JP2506337B2 - Phenylmethylbenzoquinone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention has the general formula (I) (In the formula, R ¹ , R ² and R ³ each independently represent a hydrogen atom, a methyl group or a methoxy group, A represents an ethylene group or a vinylene group, n represents 0 or 1, R ⁴ represents a hydrogen atom,
Represents a hydroxymethyl group or a carboxyl group which may be esterified or amidated, provided that when n is 0, R ⁴
Is not a hydrogen atom. The present invention relates to a phenylmethylbenzoquinone derivative represented by: and a brain function improving drug containing the derivative as an active ingredient.

[Prior art]

Brain cells maintain an intracellular environment that is completely different from the surrounding environment (extracellular fluid), maintain the difference and live, but in order to do so, they must continually generate and supply energy . Most of the energy needed by the nerve cells in the brain is supplied by oxygen and glucose,
These energy sources are rarely stored in the brain and must be constantly supplemented with blood.

If the brain is damaged and the supply of oxygen and glucose is cut off, the energy metabolism disorder generally progresses in stages, and the cells lose their function over time and eventually collapse organically. However, that function cannot be performed normally.

For this reason, a mechanism for regulating the cerebral blood flow of the cerebral blood vessels themselves is well developed in order to stably supply the energy source of the brain tissue and keep the external environment of the cerebral nerve cells constant.

When treating cerebrovascular disorders medically, various cerebral circulation improving agents, cerebral vasodilators, cerebral metabolism improving agents and the like have been used so far. However, although these drugs can improve subjective symptoms, they hardly improve neurological symptoms and psychological symptoms.

[Problems to be solved by the invention]

The present inventor has, as a result of years of earnest research on a compound effective in ameliorating and / or treating symptoms caused by various disorders in the brain, as a result, the novel phenylmethylbenzoquinone derivative according to the present invention is effective in treating the various disorders. The present inventors have found that it is extremely effective in preventing hypofunction of brain cells in the anoxic state (brain anoxia) of various brain neurons that are thought to be closely related to the present invention, and completed the present invention. .

INDUSTRIAL APPLICABILITY The novel phenylmethylbenzoquinone derivative of the general formula (I) of the present invention shows a cerebral function-improving action on anoxia experimental animals even at a low dose, and is used as an agent for improving and treating organic disorders in the brain and mental dysfunction. Expected to be effective.

[Means for solving problems]

According to the invention, the general formula (I) (In the formula, R ¹ , R ² and R ³ each independently represent a hydrogen atom, a methyl group or a methoxy group, A represents an ethylene group or a vinylene group, n represents 0 or 1, R ⁴ represents a hydrogen atom,
Represents a hydroxymethyl group or a carboxyl group which may be esterified or amidated, provided that when n is 0, R ⁴
Is not a hydrogen atom. ) A phenylmethylbenzoquinone derivative represented by: and a brain function improving drug containing the derivative as an active ingredient.

These compounds are compounds that are effective in ameliorating and treating the symptoms associated with organic disorders and mental dysfunction in the brain, and have broad utility.

Here, "organic disorder in the brain" is a cerebral infarction sequelae, sequelae of cerebral hemorrhage, various symptoms derived from cerebral ischemic disorders such as sequelae of cerebral arteriosclerosis and senile dementia, presenile dementia, amnesia, sequelae of head trauma, Means various organic disorders derived from aftereffects of brain surgery, and "mental dysfunction" means mania, depression,
Neurosis, Parkinson's disease, schizophrenia and schizophrenia-like disorders,
It means chorea and mental illnesses derived from drugs and alcohol.

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

Method I General formula (II) (Wherein R ¹ , R ² and R ³ are as defined above), the aldehyde represented by the general formula (III) (In the formula, X represents a bromine atom or a chlorine atom, and R ⁷ is a group. Or --CH (OC ₂ H ₅ ) ₂ ) represented by the general formula (IV) (Wherein R ¹ , R ² , R ³ and R ⁷ are as defined above) can be obtained. Compound (IV)
Is treated with an acid such as hydrochloric acid to give a compound of general formula (V) (Wherein R ¹ , R ² and R ³ are as defined above), and the Wittig reagent of triethylphosphonoacetate is reacted with this aldehyde to give the general formula (VI) (Wherein R ¹ , R ² and R ³ are the same as described above) can be obtained.

When the compound (VI) is treated with acetic anhydride in the presence of a base such as pyridine to give an acetylated product, and then the acetylated product is catalytically reduced in glacial acetic acid in the presence of palladium black, the compound of the general formula (VII) (In the formula, R ¹ , R ² and R ³ are the same as described above.

A compound represented by can be obtained.

Hydrolysis of the compound (VII) by a commonly used method,
General formula (VIII) after reduction or esterification (Wherein R ¹ , R ² and R ³ are as defined above, and R ⁸ represents a hydroxymethyl group, a carboxyl group or a lower alkoxycarbonyl group).

Then, the compound (VIII) is oxygen-oxidized in the presence of potassium nitrosodisulfonate or salcomine to give the compound of the general formula (Ia) (Wherein R ¹ , R ² , R ³ and R ⁸ are as defined above), the compound of the present invention can be obtained.

The compound of the present invention can also be synthesized by the following method.

Method II Using 2,5-dimethoxybenzaldehyde as a raw material and following the same procedure as above A compound of formula (IX) can be obtained.

The compound (IX) is converted to a chloride by using thionyl chloride or the like and then dechlorinated, for example, reduced with zinc-glacial acetic acid to give a compound of the formula (X) And then oxidize compound (X) with ceric ammonium nitrate (hereinafter abbreviated as CAN) to give formula (Ib) The compound of the present invention represented by can be obtained. Further, the compound (Ib) can be converted into various compounds of the present invention by appropriately performing hydrolysis, reduction reaction, amidation reaction and the like under commonly used conditions.

[Action]

The brain function-improving action of the compound of the present invention is shown by the following test: Anti-hypoxia action (cerebral protective action against decompressed hypoxia) 7 to 10 male ddY mice each weighing 22 to 30 g were used. The mouse was placed in a desiccator (volume: about 1), suctioned by a vacuum pump, and the inside of the desiccator was adjusted to 180 mmHg. The test drug was intraperitoneally administered, and the pressure was reduced 30 minutes after the administration.
The survival time is the time from the start of decompression to the stop of breathing.
Minutes were calculated and compared with the solvent administration group.

Results Among the test compounds, it was the compounds of Examples 1, 4, 5 and 6 that significantly prolonged the survival time at the amount of 25 mg / kg, and the compound of Example 1 was 12.5 mg / kg and less. The amount significantly increased the survival time.

In administration of the novel phenylmethylbenzoquinone derivative represented by the above general formula (I) of the present invention, it may be administered alone, but if necessary or desired, other conventional pharmacologically acceptable It can be administered orally or parenterally in the form of powder, granules, tablets, capsules, injections, suppositories, etc. by mixing with the carrier, excipient, diluent.

The dose of the cerebral function-improving drug of the present invention depends on various factors such as symptoms of a patient to be treated, age, administration route, dosage form, administration frequency, etc.
It can be administered in g, preferably in the range of 10 to 500 mg.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples. The physicochemical properties of the compounds of the present invention shown in Examples are shown in Table 1.

The abbreviations in the NMR spectrum have the following meanings: s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet,
br: Broad Example 1 3- {3-[(1,4-benzoquinone-2-yl) methyl] phenyl} acrylic acid ethyl ester (method II) Step 1 2- {3- [hydroxy- (2,5-dimethoxyphenyl) methyl] phenyl} -1,3-dioxolane Magnesium foil 2.85 g was suspended in 200 ml of tetrahydrofuran (hereinafter abbreviated as THF) to prepare a catalyst. After adding a certain amount of iodine, gradually add a solution of 2-5.0- (3-bromophenyl) -1,3-dioxolane (25.0 g) in 50 ml of THF to the reaction solution.
Heated to 70 ° C. After heating and stirring at 70 ° C for 1 hour, cool with ice,
2,5-dimethoxybenzaldehyde 13.0g in THF (50m
l) was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of ammonium chloride (500 ml), and the mixture was extracted with ether. The ether extract was washed with water and dried over magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate / 2: 1) to obtain 17.5 g (70.7%) of the title compound as an oily substance.

NMR (δ ppm, CDCl ₃ ): 3.17 (1H, d), 3.69 (6H, s), 3.80
−4.20 (4H, m), 5.73 (1H, s), 5.78 (1H, d), 6.60−7.6
0 (7H, m), (60MHz) Step 2 3- [Hydroxy- (2.5-dimethoxyphenyl) methyl] benzaldehyde 3.45 g of the dioxolane derivative obtained in Step 1 was dissolved in 60 ml of THF and 2N- was added under ice cooling. 45 ml of hydrochloric acid was added. The mixture was stirred at room temperature for 3 hours, diluted with 200 ml of water, and extracted with ether. The ether extract was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2.95 g of the title compound as an oil (99.
3%) was obtained.

NMR (δ ppm: CDCl ₃ ): 3.23 (1H, d), 3.76 (6H, s), 6.07
(1H, d), 6.70-6.70 (3H, m), 7.49 (1H, t), 7.67 (1H,
d), 7.78 (1H, d), 7.91 (1H, s), 9.78 (1H, s) Step 3 3- {3- [hydroxy- (2,5-dimethoxyphenyl) methyl] phenyl} acrylic acid ethyl ester To a 150 ml THF solution of 5.98 g of triethylphosphonoacetate, 1.07 g of oil suspension 60% sodium hydride was added and stirred for 15 minutes at room temperature. A 50 ml THF solution of 2.90 g of the benzaldehyde derivative obtained in step 2 was added under ice cooling, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, diluted, and extracted with ether. The ether extract was washed with water and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate / 2: 1) to give the title compound.
Obtained 2.51 g (68.6%).

NMR (δ ppm, CDCl ₃ ): 1.32 (3H, t), 3.18 (1H, d) 3.74
(6H, s), 4.25 (2H, q), 6.00 (1H, d), 6.40 (1H, d), 6.
70-6.70 (3H, m), 7.20-7.50 (3H, m), 7.56 (1H, s),
7.66 (1H, d) Step 4 3- {3-[(2,5-dimethoxyphenyl) methyl] phenyl} acrylic acid ethyl ester A solution of the compound of Step 3 (4.0 g) in thionyl chloride (27.8 g) was heated under reflux for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with an aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in 70 ml of acetic acid. 2.04 g of zinc powder was added, and the mixture was stirred at room temperature for 3 hours and then passed. Concentrate the liquid under reduced pressure,
The residue was purified by silica gel column chromatography (hexane: ethyl acetate / 2: 1) to give the title compound 0.936 g (2
4.5%).

NMR (δ ppm, CDCl ₃ ): 1.32 (3H, t), 3.72 (3H, s), 3.78
(3H, s), 3.75 (2H, s), 4.25 (2H, q), 6.37 (1H, d), 6.
55-6.85 (3H, m), 7.10-7.45 (4H, m), 7.63 (1H, d) Step 5 3- {3-[(1,4-benzoquinone-2-yl) methyl] phenyl} ethyl acrylate Ester Dissolve 243 mg of the compound of Step 4 and 374 mg of picolinic acid in 10 ml of acetonitrile-water (4: 1), add CAN2.
Stir for 0 minutes. The reaction mixture was diluted with 80 ml of water and extracted with ether. The ether extract was washed with water and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate = 5: 2) to give 97 mg (44.0%) of the title compound.

Examples 2 to 6 The compounds of Examples 2 to 6 were synthesized from the synthetic intermediates of Example 1 or related compounds by the following methods.

Example 2 3-[(1,4-benzoquinone-2-yl) methyl] benzyl alcohol 3-[(2,5-Dimethoxyphenyl) methyl] benzyl alcohol was oxidized with CAN by a conventional method to give the title compound. Yield: 24.2% Example 3 3-[(1,4-benzoquinon-2-yl) methyl] benzoic acid Chromic acid oxidation of the compound of Example 2 gave the title compound. Yield 75.8% Example 4 3- {3-[(1,4-benzoquinone-2-yl) methyl] phenyl} propionic acid 3- {3-[(2,5-dimethoxyphenyl) methyl] phenyl} propionic acid was oxidized with CAN to give the title compound. Yield: 25.7% Example 5 3- {3-[(1,4-benzoquinone-2-yl) methyl] phenyl} propyl alcohol 3- {3-[(2,5-dimethoxyphenyl) methyl] phenyl} propyl alcohol was CAN-oxidized to give the title compound. Yield: 26.2% Example 6 3- {3-[(1,4-benzoquinone-2-yl) methyl] phenyl} acrylic acid The title compound was synthesized by CAN-oxidizing 3- {3-[(2,5-dimethoxyphenyl) methyl] phenyl} acrylic acid. Yield: 45.6% Example 7. 3- {4-[(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl) methyl] phenyl} propionic acid Step 1 4- [Hydroxy- (2-hydroxy-3,4-
Dimethoxy-6-methylphenyl) methyl] benzaldehyde diethyl acetal Magnesium foil 229 mg was suspended in 20 ml of THF, and a catalytic amount of iodine was added thereto, and then 4-bromobenzaldehyde was added.
2.22 g of diethyl acetal was added, and Example 1 (step 1)
The same process was carried out. A THF solution of 336 mg of 2-hydroxy-3,4-dimethoxy-6-methylbenzaldehyde was added under ice cooling, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was post-treated in the same manner as in Example 1 (Step 1) to give 616 mg of the title compound as an oil (95.
6%).

_{NMR (δppm, CDCl 3):} 1.05-1.35 (6H, m), 2.23 (3H,
s), 3.40-3.70 (4H, m), 3.81 (1H, d), 3.87 (3H, s),
3.88 (3H, s) 5.47 (1H, s), 6.02 (1H, d), 6.31 (1H,
s), 6.82 (1H, s), 7.33 (2H, d), 7.40 (2H, d) Step 2 4- [Hydroxy- (2-hydroxy-3,4-
Dimethoxy-6-methylphenyl) methyl] benzaldehyde 480 mg of the compound obtained in Step 1 was dissolved in 15 ml of THF to give 5%.
Hydrochloric acid was added and the mixture was stirred at room temperature for 7 hours. The reaction solution was diluted with water and extracted with ether. The ether extract was washed with water and dried over magnesium sulfate, and the solvent was evaporated to give 401 mg (84.6%) of the title compound as an oil.

NMR (δ ppm, CDCl ₃ ): 2.27 (3H, s), 3.85 (6H, s), 6.07
(1H, s), 6.32 (1H, s), 6.78 (1H, s), 7.50 (2H, d), 7.
80 (2H, d), 9.96 (1H, s) Step 3 3- {4- [hydroxy- (2-hydroxy-
3,4-Dimethoxy-6-methylphenyl) methyl] phenyl} acrylic acid ethyl ester 400 mg of the compound obtained in Step 2 is dissolved in 30 ml of THF, and oil suspension 60% sodium hydride 286 mg and triethylphosphonoacetate 1.48 g are dissolved. Was treated in the same manner as in Example 1 (Step 3) to give 410 mg (83.2%) of the title compound as an oil.

NMR (δppm, CDCl ₃ ): 1.32 (3H, t), 2.23 (3H, s), 3.85
(6H, s), 4.03 (1H, d), 4.22 (2H, q), 6.01 (1H, d), 6.
30 (1H, s), 6.38 (1H, d), 6.85 (1H, s), 7.36 (2H, d),
7.42 (2H, d), 7.36 (1H, d) Step 4 3- {4-[(2-hydroxy-3,4-dimethoxy-6-methylphenyl) methyl] phenyl} propionic acid Compound 359 mg obtained in Step 3 above 10 ml of acetic anhydride and 1
It was dissolved in 0 ml of pyridine and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure to obtain an oily acetylated product. The acetylated product was dissolved in 9 ml of glacial acetic acid, 300 mg of palladium chloride was added, and the mixture was stirred under a hydrogen gas stream at room temperature for 16 hours. The reaction solution was passed and the solution was concentrated under reduced pressure. The residue
It was dissolved in 10 ml of methanol, 10 ml of 5% aqueous potassium hydroxide solution was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and washed with ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ether. The ether extract was washed with water, dried over magnesium sulfate, and the solvent was evaporated to give 253 mg (72.4%) of the title compound as an oil.

NMR (δ ppm, CDCl ₃ ): 2.17 (3H, s), 2.62 (2H, t), 2.87
(2H, t), 3.82 (3H, s), 3.87 (3H, s), 3.96 (2H, s), 5.
95 (1H, brs) 6.32 (1H, s), 6.95-7.20 (4H, m) Step 5 3- {4-[(5,6-dimethoxy-3-methyl-1,4-benzoquinone-2-yl) Methyl] phenyl}
Propionic acid 70 mg of the modified product of step 4 was dissolved in 3 ml of dimethylformamide, 40 mg of salcomine was added, and the mixture was stirred at room temperature for 12 hours under an oxygen gas stream. Water was added to the reaction solution for dilution and extraction with ether. The ether extract was washed with water and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give 52 mg (71.2%) of the title compound.

Examples 8 to 10 The compounds of Examples 8 to 10 were synthesized using the synthetic intermediate of Example 7 or a related compound that can be synthesized by a conventional method.

Reference Example 1 2,3-dimethoxy-6-benzyl-5-methyl-1,4-benzoquinone The title compound was synthesized by oxidizing 2,3-dimethoxy-5-benzyl-6-methylphenol in the same manner as in Example 7 (Step 5). Yield: 86.4% Example 8 3- {4-[(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl) methyl] phenyl} propanol 3- {4-[(2-hydroxy-3,4-dimethoxy-
6-Methylphenyl) methyl] phenyl} propanol was used and treated in the same manner as in Example 7 (step 5) to synthesize the title compound.

Yield: 70.7% Example 9 3- {3-[(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl) methyl] phenyl} propionic acid ethyl ester 3- {3-[(2-hydroxy-3,4-dimethoxy-
6-Methylphenyl) methyl] phenyl} propionic acid ethyl ester was oxidized in the same manner as in Example 7 (Step 5) to give the title compound.

Yield: 65.7% Example 10 3- {4-[(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl) methyl] phenyl} -1-thiomorpholino-1-oxopropane 27 mg of the compound obtained in Example 7 and 14.5 of ethyl chloroformate
Dissolve mg in 1 ml THF and add triethylamine 13.5 at -10 ° C.
mg and stir for 30 minutes, followed by thiomorpholine 20.2 mg
Was added and stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with ether. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography (hexane: ethyl acetate / 1: 2) to obtain 25.8 mg (76.7%) of the title compound.

Formulation Example 1 (capsule) (1) Compound of Example 1 50 mg (2) Lactose 59.5 mg (3) Corn starch 40 mg (4) Light anhydrous silicic acid 0.5 mg Total 150 mg Filled into gelatin capsules.

Formulation Example 2 (tablet) (1) Compound of Example 1 50 mg (2) Lactose 48 mg (3) Corn starch 50 mg (4) Polyvinylpyrrolidone 1.5 mg (5) Magnesium stearate 0.5 mg Total 150 mg The tablets were mixed and compressed by the method.

〔The invention's effect〕

The compound of the present invention has a brain protective effect on cerebral anoxia even at a low dose, and is believed to be widely used in the medical field as an agent for improving and treating organic disorders in the brain and mental dysfunction.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 50/30 C07C 50/30 66/00 66/00 69/95 69/95 235/78 235 / 78 235/84 235/84 C07D 295/18 C07D 295/18 Z (72) Inventor Fumio Sato 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka Suntory Ltd. Biomedical Research Institute (72) Inventor Seiji Miyano 2-6-13 Nagaoka, Minami-ku, Fukuoka (72) Inventor Kunihiro Sumoto 2-4 65 Tsutsujigaoka, Onojo-shi (56) References US Patent 3576016 (US, A) -J. Chem. Soc. , Perk in Trans. 1, (1974), (22), p. 2556 to 2559 ・ Gazz. Chim. Ital. , (1980), 110 (4), p. 253-258

Claims (4)

(57) [Claims] 1. A general formula (I) (In the formula, R ¹ , R ² and R ³ each independently represent a hydrogen atom, a methyl group or a methoxy group, A represents an ethylene group or a vinylene group, n represents 0 or 1, and R ⁴ represents a hydrogen atom, A phenylmethylbenzoquinone derivative represented by a hydroxymethyl group or a carboxyl group which may be esterified or amidated, provided that when n is 0, R ⁴ is not a hydrogen atom.). 2. The compound according to claim 1, wherein R ^{4 in the} general formula (I) is a carboxyl group esterified with a linear or branched lower alkyl group. 3. In the general formula (I), R ⁴ is (Wherein R ⁵ and R ⁶ each independently represent a hydrogen atom, a lower alkyl group or a benzyl group, or a heterocyclic group containing a nitrogen atom, which is a group bonded through a nitrogen atom) A compound according to claim 1. 4. The general formula (I) (In the formula, R ¹ , R ² and R ³ each independently represent a hydrogen atom, a methyl group or a methoxy group, A represents an ethylene group or a vinylene group, n represents 0 or 1, and R ⁴ represents a hydrogen atom, A brain function containing a phenylmethylbenzoquinone derivative represented by a hydroxymethyl group or a carboxyl group which may be esterified or amidated, provided that when n is 0, R ⁴ is not a hydrogen atom.) Improver.