NO811571L - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2 (3H) -BENZOTIAZOLONE DERIVATIVES - Google Patents

Abstract

'9. Therapeutically active, in 4-, 5-, 6- and / or 7-position mono- or disubstituted 2 (3H) -benzothiazolone derivatives of the general formula. wherein one or two of the radicals R, R possession of a good analgesic and antipyretic effect.Preparation of the compounds is described.

Description

This invention relates to the preparation of 2(3H)-benzothiazolones which are mono- or di-substituted in the 4-, 5-, 6- and/or 7-position and which have the general formula I

In the general formula I means either

R4 a methyl group, Rg a methoxy group and R5 and R_, hydrogen atoms, or

R4 and R6 each a methyl group, and R5 and R? hydrogen atoms, or

R 4 a methoxy group and R 5 , R 8 and R 7 hydrogen atoms, or

R4 a methoxy group, R^ a chlorine atom and Rg and R-, hydrogen atoms, or

R,, and Rg together a methylenedioxy group, and R4 and R7 hydrogen atoms, or

R7 a methyl group and R4, R5 and Rg hydrogen atoms, or R5 and Rg each a methyl group and R4 and R? hydrogen atoms, or

R6 and R? each a methyl group and R4 and R5 hydrogen atoms, or

Rg a dimethylamino group and R4, R5 and R7 hydrogen atoms, or

R'5 a chlorine atom, Rg a methoxy group and R4 and R? hydrogen atoms, or R4 and Rg each a methoxy group and R5 and R7 hydrogen atoms, or

R 1 a methoxy group, R 8 a methyl group and R 4 and R ? hydrogen atoms, or

R^ and Rg together an ethylenedioxy group and R4 and R7 hydrogen atoms, or

Rg and R7 together an ethylenedioxy group and R4 and R5 hydrogen atoms.

The connections are new. They are distinguished by good analgesic and antipyretic effects with low acute toxicity.

The compounds of the general formula I are prepared

according to the following procedures:

1) A 2-amino-thiophenol of the general formula II

where R^, R,., Rg and R^ are as indicated above, ring-closed with a carboxylic acid derivative of the general formula III

where X-^ and X are the same or different and mean halogen, especially chlorine, a 1-imidazolyl-, 1,2,4-triazol-4-yl or 1,2,4-triazol-1-yl group; an alkoxy group of 1 to 10 carbon atoms. such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy group; a phenoxy or p-tolyloxy group; a benzyloxy, phenethyloxy group or together a sulfur atom, at temperatures between 0 and 150°C, preferably

between 20°C and the boiling temperature of the solvent used, and possibly in the presence of further inorganic or organic bases, e.g. alkali or alkaline earth hydroxides, carbonates,

-hydrogen carbonates or -alcoholates, tertiary amines so

such as pyridine, triethylamine, N,N-dimethylaniline, N,N-diethylaniline or quaternary ammonium hydroxides, e.g. benzyltrimethylammonium hydroxide.

Suitable solvents are water, alcohols such as methanol. ethanol, 1-propanol and 2-propanol, but anhydrous, aprotic solvents such as benzene, toluene or other hydrocarbons, tetrahydrofuran, 1,4-dioxane or other cyclic ethers, dimethylformamide and dimethylsulfoxide are preferred.

Mixtures of the aforementioned solvents can also be used.

In a variant of this method, chlorocarbonic acid esters with the general formula Illa are used as carboxylic acid derivatives,

where R means an alkyl residue with 1 to 10 carbon atoms, e.g. a methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, dimethylethyl, 1-pentyl or 1-hexyl group or a phenyl, 4-methylphenyl-,' phenylmethyl-, 2-phenylethyl group; thereby intermediate products of the general formula IV are first formed where R, R^, R^, R^ and R^ are as stated above. These intermediate products are then cyclized in the presence of acid catalysts to the desired compounds of the general formula I. Strong or medium-strength mineral acids are preferred as acid catalysts, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. The cyclization reaction is usually carried out in inert, organic solvents, e.g. in methanol, ethanol, toluene, acetic acid or propionic acid. The reaction temperatures are between 20 and 150°C, preferably at the boiling point of the solvent used. 2) A benzothiazole substituted in the 2-position with chlorine, bromine or alkoxy of the general formula V where , R,., Rg and R^ are as indicated above, and X^ means a chlorine or bromine atom or an alkoxy group containing up to 3 carbon atoms, are hydrolysed at temperatures between 0 and 120°C, preferably at the boiling temperature of the reaction mixture, by treatment with aqueous mineral acids, e.g. with concentrated hydrochloric or hydrobromic acid, 20 to 60% sulfuric acid or semi-concentrated phosphoric acid, to a compound of the general formula I. The reaction can be carried out in the presence of inert, water-miscible solvents, e.g. methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, 1,4-dioxane or 1,2-ethanediol, but can also be carried out without additional solvents. 3) o-nitrophenylthioacetic acids of the general formula VI where , R,., Rg and R^ are as indicated at the outset, are cyclocondensed by heating with acetic anhydride, preferably at reflux temperature, to 3-acetyl-2(3H)-benzothiazolone derivatives with the general formula VII where R 1 , R 1 -, R 8 and R 7 have the meanings indicated at the beginning. The reaction is catalytically accelerated by the addition of alkali acetates, e.g. sodium acetate, or tertiary organic bases, e.g. pyridine or triethylamine, but it can also be carried out with the same yield in the absence of catalysts. The acetyl group in a compound of the general formula VI can be cleaved off by reaction with aqueous alkali or alkaline earth hydroxides, e.g. aqueous caustic soda, potash or baryte lye, with aqueous amines or ammonium hydroxide solutions, e.g. concentrated ammonia or with a solution of benzyltrimethylammonium hydroxide, or by treatment with aqueous mineral acids, e.g. concentrated hydrochloric or hydrobromic acid, semi-concentrated sulfuric or phosphoric acid, forming the desired compounds of the general formula I. For the hydrolysis, temperatures between 0 and 120°C, preferably between 60 and 100°C, are appropriate. The reaction can be carried out with and without water-miscible co-solvents. Solvents that come into consideration are e.g. alcohols such as methanol, ethanol, 2-propanol and 1,2-ethanediol, or ethers, e.g. 1,4-dioxane or tetrahydrofuran. 4) A 2(3H)-benzothiazole thione of the general formula VIII

where R., Rr , R, and R_ have the initially stated be-

4b b I

interpretations, are oxidized and hydrolyzed to a 2(3H)-benzothiazolone with the general formula I. Preferred oxidizing agents are bromine, chlorine, hydrogen peroxide and alkali permanganates. The reaction is carried out in an aqueous, alkaline medium. Suitable bases

are sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide. While the oxidation with bromine, chlorine and hydrogen peroxide, which is carried out at -10 to +30°C, no intermediate products can be detected, the reaction with potassium permanganate first leads to a sulphonic acid with the general formula Villa

which - usually without insulation - when heated with aqueous mineral acids, e.g. with concentrated hydrochloric or hydrobromic acid, with 30 to 70% sulfuric acid or semi-concentrated phosphoric acid, to temperatures between 40 and 100°C are transferred to the desired 2(3H)-benzothiazolone derivatives with the general formula I.

In the oxidation with bromine or chlorine, to avoid core halogenation, no more than 3 mol of halogen should be used per

mol of 2(3H)-benzothiazolone with the general formula VIII, while the reaction with hydrogen peroxide requires at least 3 mol and with the permanganates at least 2 mol of the oxidizing agent to obtain

a quantitative turnover.

In a variant of this method, alkali salts of 2(3H)-benzothiazolethione derivatives with the general formula VIII are first reacted with alkyl iodides or dialkyl sulfates or benzyl halides to 2-substituted benzothiazole derivatives with the general formula IXa

where R4, R^, Rg and R^ are as indicated at the outset, and R^ means a lower alkyl residue with 1 to 3 carbon atoms or a benzyl residue, is then oxidized with potassium permanganate in alkaline solution or in glacial acetic acid. to sulfones of the general formula IXb and finally transferred by heating to 4.0 to 100°C with aqueous mineral acids to compounds of the general formula I. The hydrolysis of the sulfones of the general formula IXb is preferably carried out in the presence of water-miscible co-solvents, f .ex. methanol, ethanol, 1-propanol, 2-propanol, 1,4-dioxane and tetrahydrofuran, but can also be carried out without additional solvents. 5) For the preparation of the compound with the general formula I where Rg means a dimethylamino group and R^, R^ and R^ mean hydrogen atoms, one can also methylate the known compound 6-amino-2(3H)-benzothiazolone (Jacobson and Kwaysser, Liebigs Ann. Ghem. 277, 249 (1893)) with formaldehyde and formic acid at temperatures of 60-100°C, preferably 70-90°C. Formaldehyde and formic acid are each used in an amount of at least 2 mol per moles of 6-amino-2(3H)-benzothiazolone. The reaction is usually carried out without additional solvents, and reaction in aqueous formic acid, such as is achieved by using aqueous

However, 85% formic acid and 40% formalin solution as reagents - both in excess - have proved particularly beneficial.

The 2-amino-benzerithiols of the general formula II required as starting materials can be prepared by analogy with methods known from the literature. Thus, you get e.g. 2-amino-4-chloro-5-methoxybenzenethiol with m.p. 123-125 oC (diisopropyl ether). by hydrolysis of 5-chloro-6-methoxy-2-benzo-thiazolamine with boiling aqueous calyx, analogously to R.L. Mital and S.K. Jain, J. Chem. Soc. (C) 1 969, 2148 resp. S.K. Jain and R.L. Mital, Z. Naturforsch. 32B, 821 (1977)

respectively H- Hauser, Heiv. Chim. Acta _11, 208 (1928) resp.

R. Schuloff et al., Ber. dtsch. chem. Ges. 61, 2541 (1928). Similarly, 2-amino-3-methoxy-benzenethiol (m.p. for the hydrochloride 141-142°C) is prepared from 4-methoxy-2-benzo-thiazolamine.

The 2-benzothiazolamines, in turn, are known or can be prepared analogously by methods known in the literature (e.g. H.P. Kaufmann et al., Arch. Pharm. 273, 31 (1935), H.P. Kaufmann, Ber. dtsch. chem. Ges. 62B, 390 (1929); I. G. Farbenindustrie AG/Erf. H. P. Kaufmann and W- Schubert, German Reichspar. 493 025 of 08.04.1927, C.A. 24, 2754 (1930); R. L. Mital and S. K. Jain, J. chem. Soc. (C ) 1969, 2148-2149).

The starting materials of the general formulas III and Illa are known.

The starting materials of the general formula V, where X^ means a chlorine or bromine atom, can be prepared analogously to descriptions by G. Mazzone and G. Pappalardo, IlFarmaco,.

Oath. Sc. 32_, 348-354 (1977) from the corresponding 2-benzothiazolamines by reaction with hot, concentrated hydrohalic acid and sodium nitrite;

The starting materials of the general formula V where X^ denotes an alkoxy group can be prepared from the corresponding N-ary1-thiourethanes by reaction with a hot, aqueous-alcoholic solution of potassium hexacyanoferrate (III) and sodium hydroxide (analogously to R.F. Hunter and E.R. Parken, J. chem. Soc. (London) 1935. 1755-1761) or from compounds of the general formula V where X represents a chlorine or bromine atom, by reaction with alkali or alkaline earth alkanolates, preferably in the corresponding boiling alcohols.

Thus, e.g. prepared: 2-ethoxy-6-methoxy-4-methylbenzothiazole (23% of theory), m.p. 56-57°C (methanol) from 4-methoxy-2-methylphenyl)-thiocarbamic acid O-ethyl ester, m.p. 91°C (ethanol);

4,6-dimethyl-2-ethoxybenzothiazole (45% of theory; further worked up without purification) from (2,4-dimethylphenyl)-thiocarbamic acid O-ethyl ester, m.p. 50.5-41.5°C (gasoline);

2-ethoxy-4-methoxybenzothiazole, m.p. 62-63°C (petroleum ether)

from (2-methoxyphenyl)-thiocarbamic acid O-ethyl ester, m.p. 63-64°C (diisopropyl ether);

5-Chloro-2-ethoxy-4-methoxybenzothiazole (27% of theory; non-crystallizing oil) from (3-chloro-2-methoxyphenyl)-thiocarbamic acid O-ethyl ester, m.p. 67-68°C (methanol);

2-ethoxy-5,6-methylenedioxybenzothiazole (90% of theory; used in the next step without purification) from (3,4-methylenedioxyphenyl)-thiocarbamic acid O-ethyl ester, m.p. 96°C (petroleum ether);

2-ethoxy-7-methylbenzothiazole (oil) in mixture with 2-ethoxy-5-methylbenzothiazole from (3-methylphenyl)-thiocarbamic acid-O-ethyl-ester, m.p.. 66-67°C (gasoline/activated carbon );

2-ethoxy-5,6-dimethylbenzothiazole in mixture with 2-ethoxy-6,7-dimethylbenzothiazole (oil) from (3,4-dimethylphenyl)-thiocarbamic acid-O-ethyl ester, m.p. 82-84°C (gasoline/activated carbon);

2-ethoxy-6,7-ethylenedioxybenzothiazole (43% of theory; m.p. 99-100°C, from petroleum ether) and 2-ethoxy-5,6-ethylenedioxybenzothiazole (21% of theory; non-crystallizing oil) from (3,4-ethylenedioxyphenyl)-thiocarbamic acid O-ethyl ester (m.p. 85°C from gasoline);

2,5-dimethoxy-6-methylbenzothiazole (95% of theory) from 2-chloro-5-methoxy-6-methylbenzothiazole (m.p. 101°C from petroleum ether);

2,4,6-trimethoxybenzothiazole (83% of theory; non-crystallizing oil) from 2-chloro-4,6-dimethoxybenzothiazole.

The necessary N-aryl-thiourethans are obtained from - usually - known N-aryl isothiocyanates and anhydrous alcohols in the presence of quinoline (analogous to R.F. Hunter and E.R. Parken, J. chem. Sc (London) 1935, 1755-1761).

The starting materials required o-nitrophenylthio-acetic acids with the general formula VI are prepared, e.g. from corresponding o-halo-nitrobenzene derivatives and thioglycolic acid either in :boiling, aqueous-alcoholic sodium hydroxide solution (analogous to A.F. Aboulezz, S.M.A. Zayed,

W. S. El-Hamouly and M.J. El-Sheikh, Egypt, J. Chem. 16, 355-359

(1973) or advantageously in anhydrous dimethyl sulfoxide and in the presence of sodium methylate.

They used 2(3H)-benzothiazole-thione- as starting materials. derivatives with the general formula VIII are obtained analogously to literature references (L.B. Sebrell and CE. Boord, J. Amer. chem. Soc. £5, 2390-2399 (1923); J. Teppema and L.B. Sebrell, J. Amer. chem. Soc. £9, 1748-1758 (1927), for example from suitable anilines, carbon disulphide and sulfur under pressure and at elevated temperature or from suitable o-halo nitrobenzene derivatives, sodium sulphide, hydrogen sulphide and carbon disulphide. .: 4,6-dimethyl-2(3H)-benzothiazolethione, mp 250-251°C (yellow crystals from ethanol);

7-methyl-2(3H)-benzothiazolethione, m.p. 184°C (aniline); 6-Methoxy-4-methyl-2(3H)-benzothiazolethione, reacts without further purification. •

The compounds of the general formula I represent very good analgesic and antipyretic active compounds which are largely non-toxic.

As examples were the compounds

A = 6-methoxy-4-methyl-2(3H)-benzothiazolone

B = 4,6-dimethyl-2(3H)-benzothiazolone

D - 5-(and 7-) methyl-2(3H)-benzothiazolone

E = 6-dimethylamino-2(3H)-benzothiazolone

F = 5-chloro-2,3-dihydro-6-methoxy-2-oxo-benzothiazole

G = 4-methoxy-2(3H)-benzothiazolone and

H = 5-chloro-4-methoxy-2(3H)-benzothiazolone'

investigated with regard to analgesic effect against inflammatory pain in rats, analgesic effect against heat-induced pain in mice, body temperature-lowering effect in rats and acute toxicity in mice.

Methodology

1) Effect against inflammatory pain in rats The test device corresponded to that described by Randall-Selitto (Arch. int. Pharmacodyn. 111, 409 (1957).

Chbb:THOM male rats weighing between 100 and 130 g

received a subplantar injection of 0.1 ml of a 5% suspension of yeast cells in 5.55% glucose solution into a hind paw.

1.5 hours or 2.25 hours after the injection of phlogistic, the animals received different doses of the test compound as a suspension in 1% methylcellulose (1 ml/100 g animal) via pharyngeal tube. Control animals received corresponding volumes of vehicle 90 resp. 45 minutes after the administration of the test compound* (i.e. 3 hours after the subplantar injection of the yeast suspension, the pain in the rats due to swelling was determined in grams of applied pressure per paw. On the basis of the measured pain swelling after the different doses of the test compound, an ED^Q with reliability limits according to Fieller (Quart. J. Pharm. Pharmacol. 1_7, 117 (1944)) as the dose which caused a 50% improvement in the onset of pain compared to the controls. ;2. Effect on heat pain in mice; 1951) on Chbb:NMRI (SPF) male mice with a mean weight of;20 g. The "hot plate" consisted of aluminum and had a surface temperature of 52°C. ;The test compound was administered as a suspension in;1% methylcellulose (0 .1ml/10g mouse) via throat tube. Before treatment with the test compound, the animals were placed twice on the hot plate at 30 minute intervals. Their individual reaction time was determined. After administration of the test compound, the reaction time was determined again at 30 minute intervals. ;On the basis of the found maximum prolongation of the reaction time which was obtained with the different doses of the test compound, an ED10Q was calculated by linear regression analysis according to Linder (s.o.) with the reliability limits according to Fieller (s.o.) as the dose that led to a 100% prolongation of the reaction time. ; 3. Effect on body temperature in rats; Investigation of the temperature-lowering effect took place by checking the course of the rectally measured body temperature in Chbb:THOM rats with a weight between 125 and 150 g using a thermocouple placed in the rectum. The test compounds were administered as a suspension in 1% methyl cellulose (1.0 ml/100 g animal) via throat tube. On the basis of the values found for the mean, maximum temperature reduction after administration of the different doses of the test compound, a linear regression analysis according to Linder (s.o.) was determined as the dose which causes a lowering of the body temperature by 1 .5°C; 4) Acute toxicity in mice; Determination of the acute toxicity took place with Chbb:NMRI (SPF) mice of both sexes with an average weight of 20 g. The test compounds were administered as a suspension in 1% methyl cellulose (0.5 ml/10 g animal) . via pharyngeal tube. Calculation of LD^q took place according to Litchfield and Wilcoxon (J. Pharmacol. exp. Therap. 96_, 99 (1949)) on the basis of the percentage of animals that died within 14 days of receiving the various doses. ;Results;The findings made in these investigations are summarized in tables 1 to"5. ;Table 1;Effect against inflammatory pain in rats in the experimental device according to Randall and Selitto 45 minutes after oral administration; The following examples will further illustrate the invention: Example 1; 4-methoxy-2(3H)-benzothiazolone; To a solution of 271.6 g (1.75 mol) 2-amino-3-methoxy-benzenethiol in 1.5 1 anhydrous tetrahydrofuran is added, while stirring and while maintaining a temperature between 45 and 50°C, in portions of 300.0 g (1.87 mol) of N,N'-carbonyldiimidazole and then boiled for 30 minutes under reflux cooling. 1.7 1 of the solvent is distilled off, the remaining solution is filtered while hot and stirred into 3 1 of water. After \ hour, the precipitated product is suctioned off and washed thoroughly with water. One recrystallises from methanol using activated carbon and obtains 91.5 g (29% of the theoretical) of colorless crystals with m.p. 175-176°C ;CgH7N02S (181.21) ;Calculated: C 53.03, H 3.89, N 7.73, S 17.69 ;Found: 53.21 3.95 7.68 17.60 ; Example 2; 5-chloro-6-methoxy-2(3H)-benzothiazolone; In a solution of 9.5 g (0.05 mol) 2-amino-4-chloro-5-methoxy-benzenethiol and 5.0 g of triethylamine (0.05 mol) in 60 ml of anhydrous tetrahydrofuran, under external cooling with ice, a total of 3.3 g (0.055 mol) of carbonyl sulphide is added, the mixture is then stirred for 16 hours at room temperature and boiled for 8 hours under reflux. After standing for 72 hours at room temperature, the precipitate is suctioned off and recrystallized from tetrahydrofuran. When working up the mother liquor, additional material of the same purity can be recovered. In total, you get 6.0 g (56% of the theoretical) of colorless crystals with m.p. 260-261°C (tetrahydrofuran). ;CoH^ClN0^S (215.65);Calculated: C 44.56, H 2.80, Cl 16.44, N 6.49, S 14.87 Found: 44.52, 2.85 16.38 6.51 14.95. ;Example 3;5-chloro-6-methoxy-2(3H)-benzothiazolone;18.97 g (0.1 mol) of 2-amino-4-chloro-5-methoxybenzenethiol is dissolved in 100 ml of a mixture of equal parts by volume anhydrous tetrahydrofuran and toluene and 5.0 g (approx. 0.1 mol) of 50% sodium hydride are added while stirring, and after completion of hydrogen evolution the whole is cooled to approx. 0°C. While cooling externally with ice and while maintaining a reaction temperature of 0 to +5°C, 50 ml (approx. 0>1 mol) of a 20% solution of phosgene in toluene is added dropwise, then stirred for further 2 hours at room temperature and suction off the formed precipitate. After two recrystallizations from ethanol, each time using activated charcoal, 2.1 g (10% of the theoretical) of colorless crystals with m.p. 259-260°C, according to mixture melting point and thin-layer chromatographic examination identical to a product prepared in example 2. ;CgH6ClN0.2S (215.65) ;Calculated: C 44.56, H 2.80, Cl 16.44, N 6.49, S 14.87 Found: 44.76 3.16 16.25 6.34 14.62 ;Example 4 ;5-chloro-6-methoxy-2(3H)-benzothiazolone;To an ice-cold solution of 2.12 g (0.053 mol) of sodium hydroxide in 50 ml of water, 10.05 g (0.053 mol) 2-amino-4-chloro-5-methoxybenzenethiol and 1 g of a 40% methanolic solution of benzyltrimethylammonium hydroxide. While maintaining a reaction temperature of 5 to 6°C, 8.6 g (0.079 mol) chlorocarbonic acid ethyl ester is then added dropwise over 40 minutes, the cooling is removed and the mixture is stirred for a further 30 minutes at room temperature. The precipitate formed is filtered off, washed with 25 ml of diisopropyl ether and dried. Yield of 5-chloro-2-ethoxycarbonylthio-4-methoxyaniline: 12.2 g (88% of theory). ; 8.17 g (0.0312 mol) of 5-chloro-2-ethoxycarbonylthio-4-methoxy-aniline are added to a mixture of 19 ml of methanol and 2.6 ml of concentrated sulfuric acid and boiled for 40 minutes under reflux cooling. The whole is allowed to cool, the mixture is stirred into ;50 ml of ice water and filtered. The precipitate is taken up in a solution of 1.7 g of sodium hydroxide in 150 ml of water, treated with activated charcoal and filtered, after which the filtrate is extracted twice with 50 ml of ether. The aqueous phase is brought to pH 7 with 3N hydrochloric acid, after which the formed precipitate is suctioned off, dried and then recrystallized from ethanol. ;You get 5.4 g (80% of the theoretical) of colorless crystals with m.p. 260-261°C, according to mixture melting point, elemental analysis and IR spectrum identical to a product prepared according to example 2. ;Example 5;4-Methoxy-2(3H)-benzothiazolone;a) 3-Acetyl-4-methoxy-2(3H)-benzothiazolone;A solution of 24.5 g (0.1007 mol) [(3-methoxy -2-nitro-phenyl)thio]-acetic acid in 150 ml of acetic anhydride is boiled for 6 hours under reflux. Excess acetic anhydride is distilled off in a water jet vacuum, and the remaining residue is distributed between water and dichloromethane. The methylene chloride phase is evaporated and the residue is purified chromatographically on silica gel using dichloromethane/ethyl acetate (volume ratio 1:1) for elution. The product that crystallizes after evaporation of the eluates (11.5 g, i.e. 51% of what is theoretically used in the next step without further purification. ;b) 4-methoxy-2( 3H)-benzothiazolone; 7.0 g (0, 0314 mol) 3-acetyl-4-methoxy-2(3H)-benzothiazolone; is suspended in a mixture of 210 ml of 5N hydrochloric acid and 70 ml of ethanol and boiled for 1 hour under reflux. The still hot mixture is filtered, diluted with 200 ml of water and brought under external cooling with ice to a temperature of +5°C. After a 2-hour delay, the precipitate, the dried product, is suctioned off

purified chromatographically on silica gel using 1,2-dichloroethane/acetori (volume ratio 9:1) for elution, and finally recrystallized from methanol and from 1,2-dichloroethane, each time adding activated carbon. The crystals obtained in a yield of 2.9 g (51% of the theoretical) melt at 175-176°C..

CoH_,N0„S (181.21)

Oli-.

Calculated: C 53.03, H 3.89, N 7.73, S 17.69

Found: 53.10 3.94 7.78 17.78

Example 6

4-Methoxy-2(3H)-benzothiazolone

a) 3-acetyl-4-methoxy-2(3H)-benzothiazolone

One works as in example 5a), but however sets

50.0 g (0.61 mol) anhydrous sodium acetate to the reaction mixture. The reaction temperature can thereby be lowered to 100°C and the reaction duration to 30 minutes. The yield of impure 3-acetyl-4-methoxy-2(3H)-benzothiazolone is 11.0 g (49% of theory).

b) 2.223 g (0.01 mol) of 3-acetyl-4-methoxy-2(3H)-benzothiazolone are boiled in a mixture of 40 ml of ethanol and 50 ml of concentrated

ammonia for 2 hours under reflux. The mixture is evaporated to a quarter of its original volume, allowed to cool, filtered and the dried precipitate purified by chromatography on silica gel using 1,2-dichloroethane/acetone (v/v ratio 9:1) for elution. The evaporated eluates are recrystallized from methanol using activated charcoal and yield 1.55 g (85% of the theoretical) of the desired product, m.p. 175-176°C, according to mixture melting point and elemental analysis identical to a product obtained in example 1.

Example 7

6- methoxy- 4- methyl- 2( 3H)- benzothiazolone

A solution of 12.3 g (55 mmol) of 2-ethoxy-6-methoxy-4-methyl-benzothiazole in 250 ml of boiling ethanol is added dropwise to 45 ml of concentrated, aqueous hydrochloric acid. It is then boiled for 2 hours under reflux and the solvent is distilled off. The residue is taken up in ether, washed acid-free with water and evaporated again to dryness. The residue is recrystallized from ethanol. 7.6 g (70% of the theoretical) of 6-methoxy-4-methyl-2(3H)-benzothiazolone with m.p. 204°C.

CgH10N02S (196.25)

Calculated: C 55.36, H 4.65, N 7.17, S 16.42

Found: 55.26 4.41 7.12 16.27

IR (CH2C12): NH 3420, CO 1700 and 1675 cm"<1>

1 H-NMR (CDCl 3 ): 10.0 (1H-s, br, NH), 6.8 (1H-d, J = 1.5Hz), 6.68 (1H-d, J = 1.5Hz) , 3.77 (3H-S, 0CH3), 2.38 (3H-S, CH3>.

Example 8

4, 6-dimethyl-2(3H)-benzothiazolone

Prepared analogously to example 7 from 4,6-dimethyl-2-ethoxy-benzothiazole and concentrated hydrochloric acid in a yield of 74% of the theoretical. Sm.p. 219°C (ethanol).

C9HgN0S (179.25)

Calculated: C 60.31, H 5.06, N 7.81, S 17.89

Found: 60.70 5.20 7.62 17.77

IR(KBr): NH 3150, CO 1670 cm"<1>

1 H-NMR (CDCl 3 + CD 3 OD): 7.05 (1H-s, br), 6.88 (1H-s, br), 2.35 (6H-s, br, 4- and 6-CH 3 ).

Example 9

4-Methoxy-2(3H)-benzothiazolone

Manufactured analogously to. example 7 from 2-ethoxy-4-methoxy-benzothiazole and concentrated hydrochloric acid in a yield of

69% of the theoretical. Sm.p. 175-176°C (methanol).

CgH7N02S (181.21)

Calculated: C 53.03, H 3.89, N 7.73, S 17.69

Found: 53.07 3.87 7.75 17.72

Example 10

5-chloro-4-methoxy-2(3H)-benzothiazolone

Prepared analogously to example 7 from 5-chloro-2-ethoxy-4-methoxy-benzothiazole and concentrated hydrochloric acid in a yield of 33% of the theoretical. Sm.p. 191-192°C (methanol).

CgH6ClN02S (215.65)

Calculated: C 44.56, H 2.80, Cl 16.44, N 6.49, S 14.87 Found: 44.71 2.90 16.33 6.80 15.05.

Example 11

5, 6-methylenedioxy-2(3H)-benzothiazolone

Prepared analogously to example 7 from 2-ethoxy-5,6-methylene-dioxybenzothiazole and concentrated hydrochloric acid in a yield of

71% of the theoretical. Sm.p. 261°C (ethanol).

CoHcN0,S (195.2)

od -i

Calculated: C 49.22, H 2.58, N 7.18, S 16.43

Found: 48.96 2.53 7.03 16.45

IR (KBr): NH 3400 and 3180, CO 1670 cm"<1>

1H-NMR (do,-DMSO): 11.5 (1H, br, NH, exchangeable); 7.15 (lH-s),

6.7 (1H-s), 6.00 (2H-s, 0CH 2 O).

Example 12

7-methyl-2(3H)-benzothiazolone

Prepared analogously to example 7 from a mixture of 2-ethoxy-7-methylbenzothiazole and 2-ethoxy-5-methylbenzothiazole and concentrated hydrochloric acid in a yield of 65% of the theoretical. Sm.p. 137-138°C (ethanol/water 1:1); the product contains approx.

10% of the isomeric 5-methyl-2(3H)-benzothiazolone.

CoH_N0S (165.21)

o /

Calculated: C 58.16, H 4.27, N 8.48, S 19.41

Found: 58.27, 4.18. 8.35 19.18

Example 13

5, 6-dimethyl-2(3H)-benzothiazolone and 6,7-dimethyl-2(3H)-benzothiazolone

From a 5,6-dimethyl-2-ethoxybenzothiazole/6,7-dimethyl-2-ethoxy-benzothiazole mixture and concentrated hydrochloric acid is obtained analogously to example 7. in a yield of 28% of the theoretical a 1:1 mixture of the two title compounds.

Melting point: 168-194°C (ethanol/activated carbon).

CgHgNOS (179.24)

Calculated.: C 60.31, H 5.06, N 7.81, S 17.89

Found: 60.39 5.18 7.82 17.75

Example 14

6-(dimethylamino)-2(3H)-benzothiazolone

To a mixture of 27.0 g (0.9 mol) paraformaldehyde and 67.0 g (1.46 mol) formic acid is added in small portions and while maintaining a reaction temperature of 80 to 90°C

during approx. 4.0 minutes 60.0 g (0.361 mol) 6-amino-2(3H)-benzothiazolone. The whole thing is then held for a further 10 minutes at 80°C. Excess formic acid is distilled off in a vacuum, and the residue is dissolved in hot acetonitrile and filtered. The filtrate is evaporated, and the remaining residue is column chromatographed on silica gel using a mixture of 180 parts by volume of chloroform, 75 parts of ethyl acetate,

25 parts cyclohexane, 25 parts methanol and 3 parts concentrated ammonia for elution. After final recrystallization from ethanol, 19.3 g (28% of the theoretical) of colorless crystals with m.p. 194-196°C

<C>9<H>10N2OS <194'25)

Calculated: C 55.65, H 5.19, N 14.42, S 16.50

Found: 55.92 5.31 14.25 16.22

Example 15

4, 6-dimethyl-2(3H)-benzothiazolone

While maintaining a reaction temperature of approx. 50°C in small portions during approx. 3 hours a total of 20.0 g (0.29 mol) of sodium nitrite. The whole thing is left to stand overnight at room temperature, the precipitate is sucked off and washed thoroughly with water. The product is dried in air and can be used without further purification in the next step. Yield of 2-chloro-4,6-dimethyl-benzothiazole: 9.75 g. (49% of theory).

3.954 g (0.02 mol) of 2-chloro-4,6-dimethylbenzothiazole is boiled

in 100 ml of a mixture of equal parts ethanol and concentrated hydrochloric acid for 4 hours under reflux. Dilute with 100 ml of water, filter off the formed precipitate and wash it thoroughly with water. For further purification, the product is taken up in 10% caustic soda, filtered and the filtrate is titrated twice with 100 ml of ether each time. Acidify the aqueous phase

with hydrochloric acid, the precipitate formed is filtered off, washed with water and recrystallized once from ethanol and once from toluene, each time using activated carbon. 2.85 g (79% of the theoretical) of crystals with m.p. 219°C, according to mixture melting point, elemental analysis and thin-layer chromatographic examination identical to a product prepared according to example 8.

Example 16

4, 6-dimethyl-2(3H)-benzothiazolone

229.8 g (1.177 mol) of 4,6-dimethylr2(3H)-benzothiazolethione are introduced into a solution of 120 g (3 mol) of caustic soda in 1200 ml of water and added at a reaction temperature between 20 and 30°C with stirring 340 g ( approx. 3 mol) 30% hydrogen peroxide solution. The mixture is stirred for a further 2 hours at 30°C and 2 hours at 60°C, the whole is allowed to cool and the pH is adjusted to 6.5 with hydrochloric acid. The precipitate is filtered off and recrystallized twice from ethanol using activated charcoal. 164.3 g (92% of the theoretical) of crystals with m.p. 219-220°C, according to mixture melting point, elemental analysis and IR spectrum identical to a product prepared according to example 8.

Example 17

7-methyl-2(3H)-benzothiazolone

21.3 g (0/3 mol) of gaseous chlorine while maintaining a temperature between -10 and +10°C. The precipitate is filtered off, washed thoroughly with water and, after recrystallization from ethanol using activated charcoal, 14.5 g (88% of the theoretical) crystals with m.p. 169-170°C.

CgH7N0S (165.21)

Calculated: C 58.16, H 4.27, N 8.48, S 19.41

Found: 58.30. 4.16 8.52 19.60

The product is, by thin-layer chromatographic examination, identical to the main component in the product obtained in example 12.

Example 18

4, 6-dimethyl-2(3H)-benzothiazolone

9.765 g (0.05 mol) of 4,6-dimethyl-2(3H)-benzothiazolethione is triturated with 100 ml of a 1N sodium hydroxide solution, filtered and shaken at room temperature after adding a solution of 4.0 ml (9.12 g, i.e. 0.064 mol) of methyl iodide in 10 ml of ethanol for 15 minutes. After standing for 1 hour, the reaction product is filtered off, washed with water and dried at 50°C. Yield of colorless product:

6.6 g (63% of the theoretical).

5.23 g (0.025 mol) of 4,6-dimethyl-2-methylthiobenzothiazole are dissolved without further purification in 40 ml of glacial acetic acid. While stirring, a solution of 8.25 g (0.052 mol) potassium permanganate in 125 ml of water is added dropwise over 30 minutes. With external cooling with ice, it is ensured that the temperature of the reaction mixture does not exceed 35°C in this phase. The mixture is stirred for a further 1 hour at room temperature, the whole is allowed to cool and, by external cooling with ice, sulfur dioxide is introduced through the mixture until the brown color has disappeared. The sulfone formed is filtered off and dried in air. Yield: 4.9 g (81% of theoretical).

The 4,6-dimethyl-2-methylsulfonylbenzothiazole obtained is processed further without further purification. The solution of 4.82 g (0.02 mol) 4,6-dimethyl-2-methylsulfonyl-benzothiazole in 40 ml of concentrated, aqueous hydrochloric acid and 4 ml of ethanol is boiled for 4 hours under reflux, diluted with 200 ml of water

and make the mixture alkaline by adding ION sodium hydroxide solution after cooling. Filter, filter the filtrate with acetic acid and suction off the precipitate. Wash thoroughly with water, dry the product in air and recrystallize it twice from ethanol. 2.3 g (64% of the theoretical) of colorless crystals with m.p. 219-220°C, which by mixture melting point, elemental analysis and thin-layer chromatographic examination is completely consistent with a product prepared according to example 8.

Example 19

5. 6-dimethyl-2(3H)-benzothiazolone

Prepared analogously to example 1 from 2-amino-4,5-dimethyl-benzenethiol and N,N 1-carbonyldiimidazole in a yield of

72% of the theoretical.

Sm.p. 226-228°C (chloroform/methanol 1:1).

C9HgNOS (179.25)

Calculated: C 60.31, H 5.06, N 7.81, S 17.89

Found: 60.01 5.09 8.06 17.85

Example 20

6. 7- ethylenedioxy- 2( 3H)- benzothiazolone

Prepared analogously to example 7 from 2-ethoxy-6,7-ethylenedioxy-benzothiazole and concentrated hydrochloric acid in a. yield of 74% of the theoretical.

Sm.p. 245°C (ethanol)

C9H7N03S (209.22)

Calculated: C 51.67, H 3.37, N 6.69, S 15.33

Found: 51.95 3.35 6.93 15.38

Example 21

5, 6- ethylenedioxy- 2( 3H)- benzothiazolone

Prepared analogously to example 7 from 2-ethoxy-5,6-ethylenedioxy-benzothiazole and concentrated hydrochloric acid in a yield of 78% of the theoretical.

Sm.p. 244°C (1,2-dichloroethane)

C9H?N0S (209.22)

Calculated: C 51.67, H 3.37, N 6.69, S 15.33

Found: 51.48 3.30 . 6.60 15.48

Example 22

5- methoxy- 6- methyl- 2( 3H)- benzothiazolone

a) 2-chloro-5-methoxy-6-methylbenzothiazole

To an ice-cooled solution of 19.43 g (0.1 mol)

5-methoxy-6-methyl-2-benzothiazolamine in 100 ml of glacial acetic acid, with vigorous stirring add 25.5 ml (approx. 0.3 mol) of concentrated hydrochloric acid so that the formed hydrochloride precipitates in finely dispersed

shape. While maintaining a reaction temperature of

+8 to +10°C, a solution of 7.3 g (0.106 mol) of sodium nitrite in 11 ml of water is then injected through a fine nozzle into the bottom third of the well-stirred mixture. The diazonium salt solution thus obtained is slowly introduced with good stirring and under external cooling with ice into a mixture of 13.3 g (0.134 mol) copper (I) chloride and 55 ml concentrated hydrochloric acid, with a reaction temperature of +5 to +10°C is maintained. After the vigorous nitrogen evolution has subsided, the mixture is stirred for a further 2 hours at room temperature. The whole is then stirred in 500 g of crushed ice and a solution of 50 g of anhydrous sodium acetate in 300 ml of water is added. The mixture is decanted three times with 300 ml each time, the combined ether extracts are washed thoroughly with water, saturated sodium hydrogen carbonate solution and water and dried over sodium sulphate. After evaporation of the solvent, a slightly brownish liquid remains which solidifies crystalline after a longer period of time at 0 to 5°C and which is further processed without further purification. Yield: 15.17 g (71% of the theoretical).

b) 2,5-dimethoxy-6-methylbenzothiazole

A mixture of 95.3 g (0.446 mol) of 2-chloro-5-methoxy-6-methylbenzothiazole, 680 ml of anhydrous methanol and 44.2 g (0.63 mol) of potassium methanolate is boiled for 1 hour under reflux and stirring. The methanol is essentially distilled off, the mixture is diluted with 1 liter of ice water and extracted three times with 300 ml of ether each time. After drying and distilling off the solvent, the combined ether extracts leave a colorless residue which, after recrystallization from petroleum ether using activated carbon, melts at 101°C.

Yield: 73% of the theoretical.

c) 5-Methoxy-6-methyl-2(3H)-benzothiazolone

A solution of 74.7 g (0.357 mol) of 2,5-dimethoxy-6-methylbenzothiazole in 100 ml of boiling ethanol is added dropwise to 35 ml of concentrated hydrochloric acid. Boil for 2 hours under reflux, distill off the solvent and work up as in example 7. You get 64.1 g (92% of the theoretical

of crystals with m.p. 223-224°C (ethanol).

C9H9N02S (195.25)

Calculated: C 55.36, H 4.65, N 7.17, S 16.42

Found: 55.60 4.46 7.07 16.10

Example 23

4, 6-dimethoxy-2(3H)-benzothiazolone

Prepared analogously to example 22c) from 2,4,6-trimethoxybenzothiazole and concentrated hydrochloric acid in a yield of 79% of the theoretical.

Sm.p. 183°C (from tetrachloromethane)

CgH9N03S (211.25)

Calculated: C 51.17, H 4.29, N 6.63, S 15.18

Found: 51.11 4.24 6.75 15.16

The starting compound 2,4,6-trimethoxybenzothiazole is obtained from 2-chloro-4,6-dimethoxybenzothiazole and sodium methanolate according to example 22b) in a yield of 83% of the theoretical.

Example 24

6- methoxy- 4- methyl- 2( 3H)- benzothiazolone

In a solution of 31.2 g (0.78 mol) sodium hydroxide

99.3 g (0.47 mol) of 6-methoxy-4-methyl-2(3H)-benzothiazolethione are introduced into 400 ml of water. Over the course of 2 to 3 hours, a potassium permanganate solution is then introduced dropwise at 25 to 30°C, which has been prepared by dissolving 196 g

(1.24 mol) of potassium permanganate in 2 liters of water at 40°C, with stirring. After the addition is finished, the whole thing is heated to 80°C, and then the formed scum is suctioned off. The filter residue is taken up in 1 liter of water, heated to 80°C and filtered while hot. The combined aqueous filtrates are heated to 60 to 70°C, 200 ml of concentrated aqueous hydrochloric acid are added and boiled for 6 hours under reflux. After cooling the reaction mixture, the precipitate is filtered off and washed further with 500 ml of ice water and with 300 ml of ice-cold ethanol. The raw material is recrystallized once from 1,2-dichloroethane and once from ethanol. 66.4 g (72% of the theoretical) of crystals with m.p. 204°C, at melting point, mixture melting point and elemental analysis identical to the product obtained according to example 7.

The compounds of the general formula I can be incorporated into usual pharmaceutical preparation forms such as tablets, dragees, suppositories, capsules or juices. The single dosage for adults amounts to 20 to 600 mg, preferably 50 to 300 mg, which corresponds to a daily dose of 60 to 1800 mg, preferably 180 to 900 mg.

Claims (4)

1. Analogous process for the preparation of therapeutically active 2(3H)-benzothiazolone derivatives of the general formula I where either R4 means a methyl group, Rg a methoxy group and R5 and R? hydrogen atoms, or R4 and Rg each mean a methyl group and R,- and R-, hydrogen atoms, or R4 means a methoxy group and R5, Rg and R7 hydrogen atoms, or R4 means a methoxy group, R5 a chlorine atom and Rg and R? hydrogen atoms, or R,, and Rg together mean a methylenedioxy group, and R4 and R^ hydrogen atoms, or R7 means a methyl group and R4, R5 and Rg hydrogen atoms, or R5 and Rg each mean a methyl group and R4 and R7 hydrogen atoms, or Rg and R7 each mean a methyl group and R4 and R5 hydrogen atoms, or Rg means a dimethylamino group and R4, R5 and R7 hydrogen atoms, or R^ means a chlorine atom, Rg a methoxy group and R4 and R? hydrogen atoms, or R4 and Rg each mean a methoxy group and R5 and R? hydrogen atoms, or R,, means a methoxy group, Rg a methyl group and R4 and R7 hydrogen atoms, or R,- and Rg together mean an ethylenedioxy group and R^ and R^ hydrogen atoms, or Rg and R^ together mean an ethylenedioxy group and R^ and R^ hydrogen atoms, characterized by ata) a 2-aminothiophenol of the general formula II where R^ , R,., Rg and R^ are as indicated above, are reacted with a carboxylic acid derivative of the general formula III where X 1 and X 2 are the same or different and mean halogen atoms, a 1-imidazolyl, 1,2,4-triazol-4-yl or 1,2,4-triazol-1-yl group, an alkoxy group with 1 to 10 carbon atoms, a phenoxy or p-tolyloxy group, a benzyloxy or phenethyloxy group or together a sulfur atom, in a solvent at temperatures between 0 and 150°C, or a compound of the general formula II is reacted with a chlorocarbonic acid ester of the general formula Illa where R means an alkyl radical with 1 to 10 carbon atoms or a phenyl, 4-methylphenyl, phenylmethyl or 2-phenylethyl group, whereby compounds of the general formula IV are first formed where R, R., Rc , Rr and R_ are as above indicated, which then 4 D o / cyclization to compounds of the general formula I in the presence of acid catalysts at temperatures between 20 and 150°C, or b) one in the 2-position with chlorine, bromine or an alkoxy group substituted benzothiazole of the general formula V where R^ , R,., Rg and R^ are as indicated above, and X^ means a chlorine or bromine atom or an alkoxy group containing up to 3 carbon atoms, is hydrolysed by treatment with aqueous mineral acids at temperatures between 0 and 120°C, orc ) o-nitrophenylthioacetic acids of the general formula VI where R^ , R^-, Rg and R^ are as indicated above, are cyclocondensed with acetic anhydride to give 3-acetyl-2(3H)-benzothiazolone derivatives of the general formula VII after which the acetyl group is split off with the help of bases or acids at temperatures between 0 and 120°C, ord) a 2(3H)-benzothiazole thione with the general formula VIII where R^, R,-, Rg and R^ have the meanings given above, are oxidized at temperatures between -10 and +30°C and hydrolyzed to a 2(3H)-benzothiazolone of the general formula I with aqueous mineral acids at temperatures between 40 and 100°C, optionally also an alkali salt of a 2(3H)-benzothiazole thione with the general formula VIII is first reacted with alkyl iodides, dialkyl sulfates or benzyl halides to a 2-substituted benzothiazolone with the general formula IXa where R^ , R1-, Rg and R^ are as indicated above, and R^ means a lower alkyl residue with 1 to 3 carbon atoms or a benzyl residue, and this is then oxidized to a sulfone of the general formula IXb and the latter compound is hydrolysed with aqueous mineral acids at temperatures between 40 and 100°C, with the use of potassium permanganate for oxidation of the compound with formula VIII first a sulfonic acid of the general formula Villa is formed which then by heating to 40 to 100°C in the presence of aqueous mineral acids is transferred to a compound of the general formula I, or e) for the preparation of a compound of the general formula I where R, means a dimethylamino group and R^ , R^ and R^ mean hydrogen atoms, 6-amino-2(3H)-benzothiazolone is methylated with formaldehyde and formic acid at temperatures between 60 and 100 C. 2. Process as set forth in claim 1 for the production of 6-methoxy-4-methyl-2(3H)-benzothiazolone, characterized in that starting materials are used where R^ means methyl, R, and R^ mean hydrogen and R,, means methoxy. b 3. Process as stated in claim 1 for the production of 4,6-dimethyl-2(3H)-benzothiazolone, characterized in that starting materials are used where R^ and R^ each mean methyl, and R^ and R^ mean hydrogen. 4. Process as stated in claim 1 for the production of 5,6-methylenedioxy-2(3H)-benzothiazolone, characterized by . that starting materials are used where and R7 each mean hydrogen and R^ and R^ together mean methylenedioxy.