JPH03291223A - Antiphlogistic-analgesic agent - Google Patents

Abstract

PURPOSE:To provide the subject antiphlogistic and analgesic agent containing 2-(4-halogenophenyl)-4,5-diphenylimidazoline or a pharmacologically allowable salt thereof as the active component. CONSTITUTION:An antiphlogistic and analgesic agent containing 2-(4- halogenophenyl)-4,5-diphenylimidazoline or its salt (e.g. hydrochloride, sulfate, oxalate or benzoate) as the active component and capable of oral and parenteral administration. The above agent can be prepared into a dosage form such as tablet, granule, capsule, powder or injection and the dosage is 0.5-50mg/kg per day on active component base. As the halogen in the imidazoline derivative, Cl is preferable and either of four optical isomers and two tautomers can be used as the active component.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a novel anti-inflammatory/analgesic agent.

[Structure and effects of the invention]

The present invention relates to 2-(4-halogenophenyl)-45-diphenylimidazoline (hereinafter referred to as "imidacillin derivative").
It is abbreviated as. ) or a pharmacologically acceptable salt thereof as an active ingredient.

The imidapurine derivative and its pharmacologically acceptable salt, which are the active ingredients of the anti-inflammatory and analgesic agent of the present invention, are new compounds and exhibit excellent suppressive effects on carrageenan-induced paw edema in rats and/or are used in rats. It shows excellent analgesic effect in the Randall-Selitto test. Furthermore, the imidacillin derivatives and pharmacologically acceptable salts thereof of the present invention have low toxicity,
For example, 7500 mg/kg of cis-2(4-chlorophenyl)-4,5-diphenylimidazolyne was administered to rats (C
rj: SD strain) was orally administered once a day and observed for 14 days, no deaths were observed.

The pharmaceutical composition of the present invention is based on the excellent anti-inflammatory and analgesic effects of imidacillin derivatives and their pharmacologically acceptable salts,
For example, various inflammatory diseases (e.g., rheumatism, gout, arthritis, or inflammation caused by fractures, lesions, injuries, trauma, etc.) in skeletal muscles, joints (e.g., knee, shoulder, ankle joints, etc.) and other organs. It can be used to treat or alleviate pain, fever, and other symptoms associated with various inflammatory diseases.

Among the imidacillin derivatives that are the active ingredients of the present invention, therapeutically preferable ones are 2-(4-chlorophenyl)-4
, 5-diphenylimidazoline.

Imidacillin derivatives can be used for pharmaceutical purposes both in free form and in the form of their pharmacologically acceptable salts. Such pharmaceutically acceptable salts include, for example, inorganic acid addition salts such as hydrochlorides, hydrobromides, phosphates and sulfates, or oxalates, acetates, lactates, citrates. , organic acid addition salts such as tartrates, fumarates, maleates, aspartates, methanesulfonates and benzoates.

The pharmaceutical preparation of the present invention containing imidacillin derivatives and pharmacologically acceptable salts thereof as active ingredients can be administered orally or parenterally, and can be administered in the form of tablets, granules, etc. by conventional methods. It can be used in appropriate pharmaceutical formulations such as capsules, powders, and injections.

Although the dosage varies depending on the administration method, patient's age, weight, condition, and type of disease to be treated, the dosage of imidacillin derivatives and their pharmacologically acceptable salts is usually about 0. .1 to about 100 .mu./kg, particularly about 0.5 to about 50 .mu./kg.

In addition, the imidacilline derivative can be used in the present invention in any of the four optical isomers based on two asymmetric carbon atoms and the two tautomers based on the two nitrogen atoms constituting the imidacilline ring. Can be used as an active ingredient.

The imidacillin derivative which is the active ingredient of the present invention has 1.2
-Diamino-1,2-diphenylethane and 4-halogenobenzinoethyl ether in a suitable solvent (e.g., lower alkanol, etc.) in the presence or absence of a base (e.g., tri(lower alkyl)amine, etc.). , can be produced by heating.

[Effect]

Experimental Example 1 Karinho (Method) Cis-2-(4-chlorophenyl)-4,5-diphenylimidazoline 10 mg/kg was administered to rats that had been fasted overnight.
was orally administered, and 1 hour later, a suspension of carrageenan in physiological saline was subcutaneously injected into the sole of the left foot. After 4 hours, the volume from the ankles on both sides was measured, the difference between the left and right sides was determined, and the efficacy was determined by comparing with the control group.

(Results) Cis-2-(4-chlorophenyl)-4,5- of the present invention
Diphenylimidazoline showed an approximately 45% inhibitory effect on carrageenan-induced paw edema.

Experimental Example 2 (Method) Cis-2-(4-chlorophenyl)-4,5-diphenylimidazoline was orally administered at 25 μg/Kg to rats that had been fasted overnight, and immediately thereafter 20 μg/Kg was administered. A 0.1-ml suspension of dry yeast in physiological saline was subcutaneously injected into the sole of the left foot. Two hours later, pressure stimulation was applied to the rat's paws to measure the pain threshold, and the difference between the pain thresholds between the left and right paws was determined, and the efficacy was determined by comparing with the control and group.

(Results) Cis-2-(4-chlorophenyl)4.5-diphenylimidazoline of the present invention reduced the difference in pain intensity values by about 40x.

[Manufacturing example]

Production Example 1 Erythro 1,2-diamino-1,2-diphenylethane diacetate 16.1 g, 4-chlorohenziminoethyl ether hydrochloride 13.7 g.

A mixture of 260 d of ethanol and 14.8 d of triethylamine
- and reflux for 4 hours. After the reaction, the solvent is distilled off, and 77 d of IN-sodium hydroxide aqueous solution is added to the residue, followed by extraction with chloroform. After washing the extract with water and drying, the solvent is distilled off. The residue was recrystallized from methanol to give cis-2-(4
12.0 g of -chlorophenyl)-4,5-diphenylimidazoline are obtained.

Yield 75% M, p, 152-153°C IRν, --(cab-'): 3200. 1619
．． 1595 Hydrochloride: M, p, >280°C Maleate: ? f, p, 199-200°C (decomposition) Fumarate: M, p, 233-235°C (decomposition) DL
-Lactate: M, P, 143-144°C (decomposition)
L-tartrate: M+p, 92-95°C (decomposition) Methanesulfonate: M, p, >280"C Production example 2 Threo-1,2-diamino-1,2-diphenylethane 2 salt 8 salt Add 1.1 d of triethylamine to a mixture of 1.0 g of 4-chlorobenziminoethyl ether, 0.84 g of 4-chlorobenziminoethyl ether and 30111 ethanol, and reflux for 1 hour. After the reaction, the solvent is distilled off, and the residue is treated with IN-hydroxylated Add 35 d of aqueous sodium solution and extract with chloroform. The extract is washed with water, dried, and the solvent is distilled off. The residue is purified by silica gel column chromatography [solvent: chloroform-ethanol (9:1)]. The obtained The product was dissolved in ethanol, made acidic by adding 20% hydrochloric acid/ethanol solution, the solvent was distilled off, the residue was washed, and the trans-
10 g of 2-(4-chlorophenyl)-4,5-diphenylimidazoline hydrochloride is obtained.

Yield near 8% M, p, 281-284°C Production Examples 3 to 4 The corresponding erythro-type raw material compound is treated in the same manner as in Production Example 2 to obtain the following imidacillin derivative.

(3) cis-2-(4-fluorophenyl)-4゜5-
Diphenylimidazoline hydrochloride M, p, >280″C (4) cis-2-(4-bromophenyl)-4,5 diphenylimidacillin hydrochloride M, p, >280°C

Claims (1)

[Scope of Claims] An anti-inflammatory/analgesic agent containing 1,2-(4-halogenophenyl)-4,5-diphenylimidazoline or a pharmacologically acceptable salt thereof as an active ingredient. An anti-inflammatory/analgesic agent containing 2,2-(4-chlorophenyl)-4,5-diphenylimidazoline or a pharmacologically acceptable salt thereof as an active ingredient.