JPH0576471B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to malonic acid derivatives. More specifically, there are malonic acid derivatives such as malonic acid amide, malonic acid ester amide, or malonic acid diamide having a heteroaromatic ring residue in the amide moiety, methods for producing these malonic acid derivatives, and at least one type of these malonic acid derivatives. This invention relates to an analgesic and anti-inflammatory agent as an active ingredient. Conventionally, malonic acid derivatives are well known as synthetic intermediates for various drugs, but analgesic and anti-inflammatory agents that retain the basic skeleton of malonic acid are not known. In addition, some heteroaromatic ring derivatives such as 2-aminothiadiazole derivatives have analgesic and anti-inflammatory effects, as well as local anesthetic effects, blood sugar regulating effects,
Some are known to have antimicrobial effects, but none of these have a basic malonic acid skeleton in their molecules. The present inventors focused on the above findings, and in order to search for novel biologically active compounds, they attempted to produce a malonic acid derivative having a heteroaromatic ring residue in the amide moiety. As a result, the general formula R-NHCOCH ₂ CO- Y (in the formula, R- represents a heteroaromatic ring residue, -Y is a hydroxyl group, an alkoxyl group having 1 to 4 carbon atoms, a carbon number 1
The inventors have learned that malonic acid derivatives represented by a monoalkylamino group, a dialkylamino group, a piperidyl group, or a morpholyl group (4) have analgesic and antiinflammatory effects, leading to the present invention. Among the compounds of the present invention represented by the general formula R-NHCOCH ₂ CO-Y, those in which Y is a group other than a hydroxyl group are heteroaromatic ring amines corresponding to R-NH ₂
It can be obtained by combining malonic acid monoester or malonic acid monoamide corresponding to HOCOCH ₂ CO-Y. Conventionally, a strong alkali such as sodium ethoxide has been used as a binder in the condensation reaction between an amine and malonic acid monoester or malonic acid monoamide, but when the amine is a heteroaromatic ring amine, the yield is generally low. It is only a few percent or less, which is not practical. The present inventors used thionyldiimidazole (hereinafter abbreviated as TDI) as a binder,
By using an activated dehydration condensation agent such as carbonyldiimidazole (hereinafter abbreviated as CDI) or dicyclohexylcarbondiimide, the yield of the condensation reaction between a heteroaromatic amine and malonic acid monoester or malonic acid monoamide can be significantly improved. I learned. In the compound of the present invention represented by the above general formula, the compound in which Y is a hydroxyl group can be obtained by hydrolyzing the malonic acid ester amide of the present invention in which Y is an alkoxyl group with caustic alkali in an alcohol. . If the reaction route of the present invention is exemplified using TDI as a condensing agent, it can be abbreviated as follows.

[Chemical formula] In the formula, R is a heteroaromatic ring residue, R' is a carbon number of 1 to 4
represents an alkyl group, R'' and R each represent a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, or
R'' and R represent a morpholine ring or a pyrimidine ring excluding N.Heteroaromatic ring amines having a heteroaromatic ring residue represented by R include (a) 2-amino-4-substituted thiazole, ( b) 2-amino-4,6-disubstituted benzothiazole, (c) 4-amino-2,3-dimethyl-1
-phenyl-3-pyrazolin-5-one, (d)4-
Amino-1,2,4-triazole, (e) 3-amino-1,2,4-triazole, (f) 2-amino-
5-Methyl-1,3,4-thiazizole, (g)2-
Examples include aminopyrimidine, (h) 2-(aminomethyl)-benzimidazole, and (i) 6-aminoindazole, and the substituents in (a) and (b) above include H, Cl, -NO ₂ , - _CH3 , _−OCH3 , _−OC2
Examples include H ₅ or -CH ₂ COOC ₂ H ₅ . As the solvent used in the reaction system, any solvent that is inert to the reaction and that allows the reaction to proceed in a homogeneous system can be used, but from the viewpoint of efficiently dissolving the raw materials, amide solvents such as dimethylformamide or Ether solvents such as tetrahydrofuran are suitable. It is preferable to carry out the reaction at a temperature near the boiling point of the reaction system because the reaction time can be shortened. The reaction to obtain a malonic acid heteroaromatic ring monoamide from a malonic acid ester amide requires selective hydrolysis of the ester moiety, so it is advisable to use an alkali. The pharmacological action of the compound of the present invention obtained as described above is described in CAWinter et al [Proc.Soc.Exp.Biol.
Med., 111, 544 (1962)], the inhibitory effect on carrageenan edema was tested. Namely, Wister male rats pre-housed for about 1 week, body weight 140±10
The test drug suspended in a 0.5% aqueous solution of carboxymethylcellulose sodium salt (25 mg per 1 kg of rat body weight) was orally administered to 5 rats per group, and 30 minutes later, 0.1 ml of a 1% carrageenan solution was administered to the hind paws. It was injected subcutaneously into the foot pads, and the edema suppression rate compared to the control group after 1, 2, and 3 hours was determined by the foot volume measurement method, and the suppression rate compared to the control group was calculated. Ibuprofen was used as the reference inhibitor. Among the compounds of the present invention, N-[2-(6-methoxy)benzthiazolyl]malonic acid and N-[2
Ethyl -(6-methoxy)benzthiazolyl]malonate showed remarkable efficacy. The present invention will be further explained below with reference to Examples. Example 1 - TDI method (hereinafter abbreviated as method A) - Production of ethyl N-[2-(4-methyl)thiazolyl]malonate. Imidazole (TDI) 3.64g (20mmol)
and malonic acid monoethyl ester 2.64g (20mmol)
was dissolved in 20 ml of tetrahydrofuran and reacted by stirring at room temperature for 30 minutes. Add 2-amino-4 dissolved in 20 ml of tetrahydrofuran to this reaction solution.
- 2.28 g (20 mmol) of methylthiazole was added at room temperature with stirring, and after standing overnight, tetrahydrofuran was distilled off under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate, washed with 10 ml of 5% aqueous sodium bicarbonate solution, then with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solid obtained by distilling off ethyl acetate is recrystallized from ethyl acetate to obtain the desired product as colorless needle crystals.
1.33g (yield 29%) was obtained. The physical properties of this material are shown below, except for special cases in each example below.
IR spectrum is KBr method, NMR spectrum is
The CDCl ₃ method was used. Melting point (°C): 140.5-142.5 IR spectrum (cm ^-1 ): 3260, 1735, 1630 Mass spectrum (m/z): 228 (M ⁺ ), 140,
114 (base peak) NMR spectrum (δ, ppm): 1.32 (3H, t, J = 7.1Hz, COOCH ₂ CH ₃ ) 2.36 (3H, d, J = 1.0Hz, 4- CH ₃ ) 3.54 (2H, s , CO CH ₂ CO) 4.27 (2H, q, J = 7.1Hz, COO CH ₂ CH ₃ ) 6.55 (1H, q, J = 1.0Hz, 5- H ) Example 2 - CDI method (hereinafter abbreviated as B method) )-N-[2-(6-methoxy)benzothiazolyl]
Production of ethyl malonate Using 3.76 g (20 mmol) of carbonyldiimidazole (CDI) in place of TDI in Example 1,
Also, instead of 2-amino-4-methylthiazole, 2-amino-6-methoxybenzothiazole 3.60
The same procedure as in Example 1 was performed except that 4.41 g (yield: 15 mmol) of the target product was obtained as colorless needle crystals.
%) was obtained. The physical properties of this product are shown below. Melting point (°C): 197-199 IR spectrum (cm ^-1 ): 1730, 1660, 1610 Mass spectrum (m/z): 294 (M ⁺ ), 206,
165 (base peak) NMR
Spectrum (δ, ppm): 1.33 (3H, t, J = 7.3Hz, COOCH ₂ CH ₃ ) 3.58 (2H, s, , COC H ₂ CO) 3.87 (3H, s, , O CH ₃ ) 4.29 (2H, q, J = 7.3Hz, COO CH ₂ CH ₃ ) 7.02-7.72 (3H, m, Ar H ) Example 3 - CCD method (hereinafter abbreviated as C method) - N-[4-(1,2,4- Triazolyl) Production of ethyl malonate 1.58 g (12 mmol) monoethyl malonate
2.47 g of dicyclocarbondiimide (CCD) was dissolved in 10 ml of dry dimethylformamide under ice cooling.
(12 mmol) and continued stirring for 1 hour.
4-amino-1,2,4-triazole 0.84g
(10 mmol) was added, and the mixture was stirred for an additional hour to react, and then left at room temperature overnight. The precipitate deposited in the reaction solution was separated, and the solvent was distilled off from the solution under reduced pressure. The resulting residue was dissolved in 30 ml of ethyl acetate, the insoluble matter was separated, and the liquid was concentrated under reduced pressure to about 5 ml. This concentrated solution was purified by silica gel column chromatography using ethyl acetate-benzene (1:1) as a mobile phase solvent, and recrystallized from methyl alcohol to obtain 0.20 g of the desired product as colorless needle-shaped crystals.
(yield 38%). The physical properties of this material are shown below. Melting point (℃): 115-118 IR spectrum (cm ^-1 ): 3100, 1740, 1700 Mass spectrum (m/z): 198 (M ⁺ ), 111, 85 (base peak) NMR spectrum (δ, ppm): 1.33 (3H, t, J = 7.1Hz, COOCH ₂ CH ₃ ) 3.59 (2H, s, CO CH ₂ CO) 4.27 (2H, q, J = 7.1Hz, COO CH ₂ CH ₃ ) 8.22 (2H, s, 3- H , 5- H ) Examples 4 to 17 Examples 1 to 3 were prepared using various heteroaromatic ring amines and malonic acid monoethyl ester shown in FIG.
Each malonic acid amide ester corresponding to the raw material was obtained by one of the treatment methods shown in . However, the recrystallization solvent was changed as appropriate. The chemical formulas, production methods, yields, melting points, elemental analysis values, etc. of the compounds of these examples and Examples 1 to 3 are shown in Table 1.

【table】

[Table] Example 18 - Hydrolysis of malonic acid amide ester - Production of N-(2-benzothiazolyl) malonic acid monoamide 1.32 g (5 mmol) of ethyl N-(2-benzothiazolyl) malonate produced in Example 6 was dissolved in 5 %
After adding 15 ml of KOH aqueous solution and stirring at room temperature for 30 minutes, 10% HCl was added dropwise under ice cooling until the reaction solution became acidic. The precipitated white solid was separated by filtration, washed with water, and then recrystallized from methyl alcohol to obtain 0.73 g (yield: 61.6%) of the desired product. The physical properties of this material are shown below. In this example, the NMR spectrum was determined by the heavy methanol method. Melting point (°C): 187-189 IR spectrum (cm ^-1 ): 1710, 1560 Mass spectrum (m/z): 236 (M ⁺ ), 192,
150 (base peak) NMR spectrum (δ, ppm): 4.09 (2H,
s, COC H ₂ CO) 7.27K to 7.89 (4H, m, Ar H ) Examples 19 to 24 Using various malonic acid amide esters produced in Examples 1, 2, 4, 5, 7, 8, and 9 Example
The corresponding malonic acid monoamides were obtained by hydrolysis in the same manner as in 18. However, the recrystallization solvent was changed as appropriate. The chemical formulas, recrystallization solvents, yields, melting points, and elemental analysis values of these examples and the compound of Example 18 are shown in Table 2.

【table】

[Table] Example 25 - Malonic acid diamide - Production of N-diethyl-N'-[2-(6-methoxy)benzothiazolyl] malonic acid diamide 1.91 g of N-diethyl malonic acid monoamide
20 ml of tetrahydrofuran containing (12 mmol)
1.94 g (12 mmol) of CDI was added to the mixture, and the mixture was stirred at room temperature for 1 hour. To this solution, 20 ml of tetrahydrofuran containing 1.80 g (10 mmol) of 2-amino-6-methoxybenzothiazole was added dropwise, stirring was continued for an additional hour, and then left overnight. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate.
After washing successively with 10 ml of water, 10% citric acid aqueous solution, 5% sodium bicarbonate solution, and further water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 2.27 g (yield: 70.8%) of the desired product as colorless needle crystals. The physical properties of this material are shown below. Melting point (°C): 168-169 IR spectrum (cm ^-1 ): 3150, 1700, 1630 Mass spectrum (m/z): 321 (M ⁺ ), 206,
180 (base peak) NMR spectrum (δ, ppm): 1.21 (6H, h, J=7.3Hz, NCH ₂ CH ₃ ×2) 3.42 (4H, h, J=7.3Hz, NCH ₂ CH ₃ ×2 ) 3.54 (2H, s, COC H ₂ CO) 3.87 (3H, s, OCH ₃ ) 7.00-7.72 (3H, m, Ar H ) Example 26 N-n-butyl-N'-[2-(6 -methoxy)
Production of benzothiazolyl malonic acid diamide 1.59 g of N-n-butyl malonic acid monoamide
(10 mmol), CDI 1.62 g (10 mmol) and 2-amino-6-methoxybenzothiazole 1.80 g
(10 mmol) was used to react in tetrahydrofuran in the same manner as in Example 25. The solid precipitated in the reaction solution left overnight was collected by filtration and recrystallized from methyl alcohol to obtain 1.42 g (yield: 44.1%) of the desired product in the form of colorless needle crystals. The physical properties of this material are shown below. In this example, NMR was performed using the dimethyl sulfoxide method. Melting point (°C): 239-240 IR spectrum (cm ^-1 ): 3300, 1700, 1640 Mass spectrum (m/z): 321 (M ⁺ ), 206,
180 (Base peak) NMR spectrum (ppm): 0.88 (3H, t, J = 7.1Hz, N(CH2)3CH3) 3.81 (3H, s, _{OCH3 ) 7.00-7.66 (} 3H, m, Ar H ) Examples 27 to 43 Using various heteroaromatic ring amines and various malonic acid monoamides, the same procedure as in Example 25 or 26 was carried out to obtain each malonic acid diamide corresponding to the raw material. Note that the recrystallization solvent was changed as appropriate. The chemical formulas, recrystallization solvents, yields, melting points, and elemental analysis values of these examples and the compounds of Examples 25 and 26 are shown in Table 3.

【table】

【table】

【table】

【table】

[Table] *Ibuprofen Example 44 - Pharmacological effect - The malonic acid derivative of the present invention obtained in the above example was tested for edema suppressing effect by the method of Winter et al. These results are shown in Table 4. An example of ibuprofen is included as reference data.

[Brief explanation of drawings]

FIG. 1 shows the structural formula of the heteroaromatic ring amine used in the examples. In the formula, R ₁ and R ₂ represent substituents.

Claims (1)

[Claims] 1 General formula R-NH-CO-CH ₂ -CO-Y (wherein R is (a) 2-amino-4-substituted thiazole, (b) 2-amino-4,6-di Substituted benzothiazole, (c) 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one, (d) 4-amino-1,2,4-triazole, (e) 3-amino −
1,2,4-triazole, (f)2-amino-5-
Any complex selected from the group consisting of methyl-1,3,4thiazole, (g) 2-aminopyrimidine, (h) 2-(aminomethyl)-benzimidazole, and (i) 6-aminoindazole represents a heteroaromatic ring residue of an aromatic ring amine, Y represents a hydroxyl group, an alkoxyl group having 1 to 4 carbon atoms, a monoalkylamino group or dialkylamino group having 1 to 4 carbon atoms, a piperidyl group or a morpholyl group). malonic acid derivatives. 2 In the presence of an activated dehydration condensation agent, the general formula HOCOCH ₂ COZ (wherein Z is a carbon number of 1 to 4
a malonic acid monoester or malonic acid monoamide represented by an alkoxyl group, a monoalkylamino group or dialkylamino group having 1 to 4 carbon atoms, a piperidyl group, or a morpholyl group) and a malonic acid monoamide represented by the general formula R-NH ₂ (in the formula R is (a) 2-amino-4-
Substituted thiazole, (b) 2-amino-4,6-disubstituted benzothiazole, (c) 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one, (d) 4-amino -1,2,4-triazole,
(e) 3-amino-1,2,4-triazole, (f) 2
-amino-5-methyl-1,3,4thiazole, (g) 2-aminopyrimidine, (h) 2-(aminomethyl)-benzimidazole and (i) 6-aminoindazole. (indicates the heteroaromatic ring residue of any heteroaromatic ring amine)
A malonic acid derivative represented by the general formula R-NH-CO- _CH2 -CO-Z (wherein R and Z are the same as above), characterized by condensation with a heteroaromatic ring amine represented by manufacturing method. 3. The malonic acid derivative according to claim 2, wherein the activated dehydration condensation agent is any activated dehydration condensation agent selected from the group consisting of carbonyldiimidazole, thionyldiimidazole, and dicyclohexylcarbodiimide. Production method. 4 General formula R-NH-CO-CH ₂ -CO-X (wherein R is (a) 2-amino-4-substituted thiazole, (b) 2-amino-4,6-disubstituted benzothiazole, (c ) 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one, (d) 4-amino-1,2,4-triazole, (e) 3-amino-
1,2,4-triazole, (f)2-amino-5-
Any complex selected from the group consisting of methyl-1,3,4thiazole, (g) 2-aminopyrimidine, (h) 2-(aminomethyl)-benzimidazole, and (i) 6-aminoindazole represents a heteroaromatic ring residue of an aromatic ring amine; Analgesic and anti-inflammatory agent containing a malonic acid derivative as an active ingredient.