GB2098989A

GB2098989A - Lysine salts

Info

Publication number: GB2098989A
Application number: GB8214547A
Authority: GB
Original assignee: Poli Industria Chimica SpA
Current assignee: Poli Industria Chimica SpA
Priority date: 1981-05-26
Filing date: 1982-05-19
Publication date: 1982-12-01
Also published as: IT1137229B; KR830010067A; FR2506766A1; ES8302653A1; KR860000292B1; GB2098989B; CA1171421A; JPS57200359A; ES512510A0; DE3219605A1; PT74949B; PT74949A; BE893039A; IT8121949A0

Abstract

Salts of L'lysine or DL-lysine with 5-(p-chlorobenzoyl)-1 ,4-dimethyl- pyrrole-2-acetic acid, having the formula (A): <IMAGE> in which I is the said acid and II represents L-lysine or DL-lysine are prepared by reacting equimolecular quantities of L-lysine or DL-lysine with 5-(p- chlorobenzoyl)-1,4-dimethyl-pyrrole-2-acetic acid in the presence of water or water and alcohol at temperatures between 0 DEG C and 100 DEG C. They have analgesic activity and can be incorporated into pharmaceutical compositions.

Description

SPECIFICATION Soluble compounds having analgesic activity This invention relates to salts of 5-(p-chlorobenzoyl)-1 ,4-dimethyl-pyrrole-2-acetic acid (I) with the basic aminoacid lysine (II) having the structural formula (A), and a method of preparing same.

The lysine may be either L-lysine or DL-lysine.

According to the present invention there is provided salts of L-lysine or DL-lysine with 5-(pchlorobenzoyl)-1 ,4-dimethyl-pyrrole-2-acetic acid, having the formula (A):

in which I is the said acid and II represents L-lysine or DL-lysine.

The salt obtained by using L-lysine will hereinafter be called L-(A) and the salt obtained with DLlysine will be called DL-(A). Compounds of the invention have excellent analgesic activity, as shown by phenylquinone writhing tests. In these tests, no substantial differences in activity were observed between the salt obtained with L-lysine and the salt obtained with DL-lysine. The acute toxicities of L (A) and DL-(A) in the mouse and the rat was also similar.

The compounds according to the invention are much more soluble in water than salts of (1) with inorganic cations. This, together with the near-neutral pH of the aqueous solutions, enables the compounds to be used in preparations for parenteral use.

The compounds according to the invention can be used in human therapy for the treatment of acute or chronic pain resulting from malignant neoplasia, oral surgery, osteoarthritis, headache of various origin, or general or orthopaedic surgery. The proposed forms of administration are oral, parenteral and rectal. For oral administration tablets, pills or capsules containing a quantity of (A) between 50 mg and 800 mg may be used. The estimated dose is 1-6 tablets, pills or capsules in 24 hours.

For parenteral administration, pre-packed solutions or vials containing compound (a) in lyophilised form accompanied by vials of solvent excipient may be provided. The proposed amount of compound (A) in each vial is between 50 mg and 500 mg. The estimated dose is 1-3 vials per 24 hours.

For rectal administration suppositories containing between 100 mg and 1000 mg of compound (A) may be used. The estimated dose is 1-5 suppositories in 24 hours.

The analgesic activity of the compound (A) was studied in the phenylquinone writhing test, by the method described by Hendershot and Forsaith in J. Pharmacol. Exp. Therap, 123, 237 (1959). Male COBS CD-1 mice, unfed for 3 hours, were orally given the compound under test 30 minutes before endoperitoneal injection of 0.25 ml of a 0.02% solution of phenylquinone in ethanol: water (5:95). Five minutes after injection of phenylquinone, the abdominal spasms (writhing) of each animal were counted for 1 5 minutes. Groups of 10 animals were used for each tested dose. The analgesic activity of the compound under examination, expressed as the EDso (the dose which reduces the number of abdominal contractions by 50% compared with the non-treated animals) was 0.72 mg/kg for L-(A) and 0.77 mg/kg for DL-(A).The oral LD50 for both compounds was above 1 g/kg for both the rat and the mouse.

The above-described high analgesic activity of compounds L-(A) and DL-(A) is accompanied by the complete absence of ulcerogenic activity. Male COBS CD (SD) rats weighing 1 60-200 g and unfed since the preceding evening were slightly anaesthetised with ether after which the pylorus was ligated. They were given drinking water after the operation.

Two hours later the rats were orally given L-(A), DL-(A), the sodium salt of I and aspirin in equimolecular doses, suspended in 5% gum arabic.

After an hour the rats were sacrificed and their stomachs were examined for the presence of ulcers.

The number of rats having ulcers and the average number of ulcers per rat were measured as follows: % of rats Number of with ulcers ulcers per rat 121 mg/kg of L-lysine O 0 1 21 mg/kg of DL-lysine O 0 97 mg/kg of sodium salt of 1 60 14 50 mg/kg of aspirin 100 34 This invention also provides a method of preparing compounds of formula (A), comprising reacting equimolecular quantities of I and II in the presence of water or water and alcohol, at a temperature of from 00 to 1 OO"C. The resulting salt may be isolated by concentration or cooling the solution or by the addition of a non-solvent.

The following examples illustrate the method according to the invention.

Example I 29.2 kg of 5-(p-chlorobenzoyl)-1 ,4-dimethyl-pyrrole-2-acetic acid were added at intervals over one hour to an aqueous solution of 50% L-lysine containing 14.6 kg L-lysine, heated to a temperature between 400C and 550C and continuously and efficiently stirred.

Agitation and heating were continued until a clear, yellow solution was obtained. After filtering, the solution was cooled to room temperature and 90 litres of acetone were added with slow agitation.

The mixture was cooled to 2-50C and left to stand at this temperature for 2 hours. The precipitate was collected by filtration, washed with 10 litres of acetone and then with 10 litres of ethyl ether. It was dried in a vacuum chamber at a temperature not above 400 C. The product was an ivory-white crystalline powder, melting with decomposition at 21 8-2200C. By a similar procedure DL-(A) melting at 205-2070C was obtained by using DL-lysine.

Example 2 35 kg distilled water and 10 kg ethanol were added to a 50% aqueous solution of L-lysine containing 7.3 kg of L-lysine. The mixture was heated to 45-500C and 14.6 kg of 5-(p chlornbenzoyl)-1 ,4-dimethyl-pyrrole-2-acetic acid were added in portions, with efficient agitation.

Agitation and heating were continued until the mixture dissolved. The resulting solution was filtered and concentrated to dryness in vacuo in a rotating evaporator. The yellowish residue obtained was dissolved in 120 kg absolute ethanol, the material being suspended with violent agitation. The mixture was cooled, with continued agitation, to 00C and 1 5 kg ethanol were added and the mixture was left to stand at 00C, for 8 hours. It was filtered and washed with 6 kg of ethanol and dried in a vacuum chamber at a temperature not above 450C.

Claims

1. Salts of L-lysine or DL-lysine with 5-(p-chlorobenzoyl)-1 ,4-dimethyl-pyrrole-2-acetic acid, having the formula (A):

in which I is the said acid and il represents L-lysine or DL-lysine.

2. A method of preparing the compounds claimed in claim 1, comprising reacting equimolecular quantities of L-lysine or DL-iysine with 5-(p-chlorobenzoyl)-1 ,4-dimethyl-pyrrole-2-acetic acid in the presence of water or water and alcohol at temperatures between OOC and 1 000C.

3. A method as claimed in claim 2 in which the salt is isolated either by concentration or cooling the solution or by addition of a non-solvent.

4. Salts of formula (A) whenever prepared by the method claimed in claim 2 or 3.

5. A pharmaceutical composition having analgesic activity and suitable for treating acute or chronic pain resulting from malignant neoplasia, general, oral or orthopaedic surgery, osteoarthritis or headache of various origin comprising a compound claimed in claim 1 or claim 4 and a pharmaceutical vehicle.