JPS589100B2 - Shinkina Kinazorindion Yudotai no Seizouhou - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (I) (wherein R is a hydrogen atom, a lower alkyl group, a hydroxyl group, a halogen atom, a lower cycloalkyl group, a lower alkoxy group, an alkoxycarbonyl group, an acetoxy group) , a lower alkyl group substituted with a hydroxyalkoxy group or a phenyl group, or an alkenyl group or an alkynyl group).

More specifically, 2 represented by the general formula (n) (wherein R has the same meaning as above)
-(m-nitroanilino)benzoic acid amide derivative with the general formula (I) xcoy(i) (wherein, , trihaloalkyl group, lower alkoxy group, alkoxycarbonyloxy group, aromatic amine group, aliphatic amine group, secondary lower amino group, piperidino group, pyrrolidino group, morpholino group, imidazole group, 1,2,3-triazolyl group The present invention relates to a method for producing a compound represented by the general formula (I) by reacting a compound represented by the formula (I).

To explain R in the general formulas (I) and (I) in more detail, the lower alkyl group of R is a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, etc. , the lower cycloalkyl group of the substituted lower alkyl group is a cycloalkyl group consisting of C3 to C6 carbon atoms, and the substituted phenyl is a phenyl group substituted with lower alkyl, lower alkoxy, halogen atom, nitro, trifluoromethyl, etc. The alkenyl group represents allyl, 3,3-dimethylallyl, crotyl, etc., and the alkynyl group represents glopargyl, etc.

In addition, to further explain X and Y in general formula (I), the halogen atom of X is chlorine, bromine, etc., the lower alkoxy group is an alkoxy group such as methoxy or ethoxy, and the halogen atom and lower alkoxy group of Y are chlorine, bromine, etc. has the same meaning as X, and trihaloalkyl groups include chlorine, bromine, fluorine, etc.
A methyl group substituted with a halogen atom, an alkoxycarbonyl group such as a methoxycarbonyloxy group, a lower alkoxycarbonyloxy group such as an ethoxycarbonyloxy group, an aromatic amino group such as anilino, lower alkyl, lower alkoxy, halogen atom, nitro, etc. represents substituted phenylamino, N-methylanilino, etc., the aliphatic amine group represents methylamine, ethylamino, etc., and the secondary lower alkylamino group represents dimethylamino, diethylamine, etc.

Further, the halogen atom and alkoxy group of Y have the same meaning as that of A lower alkoxy group such as luponyloxy, an acyloxy group such as acetoxy or trihalogenoacetoxy, an amine group, an aromatic amine group (e.g. anilino, m-chloroanilino, etc.),
Aliphatic amino groups (e.g., methylamine, ethylamino, etc.), secondary lower alkylamino groups (e.g., dimethylamino, diethylamino, etc.), cyclic amino groups (e.g., piperidino, morpholino, etc.), and nitrogen-containing heterocyclic groups ( For example, it represents imidazolyl, 1,2,3-triazolyl, etc.).

The quinazolinedione derivative of general formula (I) obtained by the method of the present invention is a novel compound that has not been described in any literature, and has remarkable analgesic effect, anti-inflammatory effect, and central nervous system depressing effect, and is industrially useful as a pharmaceutical. It is a compound.

The object compound of the present invention is disclosed in Patent Application Publication No. 24 of 1971.
It has stronger analgesic and anti-inflammatory effects than the known similar compounds described in Publication No. 031 and the like.

This is illustrated in the following table with examples.

Experimental method (1) Anti-inflammatory effect 5 ml of water was forcibly administered to male Wistar rats (5 rats per group) having an anti-inflammatory effect of 120 to 1501, and 30 minutes later, the test compound was orally administered.

After another hour, add 0.1 ml of 1% lagenin distilled water for injection.
was injected subcutaneously into the footprint, and the edema suppression rate was determined 3 hours later.

(2) Analgesic effect in ddY male mice (10 mice per group) with 17 to 222 0.
0.1ml/1 test compound suspended in 5% tragacanth
0? After 30 minutes, a 0.6% acetic acid aqueous solution was intraperitoneally injected, and from 10 minutes later, the number of stretches (body movements) for 10 minutes was counted to calculate the 50% analgesic amount and its confidence limit. was calculated (p=0.05).

As is clear from the above table, the novel compound of the present invention has much stronger drug-trapping activity than known similar compounds, and is an extremely useful compound as an analgesic and an anti-inflammatory agent.

The 1-(m-nitroanilino)benzoic acid amide derivative (n), which is the starting material of the present invention, can be obtained in good yield by reacting N-(m=nitrophenyl)anthranilic acid chloride with the corresponding amines. The method is not limited.

The reaction formula of the method of the present invention is as follows.

The reaction in the present invention is generally carried out in an inert solvent such as tetrahydrofuran, diglyme, benzene, dimethylformamide, alcohol, and alkali metals and metals such as sodium metal, potassium metal, sodium hydride, sodium amide, sodium alcoholate, etc. Compound,
It is preferable to carry out the reaction in the presence of an organic base such as pyridine or trialkylamine or an inorganic base such as an alkali hydroxide or an alkali carbonate. In particular, the use of the above alkali metals and metal compounds allows the target compound to be obtained in extremely good yields. .

The reaction temperature is not particularly limited, and the reaction proceeds at room temperature, but
Desirably, the reaction proceeds quickly when the reaction is carried out near the boiling point of the solvent used.

A pure product can be obtained from the generated reaction mixture by distilling off the organic solvent, adding water to the residue, collecting precipitated crystals, and recrystallizing from an organic solvent such as methanol, or by column chromatography.

Examples of the present invention are shown below.

Example 1 2-(m-nitroanilino)benzoic acid ethylamide2.
1.0 g of 50% sodium hydride was added to a solution of 9 g and 25 ml of tetrahydrofuran, and after stirring at room temperature for 30 minutes, 5.4 g of ethyl chlorocarbonate was added dropwise while cooling.

Thereafter, the mixture was allowed to stand at room temperature for 1 hour, and then reacted under reflux for 3 hours.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from methanol to give colorless prismatic crystals of 1=(m-nitrophenyl)-3-ethylquinazoline-2.4 (1H -2.51 of 3H)-dione was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 193-194℃ Elemental analysis value ctaH13N3o4 Theoretical value C: 61.73 H: 4.21 N: 13.50 Actual value C: 61, 76 H: 4.11 N: 13.46 Example 2 2-(m -nitroanilino)benzoic acid allylamide 3.
1.1 g of 50% sodium hydride was added to a solution of 0 g and 25 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 30 minutes.

Next, 16 g of a 30% phosgene-toluene solution was gradually added dropwise while cooling.

After the addition, the mixture was stirred at room temperature for 1 hour, and then reacted under reflux for 2 hours.

After the reaction, the solvent was distilled off, water was added to the residue, and the precipitated crystals were recrystallized from methanol to give colorless needle-like crystals of 1-(m-
Nitrophenyl)-3-allylquinazoline-2,4(I
2.8 g of H.3H) monodione was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 165-166℃ Elemental analysis value C17H13N304 Theoretical value C: 63.15 H: 4.05 N: 13.00 Actual value C: 63.25 H: 4.11 N: 12.92 Example 3 2-(m -nitroanilino)benzoic acid methylamide2.
After dissolving 7 g in 25 ml of dry tetrahydrofuran, 50
% sodium hydride and 5.9 g of diethyl carbonate were added and reacted under reflux for 12 hours.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized with methanol to obtain colorless needle-like crystals of 1-
(m-nitrophenyl)-3-methylquinazoline-2.
2.4 g of 4(IH·3H)-dione was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 241-242℃ Elemental analysis value C15H11N304 Theoretical value C: 60.

60 H: 3.73 N: 14.14 Actual value C: 60.83 H: 3.58 N: 14.17 Example 4 2-(m-nitroanilino)benzoic acid-n-propylamide 3, O? After dissolving in 50 ml of tetrahydrofuran,
50% sodium hydride 1. Og and 1,1'-carponyldiimidazole 4,9N were added and stirred at room temperature for 1 hour.
Then, the mixture was allowed to react under reflux for 5 hours.

After the reaction, the solvent was distilled off under reduced pressure, ice water was added to the residue, and the precipitated crystals were recrystallized from methanol to obtain colorless prismatic crystals of 1-(m-nitrophenyl)-3-n-probylquinazoline-2°. 4(IH·3H)-dione 2.6S was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 162-163C Elemental analysis value C17Hl5N3o4 Theoretical value C: 62.76 H: 4.65 N: 1292 Actual value C: 62.68 H: 4.62 N: 12.87 Example 5 2-(m-nitroanilino)benzoic 3.0 g of acid cycloglovir methylamide and 25 ml of dry tetrahydrofuran
About 55% sodium hydride (1.0N) was added to the solution, and after stirring at room temperature for 30 minutes, 4.22% of 1-ethoxyluponylimidazole was gradually added dropwise, and the mixture was refluxed for 3 hours.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from methanol to give colorless needle-like crystals of 1-(m-nitrophenyl)-3-cyclopropylmethylquinazoline. 26 g of -2.4(IH.3H) monodione was obtained.

The melting point and elemental analysis values of this substance are as follows.

Melting point 163-164℃ Elemental analysis value C18H15N3o4 Theoretical value C: 64.09 H: 4.49 N: 12.46 Actual value C: 63.86 H: 4.52 N: 12.57 Example 6 2-(m About 55% sodium hydride (1.01 ml) was added to a solution of 3.01 ml of -nitroanilino)benzoic acid glopargylamide and 25 ml of dry tetrahydrofuran at room temperature for 30 min.
After stirring for a minute, ■-trichloroacetylimidazole 2.
After gradually dropping 1f, the mixture was refluxed for 1 hour.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from methanol to give colorless needle-like crystals of 1-(m-nitrophenyl)-3-7 lobargylquinazoline. 2.8 g of 2.4 (IH.3H) dione was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 222-223°C Elemental analysis value C17H11N304 Theoretical value C: 63.55 H: 3.45 N: 13.08 Actual value C: 63.48 H: 3.51 N: 13.11 Example 7 2-(m = 0.5% sodium hydride (approximately 55%) in a solution of 3.4N nitroanilino)benzoic acid-2,2,2-trifluoroethylamide and 25ml of dry tetrahydrofuran.
After adding f and stirring at room temperature for 1 hour, 5.5 g of trichloroacetyl chloride was added dropwise under cooling, left at room temperature for 1 hour, and then refluxed for an additional 5 hours.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from ethanol to give pale yellow prismatic crystals of 1-(m-nitrophenyl)-3-(2.2.2
-}J fluoroethyl) quinazoline-2, 4 (IH, 3
3.2 g of H) monodione were obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 182-184℃ Elemental analysis value C16H1oF3N304 Theoretical value C: 52.61 H: 2.76 N: 11.51 Actual value C: 52.75 H: 2.89 N: 11.45 Example 8 2-(m -Nitroanilino)benzoic acid pendylamide 3
．． In a solution of 5 g and 30 ml of dry tetrahydrofuran, approx.
After adding 1.02 g of 5% sodium hydride and stirring at room temperature for 30 minutes, 4.9 g of 1-(N-(m-chlorophenyl)carbamoyl]imidazole was added to 30 g of dry tetrahydrofuran.
ml and added dropwise, then left at room temperature for 30 minutes,
Then, the mixture was allowed to react under reflux for 2 hours.

After the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from methanol.
Colorless prismatic 1-(m-nitrophenyl)-3-penzylquinazoline-2.4(IH.3H) monodione2.
6g was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 206-207°C Elemental analysis value C21Hl5N3o4 Theoretical value C: 67.55 H: 405 N: 11.26 Actual value C: 67.45 H: 4.10 N: 11.32 Example 9 2-(m-nitroanilino ) 3.3 g of benzoic acid-2-ethoxyethylamide in 30 ml of dry tetrahydrofuran.
Next, 1.02 g of about 50% sodium hydride was added, and after stirring for 30 minutes, 3.2 g of N-N-dimethylcarbamoyl chloride was added dropwise under ice cooling.

Thereafter, the mixture was allowed to react under reflux for 4 hours. After the reaction, the solvent was distilled off under reduced pressure, ice water was added to the residue, and the precipitated crystals were recrystallized from ethanol to give pale yellow prismatic crystals of 1-(m-nitrophenyl)-3-(2-ethoxyethyl)quinazoline-
3.11 of 2.4(IH.3H)-dione was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 161-162℃ Elemental analysis value 018Hl7N305 Theoretical value C: 60.84 H: 4.82 N: 11.83 Actual value C: 60.67 H: 4.72 N: 11.78 Example 10 2-(m -Nitroanilino)benzoic acid me-xymethylamide (3.0 g) was dissolved in 30 ml of dry tetrahydrofuran, and approximately 50% sodium hydride (1.0 g) was added thereto at room temperature.
Stirred for 0 minutes.

Next, 8.1 g of diethyl pyrocarbonate was added and reacted under reflux for 5 hours.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from methanol to give colorless prismatic crystals of 1-(m-nitrophenyl)-3-methoxymethylquinazoline-2.4 (1H -2.3 g of 3H)-dione was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 165-166°C Elemental analysis value C16H13N305 Theoretical value C: 58.71 H: 4. OO N: 1284 Measured value C: 58.53 H: 3.81 N: 12.91 The following compound was obtained in good yield according to the method of Examples 1 to 10.

1-(m-nitrophenyl)quinazoline-2.4(LH
・3H) monodione Melting point 285-287℃ ■-(m-nitrophenyl)-3-(2-hydroxyethyl)quinazoline-2,4(IH・3H)-dione Melting point 170-172℃ 1-(m-nitrophenyl)- 3-(2-acetoxyethyl)quinazoline-2.4(IH・3H) monodione Melting point 140-141°C 1-(m-nitrophenyl)-3-(isopropyl)quinazoline-2.4(IH・3H) monodione Melting point 177-178℃ I-(m-nitrophenyl)-3-(2-(2-hydroxyethoxy)ethyl)quinazoline-2.4(IH・
3{) monodione melting point 137-138°C 1-(m-nitrophenyl)-3-(ethoxycarbonylmethyl)quinazoline-2,4(IH・3H) monodione melting point 211-212°C 1-(m-nitrophenyl)- 3-(3-hydroxyglobyl)quinazoline-2,4(IH・3H) monodione Melting point 144-145℃ ■-(m-nitrophenyl)-3-(3,3-dimethylallyl)quinazoline-2,4(IH・3H) Monodione Melting point 185-186℃

Claims (1)

[Scope of Claims] 1 General formula (wherein R is a hydrogen atom, a lower alkyl group, a hydroxyl group, a halogen atom, a lower cycloalkyl group, a lower alkoxy group, an alkoxycarbonyl group, an acetoxy group, a hydroxyalkoxy group, or a phenyl group) A compound represented by the general formula xcoy (meaning a lower alkyl group, an alkenyl group, or an alkynyl group substituted with Y is a halogen atom, trihaloalkyl group, lower alkoxy group, alkoxycarponyloxy group, aromatic amine group, aliphatic amine group, secondary lower amine group, piperidino group, pyrrolidino group, morpholino group, imidazolyl group, 1 A method for producing a novel quinazolinedione derivative represented by the general formula (wherein R has the same meaning as above), which comprises reacting a compound represented by the following formula (representing a 2,3-triazolyl group).