JPH058181B2 - - Google Patents

Description

[Detailed description of the invention] Technical field The present invention relates to indane derivatives. Composition of the invention The indane derivative of the present invention is a novel product not yet described in the literature.
It is a compound represented by the following general formula (1). [R in the formula¹may have a lower alkyl group.
amino group, hydroxyimino group, halogen atom
Alkanoyl having 1 to 10 carbon atoms, which may have
Amino group, lower alkylsulfonylamino group,
Has a lower alkyl group as a substituent on the enyl ring
phenylsulfonylamino group,
Having a lower alkyl group as a substituent on the nyl ring
Benzoylamino group, as a substituent on the phenyl ring
A phenyl compound having a hydroxyl group or a lower alkyl group
represents a class alkylamino group. R²is a hydrogen atom, low
alkyl group, halogen atom, nitro group, amino
group, amino lower alkyl group, lower alkanoyl group
A lower atom group that may have a mino group or a halogen atom.
Lucanoylamino lower alkyl group, lower alkyl
thio group, 1-piperidinesulfonyl group or lower a
Indicates a lekenyl group. R³is a hydrogen atom, lower alkyl
represents a group or a halogen atom. R^Fourand R^FiveThat's it
Each represents a hydrogen atom or a lower alkyl group. however
R¹is a hydroxyimino group, R²and R³
must not both be hydrogen atoms. ] The compound of the present invention represented by the above general formula (1) is:
Has the effect of improving oxygen deficiency conditions and associated symptoms.
It has the ability to improve oxygen deprivation and the symptoms associated with it.
ameliorating agents (i.e. hypoxia improving agents)
More specifically, for example, brain-enhancing drugs, amnesia
Respiratory arrest due to drugs, senile dementia drugs, and potassium cyanide poisoning
Hypoxia and hypoxia improving drugs, irregularities caused by lack of oxygen
It is effectively used as a medicine to prevent heart failure and heart failure. For living organisms, enzymes are responsible for energy production, metabolism, etc.
It is essential for sustaining life. The enzyme is an energy
Reactions in the ghee production system, oxygen reactions, ultraviolet rays, radiation
Oxygen anion radicals and peroxide ions are generated by reactions such as
so-called active oxygen species such as on, hydroxyl radicals, etc.
Become. The reactive oxygen species are oxygenated enzymes and white blood cell killers.
Although it is useful for living organisms such as bacterial action, it is abundant in living organisms.
Oleic acid, linoleic acid, and linolenic acid present in
Acids, arachidonic acid, etc. that form phospholipids in biological membranes.
Promotes peroxidation of unsaturated fatty acids and reduces peroxidized lipids.
Form. This lipid peroxide is the active oxygen species mentioned above.
Similarly, alkoxy radicals and hydroxyl radicals
attack biological membranes, causing membrane damage and
leading to deactivation of various useful enzymes [metabolism,15(Ten),
See 1978 Special Feature on Active Oxygen]. However, in vivo
For example, superoxide dismutase
(SOD), catalase, glutathione peroxy
Involved in the metabolic deactivation of the above-mentioned reactive oxygen species such as Dase, etc.
Enzymes are present, and α-tocopherol
It has various antioxidant abilities including (vitamin E).
There are vitamins, etc. that act as
Normal biological maintenance is performed, but there is no
Due to the above enzymes, vitamins, etc.
Defects in appropriate defense mechanisms or similar defences.
Generation of active oxygen species and lipid peroxides that exceed the capacity of the mechanism
It is often recognized that quality generation and accumulation occur.
Ru. If a deficiency in such a defense mechanism occurs, hyperacid
Serious failures due to the chain reaction progress of chemical reaction, e.g.
Various diseases, inflammation, liver damage, and movement caused by platelet aggregation
Pulse sclerosis, hemolysis, aging or senile dementia, retinopathy,
Lung damage, heart and lung damage caused by certain drugs, ischemia
Sexual vascular diseases etc. occur. The activities that have traditionally been considered to be the main causes of the various disorders listed above.
Removes (scavenge) reactive oxygen species (radicals),
Prevents the production and accumulation of lipid peroxide in the body.
Compounds that have the effect of stopping acid
It is called a curing agent, and its use actually cures the various diseases listed above.
Many disease prevention and treatment effects have been reported.
Reported antioxidants include the SOD mentioned above.
Targeted enzyme agent [Superoxide and medicine, University of Tokyo]
Yoshihiko Yanagi, 1981, Kyoritsu Publishing, pp. 137-141]
Butyl hydroxytoluene (BHT), butyl hydride
Roxyanisole (BHA), α-tocopherol
(vitamin E), etc. [Makoto Mino, Hidetaka Tanaka, Yakuza
Naru,19(12), 1983, p2351-2359 and end
Toshihiko Matsu, same magazine,19(5), 1983, p909-914]
There is. The compounds of the present invention scavenge reactive oxygen species and
It also has the effect of preventing or reducing the in vivo production of chemical lipids.
Ru. Therefore, the compound of the present invention has an excess of the above active oxygen species.
generation, bioaccumulation of lipid peroxide, etc.
various disorders and diseases caused by deficiencies in the defense mechanisms of
As preventive and therapeutic agents, for example, anti-arteriosclerotic agents,
Cancer preventive agent, anticancer agent, anti-inflammatory agent, analgesic, autoimmune
Disease treatment agent, platelet aggregation inhibitor, antihypertensive agent, high antilipid
Blood serum medicine, retinopathy of prematurity and cataract prevention and treatment agent
It is also useful as a medicine. Furthermore, the compounds of the present invention
Products are used not only as medicines, but also as processed foods.
For use as an antioxidant for oils and fats contained in products, etc.
is also valid. The compound also has excellent anti-inflammatory properties.
Inflammatory effect, antihypertensive effect, gastric acid secretion suppressing effect, and immunity
It also has regulatory effects, such as anti-inflammatory agents, antihypertensive agents, etc.
It is also useful. In this specification, R¹,R²,R³,R^Fourand R^Fivein
Each group shown is more specifically the following:
can be mentioned. Lower alkyl groups include methyl, ethyl, and
Lopyl, isopropyl, butyl, tert-butyl,
pentyl, hexyl, 1-methylpropyl, 2-
Methylpropyl, 1,1-dimethylpropyl, 1
-Methylbutyl, 2-methylbutyl, 3-methyl
Butyl, 2,2-dimethylpropyl, 2,3-di
Methylpropyl, 1-methylpentyl, 1,1-
Oxygen number 1 in dithylbutyl, 1-ethylbutyl group, etc.
~6 straight chain or branched alkyl groups may be exemplified.
Ru. Examples of halogen atoms include fluorine atoms, chlorine atoms,
Examples include bromine atom and iodine atom. an amino group that may have a lower alkyl group;
and 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-dihexyla
mino, N-methyl-N-ethylamino, N-methylamino
Ru-N-isopropylamino, N-methyl-N-
tert-butylamino, N-methyl-N-pentyl
Amino, N-ethyl-N-pentylamino, N-
1 carbon number such as tert-butyl-N-ethylamino group
Having ~6 straight chain or branched alkyl groups
Examples include certain amino groups. 1 to 10 carbon atoms, which may contain halogen atoms
As the alkanoylamino group, formylamine
mino, acetylamino, propionylamino, butyl
tyrylamino, tert-butyrylamino, pentano
ylamino, hexanoylamino, heptanoyl
Amino, octanoylamino, nonanoylamino
No, decanoylamino, 2,2,2-trifluoro
Loacetylamino, 2,2,2-trichloroacetate
thylamino, 2-chloroacetylamino, 2-butylamino
Lomoacetylamino, 2-fluoroacetylamino
No, 2-iodoacetylamino, 2,2-diflu
Oloacetylamino, 2,2-dibromoacetyl
Amino, 3,3,3-trifluoropropionyl
Amino, 3,3,3-trichloropropionyl
mino, 3-chloropropionylamino, 2,3-
Dichloropropionylamino, 4,4,4-tri
Chlorobutyrylamino, 4-fluorobutyrylamino
mino, 5-chloropentanoylamino, 3-chloro
rho-2-methylpropionylamino, 6-bromo
Hexanoylamino, 7-iodoheptanoylamino
mino, 8-fluorooctanoylamino, 9-k
Rorononanoylamino, 10-bromodecanoylamino
mino, 5,6-dibromohexanoylamino,
Examples include 2,2-dichloroheptanoylamino group, etc.
can do. As the lower alkylsulfonylamino group,
Tylsulfonylamino, ethylsulfonylamino
No, propylsulfonylamino, isopropyls
sulfonylamino, butylsulfonylamino, tert
-butylsulfonylamino, benzylsulfonyl
Number of carbon atoms in amino, hexylsulfonylamino groups, etc.
1 to 6 linear or branched alkylsulfonylated
An example is a mino group. Lower alkyl group as a substituent on the phenyl ring
Phenylsulfonylamino groups that may have
phenylsulfonylamino, 2-,3-
or 4-methylphenylsulfonylamino, 2
-, 3- or 4-ethyl phenyl sulfonyl amine
No, 4-propylphenylsulfonylamino, 3
-isopropylphenylsulfonylamino, 2-
Butylphenylsulfonylamino, 4-hexyl
Phenylsulfonylamino, 3-pentylphenyl
Rusulfonylamino, 4-tert-butylphenyl
Sulfonylamino, 3,4-dimethylphenyls
sulfonylamino, 2,5-dimethylphenylsul
Honylamino, 3,4,5-trimethylphenyl
Substituents on the phenyl ring such as sulfonylamino group
and a straight chain or branched alkyl group having 1 to 6 carbon atoms.
phenylsulfonylamino group that may have
can be exemplified. Lower alkyl group as a substituent on the phenyl ring
The benzoylamino group has 2-, 3-
or 4-methylbenzoylamino, 2-,3- or
is 4-ethylbenzoylamino, 4-propylben
3-isopropylbenzoylamino, 3-isopropylbenzoylamino
mino, 2-butylbenzoylamino, 4-hexy
Rubenzoylamino, 3-pentylbenzoylua
mino, 4-tert-butylbenzoylamino groups, etc.
Straight chain with 1 to 6 carbon atoms as a substituent on the phenyl ring
or benzoylamides having a branched alkyl group
An example is the group . Hydroxyl group or lower atom as a substituent on the phenyl ring
Phenyl lower alkylamino group with alkyl group
as 2-, 3- or 4-hydroxybendi
Ruamino, 2-(3-hydroxyphenyl)ethyl
Ruamino, 1-(2-hydroxyphenyl)ethyl
Ruamino, 3-(1-hydroxyphenyl)pro
Pyramino, 4-(4-hydroxyphenyl)bu
thylamino, 1,1-dimethyl-2-(3-hydro
Roxyphenyl) ethylamino, 5-(2-hydro)
Roxyphenyl) pentylamino, 6-(4-hyperoxygenyl)
droxyphenyl)hexylamino, 2-methyl
-3-(4-hydroxyphenyl)propylamide
-, 2-, 3- or 4-methylbenzylamino,
2-, 3- or ethylbenzylamino, 4-pro
Pyrbenzylamino, 3-isopropylbenzyl
Amino, 2-butylbenzylamino, 4-hexy
Rubenzylamino, 3-pentylbenzylamino
No, 4-tert-butylbenzylamino, 2-(3
-methylphenyl)ethylamino, 1-(2-ethylamino)
tylphenyl) ethylamino, 3-(2-propyl)
ruphenyl) propylamino, 4-(4-butyl)
phenyl)butylamino, 1,1-dimethyl-2
-(3-hexylphenyl)ethylamino, 5-
(2-pentylphenyl)pentylamino, 6-
(4-tert-butylphenyl)hexylamino,
2-Methyl-3-(4-methylphenyl)propyl
Ruamino, 2-methyl-3-hydroxybenzyl
Amino, 3,5-di-tert-butyl-4-hydro
xybenzylamino, 3-ethyl-5-hydroxy
Cybenzylamino, 4-(2-hydroxy-4-
propylphenyl)butylamino, 6-(2,3
-dimethyl-4-hydroxyphenyl)hexyl
amino, 3,5-, 3,4-, or 2,6-dihydroxy
Droxybenzylamino, 3,4,5-trihydride
roxybenzylamino, 3,4-, 2,5- or
2,6-dimethylbenzylamino, 3,4,5-
on the phenyl ring such as trimethylbenzylamino group
As a substituent, a hydroxyl group or a straight chain having 1 to 6 carbon atoms or
Carbon in alkyl moiety with branched alkyl group
Examples of phenylalkylamino groups having a number of 1 to 6
Wear. As the amino lower alkyl group, aminomethyl
2-aminoethyl, 1-aminoethyl, 3-
Aminopropyl, 4-aminobutyl, 1,1-di
Methyl-2-aminoethyl, 5-aminopentyl
yl, 6-aminohexyl, 2-methyl-3-amino
Straight chain or branched chain having 1 to 6 carbon atoms such as nopropyl group
List the aminoalkyl groups having an alkyl group of
be able to. As a lower alkanoylamino group, holimyl
amino, acetylamino, propionylamino,
Butyrylamino, tert-butyrylamino, penta
Number of carbon atoms in noylamino, hexanoylamino, etc.
1 to 6 linear or branched alkanoylamino groups
can be exemplified. Lower alkanosomes that may contain halogen atoms
As the yl lower alkyl group, 2,2,2-tri
Fluoroacetylaminomethyl, 2,2,2-t
Lichloroacetylaminomethyl, 2-chloroacetyl
tylaminomethyl, 2-(2-bromoacetyl
mino)ethyl, 1-(2-fluoroacetylamine)
) Ethyl, 3-(2-iodoacetylamino)
Propyl, 4-(2,2-difluoroacetylar)
mino)butyl, 1,1-dimethyl-2-(2,2
-dibromoacetylamino)ethyl, 5-(3,
3,3-trifluoropropionylamino) pen
Chil, 6-(3,3,3-trichloropropioni
(ruamino)hexyl, 2-methyl-3-(3-k)
Lolopropionylamino)propyl, 2,3-di
Chloropropionylaminomethyl, 2-(4,4,
4-Trichlorobutyrylamino)ethyl, 1-
(4-fluorobutyrylamino)ethyl, 3-(5
-chloropentanoylaminopropyl, 4-(3
-chloro-2-methylpropionylamino)butylene
1,1-dimethyl-2-(6-bromohexyl)
Noylamino)ethyl, 5-(5,6-dibromo)
halogen sources such as pentyne (hexanoylamino)
Straight chain or branched chain with 1 to 6 carbon atoms that may have children
Branched alkanoylamino substituted straight carbon number 1-6
Examples include chain or branched alkyl groups. Examples of lower alkylthio groups include methylthio and ethylthio.
Chilthio, propylthio, isopropylthio, butylthio
Tylthio, tert-butylthio, pentylthio,
Straight chain or branched chain having 1 to 6 carbon atoms such as xylthio group
Examples include alkylthio groups. Lower alkenyl groups include vinyl, allyl,
2-butenyl, 3-butenyl, 1-methylali
carbon, such as 2-pentenyl, 2-hexenyl, etc.
Examples of straight chain or branched alkenyl groups of 2 to 10
can. The compounds of the present invention can be produced by various methods.
However, a typical manufacturing method is shown below. [R in the formula²,R³,R^Fourand R^Fiveis the same as above. ] Known compounds of general formula (2) and hydroxylamine
The reaction with (3) is carried out using a basic compound in an appropriate inert solvent.
It can be carried out in the presence or absence of a substance.
Examples of basic compounds used at this time include
Sodium hydroxide, potassium hydroxide, sodium carbonate
Inorganic basic compounds such as aluminum, potassium carbonate, pipette
Lysine, pyridine, triethylamine, 1,5-
Diazabicyclo[4,3,0]nonene-5
(DBN), 1,8-diazabicyclo[5,4,0]
undecene-7 (DBU), 1,4-diazabisic
Organic materials such as [2,2,2]octane (DABCO)
An example is a base. As an inert solvent used
can be used as long as it does not adversely affect the reaction.
For example, methanol, ethanol,
Lower alcohols such as isopropanol, dioxin
San, tetrahydrofuran, diethyl ether,
Ethylene glycol monomethyl ether and other ethers
Aromas such as esters, benzene, toluene, xylene, etc.
Group hydrocarbons, dichloromethane, dichloroethane
Halogenated water such as chloroform, carbon tetrachloride, etc.
elements, dimethylformamide, dimethylsulfochloride
side, hexamethyl phosphate triamide, etc.
It will be done. The amount of hydroxylamine (3) used is generally
Usually at least an equimolar amount relative to the compound of formula (2),
It is preferable to use equimolar to 5 times the molar amount.
stomach. The reaction temperature is usually room temperature to 200°C, preferably
It is best to keep the temperature at 50 to 150℃, generally for about 1 to 10 hours.
The reaction ends at 100°C. The reduction of the compound of general formula (101) can be carried out using a suitable solvent.
carried out by catalytic hydrogenation in the presence of a medium catalyst.
can become. Examples of solvents used include
For example, water, acetic acid, methanol, ethanol, isopropyl
Alcohols such as lopanol, hexane, cyclo
Hydrocarbons such as hexane, diethylene glycol
dimethyl ether, dioxane, tetrahydrof
Ethers such as ran, diethyl ether, acetic acid ethyl
ethyl, esters such as methyl acetate, dimethylform
Examples include aprotic polar solvents such as Muamide.
Ru. In addition, examples of the solvent used include, for example, paradia
um, palladium-black, palladium-carbon, white
Gold, platinum oxide, copper chromite, Raney nickel, etc.
is used. The amount of catalyst used is based on the general formula
Generally about 0.02 to 1 times the amount of compound (101)
Good to use. Reaction temperature is usually -20℃ to room temperature
around 0°C to room temperature, and the hydrogen pressure is usually 1
The pressure is preferably ~10 atm, and the reaction generally takes place at a pressure of 0.5~10 atm.
It will be completed in about 10 hours. [R in the formula¹,R^Fourand R^Fiveis the same as above. R²'as well as
R²″ is R²Same as. However, R²′ and R³′ at least
One represents a hydrogen atom, R²″ and R³"of
At least one shall represent a halogen atom.
Ru. ] The halogenation reaction of the compound of general formula (103) is
This is done in the presence of conventional halogenating agents.
Known halogenating agents used in the reaction include
Can be used widely, such as halogens such as bromine and chlorine.
Gen molecule or iodine monochloride, sulfuryl chloride
Do, N-bromosuccinimide, N-chlorosuccinimide
N-halogenosuccinimide such as citric acid imide, etc.
Examples include halogenating agents. halogen
The amount of chemical agent used is usually the chemical compound of general formula (103).
About equimolar to 10 times the molar amount of the compound, preferably
It is preferable to use an equimolar to 5-fold molar amount. used for this reaction
Examples of solvents that can be used include dichloromethane, dichloromethane,
Halogens such as loethane, chloroform, carbon tetrachloride, etc.
Examples include hydrocarbons, acetic acid, propionic acid, water, etc.
can be lost. In this reaction, the reaction temperature is usually 0°C.
~The boiling point of the reaction solvent, preferably 0 to 40°C
The reaction is usually completed in about 1 to 10 hours. [R in the formula²,R³,R^Fourand R^Fiveis the same as above. R⁶teeth
Lower alkyl group, lower alkylsulfonyl group,
A hydroxyl group or a lower alkyl group as a substituent on the enyl ring.
Phenyl lower alkyl group or phenyl group having a kill group
Having a lower alkyl group as a substituent on the nyl ring
phenylsulfonyl group. ] Reaction between the compound of general formula (2) and the compound of general formula (4)
is without solvent or in a suitable solvent, in the absence of a dehydrating agent.
or in the presence of Solvent used here
For example, methanol, ethanol, iso
Alcohols such as propanol, benzene, tol
Aromatic hydrocarbons such as ene and xylene, dimethyl
Formamide, dimethylacetamide, N-methy
Examples include aprotic polar solvents such as lupyrrolidone.
It will be done. As a dehydrating agent, for example, molecular acid
desiccant used for dehydration of ordinary solvents such as
Mineral acids such as hydrochloric acid, sulfuric acid, boron trifluoride, p-toluene
Examples include organic acids such as sulfonic acid.
Ru. The reaction is usually carried out at room temperature to 250°C, preferably at 50°C.
It is carried out at ~200℃, generally for about 1 to 48 hours.
The amount of the compound of general formula (4) to be used, at which the reaction is completed at
Although there is no particular restriction, the general formula (2) is usually
at least equimolar amounts relative to the compound, preferably
It is best to use a large excess amount. Also, the amount of dehydrating agent used
In the case of desiccants, acid is usually used in large excess.
When used, it is preferable to use catalytic amounts. Thus
The obtained compound of general formula (5) is not isolated.
It is then subjected to the next reduction reaction. Various methods can be used for the reduction reaction of the compound of general formula (5).
However, for example, reduction using a hydrogenation reducing agent can be applied.
The original method is preferably used. Hydrogenation reduction used
Examples of agents include sodium aluminum hydride.
Examples include sodium borohydride, ciborane, etc.
The amount used is usually smaller than that of compound (5).
Equimolar, preferably equimolar to 10 times the molar range
It is. Aluminum hydride as hydrogenation reducing agent
When using lithium, twice the molar amount as compound (5)
This reduction reaction is usually
A suitable catalyst, e.g. water, methanol, ethanol
lower alcohols such as alcohol, isopropanol,
Trahydrofuran, ethyl ether, diglyme
etc., usually at about -60 to 50℃, preferably
Preferably at -30℃ to room temperature for about 10 minutes to 5 hours.
It is done in degrees. In addition, hydrogenated aluminum is used as a reducing agent.
When using minium lithium or diborane,
Ethyl ether, tetrahydrofuran, zigly
It is preferable to use an anhydrous solvent such as aluminum. [R in the formula²,R³,R^Fourand R^Fiveis the same as above. R⁷teeth
Hydroxyl group or lower alkyl group as a substituent on the phenyl ring
Indicates a phenyl lower alkyl group having a kill group. ] Compound of general formula (102) and compound of general formula (6)
The reaction is carried out using the compound of general formula (2) in the reaction scheme-3 above.
The reaction was carried out under the same conditions as the reaction with the compound of general formula (4).
be called. Also, the reduction reaction of the compound of general formula (7) is
Reduction reaction of the compound of general formula (5) in the reaction scheme-3 above.
The test is carried out under the same conditions as the test. [R in the formula²,R³,R^Fourand R^Fiveis the same as above. R⁸teeth
1 to 10 carbon atoms that may have halogen atoms
As a substituent on the alkanoyl group or phenyl ring of
and a benzoylamino group having a lower alkyl group.
show. ] Compound of general formula (102) and compound of general formula (8)
The reaction is carried out using a normal amide bond formation reaction.
more achieved. In this case, the alkoxylic acid (8) is active.
Sexualized compounds may also be used. Amide bond raw material
The conditions for the amide bond formation reaction are applied as the formation reaction.
can be done. For example, (a) mixed acid anhydride method, etc.
That is, when carboxylic acid (8) is reacted with alkylhalocarboxylic acid,
A mixed acid anhydride is obtained, and compound (102) is added to this.
(b) Active ester method or amide
method, i.e. converting carboxylic acid (8) to e.g.
enyl ester, N-hydroxysuccinimide
ester, 1-hydroxybenzotriazole
Active esters such as ster, or benzoxazo
This is converted into an active amide with phosphorus-2-thione.
Method for reacting compound (102), (c) Carbodiimide
method, that is, compound (102) is added to carboxylic acid (8).
For example, dicyclohexylcarbodiimide, carbo
Dehydrated in the presence of a dehydrating agent such as nildiimidazole
The bonding method is the (di)carboxylic acid halide method,
In other words, carboxylic acid (8) is induced into a halide form, and this
Method of reacting compound (102), (e) Others
As a method, carboxylic acid (8) can be dehydrated using e.g. acetic anhydride.
The compound is converted into a carboxylic acid anhydride by using a chemical agent.
A method of reacting (102) with carboxylic acid (8), e.g.
Compound (102) to ester with lower alcohol
Examples include methods of reacting under high pressure and high temperature.
Wear. In addition, carboxylic acid (8) is converted into triphenylphosphine.
Phosphorus compounds such as chlorine and diethyl chlorophosphate
Activate with and react with compound (102)
methods may also be adopted. Used in mixed acid anhydride method
Examples of the alkylhalocarboxylic acids used include
Methyl chloroformate, methyl bromate, chloroformate
Ethyl acid, ethyl bromoformate, isobutyl chloroformate
Examples include chill. Mixed acid anhydrides are
obtained by the Tuten-Baumann reaction, which is usually
Reaction with compound (102) without isolation
Compound (1) is produced by
Uman reactions are usually carried out in the presence of basic compounds.
Ru. The basic compound used is
-Common compounds are used in the Baumann reaction, e.g.
triethylamine, trimethylamine, pyridine
N, dimethylaniline, N-methylmorpholine,
4-dimethylaminopyridine, 1,5-diazabi
Cyclo[4,3,0]nonene-5 (DBN), 1,
8-Diazabicyclo[5,4,0]undecene-
7 (DBU), 1,4-diazabicyclo[2,2,
2] Organic bases such as octane (DABCO), carbonate
Liumium, sodium carbonate, potassium bicarbonate, charcoal
Examples include inorganic bases such as sodium hydroxide. Applicable
The reaction is carried out at about -20 to 100℃, preferably 0 to 50℃.
The reaction time is approximately 5 minutes to 10 hours.
Preferably it is 5 minutes to 2 hours. The resulting mixed acid
The reaction between anhydride and compound (102) is from -20℃ to 150℃
for about 5 minutes to 10 hours, preferably at 10 to 50℃
It is carried out for about 5 minutes to about 5 hours. Mixed
Although the synthetic acid anhydride method does not require the use of any particular solvent,
Generally carried out in a solvent, the solvent used is
Any solvent commonly used in the synthetic acid anhydride method can be used.
Yes, specifically methylene chloride, chloroform,
Halogenated carbons such as dichloroethane, benzene
aromatic hydrocarbons such as toluene, xylene,
diethyl ether, diisopropyl ether,
Ethers such as trahydrofuran and dimethoxyethane
esters such as methyl acetate, ethyl acetate,
dimethylformamide, dimer sulfoxide,
Aprotic poles such as hexamethylphosphate triamide
Examples include solvents. Carboxylic acid in this method
(8), alkylhalocarboxylic acids and compounds (102)
The usage rate is usually at least one mole of
However, for carboxylic acid (8), alkyl halocarbon
Bonic acid and compound (102) were each 1 to 2 times more active.
It is preferable to use The active ester method or activated amide method in (b) above is
For example, benzoxazoline-2-thionamide
For example, when used, it does not affect the reaction.
A suitable solvent, e.g. used in the mixed acid anhydride method described above.
In addition to the same solvent as 1-methyl-2-pyrroli
Using a don etc., 0 to 150℃, preferably 10 to 100℃
This was done by reacting for 0.5 to 75 hours at
It will be done. In this case, compound (102) and benzoxane
The ratio of the former to zolin-2-thionamide is
usually at least equimolar, preferably at least equimolar, of the latter to
is set to be equimolar to twice the molar amount. Also, N-hydroxy
When using succinimide ester, use a suitable
Bases, such as those used in the carboxylic acid halide method described below.
The reaction proceeds favorably when a base similar to that used in the reaction is used.
go In the carboxylic acid halide method (c) above, carboxylic acid
(8) is reacted with a halogenating agent to form a carboxylic acid halogen.
Isolate and purify this carboxylic acid halide.
The compound can be added to this without isolation or purification.
(102) is reacted. This carboxylic acid
The reaction between halide and compound (102) is the dehalogenation process.
carried out in a suitable solvent in the presence of a hydrogenating agent.
Ru. Usually basic compounds as dehydrohalogenation agents
is used in the above Schotten-Baumann reaction.
In addition to basic compounds that can be used, sodium hydroxide
potassium hydroxide, sodium hydride, hydrogenation
Potassium, silver carbonate, sodium methylate, nat
Alkali metal alcoholates such as lithium ethylate
etc. Note that compound (102) is used in excess amount.
It can also be used as a dehydrohalogenating agent.
can. As a solvent, the above-mentioned Schotten-Baumann
In addition to the solvent used in the reaction, e.g. water, methanol
ethanol, propanol, butanol, 3
-methoxy-1-butanol, ethylcelsol
Alcohols such as bu, methyl cellosolve, pyridine
acetone, acetonitrile, etc., or two of them.
A mixed solvent of more than one species can be mentioned. Compound (102)
The usage ratio of carboxylic acid halide and carboxylic acid halide is particularly limited.
Although the former is widely selected, the former is usually compared to the latter.
at least equimolar, preferably equimolar to twice
Mole used. Reaction temperature is usually around -30~180℃
temperature, preferably about 0 to 150°C, generally for 5 to 30 minutes.
The reaction is completed in time. The carboxylic acid group used
Ride is a carboxylic acid halide (8) and a halogenating agent
Manufactured by reacting with or without solvent or in a solvent.
Ru. As a solvent, use something that does not adversely affect the reaction.
For example, benzene, toluene,
Aromatic hydrocarbons such as xylene, chloroform,
Halogenated hydrocarbons such as methylene chloride and carbon tetrachloride
elements, dioxane, tetrahydrofuran, diethyl
Ethers such as ether, dimethylformamide
and dimethyl sulfoxide. Halo
As a gen-forming agent, the hydroxyl group of a carboxyl group can be
You can use ordinary halogenating agents that can be converted into
For example, thionyl chloride, phosphorus oxychloride, oxy-odor
Examples include phosphorus chloride, phosphorus pentachloride, phosphorus pentabromide, etc.
Ru. The usage ratio of carboxylic acid (8) and halogenating agent is
Although not particularly limited and can be selected as appropriate, reaction is performed without a solvent.
When dealing with the former, the latter is usually
When the reaction is carried out in large excess or in a solvent,
Usually at least an equimolar amount of the latter to the former
The amount used is preferably 2 to 4 times the molar amount. The opposite
The reaction temperature and reaction time are also not particularly limited, but usually
At room temperature to about 100℃, preferably 50 to 80℃, 30
It takes about minutes to 6 hours. Carboxylic acid (8) is converted into triphenylphosphine or diene.
Activated with phosphorus compounds such as methyl chlorophosphate
The method for reacting compound (102) with this is
It is carried out in a suitable solvent. As a solvent, it can be used in reactions.
You can use any of them as long as they have no effect.
Specifically, methylene chloride, chloroform
halogenated carbons such as dichloroethane, benzene, etc.
Aromatic hydrocarbons such as zene, toluene, and xylene
, diethyl ether, tetrahydrofuran, di-
Ethers such as methoxyethane, methyl acetate, vinegar
Esters such as ethyl acid, dimethylformamide
dimethyl sulfoxide, hexamethyl phosphate
Examples include aprotic polar solvents such as triamide.
Ru. In this reaction, compound (102) itself is a basic compound.
In order to act as a substance, it is used in excess of the theoretical amount.
The reaction progresses well by
Depending on other basic compounds, e.g. triethyl
Amine, trimethylamine, pyridine, dimethyl
Aniline, N-methylmorpholine, 4-dimethyl
Aminopyridine, 1,8-diazabicyclo[4,
3,0] nonene-7 (DBN), 1,5-diazabi
cyclo[5,4,0]undecene-5 (DBU),
1,4-diazabicyclo[2,2,2]octane
Organic bases such as (DABCO), potassium carbonate, carbonic acid
Sodium, potassium bicarbonate, sodium bicarbonate
It is also possible to use inorganic bases such as um. the reaction
is about 0 to 150°C, preferably about 0 to 100°C, and about 1
Compounds achieved by performing ~30 hours
The use of phosphorus compounds and carboxylic acids (8) for (102)
The proportion used is usually at least about equimolar amounts of each.
The amount is preferably 1 to 3 times the molar amount. [R in the formula²,R³,R^Fourand R^Fiveis the same as above. R⁹teeth
Lower alkyl group, lower alkylsulfonyl group,
Hydroxyl group or lower atom as a substituent on the enyl ring
Phenyl lower alkyl group or phenyl group having an alkyl group
Has a lower alkyl group as a substituent on the enyl ring
phenylsulfonyl group. X is
Indicates a halogen atom. ] Compound of general formula (102) and compound of general formula (9)
The reaction is expressed by the general formula in reaction scheme-5 above.
Reaction of compound (102) with carboxylic acid halide and
It can be carried out under similar reaction conditions. [R in the formula¹,R³,R^Fourand R^Fiveis the same as above. ] Nitration of the compound of general formula (109) is carried out using the usual
Under the nitration reaction conditions of aromatic compounds, e.g.
using a nitrating agent in a solvent or a suitable inert solvent.
It is done by Examples of inert solvents include vinegar.
acid, acetic anhydride, concentrated sulfuric acid, etc., and as a nitrating agent.
For example, fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, fuming
sulfuric acid, phosphoric acid or acetic anhydride and nitric acid), potassium nitrate
alkali metal nitrates such as silica, sodium nitrate, and sulfur.
Examples include acids and the like. Amount of the above nitrating agent used
is usually in excess of equimolar or more relative to the raw material compound.
The reaction is advantageously carried out at around 0°C to room temperature for 1
Performed in ~4 hours. The reduction of the compound of general formula (110) can be carried out using the above reaction procedure.
Reduction of the compound of general formula (101) in Equation-1
It can be carried out under the same reaction conditions. Also
The reduction of the compound of general formula (110) is carried out using the following method.
It can also be carried out using a base agent. Return used
Examples of base agents include iron, zinc, tin or chloride.
Stannous and acids such as acetic acid, hydrochloric acid, sulfuric acid, or iron, sulfuric acid
Ferrous iron, zinc or tin and sodium hydroxide etc.
Sulfurs such as alkali metal hydroxides and ammonium sulfide
ammonium chloride, aqueous ammonia, ammonium chloride, etc.
Examples include mixtures with monium salts.
Examples of inert solvents used here include
Water, acetic acid, methanol, ethanol, dioxane
etc. can be exemplified. The conditions used for the reduction reaction are
The reducing agent may be selected appropriately depending on the reducing agent used.
For example, when stannous chloride and hydrochloric acid are used as reducing agents,
In this case, the temperature is preferably between 0°C and around room temperature for about 0.5 to 10 hours.
It is better to carry out a reaction. As the amount of reducing agent used
is generally at least equimolar to the starting compound.
It is usually used in an equimolar to 5-fold molar amount. In the compound of general formula (1) above, R¹is halogen
Al having 1 to 10 carbon atoms, which may have carbon atoms
Canoylamino group, as a substituent on the phenyl ring
benzoylamino group having a lower alkyl group or
Hydroxyl group or lower substituent on phenyl ring
Phenyl lower alkylamino with alkyl group
The compound that is a group can be hydrolyzed to form the corresponding R¹
can be converted into a compound where is an amino group
Ru. Also R²is a lower alkanoylamino group or
Lower alkanoyl that may contain a rogen atom
Compounds that are amino lower alkyl groups can be hydrolyzed
The corresponding R²is an amino group or an amino lower atom
It can be converted into a compound that is alkyl group.
Here, the conditions for hydrolysis include, for example, the reaction described below.
of the compound of general formula (202) in equation-8
Reaction conditions similar to those for hydrolysis can be adopted.
Ru. In the above reaction schemes-1 and 3, starting materials
The compound of general formula (2) used as
For example, according to the method shown below,
Manufactured. [R in the formula³,R^Fourand R^Fiveis the same as above. R^Tenhalo
Lower alkanoyl which may have a gen atom
Indicates a mino lower alkyl group. R¹¹is amino lower a
Indicates a rukyl group. ] The compound of general formula (201) and the compound of general formula (10)
The reaction is carried out in the presence of a dehydration condensation agent without a solvent or in an appropriate manner.
It is carried out in a suitable solvent. Dehydration condensation used
As an agent, for example, condensed phosphoric acid such as polyphosphoric acid
phosphoric acid such as orthophosphoric acid, pyrophosphoric acid, metaphosphoric acid, etc.
phosphorous acids such as orthophosphorous acid, phosphorus pentoxide, etc.
Acids such as phosphoric anhydride, hydrochloric acid, sulfuric acid, boric acid,
Sodium Phosphate, Boron Phosphate, Phosphate
Metal phosphates such as diiron and aluminum phosphate,
Activated alumina, sodium bisulfate, Raneynitske
Examples include Le et al. Also used solvent
For example, dimethylformamide, tetra
Examples include phosphorus. General formula (201)
As the usage ratio of the compound and the compound of general formula (10)
There is no particular limit and can be selected as appropriate within a wide range.
However, the former is usually used in an equimolar amount of the latter.
More than a certain amount, preferably equimolar to 2 times the molar amount
It is better. There is no particular limit to the amount of dehydration condensation agent used.
The general formula is not specified and can be selected from a wide range.
(201) in a normal catalytic amount or more, preferably
It is best to use a large excess amount. The reaction is usually -
Suitable at 30°C to 50°C, preferably around 0°C to room temperature
The reaction progresses and generally completes in about 1 to 30 hours.
do. Conventionally, for hydrolysis of the compound of general formula (202),
Known hydrolysis reaction conditions can be widely applied, e.g.
suitable hydrolysis catalysts, e.g. hydrochloric acid, hydrobromic acid.
Inorganic acids such as hydrohalic acid, sulfuric acid, phosphoric acid, etc.
Acids, alkaline materials such as sodium hydroxide, potassium hydroxide, etc.
Potassium metal hydroxide, sodium carbonate, potassium carbonate
alkali metal carbonates, such as aluminum, sodium bicarbonate, etc.
or the presence of inorganic alkaline compounds such as bicarbonates.
Below, no solvent or a suitable solvent (e.g. water or water)
and lower alcohols such as methanol and ethanol.
mixed solvent) in a temperature range of 50 to 150℃, preferably 70 to 100℃.
What is necessary is to process at ℃ for about 3 to 24 hours. [R in the formula³,R^Fourand R^Fiveis the same as above. R¹²is low grade
Indicates an alkanoyl group. ] Nitration of compound of general formula (201) and general formula
The reduction of the compound (204) is carried out in the above reaction steps, respectively.
Nitro of the compound of general formula (109) in formula-7
reaction similar to the reduction of the compound of general formula (110)
It can be done under certain conditions. Also general formula (205)
The reaction between the compound of formula (11) and the compound of general formula (11) is as follows.
Compound of general formula (102) in Reaction Scheme-5
Reaction conditions similar to the reaction between the compound and the compound of general formula (8)
It can be done below. [R in the formula³,R^Four,R^Fiveand X are the same as above. R¹³Reach
BiR¹⁴represents a hydrogen atom or a lower alkyl group. ] Compound of general formula (201) and compound of general formula (12)
The reaction with a substance is carried out in the presence of a basic compound.
Ru. Widely used known basic compounds
For example, sodium hydroxide, potassium hydroxide
Mu, sodium carbonate, potassium carbonate, sodium bicarbonate
Inorganic salts such as thorium, potassium hydrogen carbonate, silver carbonate, etc.
base, alkali metals such as sodium and potassium,
Thorium methylate, sodium ethylate, etc.
alcoholate, toluethylamine, pyridine,
N,N-dimethylaniline, N-methylmorpholy
4-dimethylaminopyridine, 1,5-dia
Zabicyclo[4,3,0]nonene-5 (DBN),
1,8-diazabicyclo[5,4,0]undese
-7 (DBU), 1,4-diazabicyclo[2,
2,2] Organic bases such as octane (DABCO) are listed.
can be lost. The reaction can be carried out without a solvent or in the presence of a solvent.
It is also carried out in the presence of a
All inert substances that do not give are used, e.g.
Water, methanol, ethanol, propanol, alcohol
Alcohols such as tanol and ethylene glycol
dimethyl ether, tetrahydrofuran, dimethyl ether, dimethyl ether, tetrahydrofuran,
Oxane, monoglyme, diglyme, etc.
Ketones such as alcohols, acetone, methyl ethyl ketone, etc.
Aromatic carbon such as benzene, toluene, xylene, etc.
Hydrogens, esters such as methyl acetate, ethyl acetate, etc.
, N,N-dimethylformamide, dimethyls
Sulfoxide, hexamethylphosphate triamide, etc.
aprotic polar solvents and mixed solvents of
Can be mentioned. The reaction also involves sodium iodide, iodine,
Performed in the presence of metal iodides such as potassium iodide
is advantageous. General formula (2a) in the above method
The usage ratio of the compound and the compound of general formula (17) is
There is no particular limitation, and it is selected from a wide range of
However, the latter is usually equivalent to 5 times the amount of the former.
preferably used in an equimolar to twice molar amount.
is desirable. Also, the reaction temperature is not particularly limited.
No, but usually room temperature to 200℃, preferably 50 to 150℃
It will be held in The reaction time is usually 1 to 30 hours, preferably
Preferably 1 to 15 hours. Conversion of general formula (208) from compound of general formula (207)
The reaction to obtain compounds is generally called Claisen rearrangement.
For example, the compound can be prepared in a suitable solvent.
Heating (207) leads to compound (208)
be able to. The solvent used is dimethyl
Examples of high boiling point solvents such as formamide and tetralin
can be shown. The heating temperature is usually 100 to 250℃,
Preferably about 150-250℃, about 1-20 hours
The reaction is complete at 50°C. [R in the formula²,R³and X are the same as above. R¹⁵is low grade
Alkyl group, lower alkoxy lower alkyl group, lower
alkanoyl group, benzoyl group, phenyl lower
Indicates an alkyl group or a tetrahydropyranyl group.
R^Four′ and R^Five' each represents a lower alkyl group. ] Compound of general formula (209) and compound of general formula (13)
The reaction with a basic compound is carried out using an appropriate solvent in the presence of a basic compound.
It is done inside. Basic compounds used here
For example, sodium hydroxide, carbon hydroxide, etc.
sodium ethylate, sodium hydride
potassium hydride, sodium amide, potassium
Muamide, etc. can be mentioned. Also as a solvent
For example, methanol, ethanol, isopropylene
Alcohols such as panol, dioxane, diethyl
Ethers such as lene glycol dimethyl ether
aromatic hydrocarbons such as toluene and xylene,
dimethylformamide, dimethyl sulfoxide,
Examples include hexamethyl phosphate triamide, etc.
can. The amount of the compound of general formula (13) to be used is
There are no particular limitations, and you can choose as appropriate within a wide range.
However, it is usually small compared to the compound of general formula (209).
At least an equimolar amount, preferably an equimolar to 5 times the molar amount
Good to use. The reaction is usually carried out at a temperature of about 0 to 70°C.
The temperature is preferably 0°C to around room temperature, and
Generally, the reaction is completed in about 0.5 to 12 hours. Compound of general formula (14) and compound of general formula (15)
Reaction with and compound of general formula (16) and general formula
The reaction with the compound of (17) is the reaction of the above general formula (209).
Similar to the reaction between the compound and the compound of general formula (13)
It can be done under certain conditions. The compound of general formula (210) is the compound of general formula (18)
It is produced from the compound by the method shown below. first
R in the compound of general formula (18)¹⁵is phenyl lower alkyl
Kyl group, lower alkyl group or lower alkoxy lower
In the case of a compound that is an alkyl group, the compound is
A suitable solvent such as water, methanol, ethanol
lower alcohols such as alcohol, isopropanol,
Ethers such as oxane and tetrahydrofuran,
In a solvent such as acetic acid or a mixed solvent of these, paradi
Catalytic reduction catalysts such as aluminum-carbon and palladium-black
In the presence of hydrogen pressure of 1 to 10 atmospheres at around 0 to 100℃
Treat under pressure for about 0.5 to 3 hours or with hydrogen bromide.
Acids, acids such as hydrochloric acid and water, methanol, ethanol,
In a mixture with a solvent such as isopropanol, from 30 to
Heat treatment at 150℃, preferably 50-120℃
can lead to the compound of general formula (210).
Wear. Next, R in the compound of general formula (18)¹⁵is a lower grade
Lucanoyl group, tetrahydropyranyl group or ben
In the case of a compound that is a zoyl group, the compound is
The compound of general formula (210) can be prepared by water decomposition.
Obtainable. This hydrolysis is carried out in a suitable solvent.
It is carried out in the presence of an acid or basic compound. melt
Examples of the medium include water, methanol, ethanol,
Lower alcohols such as isopropanol, dioxin
Ethers such as San, tetrahydrofuran, etc.
For example, mixed solvents such as these can be mentioned. as an acid
For example, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, etc.
Examples of basic compounds include sodium hydroxide.
metals such as aluminum, potassium hydroxide, calcium hydroxide, etc.
Hydroxides and the like can be mentioned. Applicable
The temperature is usually room temperature to 150℃, preferably 80 to 120℃.
It progresses smoothly and generally finishes in about 1 to 15 hours.
Ru. [R in the formula³,R^Four,R^Fiveand X are the same as above. R¹⁶teeth
Indicates a lower alkyl group. ] Compound of general formula (210) and compound of general formula (19)
The reaction with a substance is carried out without a solvent or in the presence of a solvent.
It will be done. The solvent used here has no effect on the reaction.
Any solvent may be used as long as it does not cause any
For example, chloroform, dichloromethane, carbon tetrachloride
halogenated hydrocarbons such as benzene, toluene
xylene, nitrobenzene, dichlorobenzene
Examples include aromatic hydrocarbons such as carbon. general formula
The amount of compound (19) to be used is usually determined by the general formula
(201) at least equimolar, preferably
More preferably, the amount is equivalent to 1.5 times the molar amount. anti
The temperature is usually -50 to 50℃, preferably -10 to 10℃.
It progresses quickly and generally takes about 15 minutes to 19 hours.
The reaction is complete. For the reduction reaction of the compound of general formula (211), iron,
Metals such as zinc, tin or stannous chloride and acetic acid, salts
Method using acids such as acid, sulfuric acid, or aluminum hydride
sodium lithium, sodium borohydride, dibo
A method using a hydrogenation reducing agent such as Ran, etc. may be adopted.
I can do it. When using the method of
Using a large excess amount, the metal is used in a small amount relative to the compound (211).
It is best to use at least an equimolar amount, usually a large excess.
stomach. This reaction is usually carried out at -50 to 150°C, preferably
It is carried out at room temperature to around 100℃, and generally from 0.5 to 10 o'clock.
It will be completed in about an hour. If another method is adopted
In this case, the general formula (5) in the above reaction scheme-3 is converted to
Reaction conditions similar to those for compound reduction can be adopted.
Wear. Compound of general formula (212) and compound of general formula (20)
The reaction with a solvent is carried out in the presence of a dehydrohalogenating agent.
It is done inside. Solvents used here and desorption
As the hydrogen halide agent, the above reaction scheme-5
The compound of general formula (102) and carboxylic acid halide
Solvents and dehalogenation used in reactions with lides
Hydrogenation agents can be used. The reaction is usually −50 to
It is carried out at 100℃, preferably around -50 to 30℃,
Generally, the reaction is completed in about 30 minutes to 5 hours. one
The amount of the compound of general formula (20) to be used is
(212) at least equimolar, preferably
More preferably, the amount is equimolar to 1.2 times the molar amount. [R in the formula³,R^Four,R^Fiveand X are the same as above. ] Compound of general formula (211) and compound of general formula (21)
The reaction with substances is dehalogenation without solvent or in a solvent.
It is carried out in the presence of a hydrogen agent. Solvent and dehalogenation
As the hydrogenation agent, in the above reaction scheme-5,
Compound of general formula (102) and carboxylic acid halide
Solvents and dehydrohalogenation used in the reaction with
Any agent can be used. Piperidine (21) is
For compounds of general formula (211), usually at least
Used in an equimolar amount, preferably an equimolar to 2 times the molar amount.
Ru. In addition, the dehydrohalogenation agent has the general formula (211)
Usually at least equimolar, preferably at least equimolar to the compound
It is used in equimolar to 1.5 times the molar amount. The reaction is
Usually -30~150℃, preferably around -20~100℃
It is generally completed in about 0.5 to 24 hours. [R in the formula³,R^Four,R^Fiveand X are the same as above. ] Compound of general formula (201) and compound of general formula (22)
Reactions with substances can be carried out without a solvent or in the presence of a catalyst in a solvent.
It is done. The solvent used here is
Any solvent may be used as long as it does not affect the
For example, chloroform, dichloromethane, tetrasalt
Halogenated hydrocarbons such as hydrogenated carbon, benzene, and
Luene, xylene, nitrobenzene, dichlorobenzene
Examples include aromatic hydrocarbons such as carbon dioxide, carbon disulfide, etc.
can be shown. Catalysts used include, for example, chloride
Aluminum, zinc chloride, iron chloride, tin chloride, three odors
Lewis acids such as boron chloride, boron trifluoride, and concentrated sulfuric acid are listed.
It will be done. The amount of Lewis acid used can be determined appropriately.
Good, but 2 to 6 times more powerful than the normal compound (201).
The amount is preferably about 2 to 4 times the mole.
The amount of compound (22) used is usually
(201), preferably at least an equimolar amount.
Alternatively, the amount may be equal to or twice the molar amount. reaction temperature
is selected as appropriate, but is usually about 0 to 150℃, preferably
Preferably, the temperature is about 0 to 100°C. the reaction
Generally, the process is completed in about 0.5 to 10 hours. The object obtained in each step is generally
It can be easily isolated and purified by conventional separation means.
Wear. Examples of the separation means include solvent extraction, dilute
dilution method, recrystallization method, column chromatography,
Examples of reparative thin layer chromatography, etc.
Wear. Note that the compounds of the present invention naturally include optical isomers.
It is something to do. Indane derivative represented by general formula (1) of the present invention
by the action of a pharmaceutically acceptable acid.
can be easily converted into acid addition salts, and the present invention
It also includes acid addition salts of. In the above, as an acid
For example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc.
inorganic acids, acetic acid, oxalic acid, succinic acid, maleic acid
acids, fumaric acid, malic acid, tartaric acid, citric acid,
Organic acids such as malonic acid, methanesulfonic acid, and benzoic acid
Acid can be used. In the above general formula (1), R¹The base indicated by
A preferred group is an alkylamino group having 1 to 6 carbon atoms.
or an amino group, and a particularly preferable group is an amino group.
It is. R²Preferred groups among the groups represented by are hydrogen atoms,
Alkyl group having 1 to 6 carbon atoms, halogen atom or
A particularly preferred group is a tro group having 1 to 6 carbon atoms.
It is an alkyl group. R³Preferred groups among the groups represented by are hydrogen atoms,
An alkyl group having 1 to 6 carbon atoms or a halogen atom
A particularly preferred group is an alkyl group having 1 to 6 carbon atoms.
It is. R^Fourand R^FiveAmong the groups represented by, preferred groups are co-
is a hydrogen atom or a methyl group, and a particularly preferred group is
are both hydrogen atoms. The above preferred group R²and R³are both charcoal
When it is an alkyl group with a prime number of 1 to 6, the following
is even more preferable. That is, R²and R³one of which is an alkali having 1 to 6 carbon atoms
Kyl 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 R²and R³both have carbon numbers
2-6 alkyl group (preferably 3-6 carbon atoms)
branched alkyl group). In this
The most preferred is R²and R³one side is 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 R²and R³one side is ethyl
group, and the other is an alkyl group having 2 to 6 carbon atoms (preferably
or a branched alkyl group having 3 to 6 carbon atoms).
Ru. The above-mentioned branched alkyl group having 3 to 6 carbon atoms and
is preferably isopropyl, 2-methylpropyl
Lopyl, 1-methylpropyl, 1,1-dimethyl
Examples include propyl group. The compounds of the present invention are usually in the form of common pharmaceutical preparations.
used in The formulation contains the commonly used fillers and
Quantifying agent, binder, wetting agent, disintegrant, surfactant, lubricant
It is prepared using diluents such as thickeners or excipients.
Ru. This pharmaceutical preparation comes in various forms for therapeutic purposes.
A typical example is a lock.
tablets, pills, powders, solutions, suspensions, emulsions, granules,
Capsules, suppositories, injections (liquids, suspensions, etc.),
Examples include ointments. When forming into tablet form
As a carrier, a wide range of carriers known in this field are used.
For example, lactose, white sugar, sodium chloride,
Glucose, urea, starch, calcium carbonate, carbonate
Excipients such as Olin, crystalline cellulose, silicic acid,
Water, ethanol, propanol, simple syrup, alcohol
Dose solution, starch solution, gelatin solution, carboxylic acid
dimethylcellulose, shellac, methylcellulose
potassium phosphate, polyvinylpyrrolidone, etc.
binder, dry starch, sodium alginate,
Agar powder, Laminaran powder, Sodium bicarbonate
calcium carbonate, polyoxyethylene sorbate
Tan fatty acid esters, sodium lauriul sulfate
milk, stearic acid monoglyceride, starch, milk
Disintegrants such as sugar, white sugar, stearin, cocoa butter
-, disintegration inhibitor for hydrogenated oil, etc., quaternary ammonia
Promotion of absorption of sodium base, sodium lauryl sulfate, etc.
humectants such as glycerin, starch, starch
lactose, kaolin, bentonite, colloidal
Adsorbents such as silicic acid, purification tanks, stearic acid
Lubricants such as salt, boric acid powder, polyethylene glycol, etc.
Examples include agents. Additionally tablets are usually given as needed.
Tablets with a coating such as sugar-coated tablets, gelatin-coated tablets,
Packed tablets, enteric-coated tablets, film-coated tablets, or
can be double-layered or multi-layered. pill form
When molding into a shape, a conventionally known carrier is used as a carrier.
can be used widely, such as glucose, lactose, and
Punch, cocoa butter, hydrogenated vegetable oil, kaolin, tar
excipients such as gum arabic powder, tragacanth powder,
Binders such as gelatin and ethanol, lamina ranka
Examples include disintegrants such as chlorine and the like. In the form of suppositories
When molding, conventionally known carriers are used.
can be widely used, e.g. polyethylene glycol
Cocoa butter, higher alcohol, higher alcohol
esters, gelatin, semi-synthetic glyceride sugars
can be mentioned. Prepared as an injection
In cases where solutions and suspensions are sterile and
These solutions, emulsions and
When molding into a suspension form, a diluent and
and all those commonly used in this field.
For example, water, ethyl alcohol,
Pyrene glycol, ethoxylated isostearyl
alcohol, polyoxylated isostearyl alcohol
polyoxyethylene sorbitan fatty acid ester
Examples include the following. In addition, in this case etc.
enough table salt, grapes to make a tonic solution.
Containing sugar or glycerin in pharmaceutical preparations
may also be used with the usual solubilizing agents, buffering agents, painless
A curing agent or the like may be added. Further coloring as necessary
agents, preservatives, fragrances, flavoring agents, sweeteners, etc. and other pharmaceuticals.
The product may also be included in a pharmaceutical formulation. pace
When forming into creams, gels, etc.
is a widely used diluent that is conventionally known in this field.
For example, white petrolatum, paraffin,
Glycerin, cellulose derivatives, polyethylene
Examples include recalls, silicone, bentonite, etc.
Ru. General formula (1) to be contained in the pharmaceutical formulation of the present invention
The amount of the compound is not particularly limited and can be varied over a wide range.
Appropriately selected, but usually 1 to 70% by weight in pharmaceutical preparations
It is. There are no particular restrictions on the administration method of the above pharmaceutical preparations, and each
Seed preparation form, patient age, gender and other conditions, patient
The drug is administered in a manner that depends on the severity of the problem. For example, a tablet
tablets, pills, solutions, suspensions, emulsions, granules and caps
In the case of cell preparations, it is administered orally. Also, injectables
In some cases, glucose, amino acids, etc.
It is administered intravenously by mixing with normal fluids, and also
Administer alone intramuscularly, intradermally, subcutaneously or as needed.
Administered intraperitoneally. In the case of suppositories, it is administered rectally.
It will be done. The dosage of the above pharmaceutical preparations should be determined based on the usage, age and sex of the patient.
Select as appropriate depending on other conditions, severity of disease, etc.
However, the compound of general formula (1), which is usually the active ingredient,
The amount should be approximately 0.2 to 200 mg per 1 kg of body weight per day.
It is better to Example Below are reference examples, examples, pharmacological tests, and formulation examples.
Raise it. Reference example 1 4-Methyl-7-hydroxy-1-indanone
39.3g and N-hydroxymethyl-α-chloroa
While cooling, add 280ml of concentrated sulfuric acid to 30g of cetamide and dissolve.
do. After standing overnight, the reaction mixture was poured into ice,
Collect the precipitated crystals. Recrystallize from ethanol 4
-Methyl-6-α-chloroacetylaminomethyl
49 g of -7-hydroxy-1-indanone are obtained. colorless needle crystals mp 166~167.5℃ Reference example 2 4-Methyl-7-hydroxy-1-indanone
To a 250 ml solution of 25.6 g of acetic acid, add 19.4 ml of acetic anhydride and concentrated
Gradually add a solution of 15.4 ml of sulfuric acid and 50 ml of acetic acid. reaction
The mixture was concentrated to dryness and the residue was washed with ether.
4-methyl-6-nitro-7-hydroxy-1-
You get 25.7g of indanone. mp 154~157℃ yellow needles Reference example 3 4-methyl-6-nitro-7-hydroxy-1
- 26g of indanone dissolved in 50ml of dimethylformamide
Add 2.6g of 10% Pd-C to the solution and heat at normal pressure 0℃ to room temperature.
Perform catalytic reduction. Remove the catalyst and distill off the solvent
4-methyl-6-amino-7-hydroxy-1
- Obtains 17.3 g of indanone. mp 187-188℃ (decomposition) pale yellow needles Reference example 4 4-Methyl-6-α-chloroacetylaminomethane
3g of thyl-7-hydroxy-1-indanone and
Heat reflux a solution of 30 ml of concentrated hydrochloric acid and 60 ml of ethanol for 8 hours.
Flow. The solvent was distilled off, and the resulting residue was diluted with ethanol.
4-methyl-6-aminomethyl
1 g of -7-hydroxy-1-indanone is obtained. mp 300℃ or more pale yellow scaly crystals 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, 1H), 8.4~9.5 (br., 3H) Reference example 5 4-methyl-6-nitro-7-hydroxy-1
- 5% Pd in a solution of 11.5 g of indanone in 500 ml of acetic acid.
- Add 1.5g of C and perform catalytic reduction at room temperature and normal pressure.
cormorant. Remove the catalyst, distill off the solvent and wash with ether.
do. Recrystallized from methanol to give 4-methyl-6
-acetamido-7-hydroxy-1-indanone
Get 6.34g. mp 193~198℃ red-orange needles NMR (DMSO) δ; 2.1 (s, 3H), 2.17 (s, 3H), 2.45~2.77 (m, 2H) 2.77~3.1 (m, 2H), 7.67 (s, 1H), 9.25~10.0 (br., 2H) Reference example 6 4-Methyl-7-hydroxy-1-indanone
650 ml of methanol with 36 g and 17.6 g of potassium hydroxide
Add 25ml of allyl bromide to the solution and heat for 6 hours.
Reflux. Insoluble matter is removed and the solvent is distilled off. nine
Extract with loloform-water and separate the chloroform layer
and evaporate the solvent. Wash the residue with ether and
Purified by column chromatography to obtain 4-methyl
Obtained 32g of L-7-allyloxy-1-indanone.
Ru. mp 89~92℃ Pale yellow powder crystal Reference example 7 4-methyl-7-allyloxy-1-indano
Suspend 32 g of chlorine in 100 ml of tetralin and place in an argon atmosphere.
Heat under reflux for 4 hours under ambient air. The reaction solution is silica
Gel column chromatography (eluent; n-he
Xane → dichloromethane: n-hexane = 1:
2) to obtain 4-methyl-6-allyl-7-
26.8 g of hydroxy-1-indanone are obtained. mp 41~45℃ Light brown needle crystals Reference example 8 4-Methyl-7-hydroxy-1-indanone
Dissolve 10g and 5.3g of potassium hydroxide in 200ml of methanol.
Add 8.2ml of crotyl bromide to the solution and heat for 4 hours.
Heat reflux. Insoluble matter is removed and the solvent is distilled off.
Extract with chloroform-water and dilute the chloroform layer.
After cleaning with sodium hydroxide solution, rinse with water, and then rinse with water.
After drying over magnesium sulfate, the solvent was distilled off. Residue
The residue was subjected to silica gel column chromatography (elution
liquid; n-hexane-dichloromethane = 1:1)
and purified to give 4-methyl-7-crotyloxy-1
- Obtain 8.72 g of indanone. mp 87.5~92℃ pale yellow needles Reference example 9 4-Methyl-7-crotyloxy-1-inda
Suspend 8g of non-alcoholic acid in 50ml of tetralin and place in an argon atmosphere.
Heat under reflux for 9 hours under ambient air. The reaction solution is silica
Gel column chromatography (eluent; n-he
Xane → n-hexane: dichloromethane = 2:
1) and further dichloromethane-n-hexyl
4-Methyl-6-(1-methyl
Obtained 5.44 g of (2-propenyl)-1-indanone.
Ru. mp 88~92℃ colorless needle crystals Using appropriate starting materials, the above-mentioned Reference Example 8 or 9
In the same manner, the compounds listed in Table 1 below are obtained. 【formula】 【table】 Reference example 14 4-Methyl-7-hydroxy-1-indanone
15g and 7.95g potassium hydroxide 200ml methanol
Add 13.55 ml of metaallyl chloride to the solution, and at 11 o'clock
Reduce by heating for a while. Remove insoluble materials and distill off the solvent
Ru. Silica gel column chromatography of the residue
(Eluent; n-hexane: dichloromethane = 1:
1) to obtain 4-methyl-7-methallylox.
9 g of C-1-indanone are obtained. mp 74.2~75.2℃ colorless powder crystal Reference example 15 4-Methyl-7-methallyloxy-1-yne
Add 8.46g of Danone to 50ml of Tetralin and heat for 9 hours.
Heat reflux. Transfer the reaction solution to a silica gel column chroma
tographie (eluent; n-hexane: dichloro
Purify with methane = 2:1) and further dichloromethane
- Recrystallized from hexane to give 4-methyl-6-
(2-methyl-2-propenyl)-7-hydroxy
-1-Indanone 6.68g is obtained. mp 62.5~64℃ colorless needle crystals Reference example 16 A solution of 90 ml of chlorosulfonic acid in 150 ml of carbon tetrachloride
Then, under ice cooling, 7-hydroxy-4-methyl-1-
Add 30g of indanone little by little. carbon tetrachloride layer
Remove, add ice water from step 1 to the remaining layer, and stir vigorously.
Ru. The precipitated solid was taken and washed with water to remove 7-hydroxy
C-6-chlorosulfonyl-4-methyl-1-y
Get Danone 8.7g. Don't refine this thing
31.4g of stannous chloride dihydrate and 100ml of concentrated hydrochloric acid
and stirred at room temperature for 4 hours.
Pour the reaction solution into 500ml of ice water and remove the precipitated crystals.
7-Hydroxy-6-mer
Take 7.86g of capto-4-methyl-1-indanone.
Ru. This material is then converted into methane without purification.
Suspend in 100 ml of water and add 3.9 ml of methyl iodide to this.
Add a solution of 5.1 g of baking soda in 20 ml of water and leave at room temperature for 1 hour.
Stir. The solvent is concentrated to dryness under reduced pressure. Remove residue
Kagel column chromatography (eluent; chromatography)
After purification with roform), recrystallized from ethanol.
7-hydroxy-4-methyl-6-methylthio
1.52 g of -1-indanone is obtained. mp 139℃ colorless needle crystals Reference example 17 7-hydroxy-4-methyl-1-indanone
1-Piperidine in a solution of 2 g in 10 ml of dichloroethane
Add 2.27g of sulfonyl chloride and remove the anhydrous salt at room temperature.
Add 10g of aluminum chloride little by little and stir.
After heating under reflux for 8 hours, extract with 200 ml of chloroform,
After washing with water, chloroform is distilled off under reduced pressure. Remove residue
Kagel column chromatography (eluent; chromatography)
After purification with roform), it was recrystallized from ethanol.
7-hydroxy-4-methyl-6-(1-piperi
1.24 g of (dinsulfonyl)-1-indanone are obtained. mp 188~189℃ pale yellow plate crystals Reference example 18 4,6-dimethyl-7-methoxymethyleneoxy
C-1-indanone 7.56g dimethylformamide
4.94g of 60% sodium hydride in 200ml solution at room temperature
Add it little by little until no hydrogen is generated (approximately
Stir for 1 hour). Then add 14.6g of methyl iodide.
Add and stir for an additional 2 hours at room temperature. into the reaction mixture
After making it acidic by adding hydrochloric acid, the solvent was concentrated under reduced pressure.
Under vigorous stirring, pour the resulting residue into 1 liter of water;
Extract twice with 300 ml of ethyl acetate. Water washing, anhydrous sulfur
After drying with magnesium chloride, the solvent was distilled off under reduced pressure to give 7
-methoxymethyleneoxy-2,2,4,6-te
8 g of tramethyl-1-indanone are obtained. This too
Dissolve in 200ml of methanol without purification.
Then, 10ml of concentrated hydrochloric acid was added and stirred at 50℃ for 3 hours.
Afterwards, methanol is distilled off under reduced pressure. Silicage the residue
column chromatography (eluent; n-hex
Purified with san: dichloromethane = 2:1) and 7
-hydroxy-2,2,4,6-tetramethyl-
6.8 g of 1-indanone is obtained. mp 28~30℃ NMR (CDCl)₃)δ; 9.08 (1H, s) 7.19 (1H, s) 2.84 (2H, s) 2.23 (3H, s) 2.20 (3H, s) 1.28 (6H, s) Example 1 Hydroxylamine hydrochloride 28g and potassium carbonate
Add 56g of methanol to 400ml of methanol and heat under reflux for 30 minutes.
do. After cooling, separate the supernatant and add hydroxyl
Prepare a methanol solution. This hydroxy
7-hydroxy-4-
Add 16.2g of methyl-1-indanone and stir.
Heat to reflux for 5 hours. Concentrate the reaction mixture under reduced pressure.
Dry. Add 200ml of ethyl acetate to the residue to make it insoluble.
leave things behind The liquid was concentrated to dryness under reduced pressure, and the residue
was recrystallized from methanol to obtain colorless needle-like 7-hyalurine crystals.
Droxy-4-methyl-1-indanone oxime
Get 17.6g. mp 148~149.5℃ Proceed as in Example 1 using appropriate starting materials.
The compounds listed in Table 2 below are obtained. 【formula】 【table】 【table】 Example 14 7-hydroxy-4-methyl-1-indanone
Dissolve 15.0g of oxime in 200ml of acetic acid, and dissolve platinum oxide.
Add 1.0g of catalyst and leave at room temperature for 8 hours under 5 atmospheres of hydrogen pressure.
Contact reduction. After separating the catalyst, the liquid was removed under reduced pressure.
Concentrate to dryness. Add 200ml of ethanol to the residue
Dissolve and saturate by blowing in hydrochloric acid gas. under reduced pressure
Concentrate the solvent to dryness and recrystallize the residue from ethanol.
and colorless needle-like crystals of 1-amino-7-hydroxy-
3.30 g of 4-methylindane hydrochloride are obtained. mp 221~223℃ Proceed as in Example 14 using appropriate starting materials.
The compounds listed in Table 3 below are obtained. 【table】 【table】 Example 30 1-amino-7-hydroxy-4-methylin
Dissolve 1 g of Dan hydrochloride in 20 ml of water and boil at room temperature.
3N salt containing 0.85g of iodine monochloride while stirring thoroughly.
Add 5 ml of acid solution dropwise. Stirred at the same temperature for 2 hours
Then cool on ice. Take the precipitated crystals and convert them into hydrochloride,
Then wash with ether and dry. yellow needles
1-amino-7-hydroxy-6-iodo-4
- Obtain 0.70 g of methylindane hydrochloride. mp Decomposes above 200℃ Example 31 1-Amino-7-hydroxyindan hydrochloride
Dissolve 1.0g in 60ml of acetic acid and sulfurize under ice-cooling with stirring.
Drop 1.53 g of luchloride. 3 hours at the same temperature
After stirring, concentrate under reduced pressure. The residue is saturated with hydrochloric acid gas.
After dissolving in 50ml of Japanese ethanol, dry under reduced pressure.
Ru. Recrystallized from isopropanol-ether
Colorless prismatic crystals of 1-amino-4,6-dichloro
0.43 of -7-hydroxyindan hydrochloride is obtained. mp 238-239℃ (decomposition) Example 32 1-amino-7-hydroxy-4-methylin
Dissolve 5 g of Dan in 30 ml of acetic acid, and add 1.73 ml of bromine to this.
Add acetic acid solution and stir at room temperature for 1 hour. precipitation
Collect the crystals and recrystallize from isopropanol to obtain 1
-amino-6-bromo-7-hydroxy-4-methane
Obtain 2 g of tilindane hydrobromide. NMR
Determine the structure. mp 178-190℃ (decomposition) yellow needles 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 33 1-amino-7-hydroxy-4-methylin
Suspend 5.75 g of Dan hydrochloride in 40 ml of acetic acid, and add
10ml acetic acid solution of 3.27ml acetic anhydride and 2.59ml concentrated nitric acid
and stirred at room temperature for 6 hours. Distill the solvent,
After washing the residue with acetone, recrystallize from ethanol.
and 1-amino-7-hydroxy-4-methyl-
2 g of 6-nitroindane hydrochloride is obtained. mp 200-230℃ (decomposition) yellow needles NMR (DMSO) δ; 2.22 (s, 3H) 2.0~3.45 (m, 4H) 4.7~5.0 (m, 1H) 7.82 (s, 1H) 8.4~9.7 (br., 3H) Example 34 1-Amino-4,6-dimethyl-7-hydroxy
1.77g of Ciindane in 0.2N aqueous sodium hydroxide solution
Dissolve in 100 ml and then add α-chloroa while stirring on ice.
Add 1.7g of cetyl chloride. Then at room temperature 2
Stir for an hour. After the reaction, acidify with dilute hydrochloric acid and cool.
Extract with loloform. After washing and drying, remove the solvent.
To leave. Recrystallized from ethanol to give 2.34g of 1
-acetylamino-4,6-dimethyl-7-hydro
Obtain 2.34g of roxyindan. mp 131~132℃ colorless needle crystals Proceed as in Example 34 using appropriate starting materials.
The compounds listed in Table 4 below are obtained. 【table】 Example 38 1-Amino-4,6-dimethyl-7-hydroxy
1.77 g of cyindane and 2 ml of triethylamine 100
1.72g methane at room temperature in ml chloroform solution
Add sulfonyl chloride dropwise. Then the same temperature
Stir for 4 hours. The reaction mixture was diluted with dilute hydrochloric acid, water,
Saturated sodium bicarbonate water, water, then saturated saline
After washing, dry with sodium sulfate. Distill the solvent
The residue was recrystallized from ether-n-hexane.
1-methanesulfonylamino-4,6-dimethy
0.58 g of ru-7-hydroxyindan is obtained. mp 114~116℃ Colorless powder Proceed as in Example 38 using appropriate starting materials.
The compounds listed in Table 5 below are obtained. 【table】 【table】 Example 51 4,6-dimethyl-7-hydroxy-1-yne
100ml of Danone 1.76g and n-butylamine 14.6g
Heat the ethanol solution to reflux for 8 hours. to room temperature
After cooling, add 1g of sodium borohydride and
Stir at room temperature for 1 hour. Concentrate the reaction mixture to dryness.
Then, add 100ml of water to the residue and dissolve. with concentrated hydrochloric acid
Acidified and then with saturated aqueous sodium acetate solution
Adjust the pH to 9. The obtained precipitate was dissolved in ethyl acetate.
Extract with water, wash with water, and dry. The solvent was distilled off and the obtained
Dissolve the residue in 100ml of ethanol and add hydrochloric acid gas.
Make the hydrochloride with saturated ethanol. ethanol
-1-n-butylamino after recrystallization from ether
-4,6-dimethyl-7-hydroxyindan
Obtain 1.89 g of hydrochloride. mp 143~144℃ colorless needle crystals Proceed as in Example 51 using appropriate starting materials.
The compounds listed in Table 6 below are obtained. 【table】 【table】 Example 64 1-amino-7-hydroxy-4,6-dimethy
Leindan 1.77g and 3,5-di-tert-butylene
-4-Hydroxybenzaldehyde 2.57g
Stir the 50 ml solution of tanol at room temperature for 2 hours. So
After that, add sodium borohydride to the reaction solution under ice cooling.
Add the solution little by little. After stirring at room temperature for 2 hours,
The reaction solution is made acidic with hydrochloric acid, and the solvent is dried under reduced pressure. residue
Add 100ml of water and add sodium acetate aqueous solution.
Adjust the pH to 8 and extract with 100 ml of ethyl acetate. water
After washing, dry with anhydrous magnesium sulfate to reduce the solvent.
Distill under pressure. Dissolve the residue in 50 ml of ethanol and add salt
Add acid gas saturated ethanol to adjust pH≒3
and dry the solvent under reduced pressure again.
Recrystallized from xane to give 1-(3,5-di-tert-
Butyl-4-hydroxybenzyl)amino-4,
0.77g of 6-dimethyl-7-hydroxyindan
obtain. mp 154~155℃ colorless needle crystals Proceed as in Example 64 using appropriate starting materials.
The compounds of Examples 40, 41 and 43 to 50 are obtained. Example 65 1-amino-4-methyl-6-α-chloroacetate
5g of thylaminomethyl-7-hydroxyindan
and a solution of 50 ml of concentrated hydrochloric acid in 100 ml of ethanol for 8 hours.
Heat to reflux. Distill the solvent and wash with ethanol
do. Recrystallized from methanol-ether to give 1-
Amino-4-methyl-6-aminomethyl-7-h
Obtain 1 g of droxyindan dihydrochloride. mp220℃ (decomposition) Colorless powder Example 66 7-hydroxy-4-methyl-6-t-butyl
-1-Indanone oxime 19.7g dissolved in 200ml acetic acid
Add 1.0g of platinum oxide catalyst and increase the hydrogen pressure to 5 atm.
Catalytic reduction was carried out for 8 hours at room temperature, with the catalyst separated.
Afterwards, the liquid is concentrated to dryness under reduced pressure. Ethanol in the residue
Add 200ml of the solution and dissolve, then blow in hydrochloric acid gas to saturate.
sum up Concentrate the solvent to dryness under reduced pressure, then evaporate
Recrystallized from alcohol to form colorless powder 1-amino-
7-hydroxy-4-methyl-6-t-butyl-
2.2 g of 1-indane hydrochloride is obtained. mp 221-224℃ (decomposition) Elemental analysis value (C₁₄H_{twenty one}NO・HCl) C H N Calculated value (%) 65.74 8.28 5.48 Actual value (%) 65.59 8.15 5.59 Example 67 7-hydroxy-4,6-di-t-butyl-1
−23.2 g of indanone oxime was dissolved in 200 ml of acetic acid.
Add 1.0g of platinum oxide catalyst and heat at 5 atmospheres of hydrogen pressure.
Catalytic reduction for 8 hours at room temperature, after separating the catalyst,
The liquid was concentrated to dryness under reduced pressure. Ethanol to the residue
Add 200ml and dissolve, then blow in hydrochloric acid gas to saturate.
Ru. Concentrate the solvent to dryness under reduced pressure, and then add ethanol.
1-amino-7- as a colorless powder.
Hydroxy-4,6-di-t-butyl-1-yne
Obtain 18.8g of Dan hydrochloride. Elemental analysis value (C₁₇H₂₇NO・HCl) C H N Calculated value (%) 68.55 9.14 4.70 Actual value (%) 68.43 9.21 4.61 mp 225~226.5℃ Pharmacological testing Next, perform the following pharmacological tests using the test compound.
Ivy. Test compound no. 1:4,6-dimethyl-7-hydroxy-1-y
danone oxime 2:1-amino-7-hydroxy-4-methyl
Ndan hydrochloride 3:1-amino-7-hydroxy-4,6-dime
Chilindan hydrochloride 4:1-amino-7-hydroxy-4-methyl-
6-iodoindane hydrochloride 5: 1-amino-7-hydroxy-4,6-dichloromethane
Roloindane hydrochloride 6:1-methylamino-4,6-dimethyl-7-
Hydroxyindane hydrochloride 7:1-amino-2,2,4,6-tetramethyl
-7-hydroxyindan hydrochloride 8:1-amino-4-methyl-6-sec-butyl
-7-hydroxyindan hydrochloride 9:1-amino-4-methyl-6-iso-butyl
-7-hydroxyindan hydrochloride 10:1-amino-4-methyl-6-n-propyl
-7-hydroxyindan hydrochloride 11:1-n-butylamino-4,6-dimethyl-
7-Hydroxyindane hydrochloride 12:1-amino-4-methyl-6-bromo-7-
Hydroxyindane hydrobromide 13:1-amino-4-methyl-6-nitro-7-
Hydroxyindane hydrochloride 14:1-amino-6-n-propyl-7-hydro
Xiindane hydrochloride 15:1-methylamino-4-methyl-6-methyl
Thio-7-hydroxyindan hydrochloride 16:1-methylamino-4-ethyl-6-(1-
Methyl-2-propenyl)-7-hydroxy
Indane hydrochloride 17:1-amino-4-ethyl-6-n-propyl
-7-hydroxyindan hydrochloride 18:1-methylamino-4-ethyl-6-methyl
-7-hydroxyindan hydrochloride 19:1-methylamino-4-methyl-6-ethyl
-7-hydroxyindan hydrochloride 20:1-amino-4-ethyl-6-sec-butyl
-7-hydroxyindan hydrochloride 21:1-methylamino-4-ethyl-6-allyl
-7-hydroxyindan hydrochloride (A) Anti-carrageenan edema effect test Using male Wistar rats weighing around 150g.
5 animals per group, fasted for 18 hours, then fed for 1 hour.
After administration, the test compound was administered orally at a concentration of 100ml/Kg.
Administer. One hour after administration, apply 1% to the left heel subcutaneously.
Left side 3 hours after injecting 0.1ml of lagenin/rat
Measure the lateral hindlimb volume. The edema rate was determined by carrageenan treatment.
It is determined by the volume doubling rate for the hindlimb volume before placement, and the control
The inhibition rate was determined from the average edema rate of the group and the test compound administration group.
calculate. The results are shown in Table 7. 【table】 (B) Antioxygen deficiency effect Arch.int.Pharmacodyn.
233, 137 (1978). ICR male mice (body weight 20-30 g) were used.
Place four mice at a time in a glass desiccator, suck out air with a vacuum pump until the internal pressure reaches 210 or 240 mmHg, and close the container. 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 defined as 30 minutes or 15 minutes, respectively. Table 8 shows the test results under an internal pressure of 210 mmHg, and Table 9 shows the test results under an internal pressure of 240 mmHg. [Table] [Table] [Table] [Table] [Table] [Table] As is clear from Tables 8 and 9 above, the indane derivatives of the present invention significantly prolong the lethal time under oxygen-deficient conditions. , an improvement effect on oxygen-deficient conditions was observed. (C) Antioxidant effect It is well known that Luminol is a luminescent test in which hydrogen peroxide produces strong luminescence 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 due to its antioxidant properties. It is recognized that compounds with similar antioxidant ability can similarly reduce blood peroxidized lipids. The test method is as follows. (1) Test method Prepare a methanol solution containing the test compound at a concentration of 1 to 1 x 10 ^-6 mg/ml and linoleic acid hydroperoxide at a concentration of 1.0 x 10 ^-9 mol/ml (hereinafter referred to as the test solution). . In addition, a 0.1M sodium carbonate buffer containing 1×10 ⁻⁴ M luminol and a 0.1M sodium carbonate buffer containing FCS (fetal bovine serum, manufactured by Gibco) at a concentration of 1.25×10 ⁻⁶ g/ml are prepared. These prepared solutions were automatically inhaled and mixed in 0.4ml portions in the order of test solution, FCS solution, and luminol solution using the flow system shown in Figure 1. After mixing the final luminol solution, a photo counter (R649S) was used for 1 second. : Hamamatsu Photonics Co., Ltd.) to measure the amount of luminescence. In Fig. 1, 1 is the photo counter, 2 is the cell, 3 is the mixer, 4 is the test solution, 5 is the luminescent reagent (luminol solution), 6 is the catalyst (FCS solution), and 7 is the wash. 8 represents a syringe, 9 represents a drain, and 10 represents a valve. Using the test compounds shown above at predetermined concentrations, the results of measuring the amount of luminescence at each concentration are shown in the 10th test.
Shown in the table. Each luminescence amount was calculated as a percentage (%) with respect to the luminescence amount when the above-mentioned test solution containing no test compound was used as 1 according to the following formula, and the value was shown as the value. Luminescence amount = C-B/A-B x 100 (%) Count number B when no test compound is added and lipid peroxide is added: Count number C when neither test compound nor lipid peroxide is added: Number of counts when both test compound and lipid peroxide are added [Table] (2) In addition, in the same test as above, linoleic acid hydroperoxide 1 x 10 ^-9 mol/ml of 50μ
Table 11 below shows the results of determining the 50% inhibition rate (that is, the concentration of each test compound that inhibits the oxidation ability of the peroxide by 50%, the antioxidant ability IL ₅₀ ) for each test compound. [Table] From Tables 10 and 11 above, it can be seen that the indane derivatives of the present invention all have strong antioxidant ability. Furthermore, each of the above compounds was found to exhibit strong activity in vivo as well as BHT 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) Experiments were conducted with 30 mice per group. 15 minutes after subcutaneous administration of the compound of the present invention (0.3, 1 and 3 mg/Kg)
0.4 ml/10 g body weight of 50% (W/Vsaline) glucose was administered intraperitoneally, and the survival rate of the mice was then determined at 1.5, 3, and 24 hours. To determine the drug effect on survival rate, a two-tailed test was performed using the method of Fischer. The results are shown in Table 12. [Table] (E) Effect on consciousness disorder after head trauma in mice It was investigated whether the compounds of the present invention have an effect on consciousness disorder produced by applying a shock to the head of mice. The neck skin of the mouse was grasped and the head was fixed on a 2 cm thick styrofoam pillow. An acrylic cylindrical rod (20 g) was placed against 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 the righting reflex (RP time) and the time until the onset of spontaneous movement (SM time) were used as indicators of consciousness disturbance. The test compound was applied at a rate of 0.1 ml per 15 minutes of impact.
It was administered subcutaneously in a volume of 10 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. The numbers in parentheses in the table are the number of mice. [Table] [Table] Formulation example 1 7-hydroxy-4-methyl-1-indanoxime 200 mg Glucose 250 mg Distilled water for injection Appropriate total amount 5 ml After dissolving the compound of the present invention and glucose in distilled water for injection, prepare a 5 ml ampoule. After replacing with nitrogen, autoclave at 121°C for 15 minutes to obtain an injection solution with the above composition. Formulation example 2 1-Amino-7-hydroxy-4-methylindane hydrochloride 100g Avicel (trade name, manufactured by Asahi Kasei Co., Ltd.) 40g Cornstarch 30g Magnesium stearate 2g TC-5 10g (trade name, Shin-Etsu Chemical Co., Ltd.) (Hydroxypropyl Methyl Cellulose) Polyethylene Glycol-6000 3g Castor oil 40g Methanol 40g The compound of the present invention, Avicel, cornstarch and magnesium stearate were mixed, polished and sugar-coated.
Compress the tablets with an R10mm kine. The obtained tablets were TC-
5. Coat with a film coating agent consisting of polyethylene glycol-6000, castor oil and methanol to produce film-coated tablets having the above composition. Formulation Example 3 1-Amino-4,6-dichloro-7-hydroxyindane hydrochloride 2g Purified lanolin 5g White beeswax 5g White petrolatum 88g Total amount 100g White beeswax is heated to make it liquid, and then the compound of the present invention and purified lanolin are added. and white petrolatum are added, heated until it becomes liquid, and stirred until it begins to set, to obtain an ointment having the above composition.

[Brief explanation of drawings]

FIG. 1 shows a flow path diagram of an apparatus for measuring the antioxidant ability of the compounds of the present invention.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ 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, a phenyl lower alkylamino group that has a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring. shows. 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-piperidine Indicates a sulfonyl group or lower alkenyl group. R ³ represents a hydrogen atom, a lower alkyl group or a halogen atom. R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group. however
When R ¹ is a hydroxyimino group, R ² and R ³
must not both be hydrogen atoms. ] An indane derivative represented by these and its salt. 2. The compound according to claim 1, wherein R ¹ is an amino group that may have a lower alkyl group. 3. The compound according to claim 2, wherein R ¹ is an amino group. 4. The compound according to claim 2 or 3, wherein R ² and R ³ are both lower alkyl groups.