JPS6168416A - Analgesic anti-inflammatory - Google Patents

Abstract

PURPOSE:The titled anti-inflammatory that contains, as an active ingredient, a pyrazole derivative, thus showing remarkable effect against pain in deep sites and powerful anti-inflammatory action without side-effects such as teratogenicity an mutagenicity and with high safety without acute toxicity. CONSTITUTION:The objective agent contains, as an active ingredient, a pyrazole derivative of the formula (R1, R2 are lower alkyl; R3, R4, R5 are H, halogen, lower alkyl; Z is phenacyl group and lower alkylbenzenesulfonyl group which may be substituted with lower alkyls). The preferable compound is 1,3- dimethyl-4-(2,4-dichloro-3-methyl)benzoyl-5-(p-methylphenazyloxy)-pyra zole. The dose of said anti-inflammatory is, in general, 1-100mg/kg and given in portions 2-4 times a day or orally or parenterally given in the form of a durative preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an analgesic and anti-inflammatory agent containing a pyrazole derivative as an active ingredient.

[Conventional technology and its neck point]

Morphine-based drugs are well known as analgesics aimed at alleviating pain, particularly deep pain.

However, morphine drugs exert their effects by acting on the central nervous system and blocking afferent transmission of local pain to the brain stem.
It has the disadvantage that it is easily addictive and cannot be used repeatedly.

In recent years, indomethacin, which has indoleacetic acid as its base, has been developed as a non-morphine analgesic.

Indomethacin exhibits analgesic and anti-inflammatory effects by blocking prostaglandin production, and is widely used to treat deep pain, especially chronic rheumatism, gout attacks, cystitis, postoperative and post-traumatic inflammation, and swelling. ing. but,
Crystals have strong side effects, and repeated use for several days can cause peptic ulcers, gastrointestinal bleeding, gastritis, anorexia, nausea, vomiting, abdominal pain, hepatitis, and yellow scars.
It causes a variety of side effects such as insomnia, increased blood pressure, hematuria, and urinary retention, and its LD5o is relatively large at 50 cm/body length, making it dangerous to use.

[Object and Structure of the Invention] The present invention was made in an attempt to develop an analgesic and anti-inflammatory agent that does not have the above-mentioned drawbacks.

The active ingredient of the analgesic and anti-inflammatory agent provided by this invention is a compound represented by the following general formula.

[In the formula, R1 and R2 are lower alkyl groups, 3, R4
and R5 means hydrogen, /%rogen or a lower alkyl group, and Z means a phenacyl group or a lower alkylbenzenesulfonyl group, which may be substituted with a lower alkyl group, respectively] - A summary of the above compounds and terms used in their definitions The detailed explanation is as follows.

Examples of the lower alkyl group include monovalent saturated hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, etc., with methyl being preferred. The lower alkyl groups of R1 and 2, these groups when λ3-5 is a lower alkyl group, and the lower alkyl groups that may be included in Z may be the same or different.

Examples of the halogen include fluorine, chlorine, bromine, etc., with chlorine being preferred.

A preferred compound as an active ingredient of the analgesic and anti-inflammatory agent of the present invention is a compound represented by the following general formula (n).

H3 [wherein R3 and Z have the same meanings as above] the general formula (
Examples of the compounds represented by n) are as follows.

Compound number Compound name (A) 1.3-dimethyl-4-(2,4-dichloro-3-methyl)benzoyl-5-(P-methylphenacyloxy)pyrazole (B) 1.3-dimethyl-4- (2,4-dichloro)benzoyl-5-phenacyloxypyrazole (
C) 1.3-dimethyl-4-(2,4-dichloro)benzoyl-5-(p-toluenesulfonyloxy)pyrazole (D) 1.3-dimethyl-4-(2,4-dichloro-3-methyl ) Benzoyl-5-phenacyloxypyrazole (E) 1.3-dimethyl-4-(2,4-dichloro-5-methyl)benzoyl-5-(p-methylphenacyloxy)pyrazole (F) 1.3 -dimethyl-4-(2,4-dichloro-6-methyl)benzoyl-5-phenacyloxypyrazole CG) 1.3-dimethyl-4-(2,4-dichloro-3-methyl)pensoyl-5-( p-Toluenesulfonyloxy)pyrazole (H) 1,3-dimethyl-4-(2,4-dichloro-3-methyl)benzoyl-5-(0-methylphenacyloxy)pyrazole represented by general formula (I) Some of the compounds and their production methods are described in, for example, Japanese Patent Publication No. 72903/1983, Japanese Patent Publication No. 28885/1983, and Japanese Patent Publication No. 36648/1989, and these compounds are known to have herbicidal activity. Are known.

Compounds other than those mentioned above in general formula (I) can be produced by the same method as the method for producing the above-mentioned compounds.

〔effect〕

The compound of general formula (I) has extremely strong analgesic and antiinflammatory effects and is used as a medicine. In particular, compounds of general formula (I+) show significant effects on deep pain.

In addition, the compound of general formula (I) is free from various side effects, mutagenicity, teratogenicity, etc. that known compounds have, and has no acute toxicity or L.
The D s o value is only 5000 μ/body ffKp, which is 1/100 of that of indomethacin, so it is extremely safe.

In the above uses, the dosage of the compound of general formula (I) will of course vary depending on the patient's symptoms, administration method, etc. but,
Generally a dose of 1 to 10 (IIq/~), preferably per day.
Satisfactory results are obtained when administered in 2 to 4 divided doses or in the form of a sustained release formulation.

When administering a compound of general formula (I) for the purpose of prevention or treatment, the compound of general formula (I) is used as an active ingredient,
They can be administered in the form of pharmaceutical preparations in admixture with conventional pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral or parenteral administration. Such formulations include tablets, capsules, pills, granules, powders,
It can be in the form of a solid such as a suppository, or a liquid such as a solution, suspension, or emulsion. Additionally, additives such as stabilizers and buffers may be added to the above formulation as necessary.

〔Example〕

Hereinafter, the present invention will be roughly explained in detail with reference to Examples and Test Examples.

Example 1 Compound (A) 25■Lactose 153m! ? Corn starch 20mg Magnesium stearate 2■ Mix the above ingredients and press into tablets.

Example 2 Compound (A) 1o o■
Lactose 148 mq Cornstarch 2■ Mix the above and fill into hard gelatin capsules.

Example 3 Compound (B) 50fn
g Lactose 2oorr
Uj cornstarch 47r
ng Magnesium stearate 3■
The above ingredients are mixed, granulated, and then compressed to form tablets.

Example 4 Compound (C) 50mg Lactose 148m Magnesium gestearate 2ffl! ?
Mix the above ingredients and fill into hard gelatin capsules.

Test Example 1 Compounds (A), (B) and (C) each 80 mg,
4.71 nq and 16 mg were accurately weighed out, gradually ground with 5 Q Q mg of polyvinylpyrrolidone powder, and 4.0 me of water was added little by little to form a suspension. This suspension was orally administered to ICR strain (spp) male mice at a dose of 100 μl per 25 days, and the mice were allowed to rest for 1 hour. As a control, Penta 7273% injection solution was diluted 10 times and its (i) 501ZJ/252 or (ii) 100μ/! /25ri by subcutaneous injection, or
or 8 mq of indomethacin/8 mq of polyvinylpyrrolidone
00mq/water 4.0 me suspension solution 100μl/25
9 was orally administered. Next, the mice were given 0.0 ml of 1% aqueous acetic acid solution.
1 me/10 y of body time was injected intraperitoneally + m, left in a private room, and the number of stretch reactions was measured.

The results are shown in Table 1.

The results shown in Table 1 indicate that Compound (A) exhibits excellent analgesic effects at extremely low doses, and that its effects are superior to indomethacin and only slightly inferior to pentazocine, a morphine derivative. Ta. It should be noted that some mice in the compound (A) administration group did not cause stretching at all, and even in those that did, the symptoms were mild. Compounds (B) and (C) were more effective than the untreated group, but their behavior became more sluggish as the dose was increased.

Test Example 2 In the same manner as Test Example 1, compound (A) and indomethacin were administered to mice. For the purpose of recording internal combustion reactions,
[UC:]g/L, :l-su (Amersh
am) was diluted with distilled water to prepare a solution of 2μC110.1me, and immediately after intraperitoneal administration of 1% acetic acid aqueous solution 1me/100y of body nail after administration of each drug. It was injected intravenously, and the mouse was transferred to a radiorespirometer (manufactured by Aloka, a device that can automatically measure exhaled radioactive CO2 produced by internal combustion of radioactive glucose). The results showed that combustion was somewhat suppressed in the untreated group.

In the compound (A) administration group, 8 out of 10 animals showed waveforms that were almost normal, and 2 animals showed slightly lower waveforms. The indomethacin-administered group showed an even lower waveform than untreated mice.

From these results, it was found that the f-hyde compound (A) has less influence on energy metabolism in the body than indomethacin.

Compound (A) and structurally similar compounds (B) and (C
) was tested in the same way as above, and showed a slightly higher expiratory volume than indomethacin. On the contrary,
Pentasocine had a slight suppressive effect on expiration when compared to the healthy group without acetic acid treatment, and showed strong suppression on exhalation after acetic acid administration.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 and R_2 are lower alkyl groups, R_3
, R_4 and R_5 are hydrogen, halogen, or a lower alkyl group, and Z is a phenacyl group or a lower alkylbenzenesulfonyl group, which may be substituted with a lower alkyl group, respectively] as an active ingredient. .