JPH0586375B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD OF THE INVENTION The present invention relates to anticonvulsants. BACKGROUND ART Various anticonvulsants are known, including phenytoin (diphenylhydantoin) and the like. It has recently been discovered that a compound previously known to have herbicidal activity has antispasmodic activity. Means for Solving the Problems The present invention provides an effective amount of the general formula ()

[ka] [In the formula, one of A and B is

[Formula] (wherein Y ₁ , Y ₂ and Y ₃ represent a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, an amino group, a carboxyl group, a lower alkoxycarbonyl group or a trifluoromethyl group), a naphthyl group or a diphenylmethyl group, and the other is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cyclopentyl group, a cyclohexyl group, or

[Formula] (wherein Z ₁ , Z ₂ and Z ₃ are hydrogen atoms, lower alkyl groups,
(represents a halogen atom or trifluoromethyl group)
, R ₁ , R ₂ and R ₃ represent a hydrogen atom or a lower alkyl group, and X represents an oxygen atom or a sulfur atom. ] Dihydrouracil derivative [hereinafter,
Compound (2) and at least one pharmaceutically acceptable carrier. In the general formula (), Y ₁ , Y ₂ , Y ₃ , Z ₁ ,
The lower alkyl group in the definition of Z ₂ and Z ₃ is a straight chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-
Indicates butyl, i-butyl, etc. Y ₁ , Y ₂ , Y ₃ ,
In the definitions of Z ₁ , Z ₂ , and Z ₃ , halogen atoms include chlorine, bromine, and the like. In the definitions of Y ₁ , Y ₂ , and Y ₃ , the lower alkoxycarbonyl group represents a straight-chain or branched alkoxycarbonyl group having 2 to 7 carbon atoms, such as methoxycarbonyl and ethoxycarbonyl. In the definitions of A and B, the naphthyl group is α-naphthyl, β-
lower alkyl groups include straight chain or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n- pentyl, n
- indicates hexyl, etc. In the definitions of A and B, the lower alkenyl group represents a straight chain or branched alkenyl group having 1 to 6 carbon atoms, such as an allyl group. _R1 ,
In the definition of R ₂ and R ₃ , lower alkyl group has 1 carbon number
~3 straight-chain or branched alkyl groups, i.e. methyl, ethyl, n-propyl, or i-
Indicates propyl. Most of the compound () and its manufacturing method are described in JP-A-55-108858. Preferred examples of the compound () as an active ingredient of the anticonvulsant composition of the present invention are shown below. (1) 1-(2-chlorophenyl)-3-methyl-dihydrouracil (2) 1-(3-chlorophenyl)-3-methyl-dihydrouracil (3) 1-(4-chlorophenyl)-3-methyl-dihydro Uracil (4) 1-(3,4-dichlorophenyl)-3-methyl-dihydrouracil (5) 1-(3,4-dichlorophenyl)-3-methyl-2-thio-dihydrouracil (6) 1-(3,4-dichlorophenyl)-3-ethyl-dihydrouracil(7) 1-(3-trifluoromethylphenyl)-3
-Methyl-dihydrouracil (8) 1-(3-chloro-4-methylphenyl)-3
-Methyl-dihydrouracil (9) 1-(2-methyl-4-chlorophenyl)-3
-Methyl-dihydrouracil (10) 1-phenyl-3-methyl-dihydrouracil (11) 1-methyl-3-(3-chlorophenyl)-dihydrouracil (12) 1-methyl-3-(4-chlorophenyl)- Dihydrouracil (13) 1-methyl-3-(4-chlorophenyl)-2
-thio-dihydrouracil (14) 1-ethyl-3-(4-chlorophenyl)-dihydrouracil (15) 1-isopropyl-3-(4-chlorophenyl)-dihydrouracil (16) 1-cyclohexyl-3-(4 -chlorophenyl)-dihydrouracil (17) 1-allyl-3-(4-chlorophenyl)-dihydrouracil (18) 1-allyl-3-(4-chlorophenyl)-2
-thio-dihydrouracil (19) 1-methyl-3-(4-chlorophenyl)-5
-Methyl-dihydrouracil(20) 1-methyl-3-(4-chlorophenyl)-
5,5-dimethyl-dihydrouracil(21) 1-methyl-3-(4-chlorophenyl)-
6-Methyl-dihydrouracil(22) 1-methyl-3-(4-bromophenyl)-
Dihydrouracil (23) 1-methyl-3-(4-methylphenyl)-
Dihydrouracil (24) 1-Methyl-3-(2,5-dichlorophenyl)-dihydrouracil (25) 1-Methyl-3-(3,4-dichlorophenyl)-dihydrouracil (26) 1-cyclohexyl -3-(3,4-dichlorophenyl)-dihydrouracil (27) 1-methyl-3-(3,4-dichlorophenyl)-5,5-dimethyl-dihydrouracil (28) 1-methyl-3 -(3,4-dichlorophenyl)-5-methyl-dihydrouracil(29) 1-methyl-3-(2-chlorophenyl)-
Dihydrouracil (30) 1-(2,4-dimethylphenyl)-3-methyl-dihydrouracil (31) 1-(2,4-dichlorophenyl)-3-methyl-dihydrouracil (32) 1-( 4-chlorophenyl)-dihydrouracil(33) 1-(4-trifluoromethylphenyl)-
3-Methyl-dihydrouracil (34) 1-Methyl-3-(2,3-dichlorophel)-dihydrouracil (35) 1-Methyl-3-(2-trifluoromethylphenyl)-dihydrouracil (36) 1-Methyl-3-(2,4-dichlorophenyl)-dihydrouracil (37) 1-methyl-3-(2-chloro-6-methylphenyl)-dihydrouracil (38) 1-methyl-3-(2 -fluorophenyl)
-dihydrouracil(39) 1-(4-chlorophenyl)-3-(2,5
-dichlorophenyl)-dihydrouracil (40) 1-(4-chlorophenyl)-3-(2-chlorophenyl)-dihydrouracil (41) 1-(4-chlorophenyl)-3-(2-fluorophenyl)- Dihydrouracil (42) 1-(4-nitrophenyl)-3-methyl-
Dihydrouracil (43) 1-(4-carboxyphenyl)-3-methyl-dihydrouracil (44) 1-(4-aminophenyl)-3-methyl-
Dihydrouracil hydrochloride (45) 1-methyl-3-(2-nitrophenyl)-
Dihydrouracil (46) 1-methyl-3-(2-aminophenyl)-
Dihydrouracil hydrochloride (47) 1-methyl-3-α-naphthyl-dihydrouracil (48) 1-methyl-3-(2-ethoxycarbonylphenyl)-dihydrouracil (49) 1-methyl-3-diphenylmethyl- As demonstrated by the examples, the dihydrouracil compound () has low toxicity and exhibits strong anticonvulsant action. In particular, the following compounds contained in compound () exhibit particularly strong anticonvulsant effects: (1) A is a methyl group, and B is a

[Formula] [In the formula, Y ₁ ' is a halogen atom (especially a chlorine atom),
A nitro group, an amino group, a trifluoromethyl group or a lower alkoxycarbonyl group (especially an ethoxycarbonyl group), and Y ₂ and Y ₃ have the same meaning as defined in formula (). ] or a compound () which is a naphthyl group. In the above, compounds in which Y ₂ and Y ₃ are hydrogen atoms, or Y ₁ ' is a halogen atom (especially a chlorine atom), Y ₂ is a hydrogen atom, and Y ₃ is 3, 4, or 5
Particularly preferred are compounds in which a halogen atom (particularly a chlorine atom) is present in the position. (2) B is a hydrogen atom or a methyl group, A is

[Formula] [In the formula, Y ₁ ″ is a trifluoromethyl group at the 3-position, or a halogen atom (especially a chlorine atom), an amino group, or a trifluoromethyl group at the 4-position, and Y ₂ and Y ₃ are the formula ()
A compound () which is the same meaning as defined in ). In the above, a compound in which Y ₂ and Y ₃ are hydrogen atoms, or a halogen atom in the 4th position of Y ₁ ″,
Particularly preferred are compounds in which Y ₂ is a hydrogen atom and Y ₃ is a halogen atom (especially a chlorine atom) or a methyl group at the 2- or 3-position. (3) Compounds in which X is an oxygen atom (). (4) Compounds in which R ₁ , R ₂ and R ₃ are hydrogen atoms (). When compound () is used as an anticonvulsant, the dose is usually 100 to 800 mg/60 kg once a day,
Administer in 2 or 3 doses. Depending on the purpose and method of administration, tablets, granules, powders, capsules, syrups, injections, etc. prepared by conventional methods are used. For example, when used in tablet form, tablets containing 1 to 85% by weight of active ingredient per tablet are preferably used. For the preparation of tablets, excipients (e.g., lactose, glucose, sucrose, mannitrate, light silicic anhydride, etc.), disintegrants (e.g., starch, sodium alginate, carboxymethylcellulose, calcium, crystalline cellulose, sugar ester, etc.),
Lubricants (e.g., magnesium stearate, talc, etc.), binders (e.g., syrup, gelatin solution, polyvinyl alcohol, polyvinylpyrrolidone, etc.), dispersants (e.g., methylcellulose, etc.), plasticizers (e.g., glycerin, etc.), Coating materials (eg, hydroxypropyl cellulose, etc.), dyes, etc. are used according to conventional methods. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 Anticonvulsant effect The anticonvulsant effect was tested using the following method. (1) Maximum electroconvulsive effect A group of 5 DD male mice weighing 20±1 g were used.
The drug is administered orally and 60 minutes later it is administered to both eyes of mice.
A current of 2000V and 50mA is applied for 0.2 seconds to measure the presence or absence of tonic extension convulsions that occur.When the onset of tonic extension convulsions is suppressed in 3 or more animals, it is judged to be effective, and MED (minimum effective dose) (convulsion The minimum necessary dose to suppress (2) Pentetrazole convulsion method A group of five DD male mice weighing 20±1 g were used. Pentetrazole 120mg/Kg was administered subcutaneously to mice, the presence or absence of clonic convulsions was measured, and when the expression of clonic convulsions was suppressed in 3 or more mice, it was judged to be effective and the MED was calculated. . The results are shown in Table 1.

[Table] Example 2 Anticonvulsant effect (1) Test method This test was conducted using male mice (Carworth farm). The drug was administered in at least three doses (30,
100, 300 mg/Kg), and when the sample amount was sufficient, a fourth dose of 600 mg/Kg was also tested. The solvent used to dissolve each drug was a 30% polyethylene glycol aqueous solution (compounds No. 31 to 38,
45, 47, 48) and 9% saline (compound No. 44, 46)
It is. The following two tests were conducted. MES (maximum electric shock method) Maximum electric shock is performed for 0.2 seconds through a corneal electrode.
It was induced with a 50 mA, 60 Hz alternating current wave (which is 5 to 7 times the shock of the smallest electric shock). A drop of 0.9% saline was placed in the eyes of the mice before the electric shock. Protection was defined as the disappearance of hindlimb tonic extension spasms, and the results are expressed as follows. Number of animals protected from hindlimb tonic extension spasms/number of animals used in the study sc Met (subcutaneous pentylenetetrazole convulsion threshold method)
0.5% (dose that causes convulsions in 95% or more)
Administer as a solution subcutaneously in the posterior midline, 30 minutes after administration.
Observations were made for minutes. Protected was defined as no threshold seizure (one clonic seizure lasting at least 5 seconds), and results are expressed as follows: Number of animals prevented from developing convulsions / Number of animals used in the study (2) Evaluation method Results are classified into the following three criteria: Anticonvulsant activity of 100 mg/Kg or less Anticonvulsant activity of 100 mg/Kg or less Kg or more or 100
When the anticonvulsant effect at mg/Kg is not enhanced even when the dose is increased to 300 mg/Kg When the anticonvulsant effect is not observed at a dose of 300 mg/Kg or higher (3) The results are shown in Table 2.

[Table] Example 3 Acute toxicity test A drug was suspended in a 0.3% CMC solution and orally administered to 3 to 6 DD male mice weighing 20±1 g per group. Mortality was observed for 7 days after administration, and the LD ₅₀ value was determined. The results are shown in Table 3.

[Table] Example 4 10,000 tablets were prepared according to the following composition using a conventional method. The active ingredient in one tablet is 50mg. 1-(4-chlorophenyl)-3-methyl-dihydrouracil (Compound No. 3) 500g Lactose 343g Calcium carboxymethylcellulose 93g Magnesium stearate 4g Talc 8g Polyvinyl alcohol 25g Glycerin 2g Tar pigment Trace amount Example 5 The following composition was prepared by a conventional method. 10,000 tablets were made. The active ingredient in one tablet is 50mg. Main drug (Compound No. 7) 500g Lactose 980g Starch 520g Hydroxypropyl cellulose 80g Magnesium stearate 20g Tar pigment Trace amount 2100g Example 6 10,000 tablets were prepared according to the following composition according to a conventional method. The active ingredient in one tablet is 50mg. Main drug (Compound No. 24) 500g Light anhydrous silicic acid 20g Crystalline cellulose 640g Lactose 1020g Magnesium stearate 20g Tar color Trace amount 2200g Reference example 1 1-(4-chlorophenyl)-3-methyl-dihydrouracil (Compound No. 3) Synthesis 8 g (0.032 mol) of N-(methylcarbamoyl)-N-(4-chlorophenyl)-β-alanine was converted into 6N-
The mixture was heated under reflux for 2 hours in a mixture of 100 ml of hydrochloric acid and 50 ml of acetic acid. After the reaction was completed, 300 ml of water was added and the mixture was left in a cool place. Suction the precipitated crystals and add ethyl acetate.
Recrystallization was performed from 70 ml and 100 ml of n-hexane to obtain 4.8 g of crystals (yield: 64.6%) with a melting point of 145-146°C. Reference example 2 1-(3-trifluoromethylphenyl)-3-
Synthesis of methyl-dihydrouracil (compound No. 7) 32 g (0.1 mol) of N-(methylcarbamoyl)-N-(3-trifluoromethylphenyl)-β-alanine was mixed with 100 ml of 6N hydrochloric acid and 50 ml of acetic acid. The mixture was heated under reflux for 2 hours. After the reaction was completed, 300 ml of water was added and the mixture was left in a cool place. The precipitated crystals were sucked out and recrystallized from 70 ml of ethyl acetate and 100 ml of n-hexane to give 16.2 g of crystals with a melting point of 124-125°C (yield: 60.4
%) was obtained. Reference example 3 1-methyl-3-(2,5-dichlorophenyl)
-Synthesis of dihydrouracil (compound No. 24) N-(2,5-dichlorophenylcarbamoyl)
8.7 g (0.027 mol) of -N-methyl-β-alanine was heated under reflux for 1 hour in 50 ml of thionyl chloride. After the reaction was completed, excess thionyl chloride was distilled off under reduced pressure, and 100 ml of ethyl acetate was added. twice with saturated sodium bicarbonate solution,
After further washing with water, it was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the precipitated crystals were recrystallized from 100 ml of ethyl acetate and 100 ml of n-hexane.
6.6 g (yield: 80.9 g) of crystals with a melting point of 120.5-123°C were obtained. Reference example 4 1-(2-methyl-4-chlorophenyl)-3-
Synthesis of Methyl-dihydrouracil (Compound No. 9) 8.0 g (0.03 mol) of N-(2-methyl-4-chlorophenylcarbamoyl)-N-methyl-β-alanine was heated under reflux in 250 ml of acetic anhydride for 2.5 hours. Acetic anhydride was distilled off under reduced pressure, and the precipitated crystals were recrystallized from 60 ml of ethyl acetate and 150 ml of n-hexane.
1.8 g (yield 24.1%) of crystals with a melting point of 126-127°C was obtained. Reference Example 5 Synthesis of 1-methyl-3-(2-chlorophenyl)-dihydrouracil (Compound No. 29) N-(2-chlorophenylcarbamoyl)-N-
8.7 g (0.03 mol) of methyl-β-alanine was suspended in 50 ml of ethyl acetate, and 10.7 ml of thionyl chloride was added to the suspension.
(0.15 mol) was added and stirred at room temperature for 6 hours. Thereafter, 50 ml of n-hexane was added and left in a cool place overnight. The precipitated crystals were collected by suction, washed with n-hexane and dried, resulting in crystals with a melting point of 120.5-123°C.
6.6g (yield 80.9%) was obtained. Reference Example 6 Synthesis of 1-(2,4-dichlorophenyl)-3-methyl-dihydrouracil (Compound No. 31) N-(2,4-dichlorophenyl)-β-alanine methyl ester 7.44 g (0.03 mol) in 150 ml of tetrahydrofuran (THF) and stirred at -78°C.
19.2 ml (0.03 mol) of butyl lithium was added, followed after a few minutes by 5.4 ml (0.045 mol) of methyl isocyanate. After stirring at the same temperature for 1 hour, a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. After washing with water and a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from toluene to determine the melting point.
1.32g of colorless prism crystals at 154-157℃ (yield 16.1%)
I got it. Reference example 7 1-methyl-3-(2,3-dichlorophenyl)
-Synthesis of dihydrouracil (compound No. 34) 7 g (0.032 mol) of N-methoxycarbonyl-2,3-dichloroaniline was dissolved in 150 ml of anhydrous toluene, 3.84 ml (0.038 mol) of trichlorosilane and 6.6 ml (0.048 mol) of triethylamine. ) added
The mixture was stirred at 80°C for 1 hour. After distilling off excess trichlorosilane under reduced pressure, N-
Methyl-β-alanine nitrile 3.2g (0.038mol)
was added and stirred at room temperature for 1 hour. After adding ethyl acetate and washing sequentially with 3N hydrochloric acid aqueous solution, water, and saturated saline,
It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and recrystallized from toluene-n-hexane to yield 4.12 g of N-(2,3-dichlorophenylcarbamoyl)-N-methyl-β-alanine nitrile.
(yield 47.4%) was obtained as colorless prism crystals with a melting point of 97°C. 3.5 g of the above N-(2,3-dichlorophenylcarbamoyl)-N-methyl-β-alanine nitrile
(0.013 mol) was heated under reflux for 4 hours in a mixture of 30 ml of 6N hydrochloric acid and 10 ml of acetic acid. After the reaction is complete, add 50% water
ml, the precipitated crystals were collected by suction, recrystallized from ethyl acetate-n-hexane, and 1-methyl-3-
(2,3-dichlorophenyl)-dihydrouracil
2.43 g (69.4%) were obtained as pale yellow crystals with a melting point of 163-165°C. Reference example 8 1-(4-trifluoromethylphenyl)-3-
Synthesis of methyl-dihydrouracil (compound No. 33) N-(methylcarbamoyl)-N-(4-trifluoromethylphenyl)-β-alanine 4g (0.014
mol) was heated under reflux for 2 hours in a mixture of 45 ml of 6N hydrochloric acid and 15 ml of acetic acid. After the reaction was completed, 50 ml of water was added, the precipitated crystals were collected by suction, and ethyl acetate-n-
Recrystallization from hexane gave 3.38 g (90.1%) of colorless needle crystals with a melting point of 115-117°C. Reference example 9 1-methyl-3-(2,4-dichlorophenyl)
-Synthesis of dihydrouracil (compound No. 36) Using the same method as in Reference Example 7, 7 g (0.032 mol) of N-methoxycarbonyl-2,4-dichloroaniline and N-methyl-β-alanine nitrile were synthesized.
From 4.0 g (0.048 mol), 1.16 g (15%) of colorless prism crystals with a melting point of 122 to 125°C was obtained. Reference Example 10 Synthesis of 1-methyl-3-naphthyl-dihydrouracil (Compound No. 47) In the same manner as in Reference Example 8, 5 g (0.02 mol) to obtain 3.75 g (73.8%) of crystals with a melting point of 228-229°C.

Claims (1)

[Claims] 1 An effective amount of the general formula [Formula] [In the formula, one of A and B is [Formula] (In the formula, Y ₁ , Y ₂ and Y ₃ are hydrogen atoms, lower alkyl groups, halogen atom, a nitro group, an amino group, a carboxyl group, a lower alkoxycarbonyl group, or a trifluoromethyl group), a naphthyl group, or a diphenylmethyl group, and the other is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cyclopentyl group, a cyclohexyl group, or [Formula] (wherein Z ₁ , Z ₂ and Z ₃ are hydrogen atoms, lower alkyl groups,
(represents a halogen atom or trifluoromethyl group)
, R ₁ , R ₂ and R ₃ represent a hydrogen atom or a lower alkyl group, and X represents an oxygen atom or a sulfur atom. An anticonvulsant composition comprising a dihydrouracil derivative represented by the following formula and at least one pharmaceutically acceptable carrier. 2 A is a methyl group, and B is [Formula] [In the formula, Y ₁ ' is a halogen atom, a nitro group, an amino group, a trifluoromethyl group, or a lower alkoxycarbonyl group, and Y ₂ and Y ₃ are the claims. The anticonvulsant composition according to claim 1, wherein the anticonvulsant composition is a naphthyl group] or a naphthyl group. 3 Y ₂ and Y ₃ are hydrogen atoms, or
Y ₁ ′ is a halogen atom, Y ₂ is a hydrogen atom, and Y ₃ is 3,
The anticonvulsant composition according to claim 2, which is a halogen atom at the 4 or 5 position. 4 B is a hydrogen atom or a methyl group, A is [Formula] [wherein Y ₁ ″ is a trifluoromethyl group at the 3-position, or a halogen atom, an amino group, or a trifluoromethyl group at the 4-position, and
The anticonvulsant composition according to claim 1, wherein Y ₂ and Y ₃ have the same meanings as defined in claim 1. 5 Y ₂ and Y ₃ are hydrogen atoms, or
The anticonvulsant composition according to claim 4, wherein Y ₁ ″ is a halogen atom at the 4-position, Y ₂ is a hydrogen atom, and Y ₃ is a halogen atom or a methyl group at the 2- or 3-position. 6 X is an oxygen atom The anticonvulsant composition according to claim 1, wherein 7. The anticonvulsant composition according to claim 1, wherein R ₁ , R ₂ and R ₃ are hydrogen atoms.