JPS6112660A - Novel 2-pyrrolidone derivative and antiinflammatory therefrom - Google Patents

Abstract

NEW MATERIAL:A 3-pyrrolidone derivative of formula I (R<1> is H, 1-3C alkyl, benzyl; R<2> is H, 1-6C alkyl; R<3> is H, 1-3C alkyl; R<4>, R<5> are independently H, or incorporate to form a chemical bond) and its salt. EXAMPLE:The compound of formula II. USE:Anti-inflammatory. PREPARATION:For example, the reaction of a benzaldehyde of formula III (R<6> is alkyl, benzyl, trialkylsilyl) with 1-acyl-2-pyrrolidone is effected in the presence of an alkali metal hydride such as sodium hydride, when needed, alkyl, benzyl or trialkylsilyl of R<6> is eliminated to give a compound of formula IV among formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel 2-pyrrolidone derivative or a salt-formable salt thereof, and an anti-inflammatory agent containing the same as an active ingredient. More specifically, the present invention relates to the general formula (1
) (In the formula, R1 represents hydrogen + an alkyl group of OH to CB or a benzyl group, R2 represents hydrogen or an alkyl group of 01 to C6, R8 represents hydrogen or an alkyl group of C1 to C3, and R4 and R5 are independently hydrogen or together represent one chemical bond) and anti-inflammatory agents containing the same as an active ingredient. It is something.

(Problems to be Solved by the Invention) As a result of extensive testing of the pharmacological effects of 2-pyrrolidone derivatives, the present inventors found that the compound represented by general formula (1) and its salts have excellent anti-inflammatory effects. Heading, we arrived at the present invention. This will be explained in detail below.

(Means and effects for solving the problems) The novel compound according to the present invention is represented by the following general formula (1).

(In the formula, 几1 represents hydrogen, a C1-C3 alkyl group or a pencil group, R2 represents hydrogen or an 01-c6 alkyl group, R8 represents hydrogen or an 01-c8 alkyl group, 几4 and R5 describe the synthesis of compounds that are independently hydrogen or together represent a chemical bond.

Examples of methods for synthesizing the compound represented by general formula (1) of the present invention include the following.

For example, (1) Among the compounds represented by the general formula (1), the general formula [where R1 represents hydrogen, an alkyl group of 01 to C3, or a benzyl group, and R2 represents hydrogen or an alkyl group of 01 to C6] The compound represented by ] is HoZimm
According to the method of Er et al. [Journal of Heterocyclic Chemistry, 2.171 (1965)],
Benzaldehydes represented by the general formula (3) [wherein R2 represents hydrogen or a 00 to C6 alkyl group, and R6 represents a C1-08 alkyl group, benzyl group, or trialkylsilyl group] and 1- It can be synthesized by reacting acyl-2 to pyrrolidone in the presence of an alkali metal hydrogen compound such as sodium hydride, and optionally removing the alkyl group, benzyl group or trialkylsilyl group of R6.

As a method for eliminating R6, when B, 6 is an alkyl group, a cleavage method using an aluminum halide such as aluminum chloride, a Lewis acid such as ferric chloride, or boron tribromide;
Alternatively, there are other ether cleavage methods. Further, when R6 is a benzyl group, it can be eliminated by a catalytic reduction method using a noble metal catalyst such as palladium on carbon.

When R6 is a trialkylsilyl group, it can be removed using water, methanol, acid, fluorine ions, or the like.

(2) Similarly, the compound represented by general formula (2) is Hl
The method of Wamhoff et al. [Synthesis, 881'
(1976)) according to the general formula (4) [where R2
represents hydrogen or a C1-06 alkyl group, and R7 represents hydrogen, an 01 to C8 alkyl group, benzyl group, or trialkylsilyl group] and the general formula R8 represents an alkyl group or an aryl group. ) is reacted with l-acyl-3-triarylphosphoranylidene-2-pyrrolidone represented by the general formula [
Here, R2 represents hydrogen or an 01-C6 alkyl group, R7 represents hydrogen, an 01-C8 alkyl group, benzyl group, or trialkylsilyl group, and R8 represents an alkyl group or an aryl group. It can be synthesized by obtaining 1-acyl-3-benzylidene-2-pyrrolidones and then removing the acyl group represented by R8C0 by hydrolysis using sodium hydroxide, potassium hydroxide, or the like. When R7 is an alkyl group, benzyl group or trialkylsilyl group, it may be eliminated if necessary, and the elimination method is as described in the synthesis method (1) above. The first stage of this synthesis method uses the so-called Witteigh reaction, but in addition to the above-mentioned compounds, ylides derived from trialkylphosphines and triarylarsines can also be used as the one-dip ylide reacted with the above-mentioned benzaldehydes. It can be used for.

(3) General formula (6) [Here, Hl represents hydrogen, an 01-C8 alkyl group or a benzyl group, R2 represents hydrogen or an 01-C6 alkyl group, and R9 represents an 01-C8 alkyl group] The compound represented by H. is a benzaldehyde represented by the general formula (4) according to the method of Wamho ff et al. [Synthesis, 331 (1976)],
R9 represents an alkyl group of 01 to C3) 1-alkyl-3-triarylphosphoranyritene-2
-pyrrolidone to form the general formula (7) [where R2 represents hydrogen or an alkyl group of 01 to C6, R7 represents hydrogen, an alkyl group of 01 to CB, a benzyl group or a trialkylsilyl group, R9 is 01
1-alkyl-3-benzyritine-2-pyrrolidones represented by R
When 7 is an alkyl group, benzyl group or trialkylsilyl group, it can be synthesized by elimination as necessary.

The elimination method is as described in the synthesis method (1) above. The first stage of this synthesis method uses the so-called Witteigh reaction, but in addition to the above-mentioned compounds, ylides derived from trialkylphosphines and triarylarsines can also be used as the ylide to be reacted with the benzaldehydes. It can be used for.

(4) Similarly, the compound represented by the general formula (2) is prepared by combining a benzaldehyde represented by the general formula (4) and a 1-alkyl-3-carboxy-2-pyrrolidone represented by the general formula in the presence of a base catalyst. It can be synthesized by reacting with. Examples of base catalysts that can be used include organic bases such as pyrrolidine and piperidine, alkali metal hydrides such as lithium hydride and sodium hydride, and sodium carbonate.

Examples include alkali metal carbonates such as potassium carbonate.

In addition, 1-alkyl-3-carboxy-2 used here
- Pyrrolidone is 1-alkyl-3-alkoxycarbonyl-2-pyrrolidone, which was synthesized according to the method of M. L. Ruep pel et al. [Journal of American Chemical Society, 93.7021 (1971)]. , can be obtained by hydrolysis using an alkali metal hydroxide such as potassium hydroxide.

(5) The compound represented by the general formula (1) is a compound represented by the general formula (
8) [Here, R1 represents hydrogen, an alkyl group of cl-03, or a benzyl group, and R2 represents hydrogen or 01-C6
represents an alkyl group, R4 and R5 are independently hydrogen or together represent one chemical bond] and R8NH2 [R8 is hydrogen or 01-
C3 alkyl group] and the method of F. B. Zienty et al. [Journal of American Chemical Society, 69.7]
15 (1947)). As a method for synthesizing compound (8) used in this method, for example, G
, A. Howie et al. [Journal of
Medicinal Chemistry, 17°840 (1974
)].

(6) General formula (9) [where R1 represents hydrogen, an 01-C3 alkyl group or a benzyl group, R2 represents hydrogen or a C1-C6 alkyl group, and R8 represents hydrogen or an 01-C3 alkyl group The compound represented by the general formula 00 [where R,1 represents hydrogen, an alkyl group of 01 to C8 or a benzyl group, and R2 represents hydrogen or a group of 01 to C6]
R8 represents hydrogen or an alkyl group of 01 to C8] is synthesized by subjecting it to catalytic reduction using a noble metal catalyst such as palladium on carbon. If necessary, in order to obtain the compound (9) in which R1 is an alkyl group or a pencil group of 01 to C3, the compound represented by the general formula (9) in which il is hydrogen is converted to R11X (R11 is a C4 -C3 alkyl group or benzyl group, and X represents a halogen atom). Other alkylation methods for phenolic hydroxyl groups can also be used in place of the alkylation method using halogenated hydrocarbons.

Next, as an example of a specific method for producing the compound of the present invention, 3-
The method for producing (3,5-di-tert-butyl-4-methoxybenzilitine)-2-pyrrolidone (compound ①) will be described.

3.5- in dry benzene with sodium hydride suspended in it.
After dropping a benzene solution of di-tert-butyl-4-methoxybenzaldehyde and 1-acetyl-2-pyrrolidone, the mixture is refluxed and reacted.

Next, excess sodium hydride was decomposed by adding methanol, acidified with sulfuric acid, extracted with chloroform,
It was dried under reduced pressure and crystallized from ethyl acetate. The substance obtained here is a colorless needle-shaped crystal that is insoluble in water, slightly soluble in methanol, ethanol, acetone, and chloroform, and slightly soluble in te-1-rahydrofuran, and its properties are as follows.

Melting point: 206-208°C Molecular weight: 315.44 Elemental analysis value: OHN.

Experimental value 76.26% 9.20% 1013% 4.
41% theoretical value 76.15% 9.27% 10.14
% 4.44% (C2oH2902N) Furthermore, the structure of this compound (compound ■) was confirmed by ultraviolet absorption spectrum (Figure 1), infrared absorption spectrum (Figure 2), and nuclear magnetic resonance spectrum.

Explain about anti-inflammatory agents.

The anti-inflammatory agent according to the present invention contains as an active ingredient a novel compound represented by the above-mentioned general formula (1) or a salt-formable salt thereof. The pharmacological action and toxicity of these compounds are as shown in the test examples below.

Furthermore, the anti-inflammatory effect of carrageenan to suppress foot edema was determined by the method of C. A. Winter et al. [Proceedings of Society for Experimental Biology and Methodology].

111.544 (1962)).

Anti-inflammatory effect Carrageenin suppressing effect on paw edema Male Wistar rats (body weight 160-19 op) were used, with 4-5 rats per group. A test compound suspended in a 2.5% gum arabic aqueous solution containing 082% Tween 80 was orally administered at a rate of 1.25 gJ/100 g body weight. One hour later, 01ml of 1% carrageenan was subcutaneously injected into the footpad of one hind leg to cause inflammation. At 3 and 5 hours after the onset of inflammation, the swelling volume of the hind paw was measured. The inhibition rate was determined using the following formula.

The results are shown in Table 2. It can be seen that the compounds according to the present invention have a strong carrageenan edema inhibitory effect. The compounds of the present invention in Table 2 correspond to the compound numbers shown in Table 1.

Table 2 Carrageenin foot edema suppressive effect and acute toxicity Acute toxicity I
There were 6 animals in the group. The test compound was suspended in a 2.5% gum arabic aqueous solution containing 0.2% Tween 80, and
It was administered orally at a rate of 7109 ml body weight. After administration 2
General symptoms were observed for a week, the number of deaths/number of test cases was determined, and the 50% lethal dose LD50 (nrg,/kq) was estimated. The results are shown in Table 2. It can be seen that all the compounds of the present invention have low toxicity.

From the above results, it is clear that the compound according to the present invention has excellent pharmacological action and high safety.

Preparation and dosage Preparations of the anti-inflammatory agent according to the invention include oral administration.

Either enteral or parenteral administration can be selected. Specific formulations include tablets, capsules, fine granules, syrups, crude drugs, and ointments. Carriers for the formulation of anti-inflammatory agents according to the invention include oral,
Organic or inorganic solid or liquid, usually inert, pharmaceutical carrier materials suitable for enteral or other parenteral administration are employed. Specifically, for example, crystalline cellulose, seratin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum,
There are polyalkylene glycols. The proportion of anti-inflammatory agent according to the invention to carrier in the formulation can vary between 0.2 and 100%.

The anti-inflammatory agent according to the present invention may also include other anti-inflammatory agents and other drugs that are compatible therewith.

In this case, it goes without saying that the anti-inflammatory agent according to the present invention does not have to be the main ingredient in the preparation.

Anti-inflammatory agents according to the invention are generally administered at dosages that achieve the desired effect without side effects. The specific value should be determined by a doctor's judgment, but in general, it is 10 ~ 10g1 per day for adults, preferably 20MF1 ~
It would be normal to administer around 5g. In addition, the anti-inflammatory agent of the present invention contains 19 to 5 g as an active ingredient, preferably,
It can be administered as a pharmaceutical formulation in units of 3 Da to 1 Da.

(Example) Next, the present invention will be specifically explained with reference to production examples of the compounds of the present invention, but these Examples are not intended to limit the present invention.

Example 1 Synthesis of Compound (1) 30 ml of dry tetrahydrofuran (THF) was added to 8.36 g of thorium hydride (oil-based, 60% content) and suspended, and to this suspension was added 3-tert-ter-butyl-4. -(dimethyl tert-butylsilyloxy)
8.19 g of benzaldehyde and 8.56 fl of 1-acetyl-2-pyrrolidone dissolved in dry TT (30 mJ of F) were added without stirring on a water bath, and the mixture was slowly heated to room temperature and reacted for 16 hours. The reaction was completed. After that, 5 ml of methanol was added to the cooled reaction solution, and the mixture was poured with 1 ml of cold water.
I poured it into 50 go. This was adjusted to pH 2 with 6N sulfuric acid and extracted four times with 50 ml of chloroform. After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure. Add ethyl acetate to the residue and perform crystallization to obtain the desired compound I.
20 pieces were obtained (yield 47%).

Examples 2 to 4 Synthesis of Compounds ■ to ■ Using the reaction reagents and reaction conditions shown in Table 3, Example 1
The target compound was synthesized by the same procedure as above. Examples are shown in Table 3.

Example 5 Synthesis of Compound (1) Compounds vi and osg were suspended in 10 Om/ml of ethanol, 5421 Da of palladium on carbon (5%) was added as a catalyst, and hydrogen gas was bubbled through the suspension at room temperature for 3 hours with stirring.

The catalyst was separated from P, and the P solution was concentrated to dryness.

Add chlorocrystalline porum to the residue and crystallize the desired compound■
052 pieces were obtained (yield 64%).

Example 6 Synthesis of compound (1) 0.7Of' of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 0.729 of 3-carboxy-1-methyl-2-pyrrolidone were mixed with 10% of pyridine and 0.0% of piperidine. The solution was dissolved in 21 g/ml and reacted on an oil bath at 110°C for 18 hours with stirring. After the reaction was completed, the cooled reaction solution was poured into 100 ml of cold water, and purified with 6N sulfuric acid.
The mixture was adjusted to H4, extracted three times with 50 ttri of chloroform, and washed twice with 30 s+t of water. The extract was dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was subjected to preparative thin layer chromatography using a mixed solvent of hexane:ethyl acetate (1:1) as a developing solvent, and Rf=0.
Eighteen fractions were collected and fractionated. This fraction was crystallized by adding ethyl acetate to obtain 0.28f of the target compound (2).
yield 30%).

Example 7 Synthesis of compound (1) Compound V0.7Of was suspended in 50% ethanol, and palladium carbon (5%) 85011Ig was added as a catalyst.
Hydrogen gas was bubbled through the mixture for 8 hours at room temperature while stirring. The catalyst was separated and the P solution was concentrated to dryness under reduced pressure. Add ethyl acetate to the residue and perform crystallization to obtain 0.4 of the target compound ■.
59 was obtained (yield 64%).

[Brief explanation of drawings]

FIG. 1 shows the ultraviolet absorption spectrum of the compound of the present invention (compound 2), FIG. 2 shows the infrared absorption spectrum of the same compound, and FIG. 3 shows the proton nuclear magnetic resonance spectrum of the same compound.

Claims (11)

[Claims] (1) A 2-pyrrolidone derivative represented by the following general formula (1) and its salt-formable salt. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) (In the formula, R^1 represents hydrogen, an alkyl group of C_1 to C_3, or a benzyl group, and R^2 represents hydrogen or a C_1 to
C_6 represents an alkyl group, R^3 is hydrogen or C_
It represents an alkyl group of 1 to C_3, and R^4 and R^5 are independently hydrogen or together represent one chemical bond. ) (2) A 2-pyrrolidone derivative and a salt-formable salt thereof according to claim 1, wherein R^4 and R^5 are independently hydrogen. (3) A 2-pyrrolidone derivative and a salt-formable salt thereof according to claim 1, wherein R^4 and R^5 together form one chemical bond. (4) The 2-pyrrolidone derivative and its salt according to claim 1 or 3, represented by formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I). (5) The 2-pyrrolidone derivative and its salt according to claim 1 or 3, which is represented by formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (6) The 2-pyrrolidone derivative according to claim 1 or 3, which is represented by formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III). (7) The 2-pyrrolidone derivative according to claim 1 or 3, which is represented by formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (8) The 2-pyrrolidone derivative according to claim 1 or 3, which is represented by formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V). (9) The 2-pyrrolidone derivative and its salt according to claim 1 or 3, which is represented by formula (VI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VI) (10) The 2-pyrrolidone derivative and its salt according to claim 1 or 2, represented by formula (VII) ▲Mathical formula, chemical formula, table, etc.▼(VII) (11) An anti-inflammatory agent containing a 2-pyrrolidone derivative represented by the following general formula (1) or a salt-formable derivative thereof as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) (In the formula, R^1 represents hydrogen, an alkyl group of C_1 to C_3, or a benzyl group, and R^2 represents hydrogen or a C_1 to
C_6 represents an alkyl group, R^3 is hydrogen or C_
It represents an alkyl group of 1 to C_3, and R^4 and R^5 are independently hydrogen or together represent one chemical bond. )