KR840001072B1 - Process for the preparation amide of p-isobuthy phenyl propionic acid - Google Patents

Abstract

Title compds.(I; X=lysine, m=trifluorotoluidine, glutamic acid and asparaginic acid -sub- stituted amine) having antiinflammatory and analgesic activities about the same as that of aspirin but with much greater gastric tolerability, were prepd. by chlorination of p-isobutyl-phenyl-propionic acid with excess chlorinating agent and reaction with amines. Thus, 50g p-isobutyl-phenyl-propionic acid was chlorinated with 120ml thionylchloride to give p-isobutyl-phenyl-propionyl chloride, and the reactant reacted with 14.7g glutaminic acid to give glutaminic amide of p-isobutyl-phenyl-propionic acid.

Description

Method for preparing amide derivative of P-isobutyl-phenyl-propionic acid

The present invention relates to a method for producing a mamid derivative of p-isobutyl-phenyl-propionic acid of the following general formula.

Wherein X represents a substituted amine group selected from lysine, metatrifluorotoluidine, glutamic acid and aspartic acid.

The anti-inflammatory properties of p-isobutyl-phenyl-propionic acid are known.

Also, like most drugs used to treat inflammation, this acid is an important factor, for example, for long-term treatment, such as poor tolerability in the stomach and insignificant toxicity. It has been known to indicate adverse side effects.

However, the present inventors have found that the amide derivative of the present invention is less toxic and has greater tolerability in the stomach in addition to the anti-inflammatory action that is typical of p-isobutyl-phenyl-propionic acid.

The production process of the present invention for preparing the amide derivative of the general formula (I) is as follows.

a) warming the p-isobutyl-phenyl-propionic acid with an excess of chlorinating agent (e.g., thionyl chloride or phosphorus pentachloride),

b) The chloride of D-isobutyl-phenyl-lopionic acid is reacted at low temperature with an amine derivative in a reaction medium selected from alkaline water and pyridine.

It can also be foreseen that the reaction can proceed further by the chlorination of the free acid reactor of the amide produced by the pharmacologically acceptable organic or inorganic base.

Examples of the present invention are as follows.

Example 1

a) chlorides of p-isobutyl-phenyl-propionic acid

120 ml of thionyl chloride was added to 50 g of p-isobutyl-phenyl-propionic acid, and the mixture was gradually heated to 75 ° C. In order to control the reaction state, the generation of gas from the reaction mixture was monitored by the gas trap until the generation of this gas stopped, and the end of this reaction was found when the generation of this gas stopped. Excess thionyl chloride was distilled off and then the chloride of p-isobutyl-phenyl-propionic acid was recovered by vacuum distillation.

b) Glutamic acid amide of p-isobutyl-phenyl-propionic acid

A solution of 14.7 g of glutamic acid dissolved in 20 ml of water was added to a solution of 8 g of solid NaOH dissolved in 20 ml of water.

The mixture was cooled by adding ice (2 cubic), and the chloride of p-isobutyl-phenyl-propionic acid was added dropwise thereto under stirring. The temperature was maintained at about 0 ° C. and the mixture was kept under stirring until after several hours the pH showed acidic. Sodium hydroxide (1.6 g in aqueous solution) was added and the mixture was left for 2 days.

Acidified with diluted hydrochloric acid, the white viscous product was precipitated, cyclohexane was added and mixed thoroughly.

This gave 29 g of a product insoluble in water, dilute hydrochloric acid and cyclohexane.

The sodium salt of the product thus obtained was obtained as an aqueous NaOH solution in ethanol-acetone.

By the same method, amides of aspartic acid and lysine are prepared, and attention should be paid to lysineamide, which is a complex of lysine as a copper complex, before the reaction.

Example 2

P-isobutyl-phenyl-propion amide of metatrifluorotoluidine

A chloride of p-isobutyl-phenyl-propionic acid was prepared as in Example 1, 27 g of this chloride was dissolved in 500 ml of chloroform, and 9.5 ml of pyridine was added to this solution.

While stirring this solution, the solution of 16.1 g of metatrifluorotoluidine dissolved in 50 ml of chloroform was added. This reaction was exothermic, and the reaction temperature naturally rose to 60 ° C., and then the temperature of the reaction mixture was naturally cooled to room temperature and left overnight.

Subsequently, the reaction mixture was washed thoroughly with water, and the chloroform extract was concentrated to dryness to obtain an oily substance that was crystallized.

After crystallization, 31 g of p-isobutyl-phenyl-propionamide of metatrifluorotoluidine were obtained in powder form, which was insoluble in water, soluble in most organic solvents, and had a melting point of 84-86 ° C.

Pharmacological testing of the compounds of the present invention showed moderate or almost negligible toxicity.

In fact, all four compounds of the present invention showed an LD ₅₀ value of 900 mg / kg or more when administered to a rat.

The anti-inflammatory activity of these compounds was tested in the classical test for edema caused by kaolin and egg whites, which tested two different forms of inflammation. Caoline injected into the tibialis anterior junction of the rat caused chronic inflammation, while geran white injected into the rat's foot caused an acute inflammatory condition.

The compounds of the present invention had good tolerability in the stomach.

As described above with respect to the compound of the present invention, a more specific pharmacological test was conducted, among which p-isobutyl-phenyl- of metatrifluorotoluidine, abbreviated as BT-03, was used. The test results regarding propionamide are described below.

The compound showed very low venus toxicity as a result of oral and intraperitoneal administration. In fact, rats were orally dosed at 4000 mg / kg, but LD ₅₀ levels could be measured.

Oral dosing was not acceptable in rats, so LD ₅₀ levels could not be measured. As a result, the LD ₅₀ values were 940 mg / kg and 1190 mg / kg in males and females, respectively.

When rats were dosed within 100 mg / kg repeatedly for 28 days, there was no change in body growth or hematological and hemochemical parameters of the animals as considered. Two animals died during the trial when 200 mg / kg was administered.

The acute toxicity data of rats are shown in Table 1 below compared to free acid (common name is ibuprofen).

Table 1 Acute Toxicity of BT-03 and Ibuprofen Injected by Intraperitoneal Pathways in Rats

Note: f.1 = confidence limit.

Table 2 shows ibuprofen and naproxene (ie, d-2 (6'-methoxy-2'-) as a control for the data of subacute virulence (TD ₅₀ ) of BT-03 tested in rats for 28 days. It is shown in comparison with the data of the TD ₅₀ acid) -naphthyl).

TABLE 2

Overall mortality rate in females and males

Compared to naproxen, which is known to have anti-inflammatory properties for a wide range of treatments, the latter is more toxic, and in fact its toxicity is about 3.8 times stronger than the compounds of the present invention.

Investigations in birds and rabbits showed no embryonic malformations or embryotoxic effects.

In the pharmacological test, the compound of the present invention showed obvious anti-inflammatory and analgesic action.

The following test theta confirmed this.

(A) Inhibition of the species produced by carrageenan in the rat's foot.

(See Coubon R. Carlier R., wandersmissen L. Arch. Int. Pharmacodyn. 99,474, 1954).

The anti-inflammatory activity of the compounds of the present invention was evaluated with reference to the species which occurred in the control animals in comparison with the compounds known to have good anti-inflammatory action, ie, ibuprofen and naproxen, with respect to the percentage of inhibition caused by carrageenan.

This species occurred in rats, with swelling of 57.55% in the control animals.

The ED ₅₀ value calculated for the BT-03 compound was 103 mg / kg, and the ED ₅₀ values for naproxen and ibuprofen were 47.9 and 170 mg / kg, respectively.

However, if the molecular weight of the compound under test is considered, the ED ₅₀ values for naproxen, ibuprofen and BT-03 are 0.21, 0.82 and 0.29 mM / kg, respectively.

From this point of view, BT-03 is 1.4 times weaker than naproxen and 2.8 times stronger than ibuprofen. However, repeated dosing at the doses used in this test results in naproxen having 3.8 times stronger self-testing than BT-03, and BT-03 having lower toxicity than ibuprofen.

(B) Inhibition of arthritis by Freund's adjuvant in rats.

(See Newbould B.B.Britt Journ. Of Pharmacol. 21,127, 1963).

Both the BT-03 compound and ibuprofen, a control compound, inhibit lesions directly induced by Freund's auxiliary solution in the injected foot. The ED ₅₀ value of BT-03 is 87 mg / kg, which means a dosage that reduces the volume of swollen feet by 50%. Calculated in molar ratio, this corresponds to 0.25 mM / kg for BT-03 and an ED ₅₀ value of 0.30 mM / kg for ibuprofen.

As a result, although both BT-03 and the control substance can suppress the occurrence of the second lesion characteristic of the Freund's auxiliary solution, the compound of the present invention has better activity and lower toxicity than ibuprofen in terms of dosage.

(C) Sedation of the "tension" caused by acetic acid in birds.

(See Fennessy M.R., Lee C.R. “Meghods in Narcotic Research” Eds. Ehrenpreisee Neidle Dekker New York 1975).

Compound BT-03 inhibited the tension caused by acetic acid in proportion to dosage.

The calculated value for ED ₅₀ was 123 mg / kg. The ED ₅₀ value of ibuprofen is 105 mg / kg.

However, considering the different molecular weights, the ratio between the related ED ₅₀ values showed that BT-03 was about 1.4 times more active than ibuprofen, because the molar ratio of ED-based ED ₅₀ corresponds to 0.35 mM / kg and that of the contrasting compound is 0.50 mM / kg.

(D) Sedation in the Flinch-jump test in rats.

Both BT-03 and ibuprofen increase one hypothermia in proportion to dosage.

(See Turner R.A. “Screeing Methods in Pharmacology” Academic Press-New York 1965).

The ED ₅₀ value of compound BT-03 is 129 mg / kg and the ED ₅₀ value of ibuprofen is 108 mg / kg, which is defined as the dose that increases the hypothermic stimulation by 50%.

However, based on the molar ratio of these two ED ₅₀ values (BT-03 and ibuprofen are 0.37 mM / kg and 0.52 mM / kg, respectively), the activity of BT-03 was about 1.4 times higher than that of debates. appear.

On the other hand, repeated dosing with the dosage used in this test showed that ibuprofen was more toxic than compound BT-03.

As briefly shown in the text, the general view of the pharmacological and pharmacodynamic properties of compound BT-03 surprisingly demonstrates that it exhibits an adequately improved property than free acid.

To confirm, Table 3 shows the therapeutic index obtained from the comparative test between the toxic dose TD ₅₀ found in the subacute toxicity test for 28 days and the effective dose ED ₅₀ found in the test.

Certain advantages of compound BT-03 can be observed.

TABLE 3

Claims (1)

A process for preparing an amide derivative of p-isobutyl-phenyl-propionic acid of the following general formula, characterized in that chlorinated p-isobutyl-phenyl-propionic acid with an excess of chlorinating agent and reacting the resulting chloride with amines.

In the formula, X represents a substituted amine group selected from lysine, metatrifluorotoluidine, glutamic acid and aspartic acid.