JPS646193B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel heterocyclic compound, specifically a 2-benzimidazolinone ring or a 3,4-dihydro-
This invention relates to a novel compound having a specific carbamoyl group or thiocarbamoyl group as a substituent at the 3-position of the 2-quinazolinone ring, which has not been described in any literature. The heterocyclic compounds of the present invention, namely 2-benzimidazolinone derivatives, include 3,4-dihydro-2-
The quinazolinone derivative is represented by the following general formula (1). (In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a phenyl group. ^{R 2} represents a hydrogen atom or a lower alkyl group. ^{R 3} represents a lower alkyl group, a benzyl group, or a halogen atom, a lower alkyl group as a substituent, Indicates a phenyl group that may have a lower alkoxy group or a trifluoromethyl group.
R ² and R ³ may form an imidazolyl group together with the nitrogen atom to which they are bonded. Z represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, n represents 0 or 1, and X represents an oxygen atom or a sulfur atom. ) In the above general formula (1), the lower alkyl group defined by R ¹ , R ² , R ³ and Z and the lower alkyl group represented as a substituent of the phenyl group defined by R ³ have 1 to 1 carbon atoms. Examples include chain or branched alkyl groups of 6, such as methyl, ethyl, propyl, butyl, pentyl, and hexyl groups.
The lower alkoxy group that is a substituent of the phenyl group defined by R ³ and the lower alkoxy group defined by Z include alkoxy groups having 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy groups, etc. can be exemplified. Examples of the halogen atom which is a substituent of the phenyl group defined as R ³ include fluorine, chlorine, bromine and iodine atoms. The compound of the present invention represented by the above general formula (1) has anti-inflammatory effects, analgesic effects, etc., and is useful as an anti-inflammatory agent, analgesic agent, etc. The pharmacological effects thereof are as described below. The method for producing the compound of the present invention will be described in detail below. The compounds of the present invention can be produced, for example, by the following methods A to D, depending on the type of carbamoyl or thiocarbamoyl group as a substituent. Each method is shown by a reaction scheme. (In each formula, R ¹ , R ³ , The compound (1-a) of the present invention, in which R ² in general formula (1) is a hydrogen atom, can be produced by reacting with a known isocyanate or isothiocyanate represented by (3). The above reaction is usually carried out in a suitable solvent or without a solvent. Various solvents that are not involved in the reaction can be used, and generally include ethers such as ether, dioxane, and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane. etc. can be used.
This reaction can also be carried out, if necessary, by using reaction aids such as Lewis acids such as stannic chloride, titanium tetrachloride, and aluminum chloride, and bases such as sodium hydride and sodium amide. general formula
The proportions of the compound represented by (2), the compound represented by general formula (3), and the reaction aid may be selected as appropriate, but it is generally advantageous to use equimolar amounts of each. The reaction temperature may be selected appropriately, but it is generally about -20°C to the reflux temperature of the solvent.
The reaction proceeds advantageously within this range. Further, the reaction time may be selected appropriately, but the reaction is generally completed in 1 to 80 hours. In a reaction using an acidic reaction aid, a complex of the target compound and the metal precipitates from the reaction solution after the reaction is completed. By taking this and mixing it in a mixture of the above-mentioned water-unsaturated solvent and water or an acidic aqueous solution, the target compound can be easily released from the metal complex. (In each formula, R ¹ , Z and n are the same as above. ^{R 4} and R ⁵ each represent a lower alkyl group) The dialkylcarbamoyl halide represented by the general formula (4) above is a known compound, and this reaction , a compound (general formula (1-b)) of the present invention in which R ² and R ³ in general formula (1) are lower alkyl groups and X is an oxygen atom is obtained. This reaction is usually carried out in a solvent or without a solvent. As the solvent to be used, the same ones as in <Method A> can be exemplified. Bases such as sodium hydride, sodium amide, trimethylamine, triethylamine, pyridine are preferably used as reaction auxiliaries. The proportions of the compound represented by general formula (2), the compound represented by general formula (4) and the reaction aid may be selected as appropriate, but it is generally advantageous to use equimolar amounts of each. Although the reaction temperature may be selected appropriately, the reaction generally proceeds advantageously when carried out at a temperature of about -20°C to the reflux temperature of the solvent. Further, the reaction time may be selected appropriately, but the reaction is generally completed in 1 to 24 hours. (In each formula, R ¹ , R ² , R ³ , Z and n are the same as above) 1,1'-carbonylimidazole represented by formula (5) used in the above method and general formula (6)
All of the amines represented are known compounds, and by this method, compounds in which X in general formula (1) is an oxygen atom and R ² and R ³ form an imidazolyl group together with the bonded nitrogen atoms, etc. Invention compound (compound of general formula (1-c)) and through this,
The compound (1-d) of the present invention in which X is an oxygen atom can be produced. In the above, the compound represented by general formula (2) and the formula
The reaction of the compound represented by (5) is usually carried out in a solvent. The solvent used may be the same as in <Method A>. This reaction proceeds satisfactorily even without the use of a reaction aid. Further, the ratio of the compound represented by the general formula (2) and the compound represented by the formula (5) may be selected as appropriate, but it is generally preferable to use equimolar amounts. The reaction temperature and reaction time may be selected appropriately, but generally from room temperature to the reflux temperature of the solvent.
The reaction is complete in ~5 hours. In this way, a compound represented by the general formula (1-c) of the present invention is obtained. Furthermore, the reaction between the compound (1-c) obtained above and the amines represented by the general formula (6) is the same as the reaction between the compound represented by the above general formula (2) and the compound represented by the formula (5). The reaction is carried out under similar conditions, whereby the compound of the present invention represented by general formula (1-d) can be obtained. (In each formula, R ¹ , R ² , R ³ , The desired compound (1) of the present invention can be obtained via the compound represented by the general formula (8). Although the compound represented by the above general formula (8) is a new compound, it is not necessary to specifically isolate it in this method. The reaction between the compound represented by general formula (2) and the compound represented by general formula (7) in the above is usually carried out in a solvent. The solvent used may be the same as in <Method A>. Although this reaction proceeds without the use of a reaction auxiliary agent, a reaction auxiliary agent such as a base such as sodium hydride or sodium amide can also be used. The proportions of the compound of general formula (2), the compound of general formula (7) and the reaction aid may be selected as appropriate, but it is generally preferable to use equimolar amounts of each. The reaction temperature and reaction time may be selected appropriately, but generally the reaction temperature is 0°C to 1 to about reflux of the solvent.
The reaction is completed in 24 hours, and a compound represented by general formula (8) can be obtained. The reaction between the compound of general formula (8) and the compound of general formula (6) can be carried out in the same reaction vessel without isolating the compound of general formula (8). In this reaction, the compound of general formula (6) also acts as a reaction aid, and in this case, the compound of general formula (6) is used in a molar amount approximately twice that of the compound of general formula (2) used as the starting material. is preferable. In addition, in the above reaction, a base such as triethylamine or pyridine can be used as a reaction aid. In this case, the compound of general formula (2) using the compound of general formula (6) and the above reaction aid as raw materials. It is desirable to use approximately equimolar amounts of each of them. In either case, the reaction temperature and reaction time are appropriately selected, but the reaction is generally completed in 1 to 5 hours at 0°C to room temperature. After completing each step, the compounds obtained by each of the above methods can be isolated by conventional separation methods such as extraction, recrystallization, column chromatography, etc. Examples of the production of the compounds of the present invention are listed below as examples. The compounds obtained in each example are shown in Table 1 below. Table 2 also shows the physical properties and recrystallization solvents of each compound. [Table] [Table] [Table] [Table] [Table] Example 1 Sodium hydride (50% oil-based) 2.4 g (0.05
2-benzimidazolinone (6.71 g (0.05
mol) was added and stirred at the same temperature for 1 hour. Next, the reaction mixture was cooled to below 0°C and methyl isocyanate was added.
After dropping a solution of 2.9 g (0.05 mol) in 10 ml of tetrahydrofuran, the mixture was gradually warmed to room temperature and stirred overnight. After evaporating the solvent under reduced pressure, water was added to the residue, neutralized with acetic acid, the precipitated crystals were collected, washed, dried, and recrystallized from methanol to give 1-methylcarbamoyl-2-benzimidazolinone (compound No.
1) 7.5g was obtained (yield 78%). Examples 2 and 3 The same procedure as in Example 1 was carried out using ethyl isocyanate or isopropylisocyanate in place of methyl isocyanate, respectively, to obtain 1-
Ethylcarbamoyl-2-benzimidazolinone (Compound No. 3) was obtained with a yield of 92%, and 1-isopropylcarbamoyl-2-benzimidazolinone (Compound No. 5) was obtained with a yield of 83%. Example 4 1.5 g (0.03 mol) of sodium hydride (50% oil) was stirred in 100 ml of tetrahydrofuran at room temperature.
3,4-dihydro-2-quinazolinone 4.7g
(0.031 mol) was added and stirred for 5 hours. Next, the reaction mixture was cooled to below 0°C, 1.8 g (0.031 mol) of methyl isocyanate was added, and the mixture was gradually warmed to room temperature and stirred for 68 hours. The solvent was distilled off under reduced pressure, water was added to the residue, acidified with 1NHCl, and the precipitated crystals were collected. Recrystallization from methanol gave 4.9 g of 3-methylcarbamoyl-3,4-dihydro-2-quinazolinone (Compound No. 2) (yield 78%). Examples 5 and 6 1-Ethylcarbamoyl-3,4-dihydro-2-quinazolinone (Compound No. 4) was prepared in the same manner as in Example 4 using ethyl isocyanate and isopropylisocyanate in place of methyl isocyanate, respectively. and 1-isopropylcarbamoyl-3,4-dihydro-2-quinazolinone (Compound No. 6) were obtained in yields of 89% and 95%, respectively. Example 7 3,4-dihydro-2-quinazolinone 3g
(0.02 mol) and phenyl isocyanate 2.4 g
(0.02 mol) in 50 ml of dioxane after refluxing for 18 hours.
The solvent was distilled off under reduced pressure, and the residue was crystallized from ether and then recrystallized from methanol to obtain 4.6 g of 3-phenylcarbamoyl-3,4-dihydro-2-quinazolinone (Compound No. 8). (yield 87%). Examples 8 to 14 2- in place of 3,4-dihydro-2-quinazoline
Benzimidazolinone was used, and the isocyanates were phenyl isocyanate, 2-chlorophenyl isocyanate, 3-chlorophenyl isocyanate, 4-chlorophenyl isocyanate, 4-methoxyphenyl isocyanate, and 4-chlorophenyl isocyanate, respectively.
1-phenylcarbamoyl-2-benzimidazolinone (Compound No. 7) was prepared using methylphenyl isocyanate and 3-trifluoromethylphenyl isocyanate in the same manner as in Example 7. 1-(2-chlorophenylcarbamoyl)-2-benzimidazolinone (Compound No. 9) with a yield of 79% and 1-(3-chlorophenylcarbamoyl)-2-benz with a yield of 84%. Imidazolinone (compound No. 10) was produced with a yield of 82% and 1-(4
-Chlorphenylcarbamoyl)-2-benzimidazolinone (Compound No. 11) with a yield of 65%, 1-
(4-Methoxyphenylcarbamoyl)-2-benzimidazolinone (Compound No. 12) with a yield of 92%
So, 1-(4-methylphenylcarbamoyl)-
Yield of 2-benzimidazolinone (compound No. 13)
and 1-(3-trifluoromethylphenylcarbamoyl)-2-benzimidazolinone (Compound No. 14) with a yield of 83%. Example 15 1.9 g (0.04 mol) of sodium hydride (50% oil) was stirred at room temperature in 100 ml of tetrahydrofuran.
3,4-dihydro-2-quinazolinone 6.0g
(0.04 mol) was added and stirred for 2 hours. Next, the reaction mixture was cooled to below 0°C, 4.3 g (0.04 mol) of dimethylcarbamoyl chloride was added, and the mixture was gradually warmed to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, ice water was added to the residue, the precipitated crystals were collected and recrystallized from benzene, and 7.8 g of 3-dimethylcarbamoyl-3,4-dihydro-2-quinazolinone (compound No. 15) was obtained. (yield 89%). Examples 16 and 17 Instead of 3,4-dihydro-2-quinazolinone,
7-Methyl-3,4-dihydro-2-quinazolinone and 7-methoxy-3,4-dihydro-2-
Using each of the quinazolinones, 7-methyl-3-dimethylcarbamoyl-
3,4-dihydro-2-quinazolinone (Compound No.
16) with a yield of 75% and 7-methoxy-3-dimethylcarbamoyl-3,4-dihydro-2-quinazolinone (Compound No. 17) with a yield of 83%. Example 18 1.62 g of 1,1′-carbonyldiimidazole
(0.01 mol) was added to 30 ml of tetrahydrofuran and 1.62 g (0.01 mol) of 1-methyl-3,4-dihydro-2-quinazolinone while stirring at medium room temperature, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, ice water was added to the residue, acidified with hydrochloric acid, the precipitated crystals were collected, and recrystallized from ethanol to give 3-(1-imidazolylcarbonyl)-1-methyl-3,4-dihydro-2. ―
2.3 g of quinazolinone (compound No. 18) was obtained (yield
90%). Example 19 5 g (0.033 mol) of 1-methyl-3,4-dihydro-2-quinazolinone was dissolved in 30 g of tetrahydrofuran.
19.8 ml (0.06 mol) of phosgene (30% carbon tetrachloride solution) was added to the mixture under stirring at 0° C. or below, and the mixture was gradually warmed to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, the residue was dissolved in tetrahydrofuran, and it was added dropwise to a solution of methylamine (toluene solution) stirred at below 0°C. After stirring for 2 hours, the solvent was distilled off under reduced pressure, and the residual oil was dissolved. is benzene:acetone=5:1
The product was isolated by silica gel column chromatography using a solvent of 5.6 g of 1-methyl-3-methylcarbamoyl-3,4-dihydro-2-quinazolinone (Compound No. 19) (yield: 78%). Examples 20 and 21 In the same manner as in Example 19, using ethylamine and benzylamine in place of methylamine,
3-ethylcarbamoyl-1-methyl-3,4-
Dihydro-2-quinazolinone (Compound No. 21) was obtained with a yield of 81%, and 3-benzylcarbamoyl-1-
Methyl-3,4-dihydro-2-quinazolinone (Compound No. 23) was obtained in a yield of 75%. Example 22 0.96% (0.02 mol) of sodium hydride (50% oil) was stirred in 40 ml of tetrahydrofuran at room temperature, and 3.24 g (0.02 mol) of 1-methyl-3,4-dihydro-2-quinazolinone was added thereto for 1 hour. It refluxed.
Next, the reaction mixture was cooled to 0° C. or below, and a solution of 1.6 g (0.022 mol) of methylisothiocyanate in 10 ml of tetrahydrofuran was added dropwise, and the mixture was gradually warmed to room temperature and stirred for 1 hour. After cooling to below 0°C again, the reaction solution was neutralized with acetic acid, the solvent was distilled off under reduced pressure, water was added to the residue, the precipitated crystals were collected, and recrystallized from ethanol to obtain 1-methyl-3. -Methylthiocarbamoyl-3,4-dihydro-2-quinazolinone (Compound No. 20) 4.2g was obtained (yield 90%). Example 23 1-Methyl-3,4-dihydro-2-quinazolinone and ethyl isothiocyanate were reacted in the same manner as in Example 22 to form 3-ethylthiocarbamoyl-1-methyl-3,4-dihydro-2. -Quinazolinone (Compound No. 22) was obtained in a yield of 93%. Example 24 2.24 g (0.01 mol) of 1-phenyl-3,4-dihydro-2-quinazolinone was added to 30 ml of dichloroethane.
Methyl isocyanate 0.57g under stirring at medium temperature below 0℃
(0.01 mol) and anhydrous stannic chloride 2.6 g (0.01 mol)
was added, the temperature was gradually raised to room temperature, and the mixture was stirred overnight. Take the precipitate and add 60ml of chloroform and 10% aqueous hydrochloric acid solution.
After stirring for about 1 hour in 15 ml, separate the organic layer and wash with water.
It was dried with Glauber's salt. Chloroform was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 2.3 g of 3-methylcarbamoyl-1-phenyl-3,4-dihydro-2-quinazolinone (Compound No. 24) (yield 78%). ). Examples 25 and 26 3-ethylcarbamoyl-1-phenyl-3,4-dihydro-2- was prepared in the same manner as in Example 24, using ethyl isocyanate and n-butyl isocyanate in place of methyl isocyanate, respectively. Quinazolinone (compound No. 25) yield 84%
And also 3-(n-butylcarbamoyl)-1-
Phenyl-3,4-dihydro-2-quinazolinone (Compound No. 26) was obtained in a yield of 79%. Next, the antiedema effect, analgesic effect, and acute toxicity of the compound of the present invention were measured by the following test methods. <Anti-edema effect> Acute carrageenan edema test method [Japanese Pharmacological Journal,
56, 575 (1960)], 100 mg/Kg of the test compound was orally administered to 6 to 8 male Wistar rats (body weight 150 to 180 g) in each group after overnight fasting.
One hour later, inflammatory substances (1% carrageenan solution,
0.1 ml/rat) was injected subcutaneously into the footpad, and the foot volume was then measured over time. The anti-edema effect was expressed as the edema suppression rate (%) 3 hours after injection of the inflammatory substance. <Analgesic effect> 1 Acetic acid stretching method Koster et al.'s method [Federation
Proceedings) 18 , 412 (1959)], 100 mg/Kg of the test compound was orally administered to each group of 6 to 8 male DDY mice (body weight 20 to 25 g) after an overnight fast. One hour after administration, 0.2 ml of 0.7% acetic acid was intraperitoneally administered to each animal, and stretching symptoms were observed to determine the inhibition rate (%). 2 Modification of Hafner method Fujimura et al.'s modification [Kyoto University Chemical Research Institute Report No. 25]
36 (1951)], 100 mg/kg of the test compound was orally administered to 6 to 8 male DDY mice (body weight 20 to 25 g) in each group after overnight fasting. 45 minutes after administration, a threshold dose of morphine hydrochloride (1.5 to 2.5 mg/Kg) was subcutaneously injected, and the pain response due to cramping was observed for the next 1 hour to determine the inhibition rate (%). <Acute Toxicity Test> The test compound was orally administered to male DDY mice (body weight 20 to 25 g) after an overnight fast. General symptoms after administration were observed for 7 days, and the number of deaths/number of animals per group was calculated for the dose (mg/Kg). In the above tests, all test compounds were 0.25
% carboxymethylcellulose solution. The results of each test are shown in Table 3 below. 【table】

Claims (1)

[Claims] 1 (In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a phenyl group. ^{R 2} represents a hydrogen atom or a lower alkyl group. ^{R 3} represents a lower alkyl group, a benzyl group, or a halogen atom, a lower alkyl group as a substituent, Indicates a phenyl group that may have a lower alkoxy group or a trifluoromethyl group.
R ² and R ³ may form an imidazolyl group together with the nitrogen atom to which they are bonded. Z represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, n represents 0 or 1, and X represents an oxygen atom or a sulfur atom. ) A heterocyclic compound represented by