IL32203A - 5-imino-1,2,4-triazine derivatives,their preparatibenzoxazol-2-yl-n-methyl-n-naphth-1-yl dithiocarbamate,its production and pharmaceutical compositionon and use as herbicides s containing it - Google Patents

Description

o' aon ninjm »i'wsnr ,ιηροπ Benzoxaaol-2-yl-NTmet yl-N-naphth-l-yl ditniocarbamate, itB production, and pharmaceutical compositions containing it DR. KARL THOMAB GmbH C. 30446 This inventio is concerned with the new compound benzoxazol-2-yl N-methyl-lT-naphth-l-yldithiocarbamate which shows interesting antimycotic activity and processes for the preparation thereof,, According to the present invention there is thus provided benzoxazol-2-yl N-methyl-N-naphth-l-yldithiocarbamate of formula The compound of formula I shows interestin antimycotic activity. 'The compound has thus been examined for fungistatic activity in the absence of serum (o0S„) and in the presence of 10$ of serum (m0Se) by plate-dilution assay and tube-dilution assay,, The following dermatophytes were used as teat organisms:- Trichophyton me tagro h tes ATCO 9129 and Trichophyton rubrum ATCC 10,218, Diffusability of the compound was shown from the plate-dilution test. The diameter of the zone of inhibition was measured in millimeters,, 20 ml of nutrition medium (Sabouraudagar') were placed in 100 mm diameter petri-dishes and innoculated with a drop (0„05 ml') of adjusted organism-suspension,, 0„1 ml of a solution of the compound at various concentrations were pipetted into 10 mm diameter plate-holes. The plate was incubated for 7 days at 26°C and the minimal for the tube-dilution test. Tubes were innoculated with 2 drops of an adjusted organism-suspension. Observation was carried out macroscopically , registering the minimal inhibitary concentration (MIG) after incubation ■ for 7 days at 26°C.

The plate-'' and the tube-dilution tests showed the following results :- Dermatophyte plate-?dilution test tube-dilution test Trichophy on ment- w.o.s, 1 s 16,000 1 s 1β6 x 106 agrophytes ATCC 9129 w.s. 1 : 16,000 1 : 100,000 Trichophyton rubrum w.o.s, 1 : 16,000 1 : 2 x 100 ATCC 10 218 w.s. 1 : 16,000 1 s 100,000 The suspension of organisms was adjusted for the plate-and tube-dilution test with a photometer and a barium sulfate-comparison solution,, The head-neck zones of guinea pigs were depilitated and infected in this area with a dense suspension of Trichophyton mentagrophytes. The animals were treated daily for 3 weeks with approximately 1.0 ml of a 2 solution of the compound of formula Ie This leads to a complete healing of the mycotic efflorescences, Dimethylsulfoxide may, for example, serve as solvent. No skin sensitization was observed.

Compound of formula I appears to be substantially non-toxic. Administration of 4000 mg/kg per os to a grou of 10 mice resulted in the death of none of the animals after 6 days. The peroral administration of an average daily dose of 61.4 mg/kg over a period of 42 days appeared compatible for guinea pigs, The in enti n further rovides rocesses for the 32203 ?^ a) Reaction of a salt of 2-inercaptobenzoxazole (II) preferably an alkali metal salt and advantageously the jObasslum or sodium salt, with an N-methyl-N-naphth^l-ylthiocarbamoyl hallde of formula (wherein X represents a halogen atom, preferably a chlorine or bromine atom) .

She reaction may, for example, be carried out in an organic solvent and at an elevated temperaturej up to the boiling point of the solvent used, Suitable solvents Include for example, dimethyl ormamide . and benzene* b) Reaction of N-methyl-a-naphthylamine of formula with a benzoxazol-2-yldithlocarbonyl halide of formula (wherein Hal represents a halogen atom9 preferably a chlorine or bromine atom) 9 conveniently in the presence of a. hydrogen halide-binding agent„ The reaction may conveniently be effected in an organic solvent, advantageously in a chlorinated hydrocarbon9 for example9 chloroform9. and at a temperature for example between G and 50° 0» advantageously between 5 and 15° C„ Suitable hydrogen halide-binding agents include for example, a tertiary organic base such as triethylamine.

The starting materials of formula III may9 for example* be prepared by the reaction of N-methyl-a-naphthylamine with thiophosgene in the presence of a tertiary organic base? for example triethylamine. The compounds of formulae II and IV are known in the literature.

The starting materials of formula V may, for example be prepared (when X, for example, represents a chlorine atom) by reaction of 2-mercaptobenzoxazole with thiophosgene with the addition of a strong base.

According to a yet further feature of the invention there are provided pharmaceutical compositions comprising benzoxazol-2-yl N-methyl-N-naphth-l-ylthiocarbamate in association with a pharmaceutical carrier or excipiente The compositions may advantageously be presented in a form suitable for topical application.,gels9 ointments, powders, tinctures, solutions and drops are examples of forms suitable for topical application. The compositions may be formulated, for example 9 with pharmaceutical carriers or . excipients conventionally used in the pharmaceutical art.

The compositions according to the invention may yldithiocarbamate, advantageously between 0e5 and o by weight.

The following non-limitative examples describe the preparation of benzoxazol-2-yl N-methyl-N-naphth-l-yldithio-carbamate and compositions containing the same.

Example 1 a) N-Me hyl°IT-naphth-l~ylthiocarbamoyl chloride 78,6 g of N-methyl-a-naphthylamine and 50e g of triethyl-amine dissolved in absolute ether were added dropwise to 36'„5 ml of thiophosgene, dissolved in ether at a temperature of about 15° 0. The bat.ch was then stirred for 15 minutes, filtered and evaporated. The residue was dissolved in a solvent such as dimethylformamide or benzene and filtered free from insoluble material,, b) Sodium salt of 2-mercaptobenzoxazole 75 g of 2-mercaptobenzoxazole were mixed with 11.5 g of sodium in 500 ml of absolute ethanol» boiled for 10 minutes under reflux and then evaporated to dryness. na c) Benzoxazol-2-yl N-°methyl-N-»a-¾phth~l-yldithiocarbamate The sodium salt of the 2-mercaptobenzoxazole was pulverized and added to a solution of N-methyl-N-naphth-l-ylthiocarbamoyl chloride in dimethylformamide in lsl molar ratio and the mixture was refluxed for ■¾· hour. Water was then added to the reaction mixture and the oil which separated was removed after which it crystallized. If benzene was used as solvent the reaction product remained in the organic phase and the benzene -was separated, filtered and evaporated to dryness. After recrystallisation from ethanoly whitish crystals were obtained of.m.p. 170° - 172°Ce Example 2 ° - mixture and a solution of 40 g of sodium hydroxide in 300 ml of water was added dropwise over 30 minutes with vigorous ptirring at about 10°C, The batch was stirred for a further 15 minutes, subsequently the chloroform phase was separated, washed twice with water, dried and evaporated to a volume of 200 ml„ b) Benz,oxazol~2-yl IT°metJiyl-Hr«-naphth~l°yldithiocarbamate The benzoxazol-2-yl dithiocarbonyl chloride obtained above was not isolated, the chloroform solution being diluted with chloroform to a total volume of 1500 ml. To this solution was added dropwise with stirring over one hour at about 10° C a solution of 157 g of U-methyl-a-naphthylamine and 101 g of triethylamine in 200 ml of chloroform. The batch was stirred for another hour, Triethylamine hydrochloride was precipitated by adding ether and was filtered off. After evaporation of the filtrate, 600 ml of ethanol were added and the product crystallized after some time. It was recrystallized from ether, whitish crystals of m.p, 170 - 172°C being obtained,, Example 3 Ointment containg 1$ of benzoxazol-2-yl IT-methyl-IT-naph-th-l-yldithiocarbamate , Ingredients % Benzoxazol-2- 1 U-methy1-N-naphth-l-yl-dithiocarbamate 1,0 g Glyercine monosterate 7,0 g Polyoxyethylene sorbitan monosterate 4,0 g Isopropyl myristate 5.0 g Cet lstear l alcohol 7,0 g Preparation % Glycerine monosterate, polyoxyethylene sorbitan monosterate, isopropyl myristate and cetylstearyl alcohol were warmed to 70° C and added to the water at the same temperature with stirrings The fine pulverized active ingredient was dispersed in part of the ointment which had been stirred until cold, the dispersion was subsequently rolled out and then blended with the rest of the ointment.

Example 4 Powder containing 0,5$ of Benzoxazol-2-yl N-methyl-N-naphth- -1-yldithiocarbamate Composition; Benzoxazol-2-yl F-meth l-N-naphth-1- -yldithiocarbamate 0,5 g Talc 96,9 g Aerosil 2,5 g Perfume 0.1 g 100,0 g Preparations The fjne¾r pulverized active ingredient was intensively mixed in a pressure mixer with the other materials and the mixture was pulverized in a mill0 Example 5 Tincture containing 0,5 of Benzoxazol-2-yl N-methyl°HT-naphth °l°yldithiocarbama e Compositions Benzo xazol-2-yl N-methyl-U-naphth-l-yldithio-carbamate 0,5 g Ethanol 40,0 g Isopropanol 39„3 g Preparations The active ingredient was dissolved in the mixture of ethanol> isopropanol and methylene chloride while stirring and the propylene glycol and perfume were then added.

Example 6 Ointment containing O 0 5'fo of Benzoxazol-2-yl N-methyl-N-naphth- -1-yldithiocarbamate Composition? Benzoxazol-2-yl N-methyl-N-naphth- -1-yldithiocarbamate Dimethyl sulfoxide Decyl oleate Emulgade F Cremophor A9 firm Stearic acid Cetylstearyl alcohol liquid Paraffin Perfume dist 0 water Preparations The decyl oleate emulgade P9 cremophor As stearic acid» cetylstearyl alcohol and liquid paraffin were melted together $ warmed to 70° C and added to the water with stirrings which had previously been brought to the same temperature,, The emulsion was cooled to 40° 0 and the dimethylsulfoxide and perfume were stirred in. The finely pulverized active ingredient was triturated with part of the ointment, the triturate was milled and distributed evenly in the remainder 32203/2

Claims (1)

1. CLAIMS 1. Benzoxazol^-2-yl N-methyl-N-naphth-l-yldithiocarbamat of formula 2. A process for the preparation of benzoxazol-2-yl- N-methyl-N-naphth-l-yldithiooarbamate wherein a salt of 2-mercaptobenzo-xazole of formula II is reacted with an N-methyl-N-naphth-l-ylthiocarbamoyl halide of formula III CH^ - N - C - X S (wherein X represents -g-halogeg a halogen atom) . 3· A process as claimed in Claim 2, wherein the sodium or potassium salt of 2-mercaptobenzoxazole of formula II is reacted with the compound of formula III. 4* A process as clained in Claim 2 or 3» wherein the compound of formula III is a compound wherein X represents a chlorine or bromine atom. 5» A process as claimed in any one of Claims 2 to 4» wherein the reaction is effected in an organic solvent. -6. A process as claimed in Claim 5» wherein the solvent comprises dimethylformamide or benzene. 7. A process as claimed in Claim 5 or 6, wherein the reaction is effected at an, elevated temperature up to the boiling point of formula reacted with a benzoxaoZlz-2-yldithiocarbonyl halide of formula (wherein Hal represents a halogen atom) 0 9 o A process as claimed in claim 8 wherein the compound of formula V is a compound wherein Hal represents a chlorine or bromine atom, 10 e A process as claimed in claim 8 or claim 9 wherein the reaction is effected in an organic solvent, 110 A process as claimed in claim 10 wherein' the solvent comprises a chlorinated hydrocarbon. 12 „ A process as claimed in claim 11 wherein the solvent comprises chloroform, 13 o A process as claimed in any of claims 8 to 12 wherein the reaction is effected at a temperature between 0 and 50° C o 1 o A, process as claimed in claim 13 wherein the temperature is between 5 and 15° C e 15 » A process as claimed in any of claims 8 to 14 wherein the reaction is carried out in the presence of a hydrogen halide-binding agen „ 16 A rocess as claimed in claim 1 wherein the h dro en 32203/2 halide-binding agent comprises a tertiary organic base, •■17. A process as claimed in claim 16 wherein the base comprises trie hylamine0 18e A process as claimed in claim 2 or claim 8 substantially as herein described, 19. A process for the preparation of benzoxazol-2-yl N-methyl-N-naphth-l-yldithiocarbamate substantially as herein described in either of Examples 1 and 2, 20. Benzoxazol-2-yl N-methyl-N-naphth-l-yldithiocarbamate when prepared by a process as claimed in any of claims 21. Pharmaceutical compositions comprising benzoxazol-2-yl N-methyl-N-naphth-l-yldlthiocarbamate in association with a . pharmaceutical carrier or excipient. 22. Compositions as claimed in claim 21' in a form suitable for topical application. 23. Compositions as claimed in claim 22 in the form of gels, J V ■ ointments, powders, tinctures, solutions or drops, 24. Compositions as claimed in claim 22 or claim' 23 containing between 0.05 and 5$ by weight of benzoxazol-2-yl -methyl-N- naphth-l-yldithiocarbamate. 25. Compositions as claimed in claim 24 containing between 0.5 and 1$ by weight of benzoxazol-2-yl N-me thyl-N-naphth-1- yldithlocarbamate. ' 26. Compositions as claimed, in claim 21 substantially as herein described. as claimed in Claim 21 27, Pharmaceutical oompooitionoAiubotantially as horoin > o in an o;i? .ui i un l o i;i 3 t o 6