JPH0597783A - 2-cyclohexenone compound and cerebral function improver comprising the same compound as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a cerebral function improver, especially a therapeutic agent for sequella of cerebral apoplexy. CONSTITUTION:A compound of formula I (R1 and R3 are H or halogen; R2 is H or 1-3C alkyl; R4 and R5 are H or methyl) such as 3[(diphenylmethyl) amino]-2-cyclohexen-1-one. The compound of formula I is obtained by reacting 1 mol 1,3-cyclohexadione of formula II with 1-1.5mol benzylamine of formula III by adding p-toluenesulfonic acid as a catalyst while removing formed water by azeotropic distillation.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 2-cyclohexenone compound and a cerebral function improving drug containing the compound as an active ingredient, particularly a therapeutic drug for sequelae of stroke.

[0002]

2. Description of the Related Art Compounds similar to the present invention are disclosed, for example, in JP-A-49-5944 and JP-A-49-85050.
No. 62-33140. It is described that these compounds are useful as intermediate raw materials for medicines such as analgesics and sedatives, and also have analgesic and sedative effects. Further, it is described that it is useful as a precursor drug for a drug having a primary or secondary amino group. However, the above publication does not describe the same compound as the present invention at all. The brain function-improving action of the compound according to the present invention is not known or even suggested in the similar compounds described in the above publications.

[0003]

The present inventors have synthesized many compounds using cyclohexanediones as raw materials,
As a result of various studies on these compounds, the compound of formula (I)
In order to complete the present invention, it was found that the 2-cyclohexenone compound represented by the formula (2) has an excellent brain function-improving action despite the fact that it has a different chemical structure from a known drug having a brain function-improving action. I arrived.

[0004]

Means for Solving the Problems That is, the present invention provides a chemical formula 2

[0005]

[Chemical 2]

(In the formula, R ₁ and R ₃ each represent a hydrogen atom or a halogen atom, R ₂ represents a hydrogen atom, or C ₁ -C
₃ represents an alkyl group, and R ₄ and R ₅ each represent a hydrogen atom or a methyl group. ) And a brain function improving drug containing the 2-cyclohexenone compound as an active ingredient.

Preferred compounds of the present invention are represented by the respective substituents of the formula (I). R ₁ and R ₃ are a fluorine atom, a halogen atom such as a chlorine atom or a hydrogen atom, and R ₂ is a hydrogen atom. Examples of R ₄ and R ₅ include a hydrogen atom and a methyl group. Therefore, in the present invention, a compound satisfying a plurality of conditions of each substituent described above is a more preferable compound. Among them, in the present invention, the most preferable compound is a compound (the following compound 1) in which R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are all hydrogen atoms.

Specific examples of preferred compounds are shown below. (Compound 1) 3-[(diphenylmethyl) amino]-
2-Cyclohexen-1-one (Compound 2) 2-Chloro-3-[(diphenylmethyl) amino] -2-cyclohexen-1-one (Compound 3) 3-[(Diphenylmethyl) amino]-
5,5-Dimethyl-2-cyclohexen-1-one (Compound 4) (±) -3-[[α- (2-chlorophenyl) -phenylmethyl] amino] -2-cyclohexen-1-one (Compound 5) (±) -3-[[α- (2-Chlorophenyl) -phenylmethyl] amino] -5,5-dimethyl-2-cyclohexen-1-one (Compound 6) (±) -3-[[α- ( 2-Fluorophenyl) -phenylmethyl] amino] -2-cyclohexen-1-one (Compound 7) (±) -3-[[α- (2-Fluorophenyl) -phenylmethyl] amino] -5,5- Dimethyl-2-cyclohexen-1-one (Compound 8) 3- [N- (diphenylmethyl) -methylamino] -2-cyclohexen-1-one

Among the 3-[(phenylmethyl) amino] -2-cyclohexenone derivatives represented by the formula (I) provided by the present invention, compounds in which R ₂ and R ₃ are both hydrogen atoms are as follows: It can be manufactured according to the method of. That is, it can be produced by reacting 1,3-cyclohexanediones represented by the formula (II) of Chemical formula 3 with benzylamines represented by the formula (III) as starting materials.

[0010]

[Chemical 3]

(R ₁ , R ₄ and R _{5 of the} formulas (II) and (III)
Represents the same meaning as in formula (I). ) In the following, the production method will be described in detail. The amount of the compound represented by the formula (III) used is usually 1 with respect to 1 mol of the compound represented by the formula (II).
It may be at least a molar amount, and there is no particular upper limit, but
Generally, about 1 to 3 mol, more preferably about 1 to 1.5 mol is practically desirable. This reaction is usually carried out in a solvent, and any solvent may be used as long as it does not inhibit this reaction, for example, aromatic hydrocarbons (eg,
Examples thereof include benzene, toluene, xylene), ethers (eg, tetrahydrofuran, dioxane, etc.), alcohols (eg, ethanol, propanol, isopropanol, etc.). The reaction conditions such as reaction temperature and time are not particularly limited, but it is common to carry out the reaction at room temperature to a temperature around the boiling point of the solvent used for the reaction for about 1 to 6 hours. A more preferable production method is to dissolve the compound of formula (II) and the compound of formula (III) in an aromatic hydrocarbon solvent such as benzene or toluene, add paratoluenesulfonic acid as a catalyst, and remove the produced water by azeotropic removal. While refluxing (paratoluenesulfonic acid method).

Further, among the compounds represented by the formula (I), R
Compounds in which ₂ is a C ₁ -C ₃ alkyl group or the like other than a hydrogen atom are compounds of the formula (I) in which R ₃ is a hydrogen atom, to which sodium hydride and the like are added in a solvent such as toluene. After the reaction, the compound can be produced by further adding an alkyl halide such as alkyl iodide and reacting. Further, among the compounds represented by the formula (I), the compounds represented by R ₃ as a halogen atom include compounds represented by R ₃ as a hydrogen atom, such as N-chlorohalogenated imides such as N-chlorosuccinimide. Can be produced by reacting The compound of formula (I) thus obtained can be isolated and purified by known processing means (eg, extraction, distillation, recrystallization, chromatography, etc.).

The compound according to the present invention shows prolongation of survival time against lethality of potassium cyanide (KCN), and has an effective effect also on cerebral ischemia. Therefore, it is an agent for improving cerebral ischemia, especially for the treatment of stroke sequelae. It is useful as a medicine.

When the compound according to the present invention is used as a brain function improving drug, it can be administered by an appropriate administration method such as oral or parenteral administration. Examples of forms for oral administration include tablets, granules, capsules, pills and powders, and examples of forms for parenteral administration include injections, suppositories, solutions and the like. In formulating these pharmaceutical compositions, the compound of the present invention (or its salt in some cases) can be prepared according to a conventional method.

For example, in the case of oral preparations, excipients such as lactose, glucose, corn starch and sucrose, disintegrants such as calcium carboxymethyl cellulose and hydroxypropyl cellulose, calcium stearate, magnesium stearate, talc, polyethylene glycol, hardened. Lubricants such as oil, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin,
A binder such as gum arabic, a wetting agent such as glycerin and ethylene glycol, and a surfactant if necessary,
It can be prepared into a desired dosage form using a corrigent or the like.

In the case of parenteral preparations, diluents such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar and tragalant gum are used, if necessary, with solubilizers, buffers, Preservatives, fragrances, colorants and the like can be used.

When the compound of the present invention is formulated as a brain function-improving agent, the dosage unit of the compound of the present invention is 5 to 500 mg, preferably 5 to 50 mg per day for oral administration per adult, parenterally. In the case of 1 to 100m per day
The desired therapeutic effect can be expected by the administration in a range of g, preferably 1 to 10 mg, and the administration is divided into 1 to 3 times a day.

[0018]

EXAMPLES Next, synthesis examples of the compounds according to the present invention, formulation examples,
A test example will be shown as an example. (Synthesis example)

Example 1 Synthesis of 3-[(diphenylmethyl) amino] -2-cyclohexen-1-one (Compound 1) Benzhydrylamine (= diphenylmethylamine)
2.00 g (10.59 mmol), 1,2,3-cyclohexanedione 1.22 g (10.59 mmol) and p-toluenesulfonic acid 0.10 g were dissolved in benzene 50 ml, and water was removed azeotropically with a Dean-Stark tube. Reflux for 5 hours. After the reaction, the reaction solution is washed with saturated sodium carbonate water and dried with sodium sulfate, and the solvent is distilled off to obtain crystals. The crystals are recrystallized with an ethyl acetate solvent to obtain 2.79 g (yield 94.9%) of pale yellow crystals of the target compound. Analysis value Melting point: 178 ° C. H-NMR (PPM, CDCl ₃ ) 1.97 (2H, m), 2.17-2.46 (4H,
m), 4.70 (1H, br), 5.00 (1H,
s), 5.47 (1H, d, J = 6Hz), 7.00-
7.31 (10H, m) IRv _max cm ^-1 (KBr) 3270, 1595, 1570, 1530, 1495,
1260, 1185

Examples 2 to 6 In the same manner as in Example 1, the following compounds were synthesized.
The yield and analysis values such as NMR are shown below.

Example 2 Synthesis of 3-[(diphenylmethyl) amino] -5,5-dimethyl-2-cyclohexen-1-one (Compound 3) Yield 65% Analytical value Melting point: 198-202 ° C H-NMR (PPM, CDCl ₃ ) 1.07 (6H, s), 2.15 (2H, s), 2.
25 (2H, s), 4.75 (1H, br), 5.01
(1H, s), 5.57 (1H, d, J = 6Hz),
7.13-7.39 (10H, m) IRν _max cm ^-1 (KBr) 3230, 3040, 2975, 1590, 1655,
1495, 1275, 1155

Example 3 Synthesis of (±) -3-[[α- (2-chlorophenyl) -phenylmethyl] amino] -2-cyclohexen-1-one (Compound 4) Yield 89% Analytical value Melting point: 183 C 1 H-NMR (PPM, CDCl ₃ ) 1.98-2.01 (2H, m), 2.28-2.31
(2H, m), 2.40-2.43 (2H, m),
4.77 (1H, br), 4.97 (1H, s),
5.91 (1H, d, J = 4.88Hz), 7.21-7.
39 (9H, m) IRν _max cm ^-1 (KBr) 3230, 3050, 1600, 1585, 1580,
1570, 1535, 1510, 1260, 1190

Example 4 Synthesis of (±) -3-[[α- (2-chlorophenyl) -phenylmethyl] amino] -5,5-dimethyl-2-cyclohexen-1-one (Compound 5) Yield 60 % Analytical value Melting point: 179 ° C. H-NMR (PPM, CDCl ₃ ) 1.07 (3H, s), 1.08 (3H, s), 2.
14 (2H, s), 2.24 (1H, d, J = 6.11H
z), 2.27 (1H, d, J = 6.11Hz), 4.7
9 (1H, br), 4.95 (1H, s), 5.92
(1H, d, J = 5.37Hz), 7.20-7.39
(9H, m) IRν _max cm ^-1 (KBr) 3220, 3050, 1590, 1565, 1545,
1535, 1270, 1150

Example 5 Synthesis of (±) -3-[[α- (2-fluorophenyl) -phenylmethyl] amino] -2-cyclohexen-1-one (Compound 6) Yield 97% Analytical value Melting point: 185 ° C. H-NMR (PPM, CDCl ₃ ) 1.99 (2H, m, J = 6.35Hz), 2.29 (2
H, t, J = 6.35Hz), 2.42 (2H, t, J =
6.35Hz), 4.86 (1H, br), 5.04
(1H, s), 5.81 (1H, d, J = 5.86H
z), 7.03-7.36 (9H, m) IRv _max cm ^-1 (KBr) 3280, 1600, 1570, 1535, 1490,
1260, 1190

Example 6 Synthesis of (±) -3-[[α- (2-fluorophenyl) -phenylmethyl] amino] -5,5-dimethyl-2-cyclohexen-1-one (Compound 7) Yield 60% analytical value Melting point: 178 ° C. H-NMR (PPM, CDCl ₃ ) 1.07 (3H, s), 1.09 (3H, s), 2.
16 (2H, s), 2.27 (2H, s), 4.76
(1H, br), 5.02 (1H, s), 5.83 (1
H, d, J = 5.86 Hz), 7.03-7.36 (9
H, m) IRν _max cm ^-1 (KBr) 3220, 3030, 2960, 1590, 1550,
1490, 1450, 1275, 1150

Example 7 2-Chloro-3-[(diphenylmethyl) amino] -2
-Synthesis of cyclohexen-1-one (compound 2) 3- (diphenylmethylamino) -2-cyclohexen-1-one (compound 1) 1.50 g (5.41 mmol) dissolved in ethanol, water 9: 1 mixed solvent 20 ml to N
-0.79 g (5.80 mmol) of chlorosuccinimide was added, and the mixture was reacted with stirring at room temperature for 21 hours. The solvent is distilled off under reduced pressure, the obtained residue is dissolved in chloroform, this is washed with water and dried over sodium sulfate, and the solvent is distilled off to obtain crystals.
The crystals are recrystallized with an ethanol solvent to obtain 1.45 g (yield 86%) of light brown needle crystals of the target compound. Analytical value Melting point: 158 ° C. H-NMR (PPM, CDCl ₃ ) 1.80-2.03 (2H, m) 2.45 (2H, t,
J = 6Hz), 2.51 (2H, t, J = 6Hz), 5.
75 (1H, d, J = 7Hz), 6.01 (1H, b
r), 7.13-7.45 (10, m) IRv _max cm ^-1 (KBr) 3380, 2950, 1700, 1635, 1570,
1495, 1450, 1405

Example 8 3- [N- (diphenylmethyl) -methylamino] -2
-Synthesis of cyclohexen-1-one (Compound 8) Sodium hydride (60%) was added to a solution of 3- (diphenylmethylamino) -2-cyclohexen-1-one (Compound 1) 1.50 g (5.41 mmol) in dimethoxyethane 50 ml. 0.48 g (11.9 mmol) was added and 1
Reflux for an hour. After cooling, 0.78 g (5.41 mmol) of methyl iodide was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is added to ice water, stirred and extracted with chloroform. The extract is dried over sodium sulfate and the solvent is distilled off under reduced pressure to obtain an oily residue. The residue is subjected to silica gel column chromatography with a solvent of ethyl acetate to obtain crystals. The crystals are recrystallized in an ethyl acetate solvent to obtain 0.72 g (yield 45.3%) of colorless and transparent prismatic crystals of the target compound. Analytical value Melting point: 135 to 137 ° C. H-NMR (PPM, CDCl ₃ ) 2.00 (2H, m), 2.32 (2H, t, J = 6.8)
4Hz), 2.61 (2H, t, J = 5.86Hz) 2.
71 (3H, s), 5.31 (1H, s), 6.27
(1H, s), 7.11-7.39 (10H, m) IRv _max cm ^-1 (KBr) 2960, 1601, 1518, 1415, 1265,
1190,1095

(Formulation Example) Example 9 (Preparation of tablets) Compound of the present invention (Compound 1) 250 g Lactose 620 g Corn starch 400 g Hydroxypropyl cellulose 20 g Magnesium stearate 10 g The above compound of the present invention, lactose and corn starch are mixed until uniform. After that, a 5 W / V% ethanol solution of hydroxypropyl cellulose is added, and the mixture is kneaded and granulated. 1
After sieving through a 6-mesh sieve and sizing
Weight per tablet 130 mg, diameter 7 mm, main drug content 25 mg
As tablets.

Test Example Test Example 1 Effect on survival time after administration of potassium cyanide (KCN) Test method: ddY male mice (5 weeks old, 10 mice per group)
KCN (3.0 mg / kg) was intravenously administered to the caudal vein for 5 seconds, and the time until respiratory arrest (survival time) was measured. The test compound was dissolved in physiological saline, and if it could not be dissolved, it was suspended in 0.5% Tween 80 and intraperitoneally 30 minutes before the start of the experiment at a rate of 10 ml / kg with a volume of 50 mg / kg. Was administered. As a control, physiological saline was intraperitoneally administered at a rate of 10 ml / kg 30 minutes before the start of the experiment.

Test results: Shown below. The survival rate (%) of each test compound was calculated by setting the average survival time (50 seconds) of the control group as 100%. Test compound Life extension rate (%) Control 100 Compound 1 219 Compound 3 135 Compound 4 122 Compound 5 145

Test Example 2 Anti-cerebral ischemia test Test method: Method of Tobe et al.
-429, 1983), male ddY mice (body weight 24-27 g, control group 12 mice, test compound group 8-)
The test compound (50 mg / kg) was intraperitoneally administered to 11 animals, and the animals were decapitated 30 minutes after the administration. After decapitation, head gasping
The time to stop breathing (survival time) was measured.

Test results: Shown below. The survival rate (%) of each test compound was calculated by setting the average survival time (18 seconds) of the control group as 100%. Test compound gasping duration (%) Control 100 Compound 1 129 Compound 2 112 Compound 3 121 Compound 5 122 Compound 6 119 Compound 7 118

Test Example 3 Anti-cerebral ischemia test (effect on model animal for sequelae of stroke) Test method: Electric scalpel under anesthesia of middle cerebral artery of Fisher 344 strain rat (8 to 10 weeks old, 12 to 13 animals per group). Coagulated, cut and blocked. From the next day, the test compound (Compound 1) was orally administered once a day for 2 weeks. The test compound was suspended in 0.2% Tween 80 and orally administered at a rate of 5 ml / kg with a volume of 10 mg / kg or 50 mg / kg. Water containing 0.2% Tween 80 was administered to the control group and the sham operation group at a rate of 5 ml / kg. To assess motor function in rats, 2, 7, 1 after occlusion of the middle cerebral artery
On the 4th and 28th days, the paralysis of the extremities (rigidity of the extremities when lifted with the tail), reflexes of the extremities (retraction reflex when pinching the extremities with tweezers), and the position of the extremities during walking were observed. Each limb was scored as 1 point for normal and 0 point for abnormal, regardless of the degree. Test result: Shown in FIG.

Test Example 4 (Acute toxicity) Test method: Male ddY mice (5 to 6 weeks old, 3 or 4)
) Were used. The test compound was dissolved in physiological saline, and if it could not be dissolved, it was suspended in 0.2% Tween 80 to give 10 ml / k.
It was intraperitoneally administered at a rate of g. The life and death of the animals was observed up to 3 days after the administration. The test results (dead case / experimental case) are shown in Table 1.

[0035]

[Table 1]

[0036]

The compound of the present invention has a strong improving effect on hypoxic injury and cerebral ischemia, and exhibits an improving effect on brain function against cerebral injury caused by stroke and the like. In addition, since the compound of the present invention has low toxicity and exhibits effects both in oral and parenteral administration, it is useful as a medical drug for human use.

[0037]

[Brief description of drawings]

FIG. 1 is a diagram scoring motor function when a compound of the present invention is administered to a model animal for sequelae of stroke.

Claims (4)

[Claims] 1. Chemical formula 1 [Formula (I)] (In the formula, R ₁ and R ₃ each represent a hydrogen atom or a halogen atom, R ₂ represents a hydrogen atom or a C ₁ -C ₃ alkyl group, and R ₄ and R ₅ each represent a hydrogen atom or a methyl group. 2-cyclohexenone compound represented by 2. A 2-cyclohexenone compound according to claim 1, wherein R ₂ and R ₃ are both hydrogen atoms. 3. The 2-cyclohexenone compound according to claim 2, wherein R ₁ , R ₄ and R ₅ are all hydrogen atoms. 4. A brain function improving drug comprising the compound according to claim 1 as an active ingredient.