DE2238761B2 - Process for the preparation of 2-substituted S-benzothiazole-acetic acid compounds - Google Patents

Description

NH,

CH ₂ COOZ

where A is a hydrogen atom, a 2-hydroxy or 4-dimethylamino group and Z is a hydrogen atom or is a cation, characterized in that that in a known manner an aldehyde of the general formula

with bis (2 - amino - 4 - carboxymethyl - phenyl) disulfide converts and, if desired, the 2-substituted 5-benzothiazole acetic acid obtained in a Salt stirred over.

The invention relates to a process for the preparation of 2-substituted 5-benzothiazole acetic acid compounds the general formula

CH, COOZ

wherein A is a hydrogen atom, a 2-hydroxy or 4-dimethylamino group and Z is a hydrogen atom or is a cation.

The invention is characterized in that, in a manner known per se, an aldehyde of the general formula

CHO

with bis (2 - amino - 4 - carboxymethyl - phenyl) disulfide and, if desired, the resulting 2-substituted 5-benzothiazole acetic acid converted into a salt.

The aldehyde can be benzaldehyde, 2-hydroxy-benzaldehyde or 4-dimethylaminobenzaldehyde.

The bis (2 - amino - 4 - carboxymethyl - phenyl) disulfide, which is the other component in the

10 This disulfide compound can be produced by the reaction of 4-halogeno-3-nitro-phenylacetic acid or its

Derivatives with alkali sulfide, such as sodium sulfide, are shown will. ^ Halogeno-S-nitro-phenylacetonitrile can also be used in place of the nitro-phenylacetic acid compounds be used. The cation Z in the formula of the products of the process can, for. B. alkali metal such as sodium odct Potassium, aluminum, alkaline earth metal such as calcium. Such salts of 2-substituted 5-benzothiazole acetic acid can be produced by reacting this free acid with the basic compounds under mild conditions can be obtained. Similarly, salts can be made with organic amines, if you combine the free acid with organic amines, such as diethylamine, Äthylendiamiu or triethanolamine implements. These salts of benzothiazole acetic acids constitute an additional aspect of the invention represent.

In addition, the compounds prepared by the process according to the invention can with inorganic acids, such as hydrochloric acid or sulfuric acid, such as citric acid or lactic acid, be converted into addition salts.

The reaction of the aldehyde with the sulfide compound is preferably carried out at temperatures of 60 to 200 ° C., but it can even be carried out at lower temperatures. The reaction proceeds advantageously in suitable solvents. but also takes place without any solvent. As such solvents, for. B. pyridine, quinoline, Dimethylformamide, isopropanol, butanol, 2-methoxyethanol, 2-ethoxyethanol, dioxane, Be'nzol and Nitrobenzene can be used. Furthermore, the reaction can be carried out by heating the reaction components alone take place in alkaline or acidic solution. With regard to the proportions of the two reaction components it is advantageous to use more than 2 moles of the aryl aldehyde per mole of disulfide compound. Around to activate the reaction is the application of ultraviolet radiation or the addition of radical generators Agents such as benzoyl peroxide are beneficial.

The products of the process have useful pharmacological properties as they have good anti-inflammatory, analgesic and antipyretic

, Have activity.

The following tables 1 to 4 show the results of toxicological and pharmacological Tests of the compounds prepared by the method according to the invention; Table 1 shows the acute toxicity test on mice (50% of the lethal dose), Table 2 shows the test of the anti-inflammatory Activity in the edema of the rat hind paw caused by carrageenin, Table 3 shows the test of analgesic activity in mice against pain determined by the hot plate method

as well as the acetic acid stretching process and Table 4 shows the antipyrus activity in febrile rats elicited by Yeast. In all of the compounds tested, Z is hydrogen.

Table 1

Tested connections A.

LD ₅₀

(mg / kg)

4-N (CH ₃ ) ₂
2-OH

Phenylbutazone

Table 2

1365 p.o. 900 p.o. 450 i.p.

370 i.p.

Tested connections A.

Inhibition rate (%) (100mg / kg p.o.)

H 46.7 ± 0.07 2 hours. %) 0.15 4-N (CH ₃ J ₂ 52.0 ± 0.19 4h Acetic acid- 0.09 2-OH 44.5 ± 0.15 3 hours. 0.21 Phenylbutazone 45.3 ± 0.09 3 hours. 0.11 Table 3 Inhibition rate ( ± 0.12 Hot plates procedure (400 mg / kg p.o.) 67.2 Stretching process Tested connections 66.7 (100 rag / kg p.o.) A. 50.0 64.2 63.2 63.6 H 4-N (CHj) ₂ Phenylbutazone Table 4 Rectal temperature ("C) thereafter Tested dose 37.1 ± links I before 36.4 ± A (mg / kg: 38.5 37.6 ± H 100 38.3 36.3 ± 200 38.4 Acetyl-100 38.3 salicylic 200 acid 38.3 control

example 1

2-Phenyl-5-benzothiazole-acetic acid: A mixture of 1G, O g (0 /) 274 mol) bis (2 - amino - 4 - carboxymethylphenyl) disulfide and 5.8 g (0.0546 mol) Benzaldehyde is heated to 140 to 160 ^{° C. for about 40 minutes.} A small amount of concentrated hydrochloric acid is added to the reaction mixture and the resulting mixture is heated to dissolve. After decolorization of the reacted solution with a small amount of activated charcoal, the filtrate is poured into ice water to crystallize 2-phenyl-5-benzothiazole-acetic acid. The crude crystals obtained in this way are recrystallized from a mixture of benzene and dioxane, as a result of which the melting point thereof reaches 178 to 179.degree. The yield is 7.9 g (58.8% of the theoretical amount). The elemental analysis (%) for C ₁₅ H _n NO ₂ S is:

Calculated ... C 66.90, H 4.12, N 5.20;
found .... C 66.73, H 4.10, N 5.37.

Example 2

2-phenyl-5-benzothiazole-acetic acid: 10.0 g of bis (2-amino-4-carboxymethyl-phenyl) -disulfide are dissolved in 27 ml of 2N sodium hydroxide solution and added this solution added 5.8 g of benzaldehyde. The liquid mixture is refluxed for about 5 hours heated, then with a considerable amount of water and further by acidification with dilute Hydrochloric acid diluted to crystallize 2 - phenyl - 5 - benzothiazole acetic acid. After washing with a The raw crystals are made from a mixture of benzene and dioxane in a small amount of warm water recrystallized, whereby the melting point reaches 178 to 179 ° C. The yield is 6.1 g (41.0% the theoretical amount).

Example 3

2 - phenyl - 5 - benzothiazole - acetic acid: 10.0 g bis (2 - amini - 4 - carboxymethyl - phenyl) - disulfide are dissolved in 30 ml of concentrated hydrochloric acid, below 5.8 g of benzaldehyde are added. The resulting mixture is refluxed for about 5 hours and dilute the reacted solution with a significant amount of water to form 2-phenyl-5-benzothiazole acetic acid to crystallize. The crystals thus obtained are washed with a small amount of warm water washed and then recrystallized from a mixture of benzene and dioxane, whereby the Melting point 178 to 179 "C. The yield is 6.5 g (45.0% of the theoretical amount).

Example 4

In the same manner as in the previous examples, the following compounds are prepared accordingly synthesized:

The following examples serve to illustrate the invention.

2 - (2 - Hydroxyphenyl) - 5 - benzothiazole - acetic acid (melting point 215 to 216 ° C).

2 - (4 - dimethylaminophenyl) -5 - benzothiazole acetic acid (M.p. 230 to 23 ° C).

Claims (1)

Claim: Process for He _1. , Division of 2-substituted 5-benzothiazole acetic acid compounds of the general formula application-related procedure has the following structural formula: