JPS6160610A - Pyroxia ameliorant - Google Patents

Abstract

PURPOSE:A pyroxia ameliorant or antioxidant that contains, as an active ingredient, a specific indane derivative or its salt, thus showing actions to relieve pyroxia and resist oxidation, and being suitable for use as a brain activator, preventive for arrhythmia, or antiarteriosclerotic. CONSTITUTION:The objective pyroxia amelorant or antioxidant contains, as an active ingredient, an indane derivative of the formula (R<1> is amino, hydroxyimino; R<2> is H, lower alkyl, halogen; R<3> is H, lower alkyl, halogen; R<4-5> are H, lower alkyl where when R<1> is hydroxyimino, both of R<2> and R<3> are not H) or its salt. The compound of the formula has an action to improve pyroxia and is suitably used as a pyroxia ameliorant, e.g., brain activator, senile aphrenia improver, or as a preventive for arrhythmia and heart failure. Further, it has action to remove action oxygens and lower peroxidized lipids and is suitably used as an antiarteriosclerotic, anticancer or anti-inflammatory.

Description

[Detailed description of the invention] Ward 5 IF The present invention relates to hypoxia improving agents and antioxidants.

1. The hypoxia improving agent and antioxidant of the present invention can be expressed by the following general formula (
It contains the indane derivative represented by 1) and its salt as an active ingredient.

OHR2 (in the formula, R+ is an amino group that may have a lower alkyl group, a hydroxyimino group, a flucanoylamimum L having 1 to 10 carbon atoms that may have a halogen atom, a lower alkylsulfonylamino group, a phenyl ring) Phenylsulfonylamino group that may have a lower alkyl group as a substituent, penzoylamimum that has a lower alkyl group as a substituent on the phenyl ring; Phenyl that has a hydroxyl group or lower alkyl group as a substituent on the phenyl ring Indicates a lower alkylamino group.

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 alkanoylamine LL lower alkanoylamino lower alkyl group that may have a halogen atom, a lower alkylthio group,
sR3 representing a 1-piperidinesulfonyl group or a lower alkenyl group 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 compound represented by the above general formula (1) has the effect of improving the oxygen deficiency state and the symptoms associated therewith, and is used as a drug for improving the surface element deficiency state and the symptoms associated therewith [i.e., hypoxia ( hypoxia) improving agent], more specifically, for example, a brain stimulant, amnesia! i! It is effectively used as a drug, a drug for senile dementia, a drug to improve respiratory arrest and hypoxia associated with potassium cyanide poisoning, and a drug to prevent AS and heart failure caused by oxygen deficiency.

For living organisms, oxygen is essential for maintaining life, such as energy production and metabolism. *A element becomes so-called active 1ff2 element such as oxygen anion radical, peroxide ion, hydroxyl radical, etc. by reaction in an energy production system, enzyme reaction, ultraviolet rays, radiation, etc. While these reactive oxygen species are useful for living organisms, such as oxygenating enzymes and bactericidal effects on white blood cells, they also contain unsaturated substances that form the phospholipids of biological membranes, such as oleic acid, linoleic acid, lylunic acid, and arachidonic acid, which are abundant in living organisms. Promotes peroxidation of fatty acids and forms 1r14 lipids. This lipid peroxide causes the generation of alkoxy radicals and hydroxyl radicals, similar to the above-mentioned active oxygen species, and attacks biological membranes. f and various useful enzymes [Metabolism, 15(10).

1978 special feature on active oxygen! ! 3). However, if it collapses in the living body, superoxide dismutase (S0D),
There are enzymes involved in the metabolic deactivation of the above-mentioned reactive oxygen species, such as catalase and glutathione peroxidase.
In addition, there are various vitamins that have anti-inflammatory properties, such as α-tocopherol (vitamin E), and their effects normally maintain normal living bodies.
For some reason, there is often a deficiency in the appropriate defenses by the enzymes, vitamins, etc. mentioned above, or the generation of active m* species or the production and accumulation of lipid peroxides that exceed the ability of the secondary defense mechanism. Is recognized.

When such anti-WaS deficiency occurs, the peroxidation reaction progresses in a chain reaction, leading to serious disorders such as various diseases caused by platelet aggregation, inflammation, liver IQ, arteriosclerosis, hemolysis, aging and senile dementia, ! fig I disease, pulmonary embolism, heart and lung damage caused by certain drugs, ischemic vascular disease, etc. occur.

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

Reported antioxidants include enzyme agents such as the above-mentioned SoO [Superoxide and Medicine, Yoshihiko Oyanagi, 1
981, Kyoritsu Shuppansha, pp. 137-141, Latest Medicine, Special Feature on Active Oxygen and its Medical Role, Volume 39, No. 7 (19
84), Inflammation, Yu, p699 (1981), 1bi
d, :l, p367 (1982), Curren
t Therap, Rep,, 20. p62-6
9 (1976), “perspective tnI
nflatiOn” Red-ffood Bu
rn, Ltd,, p 5 2 7-544 (19
77), Acta, Physiol, 5cand
, Tsuchiyu 2, 5upp+ 59-65 (1980),
Pr0C, Natt.

Acad, Sci, tlSA, 79. l) 750
9-7513 (1982'), PathOIO (1y
of Oxygen ACad, PreSSp85~9
7 (1982), J. Clnic, Invest.
.

67, p983 (1981), J, C11
nic, Invest.

Ldan, p650-658 (1982), Pathol
oay of Oxygen, p 261-275 (
1982), Biochet Blophys, Act
a,, i soil yu.

028-38 (1978), 8th u, euro.

phys+opatho+Re5l) 1f, 5u
Dpl p287-288 (1981), pat
ho+oay or OX'1Qen, p277~3
02 (1982), Ministry of Health and Welfare Specified Disease Bechutto 1i
TA1i'Fif MR [I 08m 1957, 1958]
, J, lm1unol, 128. p2770<198
2), etc.], butylated hydroxytoluene <8HT), butylhytomyxyanisole (BHA), α-tocopherol (vitamin E), etc. [Makoto Mino, Hidetaka Tanaka, Pharmaceutical Journal, 19 (12>).

1) 2351-2359 (1983), Toshihiko Suematsu, same as above, Eyu (5), p909-914 (1983)
,Arch,Blochem,Biophys,,2
27, I) 534-541 (1983), J
, Clnic, Invest, 57° p732-73
7 (1976), ^dV, cancelr, RO80
, Dan, D197 (1978), etc.).

The compounds of the present invention also have the effect of removing active oxygen species and preventing or reducing lipid peroxide production in vivo.

Therefore, the compound of the present invention can be used as a prophylactic and therapeutic agent for various 8IFa and diseases caused by excessive production of the above-mentioned active m range, accumulation of lipid peroxide in the body, or deficiency in the defense mechanism against the above. Sclerosing agents, cancer prevention agents, anticancer agents, anti-inflammatory agents, analgesics, autoimmune disease therapeutics, platelet aggregation inhibitors,
It is also useful as a medicine such as an antihypertensive agent, a hyperlipidemic agent, and a preventive and therapeutic agent for retinopathy of prematurity and cataracts. Furthermore, the compound of the present invention is effective not only as the above-mentioned medicine but also as an agent for converting fats and oils contained in processed foods into FLn. The compound also has excellent anti-inflammatory, antihypertensive, gastric acid secretion suppressing and immunomodulating effects, such as FC'! It is also useful as a drug for A symptoms, an antihypertensive agent, etc.

Honmei Mi 11. :, 15 ite, R1, R2, R3R
More specifically, each group represented by ' and R5 can be exemplified by the respective groups.

Lower alkyl groups include methyl, ethyl, propyl,
Isopropyl, butyl, t8rt-butyl, pentyl,
hexyl, 1-methylpropyl, 2-methylpropyl,
1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2.2-dimethylpropyl, 2.3-dimethylpropyl, 1-methylpentyl, 1,1-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.

Amino groups that may have lower alkyl groups include:
N-methylamino, N-ethylamino, N-propylamino, N-isoprotylamino, N-butylamino, N
-tert-butylamino, N-bentylamino, N
-hexylamino, N, N-dimethylamino, N, N-
Dipropylamino, N, N-dibutylamino, N, N-
dibutylamino, N-methyl-N-ditylamino, N-
Methyl-N-isopropylamine, N-methyl-Nt
ert-butylamino, N-methyl-N-pentylamino, N-ethyl-N-pentylamino, N-tert-
Examples include amine groups that may have a straight or branched alkyl group having 1 to 6 carbon atoms, such as a butyl-N-ethylamino group.

Examples of alkanoylamino groups having 1 to 10 carbon atoms that may have a halogen atom include formylamino, acetylamino, propionylamino, butyrylamino, te
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
-Trichlorobutyrylamino, 4-fluorobutyrylamino, 5-chloropentanoylamino, 3-chloro-2
-Methylpropionylamino, 6-bromohexanoylamino, 7-iothohebutanoylamino, 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 1 carbon atoms, such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isobutylsulfonylamino, butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, and hexylsulfonylamino groups. A straight or branched alkylsulfonylamino group of 6 can be exemplified.

Examples of the phenylsulfonylamino group that may have a lower alkyl group as a substituent on the phenyl ring include phenylsulfonylamino, 2-13- or 4-methylphenylsulfonylamino, 2-13- or 4-ethylphenylsulfonylamino, 4-propylphenylsulfonylamino, 3-isopro and ruphenylsulfonylamino,
2-butylphenylsulfonylamino, 4-hexylphenylsulfonylamino, 3-pentylphenylsulfonylamino, 4-tert-butylphenylsulfonylamino, 3,4-dimethylphenylsulfonylamino,
2.5-dimethylphenylsulfonylamino, 3.4.
Examples include phenylsulfonylamino groups that may have a straight or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring, such as 5-trimethylphenylsulfonylamino groups.

Examples of the benzoylamino group having a lower alkyl group as a substituent on the phenyl ring include 2-. 3- or 4-methylbenzoylamino, 2-13- or 4-ethylbenzoylamino, 4-butylbenzoylamino, 3-isopropylbenzoylamino, 2-butylbenzoylamino,
Examples include benzoylamino groups having a straight or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring, such as 4-hexylbenzoylamino, 3-pentylbenzoylamino, and 4-tert-butylbenzoylamino groups. can.

Water r! as a substituent on the phenyl ring! As a phenyl lower alkylamino group having an i group or a lower alkyl group,
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-hydroxyphenyl)ethylamino, 5-(2-
hydroxyphenyl)pentylamino, 6-(4-hydroxyphenyl)hexylamino, 2-methyl-3-(
4-hydroxyphenyl)propylamino, 2-23-
or 4-methylbenzylamino, 2-13- or 4-ethylbenzylamino, 4-propylbenzylamino, 3
-isopropylbenzylamino, 2-butylbenzylamino, 4-hexylbenzylamino, 3-pentylbenzylamino, 4-tert-butylbenzylamino,
2-(3-methylphenyl)ethylamino, 1-(2-
ethylphenyl)ethylamine, 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 roux 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-trihydroxybenzylamino, 3.
4-12.5- or 2,6-dimethylbenzylamino,
3.4.5-trimethylbenzylamino group or other 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 has 1 carbon number
-6 phenylalkylamino groups can be exemplified.

Examples of amino lower alkyl groups include aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-7 minobrovir,
Direct or branched alkyl having 1 to 6 carbon atoms such as 4-aminobutyl, 1,1-dimethyl-2-7minoethyl, 5-7minobentyl, 6-aminohexyl, 2-methyl-3-7minoprobyl group, etc. Mention may be made of aminoalkyl groups having groups.

Examples of lower alkanoylamino groups include formylamino,
Examples include straight 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-trifluoroacetylaminomethyl, 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-tric-O-lobrobionylamino)hexyl, 2
-Methyl-3-(3-chloropropionylamino)propyl, 2,3-dichloropropionylaminomethyl, 2
- (4,4゜4-trichlorobutyrylamine)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)pentyl MW carbon r1
．． Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms and substituted with 1 to 6 straight chain or branched alkanoylamino.

Lower alkylthio groups include methylthio, ethylthio, propylthio, isoprobylthio, butylthio, ta
Examples include straight-chain or branched alkylthio groups having carbon r&1 to 6, such as rt-butylthio, pentylthio, and hexylthio groups.

Examples of lower alkenyl groups include straight 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 In formula C, 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 unpunished basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, piperidine, pyridine, triethylamine, 1°5-diazabicyclo(4,3, O) nonene-5(
DBN), 1,8-diazabicyclo (5,4゜0) undecene-7 (DBLI), 1,4-diazabicyclo (
Examples include modified 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 molar, relative to the compound of general formula (2). The reaction concentration is usually room temperature to 200°C, preferably 50 to 150°C, and generally 1 to 200°C.
At 10 o'clock, the 5i-hen 5i response ends.

The reduction of the compound of general formula (101) is carried out in a suitable solvent.
This can be carried out by catalytic hydrogenation in the presence of kts. Examples of solvents used include water, alcohols such as acetic acid, methanol, ethanol, and isopropanol; hydrocarbons such as hexane and cyclohexane;
diethylene glycol dimethyl ether, dioxane,
Examples include ethers such as tetrahydrofuran and diethyl ether, esters such as ethyl acetate and methyl acetate, and aprotic polar solvents such as dimethylformamide.

Examples of the solvent used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. The amount m of the catalyst to be used is generally about 0.02 to 1 times m relative to the compound of formula -a (101). The reaction temperature is usually -20°C to around air temperature, preferably 0°C to around room temperature, the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 10 hours.

Reaction formula-2 [In the formula, R1, RA and R5 are the same as above.

R2' and R2'' are the same as R2, except that R2 and R31
At least one of R2" and R3" represents a hydrogen atom, and at least one of R2" and R3" represents a halogen atom. ) The halogenation reaction of the compound of general formula (103) is carried out in the presence of a conventional halogenating agent. A wide variety of known halogenating agents can be used as the halogenating agent used in such a reaction. - Halogenating agents such as halogenosuccinimide and the like can be mentioned. The amount of the halogenating agent to be used is usually determined by 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, propionate, 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 scheme-3 011 N1f-R6 (In the formula, R'', R3, 'R' 21R5k-Jm is M
I;.

R@ is an amino group that may have a lower alkyl group, a lower alkylsulfonyl group, a phenyl lower alkyl group having a hydroxyl group or a lower alkyl group as a W substituent on the phenyl ring, or a lower alkyl group as a W1 substituent on the phenyl ring. Indicates a phenylsulfonyl group that may have

] 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 sheep, mineral acids such as hydrochloric acid, sulfuric acid, and boron trifluoride, and p-toluenesulfone r! ! The 6gi reaction, which can include organic acids such as
! i! The reaction is generally completed in about 1 to 48 hours. The amount of the compound of general formula (4) to be used is:
Although not particularly limited, it is generally advisable to use at least an equimolar amount of the compound of general formula (2), preferably 6'IA m.

As for the amount of dehydrating agent used, in the case of a desiccant, it is usually a large excess amount, and in the case of using an acid, it is preferable to use r11 medium. 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 1°, relative to compound (5). It is in the double molar range. When lithium aluminum hydride is used as a hydrogenation reducing agent, compound (5)
It is convenient to use twice the molar amount. This reduction reaction is usually carried out at -60 to 50°C, preferably using a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol, and ethers such as tetrahydrofuran, ethyl ether, and diglyme. 0℃
~ It is carried out at the lowest 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 (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 [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 a benzoylamino group having a lower alkyl group as a substituent on the alkanoyl group or 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.1 For example, (a) mixed anhydride method, that is, reacting the carboxylic acid (8) with a fulkylhalocarboxylic 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, carbon Wi (
8) becomes an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione, and compound (102) is added to this. (c) Carbodiimide method, that is, 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, the carboxylic acid (8) is induced into a halide.

(e) Another method is to react the carboxylic acid (8) with a dehydrating agent such as acetic anhydride to form a carboxylic anhydride, and then react the compound (102) with the carboxylic acid (8).
Examples include a method of reacting compound (102) with an ester of carvone B (8) and, for example, a lower alcohol under high pressure and high temperature. Alternatively, a method of activating carboxylic acid (8) with a phosphorus compound such as triphenylphosphine or diethyl chlorophosphate and reacting the activated compound with compound (102) can also be adopted.

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

The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and is usually used to convert the compound (102>
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)/ne-5 (DBN), 1,8-diazabicyclo(5,4
, O) undecene-7 (Data), 1,4-diazabiscif O(2,2,2) octane (DABGO), etc.; inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. Examples include bases.The reaction is carried out at about -20 to 100°C, preferably 0 to 50°C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 2 hours.The resulting mixed acid The reaction between the anhydride and compound (102) is carried out at about 0°C to 150°C, preferably from 10 to 50°C, for about 5 minutes to 10 hours, preferably for about 5 minutes to 5 hours.Mixed acid anhydride Although the 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 till anhydride method can be used, specifically methylene chloride, chloroform, and dichloroethane. halogenated carbons such as benzene, toluene, xylene, aromatic hydrocarbons, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, methyl acetate, rnan minityl esters, dimethylformamide, dimersulfoxide , aprotic polar solvents such as hexamethylphosphorus triamide, etc. In this method, the proportions of carbon El! (8), alkylhalocarboxylic acid and compound (102) are usually at least the same molar amount. However, it is preferable to use the alkylhalocarboxylic acid and the compound (102) in an amount of 1 to 2 times the amount of the carboxylic acid (8), respectively.

In the above (b) active ester method or active amide method, for example, when using benzoxazoline-2-thionamide, an appropriate solvent that does not affect the reaction, preferably used in the above mixed acid anhydride method, is used. Using 1-methyl-2-pyrrolidone etc. in addition to the same solvent as above, 0-150'C
1 Preferably, the reaction is carried out at 10 to 100°C for 0.5 to 75 hours. In this case, the compound (1
02) and benzoxazoline-2-thionamide. The ratio of the latter to the former is usually at least equimolar;
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, the carboxylic acid halide is filtered, and the carboxylic acid halide is prepared as a single ira, or the compound (102) is reacted with the carboxylic acid halide without isolation or production. This carboxylic acid halide and the compound (1
The reaction with 02) 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 m. In addition to the solvent used in the Schotten-Baumann reaction, examples of the solvent include water,
methanol, ethanol, propatool, butanol,
Examples include alcohols such as 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, acetonitrile, and mixed solvents of two or more thereof. The usage ratio of compound (102) and carboxylic acid halide is not particularly limited and can be selected from a wide range,
Usually, the latter is used in at least an equimolar amount, preferably equimolar to twice the amount of the former. The reaction temperature is usually -30~
About 180°C, preferably about 0 to 150°C, generally 5
The reaction is completed in minutes to 30 hours.

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. , 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 usually from air temperature to about 100°C, preferably from 50 to 80°C.
It is carried out for about 30 minutes to 6 hours.

The method of activating carvone l1l (8) with a phosphorus compound such as triphenylphosphine or diethyl chlorophosphate and reacting it with compound (102) is carried out in an appropriate 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. , diethyl ether, tetrahydrofuran,
Examples include ethers such as dimethoxyethane, esters such as methyl rnate and ethyl fraud, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. In this reaction, the compound (
102) Since it itself acts as a basic compound, the reaction proceeds well by using it in excess of the theoretical amount, but if necessary, other basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline may be added. , N-methylmorpholine, 4-dimethylamino and lysine, 1,8-diazabicyclo[4°3.0]nonene-7 (DBN), 1,5-diazabicyclo(5,4,
O) Using organic bases such as undecene-5 (DBLI) and 1,4-diazabicyclo(2,2,2)octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. You can also do it. The ia reaction is carried out at a temperature of about 0 to 150°C, preferably about 0 to 10
This is achieved by carrying out the reaction at 0° C. for about 1 to 30 hours.

Phosphorus compound and carboxylic acid (
The proportion of 8) used is usually at least equimolar m
degree, preferably 1 to 3 times the molar amount.

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

R9 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 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 reaction conditions similar to the reaction of the compound of general formula (102) and carboxylic acid halide in reaction scheme-5 and rf11. can be done.

Reaction Scheme-7 - [In the formula, R word, R3, R' and R5 are the same as above] The nitration of the compound attraction of the general formula (109) is carried out under the usual nitration reaction conditions of aromatic compounds. For example, it is carried out without a solvent or in a suitable inert solvent using a nitrating agent. Examples of the inert solvent include acetic acid, acetic anhydride, AI acid, etc., and examples of the nitration agent include fuming nitric acid, concentrated nitric acid, 1lf
2 (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 use of the above nitrating agent m is
It is sufficient that the amount is usually in excess of equimolar or more relative to the raw material compound.
The reaction is advantageously carried out for about 4 hours from O'C to the temperature.

The reduction of the compound of general formula (110) is carried out by the above reaction scheme -
The reduction of the compound of general formula (101) in 1 can be carried out under the same reaction conditions.

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, Il1 sulfur, etc., or iron, ferrous sulphate, zinc or tin and alkali metals such as sodium hydride. Examples include wood grains, sulfides such as ammonium sulfide, aqueous ammonia, and mixtures with ammonium salts such as ammonium chloride. Examples of the inert wJts 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 salting are used as the reducing agent, the conditions are preferably 0°C to
It is preferable to carry out the heating at around air temperature for about 0.5 to 10 hours. The reducing agent used is at least equimolar to the raw material compound.

It is usually used in equimolar to 5-fold molar amounts.

In the compound of the above general formula (1), R1 is a flukylamino group having 1 to 10 carbon atoms which may have a halogen atom, and a benzoyl group having a lower alkyl group as a substituent on the phenyl ring. A phenyl lower alkylamino group having a hydroxyl group or a lower alkyl group as a substituent on the amino group or phenyl ring can be converted by hydrolysis into a compound in which R1 is an amino group.Also, if R2 is lower A compound which is an alkanoylamino group or a lower alkanoylamino lower alkyl group which 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. As the conditions, for example, the general formula (2
Reaction conditions similar to those for hydrolysis of the compound in 02) 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 <201) (202) R3, R in C formula
4 and R5 are the same as above, and the R group represents a lower alkanoylamino lower alkyl group which may have a halogen atom. RI+ represents an amino lower alkyl group. ) The reaction between the compound of general formula (201) and the compound of general formula (1o) is carried out in the presence of a dehydration condensation agent without a solvent or in a suitable solvent. The dehydration condensation agent used is
Condensed phosphoric acids such as polyphosphoric acid, phosphorus a such as phosphoric acid, pyrophosphoric acid, metaphosphoric acid, phosphorous acids such as phosphorous acid, phosphoric anhydrides such as phosphorus pentoxide, hydrochloric acid, sulfuric acid, boron Acids such as acids, sodium phosphate, boron phosphate,
Examples include metal phosphates such as ferric phosphate and aluminum phosphate, activated alumina, sodium insect sulfur, and Raney nickel. In addition, the solvent used is
Examples include dimethylformamide and tetralin. Compound of general formula (201) and general formula (10
) with the compound, there is no particular limit and it can be selected as appropriate within a wide range, but usually the latter is used in an amount equal to or more than m, preferably equivalent to twice the amount of the former. Good. The dehydration condensation agent m used is not particularly limited and can be appropriately selected from a wide range of
It is usually advisable to use the catalyst in an amount of m or more, preferably in large excess mm, relative to the compound of 01).

The reaction normally proceeds suitably at -30 to 50°C, preferably from 0°C to near atmospheric temperature, and is generally completed in about 1 to 30 hours.

For the hydrolysis of the compound of general formula (202), conventionally known hydrolysis reaction conditions can be widely applied, such as suitable hydrolysis Wi catalysts, hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulfuric acid, etc. , phosphoric acid, etc., alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkaline carbonaceous sodium, potassium carbonate, sodium bicarbonate, etc., inorganic alkalis such as charcoal divertic salts or bicarbonates. In the presence of the compound, in a hot solvent or a suitable solvent (e.g., water or a mixed solvent of water and a lower alcohol such as methanol or ethanol), 50 to 15.0" C1, preferably 70 to 100 °C
It is sufficient to delay the time by about 3 to 24 hours.

Reaction Scheme-9 (In the formula, R3, RA, and R5 are the same as above, aR'' represents lower alkanoyl group.) Nitration of the compound of the general formula (201) and the reaction of the 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 (
It can be carried out under the same reaction conditions as for the reduction of the compound in 110). In addition, compounds of general formula (205> and general formula (205)
The reaction with the compound of formula (11) can be carried out under the same reaction conditions as the reaction of the compound of general formula (102> with the compound of general formula (8) in Reaction Scheme-5 above).

Reaction scheme-10R55 l Ra (201> (207) (20
8> (wherein R3, Rm, R5 and X are the same as above.

Ra and RvL represent a hydrogen atom or a low 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, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, carbon! Inorganic i3i groups such as silver, alkali residues such as sodium and potassium, alcoholades such as sodium methylate and sodium ethylate, triethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine,
4-dimethylaminopyridine, 1,5-diazabicyclo(4,3,0)nonene-5 (DBN), 1,8-diazabicyclo(5,4,O) undecene-7 (DBtJ),
1.4-diazabicyclo(2゜2.2)octane<()
Examples include d bases such as A8CO). 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, methanol, ethanol, propatool, butanol, ethylene glycol, etc. alcohol,
dimethyl ether, tetrahydrofuran, dioxane,
Ethers such as monoglyme and diglyme, acetone,
Ketones such as methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, N,N-dimethylformamide,
Examples include aprotic polar solvents such as dimethyl sulfoxide and hexamethylphosphoric triamide, and mixed solvents thereof. It is also advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide. In the above method, the compound of general formula (2a) and the general formula (
The proportion of compound 17) to be used is not particularly limited and can be appropriately selected from a wide range, but usually the latter is used in an equimolar to 5-fold molar ratio to the former, preferably an equimolar to 2-fold molar ratio. It is desirable to use the The reaction temperature is also not particularly limited, but is usually from 50 to 200°C, preferably from 50 to 15°C.
Performed at 0°C. The reaction time is usually 1 to 30 hours, preferably 1 to 15 hours.

The reaction to obtain the compound of general formula (208) from the compound of general formula (207) is called Claisen rearrangement, for example, by heating the metal compound (207) in a solvent of 13 (208). Examples of solvents that can be 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.
The temperature is about 250°C, and the reaction is completed in about 1 to 20 hours.

Reaction Scheme-11 (16) <18) R3 (In the formula, R2, R3 and Rlr and R51 each represent a lower alkyl group.] The reaction between the compound of general formula (209>) and the compound of general formula (13) is carried out in an appropriate rBts in the presence of a basic compound. The basic compounds used here are:
Examples include sodium hydroxide, potassium hydroxide, sodium ethylate, sodium hydride, potassium hydride, sodium amide, potassium amide, and the like. Examples of solvents include methanol, ethanol,
Examples include alcohols such as isopropanol, ethers such as dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphorus triamide. The use of the compound of general formula (209) is not particularly limited and may be appropriately selected within a wide range, but usually at least equimolar n1 preferably equimolar - 5 times the amount of the compound of general formula (209). It is preferable to use a molar base. The reaction is usually carried out at a temperature of about 0 to 70°C, preferably from about 0"C to room temperature, and is generally completed in about 0.5 to 12 hours.

The reaction between the compound of general formula (14) and the compound of general formula (15) and the reaction of the compound of general formula (16) with the compound of general formula (17) are the reactions between the compound of general formula (209>) and the compound of general formula (17). It can be carried out under the same conditions as the reaction with compound (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 R15 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, 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~
Treat at 10 atm for about 0.5 to 3 hours, or at 30 to 150°C in a mixture of an acid such as hydrobromic acid or hydrochloric acid and a solvent such as water, methanol, ethanol, or isopropanol.
, preferably by heat treatment at 50 to 120°C, a compound of formula -a (210) can be obtained. Next, in the case of a compound of the general formula (18) in which R+5 is a lower alkanoyl group, a tetrahydropyranyl group, or a benzoyl group, the compound of the 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 basic compounds include mineral acids such as fundamental acid, IJ sulfate, and hydrobromic acid, and examples of basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. I can do it. The reaction normally proceeds suitably at a temperature of 150 DEG C. to 150 DEG C., preferably 80 DEG to 120 DEG C., and is generally completed in about 1 to 15 hours.

Reaction formula-12 (In the formula, R3, RA, R5 and X are the same as above.

R111 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 an FB medium. The solvent used here may be any solvent as long as it does not affect the reaction, such as chloroform, dichloromethane, halogenated hydrocarbons such as carbon tetrachloride,
Examples include aromatic hydrocarbons such as benzene, toluene, xylene, nitrobenzene, and dichlorobenzene. The amount of the compound of general formula (19) to be used is usually
The amount is preferably at least 1 molar equivalent to the compound of 01), preferably 1.5 times molar molar equivalent. The reaction normally proceeds suitably at -50 to 50°C, preferably around -10 to 10°C, and is generally completed in about 15 minutes to 10 hours.

For the reduction reaction of the compound of general formula (211), ■ a metal such as iron, zinc, tin or tin chloride and acetic acid, hydrochloric acid, l? l
rj! A method using a modified compound such as No. 1 or a method using a hydrogenation reducing agent such as lithium aluminum hydride, sodium borohydride, diborane, etc. can be adopted. When method (2) is employed, it is preferable to use H in a large excess amount and to use at least an equimolar amount of the metal relative to the compound (211), usually in a large excess amount. This reaction is usually -50 to i50
'c, preferably at air temperature to around 100°C, and generally takes about 0.5 to 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.The rg medium and dehydrohalogenating agent used here are , the general formula (10
The solvent and dehydrohalogenating agent used in the reaction of the compound and carboxylic acid halide in 2) can be used. The reaction is usually -50 to 100'C1, preferably -50 to 30'
The reaction is carried out at a temperature of about C and generally completes in about 30 minutes to 5 hours. When using the compound of general formula (20), it is preferable that the amount is at least equimolar, preferably 1.2 times molar to equimolar, relative to the compound of general formula (212).

Reaction scheme-13 (211n (214) (in the formula, R3, RA 1R5 and X are the same as above) General formula (2
The reaction between the compound of 11) and the compound of general formula (21) is
It is carried out without rFJIs or in a solvent in the presence of a dehydrohalogenating agent. As a solvent and a dehydrohalogenating agent,
Any of the solvents and dehydrohalogenation agents used in the reaction of the compound of general formula (102) and the carboxyl halide in Reaction Scheme-5 above can be used. piperidine (
21) is usually used in at least an equimolar amount, preferably an equimolar to twice the molar amount, of the compound of general formula (211). The dehydrohalogenating agent is usually used in an amount equal to at least 1 mole, preferably 1 to 1.5 times the mole of the compound of general formula (211). The reaction is usually -30~
It is carried out at 150 DEG C., preferably about -20 to 100 DEG C., and the clothes are first bonded for about 0.5 to 24 hours.

Reaction Scheme-14 In formula C, R3, RA, R5 and It is done below.

The solvent used here may be any solvent as long as it does not affect the reaction, such as chloroform,
Examples include halogenated hydrocarbons such as dichloromethane and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, xylene, nitrobenzene, and dichlorobenzene, and carbon disulfide. Catalysts used include aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, VAi trifluoride, concentrated sulfuric acid, and other Lewis compounds. The amount of Lewis Kei to be used may be determined as appropriate, but usually the amount of the compound (
201), about 2 to 6 times the mole, preferably 2 to 4
It is said to be about double the mole. The amount of compound (22) to be used is usually at least cumole f based on compound (201).
fi, preferably in equimolar to twice molar increments. The reaction temperature may be interpreted as appropriate, but it is usually around 0 to 150°C.
Preferably, the temperature is 1 degree from 0 to 100'Cff. The reaction is generally completed in about 0.5 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 method, dilution method, recycle method, 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 can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid, and the present invention also includes this addition salt. In the above, examples of oxidation include hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc., acetic acid, sulfuric acid, etc.
Succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, methanesulfonic acid, benzoic rf
1M tfAH can be used.

In the above general formula (1), a preferable group among the groups represented by R1 is an alkylamino group or an amino group having 1 to 6 carbon atoms, and an especially preferable group is an amine 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.

Preferred groups among the groups represented by R3 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 R1 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 R2 and R3 are both alkyl groups having 2 to 6 carbon atoms (preferably branched alkyl groups having 3 to 6 carbon atoms). Among these, the most preferable one is that one of R2 and R3 is a methyl group, and the other is 7i12'Ii number 2 to
6 alkyl group (preferably a branched alkyl group having 3 to 6 carbon atoms), and one of R2 and 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). 3 to 6 branched alkyl groups). Preferred examples of the branched alkyl group having 3 to 6 carbon atoms include isopropyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylpropyl, and the like.

The compound of the present invention is usually used in the form of a common @chestnut preparation. The formulation contains commonly used fillers, thickeners, binders,
It is prepared using diluents or excipients such as wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, gunpowder, powders, liquids, suspensions, emulsions, granules, capsules, skewers, and injections (liquids). , polishing agents, etc.), cartilage agents, etc. When forming tablets, a wide variety of carriers known in the art can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose,
Excipients such as silicic acid, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, alginic bacteria Sodium, agar powder,
Laminaran powder, sodium carbonate, calcium carbonate,
Disintegrants such as polyoxyethylene sorbitan fatty esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium base, sodium lauryl sulfate absorption enhancers such as glycerin, humectants such as starch, absorbent agents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, lubricants such as ml talc, stearate, porium powder, polyethylene glycol, etc. etc. can be exemplified. In addition, the tablets may be coated with a conventional coating if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, or intestinal rFJ? It can be made into 12 tablets, film-coated tablets, 2m tablets, and multi-disease tablets. When molding into the form of gunpowder, a wide range 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, Examples include binders such as gelatin and ethanol, and disintegrants such as laminar agar. When forming into a skewer, 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 used as an injection, liquid and
The flQ agent is preferably sterilized and isotonic with blood, and when forming these into the form of solutions, emulsions, and diatherms, any diluent commonly used in this field can be used; water, ethyl alcohol,
Examples include propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.

In this case, isotonic rfJ? A sufficient amount of common salt, glucose, or glycerin to prepare [2] may be included in the pharmaceutical preparation, and usual solubilizing agents, 11-facets, soothing agents, etc. may be added. Furthermore, coloring agents, preservatives, fragrances, flavoring agents, sweeteners, and other @chemicals may be included in the pharmaceutical preparations, 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.
Examples include polyethylene glycol, silicone, bentonite, and the like.

The amount of the compound of general formula (1) to be contained in the pharmaceutical preparation of the present invention is not particularly limited, and it is widely used. It is selected as appropriate for the dish, but it is usually 1 to 70% of the amount of melon in the medicine & 5 preparation.

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, powders, 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 intramuscularly, mixed with a normal replacement fluid such as amino acids, and further administered alone as needed intramuscularly, intradermally, subcutaneously, or intraperitoneally. In the case of skewering, it is administered directly into the mouth.

The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, the patient's age, sex and other conditions, the degree of disease, etc., but usually the active ingredient, the compound of general formula (1), has a daily body f
It is preferable to set it to about 0.2 to 200 IQ per fflko.

Example References, examples, pharmacological tests, and formulation examples are listed below.

Reference example 1 4-methyl-7-hydroxy-1-indanone 39.3
0 and N-hydroxymethyl-α-chloroacetamide 3
Add and dissolve 0280 g of sulfuric acid under cooling. - After standing overnight, the reaction mixture is poured into water and the precipitated product is taken out in a furnace.

Recrystallized from ethanol to give 4-methyl-6-α-chloroO
Acetylaminomethyl-7-hydroxy-1-indanone 49Q is obtained.

Colorless needle crystals mp 166-167.5°C Reference example 2 4-methyl-7-hydroxy-1-indanone 25.6
g of acetic acid 250 + lIg solution, acetic anhydride 19.411
Gradually add the vinegar 111150- solution of Q and 1111m15.4-. The reaction mixture was evaporated to dryness and the residue was washed with ether to obtain 25.70% of 4-methyl-6-nitro-7-hydroxy-1-indanone.

mri 154-157°C Yellow needle crystals Reference example 3 10% 4-methyl-6-nitro-7-hydroxy-1-indanone 26G in dimethylformamide 50-solution
Pd-C2,6Q is added and catalytic reduction is carried out at normal pressure O<0>C to room temperature. The catalyst was removed by tP and the solvent was distilled off to give 4-methyl-6-ami2-hydroxy-1-indanone17.
Get 3G.

mp 187-188°C (decomposition) Pale yellow needle-like crystals Reference Example 4 4-Methyl-6゛-α-riOroacetylaminomethyl-
7-hydroxy-1-indanone 3g and a salt ff13
Add 0ml of ethanol 60IIm2 solution for 8 hours!
Reflux. The solvent was distilled off, and the resulting residue was recrystallized from ethanol to obtain 4-methyl-6-amitsumethyl-twohydroxy-1-indanone 19.

m+) 300'C or higher Pale yellow scale NMR (DMSO) δ; 2.22 (s, 3H), 2.6-2.8 (m, 2H) 2.85-3.1 (m, 2H) , 3.97
(s, 2)-1), 7.55 (s, 1H), 8.4-9.5 (br,, 3H) Reference Example 5 4-Methyl-6-nitro 7-hydroxy-1-indanone 11. 5a in 500ml of acetic acid 12F8 solution, 5% Pd
-C1,5! ;1 was added, and catalytic reduction was carried out at room temperature and normal pressure. The catalyst was removed at t1, the solvent was distilled off and the mixture was washed with ether. Recrystallized from methanol to give 4-methyl-6-acetamito-7-hydroxy-1-indanone 6.34C;
get.

rrl 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, 2)-1) , 7.67
(s, 1H), 9.25-10.0 (br,, 2H) Reference Example 6 25 allyl bromide bacteria were added to a methanol 6501Q solution of 36 g of 4-methyl-7-hydroxy-1-indanone and 17.6 g of potassium hydroxide. and heated under reflux for 6 hours. Insoluble materials are removed and the solvent is distilled off. Chloroform-
Extract with water, separate the chloroform layer, and evaporate the solvent. The residue was washed with ether and purified by column chromatography to obtain 32 g of 4-methyl-7-allyloxy-1-indanone.

m+) 89-92°C Pale yellow powder Reference example 7 4-methyl-7-allyloxy-1-indanone 32 g
Tetralin 10011I! In Step 2, turn off the heat and heat under reflux for 4 hours under an argon atmosphere. The reaction mixture was cleaved by column chromatography on silicage gel (eluent: n-hexane → dichloromethane: n-hexane-1:2) to give 4-
26.8 g of methyl-6-allyl-7-droxy-1-indanone are obtained.

ml) 41-45°C Pale yellow needle crystals Reference Example 8 To a 200 d methanol solution of 4-methyl-7-hydrooxy-1-indanone 10Q and potassium hydroxide 5.3 g was added crotyl bromide 8.2 times, Reflux the sum rA for 4 hours. Insoluble materials are removed and the solvent is distilled off. After extraction with chloroform and water, the chloroform n was washed with diluted sodium hydroxide solution, then with water, and then dried over anhydrous Fan magnesium, and the solvent was distilled off. The residue was subjected to 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 Reference example 9 4-methyl-7-crotyloxy-1-indanone 8 g
Tetralin 501Ql:tFJ and heated under reflux for 9 hours under an argon atmosphere. The reaction rB solution was subjected to silica gel column chromatography (elution 311j: n-hexane →
It was diluted to 1% with a 2:1 ratio of n-hex(nan:dichloromethane) and further recrystallized from dichloromethane-n-hexane to give 4
-Methyl-6-(1-methyl-2-propenyl)-1-
Get Indanone 5.449 @.

mp 88-92°C Colorless needle crystals Using appropriate starting materials, 1) J2! Compounds listed in Table 1 below were added in the same manner as in Reference Example 8 or 9.

Table 1 Reference Example 14 15 g of 4-methyl-7-hydroxy-1-indanone and 7.95 g of potassium hydroxide in methanol 200 mff
1lk: Add 13.55-methallyl chloride, 11
Heat to reflux for 1 hour. After removing the insoluble matter, the solvent is distilled off.

The tFJ pickles were ra
g to obtain 9 g of 4-methyl-7-methallyloxy-1-indanone.

mp74.2-75.2°C Colorless powder reference example 15 4-methyl-7-methallyloxy-1-indanone 8
．． 460 was added to 50ml of tetralin and heated under reflux for 9 hours. The reaction solution was subjected to silica gel column chromatography.
The eluent was subjected to fiFJ using 20-hexane:dichloromethane-2:1), and further recrystallized from dichloromethane-hexane to give 4-methyl-6-(2-methyl-2-propenyl).
-7-Hydroxy-1-indanone (6.680).

mp62.5-64°C Colorless needle crystal Reference example 16 Chlorsulfone l1i290111Q tetrajidized carbon W1
7-hydroxy-4-methyl- to a 50 m solution under water cooling.
Add 30 g of 1-indanone one by one. Remove the carbon tetrachloride layer, add ice water from Step 19 to the remaining layer, and stir vigorously. The precipitated solid was washed several times with water to obtain 8.7 g of 7-bitroxy-6-chlorosulfonyl-4-methyl-1-indanone. Without making this thing II, stannous chloride 2
Add to the old formula consisting of hydrate 31.4Q and diurnal cycle 12100, and stir at the lowest temperature for 4 hours. Pour the reaction solution into ice water 5001
Pour into 2 and precipitate crystals? F was taken, washed with water, and dried to obtain 7.86 g of 7-hydroxy-6-mercapto-4-methyl-1-indanone. Then, without purification, this product was soaked in 100 methanol and added with 3.9 times of methyl iodide and 5 times of ff1lJ. IQ water 201
Add 11Q solution and stir at air temperature for 1 hour.

The solvent is reduced to dryness under pressure. After removing the residue by silica gel column chromatography (eluent: chloroform),
Crystallization from ethanol yielded 1.520% of 7-hydroxy-4-methyl-6-methylthio-1-indanone.

mp 139°C Colorless needle crystals Reference example 17 To a dichloroethane 10-solution of 2-hydroxy-4-methyl-1-indanone 2.27 g of 1-piperidinesulfonyl chloride was added, and anhydrous aluminum chloride 1C1 was added little by little at the lowest temperature. Stir. After heating under reflux for 8 hours,
Extract with 200% chloroform, wash with water, and remove chloroform under reduced pressure.

The residue was subjected to silica gel column chromatography (eluent:
After purification with chloroform), recrystallized from ethanol to obtain 7
-Hydooxy-4-methyl-〇-(1-piperidinesulfonyl)-1-indanone (q).

mD 188-189°C Pale yellow plate-like crystals Reference example 18 4.6-dimethyl-7-methoxymethyleneoxy-1-
Indanone 7.56 g dimethylformamide 200-
Add 60% sodium hydride 4.940 little by little to the solution at air temperature until the sound of water stops (about 1 hour).
I worship. Then methyl iodide14. Add C1l and stir for an additional 2 hours at air temperature. The reaction mixture was made acidic by adding salt, the solvent was concentrated under reduced pressure, and the resulting residue was poured into 1Q of water with vigorous stirring, and diluted with 300ffl of ethyl acetate.
Extract times. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and 7-medoxymethyleneoxy 2.2
．． 8 g of 4.6-tetramethyl-1-indanone are obtained.

This product was dissolved in 200 methanol without being prepared, 81 salt blood type 10 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.

ml) 28-30°C NMR (CDCQ3) δ; 9.08 (1H,S) 7.19 (IH,s) 2.84 (2H,s) 2.23 (3H,s) 2.20 (3H, s> 1.28 (6H, s) Implementation rIA1 28 g of bitroxylamine hydrochloride and 56 g of potassium carbonate
Add g to 400 mIQ of methanol and heat for 30 minutes!
I flow. After cooling, the supernatant is collected and a hydroxylamine methanol solution is added. 16.2 7-hydroxy-4-methyl-1-indanone in this hydroxylamine methanol solution! Add ;1 and stir for 5 hours!
, reflux. The reaction mixture is evaporated to dryness under reduced pressure. Add 200% of ethyl acetate to the residue and remove insoluble matter. The furnace liquid was condensed to dryness under reduced pressure, and the residue was re-fed from methanol.
! Product i: 7-hydroxy-4-methyl- as colorless needle-like crystals
17.60 of 1-indanone oxime (7.

mp 148-149.5℃ Using appropriate starting materials, prepare the following 2nd step in the same manner as in 1.
The compounds listed in the table are obtained.

Example 16 15.0 g of dihydroxy-4-methyl-1-indanone oxime was added to 200! ! Dissolved in Q enzyme acid, platinum oxide catalyst 1. OQ is added and catalytic reduction is carried out at 5 atm hydrogen pressure and air temperature for 8 hours. After the melting medium is removed from the furnace, the p liquid is condensed to dryness under reduced pressure. Ethanol 200111Q is added to the residue to dissolve it, and j1 gas is blown into it to saturate it. The solvent was condensed to dryness with FA under reduced pressure, and the residue was recrystallized from ethanol to obtain 1-amino-7-hydroxy-4-methylindane salt a, a needle-like product.
3.30 g of salt are obtained.

ml) 221-223°C Using appropriate starting materials, the compounds listed in Table 3 below were prepared using the same method as in Example 16.

Fruit m 34 1-amino-7-hydroxy-4-methylindane salt v
Dissolve 1Q of 1 salt in 20111Q of water, stir vigorously in a lagoon, and add 0.8 of iodine monochloride! Add 5 fJ of 3NN salt solution containing M dropwise. After stirring at the same temperature for 2 hours, cool on ice. The precipitated crystals are collected and converted into hydrochloride, then washed with ether and dried. Yellow needle-shaped 1-amino-7-
Hydroroxy 6-iodo 4-methylindan salt m salt 0
．． Get 70c+.

ml) Decomposition above 200°C Example 35 1.0 g of 1-amino-7-hydroxyindan hydrochloride is dissolved in acetic acid 60111Q, and 1.1 g of sulfuryl chloride is added dropwise to 1.53 mL of sulfuryl chloride with stirring under water cooling. After stirring at the same temperature for 3 hours, 1 hour under reduced pressure. Shrink. The residue was dissolved in 50 ml of ethanol saturated with hydrochloric acid gas and dried under reduced pressure. Recrystallization from isopropanol ether gives 0.43 ml of 1-amino-4°6-dichloro-o-7-hydroxyindan hydrochloride as a colorless prism.

ml) 238-239°C (decomposition) Example 36 1-Amino-7-hydroxy-4-methylindane 5Q
was dissolved in 30IQ of acetic acid, an acetic acid solution of 1.73-bromine was added thereto, and Ij! was heated at the lowest temperature for 1 hour. worship The precipitated crystals were taken to the bottom of the furnace and recrystallized from isopropanol to give 1-amino-
6-promo-7-hydroxy-4-methylindane hydrogen bromide a salt 29 is obtained. The structure is determined by NMR.

mp 178-190°C (decomposition) Yellow needle NMR (DMSO) δ; 2.18 (s, 3H) 1.8-3.35 (m, 4H) 4.75-5.05 (m, 1H) 7.35 (s, 1H) 7.6-9.2 (b, s, 3H) Example 37 1-Amino-7-hydroxy-4-methylindane hydrochloride 5.75Q to vinegar 1924011112! ! ! Moisten, this Ic l glacial acetic acid 3.27 + 9 and 1ljlIU
2.591111Q emi om+sae addition, t, seedling 1t'61i11111f worship t6゜The solvent was distilled off, the residue was washed with amethane, and then recrystallized from ethanol to obtain 1-amino-7-hydroxy-4-methyl. -2 g of 6-nitroindane hydrochloride is obtained.

mp 200-230°C (decomposition) Yellow needle crystal NMR (DMSO) δ: 2.22 (s, 3H) 2.0-3.45 (m, 4H) 4.7-5.0 (m, 1H) 7.82 (s, IH) 8.4-9.7 (br,,3H) Example 38 1.77G of 1-amino-4,6-dimethyl-7-hydroxyindan in 100% of 0.2N aqueous sodium hydroxide solution
Dissolve in mQ, and then add 1.7 g of α-chloroacetyl chloride while stirring on ice.

Thereafter, the mixture was stirred for 2R at air temperature. The reaction solution was made acidic with dilute hydrochloric acid and extracted with chloroform. Wash, dry, and evaporate the solvent. Recrystallize from ethanol to obtain 2.34g of 1
-acetylamino-4,6-dimethyl-7-hydroxyindan 2.340 is obtained.

ffN) 131-132°C Colorless needle crystals Using appropriate starting materials, actually! The compounds listed in Table 4 below were prepared in the same manner as in Example 38.

Example 45 1.77 g of 1-amino-4,6-dimethyl-7-hydroxyindan and 100111 of triethylamine 2 precepts
Q: Add 1.720 methanesulfonyl chloride dropwise to the chloroform solution at room temperature. After that, stir at the same temperature for 4 hours. The reaction mixture is washed with diluted salt, water, saturated sodium hydrogen water, water, and saturated brine in this order, and then dried over sodium sulfate.

The solvent was distilled off, and the residue was recrystallized from ether-〇-hexane to obtain 0.589 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 Example 45 using appropriate starting materials in the form of colorless powder.

Example 60 4.6-dimethyl-7-hydroxy-1-indanone 1
．． A 100-ethanol rFI solution containing 14.69 g of 76G and n-butylamine was continuously heated for 8 hours. After cooling to 'ml', 1Q of sodium borohydride was added, and the mixture was further incubated at mold temperature for 1 hour. The reaction mixture was condensed to dryness, and 100 WQ of water was added to the residue to dissolve it. Aim to make the mixture aqueous, and then adjust the pH to #9 with a saturated aqueous sodium acetate solution.

The obtained precipitate was extracted with ethyl acetate, washed with water, and stirred dry. The solvent was distilled off, and the resulting residue was immersed in 100 Wf of ethanol.
2 and make Shioyoshi salt with ethanol saturated with hydrochloric acid gas. Recrystallized from ethanol-ether to give 1-0-butylamino-4,6-dimethyl-7-hydroxyindan.
Salt 11! 1.89 g of salt is obtained.

mp 143-144°C Colorless needle crystals Using appropriate starting materials, the compounds listed in Table 6 below are obtained in the same manner as in Example 60.

Example 75 1-amino-7-hydrooxy-4,6-dimethyl-inda>L 770 and 3,5-di-tert-butyl-4
-Hydroxybenzaldehyde 2.57% of I in 50 mg 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% of water to the residue and rnn
Add sodium sodium aqueous solution to pH #8 and ethyl acetate 1
Extract with 00. After washing with water, dry with anhydrous magnesium sulfate. The solvent 8 was distilled off under reduced pressure. Dilute the residue with ethanol 50I
Add rgWI and ethanol saturated with hydrochloric acid gas to 112 to adjust to p)-143, and dry the solvent under reduced pressure again.

Recrystallize from ether-hexane to give 1-(3,5-
Dijert-butyl-4-hydroxybenzyl)amino-4,6-cymethyl-7-hydrooxyindan 0.7
Obtain 7g.

rTl 154-155°C Colorless needle crystals Compounds of Examples 47, 48 and 50-59 are obtained in the same manner as in Example 75 using appropriate starting materials.

Example 76 5 g of 1-amino-4-methyl-6-α-chloroacetylaminomethyl-7-hydroxyindan and aJJ! A solution of 50 scales of acid and 100 scales of ethanol was heated to reflux at 8 o'clock. The solvent is distilled off and washed with ethanol. Methanol-
Recrystallized from ether to give 1-amino-4-methyl-6-
Aminomethyl-7-hydro-oxyindan 2 salt 111j
11a is obtained.

ml) 220°C (decomposed) Colorless powder Example 77 7-Hydroxy-4-methyl-6-t-butyl-1-indanone oxime 19.7a was dissolved in 200 m 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 removed from the furnace, the IP liquid is concentrated to dryness under reduced pressure.

Add 200 mQ of ethanol to the residue, dissolve in wJ, and blow in hydrochloric acid gas. The solvent was dried mWJ under reduced pressure and recrystallized from coarse ethanol to obtain colorless powder of 1-amino-7- and droxy-4-methyl-6-t-butyl-1-.
Indane salt 1!1Ji2.2f;l is obtained.

mp 221-224°C (decomposition) Elemental analysis [(C14H21N O-HCa) I-IN Calculation 1ii ($1 65.74 8.28 5.48 Actual measurement gn(X) 65.59 8,15 5.59 Example 78 7-Hydroxy-4,6-di-t-butyl-1-indanone oxime 23.2a was dissolved in 200111Q acetic acid, 1.0Q of platinum oxide catalyst was added, and the mixture was contacted at air temperature under a hydrogen pressure of 5 atm for 8 hours. Reduce. After separating the catalyst by tp, the furnace liquid is concentrated to dryness under reduced pressure. Add 200 ml of ethanol to the residue.
Add rFJFff and blow in hydrochloric acid gas to saturate.

The ratses were condensed to dryness under reduced pressure and recrystallized from ethanol to give a colorless powder of 1-amino-7-hydroxy-
4,6-di-t-butyl-1-indane JlIn salt 1
Get 8.80.

Elemental analysis value (C17H27NO・HCQ)CHN Total t'Jlill) (X) 68.55 9.14
4.70 Actual measurement 1iff(X) 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 no.

1: 4.6-dimethyl-7-hydroxy-1-indanone oxime 2: 1-amino-7-hydrooxy-4-methylindane salt l! ! Salt 32 1-Amino-7-hydrooxy-4,6-dimethylindane hydrochloride 4:1-amino-7-hydrooxy-4-methyl-〇-iodoindan hydrochloride 5:1-amino- 7-Hydroxy-4,6-dichloroindan! ! Acid acid 6: 1-methylamino-4,6-dimethyl-7-hydroxyindan ml! 2m 7:1-amino-2,2,4,6-titramethyl-7-
Hydroxyindane hydrochloride 8:1-amino-4-methyl-6-5ec-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-promoerhydroxyindan hydrobromide 13:1-amino-4-methyl-6-nitro-two-hydroxyindan salt a salt 14:1-amino -5-n-propyl-7-hydroxyindan hydrochloride 15:1-methylamino-4-methyl-6-methylthio-twohydroxyindan 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
-Hydroxyindan Jff I! JJ19: 1-Methylamino-4-methyl-6-nityl-7-hydroxyindan hydrochloride 20: 1-amino-4-ethyl-6-5ec-butyl-
7-hydroxyindan salt mJM 21:1-methylamino-4-ethyl-6-allyl-7
-Hydroxyindan ir11m (A> Anti-carrageenan edema effect test a body ff1150 (: 1 male Wistar rat, 5 rats per group, 18 hours after eating, 1:11
After administration of the starting material, the test compound is administered orally at a water temperature of 100 mMka. One hour after administration, 0.1% 1% carrageenan/rat is subcutaneously injected into the left heel, and speech failure in the left hind limb is measured 3 hours later. The float is determined by the volume doubling rate of the bale limb 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.

Table 7 (B) Antioxygen deficiency effect The antioxygen deficiency effect is expressed by Arch, int, P
harmacodyn, .

233.137 (1978) 2! The test was conducted using the same test method as described above.

ICR male mice (body weight 2o-30g) were used. Four mice each were placed in a glass desiccator at an internal pressure of 21.
Aspirate air with a vacuum pump until it reaches 0 or 240 mmHg and close the cock. After starting the vacuum pump,
The time until respiratory arrest for each mouse was measured and defined as the survival time. The test hardware was administered subcutaneously or intracavally 15 minutes before the start of suction. Start of suction 11t30 minutes (210mmH
g) or when the animal survived for more than 15 minutes (240 mm tlg), the survival time was defined as 30 minutes or 15 minutes, respectively.

The test results under an internal pressure of 210 mm+8 g are shown in Table 8, and the test results under an internal pressure of 2405511 g are shown in Table 9a.

Table 8 As is clear from the above Tables 8 and 9, the indane derivatives of the present invention significantly prolonged the lethal time in the r11 deficiency state and had an ameliorating effect in the m-deficiency state.

(C) Antioxidant effect It is well known that Luminol is a luminescent test in which it emits light strongly due to 34w hydrogen hydride 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 (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 Test compound at 1~1X10''@mg/4 concentration and linoleic acid hydroperoxide at i, oxi.

Prepare a methanol solution containing 1 mol/11112F 11 degrees (hereinafter referred to as test solution), and also 1X10-muM
Luminol 0.1M charcoal m sodium slow street solution and FC
S (fetal bovine serum, manufactured by Gipco) at 1.25x 10'
g/m+2ij 0.1M charcoal sodium containing 1 degree
is made by vA.

These prepared rFJ solutions were automatically added and mixed in 0.4-by-0 amounts in the order of test solution, FCS solution, and luminol solution using the flow system shown in the first factor, and the final luminol 1ff was mixed.
lU Wayoi, 1 second, photo counter (R649S: m
Measure the luminescence m using Matsu Photonics Co., Ltd.). In addition, in the m1 diagram, (1) is the photo counter, (2) is the cell,
(3) is a mixer, and (4) is? I[ia, (5) is luminescent reagent (luminol solution), (6) is Pt1 medium (FC
(7) is a washing buffer (0.1M sodium charcoal sulfur solution), (8) is a syringe, (9) is a drain, and (10) is a pulp.

The test compound shown above is given a predetermined I! Table 10 shows the results of measuring the luminescence Ω at each concentration.

Each luminescence amount was calculated as a percentage (%) of the luminescence Ω when using the above-mentioned test solution not containing the test compound as 1 according to the following formula, and was expressed as the value.

Luminescence amount - Standing x 100 (%) -B Number of counts for the host with no test compound added and lipid peroxide added B: Number of counts for the host without the addition of test compound and lipid peroxide C: Test sample Count number when compound and lipid peroxide were added together Table 10 In addition, control BHT and pair 1t[lVE in the table are as follows.

Control 8HT...butyl human oxygen toluene control VE...
...Vitamin E (2) In addition, in the same test as above, 50% inhibition rate against 50μ9 of linoleic acid hydroperoxide lX10'mol/II2 (that is, each test compound that inhibits the oxidation ability of the peroxide by 50%) 11i (l!, antidiaphragm ability IL5°) was determined for each test compound and the results are shown in Table 11 below.

Table 11 From Tables 10 and 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 has BHT and VE in vivo.
It was observed that it showed similar strong activity. This indicates that the compound of the present invention is useful as a prophylactic and therapeutic agent for various diseases caused by lipid peroxides and active cancer.

(0) 50% Grape B! Effect on lethal cerebral hemorrhage by intraperitoneal administration (mice) Experiments were conducted with 30 mice per group. Compound of the present invention (0
, 3, 1 and 31 B/kg) at 50 min after subcutaneous administration.
% (W/Vsaline) of glucose 0.4III2/
Administer 10g body weight in 1.2rl, and after sonication, 1.5°3
And the survival rate of the mice was determined at 24 hours. 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 had an effect on the consciousness disorder produced by impacting the head of mice.

The neck skin of the mouse was grasped and the head was fixed on a styrofoam pillow made of Junsa 2C1. Acrylic cylindrical rod (2C1
) was placed on an acrylic tube and dropped from a height of 3Qci onto the top of the mouse's head, and a cap 7 was added. Indicators of consciousness disturbance include the time until the onset of the righting reflex (RP time) and spontaneous M! I! Time 1 until lJ appears! l (3M
time) was used.

Test compound: 0.1-710g 15 minutes before impact
The dose was administered subcutaneously. As a control, physiological saline of the same Ω was administered. After the experiment, all mice were subjected to head autopsy, and the brain was
Those with one scratch were excluded from the judgment. The results are shown in Table 13. The numbers in parentheses in the table are the four numbers of mice.

Table 13 F) Effect of blue flQ potassium on lethality The test compound was orally administered to male Wistar rats (body weight!! 1170-250 g), and 1 hour later potassium cyanide 5 mQ/
kQ was administered intraperitoneally, and survival time was determined. 5 as a control
IQ/k! J physiological saline was used. Observation was made for 15 minutes after administration.

Table 14 Formulation Example 1 Ardroxy-4-methyl-1-indanoxime 200mg Grape tlJ 250i.

Distilled water for injection 1 total amount 511
2. The compound of the present invention and glucose are dissolved in distilled water for injection, and then poured into 5-sized ampoules. After replacing with nitrogen, the solution is autoclaved at 121° C. for 15 minutes to obtain an injection with the above composition.

Formulation Example 2 1-amino-7-hydroxy-4-methylindane hydrochloride 1 in 100 Avicel (trade name, manufactured by Asahi Kasei) 40Q cornstarch 30 g Magnesium stearate 2 g TC-510 + (trade name, manufactured by Shin-Etsu Kasei 5I) , hydroxypropyl methylcellulose) polyethylene glycol-60003Q castor oil
400 methanol
4 The compound of the present invention, Avicel, cornstarch and late magnesium stearin are mixed and mixed with aim R10.
Compress the tablets with a u kineer. The obtained tablets are coated with a film coating agent consisting of TC-5, polyethylene glycol-6000, mustard oil, and methanol to produce film-coated tablets having the above composition.

Formulation Example 3 1-amino-4,6-dichloro-7-hydroxyindan salt am Lafuranoline manufactured by ZQm 5g white beeswax 5g white petrolatum
88g total rll
Heat 100 g of white beeswax to make it liquid, then add the compound of the present invention, purified lanolin, and white petrolatum, heat slowly until it becomes liquid, and stir until it begins to solidify to obtain an ointment with the above composition. .

[Brief explanation of the drawing]

FIG. 1 shows a flow path diagram of an apparatus for measuring the antioxidant ability of the compounds of the present invention. (That's all) 1. Agent Patent Attorney Eiji Saegusa '1. .・、-2

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Alkanoylamino group, lower alkylsulfonylamino group, phenylsulfonylamino group that may have a lower alkyl group as a substituent on the phenyl ring, benzoylamino group that has a lower alkyl group as a substituent on the phenyl ring, A phenyl lower alkylamino group having a hydroxyl group or a lower alkyl group as a substituent. R^2 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- Indicates a piperidine sulfonyl group or a lower alkenyl group. R^3 is a hydrogen atom,
Indicates a lower alkyl group or a halogen atom. R^4 and R
^5 each represents 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. ] A hypoxia improving agent characterized by containing an indane derivative represented by the following and a salt thereof. (2) General formula ▲ Numerical formula, chemical formula, table, etc. Alkanoylamino group, lower alkylsulfonylamino group, phenylsulfonylamino group that may have a lower alkyl group as a substituent on the phenyl ring, benzoylamino group that has a lower alkyl group as a substituent on the phenyl ring, Indicates a phenyl lower alkylamino group having a hydroxyl group or a lower alkyl group as a substituent.R^2 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 halogen atom Represents a lower alkanoylamino lower alkyl group, a lower alkylthio group, a 1-piperidinesulfonyl group, or a lower alkenyl group that may have the following.R^3 is a hydrogen atom,
Indicates a lower alkyl group or a halogen atom. R^4 and R
^5 each represents 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. ) An antioxidant characterized by containing an indane derivative represented by: and its salt.