JPS58198469A - Pyridylhydrazide-based compound and antiphlogistic containing it - Google Patents

Abstract

NEW MATERIAL:A pyridylhydrazide-based compound shown by the formula I (X is halogen; R is methyl which may be replaced with halogen). EXAMPLE:2-(5-Trifluoromethyl-6-chloro-2-pyridyl)trifluoroacethydrazide. USE:Useful as an active ingredient for an antiphlogistic. PROCESS:For example, a trifluoromethyl-substituted pyridyl-hydrazine-based compound shown by the formula II is reacted with a compound shown by the formula III in the presence of a solvent such as methylene chloride, ether, pyridine, etc. at <=room temperature for 0.5-10hr, to give a compound shown by the formula I . Or, the compound shown by the formula II is obtained by reacting a trifluoromethyl-substituted-2-halogenopyridine with hydrazine hydrate in the presence of an alcohol solvent such as preferably ethanol, etc. to give the compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyrinolhydrazide compounds and anti-inflammatory agents containing them.

More specifically, the present invention relates to pyrinolhydrazide compounds represented by the general formula (wherein x is a hydrogen atom or a halogen atom, and R is a methyl group optionally substituted with a halogen atom r-), and their This relates to an anti-inflammatory agent containing as an active ingredient.

In the above general formula, the halogen atom shown in the definitions of X and H includes fluorine, chlorine, bromine, and iodine. Further, as H, a trifluoromethyl group or a monobromomethyl group is desirable.

The pyridyl hydranide compound of the present invention is usually, for example, F
Manufactured by notation.

In reaction formulas [1] and [2], X and R are as described above, [<' is a methyl group which may be substituted with a halogen atom other than trifluoro-7tyl group, and Y is a halogen source f.

Examples of the solvent used in Reaction Formulas (1) and [2] in -1- include methylene chloride, ether, pyridine, and benzene. Further, examples of the deoxidizing agent used in reaction formula [2] include birinone, triethylamine, and alkali metal hydroxides or carbonates.

The trifluoromethyl-substituted bilinolhydracune compound used as the raw material in Reaction Formulas [1] and [2] of Ajj preferably contains trifluoromethyl-substituted-2-halogenopyridine and hydrazine hydrate. It can be easily produced by reacting in the presence of a furfur solvent such as ethanol or isopropanol.

Next, a synthesis example of the compound of the present invention will be described.

Synthesis example 2-(5-)lifluoromethyl-6-chloro-
2-Birinol) triple oro7cetohydrazide (1) 2,6-dichloro-3-trifluoromethylbilinone 21.6H and 100% hydranone hydrate 25g
and were dissolved in 150° C. of ethanol and reacted at 40° C. for 15 hours with stirring. After the reaction was completed, the product was poured into water and extracted with methylene chloride. The extracted layer was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was then treated with a silica gel column to give 6-chloro-2-
Hydratuno-3-trifluoromethylbilinone 3.0g
and 2-chloro-6-hydrazuno- with a melting point of 92-93°C
2.3 g of 3-trifluoromethylbilinone was obtained.

(2) 85 g of 2-chloro-6-hydrano-3-trifluoromethylbilinone obtained in the above reaction was dissolved in 15 ml (l) of methylene chloride and cooled to 0°C. Fi5mQ dissolved in methylene chloride in which .85 g of fi5mQ was dissolved was added dropwise under stirring and allowed to react at room temperature for 2 hours. The precipitated solid was collected by filtration and dissolved in ethyl acetate. After washing with an aqueous sodium solution, further washing with water, and drying, ethyl acetate was distilled off under reduced pressure to obtain the desired product with a melting point of 76-78°C.
I got it.

Table 1 shows the compounds of the present invention synthesized according to the general production method or synthesis example described above.

Table 1 The compounds of the present invention exhibit excellent activity as active ingredients of anti-inflammatory agents, as shown in the test examples below.

When using the compound of the present invention as an active ingredient of an anti-inflammatory agent, the compound of the present invention may be used in combination with a formulation auxiliary agent to form a solid formulation (as in the case of ordinary pharmaceutical formulations).
It can be formulated into various forms such as tablet pellets, capsules, powders, sitz forms) and liquid preparations (injections, suspensions, emulsions, etc.). These preparations can be administered orally or parenterally.

The formulation adjuvants are carriers, excipients, solubilizers, or dividing agents, and specifically include water, physiological saline, starch, silica solution, glyfurs, lactose, peach/knot oil, etc. Spear oil, olive oil, castor oil, cacao butter, sesame oil, cellulose KM,
Examples include magnesium stearate, mannitol, ethanol, fragrance, and syrup. In addition to the formulation auxiliaries described above, auxiliary agents such as stabilizers, preservatives, emulsifiers, and buffering agents, or other pharmacologically active substances may be added as appropriate. 1) The age of the patient,
It varies depending on body weight, severity of symptoms, administration method, etc. - cannot be generally specified, but generally 1 kg of adult body weight per day
O12・-5001118 per g, preferably 1 to 250
It is 1.

When the anti-inflammatory agent of the present invention is injected, it may be accompanied by analgesic and/or antipyretic effects.

Next, test examples of the anti-inflammatory agent of the present invention will be shown.

Test Example 1: Using ICR male mice weighing 25 to 40 g,
After time fasting, NIKKOL HCO-60<1-1
An aqueous suspension containing fractions of Hikari Chemicals Co., Ltd. product) and the test compound at a predetermined concentration was injected into the mouse at a concentration of 1-l per 100 g of mouse. Ninety-one hours after injection, 1% caladenin aqueous solution (1,02-) was injected into the skin of the right hind paw. After 4-5 hours, the paw volume was visually observed.
The degree of inhibition was evaluated in 3 stages 1* (-: ineffective, +: effective, well: markedly effective) in comparison with KKOL I (4 groups of CO-60 aqueous solution injection), and the results shown in Table 2 were obtained.

The acute toxicity value (1-r), , ) of the test compound is also written in the second column.

Acute toxicity values were determined using ICR male mice weighing 20 to 248, and one dose of 4 L via the water suspension used in the test example above.
Observe the number of dead animals for 7 hours after casting.
The % mortality value was calculated.

Table 2: Compound No. 8: 50 mg/kg and 10B
/kit, compound no.

10 and KiN (1, 12) were administered at 50 mg 1ks each, and the degree of inhibition of caladenin edema was examined, and showed the degree of inhibition of ox, +9, 10, and +, respectively.

Test Example 2 Using male Wistar runts of 130-1 sOg, after fasting for 18 hours, NIKKOl, I
(An aqueous suspension containing a fraction of CO-6 (1 (product of 13 Maru Chemicals Co., Ltd.) and a specified concentration of the test compound)
I threw it once so that it would be 11 IIQ per 10 og.

One hour after administration, 1% caladenine aqueous solution 0. ld as A,
It was injected into the hind paw skin. After 4 hours, the left a] posterior abdomen
It was cut from a certain part and the head office was measured. The edema rate was determined from the rate of increase in swelling of the left and right hindlimbs, and
The edema suppression &II rate was calculated from the average edema rate of the 4 groups treated with He0-641 aqueous solution and the 4 groups treated with drugs, and the
Obtained the results in the table.

Third: & Next, examples of formulations of the anti-moxibustion agent of the present invention will be shown.

Formulation example (a) 2-(5-)lifluoromethyl-6-chloro-2-pyridyl)trifluoro a7cetohydrazide 25 parts 1 part (b) Lactose 120〃 (c) Starch 52〃
(d) Hydroxypropyl cellulose 3
, [- (a) to (d) were mixed and granulated and dried to obtain granules.

Patent Issue Ishihara Sangyo Co., Ltd.

Claims (2)

[Claims] (1) - A pyridyl hydrazide compound represented by the general formula (wherein X is a hydrogen atom or a halogen atom, and R is a methyl group which may be substituted with a halogen IIAf.). (2) The active ingredient is a pyridyl hydrazide compound represented by the general formula (wherein X is a hydrogen atom or a halogen atom, and l< is a methyl group which may be substituted with a halogen ItAr-) Anti-inflammatory agent.