CA1144556A - Benzothiazole derivatives, process for their preparation and their therapeutic applications - Google Patents

Abstract

Benzothiazole derivatives, process for their preparation and their therapeutic applications ABSTRACT OF THE DISCLOSURE
This invention relates to a compound having the formula:

(I) and its alkyl esters and its salts with physiologically acceptable acids and bases.
This compound is therapeutically useful.

Description

`" 11~4556 Benzothiazole derivatives, process for their prepa-ration and their therapeutic applications This invention relates to both stereoisomers and to the racemate of 2-(2-phenyl-6-benzothiazolyl)propionic acid S having the formula:

and their salts with physiologically acceptable bases, alkaline cations, alkaline-earth cations, and amines, together with their salts with inorganic or organic physiologically accept~le acids, their alkyl esters and the compounds which, by the metabolic route, generate this acid in humans.
The racemic acids of the formula (I) may be prepared by reacting aminothiol of the formula (II) or an equivalent thereof such as the disulfide corresponding to the formula (III) HOOC- I H ~`~SH HOOC-CH ~ S-S--~fH-COOii CH,3 . C~3 CH3 (II ) (III ) with benzoic acid or a derivative such as henzoyl chloride, a benzoyl ester or benzoic aldehyde, the reaction with benzoyl chloride leading to the best yield.
In the course of the action of the acid chloride on the aminothiol of the formula (II) , which occurs preferably in the presence of an inorganic br organic base, are typically formed intermediate compounds (IV) and (V) NP-C ~31 ~ NB-C~) DDC-CL 5~1 J ~OC-C S-C ~>~

., ~k -1~4556 Said compounds of the formulae (IV) and (V) are not isolated, but their mixture is cyclized either by the action of heat, or by the action of acids or bases.
In the course of the action of benzaldehyde on amino-thiol of the formula (II), which occurs either in an in~t solvent such as nitrobenzene, henzene, and the like, or in a basic solvent such as pyridine or quinoline, may be formed an intermediate benzothiazine of the formula (VI) ~OOC - c~ ~/L~ ( VI ) which on oxidation, with FeCl3 or dimethylsulfoxide, for exam-ple, will produce the desired benzothiazole.
The two enantiomers of the acid of the formula (I) may be separated by use of a salt of the corresponding acid with a chiral amine, and more particularly each of the two enan-tiomers of 2-phenyl-ethylamine. According to a method known per se , said salts are recrystallized to separate the two diastereoisomers.
The salts of the acids of the formula (I) may be prepared by action of a stoichiometric amount of the selected acid or base on the acids of the formula (I) as a solution in an alcohol, a ketone or an aliphatic ether.
The esters of the acids of the formula (I) may be prepa-red by action of an alcohol or a haloalkane on the acid of the formula (I) or a reactive derivative thereof, according to methods known Per se.
The aminothiols of the formula (II) may be prepared by decomposition, in a basic medium, in the presence or the absence of a reducing agent, of a compound having the formula:

~oo~ -fH--~S~L ~2 Said aminoacids are new chemicals, which may be prepared by action of bromine and ammonium thiocyanate on a compound of the formula:
,~,, N~i2 HCOC C~I J~ (VIII ) ln acetic acid solution.
The following non-limiting Examples illustrate the preparation of the compounds of the formula (I).
_XAMPLE l a) Preparation of 2-(2-amino-6-benzothiazolyl)propionic acid . . _

2-(4-Amino~phenyl)propionic acid (24.7 g), prepared for example as disclosed in Org. Prep. Proc. Int. pp.303-307 (1977) is dissolved in 300 ml acetic acid followed by 22.8 g ammonium thiocyanate. Bromine t2A g) dissolved in acetic acid (60 ml) is added dropwise to this solution at 15C,after which the mixture is allowed to warm to room temperature for several hours, with stirring. The solvent is then removed under reduced pressure and the residual oil is suspended in an acidic aqueous solution; the resultant precipitate is removed and the aqueous phase is adjusted to pH 4.5 bv addi-tion of a sodium hydroxide solution. The resulting precipitate is filtered off and recrystallized from methanol or ethanol, to give 26 g %-(2-amino-6-benzothiazolyl)propionic acid (pure) having a melting point of 234C.
b) Preparation of 2-(2-phenyl-6-benzothiazolyl)propionic acid with benzovl chloride . . _ A solution of 45 g 2-(2-amino-6-benzothiazolyl)propionic acid in 200 ml 40% a~ueous sodium hydroxide solution which may, if desired, contain 40 g sodium sulfide nonahydrate, is heated to the refluxing temperature until there is no more ammonia evolved.About 500 ml water are added to the solution and, at a temperature of 10C, 70 g benzoyl chloride in lO~ solution in a water-immiscible solvent, such as benzene,are slowly added to the above aqueous solution, with .

11~4556 vigorous stirring. When the addition is complete, the reac-tion mixture is allowedtowarmtoroomtem~erature ~d stirring is continued for several hours, after which the organic phase is separated and the aqueous phase is acidified to pH 4 by addition of a concentrated aqueous hydrochloric acid solu-tion. The resulting precipitate comprises benzoic acid, the uncyclized derivatives of type (IV) and tV) and even, sometimes, some final benzothiazole.
The cyclization is effected on this mixture, for exam-ple by heating the gummy solid at 120C for several hours, or in acidic medium, as followsf the solid is dissolved in 1 litre water containing 7~ ml of a 40% aquecus sodium hydro~ide solution; the solution is filtered throu~h decolo-rizing charcoal! and is then added dropwise to an about 2N
hydrochloric acid aqueous solution maintained at about 50C.
The resulting precipitate is filtered off at this temperature.
The final acid, which is thus obtained in a yield of 45g, is recrystallized from isopropanol/water (2:1.) mixture or from a 2-butanone/cyclohexanone (1:2) mixture, to give 36 g of pure product melting at about 160C. According to the recrystallization solvents and the precipitation rate, the acid will occur in different crystalline forms, of sometimes very close melting points, but the solid phase infrared spectra of which are not superimposable.
The cyclizatlon may also be effec~ed in basic medium:
the resulting solid is thoroughly washed with water and dis-solved in 350 ml of a 95~ aqueous ethanol solution containing 25 g potassium hydroxide; after heating for several hours, the reaction medium is made acidic, the ethanol is removed, and the resulting material is poured over about 1 litre water.
The resulting precipitate of the desired final acid is iso-lated and recrystallized as previo~sly mentioned.

. .
Preparation of 2-(2-phenyl-6-benzothiazolyl)propionic acid with benzaldehyde _ 22 g 2-(2-Amino-6-benzothiazolyl)propionic acid are dissolved in 100 ml of a concentrated sodium hydroxide solu-tion and the mixture is heated for 1 hour at the refluxingtemperature (until ammonia is no longer evolved). The solu-tion is adjusted to pH 4.5, at room temperature, with a hydrochloric acid solution. The resulting precipitate is filtered off, to give 16 g material having a melting point of about 154C.
This solid material and 8 g benzaldehyde are dissolved in 100 ml pyridine and the mixture is maintained at the refluxing temperature for 5 hours. The solvent is then remo-~10 ved under reduced pressure. The residue is dissolved in lOOml ethanol, 200 mg ferric chloride are added thereto and the solution is maintained for 2 hours at the refluxing tempera-ture. The preci~itate which appears on cooling is purified by dissolution in a basic aqueous solution prior to being recrystallized from a 2-butanone/cyclohexane ~1:2) mixture.
The desired product is obtained pure in a yield of 40~.

The hygroscopic sodium salt of-2-(2-phenyl-6-benzothia-zolyl)propionic acid is prepared by action of 0.55 g sodium hydroxide on 3.7 g acid as a solution in 100 ml methanol.
M.P. = 270C. This salt is watersoluble.

The pyrrolidine salt of 2- (2-phenyl-6-benzothlazolyl)-propionic acid is prepared by action of 1 g amine on 4 g acid dlssolved in methanol. The salt melts at 142C and is water-soluble.

The methanesulfonate of 2-(2-phenyl-6-benzothiazolyl)-propionic acid is prepared by action of 0.1 ~ole sulfonic 30 acid on 0.1 mole acid dissolved in 500 ml acetone. M.p.=182C

The hydrochloride of 2-(2-phenyl-6-benzothiazolyl)pro-pionic acid is prepared by action of gaseous hydrochloric acid on the acid in benzene solution. It melts at 150C with 35 decomposition.

Preparation of methyl _2- ~2-phenyl-6-benzothiazolyl)propionate 6 g 2-(2-Phenyl-6-benzothiazolyl)propionic acid are dissolved in 100 ml anhydrous methanol and the mixture is refluxed for 6 hours at the-temperature of the solvent after addition of a few drops of concentrated sulfuric acid. The solution is concentrated to 1/2 volume and the ester is precipitated by addition of 1 volume ice-water, to give 5 g of ester whlch melts at 86C.

.
Separation of the two enantiomers of 2-(2-phenyl-6-benzo-thiazolyl)pro ~ from their racemic mixture a) Dextrorotatory enantiomer (in dimethylformamide solution) The salt-of the acid with laevorotatory ~-phenylethyl-amine is prepared in 2-butanone. Addition of 19 g amine dis-solved in 50 ml 2-butanone to a solution of 50 g acid in 500 ml 2-butanone gives a 51 g salt precipitate. The latter is recrystallized six times from the minimum amount of 2-buta-none, to give 10 g of salt having a specific rotation of ~7 22= -22.5 in methanol (c = 2 g/100 ml).
~ The free acid is obtained by addition of hydrochloric acid to the aqueous solution of this amine salt. The resulting precipitate is isolated and repeatedly recrystallized from isopropanol-water (2:1) to give the dextrororatory enantiomer in a yield of 35~. M.P. = 179C.
b) Leavorotatory enantiomer (in dimethylformamide solution) The recrystallization solvents of the chiral salt obtained according to (a) are evaporated and the acid, sliah~y enriched with some laevorotatory enantiomer, is freed from its salt, to give 25 g acid with which are prepared 28 g of salt, by action of 10.3 ~ dextrorotatory ~-phenylethylamine dissolved in 540 ml 2-butanone.
After three recrystallizations from 2-butanone, the iso-lated salt has a specific rotation~/22= 23 (c - 2 g/100 ml, methanol).
The acid is then freed from its salt and repeatedly recrystallized successively from isopropanol-water (2:1) and 2-butanone-cyclohexane (1:2) to give , in a yield of 25%, the leavorotatory isomer having an optical puritv of about 98%.

~/D = -81 (C = 0.1 g/ml, ~imethylformamide) . M.P. = 179C.
The compounds of the formula (I) inhibit the biosynthe-sis of the prostaglandines and exhibit a ~ gesic properties at the inhibiting dosages. They have also an anti-blood-platelet aggregating activity, and protect a~ainst thecardiovascular effects of endotoxine-induced shock.
They have a low toxicity (LD50, in mice, per os, in excess of 1000 mg/kg). The efficient doses determined in the different tests being markedly lower, the therapeutic index of said compounds is excellent, which makes them therapeu-tically useful in humans.
The analgesic activity of the compounds of the formula (I) was demonstrated in the phenylbenzoquinone-induced writhing test in mice. Thus, the acid of the formula (I) (racemate) has in this test an ED50 of 3-6 mg/kg p.o. This analgesic activity is extended in duration, a dosage of 12.5 mg/kg of this compound still providing an analgesia of 42% 24 hours after its administration.
On the other hand, the compounds of the formula (I) 20 inhibited the blood-platelet aggregation induced in vitro with ADP on platelet-riched plasma of rats. Thus, sodium 2-(2-phenyl-6-benzothiazolyl)propionate is active at a concentration ten times lower than that of acetylsalicyllc acid.
l'he activlty of the compounds of the formula (I) on the blosynthesis of the prostaglandines is evidenced by a protec-tive effect against the toxicity of arachidonic acid, a pre-cursor of this biosynthesis. Thus, on oral administration at a dosage of 0.5 mg/kg, the compounds of the formula (I) decrease the mortality of mice which have been administered a lethal dose of arachidonic acid.
By the intravenous route, the soluble salts of the compounds of the formula (I), and particularly the sodium salt, are active at the same dosages. The dextrorotatory enan-tiomer of the acid (Example 8) has an activity comparable tothat of the racemate (Example 1) and superior to that of its - laevorotatory homolog.

Finally, on intravenous administration at a dosage of 1 mg/kg, the compounds of the formula (I) have a protective effect, in anesthetized dogs, against the cardiovascular effects of the shock induced with Escherichia Coli endotoxine.
The compounds of the formula (I) may be administered to humans under various pharmaceutical forms, by the oral, rectal or parenteral routes, at efficient non-toxic dosages for the treatment of pain, hyperthermia, dysmenorrhea, shock conditions, and also for the treatment of diseases in which the decrease of blood-platelet aggregation is an important factor.
The unit dose depends on the route of administration and on the nature of the compound selected as active ingredient of the therapeutic composition. The solutions for parenteral or intravenous administration are preferably prepared with aqueous diluents, the active ingredient being used in a chemical form soluble in such as a medium, for example as an alkaline cation salt.
For oral administration, the compounds of the formula (I) may be placed into capsules, or mixed with the usual excipients to form pills, tablets or cachets, whlch are gastrosoluble or enterosoluble.
Except for particular cases, the daily dosage regimen in adults is from 20 mg to 1 g, as a single dose or in several doses.

Claims (3)

Having now described our invention what we claim as new and desire to secure by Letters Patent is :

1. A process for the preparation of a compound having the formula (I) both its enantiomers and the racemate, their salts with physiologically acceptable bases and their salts with physiologically acceptable inorganic or organic acids and their alkyl esters,comprising reacting benzoic acid or a reactive equivalent thereof, with a compound of the formula or an equivalent of said compound and optionally conver-ting the resulting acid to a salt or an ester.

2. A process for the separation of the two enantiomers of 2-(2-phenyl-6-benzothiazolyl) propionic acid, comprising recrystallizing the disatereoisomeric salts prepared by reaction of the racemate with a chiral amine.

3. A compound having the formula (I) both its enantiomers and the racemate, their salts with physiologically acceptable bases and their salts with physiologically acceptable inorganic or organic acids and their alkyl esters whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.