WO1996037479A1 - Derives d'oxime de cyclohexanone - Google Patents

Derives d'oxime de cyclohexanone Download PDF

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Publication number
WO1996037479A1
WO1996037479A1 PCT/EP1996/002102 EP9602102W WO9637479A1 WO 1996037479 A1 WO1996037479 A1 WO 1996037479A1 EP 9602102 W EP9602102 W EP 9602102W WO 9637479 A1 WO9637479 A1 WO 9637479A1
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WO
WIPO (PCT)
Prior art keywords
methyl
triazol
ylmethyl
trifluoromethoxy
phenoxy
Prior art date
Application number
PCT/EP1996/002102
Other languages
English (en)
Inventor
Kazuo Hattori
Hitomi Ontsuka
Nobuo Shimma
Michio Shirai
Takuo Tsukuda
Masami Watanabe
Toshikazu Yamazaki
Original Assignee
F. Hoffmann La Roche Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by F. Hoffmann La Roche Ag filed Critical F. Hoffmann La Roche Ag
Publication of WO1996037479A1 publication Critical patent/WO1996037479A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to novel cyclohexanone oxime derivatives, a process for their manufacture, an antifungal composition containing them and use thereof.
  • the present invention relates to cyclohexanone oxime derivatives exhibiting excellent antifungal activity against Aspergi llus sp.
  • X is -0- or -CH2-; l - is lower-alkyl or lower-alkoxy which may be substituted with 1 to 4 fluorine atom(s) ; R2 is a hydrogen atom or lower-alkyl; Me/So 5.3.96 R3 is methyl or -(CH2)2 R ⁇ i n which R 4 is hydroxy, amino, mono- or disubstituted lower-alkylamino, lower-alkoxy, lower-alkylthio, lower-alkylsulfonyl, a 5- or 6-membered heterocyclic ring containing one or more nitrogen atom(s) which may further contain an oxygen or sulfur atom, or -(S or N) -Het wherein Het means heteroaryl; as well as pharmaceutically acceptable salts thereof, and hydrates or solvates of the compounds of the formula (I) or their salts.
  • lower refers to carbon chain preferably containing up to and including 3 carbon atoms, unless otherwise indicated.
  • R! is a lower-alkyl or lower-alkoxy which may be substituted with 1 to 4 fluorine atom(s) such as methyl, ethyl, propyl, trifluoromethyl, trifluoromethoxy, 1,1- difluoroethoxy, 1, 1, 2,2-tetrafluoroethoxy, 2,2,3,3- tetrafluoropropoxy and the like.
  • fluorine atom(s) such as methyl, ethyl, propyl, trifluoromethyl, trifluoromethoxy, 1,1- difluoroethoxy, 1, 1, 2,2-tetrafluoroethoxy, 2,2,3,3- tetrafluoropropoxy and the like.
  • methyl, ethyl, trifluoromethyl, trifluoromethoxy are especially preferred.
  • R2 is a hydrogen atom or a lower-alkyl such as methyl, ethyl, propyl, preferably a hydrogen atom or methyl.
  • R 3 is a methyl or -(CH2.2R 4 wherein R 4 is a hydroxy, amino; mono- or disubstituted lower-alkylamino such as methylamino, di ethylamino, diethyla ino; lower-alkoxy such as methoxy, ethoxy and propoxy, preferably methoxy; lower- alkyl hio such as methylthio, ethylthio and propylthio, preferably methylthio; lower-alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, and propylsulfonyl preferably methylsulfonyl; a 5- or 6-membered heterocyclic ring containing one or more nitrogen atom(s) which may further contain an oxygen or sulfur atom such as 1, 3-imidazol-l-yl, 1, 2-imidazol-l-yl, 1,2, 4-triazol-l-yl,
  • novel cyclohexane derivatives represented by the formula (I) can be produced according to the following methods.
  • Process A Compounds represented by the formula (I) [in which R 3 is -(CH2.2R in which R 4 is a hydroxy, and R 1 , R 2 and X are as defined above] can be produced by removal of the protecting group of the primary alcohol function of a compound represented by the formula (II) ,
  • R 2 is a lower-alkyl, R ⁇ and X are the same as defined above, with mesyl chloride in the presence of acid acceptor, followed by reacting the resulting mesylate with a nucleophile R 4 -H or its alkali metal salt (R 4 is the same meaning as defined above) in the presence or absence of base.
  • R 1 ' R 3 and X are the same as defined above, with hydroxylamine acid addition salt in the presence of an acid acceptor, followed, if necessary, by O-alkylation of the resulting oxime group.
  • R ⁇ is a lower-alkyl
  • Rl, R 2 and X are the same as defined above, with an oxidizing agent.
  • hydroxy-protecting group Y examples include benzyl, 4-methoxybenzyl, trityl or acyl such as acetyl, pivaloyl, benzoyl and the like.
  • the protecting groups Y can be removed by the procedures known to those skilled in the art.
  • Process B Specific examples of the compound represented by the general formula (III) include:
  • the mesylation can be performed by treatment of a compound represented by the general formula (III) with mesyl chloride in the presence of acid acceptor such as pyridine, 2, 6-lutidine, 2, 4, 6-collidine, triethylamine or N,N- diisopropylethylamine.
  • acid acceptor such as pyridine, 2, 6-lutidine, 2, 4, 6-collidine, triethylamine or N,N- diisopropylethylamine.
  • This reaction proceeds in a solvent such as chloroform, dichloromethane, pyridine, and the like, and at a temperature between -20 and 60°C, preferably between 0 and 25°C.
  • the nucreophilic substitution of the resulting mesylate can be performed with a nucleophile R 4 -H or its alkali metal salt (R 4 being the same as defined above) in the presence or absence of base such as sodium hydride, potassium hydride, lithium hydride and the like.
  • This reaction proceeds in a solvent such as chloroform, dichloromethane, N,N-dimethylformamide, and the like, and at a temperature between -20 and 60°C, preferably between 0 and 25°C.
  • (2S,5R, 6R) -5- [2- (4-ethylphenyl)ethyl] -2- (2-methoxyethyl) - 2-methyl-6- (1H-1,2, 4-triazol-l-ylmethyl)cyclohexanone
  • oxime can be performed by treatment of a compound (IV) with hydroxylamine acid addition salt such as hydrochloride, sulfonate, phosphate in the presence of an acid acceptor such as pyridine, 2, 6-lutidine, 2, 4, 6-collidine, triethylamine or N,N-diisopropylethylamine.
  • hydroxylamine acid addition salt such as hydrochloride, sulfonate, phosphate
  • an acid acceptor such as pyridine, 2, 6-lutidine, 2, 4, 6-collidine, triethylamine or N,N-diisopropylethylamine.
  • This reaction proceeds in a solvent such as chloroform, dichloromethane, pyridine, ethanol, methanol and the like, and at a temperature between 20 and 150°C, preferably between 50 and 120°C.
  • a solvent such as chloroform, dichloromethane, pyridine, ethanol, methanol and the like, and at a temperature between 20 and 150°C, preferably between 50 and 120°C.
  • the preparation of compound (I) wherein R2 is a lower alkoxy can be performed by O-alkylation of the resulting oxime with alkyl halide such as methyl iodide, ethyl iodide, propyl iodide and the like in the presence of base such as sodium hydride, potassium hydride, lithium hydride and the like.
  • alkyl halide such as methyl iodide, ethyl iodide, propyl iodide and the like in the presence of base such as sodium hydride, potassium hydride, lithium hydride and the like.
  • oxime ether can be performed by treatment of a compound (IV) with alkoxyhydroxylamine acid addition salt such as O-methylhydroxylamine hydrochloride, 0- ethylhydroxylamine hydrochloride in the presence of an acid acceptor such as pyridine, 2, 6-lutidine, 2, 4, 6-collidine, triethylamine or N,N-diisopropylethylamine.
  • alkoxyhydroxylamine acid addition salt such as O-methylhydroxylamine hydrochloride, 0- ethylhydroxylamine hydrochloride in the presence of an acid acceptor such as pyridine, 2, 6-lutidine, 2, 4, 6-collidine, triethylamine or N,N-diisopropylethylamine.
  • This reaction proceeds in a solvent such as chloroform, dichloromethane, pyridine, ethanol, methanol and the like, and at a temperature between 20 and 150°C, preferably between 50 and 120°C.
  • a solvent such as chloroform, dichloromethane, pyridine, ethanol, methanol and the like, and at a temperature between 20 and 150°C, preferably between 50 and 120°C.
  • the sulfide group of compound (V) can be oxidized with an oxidizing agent such as oxone® or m-chloroperbenzoic acid.
  • This reaction proceeds in aqueous alcohol, and at a temperature between 0 and 60°C, preferably between 0 and 25°C.
  • O-Alkylation of a compound represented by the formula (III) [in which R 2 is a hydrogen or lower-alkyl, R ⁇ and X are the same as defined above] can be performed by treatment with alkyl halide such as methyl iodide, ethyl iodide, propyl iodide and the like in the presence of a base such as sodium hydride, potassium hydride, lithium hydride and the like.
  • alkyl halide such as methyl iodide, ethyl iodide, propyl iodide and the like
  • a base such as sodium hydride, potassium hydride, lithium hydride and the like.
  • This reaction proceeds in a solvent such as N,N- dimethylformamide and at a temperature between 0 and 60°C, preferably between 0 and 25°C.
  • the manufacture of the pharmaceutically acceptable acid addition salts of the compound represented by the general formula (I) can be carried out by treatment of a free base of the compound represented by the general formula (I) with an acid in a per se conventional procedure for salt formation.
  • therapeutically acceptable acids useful in the above process are inorganic acids (e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid) and organic acids (e.g. oxalic acid, acetic acid, formic acid, trifluoroacetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid) .
  • the starting compounds of formulas II, III, IV and V are novel compounds, and can be prepared in accordance with the following flow sheets 1, 2, 3 and 4:
  • trans-carveol (2) was prepared by the method described in Tetrahedron 47_, (20/21) , 3485 (1991) .
  • the compound (2) was converted to the cyclic acetal (4) by a method similar to that described in Synthetic Commun . , 2J. (9), 1221 (1992) for the synthesis of the diastereomer of 4 from cis-carveol.
  • the compounds provided according to the present invention exhibits a broad antifungal activity against various fungi including Aspergillus fumigatus and can be used as agents for treatment and prophylaxis of fungal infectious diseases.
  • the in vi tro antifungal activities and acute toxicity of the compounds of the present invention are shown as follows:
  • the in vi tro antifungal activities of the representative compounds of the present invention were evaluated by determining the 80 % inhibitory concentration (IC80), which was calculated as the lowest concentration of the compounds of the present invention to inhibit the growth of fungus to 20 % turbidity compared with the drug-free control.
  • IC80 80 % inhibitory concentration
  • the IC80 values were determined by a broth micro-dilution procedure based on a standard procedure with some minor modifications.
  • the standard procedure, used for determining the broth dilution antifungal susceptibility for yeasts, is described in Document 27-P, National Committee for Clinical Laboratory Standards, Villanova, Pa., 1992.
  • Yeast Nitrogen Base (YNB; Difco Lab.) supplemented with 1 % glucose and 0.25% K2HPO4 was used as testing medium for yeast. It was solidified with 0.2 % low melting point agarose and was used for filamentous fungi. Inoculum size was 1 x 10 ⁇ cells /ml, and incubation was performed for 2 days at 27 °C.
  • the IC80 values ( ⁇ g/ml) are shown in Table 1.
  • the reference compounds are fluconazole (FCZ) and the compound of Example 81 in EP- 0524439A1.
  • the acute toxicity (LD50) of the representative compounds (Examples 14, 17 and 19) of the present invention was examined by oral administration in mice.
  • the respective LD50 values of the compounds obtained in the Examples as mentioned below are more than 500 mg/kg.
  • the compounds of the formula (I) and pharmaceutically acceptable salts thereof are very active antimycotic agents. They are active against a variety of fungal species including Candida albicans, Cryptotoccus neoformans, Aspergillus fumiga ⁇ tus, Trichophyton spp., Microsporum spp. , Exophiala spp., -3-last ⁇ yces dermati tidis , and Histoplasma capsulatum.
  • the compounds of the present invention are useful for topical and systemic treatment of mycoses in animals as well as in human.
  • they are useful in treating topical and mucosal fungal infections caused by, among other species, Candida, Trichophyton, or Microsporum.
  • They may also be used in the treatment of systemic fungal infections caused by, for example, Candida, Cryptococcus, Aspergillus, Paracoccidiodes , Sporotrix, Exophiala, Blastomyces, or Histoplasma .
  • the antifungals (I) or salt forms thereof can be administered alone, but will generally be administered in pharmaceutical admixture formulated as appropriate to the particular use and purpose desired, by mixing with an excipient, binding agent, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and/or ointment base.
  • the admixture can be used for oral, injectable, rectal or topical administration.
  • composition for oral administration may be granules, tablets, sugar coated tablets, capsules, pills, suspensions or emulsions.
  • parenteral injection for example, intravenous, intramuscular or subcutaneous injection, the antifungal may be used in the form of a sterile aqueous solution which may contain other substances, for example, salts or glucose to make the solution isotonic.
  • the antifungal can also be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • the daily dosage level of the antifungal compounds of the formula (I) is from 0.1 to 50 mg/kg (in divided doses) when administered by either the oral or parenteral route.
  • tablets or capsules can contain from 5.mg to 0.5 g of active compound for administration singly or two or more at a time as appropriate.
  • the actual dosage can be determined by the physician and it may be varied upon the age, weight and response of the particular patient.
  • the compounds of the formula (I) and their salts have activity against a variety of plant pathogenic fungi, including for example Pyricularia oryzae, Pythium aphanider a turn, Al ternaria spp., and Paecilomyces variotii .
  • compositions can be applied for agricultural and horticul ⁇ tural purposes preferably in the form of a composition formu ⁇ lated as appropriate to the particular use and purpose desired, for example dusting powders, or granules, seed dressings, aqueous solutions, dispersions or emulsions, dips, sprays or aerosols.
  • Such compositions may contain such conventional carriers, diluents or adjuvants as are known and acceptable in agriculture and horticulture.
  • Other compounds having herbicidal or insecticidal, or additional antifungal can be incorporated in the compositions.
  • the compounds and compositions can be applied in a number of ways, for example they can be applied directly to the plant foliage, stems, branches, seeds or roots or to the soil or other growing medium, and they may be used not only to eradicate disease, but also prophylactically to protect the plants or seeds from attack.
  • a solution of the above ketone in 2200 ml of dioxane was diluted with 680 ml of water.
  • the stirring was started and the mixture was cooled with ice bath. When the internal temperature has fallen to 8 °C, the cold hypobromite solution was added in a steady stream. The temperature of the reaction mixture was maintained below 10 °C throughout the reaction.
  • the mixture was stirred for 1 hr, and then the excess sodium hypobromite was destroyed by the addition of a solution of sodium sulfite in water.
  • the mixture was acidified by the addition of cone, hydrochloric acid.
  • the pH of the mixture was adjusted to pH 7 with 0.1 N hydrochloric acid.
  • the mixture was extracted with diethyl ether, and the combined organic laye'rs were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • N-Chlorosuccinimide (22.6 mg, 0.17 mmol) was suspended in dry toluene (0.5 ml) , and dimethyl sulfide (0.05 ml, 0.68 mmol) was added to this suspension at -30 °C under nitrogen atmosphere.
  • reaction mixture was extracted with dichloromethane.
  • the organic layer was washed with brine, and dried over magnesium sulfate.
  • the organic solvent was removed, and the residual colorless oil was purified by silica gel chromatography (CHCl 3 / 2-propanol / 25 % aq.
  • N-Chlorosuccinimide (22.6 mg, 0.17 mmol) was suspended in dry toluene (0,5 ml) , and dimethyl sulfide (0.05 ml, 0.68 mmol) was added to this suspension at -30 °C under nitrogen atmosphere.
  • Example 6-14 The following compounds in Example 6-14 were obtained according to a manner analogous to that of Example 4 and 5.
  • Example 16 and 17 were obtained according to a manner analogous to that of Example 15.
  • reaction was quenched by adding water and the reaction mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed and the residual colorless oil was purified by silica gel chromatography (ethyl acetate) .
  • Hard gelatin capsules each containing the following ingredients were manufactured in a conventional manner:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des composés de la formule (I) dans laquelle X représente -O- ou -CH2-; R1 représente alkyle inférieur ou alcoxy inférieur pouvant être substitués par 1 à 4 atomes de fluor. R2 représente un atome d'hydrogène ou alkyle inférieur; R3 représente méthyle ou -(CH¿2?)2R?4 où R4¿ représente hydroxy, amino, mono ou alkylamino inférieur disubstitué, alcoxy inférieur, alkylthio inférieur, alkylsulfonyl inférieur, un noyau hétérocyclique à cinq ou six chaînons contenant un ou plusieurs atomes d'azote qui peuvent également contenir un atome d'oxygène ou de soufre, ou bien -(S ou N)-Het où Het signifie hétéroaryle); l'invention se rapporte également aux sels pharmaceutiquement acceptables de ces composés, à leurs hydrates ou solvates, ou à leurs sels qui se sont avérés être utiles dans le traitement ou la prophylaxie des infections fongiques, notamment les infections dues à Aspergillus.
PCT/EP1996/002102 1995-05-26 1996-05-17 Derives d'oxime de cyclohexanone WO1996037479A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP95108065 1995-05-26
EP95108065.4 1995-05-26

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WO1996037479A1 true WO1996037479A1 (fr) 1996-11-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077599A1 (fr) 2006-12-22 2008-07-03 Recordati Ireland Limited Thérapie combinée de troubles du tractus urinaire inférieur à l'aide de ligands de l'α2δ et d'ains

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4218461A (en) * 1979-08-15 1980-08-19 E. R. Squibb & Sons, Inc. 2,3-Dihydro-2-[(1H-imidazol-1-yl)-methylene]-1H-inden-1-ones
EP0152031A2 (fr) * 1984-02-03 1985-08-21 Shionogi & Co., Ltd. Dérivés azolyl cycloalkanols et fongicides agricoles
EP0272895A1 (fr) * 1986-12-22 1988-06-29 Kureha Kagaku Kogyo Kabushiki Kaisha Dérivés de l'azole, procédé pour leur préparation et fongicides pour l'agriculture/horticulture contenant ces dérivés comme ingrédient actif
EP0524439A1 (fr) * 1991-07-24 1993-01-27 F.Hoffmann-La Roche & Co. Aktiengesellschaft Dérivés du cyclohexane et du tétrahydropyranne et compositions antifongiques contenant ces dérivés

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4218461A (en) * 1979-08-15 1980-08-19 E. R. Squibb & Sons, Inc. 2,3-Dihydro-2-[(1H-imidazol-1-yl)-methylene]-1H-inden-1-ones
EP0152031A2 (fr) * 1984-02-03 1985-08-21 Shionogi & Co., Ltd. Dérivés azolyl cycloalkanols et fongicides agricoles
EP0272895A1 (fr) * 1986-12-22 1988-06-29 Kureha Kagaku Kogyo Kabushiki Kaisha Dérivés de l'azole, procédé pour leur préparation et fongicides pour l'agriculture/horticulture contenant ces dérivés comme ingrédient actif
EP0524439A1 (fr) * 1991-07-24 1993-01-27 F.Hoffmann-La Roche & Co. Aktiengesellschaft Dérivés du cyclohexane et du tétrahydropyranne et compositions antifongiques contenant ces dérivés

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077599A1 (fr) 2006-12-22 2008-07-03 Recordati Ireland Limited Thérapie combinée de troubles du tractus urinaire inférieur à l'aide de ligands de l'α2δ et d'ains

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