JPH07121905B2 - 2-pyrrolidone derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a 2-pyrrolidone derivative useful as an intermediate for producing a compound valuable as an anti-inflammatory agent.

[Conventional technology]

Anti-inflammatory agents can be broadly classified into four categories: steroid hormones, non-steroidal agents, anti-inflammatory enzymes, and immunosuppressants. Of these, non-steroidal agents occupy the most important position. Non-steroidal anti-inflammatory drugs are being actively developed worldwide.

Currently used as nonsteroidal agents are indole enzyme compounds such as indomethacin, phenyl enzyme compounds such as ibufenac and ibuprofen, salicylic acid compounds such as aspirin, salicylic acid, salicylosalicylic acid, mefenamic acid, flufenamic acid and the like. Examples include pyrazolidinedione compounds such as anthranilic acid compounds, phenylbutazone, oxygenenylbutazone, and ketophenylbutazone, and basic drugs such as benzydamine, mepyrizole, and tinolidine.

However, these non-steroidal agents are also clinically
It has a major drawback that it has side effects such as gastrointestinal disorders and renal disorders, and further excellent drugs are being developed worldwide.

[Structure and effect of the invention] Therefore, the present inventors have been studying a new anti-inflammatory agent for many years, the following general formula (chemical formula is different from the conventional non-steroidal anti-inflammatory drug) The 2-pyrrolidone compound represented by I ') and its pharmacologically acceptable salt were found to be excellent anti-inflammatory agents, and a patent application has already been made (see Japanese Patent Application No. 60-96799).

{Wherein R 'is wherein a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkynyl group, or a group of the formula - (CH _{2) n} -Y [wherein Y is a phenyl group, a hydroxyl group or formula (Wherein R ¹ and R ² represent the same or different hydrogen atoms or lower alkyl groups), and n is 1
Or an integer of 2]. The present invention provides a 2-pyrrolidone derivative useful as an intermediate for producing a 2-pyrrolidone compound represented by the general formula (I ′) as a final compound shown above and useful as an anti-inflammatory agent. It is a thing.

That is, the compound of the present invention is represented by the following general formula (II):
-Pyrrolidone derivatives and their pharmacologically acceptable salts.

{In the formula, R means a lower alkoxy group. X represents a halogen atom} In the above general formula (II), the lower alkoxy group in the definition of R is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl,
It means an alkoxy group derived from an alkyl group such as isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups.

The compound (II) of the present invention can be converted into a pharmaceutically acceptable salt such as Na salt and K salt, if necessary.

The representative method for producing the compound of the present invention is as follows.

That is, the compound represented by the general formula (III) is converted to the general formula (IV)
The compound (V) is obtained by subjecting it to a condensation reaction with a compound represented by
The compound (II) of the present invention can be obtained by cyclizing by performing the reaction in the presence of a base such as sodium alkoxide. At this time, a preferable result can be obtained by carrying out the reaction in a solvent such as ethanol or benzene at a temperature of -50 ° C to 100 ° C.

The compound (II) obtained according to the present invention can be converted into the final compound (I) having excellent action as a medicine by the following method, for example.

That is, the 2-pyrrolidone derivative (II) obtained by the present invention is reacted with triphenylphosphine to give a Wittig salt represented by the general formula (VI), which is represented by the general formula (VII). The final compound (I) is obtained by subjecting 3,5-di-tert-butyl-4-hydroxy-benznaldehyde to Wittig reaction in the presence of a base by a conventional method.

In this case, examples of the base include organic bases such as triethylamine and pyridine, and inorganic bases such as sodium carbonate and potassium carbonate. At this time, as the solvent,
Any solvent may be used as long as it does not participate in the reaction, and preferred solvents include dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethanol, ethyl acetate, benzene and the like.
The reaction temperature is about 0 to 150 ° C, preferably 30 to 100 ° C.

Next, typical examples of the final compound (I) derived from the 2-pyrrolidone derivative (II) of the present invention will be given.

* N-methoxy-3- (3,5-di-tert-butyl-4-
Hydroxybenzylidene) -2-pyrrolidone N-ethoxy-3- (3,5-di-tert-butyl-4-
Hydroxybenzylidene) -2-pyrrolidone Nn-butoxy-3- (3,5-di-tert-butyl-
4-Hydroxybenzylidene) -2-pyrrolidone In the present invention, the final compound (I) is a highly safe anti-inflammatory / analgesic / antipyretic agent, which has high value but is further characterized in terms of medicinal properties as follows. Is.

It has a wider safety margin than conventional anti-inflammatory agents such as indomethacin, ibuprofen, and piroxicam.

It has actions such as lipoxygenase inhibitory action and antioxidant action which are not found in conventional non-steroidal anti-inflammatory agents.

When the final compound (I) derived from the 2-pyrrolidone derivative (II) of the present invention is clinically used, it is used for indications in which conventional anti-inflammatory agents are used, and examples thereof include arthritis, rheumatism, and neuritis. , Arthralgia, neuralgia and other anti-inflammatory analgesia, cold syndrome, acute chronic bronchitis, trauma and post-operative.

Next, in order to explain the usefulness of the final compound (I) derived from the 2-pyrrolidone derivative (II) of the present invention in detail,
The results of specific pharmacological experiments with animals are shown below.

Pharmacological experiment example Experimental example 1 Local surface temperature lowering effect on inflammatory site (1) Experimental method 0.05 μl of a suspension of bovine bacillus fluidized porafin (10 mg / ml) was placed in the footpad of the right hind leg of a male Fisher rat (6 weeks old). m
Injected to induce adjuvant inflammation. 3-5 after inflammation
On the day 1, the local display temperature of the inflammation-induced paw was higher by 8 to 10 ° C than that of the normal paw, and a stable value was obtained. To such rats, 5 to-be-tested compounds (including indomethacin and piroxicam as controls) were added.
% Arabic gum aqueous solution was orally administered at a rate of 5 ml / Kg body weight, and 2, 4, and 6 hours later, the method of H. Shirota et al. [H.
Shirota et.al, J.pharmacol.Methods, 12, 35-43 (198
4)], the local surface temperature of the inflamed site was measured. The volume required to lower the temperature by 2 ° C. or more compared with the value before administration was calculated from the average value of 2 cases, and the anti-inflammatory power of the test compound was calculated.

(2) Test compound Compound A: N-methyl-3- (3,5-di-tert-butyl-4
-Hydroxybenzylidene) -2-pyrrolidone Compound B (compound derived from the compound of the present invention): N-methoxy-3- (3,5-di-tert-butyl-4-hydroxybenzylidene) -2-pyrrolidone Compound C: 3- (3,5-Di-tert-butyl-4-hydroxybenzylidene) -2-pyrrolidone (3) Results Table 1 shows the results.

Experimental Example 2 Carrageenin footpad edema inhibitory action (1) Experimental method Using male Fischer rats (5 weeks old), 5 rats per group were used for the experiment. The test compound was suspended in 5% acacia, and 0.5 ml per 100 g of body weight was orally administered. One hour later, 0.05 ml of a 1% carrageenin solution was injected into the right hind footpad of the rat to induce inflammation. The hindlimb footpad volume was measured 3 hours after the carrageenin injection, the rate of increase in the footpad volume due to the carrageenin injection was calculated, and the inhibition rate was determined by comparison with the control group.
As the test compound, the same compound as used in Experimental Example 1 was used.

(2) Results The results are shown in Table 2.

Experimental Example 3 Gastric ulcer-inducing action (1) Experimental method After fasting male Fisher rats aged 7 weeks for 24 hours, 5
% Orally administered with the test compound suspended in gum arabic,
The 50% gastric ulcer-inducing capacity was calculated from the hemorrhagic lesions on the gastric mucosa after a lapse of time.

(2) Results The results are shown in Table 3.

UD ₅₀ in Table 3 indicates 50% ulcer-inducing capacity (mg / Kg).

As is clear from the results of the above pharmacological experiments,
The final compound (I) derived from the pyrrolidone derivative (II) has a strong anti-inflammatory effect, and there is almost no gastric disorder which is a side effect of conventional anti-inflammatory agents, and long-term continuous use like an anti-inflammatory agent. It is a very ideal drug when forced to do so.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Production of N-methoxy-3-bromo-2-pyrrolidone (1) A mixture of 2,4-dibromobutanoyl chloride γ-butyrolactone 500 g and tribromide (PBr ₃ ) 10 ml was heated to 100 ° C. Under stirring, 250 ml of bromine (Br ₂ ) was slowly added dropwise to the liquid surface over 6 hours. During this time, the reaction temperature is 110
The temperature was kept at ℃ to 115 ℃, and after the dropping was completed, the mixture was stirred for 1 hour at the same temperature.
Then, the reaction solution was cooled to 90 ° C., 0.5 ml of dimethylformamide (OMF) was added, 500 ml of thionyl chloride (SOCl ₂ ) was added dropwise to the oil bath at 90 ° C. over 2 hours, and then the mixture was stirred at the same temperature for 3 hours. The reaction solution was distilled (60 to 65 ° C./1 mmHg) to obtain 1.0 kg of the above title compound.

(2) N-methoxy-2,4-dibromobutanamide CH ₃ ONH ₂ · HCl 520 g, water 1, chloroform (CHCl ₃ ) 5
l was cooled with a freezing agent of ice salt (-5 ° C), to which a mixture of 1,450 g of 2,4-dibromobutanoyl chloride obtained in (1) and chloroform 1 was added, and then 500 g of NaOH 1 water was added.
The solution was added dropwise so that the reaction temperature did not exceed 10 ° C. After completion of dropping, the mixture was stirred at the same temperature for 1 hour. Take off the chloroform layer of the reaction solution, and add 0.5N HCl water, saturated sodium hydrogen carbonate water,
It was washed successively with saturated brine, dried over magnesium sulfate and concentrated in chloroform to give 1400 g of oil in the residue. This was used for the next reaction without further purification.

(3) N-methoxy-3-brom-2-pyrrolidone 1400 g of N-methoxy-2,4-dibromobutanamide obtained in (2) was dissolved in 5 l of benzene and cooled at 15 ° C with an ice-water bath. At 20 ° C., 125 g of sodium hydride (NaH) was added in small portions. After the reaction was completed, ice was added to decompose excess sodium hydride (NaH), and then washed with saturated saline,
After drying with magnesium sulfate and concentrating benzene,
Purification by silica gel-acetone / benzene column chromatography gave 500 g of the title compound.

NMR (δ, CDCl ₃ ); 3-position methine 4.38 (1H, dd, J = 3.6Hz7.2Hz) 4-position methylene 2.2-2.9 (2H, m) 5-position methylene 3.4-3.9 (2H, m) 1-position methoxy 3.82 (3H, s) The reaction formula of Example 1 is as follows.

Next, the steps from the intermediate obtained according to the present invention to the final compound are shown in the following reference examples.

Reference Example 1 Production of N-methoxy-3- (3,5-di-tert-butyl-4-hydroxybenzylidene) -2-pyrrolidone (1) (N-methoxy-2-pyrrolidone-3-yl) triphenylphosphonium Bromide N-methoxy-3-bromo-obtained according to Example 1
A mixture of 75 g of 2-pyrrolidone, 105 g of triphenylphosphine and 700 ml of tetrahydrofuran (THF) was heated under reflux for 24 hours. After cooling, the crystals were collected by filtration, washed with tetrahydrofuran and then inserted to obtain 54 g of the title compound.

(2) (N-methoxy-3- (3,5-di-tert-butyl-4-hydroxybenzylidene) -2-pyrrolidone 3,5-di-tert-butyl-4-hydroxybenzaldehyde 27.6 g, (N (Methoxy-2-pyrrolidone-3-yl) triphenylsulfonium bromide (54 g) and triethylamine (33 ml) were heated in ethanol for 4 hours at 50 ° C. After the ethanol was distilled off, the residue was dissolved in chloroform, washed with water and saturated brine, and dried. After drying over magnesium sulfate, chloroform was evaporated and the residue was purified by silica gel / acetone / benzene column chromatography and recrystallized from ethyl acetate-hexane to obtain 26.5 g of the title compound.

 ─────────────────────────────────────────────────── (72) Inventor Hiroshi Shirota 2-32-6 Sakuramura Umezono, Shinji-gun, Ibaraki Prefecture (72) Inventor Koichi Katayama 2-33 Sakura-ume Umezono, Shinji-gun, Ibaraki (56) References JP-A Sho-60 -120888 (JP, A) JP-A-59-51292 (JP, A) JP-B-44-29455 (JP, B1) Chem. Lett. , 1981 (2), 185-88 Khim. Geterotsikl. Soedin. , 1976 (8), 1127-31

Claims (1)

[Claims] 1. A general formula {In the formula, R means a lower alkoxy group. X means a halogen atom}, and a 2-pyrrolidone derivative represented by the formula or a pharmaceutically acceptable salt thereof.