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Use of Carbamate Or Thiocarbamate Derivatives for Treatment of Fungal Infections

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Use of Carbamate Or Thiocarbamate Derivatives for Treatment of Fungal Infections Europaisches Patentamt European Patent Office © Publication number: 0 341 754 B1 Office europeen des brevets © EUROPEAN PATENT SPECIFICATION © Date of publication of patent specification: 09.12.92 © Int. CI.5: A01 N 47/18, C07D 213/75, C07D 405/12, C07D 401/12 © Application number: 89109926.9 @ Date of filing: 12.09.84 © Publication number of the earlier application in accordance with Art.76 EPC: 0 144 570 The file contains technical information submitted after the application was filed and not included in this specification © Use of carbamate or thiocarbamate derivatives for treatment of fungal infections. ® Priority: 13.09.83 JP 167415/83 Utsunomiya-shi Tochigi-ken(JP) Inventor: Nonaka, Yuji @ Date of publication of application: 230-1, Oaza Joson 15.11.89 Bulletin 89/46 Tokuyama-shi Yamaguchi-ken(JP) Inventor: Nakanishi, Akira © Publication of the grant of the patent: 4-10-3-306, Madokoro 09.12.92 Bulletin 92/50 Shinnanyo-shi Yamaguchi-ken(JP) Inventor: Morinaka, Hideo © Designated Contracting States: 3056-1, Oaza Tonda BE CH DE FR GB LI Shinnanyo-shi Yamaguchi-ken(JP) Inventor: Tsuzuki, Kenji © References cited: 3329-23, Oaza Tonda EP-A- 0 090 263 DE-A- 1 643 797 Shinnanyo-shi Yamaguchi-ken(JP) FR-A- 2 220 191 FR-A- 2 528 426 Inventor: Murakami, Mitsuyuki GB-A- 967 897 US-A- 3 855 263 3056-1, Oaza Tonda Shinnanyo-shi Yamaguchi-ken(JP) © Proprietor: Tosoh Corporation Inventor: Uotani, Takeshi 4560, Kaisei-cho 1768-2, Oaza Fukugawa Shinnanyo-shi, Yamaguchi-ken(JP) Shinnanyo-shi Yamaguchi-ken(JP) 00 @ Inventor: Iwata, Kazuo 4-19-20, Shimo-ochiai © Representative: Vossius & Partner Shinjuku-ku Tokyo(JP) Siebertstrasse 4 P.O. Box 86 07 67 Inventor: Takematsu, Tetsuo W-8000 Munchen 86(DE) 612, Mine-machi Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid (Art. 99(1) European patent convention). Rank Xerox (UK) Business Services EP 0 341 754 B1 Description The present invention relates to the use of carbamate or thiocarbamate derivatives for the preparation of compositions for the treatment of fungal infections. 5 EP-A-90 263 discloses herbicidal compositions containing 2-naphthyl N-methyl-N-(6-methoxy-2-pyridyl)- carbamate and 0-2-naphthyl N-methyl-N-(6-methoxy-2-pydridyl)-thiocarbamate. In GB-A-967 897 2-naphthyl thiocarbamates are disclosed which contain an N-methyl-N-(2-pyridyl) group. These compounds are said to be useful agricultural fungicides for treating e.g. rice blast. In DE-A-16 43 797 2-naphthyl and 5-indanyl thiocarbamates are disclosed which, however, do not io contain an N-alkyl-N-pyridyl group. The compounds are said to exhibit antimycotic activity against dermatophytes. US-A-3 855 263 describes 5,6,7,8-tetrahydro-2-naphthyl thiocarbamates which do not contain an N- alkyl-N-pyridyl group. These compounds are said to be active against dermatophyte fungi. Various carbamate derivatives are known to exhibit antifungal activity. Among them, especially known in 75 the medical treatment against cutaneous fungal infections are, O-2-naphthyl N-methyl-N-3-methylphenyl- thiocarbamate (tolnaftate) and 0-1 ,4-methano-1 ,2,3,4-tetrahydro-6-naphthyl N-methyl-N-3-methylphenyl- thiocarbamate (tolciclate). More specifically, the present invention relates to the use of carbamate or thiocarbamate derivatives having the general formula (I): 20 Y Z II I X-O-C-N-W (I) 25 where X is 2-naphthyl, 5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl, 1 ,4-methano-1 ,2,3,4-tetrahydro-6-naphthyl, 1 ,4-ethano-1 ,2,3,4-tetrahydro-6-naphthyl, 2-quinolyl, or a phenyl group having one or two of the same or different substituents selected from the group of halogen atom, lower alkyl, lower alkenyl, lower alkoxy, 30 lower alkenyloxy, halogenated lower alkyl, lower alkylthio, lower alkylsulfonyl, lower alkylamino, nitro, and methylenedioxy; Y is an oxygen atom or a sulfur atom; Z is lower alkyl group; W is pyridyl group having one or two of the same substituents selected from the group of lower alkyl, lower 35 alkoxy, lower alkenyloxy, and lower alkylamino, and the term "lower" denotes a group containing up to 1 to 8 carbon atoms, preferably 1 to 5 carbon atoms, and more preferably 1 to 4 carbon atoms, for the preparation of compositions for the treatment of fungal infections. The carbamate and thiocarbamate derivatives of the general formula (I) can be produced according to the following reaction schemes (1) and (2): 40 Y IJ X - OH + Hal - C- N- 45 W-kX-O-C-N-W (I) ... (1) Y Z II I II I so X - 0 - C - Hal + HN - W+X-O-C-N-W (I) ... (2) where X is 2-naphthyl, 5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl, 1 ,4-methano-1 ,2,3,4-tetrahydro-6-naphthyl, 55 1 ,4-ethano-1 ,2,3,4-tetrahydro-6-naphthyl, 2-quinolyl, or a phenyl group having one or two of the same or different substituents selected from the group of halogen atom, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogenated lower alkyl, lower alkylthio, lower alkylsulfonyl, lower alkylamino, nitro, and methylenedioxy; 2 EP 0 341 754 B1 Y is an oxygen atom or a sulfur atom; Z is lower alkyl group; W is pyridyl group having one or two of the same substituents selected from the group of lower alkyl, lower alkoxy, lower alkenyloxy, and lower alkylamino; 5 Hal is a halogen atom. The above reactions proceed in the presence of a dehydrohalogenation agent , and further in the presence or absence of a reaction solvent, usually at a reaction temperature of 0 to 150°C and a reaction time from about several minutes to 48 hours. The dehydrohalogenation agents include alkali hydroxides such as sodium hydroxide, potassium io hydroxide, and the like, alkaline earth hydroxide such as calcium hydroxide, and the like, alkali carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen car- bonate, and the like, metal hydrides such as sodium hydride, and the like, tertiary amines such as triethylamine, dimethylaniline, pyridine, and the like. In the reaction scheme (2), the starting aminopyridine derivative may be used as a dehydrohalogenation agent. is Reaction solvents to be used in the reaction represented by schemes (1) and (2) include alcohols such as methanol, ethanol, isopropanol, and the like, ketones such as acetone, methylethylketone, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as ethyl ether, tetrahydrofuran, dioxane, and the like, halogenated hydrocarbons such as chlorobenzene, chloroform, carbon tetrachloride, dichloroethane, and the like, polar solvents such as dimethylformamide, dimethylsul- 20 foxide, and the like. The process for producing the carbamate and thiocarbamate derivatives of the general formula (I) will be explained in the examples. Example 1 25 2-Naphthyl N-methyl-N-(4-methyl-2-pyridyl)carbamate (Compound No.1) A mixture of 1 .85 g of N-methyl-N-(4-methyl-2-pyridyl)carbamoyl chloride, 1 .44 g of 2-naphthol and 1 .38 g of anhydrous potassium carbonate in methylethylketone was refluxed under heating for 48 hours. After the 30 reaction mixture was cooled to room temperature, inorganic salts were removed by filtration and then methylethylketone was removed by distillation under reduced pressure. The residue was purified by column chromatography (silica gel, developed with ethyl acetate/benzene = 1/9 (V/V) ), to obtain 2.37 g of oily 2- naphthyl N-methyl-N-(4-methyl-2-pyridyl)carbamate (yield 81%, refraction index n^5 1.6191). The elemen- tary analysis of this material was as follows: 35 Elemental analysis: Found (%) C: 74.09 H: 5.60 N: 9.32 Calcd.(%) C: 73.95 H: 5.51 N: 9.58 40 Example 2 O-2-Naphthyl N-methyl-N-(6-methyl-2-pyridyl)thiocarbamate (Compound No. 2) 45 To a mixture of 1.22 g of 6-methyl-2-methylaminopyridine and 1.38 g of anhydrous potassium carbonate in 20 ml of acetone was added dropwise 2.23 g of 2-naphthylchlorothioformate in 20 ml of acetone under agitation at room temperature. The reaction mixture was stirred overnight at room tempera- ture and inorganic salts were removed by filtration. After acetone was removed by distillation under reduced pressure, the residue was purified by column chromatography (silica gel, developed with ethyl acetate/benzene = 1/9 (V/V) ), to obtain 2.62 g of O-2-naphthyl N-methyl-N-(6-methyl-2-pyridyl)- thiocarbamateas a solid in a yield of 85%. A portion of the product was recrystallized from ethanol to give colorless crystals having a melting point of 149.5°C - 150.5°C. Elemental analysis of the crystals is given below. 55 3 EP 0 341 754 B1 Elemental analysis: Found (%) C: 69.89 H: 5.19 N: 8.89 % Calcd.(%) C: 70.10 H: 5.22 N: 9.08 % In a similar manner as that used in Examples 1 and 2, other carbamate and thiocarbamate derivatives of the general formula (I) are synthesized. Typical examples of these carbamates and thiocarbamates together with their physical properties are shown below. EP 0 341 754 B1 Compound Compound Physical No. Property 3 ) 0- 2-Naphthyl N-methyl-N- ( 5-methy 1- 2-pyridyl) thiocarbamate m.p. 122. 5-124. 5°C 4) O- 2-Naphthyl N-methyl-N- (4-methyl- 2-pyridyl) thiocarbamate ni.p.107 - 108.
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