CA1068607A - 2-cyclopropanecarboxamido-5-halothiazole as anti-inflammatory agents - Google Patents

Abstract

Abstract of the Disclosure 2-cyclopropanecarboxamido-5-halothiazole as anti-inflammatory agents.

Description

~)6~ 7 This invention relates-to 2-cyclopropanecar~oxamido- -5-halothiazole which is useful as anti-inflammatory agents.
The co~pounds, 2-cyclopropanecarboxamido-5-halothiazole, have the following structural formula.

X ~ ~ N~_g_cH = ~2 in which X is chloro, bromo, iodo or fluoro.
These compounds are known as herbicides as evidenced 10 by Chem. Abst. Vol. 69 106540r 1968 or by French Patent 1,499,577 of October 27, 1967 to May & Baker Ltd. and may be ~ prepared according to those teachings or to teaching of the ; following example.
Example

2-cyclo~ropanecarboxamido-5 bro ~hiazole Br ~IH --CH2 10.4 g (10.10 m) cyclopropanecarboxylic acid chloride was added to a stirred mixture of 16 ml (10.20 m) piperdine 20 100 ml ethylenedichloride, and 25.9 g (0.10 m) 2-amino-5-~romothiozole hydrobromide over a period of 5 minutes with ice bath cooling to keep the temperature under 20C. After standing for 15 minutes, the mixture was diluted with a 100 ml ;
H2O to give a solid a~nd 2 liquid phases. This mixture was diluted with 100 ml n-pentane and solid filtered off, washed with ld~ ml water, and n-pentane to yield 16.5 g solid after drying in vacuo of the desired product.
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- In a similar manner the chloro, iodo and fluoro derivatives may readily he prepared employing the appropriate reactants. -; ,.~ `' ' ',^?~

~6 0 7 The product of the example will hereinafter be called Compound Number 1. The corresponding chloro compound will hereinafter be called Compound Number 2.

Anti-Inflammatory Screenin~
The compounds of the present invention have S pharmaceutical activity especially as anti-inflammatory agents. Anti-inflammatory activity is demonstrated by a test which involves the diminution of experimental edema induced in the hind paw of the rat by ~he injection of carrageenin.
Carrageenin injected into the foot o the rat produces an edematous condition which simulates part of the inflammatory process. Non-steroidal anti-inflammatory compounds inhibit the formation of this edema.
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Methods and Procedures The procedure used for measuring the inhibitio~
of carrageenin-induced edema is a standard procadure well known in the pharmaceutical art and is as follows:
~ Male rats (Long Evans Strain) weighing between : 130-200 grams are used in this assay. Five rats eaeh are used in the treatment groups and in the known standard ` 20 control; whereas ten rats are used in the control edema ; group. Unless otherwise indicated, phenylbutazone is administered orally at 100 mg/kg to the standard control group. The edema control group is administered the vehicle ; which consists of 0.25% methylcellulose solution. All of the rats are fasted for at least 15 hours prior to ~he test.
Water is available ad ~ibit~m. All of the experimental i . .

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lL06~ 7 drugs are given orally and are dissolved or suspended in 0.2570 methylcellulose solution. One hour after administra-tion of the test compound, .05 ml of a l~/o sterile solution of carrageenin is inJected into the plantar tissues o~ the left hind paw of each rat. Three hours after carrageenin administration, the paw volumes of in~ected paws are then measured by means of a water displacemen~ apparatus. The apparatus used is a modification of tha~ described by Adamkiewicz et al~, Canadian Jou~nal of Biochemistry and P~ysiology, 33 332~ 1955~ The a~ount of edema is calcu-lated and the percent reduction of edema from control values is determined. The mean volume of edema, based on 50 de-terminat~ons, is 1. 25 cc with a standard deviation of 0.226 cc.
A reduction in edema greater than 25~/o of the control value is considered significant. Based on 46 determinations, ~ phenylbutazone produced a mean inhibition of edema of 43.8%
`; with a standard deviation of 13.4%.
`~ ~e have found that the compounds of this invention produce a significant inhibition of i~duced edema in rats - 20 at a dose rate of 200 mg/kg.
Table I shows the reduction in edema in the hind paw of the rat according to ~he above-described test pro-`; cedure, at 200 mg/kg unless otherwise indicated.
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TABLE I
Percent Reduction in Edema at 200 mg/kg Compound Percent Reduction Number o~ Induced Ed~

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The compounds of the present invention, either alone or in the form of pharmaceutical composition may be administered to an animal subject in any of a number of ~orms and via any of several routes. Thus, the compounds or compositions thereof may be orally administered in the form of tablets, pills, capsules, or in the form of a sus-pension. The compounds may also be administered parenterally in ~he form of an injectable solution or suspension. The compounds or compositions thereof may also be administered topically, in the form of an ointment or rec ally, in the form of a suppository.
When orally administering the compounds or compo-sitions, use can be made of a tablet, pill or capsule consisting entirely of the desired compound, although ordinarily9 a composition comprîsing an effective amount of the compound and varying amounts of one or more physio-logically inert materials such as carriers, vehicles, binders and the like will be used. Additionally, the compounds may be orally administered in the form of a suspension thereof in a suitable vehicle such as a syrup.
When parenterally administering the compounds or compositions, use ma~ be made of a parenteral solution or suspension of the compound in a suitable solvent or suspension medium.
The compounds of the present invention may also be administered rectally in the for~ of a suppository com-prising an effective amount of the desired compound and a suitable vehicle such as petroleum jelly.

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Finally, the compounds of the present invention may be applied topically in the form of an ointment, salve, cream or lotion comprising an effective amount of the de-sired compound and a suitable vehicle such as petroleum jelly, etc.

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Claims (5)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A composition useful as an anti-inflammatory agent comprising a therapeutically effective amount of a 2-cyclo-propanecarboxamido-5-halothiazole of the formula wherein X is chloro, bromo, iodo or fluoro together with a pharmaceutically acceptable carrier.

2. The composition of claim 1 wherein X is chloro.

3. The composition of claim 1 wherein X is bromo.

4. The composition of claim 1 wherein X is iodo.

5. The composition of claim 1 wherein X is fluoro.