DE1960026A1 - Antimycotic 3-amino-1,2-benzisothiazole - derivs - Google Patents

Abstract

Title cpds. of formula (I): (where R1 is H, alkoxy or OH; R2 is H, is not 2 C alkoxy or OH; R1 and R2 not both being H, and m and n are 1 or 2) and their salts, which are useful in human and veterinary medicine and in plant-protection, are prepd. by reacting a benzisothiazolium cpd. (II): (where X is the anion of a strong acid; Y is halogen and R1 and R2 are not alkoxy) with NH3 and opt. converting an alkoxy cpd. thus obtained into a hydroxy cpd. (e.g. by heating with pyridine HCl).

Description

New derivatives of 3-amino-1,2-benzisothiazole and a method too their production and their use as medicaments are the subject of the invention are new derivatives of 3-amino-1,2-benzisothiazole, a process for their preparation as well as the use of the new compounds and their salts as medicaments, in particular as antifungal agents, the presentation of some 3-amino-1, 2-benzisothiazole hydrochloride from D-chloro-1,2-benzisothiazolium chlorides is in Chem. Ber. 99, 2566 (1966).

It has now been found that new, antifungal substituted 3-amino-1,2-benzisothiazoles are obtained if substituted 3-halogen-1, 2-benzisothiazolium salts of the general formula (I) where R1 is hydrogen or an alkoxy group and R2 is hydrogen or an alkoxy group having at least 2 carbon atoms with the restriction that R1 and R2 cannot simultaneously denote hydrogen and X is the anion of a strong acid, Y is halogen, m is 1 or 2 and n is 1 or 2, reacts with ammonia, and optionally converts the alkoxy compounds into the hydroxy compounds and optionally prepares the salt from the alkoxy compounds or the hydroxy compounds.

The new compounds obtainable by the process according to the invention correspond to the general formula (II) where R1, R2, m and n have the meaning given above and R1 and Rz can additionally stand for the OH group.

Halogen (y) is preferably chlorine and bromine, in particular chlorine. Examples of strong acids that provide the anion X e are the hydrohalic acids, such as B. hydrochloric acid and hydrobromic acid, with hydrochloric acid is preferably used, but also nitric acid, sulfuric acid and hydrofluoric acid called. The alkoxy group (R1) contains 1 to 4, preferably 1-2, carbon atoms and the alkoxy group (R2) contains 2 to 4 carbon atoms, preferably 2-3 carbon atoms. m is preferably 1 and n is preferably 2.

The substituted 3-halo-1,2-benzisothiazolium salts used as starting material are produced by a known method (Chem. Ber. 99, 2566-71 (1966).

The substituted 3-halos1,2-benzisothiazolium are used to prepare the new compounds Salts, in particular the 3-chloro-1,2-benzisothiazolium salts, preferably their Chlorides, with vigorous stirring at a temperature between about -5 and 250 C, preferably about 0-50 C, in a saturated one Ammonia solution, their ammonia content is preferably about 5 times the molar amount of the isothiazolium halide used is registered. The solvent used for the reaction described inert organic solvents in question such. B. alcohols, among which lower Alcohols, especially methyl alcohol, are used.

To complete the reaction, stirring is continued for about 5 minutes, the precipitated ammonium halide separated and from the filtrate after evaporation the reaction product, preferably as a salt, in particular as the hydrochloride, isolated.

From the alkoxy compounds obtained in this way can in conventional Way, e.g. B. by heating with pyridine. HCl, the alkoxy groups cleaved and the hydroxyl groups are released.

The course of the reaction is exemplified by the following reaction scheme: The new compounds are weak bases and only form with strong acids, e.g. B. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, hydrofluoric acid, etc., salts. Compounds that carry hydroxyl groups on the benzene nucleus are amphoteric.

The preparation of the compounds according to the invention is based on the the following examples: Example 1 3- (ß-MethOxyäthyl) -amino-1,2-benzisothiazole hydrochloride: 26.4 g (0.10 mol) of 3-chloro-ß-methoxyethyl-1,2-benzisothiazolium chloride are used in 0 - 50 C with vigorous stirring quickly in 100 ml of a saturated methanolic NH3 solution (0.5 mol) entered. It is stirred for a further 5 minutes, then the precipitated Sucked off ammonium chloride and the filtrate i. Vac.

evaporated.

The residue is taken up in chloroform, then the chloroform solution washed with water, dried and evaporated in vacuo. The 3- (ß-methoxyethyl) -amino-1, 2-benzisothiazole is initially oily and is treated with Aether / HCl converted into the crystalline hydrochloride.

Yield: 12.4 g (50.4% of theory) From ethanol colorless prisms, Melting point 1430 C.

Example 2 3- (β-hydroxyethyl) amino-1,2-benzisothiazole hydrochloride; 5.0 g of 3- (ß-methoxyethyl) -amino-1,2-benzisothiazole HCl are mixed with 25 g of pyridine HCl mixed well and the mixture heated to 1800 C for 1 hour. Then the Melt cake dissolved in water, insoluble flakes separated, the filtrate with NaOH made alkaline and extracted exhaustively with ether.

The ether extract is dried and evaporated in vacuo at 350 C; then a vacuum of 0.1 is applied to the oil pump to remove the pyridine Torr applied. In this way, 2.4 g (51.5% of theory) of 3- (β-hydroxyethyl) amino-1,2-benzisothiazole are obtained obtain. The raw base is dissolved in ether and the hydrochloride with ether / HCl failed.

Colorless prisms after recrystallization from ethoxyethanol / ethanol; Melting point 1970 C (sub.).

The starting materials required for the reaction are as follows obtained: A) Diphenyl disulfide-dicarboxylic acid- (2 2 ') -bis-ß-methoxyethylamide: 103 g (0.30 mol) of diphenyl disulfide dicarboxylic acid (2.2 ') dichloride in 300 ml of tetrahydrofuran are rapidly stirred to a solution of 45.0 g (0.60 mol) of 2-methoxyethylamine and 60 g (0.60 mol) of triethylamine in 300 ml of ethanol at a temperature of 25 - 300 C dripped.

The mixture is then stirred for one hour at room temperature precipitated product sucked off, washed well with water and dried. By Concentration of the mother liquor in vacuo gives further crude product. Get together in this way about 90 g (71.5% of theory) of diphenyl disulfide dicarboxylic acid (2.2 ') - bis-ß-methoxyethylamide obtain.

Colorless blocks made of DMF / ethanol; Melting point 1650 C. The crude product is sufficiently pure and can be processed immediately in the next reaction stage will.

B) 3-chloro-N-ß-methoxyethyl-1,2-benzisothiazolium chloride: 84.1 g (0.20 mol) of diphenyl disulfide dicarboxylic acid (2.2 ') - bis-methoxyethylamide and 125.0 g (0.60 mol) of phosphorus pentachloride are suspended in 400 ml of benzene and taken under vigorous stirring slowly warmed until the onset of the reaction. The reaction will kept under control by intermittent heating. It will take 1 hour Heated to reflux; then allowed to cool, sucked the reaction product, 3-chloro-N-ß-methoxyethyl-1,2-benzisothiazolium chloride off, washed off with benzene and dried in vacuo.

Yield: 70.5 g (67% of theory) melting point 1370 ° C. The crude product is processed immediately.

The starting compounds for the preparation of the further described Compounds according to the invention are required can be prepared in an analogous manner will.

Example 3 3-Ethylamino-6-ethoxy-1,2-benzisothiazole: The representation takes place in the manner described in Example 1 from 2-ethyl-3-chloro-6-ethoxy-1 , 2-benzisothiazolium chloride and ammonia.

The 3-ethylamino-6-ethoxy-1,2-benzisothiazole falls after recrystallization from ethanol in the form of colorless prisms with a melting point of 990 C.

Yield: (58.8% of theory) 10.3 g. Example 4 3-Ethylamino-6-hydroxy-1 , 2-benzisothiazole: 4.0 g of 3-ethylamino-6-methoxy-1,2-benzisothiazole are with 30 grams of pyridine. MCI mixed well and the mixture heated to 1800 C for 3 hours. The melt cake is dissolved in water with the addition of slightly dilute NaOH (pH> 12) dissolved and the solution extracted with ether. (The dried and evaporated ether extract returns approx. 0.3 g of starting material.

The aqueous phase is acidified with glacial acetic acid and exhausted extracted with ether. The dried and evaporated ether extract gives 4 g of crude 3-ethylamino-6-hydroxy-1,2-benzisothiazole, which recrystallizes from acetonitrile is obtained in the form of colorless prisms and melts at 1600 C.

Yield: 1.5 g (40% of theory) The invention new compounds and their salts show surprisingly low toxicity excellent antifungal effects, especially against human, animal and plant pathogens Mushrooms, which are used in human and veterinary medicine but also in plant protection enables.

The low toxicity and antifungal effectiveness of the new Compounds is exemplified by 3-ethylamino-6-hydroxy-1,2-benzisothiazole the following tables, which show the results of in vitro and in vivo tests, evident. The other compounds according to the invention show a similar effectiveness. The determination of the minimum inhibitory concentration (MIC) against various human and animal pathogenic fungal species were carried out in serial dilution tests.

1–3 × 10 5 infectious particles per 20 ml of the active substance-containing nutrient substrate were inoculated. The inoculation density was set by measuring the turbidity with the aid of a calibration curve for each test organism. As a nutrient substrate for dermatophytes, Aspergillus and Penicillium, Sabouraud's Millieu d'epreuve was used, and for Candida albicans, meat and grape-sugar broth were used. The incubation temperature was 280 C. The incubation period was 6-10 days for dermatophytes and molds and 48 hours for yeasts. 3-ethylamino-6-hydroxy-1,2-benzisothiazole: Toxicity (mouse): po 1000 mg / kg; sc 1000 mg / kg: Minimum inhibitory concentration (MIC) in y / ml nutrient solution ilzs ezies MIC (without serum / with serum) Trichophyton mentagrophytes 44 / <4 Candida albicans 20/20 Penicillium comune 40 Aspergillus niger 100 / ioo icrosporium canis <4 Effect with local application au! the experimental guinea pig trichophytosis. Treatment with a 1% solution in dimethyl sulfoxide-glycerine-water / 3: 3: 4 Test groups evaluation of the course of infection after days post infection untreated control Animal No. 1 1 1 1 1/2 2 3/4 4 5 No. 2 1 1 1 1/2 2 3/4 4/5 5 Treated animals Animal No. 1 0/1 1 1 1 2 2/3 3 3/4 No. 2 1 1 1 1 2 2/3 3 3/4 No. 3 1 1 1 1 2 2/3 3 3/4 Explanation of the numbers: 1 = reddening 2 = reddening with beginning hair loss 3 = severe hair loss 4 = beginning bloody ulceration 5 = extensive, bloody ulceration.

The compounds according to the invention show excellent results in vitro Inhibition values in Trichophyton mentagrophytes, Candida albicans, Penicillium comune, Aspergillus niger and Microsporium canis. Even with the oral treatment of the experimental Guinea pig trichophytia clearly show healing effects.

The new compounds show systemic effectiveness, the focus however, their uses are in the treatment of local mycoses.

The chemotherapy drugs can either be used as such or in combination be used with pharmaceutically acceptable carriers or binders. Powder, Sprays, aqueous suspensions and the like can be considered.

Such carriers include solid diluents or fillers, an aqueous medium as well as various non-toxic organic solvents and like that. The therapeutically effective compound should in the aforementioned case in at a concentration of about 0.5 to 90 percent by weight of the total mixture be.

Claims (1)

Patent claims New 3-Amino-1, New 3-Amino-1,2-benzisothiazole derivatives of the general formula where R1 is hydrogen, an alkoxy group or the OH group, R2 is hydrogen, an alkoxy group having at least 2 carbon atoms or the OH group, with the restriction that R1 and R2 cannot be hydrogen at the same time and m 1 or 2 and n 1 or 2, and their salts. 2. 3- (ß-Methoxysthyl) -amino-1,2-benzisothiazole hydrochloride 3. 3- (ß-Hydroxyethyl) -amino-1,2-benzisothiazole hydrochloride 4. 3-Ethylamino-6-ethoxy-1 2 -benzisothiazole 5. 3-ethylamino-6-hydroxy-1,2-benzisothiazole 6. Process for the preparation of new substituted 3-amino-1,2-benzisothiazoles, characterized in that substituted 3-halogen-1,2-benzisothiazolium Salts of the general formula where R1 is hydrogen or an alkoxy group and R2 is hydrogen or an alkoxy group having at least 2 carbon atoms with the restriction that R1 and R2 cannot simultaneously denote hydrogen and X is the anion of a strong acid, Y is halogen, m is 1 or 2 and n is 1 or 2, reacts with ammonia, and optionally converts the alkoxy compounds into the hydroxy compounds and optionally prepares the salt from the alkoxy compounds or the hydroxy compounds. 7. Medicinal product characterized by a content of a compound according to claim 1. 8. Process for the production of pharmaceuticals, characterized in that that a compound according to claim 1 is used as the active ingredient. 9. Antifungal agents characterized by a content of one Compound according to claim 1. 10. A method for the production of antifungal agents, characterized in that that a compound according to claim 1 is used as the active ingredient.