
-Hydroxyindane hydrochloride 19:1-methylamino-4-methyl-6-nityl-7
-Hydroxyindane hydrochloride 20:1-amino-4-ethyl-5-sec-butyl-
7-Hydroxyindane hydrochloride 21:1-methylamino-4-ethyl-6-allyl-7
-Hydroxyindan hydrochloride (A) Anti-carrageenan edema effect test using Salt Wistar rats weighing around 150 g.
After fasting for 18 hours and feeding for 1 hour,
The test compound is administered orally at a concentration of 100 mg/kg.

One hour after administration, 1% carrageenan (0.1%) was applied subcutaneously to the left heel.
zll/rat and measure the left hind paw volume 3 hours later. The edema rate is determined by the volume doubling rate with respect to the hindlimb volume before carrageenan 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.

Table (B) Antioxygen deficiency effect The antioxygen deficiency effect is expressed as Arch, int, P ha
rmacod7n, .

233.137 (1978).

ICR male mice (body weight 20-30 g) were used. Four mice each were placed in a glass desiccator at an internal pressure of 21.
Suction air with a vacuum pump until 0 or 240 mmHH is reached and close the cock. The time from when the vacuum pump was activated to when each mouse stopped breathing was measured and used as the survival time. The test compound was administered subcutaneously or intraperitoneally 15 minutes before the start of suction. If the animal survived for more than 30 minutes (210 mmHg) or 15 minutes (240 mmHg) after the start of suction, the survival time was set as 30 minutes or 15 minutes, respectively.

The test results under an internal pressure of 210 mml (g) are shown in Table 8, and the test results under an internal pressure of 240 mmHg are shown in Table 9.

Table 8 As is clear from Tables 8 and 9 above, the indane derivatives of the present invention significantly prolonged the lethal time under oxygen-deficient conditions, and an ameliorating effect on oxygen-deficient conditions was observed.

(C) Antioxidant effect It is well known that Luminol is a luminescent test in which strong light is emitted by hydrogen peroxide in the presence of a hemin catalyst. This test uses linoleic acid hydroperoxide, which is known to be a strong oxidizing agent like hydrogen peroxide, to determine how much the compound to be tested (antioxidant) inhibits the oxidation of luminol by this peroxide. The antioxidative ability of the compound was determined by measuring the amount. Vitamin E (VE), which was used as a control drug (antioxidant), is known to reduce blood peroxidized lipids induced by alloxan in vivo, based on its antioxidant ability. It is recognized that compounds with similar antioxidant abilities can similarly reduce blood peroxidized lipids. The test method is as follows.

(1) Test method The test compound was tested at 1 to I x 10-'mg/yl! Concentration and linoleic acid hydroperoxide 1. O×10
- Prepare a methanol solution containing a concentration of 9 mol/zl (
(hereinafter referred to as the test solution). Also, lXl0-'M luminol in O, 1M sodium carbonate buffer, and Fe2 (
Fetal bovine serum (manufactured by Gibco) at 1, 25 X I CV
Prepare a 0.1 M sodium carbonate buffer containing a concentration of 6 g/yell.

These prepared solutions were automatically inhaled and mixed in 0.4 yll portions in the order of test solution, FC3 solution, and luminol solution using the flow system shown in Figure 1. After mixing the final luminol solution, a photo counter was used for 1 second. The amount of luminescence is measured using R649S (Hamamatsu Photonics Co., Ltd.). In addition, in Figure 1,
(1) is the photo counter, (2) is the cell, (3)
(4) is the test solution, (5) is the luminescent reagent (
Luminol liquid), (6) catalyst (Fe2 liquid), (7
) is the washing buffer (0.1M sodium carbonate buffer), (8) is the syringe, (9) is the drain, (10) is
indicate the respective valves.

Table 10 shows the results of measuring the amount of luminescence at each concentration using the test compounds shown above at predetermined concentrations. Each luminescence amount is the ratio of the luminescence amount when the above test solution containing no test compound is used as 1 (
%) was calculated according to the formula below and shown as the value.

Luminescence amount = 0 - B × 100 (%) -B B: C: Number of counts when no test compound is added and lipid peroxide is added Number of counts when neither the test compound nor lipid peroxide is added Count number 0 when compound and lipid peroxide are added together. In addition, the control BHT and control VE in the table are as follows.

Control BHT...butylated hydroxytoluene control VE...
...Vitamin E (2) Also, in the same test as above, linoleic acid hydroperoxide 1 x 10-9 mol/II! 50 μl of
50% inhibition rate (i.e., the concentration of each test compound that inhibits the oxidation ability of the peroxide by 50%, antioxidant ability IL5
0) for each test compound are shown in Table 11 below.

Table 11 From Table 1O and Table 11 above, it can be seen that the indane derivatives of the present invention all have strong antioxidant ability. In addition, each of the above compounds also acts as a BHT in vivo.
It was observed that it exhibited strong activity similar to that of VE and VE. This indicates that the compounds of the present invention are useful as preventive and therapeutic agents for various diseases caused by lipid peroxides and active oxygen species.

(D) Effect of intraperitoneal administration of 50% glucose on lethal cerebral hemorrhage (mice) An experiment was conducted with 30 mice per group. Compound of the present invention (0
, 3, 1 and 3 mg/kg) 15 minutes after subcutaneous administration, 50% (W/Vsaline) glucose at 0. 4xi
/1ug body weight was administered intraperitoneally, and the survival rate of the mice was determined at 1.5°3 and 24 hours thereafter. To determine the drug effect on survival rate, a two-tailed test was performed using Fisher's method. The results are shown in Table 12.

Table 12 (E) Effect on disturbance of consciousness after head trauma in mice It was investigated whether the compounds of the present invention have an effect on disturbance of consciousness created by impacting the head of mice.

The neck skin of the mouse was grasped and the head was fixed on a 2 cm thick Styrofoam column. Acrylic cylindrical rod (20g
) was placed along an acrylic tube and dropped from a height of 30 cm onto the top of the mouse's head to apply a shock. The time until the onset of righting reflex (RP time) and the time until the onset of spontaneous movement (8M time) were used as indicators of consciousness disturbance.

The test compound was applied at a rate of 0.1 ydl/1 for 15 minutes.
It was administered subcutaneously in a volume of 0 g. As a control, the same amount of physiological saline was administered. After the experiment, all mice were subjected to head autopsy, and those with brain contusions were excluded from the evaluation. The results are shown in Table 13. In addition, the numbers in parentheses in the table are comparable to the mouse.

Table 3 Formulation Example 1 7-Hydroxy-4-methyl-1-indanoxime Glucose Distilled water for injection 00 mg 50 mg Appropriate total amount 51/ After dissolving the compound of general formula (1) and glucose in distilled water for injection 5 yIl The mixture is injected into an ampoule, and after nitrogen substitution, autoclaving is performed at 121° C. for 15 minutes to obtain an injection having the above composition.

Formulation Example 2 1-Amino-7-hydroxy-4-methylindane hydrochloride 100 g Avicel (trade name, manufactured by Asahi Kasei ■) 40 g Cornstarch 30 g Magnesium stearate 2 g TC-510 g (trade name, manufactured by Shin-Etsu Chemical ■, hydroxypropyl methyl cellulose) Polyethylene glycol - 60003g castor oil
40g methanol
40g of the compound of general formula (1), Avicel, cornstarch and magnesium stearate were mixed and polished, and then tableted using a sugar coater with a radius of 10mm. The obtained tablet is
C-5, polyethylene glycol-6000, castor oil, and methanol are coated with a film coating agent to produce film-coated tablets having the above composition.

Formulation Example 3 1-amino-4,6-dichloro-7-hydroxyindan hydrochloride 2g purified lanolin 5g white beeswax 5g total amount 1
00g Heat beeswax to make it liquid, then use the general formula (
Add the compound of 1), purified lanolin and white petrolatum,
After heating until it becomes liquid, it is stirred until it begins to solidify to obtain an ointment having the above composition.

[Brief explanation of the drawing]

FIG. 1 shows a flow path diagram of an apparatus for measuring the antioxidant ability of a compound of general formula (1). (that's all)

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^3 represents a hydrogen atom, a lower alkyl group, or a halogen atom, and R^4 and R^5 each represent a hydrogen atom or a lower alkyl group. show. R^A is -SO_2X (X is a halogen atom), -SH, lower alkylthio group, ▲There are numerical formulas, chemical formulas, tables, etc.▼, lower alkanoylamino lower alkyl group that may have a halogen atom, amino lower alkyl group, There are nitro groups, amino groups, R^1^2NH- (R^1^2 is lower alkanoyl groups), or ▲mathematical formulas, chemical formulas, tables, etc.▼(R^1^3 and R
^1^4 represents a hydrogen atom or a lower alkyl group). ] There are compounds represented by the general formula ▲ mathematical formulas, chemical formulas, tables, etc. , a lower alkanoylamino lower alkyl group, a lower alkylthio group, a 1-piperidinesulfonyl group, or a lower alkenyl group that may have a halogen atom, and R^3 represents a hydrogen atom, a lower alkyl group, or a halogen atom. R^4' and R^5' represent lower alkyl groups. R^B represents a hydrogen atom, 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. However, R^2 has ▲mathematical formulas, chemical formulas, tables, etc.▼(R^1^3 and R
^1^4 is the same as above). ] There are compounds represented by the general formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^2, R^3 and R^4' are the same as above. R^1^5 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. ] There are compounds and general formulas represented by ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^2, R^3, R^4 and R^5 are the same as above. A is ■C=N-R^6 (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 substituent on the phenyl ring (represents a phenylsulfonyl group that may have a lower alkyl group) or ■C-N=CH-R^7 (R^7 represents a phenyl lower alkyl group that has a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring ) is shown. ] An indane derivative selected from the group of compounds represented by