JPH01165538A - Tetralin derivative - Google Patents

Abstract

NEW MATERIAL:The tetralin derivative of formula I [R<1> is OH or carboxy which may be amidated or esterified; R<2> is group of formula II (R<3>, R<4> and R<5> are H, methyl or methoxy) or its hydroquinone compound); n is 1-10]. EXAMPLE:1-(3,4-Dimethoxy-6-methyl-2,5-benzoquinonyl)-1,2,3,4-tetrahydr o-2- naphthaleneacetic acid. USE:Useful as a remedy for diseases caused by cerebral hypoxia or anoxia. It can be orally administered. It is effective at a low dose and has low toxicity. Useful e.g., for the treatment of senile dementia such as dysmnesia. PREPARATION:The compound of formula I is produced by reacting alpha-tetralone with diethyl carbonate in the presence of a base, reacting the product with a compound of formula III (X is halogen; R<8> is lower alkyl), hydrolyzing the product and subjecting the hydrolyzate to several steps such as decarbonation reaction and reduction.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a compound of the general formula (I) [wherein R1 represents a hydroxyl group or a carboxyl group which may be amidated or esterified, and R2 represents a group ( Here, R3, R4 and R8 each independently represent a hydrogen atom, methyl group or methoxy group) or a hydroquinone derivative thereof, and n represents an integer from 1 to 10.

The compound of the present invention, as an oral agent, is effective in improving and treating diseases based on organic disorders in the brain.

[Conventional technology]

The average lifespan of humans is increasing, and the elderly population is increasing. Along with this, senile dementia (senile dementia; senile dementia) such as memory dementia whose main symptom is loss of memory function
+entia) is becoming a major social problem.

Currently, many drugs for treating senile dementia are being developed, but no satisfactory drug has yet been developed.

The brain is one of the most active organs in energy metabolism. If the oxygen supply mechanism in the brain is impaired and brain cells continue to be in an oxygen-deficient state (cerebral hyperxia), an anoxic state (cerebral anoxia) will eventually occur. If this condition continues, brain cells will undergo irreversible degeneration and eventually become unable to function normally.

Currently, hypnotic anesthetics such as phenobarbital are used to treat oxygen deficiency diseases associated with cerebral hyperxia or anoxia, but their use is limited due to side effects on the respiratory and circulatory systems. There is.

[Means to solve the problem]

The present inventors have conducted extensive research to develop a drug that can be administered orally, at low doses, and with low toxicity, and is effective in treating cerebral anoxia or diseases caused by anoxia. The present invention was completed based on the finding that the tetralin derivatives found in the field are extremely effective in treating such diseases.

The compound of the present invention represented by the general formula (I) can be synthesized, for example, as follows.

That is, by reacting α-tetralone and diethyl carbonate in the presence of a base (e.g., sodium hydroxide) at a temperature of room temperature to 100°C, 1.2.3°4-tetrahydro-1
-oxo-2-naphthalenecarboxylic acid ethyl ester is obtained. This and ethyl acrylate or general formula (II)
) (wherein, X represents a halogen atom, R1 represents a lower alkyl group, and n is as defined above) in the presence of a base such as sodium hydroxide or sodium ethylate, solvent that does not participate in the reaction,
For example, ether, tetrahy.

General formula (I111) (wherein R9 represents a lower alkyl group such as methyl or ethyl, and n is as defined above) is obtained by reacting Dorofuran in ethanol at θ°C to room temperature. Can be done.

This compound (II[) is heated in a mixture of an organic solvent (e.g. dioxane, tetrahydrofuran, ethanol) and water in the presence of a base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate) for 1 to 20 hours. After refluxing and hydrolyzing, the reaction solution was adjusted to pH 1 to 2 using an acid such as concentrated hydrochloric acid, and a decarboxylation reaction was performed to obtain the general formula (IV) (where n is as defined above). It is possible to obtain a compound represented by

This compound (TV) can be reduced with sodium borohydroxide in a solvent that does not participate in the reaction, such as ethanol, methanol, etc., or in a solvent, such as dioxane, ethanol, methanol, or tetrahydrofuran, at 0°C to room temperature. Catalytic reduction is carried out in a hydrogen stream using 5 to 10% palladium on carbon as a catalyst, and the alcohol compound can be obtained by post-treatment by a conventional method. This is lactonized in the presence of a catalyst (e.g. hydrochloric acid, para-toluenesulfonic acid, D, L-camphorsulfonic acid, etc.) in a solvent such as toluene or benzene at room temperature to 150°C, or dehydrated and condensed. agents [e.g. dicyclohexylcarbodiimide, chloroethylcarbonate-triethylamine,
ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, etc.) to obtain a compound represented by general formula (V) (wherein n is as defined above). Can be done.

This compound (V) is mixed with Lewis acids (e.g. p-)luenesulfonic acid, boron trifluoride-ether complex, aluminum chloride, etc. in a solvent that does not participate in the reaction, such as benzene, toluene, f-2-dichloroethane, etc. ) in the presence of a catalyst, react with a hydroquinone derivative represented by the general formula (wherein R2, R4 and RS are as defined above), and then react with ferrous chloride, ceric ammonium nitrate, etc. By oxidation, the general formula of the present invention (
A carboxylic acid derivative represented by the formula (wherein R2 and n are as defined above) can be obtained.

The compound (I a) is then subjected to esterification, amidation or reduction reaction by a conventional method to obtain the general formula (
A compound of the present invention represented by Ib) or (Ic) (wherein R2, R6, R? and n are as defined above) can be obtained.

The compound of the present invention produces cis and trans isomers depending on the substitution mode of the substituent on the tetralin ring, and the present invention includes all of these isomers and mixtures.

〔Example〕

Next, specific examples and reference examples are shown, but the following examples are for explaining the present invention more specifically, and are not intended to limit the idea of the present invention to these examples. Needless to say.

α-tetralone 10 g (0,0684 mol), 60
A suspension of 3.56 g (0,0890 mol) of sodium hydroxide and 32 g (0,2709 mol) of diethyl carbonate was heated under reflux for 1 hour, poured into ice water, and adjusted to pH 1-2 with concentrated hydrochloric acid. Extracted with ether. The ether layer was washed with water and then dried over magnesium sulfate. After distilling off the solvent, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 9:1) to obtain 1.
2.3.4-tetrahydro-1-oxo-2-naphthalenecarboxylic acid ethyl ester 8.6 g (yield 57.7%)
) was obtained.

Add this to 1.90g of 60% sodium hydroxide (0.04
10.0 g (0,0599 mol) of ethyl bromoacetate was added to a solution (220 ml) of ethyl bromoacetate (75 mol) in tetrahydrofuran at 0°C, and the mixture was stirred for 3 hours. Pour the reaction solution into ice water,
After extraction with ether, the extract was washed with water according to a conventional method, dried, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5:1) to obtain 9.03 g of the title compound ( Yield 75.2
%) was obtained.

1,2,3.4-tetrahydro-1-oxo-2-naphthalenecarboxylic acid ethyl ester obtained in Reference Example 1 5.0
g (0,0229 mol), sodium 158■ (
6°8695 mmol) in ethanol (300 mZ), and then 2.99 g (0.0 mZ) of ethyl acrylate.
299 mol) was added thereto, and the mixture was stirred at room temperature for 4 hours.

The reaction solution was concentrated under reduced pressure, diluted with water, and extracted with ether.
The extract was washed with water, dried, and the solvent was distilled off in a conventional manner to obtain 5.6 g (yield: 76.9%) of the title compound.

Reference 3:1 2 3,4-Tohiro 1 - 7.2 g (0,0237 mol) of the compound of Reference Example 1 was added to 2N
Sodium hydroxide aqueous solution (I00ml) and dioxane (
50mj) for 8 hours under reflux. The reaction solution was diluted with water, adjusted to pH 1-2 with concentrated hydrochloric acid, and extracted with ether. The extract was washed with water, dried, and the solvent was distilled off in a conventional manner to obtain 4.3 g (yield: 89.0%) of the title compound.

6.0 g (0,0189 mol) of the compound of Reference Example 2 was heated under reflux for 8 hours in a 2N aqueous sodium hydroxide solution (200 m7) and dioxane (I00mj). The reaction solution was diluted with water, adjusted to pH 1-2 with concentrated hydrochloric acid, and extracted with ether. The extract was washed with water, dried, and the solvent was distilled off in a conventional manner to obtain 3.98 g (yield: 96.8%) of the title compound.

5:2 3 3a 4 5 9b - Hexa Reference Example 3
To a solution of 4.0 g (0,0196 mol) of the compound in ethanol (I00mZ) was added 2.0 g (0.0196 mol) of the compound of
24g (0,0589 mol) was added at 0°C and stirred for 5 hours.

The reaction solution was concentrated under reduced pressure, diluted with water, and purified with concentrated hydrochloric acid.
After converting to H1,2, the mixture was extracted with ether. The extract was treated in a conventional manner, and the resulting crude product was then mixed with methylene chloride (22
9.31 g of l-ethyl-3-(3-dimethylaminopropyl)-lupodiimide hydrochloride
(0,0486 mol) was added and stirred at room temperature for 3 hours.

The reaction solution was washed with water, dried, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5:2), and the two isomers (R- 5a, R-5b) respectively 1.91
g (yield 52.0%) and 0.64g yield 17.2%
)Obtained.

Reference 6:3 4,4a,5,6.10-hexa To an ethanol solution (80 m7) of 3.81 g (0,0175 mol) of the compound of Reference Example 4, 2 ml of sodium borohydroxide was added.
．． OOg (0,0526 mol) was added at O''C and stirred for 5 hours.

The reaction solution was concentrated under reduced pressure, diluted with water, and purified with concentrated hydrochloric acid.
After adjusting to H1-2, it was extracted with ether. The extract was treated in a conventional manner, and the resulting crude product was mixed with methylene chloride (400
7.93 g of l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0
, 0414 mol) and stirred at room temperature for 3 hours.

The reaction solution was washed with water, dried, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5:2), and two isomers of the title compound (R-6a, R 1.33 g (yield 37.7%) and 0.57 g (yield 16.0%) of -6b) were obtained, respectively.

1:1-3 4-dimethoxy-6-methy 500 μ (2,6595 mmol) of the compound of Reference Example 5 (compound number R-5a) and 2,3-dimethoxy-5-methyl-1,4-
1.636 μm (3,4565 mmol) of hydroquinone.
566 μm (3,9878 mmol) of boron trifluoride-ether complex was added to a 2-dichloroethane solution (20 m/) and stirred at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, it was dissolved in a mixed solution of acetonitrile (I5m) and water (5n+7), and 4.74g (8,6496 mmol) of ceric ammonium nitrate (hereinafter referred to as CAN) was added and stirred at room temperature for 30 minutes. did.

This reaction solution was diluted with water, extracted with ether, the extract was washed with water, dried, the solvent was distilled off, and the resulting crude product was subjected to silica gel column chromatography (3% to 5% methanol-
(eluted with dichloromethane) to obtain the title compound 620n.
v (yield 63%).

・2:1-(34-dimexy-6-methy) Reference Example 6
(compound number R-6a) 500 mg (2,4
752 mmol) and 2,3-dimethoxy-5-methyl-
Boron trifluoride-ether complex 526111 (3,7060
mmol) and stirred at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, acetonitrile (I5m/), water (51+
17) and melted it in the mixed solution of CAN3.4g (6,20
43 mmol) and stirred at room temperature for 30 minutes. This reaction solution was diluted with water and extracted with ether. The extract was washed with water, dried, and the solvent was distilled off. The crude product obtained was purified by silica gel column chromatography (3-5% methanol-dichloromethane) to obtain the title compound 520. ■(Yield 54.7%)
I got it.

-j l1l-(3,4-dimethoxy-6-methy) Compound of Example 1 (Compound No. 1) 348■(0,94
05 mmol) and thiomorpholine 145 nw (I,4
077 mmol) in methylene chloride solution (20 mZ)
-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (270 μm, 4084 mmol) was added, and the mixture was stirred at room temperature for 6 hours.

The reaction solution was washed with water, dried, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to obtain the title compound 270.
(yield: 63.1%).

Interchange ■ Morpholine, N instead of thiomorpholine in Soil Technique Example 3
- By using methylpiperazine, piperidine,
Compounds of Examples 4 to 6 (compound numbers 4.5 and 6) were synthesized in the same manner as in Example 3.

Compound of Tachizume Example 2 (Compound No. 2) 200■(0,5
208 mmol) and thiomorpholine 107 mg (I,
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride 200 μm (1,0432 mmol) in methylene chloride solution (20 m7) of
was added and stirred at room temperature for 5 hours.

After washing the reaction solution with water, drying and distilling off the solvent, the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 11) to obtain the title compound 193 (yield 79.0%). Obtained.

Margin below 8:1-(3,4-dimethoxy-6-methy.

Using morpholine instead of thiomorpholine in Example 7, the title compound (compound number 8) (yield 8
2.1%) was synthesized.

Compound of Example 1 (compound number 1a) 100 mg (0,
To a solution of ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (100 μm) and 18 μm of ethanol in methylene chloride (I5m7)
216 mmol) and 4-dimethylaminopyridine 3
ow was added and stirred at room temperature for 6 hours.

After washing the reaction solution with a dilute aqueous hydrochloric acid solution, washing with water, drying, and distilling off the solvent, the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 271),
The title compound 98■ (yield 91.1%) was obtained.

Compound of Example 1 (compound number 1a015■(0,31
08 mmol) and ethyl chlorocarbonate 42 mmol (0,387
0 mmol) in tetrahydrofuran solution (20 m)
Triethylamine 39μ (0,3861 mmol) at °C
was added and stirred for 30 minutes.

The reaction solution was filtered through a glass filter, and 57 mg (I, 500 mmol) of sodium borohydride was added to the filtrate at 0°C, followed by stirring for 1 hour. The reaction solution was poured into a dilute aqueous hydrochloric acid solution and extracted with ether. The extract was washed with water, dried, and the solvent was distilled off in a conventional manner. The resulting crude product was then added to a mixed solution of acetonitrile (I5m/) and water (5rR1). After dissolving, 492 mg (0,8978 mmol) of CAN was added and stirred for 20 minutes.

The reaction solution was diluted with water, extracted with ether, the extract was washed with water, dried, and the solvent was distilled off according to a conventional method. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1:1). By doing so, the title compound 89■ (yield 80.4%) was obtained.

The physicochemical properties of the reference example and example compounds synthesized above are shown in Tables 1 and 2, respectively.

Margins below [Effects of the Invention] The antihypoxia effect of the compound of the present invention was measured using ddY male mice (body weight 22 to 30 g) by the following method.

The test drug was suspended in 1% gum arabic solution, 50mg/
It was administered orally by gavage at a rate of 1.0 kg. Test drug administration group: 1 group, 7
There were 14 mice in the control group (solvent solution administration group). One hour after administration of the test drug, the mouse was placed in a desiccator, the pressure inside the desiccator was reduced to 180 mm/g using a vacuum pump, and observation was made for up to 15 minutes. The time from the start of decompression to the stop of breathing was measured as the survival time, and if the animal remained alive after 15 minutes, the survival time was determined to be 15 minutes.

As a result, a significant survival time prolonging effect was observed in the test drug administration group of the present invention compared to the control group, especially for compounds Nos. 2 and 3.
．． 4, the effect was remarkable.

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R^1 represents a hydroxyl group or a carboxyl group that may be amidated or esterified. , R^2 is a group ▲ has a mathematical formula, chemical formula, table, etc. (here, R^3, R^4 and R^5 each independently represent a hydrogen atom, methyl group or methoxy group) or its hydroquinone form. and n represents an integer of 1 to 10. 2. In the general formula (I), R^1 is a ▲ mathematical formula, chemical formula, table, etc. ▼ (Here, R^6 and R^7 each independently represent a hydrogen atom, a lower alkyl group, or a benzyl group. or R^6 and R^7 represent a group that is bonded to each other to form morpholine, thiomorpholine, N-methylpiperazine, piperidine together with the nitrogen atom to which they are bonded. Compounds described. 3. The compound according to claim 1, wherein in the general formula (I), R^2 is ▲a mathematical formula, a chemical formula, a table, etc.▼, and n is 1 or 2.