JP3228557B2 - 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 cyclohexenone compound and a cerebral function improving drug containing the compound as an active ingredient, particularly a drug for treating sequelae of stroke.

[0002]

2. Description of the Related Art A compound similar to the cyclohexenone compound represented by the following formula 2 according to the present invention is disclosed in, for example,
No. 5,83,786. It is described that these compounds are useful as intermediate materials for pharmaceuticals such as antispasmodics and antihypertensives. However, the publication does not describe the same compound as that of the present invention, and further does not know or suggest any action for improving brain function.

[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)
Has been found that the cyclohexenone compound represented by has a superior brain function-improving action despite its chemical structural difference from a known drug exhibiting a brain function-improving action, and has completed the present invention. .

[0004]

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

[0005]

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Wherein R ₁ is a pyridyl group, a thiazolyl group,
A benzothiazolyl group or a morpholino group, R ₂ represents a hydrogen atom, a phenyl group or a pyridyl group optionally substituted by a halogen atom, R ₃ represents a hydrogen atom, a methyl group or a halogen atom, and R ₄ represents a hydrogen atom. An atom, a methyl group or a phenyl group; R ₅ represents a hydrogen atom or methyl;
R ₆ represents a hydrogen atom or a phenyl group, and n represents 0 or 1. ) And a brain function improving agent containing the compound as an active ingredient.

The preferred compounds of the present invention are represented by the following substituents of the formula (I): R ₁ is a pyridyl group or benzothiazolyl group, R ₂ is a hydrogen atom or a phenyl group, R ₄
Examples of R ₅ and R ₅ include a hydrogen atom or a methyl group, or a compound in which R ₄ is a phenyl group and R ₅ is a hydrogen atom. Therefore, in the present invention, a compound that satisfies a plurality of conditions of each of the above substituents is more preferable.

[0008] Specific examples of preferred compounds are shown below. (Compound 1) 3-[(3-pyridyl) amino] -2-
Cyclohexen-1-one (compound 4) 3-[(2-pyridyl) amino] -2-
Cyclohexen-1-one (compound 5) 3-[(2-pyridylmethyl) amino]
-2-cyclohexen-1-one (compound 6) 5,5-dimethyl-3-[(2-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 9) (±) -3-[(phenyl -2-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 10) (±) -5,5-dimethyl-3-
[(Phenyl-2-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 19) (±) -5-phenyl-3-[(3-
Pyridylmethyl) amino] -2-cyclohexene-1-
ON (Compound 22) 3- (6-benzothiazolylamino)
-2-methyl-2-cyclohexen-1-one

The cyclohexenone compound represented by the formula (I) provided by the present invention can be produced according to the following method. That is, a cyclohexenone compound represented by the formula (I) is produced by reacting 1,3-cyclohexanedione represented by the formula (II) represented by the chemical formula 3 with an amine represented by the formula (III) as a starting material. can do.

[0010]

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(In the formulas (II) and (III), R ₁ , R ₂ ,
R ₃ , R ₄ , R ₅ and R ₆ have the same meaning as in formula (I). Hereinafter, the production method will be described in detail. The amount of the compound represented by the formula (III) is usually 1 mol or more per 1 mol of the compound represented by the formula (II), and the upper limit is particularly limited. Although not limited, generally about 1-3 mol, and more preferably about 1-1.5 mol are practically desirable. This reaction is usually 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, benzene, toluene, xylene, etc.) and 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. The compound of formula (I) thus obtained can be isolated by known processing means (eg, extraction, distillation, recrystallization, chromatography, etc.).
It can be purified.

A more preferred production method will be described below. (Paratoluenesulfonic acid method) A compound of the formula (II) and a compound of the formula (III) are dissolved in an aromatic hydrocarbon solvent such as benzene and toluene, paratoluenesulfonic acid is added as a catalyst, and the produced water is azeotropic. Reflux while removing.

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. Examples of the form for oral administration include tablets, granules, capsules, pills, and powders, and examples of parenteral administration include injections, suppositories, and liquid preparations. 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 and sucrose, disintegrants such as carboxymethylcellulose calcium and hydroxypropylcellulose, calcium stearate, magnesium stearate, talc, polyethylene glycol, and 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 3- (3-pyridylamino) -2-cyclohexene-1
Synthesis of -one (Compound 1) 3-aminopyridine 1.00 g (10.62 mmol), 1,
1.23 g (10.62 mmol) of 3-cyclohexanedione
0.10 g of paratoluenesulfonic acid and 50 parts of benzene
and reflux for 3.5 hours while azeotropically removing water with a Dean-Stark tube. 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 with a benzene solvent to obtain 1.73 g (yield: 86.4%) of pale pink crystals of the target compound. Analytical value H-NMR (PPM, CDCl ₃ ) 1.90-2.17 (2H, m), 2.35 (2H,
t, J = 6 Hz), 2.52 (2H, t, J = 6 Hz),
5.44 (1H, s), 7.04 (1H, br), 7.1
8 (1H, dd, J = 8.5 Hz), 7.47 (1H,
dm, J = 8 Hz), 8.30 (1H, dd, J = 5.2H)
z), 8.32 (1H, d, J = 3 Hz) Melting point: 161-164 ° C IRν _max cm ⁻¹ (KBr) 3225, 1580, 1555, 1520, 1410

Examples 2 to 24 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-[(3-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 2) Yield: 88% Analytical value H-NMR (PPM, CDCl ₃ ) 1.90 -2.20 (2H, m), 2.25-2.45
(4H, m), 4.28 (2H, d, J = 5 Hz),
5.01 (1H, br), 5.18 (1H, s), 7.
28 (1H, dd, J = 8.5 Hz), 7.60 (1
H, dm, J = 8 Hz), 8.48 (2H, m) Melting point: 127.5-129 ° C. IRν _max cm ⁻¹ (KBr) 3270, 1600, 1580, 1545, 1540

Example 3 Synthesis of 3- (4-morpholinylamino) -2-cyclohexen-1-one (compound 3) Yield: 96% Analytical value H-NMR (PPM, CDCl ₃ ) 1.88- 2.10 (2H, m), 2.20-2.45
(4H, m), 2.72 (4H, t, J = 5 Hz),
3.72 (4H, t, J = 5 Hz), 5.30-5.90
(1H, br), 5.65 (1H, s) Melting point: 172-14.5 ° C. IRν _max cm ⁻¹ (KBr) 3200, 1600, 1580, 1570, 1550,
1530

Example 4 3- (2-pyridylamino) -2-cyclohexene-1
Synthesis of -one (Compound 4) Yield: 32% Analytical value H-NMR (PPM, CDCl ₃ ) 1.88-2.21 (2H, m), 2.41 (2H,
t, J = 6 Hz), 2.56 (2H, t, J = 6 Hz),
6.23 (1H, s), 6.80 (1H, br), 6.
92 (1H, ddd, J = 7, 5, 1 Hz), 7.06
(1H, d, J = 8.5 Hz), 7.60 (1H, dd)
d, J = 8.5, 7, 1.5 Hz), 8.24 (1H, d
m, J = 5 Hz) Melting point: 180-182 ° C. IRν _max cm ⁻¹ (KBr) 3310, 1605, 1580, 1530, 1470

Example 5 Synthesis of 3-[(2-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 5) Yield: 75% Analytical value H-NMR (PPM, CDCl ₃ ) 1.90 -2.15 (2H, m), 2.36 (2H,
t, J = 6 Hz), 2.50 (2H, t, J = 6 Hz),
4.37 (2H, d, J = 5 Hz), 5.17 (1H,
s), 6.10 (1H, br), 7.16-7.30
(2H, m), 7.70 (1H, ddd, J = 8,
8, 1.5 Hz), 8.56 (1H, dd, J = 5, 1.
5Hz) Melting point: 102.5-103.5 ° C IRν _max cm ^-1 (KBr) 3250, 1580, 1515, 1430, 1370,
1240, 1190

Example 6 Synthesis of 5,5-dimethyl-3-[(2-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 6) Yield: 83% Analytical value H-NMR (PPM, CDCl ₃ ) 1.10 (6H, s), 2.21 (2H, s), 2.
33 (2H, s), 4.36 (2H, d, J = 5H
z), 5.15 (1H, s), 6.05 (1H, b
r), 7.15-7.28 (2H, m), 7.68
(1H, ddd, J = 7, 7, 2 Hz), 8.53 (1
H, m) Melting point: 126.0-127.0 ° C IRν _max cm ^-1 (KBr) 3230, 1595, 1490, 1375, 1280,
1155

Example 7 Synthesis of (±) -3-[(phenyl-3-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 7) Yield: 82% Analytical value H-NMR (PPM, CDCl ₃ ) 1.90-2.10 (2H, m), 2.28 (2H,
t, J = 6 Hz), 2.42 (2H, t, J = 6 Hz),
4.95 (1H, br), 4.99 (1H, s), 5.
57 (1H, d, J = 6 Hz), 7.12-7.40 (6
H, m), 7.49 (1H, ddd, J = 8, 2, 2H
z), 8.46-8.54 (2H, m) Melting point: 158.5-159.5 ° C IRν _max cm ^-1 (KBr) 3250, 3060, 1575, 1545, 1265
1190

Example 8 Synthesis of (±) -5,5-dimethyl-3-[(phenyl-3-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 8) Yield: 38% Analytical value H-NMR (PPM, CDCl ₃ ) 1.09 (6H, s), 2.16 (2H, s), 2.
27 (2H, s), 4.81 (1H, br), 4.9
8 (1H, s), 5.60 (1H, d, J = 6 Hz),
7.12-7.54 (7H, m), 8.52 (2H,
m) Melting point: 192.5-193.0 ° C IRν _max cm ^-1 (KBr) 3230, 3050, 1590, 1555, 1380,
1280, 1155

Example 9 Synthesis of (±) -3-[(phenyl-2-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 9) Yield: 72% Analytical value H-NMR (PPM, CDCl ₃ ) 1.87-2.12 (2H, m), 2.29 (2H,
t, J = 6 Hz), 2.52 (2H, t, J = 6 Hz),
5.10 (1H, s), 5.52 (1H, d, J = 6H)
z), 6.85 (1H, br), 7.10-7.40
(7H, m), 7.61 (1H, ddd, J = 8,
7.2, 2 Hz), 8.56 (1 H, m) Melting point: 170.0-170.5 ° C IRν _max cm ^-1 (KBr) 3200, 3000, 1615, 1580, 1540,
1250, 1180

Example 10 Synthesis of (±) -5,5-dimethyl-3-[(phenyl-2-pyridylmethyl) amino] -2-cyclohexen-1-one (Compound 10) Yield: 56% Analytical value H-NMR (PPM, CDCl ₃ ) 1.06 (3H, s), 1.08 (3H, s), 2.
14 (2H, s), 2.36 (2H, s), 5.05
(1H, s), 5.52 (1H, d, J = 6 Hz),
6.84 (1H, br), 7.10-7.37 (7H,
m), 7.62 (1H, ddd, J = 8, 8, 2H
z), 8.53 (1H, m) Melting point: 118.5-120.0 ° C IRν _max cm ^-1 (KBr) 3230, 3050, 2960, 1590, 1560,
1275,1150

Example 11 Synthesis of (±) -5,5-dimethyl-3-[(phenyl-4-pyridylmethyl) amino] -2-cyclohexen-1-one (Compound 11) Yield: 69% Analytical value H-NMR (PPM, CDCl ₃ ) 1.10 (6H, s), 2.17 (2H, s), 2.
29 (2H, s), 4.75 (1H, br), 4.9
5 (1H, s), 5.52 (1H, d, J = 6 Hz),
7.15 (2H, d, J = 6 Hz), 7.20-7.40
(5H, m), 8.56 (2H, d, J = 6 Hz) Melting point: 187.0-189.0 ° C IRν _max cm ^-1 (KBr) 3220, 3030, 1590, 1530, 1410,
1270, 1150

Example 12 Synthesis of 3-[(2,2-dipyridylmethyl) amino] -2-cyclohexen-1-one (Compound 12) Yield: 38% Analytical value H-NMR (PPM, CDCl ₃ ) 1 .88-2.15 (2H, m), 2.31 (2H,
t, J = 6 Hz), 2.57 (2H, t, J = 6 Hz),
5.05 (1H, s), 5.70 (1H, d, J = 6H)
z), 7.10 (1H, br), 7.17 (2H, d
dd, J = 7.5, 4.5, 1.5 Hz), 7.40 (2
H, d, J = 7.5 Hz), 7.63 (2H, ddd, J
= 7.5, 7.5, 2.0 Hz), 8.54 (2H, dm,
J = 4.5 Hz) Melting point: 202.5-204.0 ° C. IRν _max cm ⁻¹ (KBr) 3210, 3020, 2960, 1610, 1590,
1550, 1440, 1265, 1190

Example 13 Synthesis of (±) -3-[(2-chlorophenyl-2-pyridylmethyl) amino] -2-cyclohexen-1-one (Compound 13) Yield: 82% Analytical value H-NMR ( PPM, CDCl ₃ ) 1.98 (2H, m), 2.28 (2H, m), 2.
51 (2H, t, J = 5.86 Hz), 5.01 (1H,
s), 6.08 (1H, d, J = 5.37 Hz), 6.8
7 (1H, br), 7.16-7.25 (3H, m),
7.34-7.41 (3H, m), 7.63 (1H,
ddd, J = 7.81, 7.81, 1.95 Hz), 8.5
6 (1H, d, J = 4.88 Hz) Melting point: 207.5-209.0 ° C. IRν _max cm ⁻¹ (KBr) 3370, 1610, 1590, 1580, 1575,
1500, 1255, 1190

Example 14 Synthesis of (±) -3-[(2-fluorophenyl-2-pyridylmethyl) amino] -2-cyclohexen-1-one (compound 14) Yield: 89% Analytical value H-NMR (PPM, CDCl ₃ ) 1.99 (2H, m), 2.29 (2H, m), 2.
53 (2H, m), 5.05 (1H, s), 5.91
(1H, d, J = 5.86 Hz), 6.86 (1H, b
r), 7.02-7.09 (2H, m), 7.19-
7.33 (4H, m), 7.63-7.67 (1H, d
dd, J = 7.81, 7.81, 1.95 Hz), 8.54
(1H, d, J = 4.40 Hz) Melting point: 195.5-196.0 ° C. IRν _max cm ⁻¹ (KBr) 3200, 3020, 1610, 1590, 1540,
1490, 1255, 1185

Example 15 Synthesis of (±) -3-[(2-fluorophenyl-2-thiazolylmethyl) amino] -2-cyclohexen-1-one (compound 15) Yield: 90% Analytical value H-NMR ( PPM, CDCl ₃ ) 1.98-2.03 (2H, m), 2.29 (2H,
t, J = 6.35 Hz), 2.48-2.51 (2H,
m), 5.05 (1H, s), 6.01 (1H, b
r), 6.11 (1H, d, J = 5.86 Hz), 7.
08-7.16 (2H, m), 7.31-7.37 (2
H, m), 7.32 (1H, d, J = 3.42 Hz),
7.73 (1H, d, J = 3.42 Hz) Melting point: 166.0-168.0 ° C IRν _max cm ^-1 (KBr) 3250, 3040, 1570, 1530, 1490,
1255, 1190, 1140

Example 16 (±) -3-[(phenyl-2-thiazolylmethyl) amino] -2-cyclohexen-1-one (compound 16)
Synthesis Yield: 88% Analytical values _{H-NMR (PPM, CDCl 3} ) 2.01 (2H, m, J = 6.35Hz), 2.30 (2
H, t, J = 6.35 Hz), 2.50 (2H, m),
5.07 (1H, s), 5.78 (1H, d, J = 5.
37Hz), 5.99 (1H, br), 7.32 (1
H, d, J = 4.32 Hz), 7.33-7.39 (5
H, m), 7.75 (1H, d, J = 4.32 Hz) Melting point: 163.5-165.0 ° C IRν _max cm ^-1 (KBr) 3250, 3070, 1600, 1580, 1535,
1430, 1365, 1260, 1190

Example 17 (±) -5,5-dimethyl-3-[(phenyl-2-thiazolylmethyl) amino] -2-cyclohexene-1-
Synthesis of ON (compound 17) Yield: 88% Analytical value H-NMR (PPM, CDCl ₃ ) 1.06 (3H, s), 1.09 (3H, s), 2.
15 (2H, s), 2.33 (2H, s), 5.03
(1H, s), 5.79 (1H, d, J = 4.88H)
z), 5.92 (1H, br), 7.30 (1H,
d, J = 4.32 Hz), 7.31-7.37 (5H,
m), 7.73 (1H, d, J = 4.32 Hz) Melting point: 172.0-173.0 ° C IRν _max cm ^-1 (KBr) 3220, 2960, 1590, 1565, 1375,
1275,1255,1150

Example 18 (±) -5-phenyl-3-[(2-pyridylmethyl)
Amino] -2-cyclohexen-1-one (Compound 1
Synthesis yield of 8): 85% Analytical values _{H-NMR (PPM, CDCl 3} ) 2.56-2.65 (3H, m), 2.80 (1H, d
d, J = 6.11, 1.72 Hz), 3.40 (1H,
m), 4.38 (2H, m), 5.25 (1H,
s), 6.22 (1H, br), 7.22-7.27
(5H, m), 7.32-7.36 (2H, m),
7.68-7.72 (1H, m), 8.54 (1H,
d, J = 4.88 Hz) Melting point: 163.5-165.0 ° C IRν _max cm ^-1 (KBr) 3270, 1595, 1575, 1525, 1430,
1270, 1230

Example 19 (±) -5-phenyl-3-[(3-pyridylmethyl)
Amino] -2-cyclohexen-1-one (Compound 1
Synthesis of 9) Yield: 81% Analytical value H-NMR (PPM, CDCl ₃ ) 2.47-2.61 (3H, m), 2.74 (1H,
m), 3.34-3.39 (1H, m), 4.30
(2H, d, J = 5.37 Hz), 5.08 (1H, b
r), 5.22 (1H, s), 7.22-7.36
(6H, m), 7.61 (1H, ddd, J = 7.8
1, 2.45, 2.45 Hz), 8.55-8.56 (2
H, m) Melting point: 170.5-172.0 ° C IRν _max cm ^-1 (KBr) 3250, 3070, 1600, 1560, 1540,
1450, 1260

Example 20 Synthesis of (±) -5-phenyl-3-[(3-pyridyl) amino] -2-cyclohexen-1-one (compound 20) Yield: 62% Analytical value H-NMR (PPM _{, CDCl 3) 2.55-2.67 (3H,} m), 2.82-2.89
(1H, m), 3.36-3.44 (1H, m),
5.57 (1H, s), 6.89 (1H, br), 7.
24-7.30 (4H, m), 7.35 (2H, m),
7.55-7.58 (1H, m), 8.40-8.43
(2H, m) Melting point: 192.5-194.0 ° C IRν _max cm ^-1 (KBr) 3250, 1600, 1565, 1525, 1480,
1420, 1275, 1260, 1245

Example 21 Synthesis of (±) -3- (6-benzothiazolylamino) -5-methyl-2-cyclohexen-1-one (compound 21) Yield: 76% Analysis H-NMR ( PPM, CDCl ₃ + CD ₃ OD) 1.12 (3H, d, J = 6.35 Hz), 2.05-
2.13 (1H, m), 2.27-1.38 (2H,
m), 2.42-2.50 (2H, m), 5.63
(1H, s), 7.29 (1H, dd, J = 8.79,
1.95 Hz), 7.79 (1H, d, J = 1.95H)
z), 8.06 (1H, d, J = 8.79 Hz),
8.97 (1H, s) Melting point: 220.0-221.5 ° C IRν _max cm ^-1 (KBr) 3250, 1590, 1555, 1525, 1470,
1405, 1275

Example 22 3- (6-benzothiazolylamino) -2-methyl-2
Synthesis of -cyclohexen-1-one (Compound 22) Yield 81% Analytical value H-NMR (PPM, CDCl ₃ + CD ₃ OD) 1.88 (3H, s), 1.80-2.08 (2H,
m), 2.35-2.65 (4H, m), 7.20
(1H, dd, J = 9.2, 2 Hz), 7.63 (1H,
d, J = 2 Hz), 8.01 (1H, d, J = 9H)
z), 8.90 (1H, s) Melting point: 223.0-22
4.0 ° C. IRν _max cm ⁻¹ (KBr) 3290, 3060, 1580, 1545, 1390,
1310, 1295, 1190

Example 23 3- (6-benzothiazolylamino) -2-chloro-2
Synthesis of -cyclohexen-1-one (compound 23) 3- (6-benzothiazolylamino) -2-cyclohexen-1-one 0.5 synthesized in the same manner as in Example 1.
0 g (2.05 mmol) dissolved in ethanol, water 9: 1
0.3 ml of N-chlorosuccinimide in 10 ml of a mixed solvent of
0 g (2.05 mmol) was added, and the mixture was stirred at room temperature for 23 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 a target compound. Yield 75% Analytical value H-NMR (PPM, CDCl ₃ ) 1.80-2.12 (2H, m), 2.43-2.66
(4H, m), 7.21 (1H, br), 7.22
(1H, dd, J = 9.0, 2.0 Hz), 7.66
(1H, d, J = 2.0 Hz), 8.05 (1H, d,
J = 9.0 Hz), 8.92 (1 H, s) Melting point: 218.0-220.0 ° C. IRν _max cm ⁻¹ (KBr) 3280, 3060, 1625, 1580, 1565,
1545, 1535, 1400, 1300, 1190

Example 24 (±) -4-phenyl-3-[(3-pyridylmethyl)
Amino] -2-cyclohexen-1-one (Compound 2
Synthesis of 4) Yield 72% Analytical value H-NMR (PPM, CDCl ₃ ) 2.20-2.46 (4H, m), 3.55 (1H, d)
d, J = 9.80, 4.90 Hz), 4.33 (1H,
d, J = 5.37 Hz), 4.62 (1H, br),
5.35 (1H, s), 7.18-7.33 (6H,
m), 7.64 (1H, ddd, J = 7.81, 1.9)
5, 1.95 Hz), 8.58 (2H, m) Melting point: 243.5-244.0 ° C IRν _max cm ^-1 (KBr) 3220, 1595, 1580, 1545, 1480,
1235,1215,1195

(Formulation example) Example 25 (Preparation of tablet) Compound of the present invention (Compound 10) 250 g Lactose 620 g Corn starch 400 g Hydroxypropyl cellulose 20 g Magnesium stearate 10 g The above-mentioned compound of the present invention, lactose and corn starch are mixed 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 was dissolved in physiological saline, and the insoluble compound was suspended in 0.5% Tween 80 and administered intraperitoneally at a rate of 10 ml / kg 30 minutes before the start of the experiment. 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. Life expectancy (%) of each test compound, with the average survival time of the control group taken as 100%
Was calculated.

Test Example 2 Anti-cerebral ischemia test Test method: Tobe et al. Method (Japanese Pharmacological Magazine 81, 421)
DdY strain 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. After decapitation, gasping the head (ga
The time until the sping-like respiration stopped (survival time) was measured.

Test results: Shown below. Life expectancy (%) of each test compound, with the average survival time of the control group taken as 100%
Was calculated.

Test Example 3 (Acute toxicity) Test method: Male ddY mice (7-8 weeks old, 3 mice) were used. The test compound is dissolved in physiological saline.
It was suspended in 5% carboxymethylcellulose (CMC) and administered intraperitoneally at a rate of 10 ml / kg. The survival of the animals was observed up to 3 days after the administration. Test results (deaths /
Experimental Example) is shown in Table 1.

[0050]

[Table 1]

[0051]

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.

Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/5375 A61K 31/5375 A61P 25/00 101 A61P 25/00 101 C07D 277/28 C07D 277/28 277/38 277/38 277/62 277/62 295/12 295/12 Z 295/22 295/22 Z (56) Reference JP-A-6-100444 (JP, A) JP-A-5-97783 (JP, A) JP-A-5-51317 (JP, A) JP-A-4-282314 (JP, A) JP-A-6-100510 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 213/00-213 / 36 A61K 31/00-31/5375 C07D 277/00-277/62 C07D 295/00-295/22 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] ## STR1 ## (1) (Wherein, R ₁ represents a pyridyl group, a thiazolyl group, a benzothiazolyl group, or a morpholino group, R ₂ represents a hydrogen atom, a phenyl group or a pyridyl group optionally substituted by a halogen atom, and R ₃ represents a hydrogen atom , A methyl group or a halogen atom, R ₄ represents a hydrogen atom, a methyl group or a phenyl group, R ₅ represents a hydrogen atom or methyl, R ₆ represents a hydrogen atom or a phenyl group, and n represents 0 or 1. A cyclohexenone compound represented by 2. The method according to claim 1, wherein R ₁ is a pyridyl group, R ₃ is a hydrogen atom and R ₄ or R ₅ is a hydrogen atom or a methyl group.
Cyclohexenone compounds as described 3. The cyclohexenone compound according to claim 1, wherein R ₁ is a benzothiazolyl group, n is 0 and R ₆ is a hydrogen atom. 4. The cyclohexenone compound according to claim 1, wherein R ₂ is a hydrogen atom or a phenyl group and n is 1. 5. The cyclohexenone compound according to claim 1, wherein R ₁ is a pyridyl group, R ₃ is a hydrogen atom, R ₄ is a phenyl group and R ₅ is a hydrogen atom. 6. A brain comprising the compound according to claim 1 as an active ingredient.
Ischemic drugs