CH626079A5 - Process for the preparation of 2-cyclopropanecarboxamido-5-halothiazole - Google Patents

Description

This invention relates to a process for the preparation of 2-cyclopropanecarboxamido-5-halothiazole which is useful as an anti-inflammatory agent.

The 2-cyclopropanecarboxamido-5-halothiazoles have the formula

CH,

CH,

where X is chlorine, bromine, iodine or fluorine. These compounds are prepared by using cyclopropanecarboxylic acid chloride of the formula II

10.4 g (10.10 mol) of cyclopropanecarboxylic acid chloride were added to a stirred mixture of 16 ml (10.20 mol) of piperidine, 100 ml of ethylene dichloride and 25.9 g (0.10 mol) of 2-amino-5-bromo- thiazole hydrobromide added over 5 minutes,

the temperature was kept below 20 ° C. by means of ice bath cooling. After standing for 15 minutes, the mixture was diluted with 100 ml of water and gave one solid and two liquid phases. This mixture was diluted with 100 ml of n-pentane, the solid was filtered off and washed with 100 ml of water and n-pentane. 16.5 g of solid were obtained after drying the desired product in vacuo, 3 s mp 211-218 ° C.

The product of this example is referred to as Compound No. 1 below. The corresponding chlorine compound is called Compound No. 2 below.

40 Experiment with regard to the anti-inflammatory effect The compounds obtainable according to the invention have a pharmaceutical effect, in particular as anti-inflammatory agents. The anti-inflammatory effect is demonstrated by an attempt to reduce 4s experimental edema caused in the hind paw of the rat by injection of carrageenin.

Carrageenin, when injected into the rat's paw, creates an edema-like condition that simulates part of the inflammatory process. Non-steroids, anti-inflammatory compounds prevent the formation of this edema.

Procedures and labor

The measurement method for the inhibition of edema caused by carrageenin ss is a standard procedure that is well known in pharmaceutical technology and is carried out as follows:

Male rats (Long Evans strain) weighing between 130 and 200 g are used for this experiment. 60 rats each are used in the treatment groups and in the (j) known standard comparative experiments, while ten rats are used in the comparison group with edema. Unless otherwise stated, 100 mg / kg phenylbutazone from the standard comparison group are administered orally. 65 The control group with edema is given a carrier consisting of a 0.25% methyl cellulose solution. The rats were given no food for at least 15 hours before the test, while water was given ad libitum

626079

is available. All experimental agents are administered orally and are dissolved or suspended in 0.25% methyl cellulose solution. One hour after administration of the test compound, 0.05 ml of a 1% sterile carrageenin solution is injected into the sole tissue of the left hind paw of each rat. Three hours after the carrageenan injection, the paw volumes of treated paws are measured using a water displacement device. The equipment used is a modification of that described by Adamkiewicz et al., Canadian Journal of Bioio chemistry and Physiology, 33, 332, 1955. The amount of edema is calculated and the percent edema inhibition is determined from comparative values. The mean edema volume, based on 50 determinations, is 1.25 ccm with a standard deviation of 0.226 ccm. An edema reduction greater than 25% of the comparative value is considered significant. Based on 46 determinations, phenylbutazone produced an average edema inhibition of 43.8% with a standard deviation of 13.4%.

It has now been found that the compounds obtained according to the invention cause a considerable inhibition of artificially produced edema in rats at a dose of 200 mg / kg.

The table shows the edema reduction in the hind paw of the rat according to the procedure described at 200 mg / 25 kg, unless stated otherwise.

table

Percentage reduction in edema at 200 mg / kg

Connection no.

Percentage reduction in edema produced

1

51

2nd

50

The compounds obtainable according to the invention can be administered to the animals either alone or in the form of a pharmaceutical preparation in any form and in various ways. Thus, the compounds or their preparations can be administered orally in the form of tablets, pills, capsules or in the form of a suspension. The compounds can also be given parenterally in the form of an injectable solution or suspension. The compounds or their preparations can also be administered locally in the form of an ointment or rectally in the form of a suppository.

In the oral administration of the compounds or their preparations, a tablet, pill or capsule consisting only of the desired compound can be used, although usually a preparation consisting of an effective amount of the compound and various amounts of one or more physiologically acceptable substances such as solid or liquid carrier, binder and. Like. Is used. Furthermore, the compounds in the form of a suspension thereof in a suitable carrier liquid, such as. B. syrup.

When the compounds or preparations are administered parenterally, a parenteral solution or suspension of the compound in a suitable solvent or suspension medium can be used.

The compounds obtainable according to the invention can also be administered rectally in the form of a suppository which consists of an effective amount of the desired compound and a suitable carrier, such as petroleum jelly.

Finally, the compounds obtainable according to the invention in the form of an ointment, ointment gauze, cream or lotion, which contain an effective amount of the desired compound and a suitable carrier, such as petroleum jelly, can be applied locally.

B

Claims (6)

626 079 2. The method according to claim 1, characterized in that 2-amino-5-bromothiazole hydrobromide is used as a compound of formula III. 2-cyclopropanecarboxamido-5-bromothiazole 0 ^ -CH, II ■ NH-C-CH ■ CH, HX (HD implements. 2nd PATENT CLAIMS 1. Process for the preparation of 2-cyclopropanecarbox-amido-5-halothiazole of the formula I 0 II NH-C-CH CHi O \ II CH-C-Cl (II) (I) with 2-amino-5-halothiazole hydrohalide of the formula III wherein X is chlorine, bromine, iodine or fluorine, characterized in that cyclopropanecarboxylic acid chloride of the formula II IS (III) implements. The following example illustrates the invention. CHa- cm O CH-C-Cl (II) with 2-amino-5-halothiazole hydrohalide of the formula III example 3. The method according to claim 1, characterized in that one produces a compound of formula I in which X is chlorine. 4. The method according to claim 1, characterized in that one produces a compound of formula I in which X is bromine. 5. The method according to claim 1, characterized in that one produces a compound of formula I in which X is iodine. 6. The method according to claim 1, characterized in that one produces a compound of formula I in which X is fluorine.