JP2756740B2 - 2-cyclohexenone compound and cerebral function improving agent containing the compound as active ingredient - Google Patents

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 agent containing the compound as an active ingredient, particularly a therapeutic agent for sequelae of stroke.

[0002]

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

[0003]

DISCLOSURE OF THE INVENTION The present inventors have synthesized many compounds from cyclohexanedione as a raw material,
After various studies on these compounds, the compound of formula (I)
It has been found that the 2-cyclohexenone compound represented by the formula (1) has an excellent brain function-improving action despite its chemical structural difference from a known drug showing a brain function-improving action. Reached.

[0004]

That is, the present invention provides a compound represented by the following formula (I):

[0005]

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(Wherein R ₁ and R ₃ each represent a hydrogen atom or a halogen atom, and R ₂ represents a hydrogen atom or C ₁ -C
_And R ₄ and R ₅ each represent a hydrogen atom or a methyl group. The present invention relates to a 2-cyclohexenone compound represented by the formula (1) and a brain function improving agent containing the 2-cyclohexenone compound as an active ingredient.

When the preferred compounds of the present invention are represented by the respective substituents of the formula (I), R ₁ and R ₃ are each a halogen atom or a hydrogen atom such as a fluorine atom or a chlorine atom, and R ₂ is a hydrogen atom. R ₄ and R ₅ can each be a hydrogen atom or both can be a methyl group. Therefore, in the present invention, a compound that satisfies a plurality of conditions of each of the above substituents is more preferable. Among them, in the present invention, a compound in which R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are all hydrogen atoms (compound 1 below) is mentioned as the most preferred compound.

[0008] 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 wherein both R ₂ and R ₃ are hydrogen atoms are as follows: It can be manufactured according to the method described above. That is, it can be produced by reacting 1,3-cyclohexanedione represented by the formula (II) of Chemical formula 3 with benzylamines represented by the formula (III) as starting materials.

[0010]

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(R ₁ , R ₄ , R _{5 of the} formulas (II) and (III))
Has the same meaning as that of formula (I). Hereinafter, the production method will be described in detail. The amount of the compound represented by the formula (III) is usually 1 to 1 mol of the compound represented by the formula (II).
It is sufficient if it is at least mol, and the upper limit is not particularly limited,
Generally, about 1 to 3 mol, and more preferably about 1 to 1.5 mol, are practically desirable. This reaction is generally performed in a solvent, and any solvent may be used as long as it does not inhibit the reaction. Examples of the solvent include aromatic hydrocarbons (eg,
Examples thereof include benzene, toluene, xylene, etc., ethers (eg, tetrahydrofuran, dioxane, etc.), alcohols (eg, ethanol, propanol, isopropanol, etc.). The reaction conditions such as the reaction temperature and time are not particularly limited, but the reaction is generally carried out from room temperature to a temperature near the boiling point of the solvent used in the reaction for about 1 to 6 hours. A more preferred production method is to dissolve the compound of the formula (II) and the compound of the formula (III) in an aromatic hydrocarbon solvent such as benzene and toluene, add paratoluenesulfonic acid as a catalyst, and azeotropically remove the produced water. This is a method of refluxing while refluxing (p-toluenesulfonic acid method).

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

The compound according to the present invention has a prolonged survival time against potassium cyanide (KCN) lethality and has an effective effect on cerebral ischemia. Useful as a medicine.

When the compound of the present invention is used as an agent for improving brain function, it can be administered by an appropriate administration method such as oral or parenteral. Forms for oral administration include, for example, tablets, granules, capsules, pills, powders and the like, and forms for parenteral administration include, for example, injections, suppositories, liquids and the like. When formulating these compositions for pharmaceutical administration, the compound of the present invention (or a salt thereof 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, sucrose, disintegrants such as carboxymethylcellulose calcium and hydroxypropylcellulose, calcium stearate, magnesium stearate, talc, polyethylene glycol, hardened Lubricants such as oil, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin,
Binders such as gum arabic, humectants such as glycerin and ethylene glycol, and other surfactants as required,
A desired dosage form can be prepared using a flavoring agent and the like.

In the case of a parenteral preparation, a solubilizing agent, a buffering agent, and the like may be used, if necessary, using a diluent such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, or tragarant gum. Preservatives, flavors, coloring agents and the like can be used.

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

[0018]

EXAMPLES Next, synthesis examples and preparation examples of the compounds according to the present invention,
Test examples are shown as examples. (Synthesis example)

Example 1 Synthesis of 3-[(diphenylmethyl) amino] -2-cyclohexen-1-one (compound 1) Benzhydrylamine (= diphenylmethylamine)
2.00 g (10.59 mmol), 1.22 g (10.59 mmol) of 1,, 3-cyclohexanedione and 0.10 g of paratoluenesulfonic acid are dissolved in 50 ml of benzene, and the mixture is dissolved in a Dean-Stark tube while azeotropically removing water. Reflux for 5 hours. After the reaction, the reaction solution is washed with saturated sodium carbonate water, dried over sodium sulfate, and the solvent is distilled off to obtain crystals. The crystals are recrystallized from an ethyl acetate solvent to obtain 2.79 g (yield: 94.9%) of pale yellow crystals of the target compound. Analytical 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 = 6 Hz), 7.00-
7.31 (10H, m) IRν _max cm ^-1 (KBr) 3270, 1595, 1570, 1530, 1495,
1260, 1185

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

Example 2 Synthesis of 3-[(diphenylmethyl) amino] -5,5-dimethyl-2-cyclohexen-1-one (Compound 3) Yield 65% Analysis 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 = 6 Hz),
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% Analysis value Melting point: 183 ℃ 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 = 4.88 Hz), 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 = 6.11 Hz), 4.7
9 (1H, br), 4.95 (1H, s), 5.92
(1H, d, J = 5.37 Hz), 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% Analysis value Melting point: 185 ° C. H-NMR (PPM, CDCl ₃ ) 1.99 (2H, m, J = 6.35 Hz), 2.29 (2
H, t, J = 6.35 Hz), 2.42 (2H, t, J =
6.35 Hz), 4.86 (1H, br), 5.04
(1H, s), 5.81 (1H, d, J = 5.86H)
z), 7.03-7.36 (9H, m) IRν _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) 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) A mixed solvent of ethanol and water in which 1.50 g (5.41 mmol) of 3- (diphenylmethylamino) -2-cyclohexen-1-one (compound 1) is dissolved, and water is 9: 1. N in 20ml
0.79 g (5.80 mmol) of -chlorosuccinimide is added, and the mixture is stirred and reacted at room temperature for 21 hours. The solvent is distilled off under reduced pressure, and the obtained residue is dissolved in chloroform, washed with water, 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-like 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 = 6 Hz), 2.51 (2H, t, J = 6 Hz), 5.
75 (1H, d, J = 7 Hz), 6.01 (1H, b
r), 7.13-7.45 (10, m) IRν _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%) in a solution of 1.50 g (5.41 mmol) of 3- (diphenylmethylamino) -2-cyclohexen-1-one (compound 1) in 50 ml of dimethoxyethane Add 0.48 g (11.9 mmol) and add 1
Reflux for hours. 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 solution 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 an ethyl acetate solvent to obtain crystals. The crystals are recrystallized with an ethyl acetate solvent to obtain 0.72 g (yield: 45.3%) of colorless and transparent prism-like crystals of the target compound. Analytical value Melting point: 135-137 ° C. H-NMR (PPM, CDCl ₃ ) 2.00 (2H, m), 2.32 (2H, t, J = 6.8)
4 Hz), 2.61 (2H, t, J = 5.86 Hz) 2.
71 (3H, s), 5.31 (1H, s), 6.27
(1H, s), 7.11-7.39 (10H, m) IRν _max cm ^-1 (KBr) 2960, 1601, 1518, 1415, 1265
1190, 1095

(Preparation example) Example 9 (Preparation of tablet) Compound of the present invention (Compound 1) 250 g Lactose 620 g Corn starch 400 g Hydroxypropyl cellulose 20 g Magnesium stearate 10 g Mix the above compound of the present invention, lactose and corn starch until uniform After that, a 5 W / V% ethanol solution of hydroxypropylcellulose is added and kneaded and granulated. 1
After passing through a 6-mesh sieve and sieving, the tablets are compressed in a conventional manner,
Weight per tablet 130mg, diameter 7mm, active substance content 25mg
Tablets.

(Test Example) Test Example 1 Effect on survival time after administration of potassium cyanide (KCN) Test method: ddY male mouse (5 weeks old, 10 mice per group)
Was administered 3.0 kg / kg of KCN into the tail vein for 5 seconds, and the time until respiratory arrest (survival time) was measured. The test compound is dissolved in physiological saline, and those that cannot be dissolved are suspended in 0.5% Tween 80, and the suspension is intraperitoneally injected 30 minutes before the start of the experiment at a rate of 10 ml / kg in 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. Assuming that the average survival time (50 seconds) of the control group was 100%, the survival rate (%) of each test compound was calculated. Test compound Life extension (%) Control 100 Compound 1 219 Compound 3 135 Compound 4 122 Compound 5 145

Test Example 2 Anti-cerebral ischemia test Test method: Tobe et al. Method (Japanese Pharmacological Magazine, Vol. 421)
-P.429, 1983), ddY male mice (body weight: 24-27 g, control group: 12, test compound group: 8-
(11 animals) were intraperitoneally administered with 50 mg / kg of the test compound, and decapitation was performed 30 minutes after the administration. Gasping of the head after decapitation
The time until the respiration stopped (survival time) was measured.

Test results: Shown below. Assuming that the average survival time (18 seconds) of the control group was 100%, the survival rate (%) of each test compound was calculated. 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 animal model of sequelae of stroke) Test method: Fisher 344 rats (8 to 10 weeks old, 12 to 13 rats per group) were anesthetized with an electric scalpel under anesthesia. Coagulated, cut and closed. 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 in a volume of 10 mg / kg or 50 mg / kg. The control group and the sham operation group were administered with water containing 0.2% Tween 80 at a rate of 5 ml / kg. To evaluate the motor function of rats, 2, 7, 1 after middle cerebral artery occlusion
Observe the paralysis of the extremities (rigidity of the extremities seen when lifting with the tail), reflexes of the extremities (withdrawal reflex when pinching the extremities with tweezers) and the position of the extremities during walking on days 4 and 28. Each limb was scored as 1 point for normal and 0 point for abnormal cases regardless of the degree. Test results: shown in FIG.

Test Example 4 (Acute toxicity) Test method: ddY male mouse (5-6 weeks old, 3 or 4
Per animal). The test compound is dissolved in physiological saline, and those which cannot be dissolved are suspended in 0.2% Tween 80, and the suspension is dissolved in 10 ml / k.
It was administered intraperitoneally at the rate of g. The survival of the animals was observed up to 3 days after the administration. Table 1 shows the test results (dead examples / experimental examples).

[0035]

[Table 1]

[0036]

EFFECTS OF THE INVENTION The compound of the present invention has a strong improving effect on hypoxic injury and cerebral ischemia, and has a cerebral function improving effect on cerebral injury caused by a stroke or the like. In addition, the compound of the present invention has low toxicity and is effective in both oral and parenteral administration, so that it is useful as a medical drug for human use.

[0037]

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a diagram showing a score of motor function when a compound of the present invention is administered to a stroke sequela model animal.

──────────────────────────────────────────────────の Continued on the front page (58) Fields surveyed (Int. Cl. ⁶ , DB name) C07C 225/20 A61K 31/135 AAM CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] ## STR1 ## (1) (Wherein, 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. The 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 cerebral function improving agent comprising the compound according to claim 1 as an active ingredient.