DE2145178C3 - 2-phenyl-5- or -6-benzothiazolylacetic acid compounds - Google Patents

Description

20th

The invention relates to 2-phenyl-5- or -6-benzothiazolylacetic acids and their salts.

The novel 2-phenyl-5- or -6-benzothiazolylacetic acid compounds exhibit the general structural formula

CH ₁ CO, H

on. wherein the acetic acid residue is either in the 5-position of the benzothiazole ring is bonded and A is a hydrogen atom, a 2-hydroxy or 4-dimethylamino group means or the acetic acid residue is bonded in the 6-position of the benzothiazole ring and A represents a hydrogen atom, and their salts.

The salts of these benzothiazolylacetic acids can be obtained by reacting the free acid with a base can be obtained under mild conditions. In this way, alkali metal salts such as sodium and Potassium salts, the aluminum salts or salts of alkaline earth metals such as calcium salts, salts of organic Amines, such as diethylammonium or triilhanolammonium salts can be obtained.

The 2-phenyl-5 or -6-benzothiazolylacetic acid compounds according to the invention are by applying the Willgerodt reaction with 2-phenyl-5 or -fi-acetylbenzothia ^ ol compounds of the general l-'ormcl

COCH, 55 -

synthesized, wherein A has the meaning given above has, and acetyl residue in the 5- or 6-position the benzothiazole ring is attached.

In particular, the 2-phenyl-5- or -6-acelylbenzothiazole compound mixed with ammonium polysulfide and the mixture in a sealed Tube heated to form the acid amide compound. These acid amide compounds can be used in Usually to the 2-phenyl-5- or -6-benzothiazole acetic acid compounds be hydrolyzed.

However, the compounds of the invention are preferably prepared by applying the Kindler modification this Willgerodt reaction synthesized, wherein a mixture of 2-phenyl-5- or -6-acetylbenzo- • hiazole compound heated to reflux with sulfur and a secondary amine and the obtained Thioamide compound by heating in water or an aqueous organic solvent hydrolyzed with the acid or base for a period of 10 to 20 hours. The above % Phenyl-5- or -o-acetylbenzothiazole compounds, which are used according to the invention as an essential crude product in the synthesis of the new compounds are made by reacting 2-amino-4- or 5-acetylthiophenol with a benzaldehyde compound or a benzoyl chloride compound as the above-mentioned secondary amines dimethylamine, morpholine or piperidine can be used.

The new compounds according to the invention have a suite of anti-inflammatory, analgesic and aniipyretic properties Activity on.

Tables 1 to IV show the results of toxicological and pharmacological tests using the new compounds according to the invention, Table I showing the acute toxicity test applied to mice (50% lethal dose), Table 11 elicited the test of anti-inflammatory activity on edema in rough hind legs by carrageenin and Table III the analgesic activity in pain in mice, induced by the hot plating process and the acetic acid stretching process and Table IV shows the antipyretic activity in hyperthermic rats, causes duvch yeast, shows.

Table I.

Checked A. H Λ H links IJ) ₁₁ , 4-N (CH ₁ ), 4-N (CH.,), 2-OH 2-OH (mg kgl H H SOO i. p. 500 i. p. H 450 i. p. 950 i. p. H Phenylbutazone 850 i. p. 450 i. p. Checked 370 i. p. Position of -CH ₂ CO ₂ H-RcStCS Inhihic- 5 value
("oil 5 (Carrageenin 5 Method, 5 (triethanol KK) mg kg ammonium salt) p.iv) 5 (diethyl 46.7 ammonium salt) 52.0 6th 44.5 3X.2 Table 11 links Position of --CH ₂ CO ₂ H-RcSlCS 5 5 5 5 (triethanol ammonium salt)

continuation

Checked connections

Phenylbutazone

Position of
CH ₂ CO, "H-Resles

(Diethyl

ammonium salt)

Table 111

Inhibition ucrl

(% l

IC iirrayeenin-

Method,

UK) mg ku

p.o. I.

42.5

39.5

45.3

H Position of Hot Inhi 4-N (CH ₃ J ₂ - CH, CO, H- plates bitter
value Checked connections H The rest procedure (%) Phenylbutazone Acetic acid 5 Piece 5 (400 mg kg procedure Λ 6th p.o.) (100 mg'kg 67.2 p.o.) 66.7 64.2 55.5 63.2 50.0 68.6 63.6

Table IV

Checked connections

Position of

- CH ₂ CO ₂ H-

Resles

Acctylsalicylic
acid

control

dose Rectal Te (mg kg) before 100 38.5 ± 0.07 200 38.3 ± 0.19 100 38.3 ± 0.18 HX) 38.4 ± 0.15 200 38.3 ± 0.09 38.3 ± 0.12

after

2 h 37.1 ± 0.15

4 h 36.4 i 0.09

4 h 37.3 ι 0.19

3 h 37.6 ± 0.21

3 h 36.3 ± 0.11

'5

35

40

45

The following examples serve to provide further explanation the invention.

Example I.

2- (2'-Hydroxyphynyl) -5-benzothiazolyl acetic acid

8.1 g of 2- (2'-hydroxyphenyl) -5-acelylbenzothiazole and 1.25 g of sulfur are added to 5.2 g of morpholine, and the mixture is placed in an oil bath under Heated using a reflux cooler for 20 hours. The converted mixture is i. V. concentrated, to allow 2- (2'-hydroxyphynyl) -5-morpholinothiocarbonylmethyl-benzothiazole to crystallize, which shows the melting point 143 to 145 "C after recrystallization from ethanol.

The thioamide thus prepared is added to a 10% sodium hydroxide solution, and the liquid mixture is heated on a water bath under reflux for 20 hours to hydrolyze the thioamide compound. A small amount of activated carbon is added to the reacted solution, and the resulting liquid mixture is filtered after heating. Wildly diluted hydrochloric acid solution was gradually added to the filtrate with crystallization of 2- (2'-hydroxyphenyl) -5-benzothiazolylacetic acid. The crude crystals are recrystallized from a mixture of ethanol and water, with a melting point = 215 to 216 ° ^C. The yield is 4.5 g (52.2% theoretical value).

Elemental analysis door C ₁₅ H _n NO ₃ S:

Calculated ... C 63.15, H 3.89, N 4.91%;
found .... C 63.42, H 3.64, N 4.84%.

Example 2

2- (4'-Dimethylaminophenyl) -5-benzothiazolylacetic acid

20.5 g of 2- (4'-dimethylaminophenyl) -5-acetylbenzothiazole and 3.0 g of sulfur are added to 50.0 g of morpholine and the mixture is poured onto a heated oil bath under reflux for 30 hours. The reacted mixture is crystallized out in vacuo of 2- (4'-dimethylaminophenyl) -5-morpholinolhiocarbonylmethylbenzothiazole concentrated.

The thioamide thus obtained is added to 200 ml of a 35% hydrochloric acid solution and the liquid Mixture heated to reflux on the steam bath for 30 hours, hydrolyzing the thioamide compound. A small amount of activated carbon is added to the reaction solution and the resultant liquid mixture is filtered after heating. The filtrate is left to stand in a refrigerator with yellow needles crystallizing out from 2- (4'-dimethylaminophenyl) -5-benzothiazolylacetic acid hydrochloride. Its decomposition point is between 220 and 221 C.

The hydrochloride obtained in the above manner is added to 700 ml of water and the mixture refluxed on the steam bath and then left to stand in the refrigerator to crystallize out of yellow needles of 2- (4'-dimethylaminophenyl) -5-benzoihialzolylacetic acid with a m.p. = 230 to 23 IC. The yield is 10.2 g (43.0% of the theoretical value).

Elemental analysis for C ₁₇ H ₁₆ N ₂ O ₂ S:

Calculated ... C 65.36, H 5.16. N 8.97%;
found .... C 65.28, H 5.11. N 8.86%.

Example 3
2-Phenyl-5-benzothiazolylacetic acid

10.0 g of 2-phenyl-5-acetylbenzothiazole and 1.6 g Sulfur is added to 20.0 g of morpholine and the mixture is refluxed on an oil bath Heated for 20 hours. The reacted mixture is concentrated in vacuo with crystallization of 2 - phenyl - 5 - morpholinolhiocarbonylmethylbenzothiazole. Recrystallization of the crude crystals from ethanol gives a melting point = 157 bis 160 C.

The thioamide thus obtained is added to 100 ml of a 10% potassium hydroxide solution and that Mixture heated to reflux on a steam bath for 20 hours. The reacted mixture is with dilute hydrochloric acid solution acidified with 2-phenyl-5-benzothiazolylacetic acid crystallizing out. The crude crystals are recrystallized from a mixture of benzene and dioxane, whereby results in a m.p. = 178 to 179 ° C. The yield is 6.7 g (62.9% of the theoretical amount).

Elemental analysis door C ₁₅ H _n NO ₂ S:

Calculated ... C 66.90, H 4.12, N 5.20%:
found .... C 66.75, H 4.14, N 5.25%.

2.7 g of the 2-phenyl-5-benzothiazolylacetic acid obtained above become a mixture of 0.73 g Diethylamine and 10 ml of water are added with stirring, and the reacted solution is reduced under Pressure concentrated to 2-phenyl-5-benzothiazolylacetic acid diethylamine salt to crystallize. The crude crystals are recrystallized from acetone and give a pure product with the melting point 100 to 104 ° C. The yield is 2.98 g (87.7% of the theoretical amount).

Example 4
2-phenyl-5-benzothiazolylacetic acid: c

2.53 g of 2-phenyl-5-acetylbenzothiazole and 13 ml of ammonium polysulfide solution (yellow) are added to 10 ml of dioxane, and the mixture is heated in a sealed tube at an oven temperature of 155 to 165 ° C. for 10 hours. The mixture obtained is cooled, while yellow needles of Z-phenyl-S-benzothiazolylacetamide crystallize out. The crude crystals are recrystallized from methanol after the methanol solution has been clarified by filtration with a small amount of activated carbon. Subsequently, the crystals prepared from a mixture of benzene and dioxane are recrystallized, wherein the melting point of the crystals obtained is from 206 to 207 ⁰ C. The yield of the acetamide compound is 2.2 g (82.1% of the theoretical value).

Elemental analysis door C) ₅ Hi ₂ N ₂ OS:

Calculated ... C 67.14, H 4.51, N 10.44%;
found .... C 66.98, H 4.43, N 10.18%.

Elemental analysis for C ₁₅ H

Calculated ... C 66.90, H 4.12, N 5.20%;
found .... C 66.86, H 4.05, N 5.22%.

Example 5
2-phenyl-6-benzothiazole acetic acid

2-phenyl-o-morpholinothiocarbonylmethylbenzothiazole with a melting point = 181 to 182 ° C is synthesized in the same way as in Example 3, with the Exception that 2-phenyl-6-acetylbenzothiazole is used instead of 2-phenyl-5-acetylbenzothiazole will.

Furthermore, the thioamide thus obtained is reacted in the same manner as in Example 3 under Obtaining 2-phenyl-6-benzothiazolylacetic acid with a m.p. = 173 to 175 "C. The yield amounts to to 6.2 g (58.8% of the theoretical value).

Elemental analysis for C ₁₅ H ₁₁ NO ₂ S:

Calculated ... C 66.90, H 4,! 2, N 5.20%;
found .... C 66.71, H 4.08, N 5.28%.

Example 6
2-phenyl-6-benzothiazolylacetic acid c

6.0 g of 2-phenyl-6-acetylbenzothiazole and 30.8 ml of ammonium polysulfide solution (yellow) are added to 24 ml of dioxane, and the mixture is ^{heated in a sealed tube at an oven temperature of 150 to 160 °} C. for 10 hours. The mixture obtained is cooled, while yellow needles of 2-phenyl-6-benzothiazolylacetamide crystallize out. The crude crystals are recrystallized from ethanol after the ethanol solution has been clarified by filtration with a small amount of activated charcoal, after recrystallization of the crystals produced in this way from dioxane having a melting point of the final crystals of 229 to 230 ° C. The yield of acetamide compound amounts to 5.3 g (83.5% of the theoretical amount).

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS:

Calculated ... C 67.14, H 4.51, N 10.44%;
found .... C 67.21, H 4.38, N 10.39%.

50

The acetamide produced in this way is added to 10 ml of a 20% strength hydrochloric acid solution and the liquid mixture is heated under reflux on the steam bath for 10 minutes, with 2-phenyl-5-benzothiazolylacetic acid crystallizing out. Recrystallization of the crude crystals from a mixture of benzene and dioxane leads to a mp. = 178-179 ¹ C. The yield is 1.8 g (81.7% of the theoretical value). The acetamide thus prepared is added to 30 ml of 20% strength hydrochloric acid solution, and the liquid mixture is refluxed on the steam bath for 20 minutes, with 2-phenyl-6-benzothiazolylacetic acid crystallizing out. After recrystallization from a mixture of benzene and dioxane, the melting point is 173 to 175 ° C. The yield is 4.4 g (82.8% of the theoretical value).

Elementary analysis for C ₁₅ H ₁₁ NO ₂ S:

Calculated ... C 66.90, H 4.12, N 5.20%;
found .... C 66.88, H 4.08, N 5.25%.

Claims (1)

Claim:
Compounds of the general formula CH ₂ CO ₂ H wherein the acetic acid residue is either in the 5-colony of the benzolhiazole ring is bonded and A is a hydrogen atom, a 2-hydroxy or 4-dimethylamino group means or the acetic acid residue in the 6-position of the benzothiazole ring is bonded and A is a hydrogen atom, and their salts.