JPS63119461A - 2-pyrrolidone derivative - Google Patents

Abstract

NEW MATERIAL:The 2-pyrrolidone derivative of formula I {R is H, lower alkyl, lower alkoxy, lower alkynyl or -(CH2)n-Y [Y is phenyl, OH or group of formula II (R<1> and R<2> are H or lower alkyl); n is 1 or 2]; X is halogen} and its salt. EXAMPLE:N-methoxy-3-bromo-2-pyrrolidone. USE:An intermediate for anti-inflammatory agent. PREPARATION:The compound of formula I can be produced e.g. by condensing a compound of formula III (Z is halogen or organic sulfonyloxy) with a compound of formula RNH2 and cyclizing the resultant compound of formula IV in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to 2-pyrrolidone derivatives useful as intermediates for the production of compounds of value as anti-inflammatory agents.

[Conventional technology]

Anti-inflammatory drugs can be broadly classified into four categories: steroid hormones, non-steroidal drugs, anti-inflammatory enzyme drugs, and immunosuppressants. Of these, non-steroidal drugs occupy the most important position, and in recent years The development of non-steroidal anti-inflammatory drugs is actively underway worldwide.

Currently, the commonly used nonsteroidal drugs include indoleacetic acid compounds such as indomethacin, phenylacetic acid compounds such as ibufenac and ibuprofen, salicylic acid compounds such as aspirin, salicylic acid, and salicyrosalicylic acid, mefenamic acid, and flufenamic acid. These include anthranilic acid compounds, pyrazolidinedione compounds such as phenylbutacin, oxyphenylbutacin, and ketophenylbutacin, and basic drugs such as pendydamine, mepirizole, and tinoridine.

However, these non-steroidal drugs are clinically
It has the major drawback of having side effects such as gastrointestinal disorders and kidney disorders, and efforts are still being made worldwide to develop better drugs.

[Structure and effects of the invention]

Therefore, the present inventors have continued to study new anti-inflammatory agents for many years, and found that 2, which is represented by the following general formula (I), which has a different chemical structure from conventional non-steroidal anti-inflammatory agents.
- We have discovered that pyrrolidone compounds and their pharmacologically acceptable salts are excellent anti-inflammatory agents, and have already filed a patent application (see Japanese Patent Application No. 1983-96799).

CH3 CH3 (wherein R is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkynyl group, or the formula -(CH□), l-Y
(In the formula, Y is a phenyl group, a hydroxyl group, or the formula -N<
(In the formula, R1 and R2 mean the same or different hydrogen atoms or lower alkyl groups), and n means an integer of 1 or 2. ) The present invention provides a 2-pyrrolidone compound useful as an intermediate for producing a 2-pyrrolidone compound represented by general formula (1) as a final compound useful as an anti-inflammatory agent shown above.
- pyrrolidone derivatives.

That is, the compound of the present invention is a 2-pyrrolidone derivative represented by the following general formula (11) and a pharmacologically acceptable salt thereof.

(In the formula, R is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkynyl group, or a formula -(CH2), -Y
In the C formula, Y is a phenyl group, a hydroxyl group, or a formula -N<
<In the formula, R1 and R2 mean the same or different hydrogen atoms or lower alkyl groups), and n
means an integer of 1 or 2]. (X means a halogen atom) In the above general formula (n), the lower alkyl group seen in the definitions of R, R' and R2 is a straight chain or branched alkyl group having 1 to 6 carbon atoms. , for example, means an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl group, etc.

The lower alkoxy group and lower alkynyl group mean those derived from the above lower alkyl group.

The compound (II) of the present invention may be used as a Na salt or a K salt as necessary.
' In addition, R can be 2-(CI+2),
-N<, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, maleic acid, fumaric acid, succinic acid, malonic acid, acetic acid, citric acid, methanesulfonic acid It can be a pharmacologically acceptable salt such as an organic acid salt.

A typical method for producing the compound of the present invention will be described below.

(In the formula, X means a halogen atom, and Z means a halogen atom or an organic sulfonyloxy group.) The compound represented by the general formula (IV
) to form a compound (V).
The compound (n) of the present invention can be obtained by reacting and cyclizing this in the presence of a base such as sodium hydride, potassium carbonate, or sodium alkoxide. At this time, preferable results can be obtained if the reaction is carried out in a solvent such as ethanol or benzene at a temperature of -50°C to 100°C.

Compound (II) obtained according to the present invention can be converted into final compound (1) having excellent medicinal effects, for example, by the following method.

υ ↓ Triphenylphosphine C11゜■ ut (In the formula, R has the above meaning.) That is, the 2-pyrrolidone derivative obtained by the present invention (
If) is reacted with triphenylphosphine to obtain a Wittig salt represented by the general formula (Vl), and to this is 3,5-';-tert-butyl-4- represented by the general formula (■). Hydroxy-benzaldehyde was subjected to Wittig reaction in the presence of a base by a conventional method to obtain the final compound (1
).

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 a solvent,
Any solvent may be used as long as it does not participate in the reaction, but a preferred solvent is dimethylformamide (
Examples include DMF), dimethyl sulfoxide (MSO), ethanol, ethyl acetate, and benzene. The reaction temperature is approximately θ to 150°C, preferably 30°C.
~100°C.

Next, representative examples of the final compound (1) derived from the 2-pyrrolidone derivative (II) of the present invention are listed.

・N-Methyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone・N-ethyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2 -pyrrolidone.3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone.N-methoxy-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone.

・N-(2-dimethylaminoethyl)-3-(3,5
-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone・N-benzyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone・N-propargyl-3-(3,5 -Geetert
-butyl-4-hydroxybenzylidene)-2=pyrrolidone/N-(2-hydroxyethyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-
2-pyrrolidone/N-n-butyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone/N-(2-diethylaminoethyl)-3-(3,5
-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone-N-ethoxy3-(3,5-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone/N-hexyl-3- (3,5-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone=Nn-butoxy3-(3,5-tert-
Butyl-4-hydroxybenzylidene)-2-pyrrolidone In the present invention, the final compound (1) is a highly safe anti-inflammatory, analgesic, and antipyretic agent, and its value is high. It is as follows.

■ It has a wider safety margin compared to conventional anti-inflammatory drugs such as indomethacin, ibuprofen, and piroxicam.

■ It has effects that conventional non-steroidal anti-inflammatory drugs do not have, such as lipoxygenase inhibitory and antioxidant effects.

When the final compound (I) derived from the 2-pyrrolidone derivative (n) of the present invention is used clinically, it is used for indications for which conventional anti-inflammatory agents are used, such as arthritis, rheumatism, neuritis, etc. , anti-inflammatory analgesic for joint pain, neuralgia, etc.
Examples include cold syndrome, acute chronic bronchitis, anti-inflammation after trauma/surgery, antipyretic, analgesic, toothache, and headache.

Next, in order to explain in detail the usefulness of the final compound (1) derived from the 2-pyrrolidone derivative (II) of the present invention, the results of specific pharmacological experiments using animals are shown below.

A liquid paraffin suspension (10 n+g/m
7) was injected at a rate of 0.05 to induce adjuvant inflammation. On the 3rd to 5th day after the onset of inflammation, the local surface temperature of the inflamed foot was 8 to 10°C higher than that of the normal foot, and a stable value was obtained. To these rats, a suspension of the test compound described below (including indomethacin and piroxicam as controls) in a 5% aqueous gum arabic solution was orally administered at a rate of 5@Z/kg body weight.
After 5 hours, the method of HoShirota et al.
ota et, al, J.

Pharmacol, Methods, 12.35
-43 (1984)), the local surface temperature of the inflamed site was measured. The dose required to lower the temperature by 2°C or more compared to the value before administration was determined from the average value of the two cases, and the anti-inflammatory power of the test compound was calculated.

Compound A: N-methyl-3-(3,5-diter
t-Butyl-4-hydroxybenzylidene)-2-pyrrolidone compound ¥! IJB2 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 The results are shown in Table 1.

Table 1 Experiments were conducted using male Finscher rats (5 weeks old) as a - group of 5 rats. The test compound was suspended in 5% gum arabic.
5 and 0.5-g per 100 g body weight was orally administered.

One hour later, a 1% carrageenan solution was injected at 0.05 mZ into the right hind paw of the rat to induce inflammation. Three hours after the carrageenin injection, the hindlimb stepping volume was measured, the rate of increase in the stepping volume due to the carrageenin injection was calculated, and the inhibition rate was determined by comparison with the control group. The same compound used in Experimental Example 1 was used as the test compound.

bunch -5=-one fruit The results are shown in Table 2.

Table 2 After fasting for 24 hours in 7-week-old male Fischer rats,
A test compound suspended in 5% gum arabic was orally administered,
The 50% ulcer-inducing dose was calculated from the bleeding spot that developed on the gastric mucosa 6 hours later.

Figure-”L-Ichika The results are shown in Table 3.

UD in Table 3. is the 50% ulcer-inducing dose (na
g/kg).

Table 3 As is clear from the results of the above pharmacological experiments, 2-
Final compound (1) derived from pyrrolidone derivative (n)
) has a strong anti-inflammatory effect, and it also causes almost no gastric disorder, which is a side effect of conventional anti-inflammatory drugs, making it an extremely ideal drug when long-term use is required, such as with anti-inflammatory drugs. I can say that.

〔Example〕

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

1 (1) 2.4-Dibrombutanoyl chloride γ-
Butyrolactone soo g, Tool Buri (Pars) 1
The mixed solution of 0@1 was heated to 100° C., and while stirring, 250 mZ of bromine (Brz) was slowly dropped under the liquid surface over 6 hours. During this time, the reaction temperature was kept at 110°C to 115°C, and the mixture was stirred at the same temperature for 1 hour after the dropwise addition was completed. The reaction solution was then cooled to 90°C, 0.5 m7 of dimethylformamide (DMF) was added, and thionyl chloride (SO
Ch) 500- was added dropwise, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was distilled (60-b) to obtain 1.0 kg of the title compound.

(2) N-methoxy-2,4-dibromobutanami C1
, ONH, 520 g of HCl, water Ik chloroform (C
1 (Ch) 5 x is cooled (-5℃) with a water salt cryogen,
To this was added a mixture of 1,450 g of 2,4-dibromobutanoyl chloride obtained in (1) and 11 chloroform, and then 500 g of Na0II and 17 ml of water. The solution was added dropwise so that the reaction temperature did not exceed 10°C. After finishing the dripping, 1
The mixture was stirred at the same temperature for a period of time.

Take the chloroform layer of the reaction solution and add 0.5N HCl water,
It was washed with saturated sodium bicarbonate water and saturated saline solution, then dried with magnesium sulfate, and the chloroform was concentrated to give 1400 g of oil as a residue. This was used in the next reaction without any particular purification.

(3) N-methoxy-3-bromo-2-pyrrolide (2)
1400 g of N-methoxy-2,4-dibromobutanamide obtained in step 1 was dissolved in benzene 51, and dissolved in sodium hydride (NaH) at 15°C to 20°C while cooling in an ice-water bath.
125 g was added portionwise.

After the reaction is complete, add ice and remove excess sodium hydride (N
ap) was decomposed, then washed with saturated brine, dried over magnesium sulfate, concentrated to remove benzene, and purified by silica gel-acetone/benzene column chromatography to obtain 500 g of the title compound.

NMR (δ, CDCh): 3rd position methine 4.38 (1)1. dd, J=3.6H
z 7.2Hz) 4-position methylene 2.2-2.9 (2H
, m) 5-position methylene 3.4-3.9 (28, m) 1-position methoxy 3.82 (3H, s) The reaction formula of Example 1 is as follows.

N a OII B r Next, the steps from the intermediate obtained by the present invention to the final compound are shown in the following Reference Examples.

N-Methoxy-3-bromo obtained according to Example 1
2-pyrrolidone 75g, triphenylphosphine 105g
A mixture of 700 m7 of tetrahydrofuran (THF) was heated under reflux for 24 hours.

After cooling, the crystals were collected by filtration and washed with tetrahydrofuran.
After drying, 54 g of the title compound was obtained.

Pyrrolidone 3.5-diter t-butyl-4-hydroxybenzaldehyde 27.6 g, (N-methoxy-2-pyrrolidon-3-yl)triphenylphosphonium bromide 54 g,) ethylamine 33 m7 in ethanol
It was heated at ℃ for 4 hours. After ethanol was distilled off, the residue was dissolved in chloroform, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then chloroform was distilled off. 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.

Next, typical production examples of the final compounds are listed.

Production Example 1 Above 1 1.2 g of 3.5-di-tert-butyl-4-hydroxybenzaldehyde, (N-methyl-2-pyrrolidon-3-yl)triphenylphosphonium bromide 2.
5g, triethylamine 1. Qa+l was refluxed in ethanol for 2 hours. After distilling off ethanol, it was dissolved in chloroform, washed with water, washed with saturated saline, dried over anhydrous magnesium sulfate, and then chloroform was distilled off. Apply the residue to silica gel.
The residue was purified by benzene-acetone column chromatography and recrystallized from ethyl acetate-hexane to obtain 1.0 g of the title compound.

・Melting point ("C): 1s5 ・NMR (δ, CDC13): 1.47 (18H, s), 3.50 (211,t, J
=6Hz), 3.01(3H,s).

5.43 (111, s), 7.30 (IH, t, J=
3) 1z), 7.36 (2tl, s) Remains 21 According to the method described in Production Example 1, the following compound was obtained.

(Production Example 2) N-ethyl-3-(3,5-di-t
ert-butyl-4-hydroxybenzylidene)-2-
Pyrrolidone Melting point (°C): 186.5 NMR (δ, CDCl:l): 1.45 (18H, s), 2.9-3. H211,m
), 3.3-3.6 (411, m), 5.40 (I
H,s), 7.26 (LH,t, J=3t!z).

7.32 (2[1,s) (Production Example 3) 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone Melting point ('C): 210 (Decomposition) NMR (δ
, CDCl:I): 1.46 (18H, s), 3.13 (211, bro
ad, dt, J=3Hz.

6Hz), 3.52 (2H, t, J=6Hz), 5
．． 45 (IH, s), 6.98 (IL broads)
, 7.32 (IH, t, J=3Hz), 7.37 (
2H,5) 3-(3,5-di-tert-butyl-4
-Hydroxybenzylidene)-2~pyrrolidone 500m
Dissolved in 5 ml of dimethylformamide, added 0.2 g of sodium hydride under water cooling, then added 0.2 g of 2-dimethylaminoethyl chloride, and reacted at room temperature for 1 hour. Next, extracted with ethyl acetate and washed with water. , washed with saturated saline, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off, and the residue was purified by silica gel-benzene-acetone column chromatography and recrystallized from ethyl acetate-hexane to obtain 300 mg of the title compound.

・Melting point ('C): ts.

・NMR (δ, CDC11): 1.46 (18H, s), 2.26 (6H, s),
2.50 (2H, t, J=711z).

2.9-3.1 (28, m), 3.54 (4H, t,
J-7Hz), 5.37 (ILs), 7.26 (1
11,t, J=311z), 7.31(2H,s) Shellfish d Reni l According to the method described in Production Example 4, the following compound was obtained.

(Production Example 5) N-benzyl-3-(3,5-diter)
t-Butyl-4-hydroxybenzylidene)-2-pyrrolidone Melting point ('C): tss NMR (δ, CDC13): 1.45 (18H, s), 2.9-3.1 (2H, m
), 3.38 (2H, t.

J=6Hz), 4.62 (2tf, s), 5.40
IH, s), 7.3-7.5 (8B, 7.31,
7.36) (Production Example 6) N-propargyl-3-(3,
5-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone Melting point ("C): 212 ・NMR (δ, CDCl, l): 1.46 (188, s), 2.23 (1B, t, J＝
311z), 2.9-3.2 (2H, m), 3.5
9 (28, t, J=7Hz), 4.26 (2H, d,
J=311z), 5.41(IH,s), 7.2~
7.4(3H,m) According to the method described in Production Example 4, N-(2-(2-tetrahydropyranyloxy)ethyl)-3-(3,5-di-tert-butyl-4-hydroxy 300 mg of benzylidene)-2-pyrrolidone was hydrolyzed with hydrochloric acid in methanol to give the above title compound 1.
5011 g was obtained.

・Melting point ('c): 191 ・NMR (δ, CDC1z): 1.45 (18H, s), 2.9-3.2 (2H,
n+), 3.38 (LH, t).

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkynyl group, or the formula -(CH_2)_n-
Y [In the formula, Y is a phenyl group, a hydroxyl group, or a formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R^2 mean the same or different hydrogen atoms or lower alkyl groups)
and n is an integer of 1 or 2]. X means a halogen atom) 2-pyrrolidone derivatives and pharmacologically acceptable salts thereof.