JP3227616B2 - Hexahydroindeno [1,2-b] pyrrole derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel hexahydroindeno [1,2-b] pyrrole derivative.

[0002]

DISCLOSURE OF THE INVENTION Hexahydroindeno [1,2]
-B] The pyrrole derivative is a novel compound not described in any literature, and is represented by the following general formula (1).

[0003]

Embedded image

[In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. R ² , R ³ and R ⁴ are the same or different,
It represents a hydrogen atom, a hydroxyl group, a lower alkenyloxy group, a lower alkoxy group, a lower alkyl group, a halogen atom, a nitro group or a lower alkenyl group. However, when R ² represents a hydrogen atom, R ³ and R ⁴ are the same or different and must not be a hydrogen atom or a halogen atom. With the development of motarization in recent years, the number of head trauma patients due to traffic accidents and the like tends to increase. The impairment of brain function due to head trauma first appears as a coma-conscious disorder, but the degree of impairment varies depending on the degree of brain function damage. Thus, if the degree of brain function damage is mild, consciousness will soon recover, but the higher the degree of brain function damage, the slower the recovery of consciousness, and the later the recovery, the longer the prognosis will be. Bad, dementia, and in the worst case, plant humans. Therefore, it is important to improve consciousness disturbance immediately after head injury. In addition, there are cases in which elderly people exhibit dementia symptoms such as delirium and intellectual dysfunction due to consciousness disorder due to cerebrovascular disorder. In this case, prompt improvement of consciousness disorder is desired.

The present inventors have found that the novel hexahydroindeno (1,2-b) pyrrole derivative represented by the general formula (1) activates brain functions and has a strong consciousness improving action. .

The compound of the present invention has a central nervous system activating effect and a consciousness ameliorating effect, and is used for head trauma, cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, hypoxia, impaired consciousness after brain surgery, and sequelae of these. It is useful as a therapeutic agent for certain mental retardation, attention deficit, language disorder, movement disorder, decreased motivation, memory disorder, emotional disorder, etc., as well as dementia of senile dementia, delirium, language disorder, movement disorder, Useful as an agent for reducing attention. Further, the compound of the present invention is useful as an agent for improving symptoms such as hyperactivity syndrome and autism, and as an antidepressant. The compound of the present invention is characterized in that it exerts a central nervous system activating effect and a consciousness improving effect even when administered orally.

The respective groups represented by the general formula (1) are more specifically as follows.

Examples of the lower alkoxy group include straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. it can.

The lower alkyl group includes, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups.

The lower alkenyloxy group includes, for example, vinyloxy, allyloxy, 2-butenyloxy, 3
-C2-C2-butenyloxy, 1-methylallyloxy, 2-pentenyloxy, 2-hexenyloxy groups, etc.
And 6 straight-chain or branched alkenyloxy groups.

The lower alkenyl group includes, for example, straight-chain or branched alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl. Groups can be exemplified.

As the halogen atom, for example, a fluorine atom,
Examples include a chlorine atom, a bromine atom and an iodine atom.

The compound of the present invention can be produced by various methods. One preferred example is the following reaction formula-1.
Can be manufactured by the method shown in FIG.

[Reaction formula-1]

[0015]

Embedded image

Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above. R ⁵ represents a lower alkyl group. X represents a halogen atom. The reaction between compound (2) and hydroxylamine (3) can be carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of the basic compound used at this time include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, piperidine, pyridine, triethylamine, 1,5-diazabicyclo [4,3,0]. Nonen-5
Organic bases such as (DBN), 1,8-diazabicyclo [5,4,0] unthecene-7 (DBU) and 1,4-diazabicyclo [2,2,2] octane (DABCO) can be exemplified. The inert solvent used may be any solvent that does not adversely affect the reaction.Examples include lower alcohols such as methanol, ethanol, and isopropanol; dioxane, tetrahydrofuran, diethyl ether, and ethers such as ethylene glycol monomethyl ether. Benzene, toluene, aromatic hydrocarbons such as xylene, dichloromethane, dichloroethane,
Examples thereof include hydrogen halides such as chloroform and carbon tetrachloride, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like, and a mixed solvent thereof. The amount of the hydroxylamine (3) to be used is generally at least equimolar, preferably equimolar to 5 times the molar amount of the compound (2). The reaction temperature is usually from room temperature to 200 ° C, preferably from 50 to 150 ° C, and the reaction is generally completed in about 1 to 10 hours.

The reduction of compound (4) can be carried out by catalytic hydrogenation in a suitable solvent in the presence of a catalyst. Examples of the solvent used include water, alcohols such as acetic acid, methanol, ethanol, and isopropanol; hydrocarbons such as hexane and cyclohexane; ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether; ethyl acetate; and methyl acetate. And aprotic polar solvents such as dimethylformamide, or a mixed solvent thereof. Further, as the catalyst used, for example, palladium, palladium-black, palladium-carbon, platinum,
Platinum oxide, copper chromite, Raney nickel and the like are used. The amount of the catalyst to be used is generally about 0.02 to 1 times that of the compound (4). The reaction temperature is usually −20 ° C. to room temperature, preferably 0 ° C. to room temperature, and the hydrogen pressure is usually 1 to 10 atm. The reaction is generally completed in about 0.5 to 10 hours.

The reaction between compound (1a) and compound (5)
It is easily carried out in a suitable inert solvent in the presence of a dehydrohalogenating agent. The use ratio of the compound of the general formula (1a) to the compound (5) is not particularly limited and may be appropriately selected within a wide range. Usually, the latter is equimolar or more, preferably equimolar to the former. It is preferable to use a 3-fold molar amount. Examples of the dehydrohalogenating agent to be used include alkali metal atoms such as sodium and potassium, alkali metal amides such as sodium amide and potassium amide, and sodium hydride.Inert solvents such as benzene and toluene And aromatic hydrocarbons such as xylene, ethers such as tetrahydrofuran, dioxane and ethylene glycol dimethyl ether, dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoric triamide. The reaction is carried out usually at 0 to 150 ° C., preferably at 0 to 100 ° C., and is generally completed in about 1 to 12 hours. Thus, the compound represented by the general formula (1b) is obtained.

The reaction between compound (2) and compound (6) is carried out without solvent or in a suitable solvent in the absence or presence of a dehydrating agent. Examples of the solvent used herein include alcohols such as methanol, ethanol, and isopropanol; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; Examples include aprotic polar solvents such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone, and mixed solvents thereof. As the dehydrating agent, for example, a desiccant used for dehydration of a normal solvent such as molecular sieve, hydrochloric acid,
Examples thereof include mineral acids such as sulfuric acid and boron trifluoride, and organic acids such as p-toluenesulfonic acid. The reaction is carried out usually at room temperature to 250 ° C., preferably at about 50 to 200 ° C., and is completed generally in about 1 to 48 hours. The amount of compound (6) to be used is not particularly limited, but is usually at least equimolar, preferably equimolar to large excess, based on compound (2). As the amount of the dehydrating agent to be used, it is generally preferable to use a large excess amount in the case of a desiccant and to use a catalytic amount in the case of using an acid. In the reaction, as an intermediate

[0020]

Embedded image

Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above. ] Is generated. The compound can be isolated, but is usually subjected to the next reaction without isolation.

Various methods can be applied to the subsequent reduction reaction, which can be carried out by catalytic hydrogenation in the presence of a catalyst in a suitable solvent. Examples of the solvent used include water, alcohols such as acetic acid, methanol, ethanol, and isopropanol; hydrocarbons such as hexane and cyclohexane; ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether; ethyl acetate; and methyl acetate. And aprotic polar solvents such as dimethylformamide, or a mixed solvent thereof. Examples of the catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney-nickel. The catalyst is generally preferably used in an amount of about 0.02 to 1 times the amount of the starting compound. The reaction temperature is usually about -20 ° C to 100 ° C, preferably about 0 ° C to 70 ° C, and the hydrogen pressure is usually 1 to 10 atm. The reaction is generally completed in about 0.5 to 20 hours.

Although the above-mentioned reduction reaction conditions can be used, preferably, a reduction method using a hydride reducing agent is suitably used.
As the hydride reducing agent to be used, for example, lithium aluminum hydride, sodium borohydride, diborane and the like can be mentioned, and the amount of use is usually at least equimolar, preferably equimolar to 10-fold relative to compound (2). Range of moles. This reduction reaction is usually carried out using an appropriate solvent, for example, water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, diethyl ether and diglyme, dimethylformamide or a mixed solvent thereof, and usually about -60. ~ 50
C., preferably at -30.degree. C. to room temperature, for about 10 minutes to 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, an anhydrous solvent such as diethyl ether, tetrahydrofuran, or diglyme is preferably used.

[Reaction formula-2]

[0025]

Embedded image

Wherein R ¹ , R ² and R ⁴ are as defined above.
R ^3a represents a halogen atom. The halogenation reaction of compound (1c) is carried out in the presence of a usual halogenating agent. As the halogenating agent used in such a reaction, known ones can be widely used, for example, halogen molecules such as bromine and chlorine, or N 2 such as iodine monochloride, sulfuryl chloride, N-bromosuccinimide, and N-chlorosuccinimide.
Halogenating agents such as halogenosuccinimide; The amount of the halogenating agent to be used is usually preferably equimolar to compound (1c). Examples of the solvent used in the reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, acetic acid, propionic acid, water and the like. In the reaction, the reaction temperature is usually from 0 ° C to the boiling point of the reaction solvent, preferably from 0 to 100 ° C, and the reaction is usually completed in about 1 to 10 hours.

[Reaction formula-3]

[0028]

Embedded image

Wherein R ¹ , R ² and R ⁴ are as defined above.
R ^3b represents a nitro group. The nitration reaction of the compound (1c) can be carried out under ordinary nitration reaction conditions of an aromatic compound. That is, for example, the reaction is carried out without a solvent or in a suitable inert solvent using a nitrating agent. As the inert solvent used here, for example, acetic acid, acetic anhydride, concentrated sulfuric acid and the like, and as the nitrating agent used, for example, fuming nitric acid, concentrated nitric acid, mixed acid (sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride and nitric acid) , Potassium nitrate, sodium nitrate and other alkali metal nitrates and sulfuric acid. The amount of the nitrating agent to be used is preferably about equimolar amount or more, usually an excess amount, based on the starting compound. Can be implemented.

[Reaction formula-4]

[0031]

Embedded image

Wherein R ¹ , R ³ , R ⁴ and X are as defined above. R ⁶ represents a lower alkyl group. The reaction between compound (1f) and compound (6) is carried out in a suitable solvent in the presence of a basic compound. Examples of the basic compound used herein include sodium hydroxide, potassium hydroxide, sodium ethylate, sodium hydride, potassium hydride, sodium amide, potassium amide and the like. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. Can be mentioned. The amount of compound (6) to be used is not particularly limited and may be appropriately selected within a wide range. Usually, it is used in an amount of at least equimolar, preferably equimolar to 5-fold molar with respect to compound (1f). Is good. The reaction is usually carried out at about 0 to 70 ° C., preferably at about 0 ° C. to about room temperature.
The reaction is completed in about an hour.

The reaction for converting the compound (1g) into the compound (1f) is carried out by a suitable solvent such as water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane and tetrahydrofuran, and solvents such as acetic acid and the like. In a mixed solvent in the presence of a catalytic reduction catalyst such as palladium-carbon, palladium-black, etc., at about 0 to 100 ° C., a hydrogen pressure of 1 to 10 atm for about 0.5 to 3 hours, Compound (1f) is obtained by heating at 30 to 150 ° C., preferably 50 to 120 ° C. in a mixture of an acid such as hydrofluoric acid and hydrochloric acid and a solvent such as water, methanol, ethanol and isopropanol. Can be.

Compound (1f) can also be obtained by hydrolyzing compound (1g). This hydrolysis is carried out in a suitable solvent in the presence of an acid or a basic compound. Examples of the solvent include water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane and tetrahydrofuran, polar solvents such as acetonitrile, and mixed solvents thereof. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, Lewis acids such as aluminum chloride, iodides such as sodium iodide and potassium iodide, and mixtures of the above Lewis acids and iodides, and the like. Examples of the compound include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. The reaction is usually performed at room temperature to 150 ° C, preferably at room temperature to 100 ° C.
And generally ends in about 0.5 to 15 hours.

[Reaction formula-5]

[0036]

Embedded image

Wherein R ¹ , R ⁴ and X are as defined above. R
⁷ and R ^3c each represent a lower alkenyl group. The reaction between the compound (1h) and the compound (7) is performed in the presence of a basic compound. As the basic compound, known compounds can be widely used, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, inorganic bases such as silver carbonate, sodium and potassium Such as alkali metals,
Examples thereof include alcoholates such as sodium methylate and sodium ethylate, and organic bases such as triethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, and DABCO. The reaction is carried out without a solvent or in the presence of a solvent. As the solvent, all inert solvents that do not adversely affect the reaction are used. For example, alcohols such as water, methanol, ethanol, propanol, butanol, and ethylene glycol are used. Ethers such as dimethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as methyl acetate and ethyl acetate;
Examples include aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric acid triamide, and a mixed solvent thereof. The reaction is advantageously performed in the presence of a metal iodide such as sodium iodide and potassium iodide. The use ratio of the compound (1h) and the compound (7) in the above method is not particularly limited and may be appropriately selected from a wide range. Mole to 2
It is desirable to use a double molar amount. The reaction temperature is not particularly limited, either, but it is usually 0 ° C to 200 ° C, preferably 0 ° C to 150 ° C. The reaction time is usually 1-3
0 hours, preferably 1 to 15 hours.

The reaction for obtaining the compound (1j) from the compound (1i) is generally called Claisen rearrangement.
For example, the compound (1i) can be converted to a compound (1j) by heating the compound (1i) in an appropriate solvent. Examples of the solvent used include high-boiling solvents such as dimethylformamide and tetralin. The heating temperature is usually 10
The reaction temperature is 0 to 250 ° C, preferably about 150 to 250 ° C, and the reaction is completed in about 1 to 30 hours.

The compound (2) used as a starting material includes a novel compound. This compound (2) can be prepared, for example, by a known method [LHGroves and GASwan, J. Chem. Soc., P867-P
870 (1951)].

The compound of the general formula (1) as an active ingredient in the present invention can easily form a salt with a usual pharmacologically acceptable acid. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, and benzoic acid. Organic acids such as acids can be exemplified. These salts can also be used as the active ingredient compound of the present invention in the same manner as the free form compound of the formula (1). The compound represented by the general formula (1) includes stereoisomers and optical isomers, and these can be used as the active ingredient compound.

The target compound obtained by the method shown in each of the above reaction schemes can be separated from the reaction system by ordinary separation means and further purified. As the separation and purification means, for example, a distillation method, a recrystallization method, a column chromatography, an ion exchange chromatography, a gel chromatography, an affinity chromatography, a preparative thin layer chromatography, a solvent extraction method and the like can be adopted.

The active ingredient compound thus obtained is effective as a central nervous system activator and a consciousness disorder improving agent, and these are used in the form of general pharmaceutical preparations. The preparation is prepared using a diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant, which are usually used. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). In molding into tablets, various carriers well-known in the art can be widely used as carriers. Examples thereof include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrating agents such as sodium, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium bases; absorption promoting agents such as sodium lauryl sulfate; Phosphorus, moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablet can be made into a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet. In molding into the form of pills, a wide variety of carriers conventionally known in this field can be used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc., binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, etc., and disintegrants such as laminaran, agar, etc. Can be used. In the case of molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. Capsules are prepared according to a conventional method, usually by mixing an active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like. When prepared as an injection, liquid preparations, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used as diluents in the art when molded into these forms. And water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. may be added. You may. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals can be contained in the pharmaceutical preparation.

The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and may be appropriately selected from a wide range.
%, Preferably about 5 to 50% by weight.

The method of administering these pharmaceutical preparations of the present invention is not particularly limited, and the pharmaceutical preparations are administered in accordance with various preparation forms, age, sex and other conditions of the patient, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered. In the case of an injection, it may be administered intravenously, alone or mixed with a normal replenisher such as glucose or amino acid, and if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

The dosage of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, etc. Usually, the amount of the active ingredient compound is 1 kg / day of body weight. It is good to be about 0.6 to 50 mg. It is desirable that the active ingredient compound is contained in the dosage unit form in a range of about 10 to 1000 mg.

[0046]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, examples of the pharmaceutical preparation of the present invention will be given, then examples of the production of the above-mentioned active ingredient compounds will be given as examples, and test examples of the active ingredient compounds will be given. .

Formulation Example 1 1,2,3,3a, 4,8b-Hexahydro-8-hydroxy-5-methylindeno [1,2-b] pyrrole-2-one 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl methylcellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Ethanol 40 g After mixing and polishing the active ingredient compound of the present invention, Avicel, corn starch and magnesium stearate, sugar coating R10 mm
Tablet with kine. The obtained tablets were treated with hydroxypropyl methylcellulose, polyethylene glycol-600.
0, coating with a film coating agent consisting of castor oil and ethanol to produce film-coated tablets.

Formulation Example 2 1,2,3,3a, 4,8b-Hexahydro-8-hydroxy-1,5-dimethylindeno [1,2-b] pyrrole-2-one 150 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pluronic F-68 30.0 g Sodium lauryl sulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g dried sodium stearate 3.0 g dried magnesium stearate 3.0 g ethanol appropriate amount The active ingredient compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.

The above mixture is sieved with a No. 60 screen and wet granulated with an alcoholic solution containing polyvinylpyrrolidone, carbowax 1500 and 6000. If necessary, alcohol is added to make the powder into a pasty mass. Add corn starch and continue mixing until uniform particles are formed. The mixture was passed through a No. 10 screen, placed in a tray, and placed in an oven at
Dry for 2-14 hours. The dried particles are sieved through a No. 16 screen, dry sodium lauryl sulfate and dry magnesium stearate are added, mixed and compressed into the desired shape on a tablet press.

The above-mentioned core is treated with varnish, and talc is sprayed to prevent moisture absorption. An undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. A further subbing layer and a smooth coating are applied to make the tablet completely round and smooth. Color coating is carried out until the desired hue is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 3 1,2,3,3a, 4,8b-Hexahydro-8-methoxy-5-methylindeno [1,2-b] pyrrol-2-one 5 g polyethylene glycol (molecular weight: 4000) 3 g sodium chloride 0.9 g polyoxyethylene-sorbitan monooleate 0.4 g sodium metabisulfite 0.1 g methyl-paraben 0.18 g propyl-paraben 0.02 g distilled water for injection 10.0 ml above parabens, metabisulfite The sodium and sodium chloride are dissolved in about half of the above distilled water at 80 ° C. with stirring. The obtained solution is cooled to 40 ° C., and the active ingredient compound of the present invention, and then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. Next, distilled water for injection is added to the solution to make the final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

Reference Example 1 10 g of methyl 7-methoxy-4-methylindanone-2-acetate was dissolved in a mixed solvent of chloroform / methanol (1: 5), and 3.2 g of hydroxylamine hydrochloride and 6.5 ml of pyridine were added. For 6 hours.
After cooling the reaction solution, 200 ml of chloroform was added for dilution, and the resulting chloroform solution was diluted with water, 10% hydrochloric acid,
After washing with a saturated saline solution and drying over anhydrous magnesium sulfate, the solvent was distilled off. 7.34 g (69%) of colorless needle-shaped methyl 1-hydroxyimino-7-methoxy-4-methylindane-2-acetate as recrystallized from methanol.
I got

Mp 190-192 ° C.

Reference Example 2 In the same manner as in Reference Example 1, colorless needles of 7-hydroxy-1-hydroxyimino-4-methylindane-2 were obtained from methyl 7-hydroxy-4-methylindanone-2-acetate.
-Methyl acetate was obtained.

Melting point 116-117 ° C.

Reference Example 3 4 g of methyl 7-hydroxy-4-methylindanone-2-acetate was added to a methanol solution of 40% methylamine to give
After heating and stirring for hours, the methylamine methanol solution was distilled off under reduced pressure. Recrystallized from methanol to obtain 3.3 g of colorless needle-like 7-hydroxy-4-methyl-1-methyliminoindan-2- (N-methyl) acetic acid amide.
(78%).

178-180 ° C.

Reference Example 4 In the same manner as in Reference Example 3, methyl 7-methoxy-4-methylindanone-2-acetate was converted to methyl 7-methoxy-4-methyl-1-methyliminoindan-2- (N-methyl). Acetamide was obtained in 32% yield.

Melting point 129-130 ° C.

Example 1 Methyl 1-hydroxyimino-4-methoxyindane-2-acetate (2.49 g) was added to methanol (80 ml) and acetic acid (20).
Then, 250 mg of a platinum oxide catalyst was added, and the mixture was reduced at room temperature at 3 atm. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. By recrystallizing from diisopropyl ether, white powdery crystals having a melting point of 191, 192 ° C and 1,2,2 were obtained.
760 mg of 3,3a, 4,8b-hexahydro-5-methoxyindeno [1,2-b] pyrrol-2-one
(37.4%).

Using the appropriate starting materials, the compounds shown in Table 1 below were obtained in the same manner as in Example 1.

[0062]

[Table 1]

Example 8 A solution of methyl 7-methoxy-4-methylindanone-2-acetate (1.76 g) in methylamine 40% methanol solution 3
After adding 0 ml, the mixture was heated and stirred for 16 hours. The solvent was distilled off, and 200 ml of ethanol and 100 mg of a platinum oxide catalyst were added to the obtained residue, and the mixture was reduced at 3 atm and room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. After purification by silica gel column chromatography (eluent; ethyl acetate), recrystallization from diethyl ether-diisopropyl ether gave pale yellow needle-like crystals having a melting point of 97-98 ° C and 1,5-dimethyl-1,2,3. , 3a, 4,8b-Hexahydro-8-methoxyindeno [1,2-b] pyrrol-2-one (760 mg, 42%).

Using the appropriate starting materials, the compounds shown in Tables 2 and 3 below were obtained in the same manner as in Example 8.

[0065]

[Table 2]

[0066]

[Table 3]

Compound ^{1 of} Example 19 ¹ H-NMR (CDCl ₃ ) δ ppm; 2.17 (3
H, s), 2.40 (1H, d), 2.71 (2H,
m), 2.92 (3H, s), 3.13 (2H, m),
4.56 (2H, d), 5.03 (1H, d). 5.2
9 (1H, d), 5.42 (1H, d), 6.06 (1
H, d, d, d), 5.42 (1H, d), 6.06
(1H, d, d, d), 6.66 (1H, d), 7.0
4 (1H, d).

Compound of Example 20 ¹ H-NMR (CDCl ₃ ) δ ppm; 1.75 (3
H, d), 2.17 (3H, s), 2.39 (1H,
d) 2.71 (2H, m), 2.86 (3H, s),
3.14 (2H, m), 4.48 (2H, d), 5.0
2 (1H, d), 5.77 (2H, m), 6.65 (1
H, d), 7.03 (1H, d).

Example 21 1,2,3,3a, 4,8b-Hexahydro-5-methoxyindeno [1,2-b] pyrrole-2-one 812
400 mg of sodium hydride was added little by little to a solution consisting of 5 ml of dimethylformamide and stirred for 30 minutes. After adding 1 ml of methyl iodide and further stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was dissolved in water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, distilled off chloroform, crystallized with diisopropyl ether, and recrystallized with the same solvent to give colorless needles, melting point 98-99. 1,2,3,3a, 4,8b-
370 mg of hexahydro-5-methoxy-1-methylindeno [1,2-b] pyrrole-2-one (4
2.6%).

Using the appropriate starting materials, the compounds of Examples 8 to 20 were obtained in the same manner as in Example 21.

Example 22 1,2,3,3a, 4,8b-Hexahydro-8-hydroxy-1,5,7-trimethylindeno [1,2-
b] 1,2 g of pyrrol-2-one was dissolved in 20 ml of dimethylformaldehyde, and 242 mg of sodium hydride (60% oil) was added at 0 ° C., followed by stirring for 30 minutes. After adding 1 ml of methyl iodide and further stirring for 1 hour, the mixture was added to ice water and neutralized with hydrochloric acid. After extraction with methylene chloride, washing with water and drying, the solvent was distilled off. After purification through a silica gel column using ethyl acetate-n-hexane as a developing solvent, recrystallization from diisopropyl ether gave a melting point of 12%.
770 mg (35 mg) of 1,2,3,3a, 4,8b-hexahydro-8-methoxy-1,5,7-trimethylindeno [1,2-b] pyrrole-2-one at 7-132 ° C.
%). Light yellow powder.

Using the appropriate starting materials, the compounds of Examples 1, 3, 5, 7, 9, 13, and 18 are obtained in the same manner as in Example 22.

Example 23 1,2,3,3a, 4,8b-Hexahydro-8-methoxy-1,5-dimethylindeno [1,2-b] pyrrole-2-one 3.2 g of acetic acid 50 ml of acetic acid 0.86 ml of bromine was added dropwise to the solution at room temperature, and the mixture was stirred for 1 hour, and further stirred at 80 ° C. for 1 hour. The mixture was poured into water, extracted with chloroform, washed with water and dried, and the solvent was distilled off. Recrystallization from methanol gave 7-bromo-1, mp 156-159 ° C.
5-dimethyl-1,2,3,3a, 4,8b-hexahydro-8-methoxyindeno [1,2-b] pyrrole-
2.66 g (62%) of 2-one were obtained. Pale yellow pyramidal crystals.

Using the appropriate starting materials, the compounds of Examples 7 and 14 were obtained in the same manner as in Example 23.

Example 24 1,2,3,3 nitric acid (d = 1.38) in 10 ml at 0 ° C.
a, 4,8b-Hexahydro-8-hydroxy-1,5
After adding 350 mg of -dimethylindeno [1,2-b] pyrrole-2-one, the mixture was stirred for 2 hours, poured into ice water, extracted with chloroform, washed with water, dried, and then the solvent was distilled off. Recrystallization from methanol gives a melting point of 191.
1,5-dimethyl-1,2,3,3a at -192 ° C.
220 m of 4,8b-hexahydro-8-hydroxy-7-nitroindeno [1,2-b] pyrrol-2-one
g (52%). Colorless prisms.

Example 25 1,2,3,3a, 4,8b-Hexahydro-8-hydroxy-1,5-dimethylindeno [1,2-b] pyrrol-2-one 2 g and dimethylformaldehyde 30
ml of sodium hydride (60%
(Oiliness) 450 mg was added, and the mixture was stirred for 30 minutes, 1 ml of allyl bromide was added, and the mixture was further stirred for 3 hours, added to ice water and neutralized with hydrochloric acid. After extraction with ethyl acetate, washing with water and drying, the solvent was distilled off. Purification through a silica gel column using ethyl acetate-n-hexane as a developing solvent gave 8-allyloxy-1,2,3,3a, 4,8b-hexahydro-1,5.
-Dimethylindeno [1,2-b] pyrrole-2-one was obtained as a pale yellow oily substance in a quantity of 2.3 g. This 8-allyloxy-1,2,3,3a, 4,8b-hexahydro-
1,5-dimethylindeno [1,2-b] pyrrole-2
-One was added to 30 ml of tetralin and stirred at 200 ° C for 24 hours. The tetralin was distilled off, and the residue was purified through a silica gel column and recrystallized from ethanol-diisopropyl ether to give 7-allyl-1,2,3,3a, 4,8b-hexahydro-8-hydroxy having a melting point of 174-175 ° C. 900 mg (38%) of -1,5-dimethylindeno [1,2-b] pyrrole-2-one were obtained. Light brown granular crystals.

Using the appropriate starting materials, the compound of Example 17 was obtained in the same manner as in Example 25.

Pharmacological Test (1) Effect of Promoting Recovery from Halothane Anesthesia (Promotion of Arousal) British Journal of Pharmacology, Vol. 58, No. 27
The test was performed using mice according to the method described on page 35 (1976). That is, 4-5 week old male mice (20-29 g body weight) were fasted for 18-20 hours and then placed in a box ventilated with 4% halothane at 2 liters per minute. The mouse quickly loses the righting reflex in the box. Remove the mouse that lost the righting reflex from the box. Although the right-sided reflection has been lost for a while, the right-sided reflection is recovered after a while. The time from the disappearance of the righting reflex to the recovery is measured, and the time is defined as the anesthesia time with halothane.
The drug was suspended or dissolved in 5% gum arabic saline and orally administered 1 hour before anesthesia loading. 5 for control mice
% Gum arabic saline alone was administered. The arousal-promoting action of the test drug was expressed as a ratio (% control) of the anesthesia time of the test drug-administered mouse to the anesthesia time of the control mouse. The results are shown in Table 1.

[0079]

[Table 4]

Table 1 shows the anesthesia time of the mice to which the test compound was administered, assuming that the anesthesia time of the control mice with halothane was 100%. As shown in Table 1, the compounds of the present invention were found to reduce the anesthesia time and have a central nervous system activating effect.

(2) Evaluation of the effect of improving consciousness disorder in a head injury coma model “Nichisai Medical Journal, Vol. 25, p. 202 (1977)” and “History of Medicine, Vol. 102, No. 867- 869 pages (1
977)). That is, 4 to 5 week old male mice (weight 20 to 29 g)
After being fasted for 8 to 20 hours, the head was fixed on a styrofoam pillow, and an acrylic cylindrical rod was dropped on the top of the mouse along a transparent plastic tube to give an impact. The observation of impaired consciousness was performed by observing the following two points. That is, there are two points, a time until the righting reflex is recovered from the coma after the impact (RR time) and a time until the spontaneous movement recovers (SM time). The test drug was suspended or dissolved in 5% gum arabic saline and orally administered one hour before anesthesia loading. Control mice received only 5% gum arabic saline. The effect of the test drug on improving consciousness disorder was represented by the ratio (% control) of the RR time or SM time of the test drug-administered mouse to the RR time or SM time of the control mouse. The results are shown in Table 2.

[0082]

[Table 5]

In Table 2, the RR time or SM time of the mice to which the test compound was administered is shown in%, assuming that the RR time or SM time is 100%, as a measure of recovery from coma due to head trauma of control mice. Have been. The compounds of the present invention apparently shortened the RR time and the SM time in this model, promoted recovery from coma due to head trauma, and were found to have an effect of improving consciousness disorder.

──────────────────────────────────────────────────続 き Continued from the front page (72) Inventor Katsura Tottori 15-1 Kamirokujo, Kamiita-cho, Itano-gun, Tokushima Prefecture (56) References JP-A-59-46269 (JP, A) (58) Fields investigated ( Int.Cl. ⁷ , DB name) C07D 209/70 A61K 31/403 A61P 25/00 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group.
R ^2, R ³ and R ⁴ are the same or different and represent a hydrogen atom, a hydroxyl group, a lower alkenyloxy group, a lower alkoxy group, a lower alkyl group, a two-Toro group or a lower alkenyl group.
However, R ² , R ³ and R ⁴ must not be simultaneously hydrogen atoms . ] The hexahydroindeno [1, 2-b] pyrrole derivative represented by these, or its salt.