Triazole derivatives having antifungal activity

专利摘要:
The compounds of formula 1a and their pharmaceutically acceptable salts and ester derivatives have excellent antifungal activity: [Wherein Ar is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a trifluoromethyl group].
公开号:KR20010067169A
申请号:KR1020000053581
申请日:2000-09-08
公开日:2001-07-12
发明作者:고노스도시유끼；오이다사다오；모리마꼬또；우찌다다꾸야；오야사또시；나까가와아끼히꼬
申请人:가와무라 요시부미；상꾜 가부시키가이샤；
IPC主号:

专利说明:

Triazole derivatives having antifungal activity {TRIAZOLE DERIVATIVES HAVING ANTIFUNGAL ACTIVITY}
[3] The present invention relates to triazole derivatives having excellent activity against a wide range of fungi, certain such derivatives in crystalline form, pharmaceutical compositions containing derivatives, the use of such derivatives in the treatment and prevention of fungal infections, and the preparation of the derivatives. It relates to useful intermediates.
[4] Antifungal triazole derivatives having the general formula are disclosed in Japanese Patent Laid-Open Nos. 8-333350 and EP-A-0841327:
[5]
[6] [Wherein, R ^a represents a hydrogen atom or an alkyl group, R ^b represents an alkyl group, Ar ¹ and Ar ² may each represent an optionally substituted phenyl group, q and r may each represent 1, and R ^c , R ^d , R ^e and R ^f may each represent a hydrogen atom. Similar compounds in which sulfur atoms are substituted with methylene groups are disclosed in Japanese Patent Laid-Open Nos. 11-80135 and WO-A-99 / 02524.
[7] These prior art compounds show good antifungal activity, but there is a further need for compounds with improved antifungal activity, stability, pharmacokinetic properties and stability.
[8] Therefore, it is an object of the present invention to provide a series of novel compounds having antifungal activity.
[9] Other objects and advantages of the invention will be apparent from the following detailed description of the invention.
[10] Compounds of the present invention are compounds of Formula 1a, and pharmaceutically acceptable salts and ester derivatives thereof;
[11] [Formula 1a]
[12]
[13] [Wherein Ar is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a trifluoromethyl group].
[14] The invention also relates to the compound in crystalline form (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene -1-yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl ) -2-butanol [Formula 1c]:
[15]
[16] The present invention also provides a pharmaceutical composition containing an effective amount of a pharmacologically active compound, and also a pharmaceutically acceptable diluent or carrier thereof, wherein the pharmacologically active compound is a compound of Formula 1a, or Pharmaceutically acceptable salt or ester derivatives thereof.
[17] The present invention is also directed to a fungal infection of a compound of Formula 1a or a pharmaceutically acceptable salt or ester derivative thereof and a compound of Formula 1a or a pharmaceutically acceptable salt or ester derivative thereof for use as a medicament. Provided are uses for the manufacture of a medicament for prophylaxis or treatment.
[1] FIG. 1 shows (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) by powder method using copper K-wire = 1.54. ) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4 The X-ray diffraction pattern of the first crystalline form of -triazol-1-yl) -2-butanol is shown. The vertical axis of the powder X-ray diffraction pattern represents the diffraction intensity in units of coefficients / sec (cps), and the horizontal axis represents the diffraction angle as the value 2θ.
[2] FIG. 2 shows (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) by powder method with copper K-wire = 1.54. ) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4 The X-ray diffraction pattern of the second crystalline form of -triazol-1-yl) -2-butanol is shown. The vertical axis of the powder X-ray diffraction pattern represents the diffraction intensity in units of coefficients / sec (cps), and the horizontal axis represents the diffraction angle as the value 2θ.
[18] Examples of the halogen atom which is an optional substituent on the Ar group include fluorine, chlorine and bromine atoms. Fluorine and chlorine atoms are preferred, and fluorine atoms are most preferred.
[19] Examples of the substituent Ar include phenyl, dichlorophenyl, difluorophenyl, dibromophenyl, chlorophenyl, fluorophenyl, bromophenyl, trifluorophenyl, trichlorophenyl, tribromophenyl, (trifluoro Methyl) phenyl, bis (trifluoromethyl) phenyl, tris (trifluoromethyl) phenyl, fluoro (trifluoromethyl) phenyl and chloro (trifluoromethyl) phenyl groups. Preferably, the substituent Ar is a phenyl group substituted with one or two substituents selected from fluorine atom, chlorine atom and trifluoromethyl group. More preferably, the Ar group is a phenyl group substituted with one or two fluorine atom (s). Even more preferably, the substituent Ar is 2-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl or 2,5-difluorophenyl group, in particular 2- Fluorophenyl or 2,4-difluorophenyl group. Most preferably, the substituent Ar is a 2,4-difluorophenyl group.
[20] The compounds of formula 1a of the present invention may exist in the form of stereoisomers or geometric isomers. In the compound of Formula 1a there are two asymmetric carbons, where each carbon atom may take the R or S-form. Preferably, both are R forms. This optical isomer can be separated by conventional optical analysis. Four possible optical isomers for all given compounds of Formula 1a can be prepared by asymmetric synthesis. This optical isomer can also be separated by conventional techniques such as fractional crystallization and chromatography.
[21] The compound of formula 1a has a 2,5-disubstituted-3,5-dioxane ring. As a result, it may exist as cis or trans isomers for the 2- and 5-positions. Trans isomers are preferred. Trans isomers are preferred. These cis and trans isomers can be separated by conventional techniques such as fractional crystallization and chromatography.
[22] Compound of Formula 1a has two double bonds. As a result, it exists as geometric isomers where each double bond is an E or Z-form. Preferred geometric isomers are those in which both double bonds are E-forms. This geometric isomer can be separated by conventional techniques such as fractional crystallization and chromatography.
[23] The present invention includes mixtures of racemic mixtures and the like, each of which isomers and any two or more of them in any proportion.
[24] Of the possible isomers of the compound of formula 1a, the isomers of formula 1b are most preferred:
[25]
[26] The present invention includes pharmaceutically acceptable ester derivatives of compounds of Formula 1a. These pharmaceutically acceptable ester derivatives are characterized in that, when the derivative is administered to a living animal body, the functional group (hydroxy group) of the compound of formula 1a is protected by a group that is separable by chemical or biological processes (eg hydrolysis) It is the so-called prodrug which will form the parent compound of 1a or its salt. Whether the derivative of the compound of formula 1a is pharmaceutically acceptable can be readily determined. The ester derivative under study is administered orally or intravenously to test animals such as mice or rats, and then the body fluids of the test animals are studied. When the parent compound of formula 1a or a salt thereof is detected in the body fluid of a test animal, the ester derivative under study is found to be a pharmaceutically acceptable ester derivative of the compound of formula 1a.
[27] The group of the compound of formula 1a, which is modified to allow obtaining a pharmaceutically acceptable ester derivative, is a hydroxyl group. Thus, pharmaceutically acceptable ester derivatives of Formula 1a are obtained with ester derivatives which allow the hydroxyl group, which can be separated from the body of a living animal, to be protected so that the parent compound or salt thereof can be obtained. That's what happens.
[28] An example of a pharmaceutically acceptable ester derivative of formula (1a) is that the hydroxy group is protected by an acyl group. Examples of the acyl group include aliphatic acyl groups, aromatic acyl groups, alkoxycarbonyl groups, aralkyloxycarbonyl groups, aminoacyl groups, and phosphoric acid groups.
[29] Aliphatic acyl groups have 1 to 20 carbon atoms and may include 1 to 3 double or triple bonds. Examples of such aliphatic acyl groups include an alkylcarbonyl group having 1 to 20 carbon atoms, an alkenylcarbonyl group having 3 to 20 carbon atoms, and an alkynylcarbonyl group having 3 to 20 carbon atoms, and the group includes a hydroxy group, an alkoxy group, a halogen atom, a phosphoric acid group and Optionally substituted with one or more substituents, such as carboxy groups.
[30] Examples of the alkylcarbonyl group having 1 to 20 carbon atoms include formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, and 3-methyl. Nonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1 -Methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl and eicosano Diary is included.
[31] Examples of the alkenylcarbonyl group having 3 to 20 carbon atoms include acryloyl, methacryloyl, crotonoyl, isocrotonoyl and (E) -2-methyl-2-butenoyl group.
[32] Examples of the alkynylcarbonyl group having 3 to 20 carbon atoms include propionyl group.
[33] Aromatic acyl groups are arylcarbonyl groups having 7 to 11 carbon atoms such as benzoyl, α-naphthoyl and β-naphthoyl groups. The aryl ring of this aromatic acyl group may contain an alkyl group having 1 to 4 carbon atoms, an aromatic acyl group (which may optionally contain one or more substituents such as an alkyl group having 1 to 4 carbon atoms), a halogen atom, an alkoxy group having 1 to 4 carbon atoms, and a hydroxy group One or more such as a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbon atoms having an alkoxy terminal, a hydroxyalkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a phosphoric acid group, or an alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group It may optionally contain a substituent.
[34] The alkoxycarbonyl group contains a carbonyl group substituted with an alkoxy group having 1 to 20 carbon atoms, and examples thereof include groups such as methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl and tert-butoxycarbonyl group. The alkoxy terminal of the alkoxycarbonyl group is an alkyl group having 1 to 4 carbon atoms, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a phosphoric acid group, a carboxy group, an alkoxycarbonyl group having 1 to 4 carbon atoms, or a hydroxy having 1 to 4 carbon atoms. One or more substituents such as an alkyl group, an alkyl group having 1 to 4 carbon atoms substituted with a phosphate group, or an alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group may optionally be contained.
[35] The aralkyloxycarbonyl group contains a carbonyl group substituted with an aralkyloxy group having 8 to 20 carbon atoms, and examples thereof include a benzoyloxycarbonyl group. The aryl ring of the aralkyloxycarbonyl group is an alkyl group having 1 to 4 carbon atoms, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a phosphoric acid group, a carboxy group, an alkoxycarbonyl group having 1 to 4 carbon atoms, or an alkoxycarbonyl group having 1 to 4 carbon atoms. It may optionally contain one or more substituents such as a hydroxyalkyl group, an alkyl group having 1 to 4 carbon atoms substituted with a phosphate group, or an alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group.
[36] Aminoacyl groups are amino acids such as glycyl, alanyl, louisyl, phenylalanyl, glutamyl and asparaginyl groups, or aminoalkanoyl groups having 1 to 10 carbon atoms, such as β-alanyl, aminobutyryl and aminooctanoyl groups Qi.
[37] The phosphate group includes a phosphate group; Monoalkylphosphoric acid groups having 1 to 20 carbon atoms in the alkyl terminal, such as methylphosphate, ethyl phosphate, propyl phosphate, butyl phosphate, decyl phosphate and octadecyl phosphate groups; And dialkylphosphonic acid groups having the same or different alkyl terminals and having 1 to 20 carbon atoms, such as dimethyl phosphate, diethyl phosphate, dipropyl phosphate, dibutyl phosphate, didecyl phosphate and dioctadecyl phosphate groups.
[38] The compound of formula (1a), pharmaceutically acceptable salt of, or pharmaceutically acceptable ester derivative thereof has the same low toxicity as that of the compound of formula (1a), or pharmaceutically acceptable derivative thereof, or Salts that are not significantly more toxic and whose pharmacological activity is not the same or significantly lower.
[39] The compound of formula 1a and its pharmaceutically acceptable ester derivatives have a basic triazole group and may optionally contain an aminoacyl group, thereby forming an acid addition salt. Examples of such salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, sulfate and nitrate; Carboxylates such as acetates, fumarates, maleates, oxalates, malonates, succinates, citrate and maleates; Sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate and toluenesulfonate; And amino acid salts such as glutamate and aspartate. Inorganic acid salts and carboxylates are preferred, with hydrochloride, nitrate, fumarate, maleate and oxalate being most preferred.
[40] Pharmaceutically acceptable ester derivatives of Formula 1a may contain a phosphoric acid group or a carboxyl group, thus forming salts with bases. Examples of such salts include alkali metal salts such as sodium, potassium and lithium salts; Alkaline earth metal salts such as calcium and magnesium salts; Other inorganic salts such as ammonium salts; Amine salts such as t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl esters, ethylenediamine, methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N, N'- Dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, benzylphenethylamine, piperazine, tetramethylammonium and tris (hydroxymethyl) aminomethane salts.
[41] When the compound of Formula 1a, or a pharmaceutically acceptable ester derivative or salt thereof, is left open in the atmosphere, water may be absorbed to form a hydrate. In addition, a compound of formula (1a), or a pharmaceutically acceptable ester derivative or salt thereof, may absorb the solvent to obtain a solvate. The present invention also encompasses such hydrates and solvates.
[42] The compound of formula 1c in the crystalline form of the present invention is a solid having a regular arrangement of atoms (atomic groups) of a three-dimensional structure, the arrangement of which is repeated. This crystal is different from an amorphous solid that does not have a regular array of atoms in a three-dimensional structure.
[43] Different crystalline forms of formula 1c of the present invention may be obtained depending on the crystallization conditions used. The different crystalline forms have different three dimensional arrangements of atoms and different physicochemical properties.
[44] The present invention includes its different crystalline forms and mixtures of two or more of the crystalline forms.
[45] One example of a compound of formula 1c in crystalline form is 3.14, 3.39, 3.71, 3.75, 4.21, 4.88, 5.28, 5.42, as determined by X-ray diffraction by powder method using copper K-ray = 1.54 Hz It is a crystalline form with major peaks at lattice distances of 5.89, 5.95, 6.79, 6.86, 8.03 and 8.41 Hz. A second example of a compound of formula 1c in crystalline form is 3.62, 3.96, 4.54, 4.59, 4.79, 4.91, 5.32, 5.48, as determined by X-ray diffraction by powder method with copper K-ray = 1.54 Hz , 6.18, 7.99 and 15.93 mm 3 with crystal major peaks at lattice distances. The main peaks are those with diffraction intensities above 2000 coefficients (cps) per second.
[46] Preferred compounds of formula 1a, and pharmaceutically acceptable salts and ester derivatives thereof, include the following:
[47] (A) A compound of formula (1a) or a pharmaceutically acceptable salt or ester derivative thereof, wherein Ar represents a 2,4-difluorophenyl group or a 2-fluorophenyl group.
[48] (B) A compound of formula (1a) or a pharmaceutically acceptable salt or ester derivative thereof, wherein Ar is a 2,4-difluorophenyl group.
[49] (C) a compound of formula (Ib) or a pharmaceutically acceptable salt or ester derivative thereof:
[50] [Formula 1b]
[51]
[52] (Wherein Ar is a phenyl group or a phenyl group substituted with 1 to 3 substituents selected from halogen atoms and trifluoromethyl groups).
[53] (D) (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl]- 1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol.
[54] More preferred are compounds of formula la and pharmaceutically acceptable salts or ester derivatives thereof:
[55] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2-fluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol,
[56] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (4-fluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol,
[57] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,3-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol,
[58] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol,
[59] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol,
[60] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (4-chlorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol,
[61] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-dichlorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol, and
[62] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (4-trifluoromethylphenyl] -1- (1H-1,2,4-triazol-1-yl) -2-butanol.
[63] However, even more preferred are compounds of formula la and pharmaceutically acceptable salts and ester derivatives thereof:
[64] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2-fluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol,
[65] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (4-fluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol,
[66] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,3-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol,
[67] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol, and
[68] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol.
[69] Most preferred compounds of formula 1a are (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-1 -Yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl)- 2-butanol.
[70] Compounds of Formula 1a may be prepared by Method A:
[71] [Method A]
[72]
[73] In Scheme 1, the substituent Ar is as previously defined.
[74] Method A comprises the reaction of a compound of formula 5a with a compound of formula 2a in the presence of an acetalization reagent in an inert solvent, wherein the water produced in the reaction is removed from the reaction mixture during the course of the reaction.
[75] In method A, salts of formula 5a or compounds of formula 5b can be used in place of compounds of formula 5a as starting materials:
[76]
[77] (Wherein Ar is as defined above and R ⁴ is an alkyl group having 1 to 6 carbon atoms, an aryl group or indenyl group having 6 to 10 carbon atoms).
[78] In the definition of substituent R ⁴ , an alkyl group having 1 to 6 carbon atoms is a straight or branched alkyl group having 1 to 6 carbon atoms, examples of which are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl and hexyl groups are included. Preference is given to linear or branched alkyl groups having 1 to 4 carbon atoms. In the definition of substituent R ⁴ , an aryl group having 6 to 10 carbon atoms is an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as a phenyl or naphthyl group, of which a phenyl group is preferred. Preferred are compounds of formula 5b, wherein R ⁴ is a phenyl group.
[79] The compound of formula 5a can be prepared according to the methods described in Japanese Patent Laid-Open No. 8-333350, or variations thereof. The compound of the formula (5b) can be obtained as an intermediate in the process for producing the compound of the formula (5a) described in Japanese Patent Laid-Open No. 8-333350. Salts of compounds of formula 5a can be obtained by removing an acetal protecting group from a compound of formula 5b with an acid.
[80] In method A, the acetal derivative of formula 2a can be used as an alternative starting material for the compound of formula 2a. Compounds of formula 2a can be prepared by the following method B, while acetal derivatives of the compounds of formula 2a can be obtained by using acetal derivatives of the compound of formula 4 as starting material of method B.
[81] In method A, the amount of the compound of formula 2a or an acetal derivative thereof is used in 0.5 to 2 molar equivalents, preferably 0.9 to 1.2 molar equivalents, of the compound of formula 5a.
[82] In Method A, the solvent used has no side effects on the reaction and there is no particular limitation as long as it dissolves the starting material at least to some extent. Suitable solvents include aprotic solvents such as halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether or tetrahydrofuran; Or mixtures thereof. Halogenated hydrocarbons and ethers are preferred, with dichloromethane or tetrahydrofuran being particularly preferred.
[83] In Method A, examples of suitable acetalization reagents include inorganic acids such as hydrogen chloride, sulfuric acid or nitric acid; Lewis acids such as boron trifluoride, zinc chloride, magnesium bromide, titanium trichloride or aluminum chloride; Sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid or trifluoromethanesulfonic acid; Carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid or citric acid; And silylating agents such as chlorotrimethylsilane or trimethylsilyl trifluoromethanesulfonate. Preferred acetalization reagents are sulfonic acid derivatives, with p-toluenesulfonic acid being particularly preferred.
[84] In method A, the amount of acetalization reagent is used in 0.5 to 3 molar equivalents of the compound of formula 5a, preferably 1.0 to 1.4 molar equivalents.
[85] The water produced during the reaction process of Method A can be removed by azeotropic distillation of the reaction solvent, evaporation under reduced pressure, or by the use of a dehydrating agent such as molecular sieve.
[86] The reaction temperature used for the reaction of Method A depends on various factors such as the solvent used, starting material and acetalization reagent. However, it is mainly the boiling point of 0 degreeC-the solvent used, Preferably it is 5-40 degreeC.
[87] The reaction time for the reaction of Method A depends on many factors such as starting materials used, acetalization reagents, solvents and reaction temperatures. However, it is mainly 0.5 to 24 hours, preferably 1 to 5 hours.
[88] After completion of the reaction of Method A, the reaction mixture is neutralized with an aqueous sodium bicarbonate solution or the like, and then the desired compound is separated by conventional separation techniques. For example, the reaction mixture or the residue of the reaction mixture obtained by evaporation from the reaction mixture is partitioned between the organic solvent and water, the organic layer is washed with water and then the solvent is distilled off to give the desired product of formula 1a. To obtain.
[89] The product thus obtained can be further purified, if necessary, using conventional techniques such as recrystallization, reprecipitation or chromatography.
[90] Pharmaceutically acceptable ester derivatives of compounds of Formula 1a may be prepared by conventional methods known in the art (see, eg, “Protective Groups in Organic Synthesis”, Theodora W. Greene and Peter GM Wuts, Second Edition, 1991, John Wiley & Sons, Inc.). Among the above pharmaceutically acceptable ester derivatives, acyl derivatives are prepared by acylation of hydroxy groups according to processes known in the art.
[91] The compound of formula (1a) or ester derivatives thereof obtained thereby can be converted to the salts above by adding a pharmaceutically acceptable acid or base to a solution of the compound of formula (1a) or ester derivatives thereof.
[92] The solvent used for the preparation of the compound of formula 1a or a pharmaceutically acceptable ester derivative thereof has no side effects in the reaction and there is no particular limitation as long as it dissolves the starting material at least to some extent. Examples of suitable solvents include aromatic hydrocarbons such as benzene or toluene; Halogenated hydrocarbons such as dichloromethane or chloroform; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Esters such as ethyl acetate; Alcohols such as methanol or ethanol; Ketones such as acetone; Nitriles such as acetonitrile; Hydrocarbons such as hexane or cyclohexane; Or mixtures thereof.
[93] Acids for the preparation of pharmaceutically acceptable salts include pharmaceutically acceptable acids such as inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid or nitric acid; Carboxylic acids such as acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid or malic acid; Sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid; And amino acid derivatives such as glutamic acid or aspartic acid. Inorganic acids and carboxylic acids are preferred, with hydrochloric acid, nitric acid, fumaric acid, malic acid or oxalic acid being particularly preferred.
[94] Bases for the preparation of pharmaceutically acceptable salts include pharmaceutically acceptable bases such as alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or magnesium hydroxide; Alkali metal carbonates or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate or magnesium carbonate; Alkali metal hydrogencarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Other inorganic bases such as ammonia; And amine salts such as t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl esters, ethylenediamine, methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N, N ' Dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, benzylphenethylamine, piperazine, tetramethylammonium and tris (hydroxymethyl) aminomethane.
[95] The desired salt of the compound of formula 1a, or a pharmaceutically acceptable ester derivative thereof, is mainly in crystal or powder form from a reaction solution of the compound of formula 1a or a pharmaceutically acceptable ester derivative thereof with an acid or base. Precipitates. The desired salt can also be obtained as a precipitate by adding a solvent that slightly dissolves the salt in the salt solution, or by removing the solvent from a solution containing the desired salt.
[96] Compounds of formula 2a or acetal derivatives thereof are particularly suitable for the synthesis of compounds of formula 1a of the invention and thus form part of the invention. Particular preference is given to compounds of the formula (2b) or acetal derivatives thereof.
[97]
[98] The compound or the acetal derivative of the compound of formula 2b in the formula (2a) is the aldehyde group has the formula CH (OR ¹⁾ a compound of the formula 2a compound or a Formula 2b of the (OR ²⁾ (wherein, R ¹ and R ² are the same or Different from each other and independently selected from the group consisting of a hydrogen atom and an alkyl group having 1 to 4 carbon atoms, or R ¹ and R ² both form an alkylene group having 1 to 4 carbon atoms.
[99] In the definition of the substituents R ¹ and R ² , the alkyl group having 1 to 4 carbon atoms includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups, of which methyl groups are preferred.
[100] In the definition of the substituents R ¹ and R ^2, the alkylene group having 1 to 4 carbon atoms includes methylene, methylene methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene and 3-methyl A trimethylene group is included and an ethylene group is preferable among these.
[101] Preferred acetal derivatives of the compounds of formulas 2a and 2b are those having the acetal group CH (OR ¹ ) (OR ² ), wherein R ¹ and R ² are methyl groups.
[102] Since the compound of formula 2a and its acetal derivatives have two double bonds, they can each exist as geometric isomers in which the double bond is an E or Z-form. The present invention encompasses both individual geometric isomers and mixtures of two or more thereof. Of these isomers, compounds of formula (2b) in which both double bonds are E-forms and acetal derivatives thereof are preferred.
[103] When the compound of formula 2a and its acetal derivative are left open to the atmosphere, water may be absorbed to form a hydrate. The solvate may also be obtained by absorbing the compound of formula 2a or an acetal solvent thereof. The present invention also includes the above hydrates and solvates.
[104] Starting materials of formula (2a) may be prepared by Method B described in the following scheme:
[105] [Method B]
[106]
[107] In the above scheme, X is a halogen atom (preferably chlorine or bromine atom), and R ³ is an alkyl group having 1 to 6 carbon atoms which may be optionally substituted with one or more fluorine atoms.
[108] Method B can be prepared according to the method disclosed in 4- (halogenomethyl) -3-fluorobenzonitrile compound of formula 6 [for example, in "J. Med. Chem., 40, 2064 (1997)". Yes] and the compound of formula (7) to obtain a compound of formula (3), and then reacting the compound of formula (3) with a compound of formula (4) to obtain the desired compound of formula (2a).
[109] In the definition of substituent R ³ , an alkyl group having 1 to 6 carbon atoms optionally substituted with one or more fluorine atoms is for example methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 1-fluoroethyl, 2 -Fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, isopropyl, 3-fluoropropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4 -Fluorobutyl, pentyl or hexyl group. Of these, alkyl groups having 1 to 4 carbon atoms optionally substituted with 1 to 3 fluorine atoms such as methyl, ethyl, propyl, butyl or 2,2,2-trifluoroethyl groups are preferable, and unsubstituted with 1 to 4 carbon atoms. Alkyl groups are more preferred, and ethyl groups are most preferred.
[110] In step B1, the 4- (halogenomethyl) -3-fluorobenzonitrile compound of formula 6 is available, for example from J. Med. Can be prepared according to the method disclosed in Chem., 40, 2064 (1997), in the presence or absence of a solvent, to prepare a compound of formula 3.
[111] Examples of the compound of formula 4 include 4- (chloromethyl) -3-fluorobenzonitrile and 4- (bromomethyl) -3-fluorobenzonitrile, of which 4- (bromomethyl)- Preference is given to 3-fluorobenzonitrile.
[112] Examples of the compound of Formula 7 include trialkyl phosphites such as trimethyl phosphite, triethyl phosphite, tripropyl phosphite or tributyl phosphite, wherein each alkyl group is the same or different and is a primary alkyl group having 1 to 4 carbon atoms; And tris (fluoroalkyl) phosphites, such as tris (2,2,2-trifluoroethyl) phosphite, wherein each fluoroalkyl group is the same or different and is an alkyl group having 1 to 4 carbon atoms, predominantly substituted with one or more fluorine atoms. Included.
[113] The amount of the compound of formula 7 used is used in 1 to 5 molar equivalents of the compound of formula 6 used, and preferably 1 to 1.5 molar equivalents of the compound of formula 6.
[114] The solvent used in step B1 has no side effects in the reaction, and there is no particular limitation as long as it dissolves the starting material at least to some extent. Suitable solvents include aprotic solvents such as hydrocarbons such as hexane, cyclohexane, heptane, octane, nonane, decane or decalin; Aromatic hydrocarbons which may be optionally substituted with one or more alkyl groups or halogen atoms such as benzene, toluene, xylene, mesitylene, ethylbenzene or chlorobenzene; Halogenated hydrocarbons such as chloroform or dichloroethane; Esters such as ethyl acetate or butyl acetate; Ethers such as tetrahydrofuran, dimethoxyethane or dioxane; Nitriles such as acetonitrile; And amide derivatives such as dimethylformamide; Or mixtures thereof. Preferably, step B1 is carried out in the absence of solvent.
[115] The reaction temperature used in step B1 depends on various factors such as the starting material and the nature of the solvent when using the solvent, but is typically 80 to 170 ° C, preferably 85 to 150 ° C.
[116] The reaction time used in step B1 mainly depends on the reaction temperature and the solvent when using the solvent, but is mainly 0.5 to 24 hours, preferably 1 to 3 hours.
[117] After completion of the reaction of step B1, excess volatiles such as compounds of formula 7, reaction by-products and solvents are evaporated off to give the desired compound of formula 3, which can be used in the subsequent step B2 without further purification.
[118] The product of formula 3 can be purified, if necessary, using conventional techniques such as recrystallization, reprecipitation or chromatography.
[119] In step B2, the compound of formula 2a or an acetal derivative thereof is prepared by condensing the compound of formula 3 with a compound of formula 4 or an acetal derivative thereof in the presence of a base in a solvent and, if desired, removing the acetal protecting group Can be.
[120] Acetal derivatives of compounds of formula 4 are compounds wherein one of the two aldehyde groups of formula 4 is protected by a group of formula CH (OR ¹ ) (OR ² ), wherein R ¹ and R ² are as defined above . Preferred acetal derivatives of compounds of formula 4 include dimethyl acetals and ethylene acetal derivatives, of which dimethyl acetal derivatives of compounds of formula 4 are most preferred.
[121] Compounds of formula 4 or acetal derivatives thereof are described in Chem. Ber., 45 , 1748 (1912); Tetrahedron Lett., 38 , 1121 (1997); Justus Liebigs Ann. Chem., 638 , 187 (1960); And J. Chem. Soc., Perkin Trans, 1, 1907 (1991)] or by variations of the processes disclosed in such documents.
[122] The amount of the compound of formula 4 or an acetal derivative thereof used in step B2 is 0.5 to 1.5 molar equivalents, preferably 0.9 to 1.2 molar equivalents, of the amount of the compound of formula 3 commonly used.
[123] The solvent used in this condensation reaction has no side effect in the reaction, and there is no particular limitation as long as the starting material is dissolved at least to some extent. Suitable solvents include ethers such as tetrahydrofuran, dioxane or dimethoxyethane; Hydrocarbons such as hexane, cyclohexane, benzene or toluene; Sulfoxides such as dimethyl sulfoxide; Or mixtures thereof. Ether solvents are preferred, of which tetrahydrofuran is particularly preferred.
[124] The base used in step B2 is not particularly limited as long as the active moiety can be subtracted from the compound of formula (3). Suitable bases include organolithium compounds such as methyllithium, butyllithium or phenyllithium; Metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkoxides such as sodium methoxide or potassium tert-butoxide; And sulfoxides metalized with alkali metals such as dimesyl sodium. Of these, organolithium compounds are preferred, and butyllithium is particularly preferred.
[125] The amount of base used is 0.9 to 1.5 molar equivalents, preferably 1 to 1.1 molar equivalents, of the amount of the compound of formula (3).
[126] The condensation reaction temperature depends mainly on the base used. The temperature is mainly from -78 deg. C to ambient temperature, preferably -20 deg. C to 10 deg.
[127] The reaction time of step B2 mainly depends on the reaction temperature and the solvent used. The time is mainly 30 minutes to 24 hours, preferably 1 to 3 hours.
[128] When the target compound is a free aldehyde of the formula (2a) using an acetal protecting group, after completion of the condensation reaction, an acid is added thereto, and then the reaction mixture is stirred to remove the acetal protecting group, thereby obtaining a compound of the formula (2a).
[129] The acid used to remove the acetal protecting group does not affect any of the other substituents, and there is no particular limitation as long as it is commonly used in inorganic synthesis processes. Suitable examples of acids that can be used include inorganic acids such as hydrochloric acid, sulfuric acid or nitric acid; Sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, camphorsulfonic acid or trifluoromethanesulfonic acid; And carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid or citric acid. Of these, inorganic acids are preferred, and hydrochloric acid is particularly preferred.
[130] The amount of acid used in the deprotection reaction is not particularly limited. Preferably, the amount of acid used is such that the resulting pH of the reaction mixture is -1 to 3, preferably 0 to 1.
[131] The temperature used for the deprotection reaction is mainly -10 to 40 ° C, preferably 0 ° C to ambient temperature.
[132] The reaction time of the deprotection reaction mainly depends on the pH and the reaction temperature of the reaction mixture. The time is mainly 0.2 to 3 hours, preferably 0.5 to 1.5 hours.
[133] The reaction product of Formula 2a or an acetal derivative thereof can be separated by conventional techniques, such as by partitioning the reaction mixture between the organic solvent and water, washing the organic layer with water and then evaporating the solvent.
[134] The reaction product of formula 2a or the acetal derivative thereof obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
[135] Alternatively, the compound of formula (2a) may be prepared by the method described in Japanese Patent Laid-Open No. 8-333350 or a modification of the method.
[136] Compounds of formula (Ib), isomers of compounds of formula (I), can be prepared using compounds of formula (5c) and compounds of formula (2b) as starting materials:
[137]
[138] In this process, a mixture of cis and trans isomers for the substituents at the 2- and 5-positions of 1,3-dioxane is obtained. The trans isomers of Formula 1b can be separated from the mixture of cis and trans isomers by chromatography or recrystallization. When the water produced during the reaction process in method A is removed under reduced pressure, trans isomers are mainly obtained.
[139] The compound of formula 5c can be prepared according to the method described in Japanese Patent Laid-Open No. 8-333350 or a modified method of the method. The compound of formula 2b can be prepared by the method of method B, using fumaraldehyde mono-dimethyl acetal as starting material in step B2.
[140] Crystals of the compound of formula 1c or a salt thereof can be obtained from its supersaturated solution. The supersaturated solution can be prepared by conventional methods, such as through the concentration of a solution of the compound of formula 1c or a salt thereof, through the cooling of a solution of the compound of formula 1c or a salt thereof, or of the compound of formula 1c or a salt thereof, A solvent having a very low solubility in the solution of the compound of formula 1c or a salt thereof can be obtained by adding to a solution of the compound of formula 1c or a salt thereof which is easily dissolved. Crystals precipitate spontaneously in the reaction vessel, or this can be accelerated through the use of ultrasonic waves or by scratching inside the reaction vessel by adding crystalline seeds to the supersaturated solution of the compound of formula 1c or salts thereof.
[141] The product of formula 1c or crude reaction product containing the compound of formula 1c separated according to Method A can be crystallized.
[142] If a supersaturated solution of a compound of formula 1c or a salt thereof can be obtained by concentration of the solution, it can be carried out using a rotary evaporator, under heating, under reduced pressure or under atmospheric pressure.
[143] If a supersaturated solution of a compound of formula 1c or a salt thereof can be obtained by cooling of the solution, the temperature used for cooling the solution depends on the solvent used, but is usually in the range of 0 ° C. to ambient temperature. .
[144] A supersaturated solution of a compound of Formula 1c or a salt thereof is obtained by adding a solvent in which the compound of Formula 1c or a salt thereof is insoluble to a solution in which the compound of Formula 1c or a salt thereof is well dissolved. If possible, this may be done by first dissolving the compound of Formula 1c or a salt thereof in a solvent in which it is readily soluble, and then adding a solvent in which it may be very slightly soluble, and then, if necessary, By cooling to obtain crystals of the compound of formula 1c.
[145] Solvents in which the compound of Formula 1c can be readily dissolved include acetates such as ethyl acetate; Ketones such as acetone or 2-butanone; Primary alcohols such as methanol, ethanol, propanol or butanol; Ring ethers such as tetrahydrofuran; Amides such as dimethylformamide or dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Nitriles such as acetonitrile; And halogenated hydrocarbons such as dichloromethane or chloroform. Of these, ethyl acetate, acetone or ethanol is preferred.
[146] The solvent in which the compound of formula 1c is poorly soluble depends on the quality of the solvent in which the compound of formula 1c is easily dissolved. Suitable solvents include aliphatic hydrocarbons such as petrolatum ether, pentane, hexane or heptane; Acyclic ethers such as diethyl ether or diisopropyl ether; Aromatic hydrocarbons such as benzene or toluene; Secondary or tertiary alcohols such as 2-propanol or 2-methyl-2-propanol; And water. Of these, hexane, heptane, diisopropyl ether, 2-propanol or water is preferable.
[147] Two preferred crystalline forms of the compound of formula 1c of the present invention are preferably prepared by adding hexane to a solution of the compound of formula 1c in ethyl acetate or by adding the compound of formula 1c to a heated mixture of 2-propanol and ethyl acetate. It is preferably prepared by dissolving and then cooling the solution, if necessary.
[148] The compounds of formula 1a and their pharmaceutically acceptable salts and ester derivatives show good activity against many sedative fungi. Examples of sedative fungi include Candida species, Aspergillus species, Cryptococcus species, Mucor species, Histoplasma species, Blastomyces Species, Coccidioides species, Paracoccidioides species, Trichophyton species, Epidermophyton species, Microsporum species, Malassezia ), Pseudallescheria species, Sporothrix species, Rhinosporidium species, Fonsecaea species, Wangiella species, Phialophora Species, Exophiala species, Cladosporium species, Alternaria species, Aureobasidium species, Chaetomium species, Curvularia Bell, Dreshsle ra ) Mycocentrospora species, Phoma species, Hendersonula species, Scytalidium species, Corynespora species, Leptospheria species Species, Madurella species, Neotestudina species, Scedosporium species, Pyrenochaeta species, Geotrichum species, Trichosporon ), Chrysosporium species, Coprinus species, Schizophyllum species, Pneumocystis species, Conidiobolus species, Basidiobolus species, par indeed My process (Paecilomyces) species, Penny room Solarium (Penicillium) species, Acre monitor Titanium (Acremonium) species, Fusarium (Fusarium) species, Scoring pool La-off system (Scopulariopsis) species, Isaac Caro My process (Saccharomyces ) species, with three arms Spokane Leeum (Cephalosporium) species, Oh (Loboa) species, Rizzo crispus (Rhizopus) species, Resorts Temuco (Rhizomucor) and abscisic species is included dia (Absidia) paper.
[149] As a result of this excellent antifungal activity, the compounds of formula 1a and their pharmaceutically acceptable salts and ester derivatives can be used as medicaments, preferably as antifungal agents.
[150] The compound of formula (1a), or a pharmaceutically acceptable salt or ester derivative thereof, may be a compound of formula (1a), or a pharmaceutically acceptable salt or ester derivative thereof, by itself or a pharmaceutically acceptable excipient thereof. (S) or as a mixture with diluent (s). The compositions according to the invention can be used as tablets, capsules, granules, powders or syrups for oral administration, or as injections, topical, vaginal or dermal preparations, or as suppositories for parenteral administration or formulations for inhalation (oral or nasal). It may be in the unit dosage form such as
[151] Pharmaceutical compositions can be prepared in a known manner using additives such as excipients, binders, disintegrants, lubricants, stabilizers, correctors, suspending agents, diluents and solvents.
[152] Examples of suitable excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; Starch derivatives such as corn starch, potato starch, α-starch, dextrin or carboxymethylstarch; Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose or inter-crosslinked sodium carboxymethylcellulose; Gum arabic; Dextran; Pullulan; Silicate derivatives such as light silicic anhydride, synthetic aluminum silicate or magnesium aluminate metasilicate; Phosphate derivatives such as calcium phosphate; Carbonate derivatives such as calcium carbonate; Sulfate derivatives such as calcium sulfate; Glycol and colloidal silica.
[153] Examples of suitable binders include starch derivatives and cellulose derivatives, such as those described above, gelatin, polyvinylpyrrolidone and macrogol.
[154] Examples of suitable disintegrants include starch derivatives and cellulose derivatives such as those described above, chemically modified starch or cellulose derivatives such as sodium cross-carmellose, sodium carboxymethylstarch and crosslinked polyvinylpyrrolidone.
[155] Examples of suitable lubricants include talc; Stearic acid; Metal stearate derivatives such as calcium stearate or magnesium stearate; Waxes such as beeswax or sperm; Glycols; Carboxylic acids such as fumaric acid; Sulfates such as calcium sulfate; Leucine; Silicic acid derivatives such as silicic anhydride or silicic anhydride; And starch derivatives such as those described above for excipients.
[156] Examples of stabilizers include para-hydroxybenzoic acid ester derivatives such as methylparaben or propylparaben; Alcohols such as chlorobutanol, benzyl alcohol or phenethyl alcohol; Benzalkonium chloride; Phenol derivatives such as phenol or cresol; Thimerosal; Acetic anhydride; Sorbic acid; Boric acid; Adipic acid; Sodium carboxylates such as sodium benzoate; Lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; Antioxidants such as retinol, tocopherol or sodium ascorbate; And synthetic hydrotalcites.
[157] Examples of corrective agents include flavoring agents, sweetening agents and sour preparations commonly used for this purpose.
[158] Examples of suspending agents include polysorbate 80 and sodium carboxymethylcellulose.
[159] Examples of suitable solvents for the preparation of formulations for parenteral administration include water, ethanol, glycerin, physiological saline, glucose solution, cyclodextrin molecules, water-containing-,-or-cyclodextrin, propylene glycol, polyethylene glycol 200 and polyethylene glycol 400 is included.
[160] The compound of Formula 1a, or a pharmaceutically acceptable salt or ester derivative thereof, may vary depending on various factors such as the age and condition of the patient, and the route of administration. Suitable dosage levels for oral administration are from adult 1 mg (preferably 5 mg) per day to 2000 mg (preferably 1000 mg) per day. Appropriate dose levels for intravenous administration range from an adult minimum of 0.1 mg (preferably 0.5 mg) per day to a maximum of 600 mg (preferably 500 mg) per day. Compounds of Formula 1a, or pharmaceutically acceptable salts or ester derivatives thereof, may be administered in a single dosage dosage form or, if desired, in a convenient sub-administration of dosages 1 to 6 times daily, depending on the condition of the patient. It can be divided into sub-units.
[161] The following Examples, Reference Examples, Test Examples, and Formulation Examples are provided to further illustrate the present invention, and are not intended to limit the scope of the present invention.
[162] Example 1
[163] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol
[164] [Formula 1c]
[165]
[166] 1 (i) diethyl 4-cyano-2-fluorobenzylphosphonate
[167] 1.5 g (7.0 mmol) of 4- (bromomethyl) -3-fluurobenzonitrile [J. Med. Chem., 40 , 2064 (1997)] and a mixture of 1.4 g (8.4 mmol) of triethyl phosphite are heated at 150 ° C. for 2 hours. After completion, the reaction mixture is concentrated under reduced pressure. The volatiles in the residue thus obtained are removed by vacuum heating at 100 ° C. for 1 hour to give 1.97 g (quantitative yield) of the title compound of the oil which solidifies in the freezer. This oil product is no longer purified and used in the next step.
[168] ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) ppm:
[169] 1.27 (6H, t, J = 7.1 Hz);
[170] 3.24 (2H, doublet, J = 22.3 Hz);
[171] 4.00-4.05 (4H, m);
[172] 7.37 (1H, doublet, J = 9.2 Hz);
[173] 7.43 (1H, doublet, J = 7.9 Hz);
[174] 7.51 (1H, td, J _t = 9.2 Hz, J _d = 2.6 Hz).
[175] IR spec _max (CHCl ₃ ) cm ⁻¹ : 2237, 1262, 1054, 1029.
[176] Mass spectrum m / z (El): 271 (M ⁺ ), 139, 109 (100%), 93.
[177] l (ii) 3-fluoro-4-[(IE, 3E) -5-oxo-1,3-pentadienyl] benzonitrile
[178] 0.5 ml (0.77 mmol) of a 1.53 N hexane solution of butyllithium was added to 4 ml of anhydrous tetrahydrofuran 209 mg (0.77 mmol) of diethyl 4-cyano-2-fluorobenzyl-phosphonate, which was said step Obtained in 1 (i)] to the solution dropwise at -78 ° C under stirring. The mixture is stirred at -78 ° C for 30 minutes. After completion, 100 mg (0.77 mmol) of a commercially available formaldehyde mono-dimethylacetal solution in 2 ml of anhydrous tetrahydrofuran are added to the mixture, and the obtained mixture is stirred at -78 ° C for 2 hours. The cooling bath is then removed and the mixture is further stirred in an ice bath for 15 minutes. 3.9 ml (0.39 mmol) of 0.1 N hydrochloric acid are added to the reaction mixture, which is then stirred in an ice bath for 30 minutes and further stirred at ambient temperature for 1 hour. After completion, saturated aqueous sodium hydrogen carbonate solution is added to the mixture in an ice bath. The resulting mixture is partitioned between ethyl acetate and water, the organic layer is washed with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crystalline residue thus obtained is recrystallized from a mixture of ethyl acetate and hexanes to give 127 mg (yield: 87%) of the title compound as light yellow crystals.
[179] mp: 174-177 ° C
[180] ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC1 ₃ ) ppm:
[181] 6.36 (1H, doublet of doublets, J = 15, 8 Hz);
[182] 7.14 (1H, d-form, J = 3 Hz);
[183] 7.16 (1H, doublet, J = 8 Hz);
[184] 7.28 (1H, double doublet of doublets, J = 15, 8, 3 Hz);
[185] 7.40 (1H, doublet of doublets, J = 10, 1 Hz);
[186] 7.47 (1H, doublet of doublets, J = 8, 1 Hz);
[187] 7.67 (1H, t, J = 8 Hz);
[188] 9.68 (1H, doublet, J = 8 Hz),
[189] IR spectrum _max (KBr) cm ⁻¹ : 2230, 1681, 1672, 1621, 1421, 1159, 1124.
[190] Mass spectrum m / z (EI): 201 (M ⁺ ), 172 (100%), 158, 145.
[191] For C ₁₂ H ₈ FNO,
[192] Theoretic value: C, 71.64; H, 4.01; N, 6.96,
[193] Found: C, 71.84; H, 4. 27; N, 6.83.
[194] l (iii) (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-l-yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -l- (1H-1,2,4-triazol-l-yl) -2-butanol
[195] 4.63 g (23.0 mmol) of 3-fluoro-4-[(1E, 3E) -5-oxo-1,3-pentadienyl] benzonitrile (prepared as described in step 1 (ii) above), 8.73 g (24.3 mmol of (2R, 3R) -2- (2,4-difluorophenyl) -3-[[l- (hydroxymethyl) -2-hydroxyethyl] thio] -l- (1H- 1,2,4-triazol-1-yl) -2-butanol [repared as described in Japanese Patent Laid-Open No. 8-333350], 5.07 g (26.7 mmol) of p-toluenesulfonic acid monohydrate and 200 ml of anhydrous The mixture of tetrahydrofuran is left for 30 minutes at ambient temperature After completion, the reaction mixture is concentrated using a rotary evaporator and dried in vacuo The resulting residue is dissolved in 150 ml of anhydrous tetrahydrofuran and then obtained The resulting mixture is evaporated to dryness using a rotary evaporator The process is repeated two more times A solution of the obtained residue in 150 ml of anhydrous tetrahydrofuran is saturated aqueous sodium hydrogen carbonate solution under stirring. The product was then extracted with ethyl acetate, the organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The residual oil was purified by silica gel (2: 1 mixture of ethyl acetate: hexane) (500). Purification by chromatography on g) affords 9.35 g (yield: 74%) of the title compound as a yellow amorphous solid.
[196] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC1 ₃ ) ppm:
[197] 1.19 (3H, doublet, J = 7 Hz);
[198] 3.33 (1H, q, J = 7 Hz);
[199] 3.40 (1H, triplet of triplets, J = l1, 5 Hz);
[200] 3.62 (1H, t, J = 11 Hz);
[201] 3.64 (1H, t, J = 11 Hz);
[202] 4.30 (1H, double doublet of doublets, J = l1, 5, 2 Hz);
[203] 4.43 (1H, double doublet of doublets, J = l1, 5, 2 Hz);
[204] 4.83 (1H, doublet, J = 14 Hz);
[205] 5.01 (1 H, s);
[206] 5.03 (1H, doublet, J = l 4 Hz);
[207] 5.07 (1H, doublet, J = 4 Hz);
[208] 5.90 (1H, doublet of doublets, J = 15, 4 Hz);
[209] 6.62 (1H, doublet of doublets, J = l5, 11 Hz);
[210] 6.7-6.8 (2H, m);
[211] 6.73 (1H, doublet, J = 16 Hz);
[212] 6.95 (1H, doublet of doublets, J = 16, 11 Hz);
[213] 7.3-7.4 (1 H, m);
[214] 7.34 (1H, doublet, J = 9 Hz);
[215] 7.40 (1H, doublet, 1 = 8 Hz);
[216] 7.58 (1H, t, J = 8 Hz);
[217] 7.79 (2 H, s).
[218] IR spectrum _max (KBr) cm ^-1 : 2232, 1616, 1499, 1418, 1140.
[219] Mass spectrum m / z (FAB), 543 (M ⁺ + 1).
[220] Specific rotation: [a] _D ²⁵ -76.6 ° (c = 1.00, CHCl ₃ ).
[221] Example 2
[222] Crystalline (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-l-yl] -1 , 3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -l- (1H-1,2,4-triazol-l-yl) -2-butanol
[223] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene- prepared as described in Example 1 l-yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -l- (1H-1,2,4-triazol-l-yl) 2-Butanol is dissolved in a hot 9: 1 mixture of 2-propanol and ethyl acetate. The obtained mixture is then irradiated with ultrasonic waves in a chordonic bath to obtain the title compound in powder form, which is collected by filtration.
[224] Melting Point: 111-112 ℃
[225] IR spectrum _max (KBr) cm ⁻¹ : 2232, 1616, 1499, 1419, 1141.
[226] The X-ray diffraction pattern of the crystalline product, shown in FIG. 1, is obtained by irradiating the crystalline product with copper K _α rays. The vertical axis of the powder X-ray diffraction pattern indicates the diffraction intensity in units of counts / second (cps). The horizontal axis indicates the diffraction angle of the value 2θ. The space d of the grating can be calculated using the equation 2d sin θ = nλ (where n = 1).
[227] Example 3
[228] Crystalline (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-l-yl] -1 , 3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -l- (1H-1,2,4-triazol-l-yl) -2-butanol
[229] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-l- as obtained in Example 1 Il] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -l- (1H-1,2,4-triazol-l-yl) -2 -Butanol is dissolved in ethyl acetate and the same amount of hexane in turn, and it is added to the solution of ethyl acetate to precipitate the title compound crystals.
[230] Melting Point: 127-128 ℃
[231] IR spectrum ν _max (KBr) cm ⁻¹ : 2232, 1616, 1499, 1419, 1140.
[232] The X-ray diffraction pattern of the crystalline product, shown in FIG. 2, is obtained by irradiation of the crystalline product using copper K _α rays. The vertical axis of the powder X-ray diffraction pattern indicates the diffraction intensity in units of counts / second (cps). The horizontal axis indicates the diffraction angle of the value 2θ. The space d of the grating can be calculated using the equation 2d sin θ = nλ (where n = 1).
[233] Example 4
[234] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-l-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -l- (1H-1,2,4-triazol-l-yl) -2-butanol (molecular sieve Synthetic by dehydration)
[235] [Formula 1c]
[236]
[237] 791 mg (4.16 mmol) of p-toluene sulfonic acid monohydrate was added to 760 mg (3.77 mmol) of 3-fluoro-4-[(1E, 3E) -5-oxo-1,3 in 13 ml of dichloromethane. -Pentadienyl] -benzonitrile [obtained as described in Example l (ii) above], and 1.36 g (3.77 mmol) of (2R, 3R) -2- (2,4-difluorophenyl)- 3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol [Japanese Patent Laid-Open No. 8-333350 Prepared as described above. The resulting mixture is concentrated on a rotary evaporator. After 13 ml of dichloromethane and 13 g of 4A molecular sieve are added to the obtained residue, the mixture is stirred overnight at ambient temperature. After completion, an aqueous sodium hydrogen carbonate solution is added to the reaction mixture. The molecular sieve is filtered off and the filtrate is partitioned between ethyl acetate and water. The organic layer is dried and concentrated under reduced pressure. The oil residue obtained is purified by chromatography on silica gel (20 g) using a 1: 1 mixture of ethyl acetate and hexane as eluent to afford 1.42 g (yield 69%) of the title compound as an amorphous solid. The spectra editor is the same as those of the title compound of Example 1.
[238] Example 5
[239] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-l-yl] -1,3 -Dioxan-5-yl] thio] -2- (2-fluorophenyl) -l- (1H-1,2,4-triazol-l-yl) -2-butanol
[240]
[241] 5 (i) (2R, 3R) -2- (2-fluorophenyl) -3-[[trans-2-phenyl) -1,3-butadien-5-yl] thio] -1- (1H-1 , 2,4-triazol-l-yl) -2-butanol
[242] 0.12 ml (0.59 mmol) of 4.9 M methanolic solution of sodium methoxide was added to 0.93 g (4.0 mmol) of (2R, 3S) -2- (2-fluorophenyl) -3-methyl- in 15 ml of ethanol. 2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane, prepared as described in "Chem. Pharin. Bull., 43 , 441-449 (1995)" and 1.14 g (4.8 mmol) to a solution of trans-5- (acetylthio) -2-phenyl-1,3-dioxane (prepared as described in Japanese Patent Laid-Open No. 8-333350). The resulting solution is stirred at 87 ° C. for 13 hours. After cooling, the reaction mixture is partitioned between ethyl acetate and aqueous ammonium solution. The organic solution is washed with saturated aqueous sodium chloride solution and then concentrated under reduced pressure. The oil residue obtained is purified by chromatography on silica gel (75 g) using a 3: 2 mixture of ethyl acetate and hexane as eluent to afford 0.68 g (40% yield) of the title compound as an amorphous solid.
[243] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC1 ₃ ) ppm:
[244] 1.21 (3H, doublet, J = 7 Hz);
[245] 3.42 (1H, q, J = 7 Hz);
[246] 3.49 (1H, triplet of triplets, J = l1, 5 Hz);
[247] 3.75 (2H, t, J = l 1 Hz),
[248] 3.72 (2H, t, J = 11 Hz);
[249] 4.41 (1H, double doublet of doublets, J = l1, 5, 2 Hz),
[250] 4.52 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[251] 4.89 (1H, doublet, J = 14 Hz);
[252] 4.92 (1H, doublet, J = l Hz),
[253] 5.07 (1H, doublet, J = 14 Hz);
[254] 5.49 (1 H, s);
[255] 6.94-7.03 (2H, m);
[256] 7.17-7.23 (1 H, m);
[257] 7.33-7. 41 (3H, m);
[258] 7.49 (2H, doublet of doublets, J = 7, 2 Hz);
[259] 7.75 (1 H, s);
[260] 7.77 (1 H, s).
[261] IR spectrum _max (CHCl ₃ ) cm ⁻¹ : 3131, 1732, 1376, 1140.
[262] Mass spectrum m / z (FAB): 430 (M ⁺ +1).
[263] 5 (ii) (2R, 3R) -2- (2-fluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -l- (1H-1,2, 4-triazol-l-yl) -2-butanol
[264] 110 ml (110 mmol) of 1 N hydrochloric acid was added 13 g (30.3 mmol) of (2R, 3R) -2- (2-fluorophenyl) -3-[(trans-2-phenyl-) in 80 ml of toluene. In a solution of 1,3-dioxan-5-yl) thio]-(1H-1,2,4-triazol-1-yl) -2-butanol [repared as described in step 5 (i) above] Add. The resulting mixture is stirred at 50 ° C. for 2.5 hours. After completion, the aqueous layer is separated, the oil layer is extracted twice with dilute hydrochloric acid, and then with an aqueous sodium chloride solution. The aqueous layer is combined and sodium hydrogencarbonate is carefully added in small portions there until the carbon dioxide bubble is no longer detected. After the obtained mixture is extracted with ethyl acetate, the extract is concentrated under reduced pressure to give a solid residue. This residue is collected by filtration and washed with a small amount of ethyl acetate to give 5.57 g (yield: 55%) of the title compound as a light brown solid.
[265] Melting Point: 121-123 ℃
[266] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC1 ₃ ) ppm:
[267] 1.21 (3H, doublet, J = 7 Hz);
[268] 2.47 (1H, t, J = 6 Hz);
[269] 2.78 (1H, t, J = 6 Hz);
[270] 3.24 (1H, q, J = 6 Hz);
[271] 3.50 (1H, q, J = 7 Hz);
[272] 3.7-4.0 (4H, m);
[273] 4.92 (1H, doublet, J = l 4 Hz);
[274] 5.14 (1H, doublet, J = 14 Hz);
[275] 5.16 (1 H, s);
[276] 6.97 (1H, double doublet of doublets, 1 = 12, 8, 1 Hz);
[277] 7.02 (1H, t d, J = 8, 1 Hz);
[278] 7.22 (1H, tdd, J = 8, 5, 2 Hz);
[279] 7.39 (1H, t d, J = 8, 2 Hz);
[280] 7.765 (1 H, s);
[281] 7.770 (1 H, s).
[282] IR spectrum _max (KBr) cm ⁻¹ : 1513, 1485, 1451, 1275, 1209, 1136, 1072,1054.
[283] Mass spectrum m / z (FAB): 342 (M ⁺ +1).
[284] Specific rotational rate: [a] _D ²⁵ -78.2 ° (c = 1.16, CHCl ₃ ).
[285] For C ₁₅ H ₂₀ F ₂ N ₄ O ₃ S,
[286] Theoretical: C, 52.77; H, 5.91; N, 12.31.
[287] Found: C, 52.74; H, 5.95; N, 12.24.
[288] 5 (iii) (2R, 3R) -2-3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-1- Il] -1,3-dioxan-5-yl] thio] -2- (2-fluorophenyl) -1- (1H-1,2,4-triazol-l-yl) -2-butanol
[289] 510.7 mg (1.50 mmol) of (2R, 3R) -2- (2-fluorophenyl) -3-[[l- (hydroxymethyl) -2-hydroxyethyl] thiol-2-butanol [Same Step] Prepared as described in 5 (ii)], 300 mg (1.5 mmol) of 3-fluoro-4-[(1E, 3E) -5-oxo-1,3-pentadienyl] benzonitrile [erformed above Prepared as described in Example l (ii)] and 283.1 mg (1.64 mmol) of p-toluene sulfonic acid monohydrate in a similar manner as described in Example 1 (iii) above to give the crude title compound as an oil do. The oil is purified by chromatography on column silica gel (50 g) using a 1: 1 mixture of ethyl acetate and hexane as eluent to afford 431 mg (yield: 55%) of the title compound as a colorless amorphous solid.
[290] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC1 ₃ ) ppm:
[291] 1.19 (3H, doublet, J = 7 Hz);
[292] 3.39 (1H, q, J = 7 Hz);
[293] 3.38-3.45 (1 H, m);
[294] 3.62 (1H, t, J = 11 Hz);
[295] 3.65 (1H, t, J = 11 Hz);
[296] 4.31 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[297] 4.44 (1H, double doublet of doublets, J = l1, 5, 2 Hz);
[298] 4.87 (1H, doublet, J = 14 Hz);
[299] 4.92 (1 H, s);
[300] 5.04 (1H, doublet, J = 14 Hz);
[301] 5.07 (1H, doublet, J = 4 Hz);
[302] 5.90 (1H, doublet of doublets, J = 15, 4 Hz);
[303] 6.62 (1H, doublet of doublets, J = 15, 11 Hz);
[304] 6.75 (1H, doublet, J = 15 Hz);
[305] 6.98 (1H, doublet of doublets, J = 15, 11 Hz);
[306] 6.92-7.02 (2H, m);
[307] 7.18-7.23 (1 H, m);
[308] 7.32-7-36 (2H, m);
[309] 7.41 (1H, doublet of doublets, J = 8, 1 Hz);
[310] 7.58 (1H, t, J = 8 Hz);
[311] 7.75 (1 H, s);
[312] 7.77 (1 H, s).
[313] IR spectrum _max (KBr) cm ⁻¹ : 3426, 2852, 2231, 1141.
[314] Mass spectrum m / z (FAB): 525 (M ⁺¹ +1).
[315] Example 6
[316] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-l-yl] -1,3 -Dioxan-5-yl] thio] -2- (4-fluorophenyl) -l- (1H-1,2,4-triazol-l-yl) -2-butanol
[317]
[318] 6 (i) cis-5- (acetylthio) -2-phenyl-1,3-dioxane
[319] 30 g (90 mmol) of trans-2-phenyl-5- (p-toluenesulfonyloxy) -1,3-dioxane (prepared as described in "Tetrahedron, 48 , 5941-5950"), 15.3 g ( 134 mmol) of potassium thioacetate, 240 ml of toluene and 60 ml of N, N-dimethylacetamide are stirred at 100 ° C. for 3 hours and then at 110-120 ° C. for 7 hours. After cooling, the reaction mixture is partitioned between toluene and water. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The oil residue obtained is purified by chromatography on column silica gel (200 g) using a 1: 4 mixture of ethyl acetate and hexane as eluent to afford the crude title compound as a solid. This solid is recrystallized from a mixture of ethyl acetate and hexanes to give 10 g (yield: 47%) of the title compound as brown needle crystals.
[320] Melting Point: 94-95 ℃
[321] ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC1 ₃ ) ppm:
[322] 2.39 (3H, s);
[323] 3.71 (1H, broad singlet);
[324] 4,19 (2H, broad doublet, J = 12 Hz);
[325] 4.38 (2H, broad doublet, J = 12 Hz);
[326] 5.55 (1 H, s);
[327] 7.30-7.42 (3H, m);
[328] 7.42-7.55 (2H, m).
[329] IR spectrum _max (KBr) cm ⁻¹ : 1676, 1402, 1130.
[330] Mass spectrum m / z (EI): 238 (W), 237, 178, 107, 105, 43 (100%).
[331] 6 (ii) (2R, 3R) -2- (4-fluorophenyl) -3-[(cis-2-phenyl-1,3-dioxan-5-yl] thio] -1- (1H-1 , 2,4-triazol-l-yl) -2-butanol
[332] 1 ml (0.59 mmol) of 4.8 M methanolic solution of sodium methoxide was added to 2.33 g (10 mmol) of (2R, 3S) -2- (4-fluorophenyl) -3-methyl- in 40 ml of ethanol. 2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane [repared as described in "Chem. Pharm. Bull., 43 , 441-449 (1995)"] and 2.38 g (10 mmol) is added to a solution of cis-5- (acetylthio) -2-phenyl-1,3-dioxane (prepared as described in step 6 (i) above). The resulting mixture is stirred at 80 ° C. for 5 hours. After cooling, the reaction mixture is partitioned between ethyl acetate and water. The organic layer is separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue is purified by chromatography on a silica gel (50 g) column using a 1: 1 mixture of ethyl acetate and hexane as eluent to afford 3.1 g (yield: 72%) of the title compound as a brown foamy solid.
[333] ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) ppm:
[334] 1.29 (3H, doublet, J = 7 Hz);
[335] 2.97 (1 H, m);
[336] 3.50 (1H, q, J = 7 Hz);
[337] 4.26 (1H, d-type, J = 12 Hz);
[338] 4.36 (1H, doublet of doublets, J = 12, 3 Hz);
[339] 4.36 (1H, doublet of doublets, J = 12, 2 Hz);
[340] 4.42 (1H, doublet of doublets, J = 12, 3 Hz);
[341] 4.56 (1 H, s);
[342] 4.57 (1H, doublet, J = 14 Hz);
[343] 5.10 (1H, doublet, J = 14 Hz);
[344] 5.61 (1 H, s);
[345] 6.89 (2H, t, J = 9 Hz);
[346] 7.16 (1H, doublet of doublets, J = 9, 5 Hz);
[347] 7.3-7.5 (3H, m);
[348] 7.4-7.6 (2 H, m);
[349] 7.69 (1 H, s);
[350] 7.80 (1 H, s).
[351] IR spectrum _max (CHCl ₃ ) cm ⁻¹ : 1732, 1605, 1509, 1278, 1135.
[352] Mass spectrum m / z (FAB): 430 (M ⁺ +1).
[353] Specific rotation: [α] _D ²⁵ -59.8。 (c = 1.29, CHCl ₃ ).
[354] 6 (iii) (2R, 3R) -2- (4-fluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -1- (1H-1,2, 4-triazol-1-yl) -2-butanol
[355] 1 mL (12 mmol) of 12 N hydrochloric acid was dissolved in 39 mL of methanol (2R, 3R) -2- (4-fluorophenyl) -3-[(cis-2-phenyl-1,3-dioxan-5-yl ) Thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol (prepared in step 6 (ii) above) was added to 3.1 g (7.2 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. Then an aqueous sodium hydrogen carbonate solution was carefully added to the reaction mixture until it became slightly alkaline. Most of the methanol was evaporated from the mixture under reduced pressure. The residue obtained was then partitioned between ethyl acetate and aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel (30 g) column chromatography using a 1: 9 mixture of methanol and ethyl acetate as eluent to give 2.15 g (87% yield) of the title compound as a hygroscopic light brown foamy solid. .
[356] ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) ppm:
[357] 1.26 (3H, doublet, J = 7 Hz);
[358] 2.6-2.8 (2H, broad singlet);
[359] 3.16 (1H, q, J = 6 Hz);
[360] 3.27 (1H, q, J = 7 Hz);
[361] 3.6-4.0 (4H, m);
[362] 4.66 (1H, doublet, J = 14 Hz);
[363] 4.92 (1 H, s);
[364] 4.94 (1H, doublet, J = 14 Hz);
[365] 6.99 (2H, t, J = 9 Hz);
[366] 7.25 (2H, doublet of doublets, J = 9, 5 Hz);
[367] 7.75 (1 H, s);
[368] 7.84 (1 H, s).
[369] IR spectrum _max (CHCl ₃ ) cm ⁻¹ : 1605, 1510, 1277.
[370] Mass spectrum m / z (FAB): 342 (M ⁺ +1).
[371] Specific rotation: [α] _D ²⁵ -26.9。 (c = 1.55, CHCl ₃ ).
[372] 6 (iv) (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2- (4-fluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol
[373] (2R, 3R) -2- (4-fluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -2-butanol [repared in step 6 (iii) above] 510.7 mg (1.50 mmol), 3-fluoro-4-[(1E, 3E) -5-oxo-1,3-pentadienyl] benzonitrile [repared in Example 1 (ii) above] 301 mg (1.5 mmol) and 283 mg (1.64 mmol) of p-toluenesulfonic acid monohydrate to give the crude title compound as an oil in a similar manner as in Example 1 (iii) above. This oil was purified by silica gel column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to give 214 mg (yield 27%) of the title compound as a colorless amorphous solid.
[374] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[375] 1.21 (3H, doublet, J = 7 Hz);
[376] 3.13 (1H, q, J = 7 Hz);
[377] 3.33 (1H, triplet of triplets, J = 11, 5 Hz);
[378] 3.58 (1H, t, J = 11 Hz);
[379] 3.60 (1H, t, J = 11 Hz);
[380] 4.26 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[381] 4.37 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[382] 4.52 (1H, doublet, J = 14 Hz);
[383] 4.60 (1 H, s);
[384] 4.98 (1H, doublet, J = 14 Hz);
[385] 5.04 (1H, doublet, J = 4 Hz);
[386] 5.89 (1H, doublet of doublets, J = 15, 4 Hz);
[387] 6.60 (1H, doublet of doublets, J = 15, 10 Hz);
[388] 6.74 (1H, doublet, J = 6 Hz);
[389] 6.94 (1H, doublet of doublets, J = 16, 10 Hz);
[390] 6.95-6.99 (2H, m);
[391] 7.21-7.24 (2H, m);
[392] 7.34 (1H, doublet of doublets, J = 10, 1 Hz);
[393] 7.40 (1H, doublet of doublets, J = 8, 1 Hz);
[394] 7.58 (1H, t, J = 8 Hz);
[395] 7.71 (1 H, s);
[396] 7.83 (1 H, s).
[397] IR spectrum _max (KBr) cm ⁻¹ : 3428, 2231, 1509, 1140.
[398] Mass spectrum m / z (FAB): 525 (M ⁺ +1).
[399] Example 7
[400] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,3-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol
[401]
[402] 7 (i) (2R) -2 ', 3'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propiophenone
[403] The production of Grignard reagents was initiated by heating a mixture of 0.5 g (2.6 mmol) of 1-bromo-2,3-difluorobenzene, 0.681 g (28 mmol) of magnesium metal and 40 mL of tetrahydrofuran. When the reaction started, the mixture was cooled to 0 ° C. A solution of 4.5 g (23 mmol) of 1-bromo-2,3-difluorobenzene in 30 mL tetrahydrofuran was added to the mixture for 0.5 h. The mixture was then stirred at ambient temperature for 1.5 hours. After cooling the mixture to −30 ° C., 4-[(2R) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionyl] in 30 ml of tetrahydrofuran] Morpholine [Chem. Pharm. Bull., 41, prepared in 1035-1042 (1993)] 4.87 g (20 mmol) solution was added dropwise for 20 minutes. The resulting mixture was stirred at ambient temperature for 2 hours and then the reaction was stopped by addition of saturated aqueous ammonium chloride solution. The reaction product was extracted with ethyl acetate and the organic layer was washed with aqueous sodium chloride solution and then concentrated under reduced pressure. The oily residue obtained above was purified by silica gel (75 g) column chromatography using a 1: 9 mixture of ethyl acetate and hexane as eluent to afford 4.80 g (yield 89%) as colorless oil.
[404] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[405] 1.44 [(3/2) H, doublet of doublets, J = 7, 1 Hz];
[406] 1.49 [(3/2) H, doublet of doublets, J = 7, 1 Hz];
[407] 1.49-1.90 (6H, m);
[408] 3.33-3.38 [(1/2) H, m];
[409] 3.50-3.55 [(1/2) H, m];
[410] 3.68-3.74 [(1/2) H, m];
[411] 3.87-3.93 [(1/2) H, m];
[412] 4.66 [(1/2) H, t, J = 4 Hz];
[413] 4.75 [(1/2) H, t, J = 4 Hz];
[414] 4.85 [(1/2) H, qd, J = 7, 2 Hz];
[415] 5.10 [(1/2) H, qd, J = 7, 2 Hz];
[416] 7.14-7.21 (1 H, m);
[417] 7.30-7.39 (1 H, m);
[418] 7.54-7.58 (1 H, m).
[419] IR spectrum _max (CHCl ₃ ) cm ⁻¹ : 1700, 1481, 1273.
[420] Mass spectrum m / z (FAB): 271 (M ⁺ +1).
[421] 7 (ii) (2R, 3R) -2- (2,3-difluorophenyl) -1,2,3-butanetriol
[422] (Dimethylisopropoxysilyl) methylmagnesium chloride was prepared from a solution of 5.74 g (34.4 mmol) of chloromethyldimethylisopropoxysilane and 0.84 g (34.4 mmol) of magnesium metal in 40 ml of tetrahydrofuran. (2R) -2 ', 3'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propiophenone in 20 ml of tetrahydrofuran [Step 7 above] 4.65 g (17.2 mmol) solution was added to the Grignard reagent solution while stirring at 0 ° C. The resulting mixture was stirred at ambient temperature for 30 minutes and then the reaction was stopped by adding saturated aqueous ammonium chloride solution to the reaction mixture. The reaction product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and concentrated to give crude (2S, 3R) -2- (2,3-difluorophenyl) -1- (isopropoxydimethylsilyl) -3- (3,4,5, 8.1 g of 6-tetrahydro-2H-pyran-2-yloxy) -2-butanol were obtained as an oil.
[423] 1.4 g (17 mmol) of sodium hydrogen carbonate and 16 ml of 31% aqueous hydrogen peroxide solution were added to the crude oil solution in a mixture of 40 ml of methanol and 40 ml of tetrahydrofuran. The resulting mixture was stirred at 80 ° C. for 40 minutes. After cooling the reaction mixture, the reaction product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and concentrated to give crude (2R, 3R) -2- (2,3-difluorophenyl) -3- (3,4,5,6-tetrahydro-2H-pyran-2 10 g of -yloxy) -1,2-butanediol were obtained as an oil.
[424] 0.20 g (1.05 mmol) of p-toluenesulfonic acid monohydrate was added to the oil solution in 40 ml of methanol. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The residue obtained was purified by silica gel (125 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexanes to give 3.74 g (quantitative yield) of the title compound as an oil.
[425] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[426] 0.96 (3H, d, J = 6 Hz);
[427] 3.80 (1H, doublet, J = 12 Hz);
[428] 3.94 (1 H, s);
[429] 4.32 (1H, doublet of doublets, J = 12, 2 Hz);
[430] 4.53 (1H, qd, J = 6, 3 Hz);
[431] 7.09-7.13 (2H, m);
[432] 7.46-7.50 (1 H, m).
[433] IR spectrum _max (KBr) cm ⁻¹ : 3402, 3174, 1481, 1272, 1104.
[434] Mass spectrum m / z (FAB): 219 (M ⁺ +1).
[435] 7 (iii) (2R, 3R) -2- (2,3-difluorophenyl) -1,3-bis (methanesulfonyloxy) -2-butanol
[436] 5.71 g (50 mmol) of methanesulfonyl chloride were added to (2R, 3R) -2- (2,3-difluorophenyl) -1,2,3-butanetriol in 18 ml of pyridine [Step 7 (ii above). To 3.51 g (16.1 mmol) was added at 0 ° C. The resulting mixture was stirred for 0.5 h, then saturated aqueous sodium hydrogen carbonate solution was added, and the product was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, then with an aqueous sodium chloride solution, and then concentrated under reduced pressure. The obtained residue was purified by silica gel (100 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to give 5.04 g (84% yield) of the title compound as a colorless oil.
[437] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[438] 1.28 (3H, doublet, J = 7 Hz);
[439] 2.99 (3H, s);
[440] 3.10 (3 H, s);
[441] 3.41 (1 H, s);
[442] 4.75 (2H, doublet, J = 1 Hz);
[443] 5.31 (1H, q, J = 7 Hz);
[444] 7.16-7.23 (2H, m);
[445] 7.46-7.50 (1 H, m).
[446] IR spectrum _max (KBr) cm ⁻¹ : 3486, 1485, 1350, 1344, 1171.
[447] Mass spectrum m / z (FAB): 375 (M ⁺ +1).
[448] 7 (iv) (2R, 3S) -2- (2,3-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane
[449] 3.32 g (48.1 mmol) of 1H-1,2,4-triazole are added to a suspension of 1.84 g (41.1 mmol) of a 55% sodium hydride dispersion in oil in 30 ml of N, N-dimethylformamide with stirring at 0 ° C. It was. After stopping the release of hydrogen gas, (2R, 3R) -2- (2,3-difluorophenyl) -1,3-bis (methanesulfonyloxy)-in 13 ml of N, N-dimethylformamide A solution of 4.50 g (12 mmol) of 2-butanol (prepared in step 7 (iii) above) was added to the reaction mixture. The resulting mixture was stirred at 70 ° C. for 1.5 hours. After cooling, aqueous ammonium chloride solution was added to the reaction mixture. The reaction product was extracted with ethyl acetate, and the organic layer was washed three times with water and once with aqueous sodium chloride solution, and then concentrated under reduced pressure. The obtained residue was purified by silica gel (100 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to give 1.80 g (yield 59%) of the title compound as an oil.
[450] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[451] 1.66 (3H, doublet, J = 6 Hz);
[452] 3.23 (1H, q, J = 6 Hz);
[453] 4.46 (1H, doublet, J = 15 Hz);
[454] 4.91 (1H, doublet, J = 15 Hz);
[455] 6.79 (1H, double doublet of doublets, J = 8, 6, 1 Hz);
[456] 6.93 (1H, tdd, J = 8, 6, 1 Hz);
[457] 7.08 (1H, qd, J = 8, 1 Hz);
[458] 7.82 (1 H, s);
[459] 7.98 (1 H, s).
[460] IR spectrum _max (KBr) cm ⁻¹ : 3111, 1486, 1273, 1136.
[461] Mass spectrum m / z (EI): 251 (M ⁺ ), 236, 188, 153, 141, 96 (100%).
[462] 7 (v) (2R, 3R) -2- (2,3-difluorophenyl) -3-[(trans-2-phenyl-1,3-dioxan-5-yl) thio] -1- ( 1H-1,2,4-triazol-1-yl) -2-butanol
[463] 0.29 mL (1.4 mmol) of a 4.9 M solution of sodium methoxide in methanol was added to (2R, 3S) -2- (2,3-difluorophenyl) -3-methyl-2-[(1H-) in 20 mL of ethanol. 1,2,4-triazol-1-yl) methyl] oxirane (prepared in step 7 (iv) above) 1.77 g (7.1 mmol) and trans-5- (acetylthio) -2-phenyl-1,3 Dioxane (prepared in Japanese Patent Application Laid-open No. 8-333350) was added to a solution of 2.20 g (9.2 mmol). The resulting mixture was heated at reflux for 7 hours. The reaction mixture was cooled and then partitioned between ethyl acetate and aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure to yield 3.65 g of the crude title compound. Aliquots (0.28 g) of the crude residue were purified by silica gel (15 g) column chromatography using a 2: 5 mixture of ethyl acetate and hexane as eluent to afford 0.21 g of the title compound.
[464] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[465] 1.23 (3H, doublet, J = 7 Hz);
[466] 3.39 (1H, q, J = 7 Hz);
[467] 3.50 (1H, triplet of triplets, J = 11, 5 Hz);
[468] 3.75 (1H, t, J = 11 Hz);
[469] 3.77 (1H, t, J = 11 Hz);
[470] 4.40 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[471] 4.52 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[472] 4.87 (1H, doublet, J = 14, 6 Hz);
[473] 5.08 (1H, doublet, J = 14 Hz);
[474] 5.12 (1H, doublet, J = 1 Hz);
[475] 5.49 (1 H, s);
[476] 6.92-6.98 (1 H, m);
[477] 7.05 (1H, qd, J = 8, 1 Hz);
[478] 7.11-7.16 (1 H, m);
[479] 7.34-7.41 (3H, m);
[480] 7.49 (2H, doublet of doublets, J = 7, 3 Hz);
[481] 7.79 (1 H, s);
[482] 7.82 (1 H, s).
[483] IR spectrum _max (KBr) cm < ^-1 >: 3405, 1480, 1275, 1140, 1075.
[484] Mass spectrum m / z (FAB): 448 (M ⁺ +1).
[485] 7 (vi) (2R, 3R) -2- (2,3-difluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -1- (1H-1 , 2,4-triazol-1-yl) -2-butanol
[486] 30 mL (30 mmol) of 1 N hydrochloric acid was added to crude (2R, 3R) -2- (2,3-difluorophenyl) -3-[(trans-2-phenyl-1,3-di in 45 mL of toluene. Oxan-5-yl) thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol (prepared in step 7 (v) above) was added to a 3.35 g solution. The resulting mixture was heated at 50 ° C. for 6 hours. The aqueous layer was then separated. The oil layer was then extracted twice with dilute hydrochloric acid solution. The aqueous layers were combined and sodium hydrogencarbonate was carefully added to the solution in small amounts until the release of carbon dioxide gas was stopped. The reaction mixture was then extracted with ethyl acetate and the extract was concentrated under reduced pressure to afford the title compound as a solid. This solid was washed with a 2: 1 mixture of ethyl acetate and hexanes and filtered to collect 1.54 g [61% overall yield in step 7 (v)] of the title compound.
[487] ¹ H-nuclear magnetic resonance spectrum (400 MHz, DMSO) ppm:
[488] 1.06 (3H, doublet, J = 7 Hz);
[489] 2.85 (1H, q, J = 6 Hz);
[490] 3.55-3.68 (5H, m);
[491] 4.80 (1H, doublet, J = 15 Hz);
[492] 4.85 (1H, t, J = 5 Hz);
[493] 5.04 (1H, t, J = 5 Hz);
[494] 5.10 (1H, doublet, J = 15 Hz);
[495] 6.01 (1 H, s);
[496] 6.97-7.01 (2H, m);
[497] 7.23-7.30 (1H, m);
[498] 7.62 (1 H, s);
[499] 8.31 (1 H, s).
[500] IR spectrum _max (KBr) cm ⁻¹ : 3238, 1480, 1272, 1206, 1138.
[501] Mass spectrum m / z (FAB): 360 (M ⁺ +1).
[502] 7 (vii) (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2- (2,3-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol
[503] (2R, 3R) -2- (2,3-difluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -1- (1H-1,2,4 -Triazol-1-yl) -2-butanol (prepared in step 7 (vi) above) 643.3 mg (1.80 mmol), 3-fluoro-4-[(1E, 3E) -5-oxo-1,3 -Pentadienyl] benzonitrile (prepared in Example 1 (ii) above) using 361.8 mg (1.80 mmol) and 376.3 mg (1.98 mmol) of p-toluenesulfonic acid monohydrate, In a similar manner, the crude title compound was obtained as an oil. This oil was purified by silica gel (50 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to afford 533.7 mg (yield 55%) of the title compound as a colorless amorphous solid.
[504] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[505] 1.21 (3H, doublet, J = 7 Hz);
[506] 3.36 (1H, q, J = 7 Hz);
[507] 3.43 (1H, triplet of triplets, J = 11, 5 Hz);
[508] 3.62 (1H, t, J = 11 Hz);
[509] 3.64 (1H, t, J = 11 Hz);
[510] 4.32 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[511] 4.43 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[512] 4.85 (1H, doublet, J = 14 Hz);
[513] 5.06 (1H, doublet, J = 14 Hz);
[514] 5.07 (1H, doublet, J = 4 Hz);
[515] 5.12 (1 H, s);
[516] 5.90 (1H, doublet of doublets, J = 15, 4 Hz);
[517] 6.62 (1H, doublet of doublets, J = 15, 10 Hz);
[518] 6.75 (1H, doublet, J = 16 Hz);
[519] 6.92-6.99 (2H, m);
[520] 7.01-7.08 (1 H, m);
[521] 7.10-7.14 (1 H, m);
[522] 7.34 (1H, doublet of doublets, J = 10, 1 Hz);
[523] 7.41 (1H, doublet of doublets, J = 8, 1 Hz);
[524] 7.58 (1H, t, J = 8 Hz);
[525] 7.79 (1 H, s);
[526] 7.82 (1 H, s).
[527] IR spectrum _max (KBr) cm ⁻¹ : 3406, 2231, 1480, 1275, 1140.
[528] Mass spectrum m / z (FAB): 543 (M ⁺ +1).
[529] Example 8
[530] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol
[531]
[532] 8 (i) (2R) -2 ', 5'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propiophenone
[533] 7.04 g (36.5 mmol) of 1-bromo-2,5-difluorobenzene and 4-[(2R) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) Propionyl] morpholine [Chem. Pharm. Bull., 41, prepared in 1035-1042 (1993)] According to the reaction and treatment of Example 7 (i) above, using 6.0 g (25 mmol), 6.50 g (yield 98%) of the title compound as an oil Obtained.
[534] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[535] 1.43 [(3/2) H, doublet of doublets, J = 6, 1 Hz];
[536] 1.48 [(3/2) H, doublet of doublets, J = 7, 1 Hz];
[537] 1.50-1.89 (6H, m);
[538] 3.36 [(1/2) H, dt, J = 12, 4 Hz];
[539] 3.53 [(1/2) H, dt, J = 12, 4 Hz];
[540] 3.73 [(1/2) H, dt, J = 12, 4 Hz];
[541] 3.90 [(1/2) H, dt, J = 11, 4 Hz];
[542] 4.66 [(1/2) H, t, J = 4 Hz];
[543] 4.75 [(1/2) H, t, J = 4 Hz];
[544] 4.87 [(1/2) H, qd, J = 7, 1 Hz];
[545] 5.12 [(1/2) H, qd, J = 7, 2 Hz];
[546] 7.08-7.15 (1 H, m);
[547] 7.17-7.25 (1 H, m);
[548] 7.50-7.54 (1 H, m).
[549] IR spectrum _max (CHCl ₃ ) cm ⁻¹ : 1698, 1491, 1417, 1257.
[550] Mass spectrum m / z (FAB): 271 (M ⁺ +1).
[551] 8 (ii) (2R, 3R) -2- (2,5-difluorophenyl) -1,2,3-butanetriol
[552] (2R) -2 ', 5'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propiophenone [repared in step 8 (i) above] 6.40 g (23.7 mmol) and 7.90 g (47.4 mmol) of (dimethylisopropoxysilyl) methylmagnesium chloride in the first stage of the reaction, 22 ml of 31% hydrogen peroxide solution and 1.8 g (21 mmol) of sodium hydrogencarbonate in the second stage ) And 0.3 g (1.57 mmol) of p-toluenesulfonic acid monohydrate in the third step, according to the reaction of Example 7 (ii) above, to obtain 4.90 g (yield 95%) of the title compound as an oil. The reaction product was purified by silica gel (100 g) column chromatography using a 1: 2 to 1: 0 mixture of ethyl acetate and hexane as eluent.
[553] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[554] 0.95 (3H, d, J = 6 Hz);
[555] 3.77 (1H, doublet, J = 11 Hz);
[556] 4.31 (1H, doublet of doublets, J = 11, 2 Hz);
[557] 4.52 (1H, qd, J = 6, 3 Hz);
[558] 6.94-7.00 (2H, m);
[559] 7.44-7.48 (2H, m).
[560] IR spectrum _max (KBr) cm < ^-1 >: 3422, 1487, 1142, 1065.
[561] Mass spectrum m / z (FAB): 219 (M ⁺ +1).
[562] 8 (iii) (2R, 3R) -2- (2,5-difluorophenyl) -1,3-bis (methanesulfonyloxy) -2-butanol
[563] In a manner similar to Example 7 (iii) above, (2R, 3R) -2- (2,5-difluorophenyl) -1,2,3-butanetriol (prepared in step 8 (ii) above) 4.80 g (10.1 mmol) was reacted with 7.75 g (67.8 mmol) of methanesulfonyl chloride, and the obtained product was a silica gel (110 g) column using a 1: 2 to 1: 1 mixture of ethyl acetate and hexane as eluent. Purification by chromatography gave 7.56 g (yield 92%) of the title compound as a colorless oil.
[564] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[565] 1.27 (3H, doublet, J = 6 Hz);
[566] 2.99 (3H, s);
[567] 3.11 (3H, s);
[568] 3.36 (1 H, s);
[569] 4.73 (2H, s);
[570] 5.32 (1H, q, J = 7 Hz);
[571] 7.03-7.26 (2H, m);
[572] 7.43-7.47 (1 H, m).
[573] IR spectrum _max (KBr) cm ⁻¹ : 3484, 1492, 1346, 1169.
[574] Mass spectrum m / z (FAB): 375 (M ⁺ +1).
[575] 8 (iv) (2R, 3S) -2- (2,5-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane
[576] In a manner similar to Example 7 (iv) above, (2R, 3R) -2- (2,5-difluorophenyl) -1,3-bis (methanesulfonyloxy) -2-butanol [Step 8 above] prepared in (iii)] 7.00 g (18.7 mmol) is reacted with 1H-1,2,4-triazole, and the obtained product is silica using a 1: 1 to 3: 2 mixture of ethyl acetate and hexane as eluent. Purification by gel (100 g) column chromatography gave 2.65 g (56% yield) of the title compound as an oil.
[577] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[578] 1.64 (3H, doublet, J = 6 Hz);
[579] 3.20 (1H, q, J = 6 Hz);
[580] 4.42 (1H, doublet, J = 15 Hz);
[581] 4.97 (1H, doublet, J = 15 Hz);
[582] 6.76-6.81 (1 H, m);
[583] 6.89-6.96 (1 H, m);
[584] 6.99 (1H, doublet of doublets, J = 9, 4 Hz);
[585] 7.83 (1 H, s);
[586] 7.99 (1 H, s).
[587] IR spectrum _max (KBr) cm ⁻¹ : 3110, 1500, 1490, 1184, 1135.
[588] Mass spectrum m / z (EI): 251 (M ⁺ ).
[589] 8 (v) (2R, 3R) -2- (2,5-difluorophenyl) -3-[(trans-2-phenyl-1,3-dioxan-5-yl) thio] -1- ( 1H-1,2,4-triazol-1-yl) -2-butanol
[590] In a manner similar to Example 7 (v) above, (2R, 3S) -2- (2,5-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazole- 1-yl) methyl] oxirane [repared in step 8 (iv)] 2.59 g (10.3 mmol) was converted to trans-5- (acetylthio) -2-phenyl-1,3-dioxane. Prepared in -333350] to give 5.36 g of the crude title compound. 0.36 g of this crude product was chromatographed on a silica gel (20 g) column using a 1: 1 mixture of ethyl acetate and hexane as eluent to afford 0.27 g of the purified title compound as a non-crystalline solid.
[591] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[592] 1.22 (3H, doublet, J = 7 Hz);
[593] 3.38 (1H, q, J = 7 Hz);
[594] 3.49 (1H, triplet of triplets, J = 12, 5 Hz);
[595] 3.75 (1H, t, J = 12 Hz);
[596] 3.77 (1H, t, J = 12 Hz);
[597] 4.41 (1H, double doublet of doublets, J = 12, 5, 2 Hz);
[598] 4.52 (1H, double doublet of doublets, J = 12, 5, 2 Hz);
[599] 4.88 (1H, doublet, J = 14 Hz);
[600] 5.06 (1H, doublet, J = 14 Hz);
[601] 5.08 (1H, doublet, J = 1 Hz);
[602] 5.49 (1 H, s);
[603] 6.85-6.91 (1 H, m);
[604] 6.95 (1H, doublet of doublets, J = 9, 4 Hz);
[605] 7.08-7.13 (3H, m);
[606] 7.36-7.41 (2H, m);
[607] 7.49 (1H, doublet of doublets, J = 7, 2 Hz);
[608] 7.80 (1 H, s);
[609] 7.82 (1 H, s).
[610] IR spectrum _max (KBr) cm < ^-1 >: 3405, 1487, 1140, 1074.
[611] Mass spectrum m / z (FAB): 448 (M ⁺ +1).
[612] 8 (vi) (2R, 3R) -2- (2,5-difluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -1- (1H-1 , 2,4-triazol-1-yl) -2-butanol
[613] In a similar manner to Example 7 (vi) above, crude (2R, 3R) -2- (2,5-difluorophenyl) -3-[(trans-2-phenyl-1,3-dioxane- 5.0 g of 5-yl) thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol [repared in step 8 (v)] with hydrochloric acid, the product obtained Was purified by silica gel (50 g) column chromatography using a 3: 100 mixture of methanol and ethyl acetate as eluent to afford 3.17 g (83% overall yield in step 8 (v)) of the title compound as an oil. .
[614] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[615] 1.22 (3H, doublet, J = 7 Hz);
[616] 3.27 (1H, q, J = 6 Hz);
[617] 3.50 (1H, q, J = 7 Hz);
[618] 3.75 (1H, doublet of doublets, J = 11, 6 Hz);
[619] 3.78-3.86 (2H, m);
[620] 3.96 (1H, doublet of doublets, J = 11, 6 Hz);
[621] 4.89 (1H, doublet, J = 14 Hz);
[622] 5.19 (1H, doublet, J = 14 Hz);
[623] 5.56 (1 H, s);
[624] 6.87-7.00 (2H, m);
[625] 7.16-7.11 (1 H, m);
[626] 7.78 (1 H, s);
[627] 7.88 (1 H, s).
[628] IR spectrum _max (KBr) cm ⁻¹ : 3302, 1488, 1047.
[629] Mass spectrum m / z (FAB): 360 (M ⁺ +1).
[630] 8 (vii) (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol
[631] In a manner similar to Example 1 (iii) above, (2R, 3R) -2- (2,5-difluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio ] -1- (1H-1,2,4-triazol-1-yl) -2-butanol [repared in step 8 (vi) above] 1.02 g (2.84 mmol), 3-fluoro-4-[( The reaction was carried out using 571.6 mg (2.84 mmol) of 1E, 3E) -5-oxo-1,3-pentadienyl] benzonitrile and 594.5 mg (3.13 mmol) of p-toluenesulfonic acid monohydrate, and the reaction product was Purification by silica gel (75 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent gave 1.03 g (66% yield) of the title compound as a colorless non-crystalline solid.
[632] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[633] 1.20 (3H, doublet, J = 7 Hz);
[634] 3.35 (1H, q, J = 7 Hz);
[635] 3.41 (1H, triplet of triplets, J = 11, 5 Hz);
[636] 3.62 (1H, t, J = 11 Hz);
[637] 3.64 (1H, t, J = 11 Hz);
[638] 4.31 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[639] 4.43 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[640] 4.86 (1H, doublet, J = 14 Hz);
[641] 5.03 (1H, doublet, J = 14 Hz);
[642] 5.06-5.08 (2H, m);
[643] 5.90 (1H, doublet of doublets, J = 15, 4 Hz);
[644] 6.62 (1H, doublet of doublets, J = 15, 10 Hz);
[645] 6.75 (1H, doublet, J = 16 Hz);
[646] 6.95 (1H, doublet of doublets, J = 16, 10 Hz);
[647] 6.85-6.98 (2H, m);
[648] 7.07-7.12 (1 H, m);
[649] 7.34 (1H, doublet, J = 10 Hz);
[650] 7.40 (1H, doublet, J = 8 Hz);
[651] 7.58 (1H, t, J = 8 Hz);
[652] 7.79 (1 H, s);
[653] 7.81 (1 H, s).
[654] IR spectrum _max (KBr) cm ⁻¹ : 3416, 2231, 1487, 1141.
[655] Mass spectrum m / z (FAB): 543 (M ⁺ +1).
[656] Example 9
[657] [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1, 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl] acetate
[658]
[659] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol [Example above 543 mg (1.00 mmol) was added to a suspension of 48 mg (1.10 mmol) of a 55% dispersion of sodium hydride (pre-washed with hexane) in 5 ml of N, N-dimethylformamide while stirring at ambient temperature. . After stopping the release of hydrogen gas, the mixture was cooled to 0 ° C and 117.8 mg (1.50 mmol) of acetyl chloride was added. The resulting mixture was stirred at 70 ° C. for 28 hours. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with water and aqueous sodium chloride solution and then concentrated under reduced pressure. The oily residue obtained was purified by silica gel (50 g) column chromatography using a 1: 2 to 2: 1 mixture of ethyl acetate and hexane as eluent to afford a 7: 3 mixture of the title compound and starting material. 226.2 mg of oil containing was obtained. The oil was subjected to recycle HPLC using chloroform as eluent [continuously bound JAIGEL-1H (20 mm i.d × 600 mm) and JAIGEL-2H (20 mm i.d × 600 mm), Japan Analytical Industry, Co. Ltd. Further purification in 18th) afforded 120 mg (yield 21%) of the title compound as a non-crystalline solid.
[660] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[661] 1.35 (3H, doublet of doublets, J = 7, 2 Hz);
[662] 2.11 (3 H, s);
[663] 3.08 (1H, triplet of triplets, J = 11, 5 Hz);
[664] 3.52 (2H, t, J = 11 Hz);
[665] 3.92 (1H, q, J = 7 Hz);
[666] 4.15-4.23 (2H, m);
[667] 5.00 (1H, doublet, J = 4 Hz);
[668] 5.32 (1H, doublet of doublets, J = 15, 3 Hz);
[669] 5.38 (1H, doublet, J = 15 Hz);
[670] 5.85 (1H, doublet of doublets, J = 15, 4 Hz);
[671] 6.58 (1H, doublet of doublets, J = 15, 12 Hz);
[672] 6.74 (1H, doublet, J = 15 Hz);
[673] 6.85-6.98 (3H, m);
[674] 7.28-7.36 (3H, m);
[675] 7.57 (1H, doublet of doublets, J = 8, 4 Hz);
[676] 7.94 (1 H, s);
[677] 7.95 (1 H, s).
[678] IR spectrum _max (KBr) cm ⁻¹ : 2231, 1746, 1504, 1141.
[679] Mass spectrum m / z (FAB): 585 (M ⁺ +1).
[680] Example 10
[681] [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1, 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl] benzoate
[682]
[683] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol [Example above 543 mg (1.00 mmol) was stirred in a suspension of 48 mg (1.10 mmol) of a 55% dispersion of sodium hydride (pre-washed with hexane) in oil in 3 ml of N, N-dimethylformamide at ambient temperature. While adding. After the release of hydrogen gas was stopped, 210.9 mg (1.50 mmol) of benzoyl chloride were added to the mixture. The resulting mixture was stirred at ambient temperature for 6 hours. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with water and aqueous sodium chloride solution and then concentrated under reduced pressure. The oily residue obtained was purified by silica gel (40 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to give 234.2 mg (yield 36%) of the title compound as a colorless non-crystalline. Obtained as a solid.
[684] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[685] 1.47 (3H, doublet of doublets, J = 7, 2 Hz);
[686] 3.08 (1 H, m);
[687] 3.53 (1H, t, J = 11 Hz);
[688] 3.54 (1H, t, J = 11 Hz);
[689] 4.03 (1H, q, J = 7 Hz);
[690] 4.18-4.22 (2H, m);
[691] 5.01 (1H, doublet, J = 4 Hz);
[692] 5.50 (1H, doublet of doublets, J = 15, 3 Hz);
[693] 5.55 (1H, doublet, J = 15 Hz);
[694] 5.86 (1H, doublet of doublets, J = 15, 4 Hz);
[695] 6.59 (1H, doublet, J = 15, 10 Hz);
[696] 6.74 (1H, doublet, J = 16 Hz);
[697] 6.88-6.97 (3H, m);
[698] 7.34 (1H, doublet, J = 10 Hz);
[699] 7.40-7.50 (4H, m);
[700] 7.56-7.64 (2H, m);
[701] 7.86 (1 H, s);
[702] 7.89 (1 H, s);
[703] 7.94 (2H, doublet, J = 8 Hz).
[704] IR spectrum _max (KBr) cm ⁻¹ : 2231, 1724, 1504, 1276.
[705] Mass spectrum m / z (FAB): 647 (M ⁺ +1).
[706] Example 11
[707] [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1, 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl] isobutyl carbonate
[708]
[709] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol [Example above Prepared in 1 or 4] 543 mg (1.00 mmol) was stirred in a suspension of 48 mg (1.10 mmol) of a 55% dispersion of sodium hydride (pre-washed with hexane) in oil in 3 ml of N, N-dimethylformamide at 0 ° C. After addition with addition, the resulting mixture was stirred at ambient temperature. After stopping the release of hydrogen gas, the reaction mixture was cooled to 0 ° C and 204.9 mg (1.50 mmol) of isobutyl chloroformate was added. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with water and aqueous sodium chloride solution and then concentrated under reduced pressure. The obtained oily residue was purified by silica gel (25 g) column chromatography using a 1: 2 mixture of ethyl acetate and hexane as eluent to give 192.3 mg (yield 30%) of the title compound as a colorless non-crystalline solid. Obtained as.
[710] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[711] 0.95 (3H, d, J = 7 Hz);
[712] 0.97 (3H, doublet, J = 7 Hz);
[713] 1.34 (3H, doublet of doublets, J = 7, 2 Hz);
[714] 3.05 (1H, triplet of triplets, J = 12, 5 Hz);
[715] 3.49 (1H, t, J = 12 Hz);
[716] 3.50 (1H, t, J = 12 Hz);
[717] 3.89-3.99 (3H, m);
[718] 4.19 (1H, double doublet of doublets, J = 12, 5, 2 Hz);
[719] 4.34 (1H, double doublet of doublets, J = 12, 5, 2 Hz);
[720] 4.97 (1H, doublet, J = 4 Hz);
[721] 5.34 (1H, doublet of doublets, J = 15, 4 Hz);
[722] 5.43 (1H, doublet, J = 15 Hz);
[723] 5.86 (1H, doublet of doublets, J = 15, 4 Hz);
[724] 6.58 (1H, doublet of doublets, J = 15, 10 Hz);
[725] 6.73 (1H, doublet, J = 15 Hz);
[726] 6.92 (1H, doublet of doublets, J = 15, 10 Hz);
[727] 6.85-6.96 (2H, m);
[728] 7.33 (1H, doublet, J = 10 Hz);
[729] 7.40 (1H, doublet, J = 7 Hz);
[730] 7.45 (1H, doublet of doublets, J = 8, 2 Hz);
[731] 7.57 (1H, t, J = 8 Hz);
[732] 7.95 (1 H, s);
[733] 7.97 (1 H, s).
[734] IR spectrum _max (KBr) cm ⁻¹ : 2231, 1749, 1504, 1141.
[735] Mass spectrum m / z (FAB): 643 (M ⁺ +1).
[736] Example 12
[737] [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1, 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl] aminoacetate
[738]
[739] 12 (i) [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl ] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl ] (1,3-dioxo-1,3-dihydro-2-isoindolyl) acetate
[740] 280 mg (2.2 mmol) of oxalyl chloride and 15 μl of N, N-dimethylformamide were added to a suspension of 410 mg (2.0 mmol) of N-phthaloylglycine in 10 mL of dichloromethane at 0 ° C. with stirring. The mixture was stirred at ambient temperature for 3 hours, then evaporated under reduced pressure to remove solvent from the reaction mixture, and the mixture was evaporated to dryness in vacuo to afford crude acid chloride as a solid.
[741] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol [Example above Prepared in 1 or 4] 542 mg (1.00 mmol) was stirred in a suspension of 87 mg (2.00 mmol) of a 55% dispersion of sodium hydride (pre-washed with hexane) in oil in 5 ml of N, N-dimethylformamide at 0 ° C. After addition while adding, the mixture was stirred at ambient temperature for 40 minutes. After the reaction mixture was cooled to 0 ° C., the obtained crude acid chloride solution in 4 ml of tetrahydrofuran was added. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was subsequently washed with a saturated aqueous sodium hydrogen carbonate solution, a 10% aqueous sodium chloride solution and a saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The oily residue obtained above was purified by silica gel (10 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to afford 187 mg (yield 26%) of the title compound as an oil.
[742] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[743] 1.37 (3H, doublet of doublets, J = 7, 2 Hz);
[744] 2.99 (1H, triplet of triplets, J = 11, 5 Hz);
[745] 3.47 (1H, t, J = 11 Hz);
[746] 3.48 (1H, t, J = 11 Hz);
[747] 3.82 (1H, q, J = 7 Hz);
[748] 4.1-4.2 (2H, m);
[749] 4.45 (1H, doublet, J = 17 Hz);
[750] 4.57 (1H, doublet, J = 17 Hz);
[751] 4.97 (1H, doublet, J = 4 Hz);
[752] 5.33 (1H, doublet, J = 15 Hz);
[753] 5.37 (1H, doublet of doublets, J = 15, 2 Hz);
[754] 5.84 (1H, doublet, J = 15, 4 Hz);
[755] 6.58 (1H, doublet of doublets, J = 15, 11 Hz);
[756] 6.74 (1H, doublet, J = 16 Hz);
[757] 6.8-7.0 (2H, m);
[758] 6.92 (1H, doublet of doublets, J = 16, 11 Hz);
[759] 7.33 (1H, doublet of doublets, J = 10, 2 Hz);
[760] 7.35-7.45 (2H, m);
[761] 7.57 (1H, t, J = 8 Hz);
[762] 7.77 (2H, doublet of doublets, J = 6, 3 Hz);
[763] 7.91 (2H, doublet of doublets, J = 6, 3 Hz);
[764] 7.99 (1 H, s);
[765] 8.12 (1 H, s).
[766] IR spectrum _max (CHCl ₃ ) cm ⁻¹ : 2233, 1726, 1504, 1417.
[767] Mass spectrum m / z (FAB): 730 (M ⁺ +1).
[768] Specific rotation: [α] _D ^{25 +} 5.5 ° (c = 1.02, CHCl ₃ ).
[769] 12 (ii) [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl ] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl ] Amino acetate
[770] 104 mg (2.22 mmol) of methylhydrazine were added to [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) in 5 ml of dichloromethane. ) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4 -Triazol-1-yl) methyl] propyl] (1,3-dioxo-1,3-dihydro-2-isoindolyl) acetate [repared in step 12 (i) above] 180 mg (0.25 mmol) The solution was added under ice bath. The resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then concentrated in vacuo and evaporated to dryness. Dichloromethane was added to the obtained residue, and then dichloromethane was evaporated under reduced pressure. The obtained residue was dissolved in dichloromethane and the solution was left at ambient temperature for 12 hours and then concentrated. The residue obtained was purified by silica gel (5 g) column chromatography using a 9: 1 mixture of ethyl acetate and ethanol as eluent to afford 126 mg (85% yield) of the title compound as a pale yellow non-crystalline solid. It was.
[771] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[772] 1.35 (3H, doublet of doublets, J = 7, 2 Hz);
[773] 3.04 (1H, triplet of triplets, J = 11, 5 Hz);
[774] 3.4-3.5 (4H, m);
[775] 3.90 (1H, q, J = 7 Hz);
[776] 4.1-4.3 (2H, m);
[777] 5.00 (1H, doublet, J = 4 Hz);
[778] 5.36 (1H, doublet, J = 15 Hz);
[779] 5.38 (1H, doublet of doublets, J = 15, 2 Hz);
[780] 5.85 (1H, doublet of doublets, J = 15, 4 Hz);
[781] 6.59 (1H, doublet of doublets, J = 15, 10 Hz);
[782] 6.74 (1H, doublet, J = 16 Hz);
[783] 6.80-6.95 (3H, m);
[784] 7.3-7.4 (2H, m);
[785] 7.40 (1H, doublet of doublets, J = 8, 1 Hz);
[786] 7.57 (1H, t, J = 8 Hz);
[787] 7.91 (1 H, s);
[788] 7.92 (1 H, s).
[789] IR spectrum _max (CHCl ₃ ) cm ⁻¹ : 2233, 1748, 1615, 1504, 1276, 1140.
[790] Mass spectrum m / z (FAB): 600 (M ⁺ +1).
[791] Specific rotation: [α] _D ²⁵ +14.6。 (c = 0.52, CHCl ₃ ).
[792] Example 13
[793] [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1, 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl] 3-amino Propionate
[794]
[795] 13 (i) [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl ] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl 3- (1,3-dioxo-1,3-dihydro-2-isoindolyl) propionate
[796] 280 mg (2.2 mmol) of oxalyl chloride and 15 μl of N, N-dimethylformamide were added to N-phthaloyl-β-alanine in 3 mL of dichloromethane [J. Agric. Food Chem. 47, prepared from 1276-1284 (1999)] to 438.4 mg (2.0 mmol) suspension with stirring. The mixture was stirred at ambient temperature for 40 minutes and then evaporated under reduced pressure to remove solvent from the reaction mixture and evaporated to dryness in vacuo to afford crude acid chloride as a solid.
[797] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol [Example above Prepared in 1 or 4] 543 mg (1.00 mmol) is stirred in a suspension of 48 mg (1.10 mmol) of 55% dispersion of sodium hydride (pre-washed with hexane) in oil in 5 ml of N, N-dimethylformamide at 0 ° C. After addition while adding, the resulting mixture was stirred at ambient temperature for 20 minutes. After the reaction mixture was cooled to 0 ° C., the obtained crude acid chloride solution in 4 ml of tetrahydrofuran was added. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with water, washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The obtained oily residue was purified by silica gel (40 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to give 100 mg (yield 13%) of the title compound as an oil.
[798] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[799] 1.33 (3H, doublet of doublets, J = 7, 2 Hz);
[800] 2.82 (1H, t d, J = 7, 1 Hz);
[801] 2.92 (1H, t, J = 7 Hz);
[802] 2.95-3.03 (1 H, m);
[803] 3.47 (1H, t, J = 11 Hz);
[804] 3.49 (1H, t, J = 11 Hz);
[805] 3.85 (1H, q, J = 7 Hz);
[806] 3.94-4.00 (2H, m);
[807] 4.05-4.11 (2H, m);
[808] 4.97 (1H, doublet, J = 4 Hz);
[809] 5.31 (1H, doublet, J = 15 Hz);
[810] 5.35 (1H, doublet, J = 15 Hz);
[811] 5.84 (1H, doublet of doublets, J = 15, 4 Hz);
[812] 6.57 (1H, doublet of doublets, J = 15, 10 Hz);
[813] 6.73 (1H, doublet, J = 16 Hz);
[814] 6.77-6.85 (2H, m);
[815] 6.92 (1H, doublet of doublets, J = 16, 10 Hz);
[816] 7.29-7.35 (2H, m);
[817] 7.40 (1H, doublet of doublets, J = 8, 1 Hz);
[818] 7.57 (1H, t, J = 8 Hz);
[819] 7.71-7.75 (2H, m);
[820] 7.83-7.89 (2H, m);
[821] 7.86 (1 H, s);
[822] 7.97 (1 H, s).
[823] 13 (ii) [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl ] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl 3-aminopropionate
[824] 222.7 mg (4.38 mmol) of methylhydrazine were added to [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) in 2 ml of dichloromethane. ) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4 -Triazol-1-yl) methyl] propyl] 3- (1,3-dioxo-1,3-dihydro-2-isoindolyl) propionate (prepared in step 13 (i) above) 100 mg (0.13 mmol) was added to the solution under ice bath. The resulting mixture was stirred at ambient temperature for 20 hours. The reaction mixture was then concentrated in vacuo and evaporated to dryness. Dichloromethane was added to the obtained residue, and then dichloromethane was evaporated under reduced pressure. The obtained residue was dissolved in dichloromethane and the solution was left at ambient temperature for 12 hours and then concentrated. The obtained residue was purified by silica gel (15 g) column chromatography using a 9: 1 mixture of ethyl acetate and methanol to give 41.5 mg (yield 50%) of the title compound as a pale yellow amorphous solid. .
[825] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[826] 1.35 (3H, doublet of doublets, J = 7, 2 Hz);
[827] 2.52-2.65 (2H, m);
[828] 3.01-3.08 (3H, m);
[829] 3.51 (2H, t, J = 11 Hz);
[830] 3.87 (1H, q, J = 7 Hz);
[831] 4.16-4.23 (2H, m);
[832] 4.99 (1H, doublet, J = 4 Hz);
[833] 5.37 (2H, s);
[834] 5.85 (1H, doublet of doublets, J = 15, 4 Hz);
[835] 6.58 (1H, doublet of doublets, J = 15, 11 Hz);
[836] 6.74 (1H, doublet, J = 16 Hz);
[837] 6.85-6.92 (2H, m);
[838] 6.92 (1H, doublet of doublets, J = 16, 11 Hz);
[839] 7.33 (1H, doublet of doublets, J = 11, 1 Hz);
[840] 7.35-7. 41 (2H, m);
[841] 7.57 (1H, t, J = 8 Hz);
[842] 7.93 (1 H, s);
[843] 8.11 (1 H, s).
[844] IR spectrum _max (KBr) cm ⁻¹ : 2232, 1504, 1141, 1050.
[845] Mass spectrum m / z (FAB): 614 (M ⁺ +1).
[846] Example 14
[847] Sodium hydrogen [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl]- 1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl] phosphate
[848]
[849] 14 (i) diallyl [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-1 -Yl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl ] Profile] Phosphite
[850] Bis (allyloxy) (diisopropylamino) phosphine [manufactured by Tetrahedron Lett., 30, 4219 (1989)] 490 mg (2.00 mmol) in 4 ml of a 1: 1 mixture of acetonitrile and dichloromethane (2R , 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3-di Oxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol [Example 1 above or Prepared in 4] was added to a suspension of 570 mg (1.00 mmol) and 350 mg (5.00 mmol) of tetrazole. The resulting mixture was stirred at ambient temperature for 15 hours. The reaction mixture was then concentrated and the residue was dissolved in ethyl acetate. The obtained solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained oily residue was purified by silica gel (15 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to give 609 mg (89% yield) of the title compound as a colorless oil.
[851] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[852] 1.29 (3H, doublet, J = 7 Hz);
[853] 3.25 (1H, triplet of triplets, J = 11, 5 Hz);
[854] 3.60-3.70 (3H, m);
[855] 4.30-4.60 (6H, m);
[856] 4.95 (1H, doublet, J = 15 Hz);
[857] 5.08 (1H, doublet, J = 4 Hz);
[858] 5.20-5.30 (2H, m);
[859] 5.30-5.40 (3H, m);
[860] 5.89 (1H, doublet of doublets, J = 15, 4 Hz);
[861] 5.90-6.10 (2H, m);
[862] 6.62 (1H, doublet of doublets, J = 15, 10 Hz);
[863] 6.70-6.85 (2H, m);
[864] 6.75 (1H, doublet, J = 16 Hz);
[865] 6.95 (1H, doublet of doublets, J = 16, 10 Hz);
[866] 7.30-7.45 (3H, m);
[867] 7.58 (1H, t, J = 8 Hz);
[868] 7.64 (1 H, s);
[869] 8.19 (1 H, s).
[870] IR spectrum _max (CHCl ₃ ) cm ⁻¹ : 2233, 1732, 1616, 1501.
[871] Mass spectrum m / z (FAB): 687 (M ⁺ +1).
[872] 14 (ii) diallyl [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-1 -Yl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl ] Profile] Phosphate
[873] 0.42 mL of a about 5 M nonane solution of t-butyl hydroperoxide was diallyl [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4- in dichloromethane) Cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl] phosphite (prepared in step 14 (i) above) was added to a solution of 530 mg (0.772 mmol) at 0 ° C. The resulting mixture was stirred at 0 ° C. for 1 hour. Subsequently, 5 ml of saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred at ambient temperature for 1 hour. The reaction product was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel (15 g) column chromatography using 4: 1 mixture of ethyl acetate and hexane as eluent to give 447 mg (yield 82%) of the title compound as a viscous colorless solid.
[874] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[875] 1.29 (3H, doublet, J = 7 Hz);
[876] 3.18 (1H, triplet of triplets, J = 11, 5 Hz);
[877] 3.63 (2H, t d, J = 11, 2 Hz);
[878] 3.79 (1H, q, J = 7 Hz);
[879] 4.28 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[880] 4.38 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[881] 4.45-4.60 (2H, m);
[882] 4.66 (2H, m);
[883] 5.05 (1H, doublet, J = 4 Hz);
[884] 5.08 (1H, doublet, J = 15 Hz);
[885] 5.27 (1H, broad doublet, J = 10 Hz);
[886] 5.31 (1H, broad doublet, J = 10 Hz);
[887] 5.34 (1H, broad doublet, J = 17 Hz);
[888] 5.43 (1H, broad doublet, J = 17 Hz);
[889] 5.72 (1H, doublet, J = 15 Hz);
[890] 5.88 (1H, doublet of doublets, J = 15, 4 Hz);
[891] 5.85-6.05 (2H, m);
[892] 6.61 (1H, doublet of doublets, J = 15, 11 Hz);
[893] 6.75 (1H, doublet, J = 16 Hz);
[894] 6.80-6.90 (2H, m);
[895] 6.94 (1H, doublet of doublets, J = 16, 11 Hz);
[896] 7.30-7.40 (3H, m);
[897] 7.57 (1H, t, J = 8 Hz);
[898] 7.69 (1 H, s);
[899] 8.40 (1 H, s).
[900] IR spectrum _max (KBr) cm ⁻¹ : 2231, 1616, 1504, 1420.
[901] Mass spectrum m / z (FAB): 703 (M ⁺ +1).
[902] 14 (iii) diallyl [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-1 -Yl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl ] Propyl] phosphate [alternative to steps 14 (i) and 14 (ii)]
[903] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-1- in 5 ml of dimethylformamide Il] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2 Butanol [repared in Examples 1 or 4 above] A suspension of 860 mg (1.52 mmol) and 40 mg (1.67 mmol) of sodium hydride was stirred at ambient temperature for 10 minutes. 300 mg (1.53 mmol) of chloride diallylphosphoryl (manufactured by Tetrahedron Lett., 28, 2259 (1987)) were added to the brown reaction mixture, and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate and the ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified in the same manner as in Step 14 (ii) to give 204 mg (yield 19%) of the title compound as a viscous colorless solid. NMR, IR and mass spectral data were identical to the compound of step 14 (ii) above.
[904] 14 (iv) sodium hydrogen [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-1 -Yl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl ] Profile] Phosphate
[905] 1 mg of dichlorobis (triphenylphosphine) palladium (II) and 192 mg (0.66 mmol) of tributyltin hydride were diallyl [(1R, 2R) -2-[[trans-2- [in 1.5 mL of dichloromethane. (1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -1- (2 , 4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propyl] phosphate [repared in step 14 (ii) or 14 (iii) above] 185 mg ( 0.263 mmol) was added to the solution. The resulting mixture was stirred at ambient temperature for 15 minutes. Hexane was then added to the reaction mixture to precipitate the insoluble material and carefully removed by decanting the supernatant solution of this mixture. 3 ml of saturated aqueous sodium hydrogen carbonate solution was added to the residue solution in 5 ml of methanol and the resulting mixture was stirred at ambient temperature for 15 hours. The reaction mixture was then concentrated under reduced pressure, methanol was added to the residue, and then filtered to remove insoluble matters. The filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase chromatography on Cosmosil 75 C ₁₈ -PREP (20 mL, manufactured by Nacalai Tesque, Inc.) using a 3: 2 mixture of methanol and water as eluent. The collected fractions containing the desired product were concentrated and lyophilized to yield 76 mg (45% yield) of the title compound as a colorless solid.
[906] ¹ H-nuclear magnetic resonance spectrum (400 MHz, D ₂ O) ppm:
[907] 1.18 (3H, doublet, J = 7 Hz);
[908] 2.89 (1 H, m);
[909] 3.40-3.60 (2H, m);
[910] 3.74 (1H, q, J = 7 Hz);
[911] 3.97 (1 H, m);
[912] 4.14 (1 H, m);
[913] 5.05 (1H, doublet, J = 6 Hz);
[914] 5.09 (1H, doublet, J = 15 Hz);
[915] 5.39 (1H, doublet, J = 15 Hz);
[916] 5.73 (1H, doublet of doublets, J = 15, 2 Hz);
[917] 6.52 (1H, doublet of doublets, J = 15, 10 Hz);
[918] 6.70-6.80 (2H, m);
[919] 6.74 (1H, doublet of doublets, J = 16 Hz);
[920] 6.95 (1H, doublet of doublets, J = 16, 11 Hz);
[921] 7.35-7.45 (2H, m);
[922] 7.55-7.70 (2H, m);
[923] 7.65 (1 H, s);
[924] 8.69 (1 H, s).
[925] IR spectrum _max (KBr) cm ⁻¹ : 3417, 2232, 1616, 1498, 1418.
[926] Mass spectrum m / z (FAB): 645 (M ⁺ +1).
[927] Reference Example 1
[928] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyanophenyl) -1,3-butadien-1-yl] -1,3-dioxane-5 -Yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol (comparative compound A)
[929] 1 (i) 4-[(1E, 3E) -5-oxo-1,3-pentadienyl] benzonitrile
[930] 13.1 g (99 mmol) of 4-formylbenzonitrile (commercially available) and (triphenylphosphoranilidene) crotonaldehyde in 200 ml of dichloromethane (manufactured by Tetrahedron Lett., 493 (1971)) of 40 g (120 mmol) The solution was stirred at ambient temperature overnight. The reaction mixture was then concentrated to dryness in vacuo. The obtained residue was purified by silica gel (250 g) column chromatography using ethyl acetate as eluent to afford a mixture of the desired compound with its geometric isomers. The solution of the two isomeric mixtures in 150 ml of toluene was heated to reflux for 12 hours under tungsten lamp (300 W) irradiation. The reaction mixture was then concentrated in vacuo. The obtained residue was purified by silica gel (1.2 kg) column chromatography using a 1: 9 mixture of ethyl acetate and toluene as eluent to give 3.46 g (yield 19%) of the title compound as light brown needles. It was collected by filtration.
[931] Melting Point: 147-150 ℃
[932] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[933] 6.36 (1H, doublet of doublets, J = 15, 8 Hz);
[934] 7.00 (1H, doublet, J = 16 Hz);
[935] 7.09 (1H, doublet of doublets, J = 16, 10 Hz);
[936] 7.27 (1H, doublet of doublets, J = 15, 10 Hz);
[937] 7.59 (2H, doublet, J = 8 Hz);
[938] 7.67 (2H, doublet, J = 8 Hz);
[939] 9.67 (1H, doublet, J = 8 Hz);
[940] IR spectrum _max (KBr) cm ⁻¹ : 2226, 1683, 1670, 1626.
[941] Mass spectrum m / z (EI): 183 (M ⁺ , 100%) 154, 140, 127, 115.
[942] Analytical Calcd for C ₁₂ H ₉ NO: C, 78.67; H, 4.95; N, 7.65
[943] Found: C, 78.56; H, 5.05; N, 7.62.
[944] 1 (ii) (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyanophenyl) -1,3-butadien-1-yl] -1,3- Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol
[945] 4-[(1E, 3E) -5-oxo-1,3-pentadienyl] benzonitrile [repared in step 1 (i)] 240 mg (1.31 mmol), (2R, 3R) -2- (2 , 4-difluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -1- (1H-1,2,4-triazol-1-yl) -2 -Butanol [repared in Japanese Patent Application Laid-Open No. 8-333350] A mixture of 392 mg (1.09 mmol), 249 mg p-toluenesulfonic acid monohydrate, 1.3 ml of dichloromethane and 3.9 g of molecular sieve 4A Stir overnight at. An aqueous sodium hydrogen carbonate solution was then added to the reaction mixture and filtered to remove insoluble matters. The obtained filtrate was extracted with ethyl acetate and the organic layer was dried and then concentrated. The obtained residue was purified by silica gel (15 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to give 465 mg (yield 81%) of the title compound as a solid. This solid was recrystallized from a mixture of ethyl acetate and hexanes to give crystals.
[946] Melting Point: 147-149 ℃
[947] ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) ppm:
[948] 1.19 (3H, doublet, J = 7 Hz);
[949] 3.33 (1H, q, J = 7 Hz);
[950] 3.40 (1H, triplet of triplets, J = 11, 5 Hz);
[951] 3.62 (1H, t, J = 11 Hz);
[952] 3.64 (1H, t, J = 11 Hz);
[953] 4.31 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[954] 4.43 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[955] 4.83 (1H, doublet, J = 14 Hz);
[956] 5.00 (1 H, s);
[957] 5.03 (1H, doublet, J = 14 Hz);
[958] 5.06 (1H, doublet, J = 4 Hz);
[959] 5.87 (1H, doublet of doublets, J = 15, 4 Hz);
[960] 6.59 (1H, doublet of doublets, J = 15, 10 Hz);
[961] 6.61 (1H, doublet, J = 15 Hz);
[962] 6.7-6.8 (2H, m);
[963] 6.87 (1H, doublet of doublets, J = 15, 10 Hz);
[964] 7.35 (1H, t d, J = 8, 7 Hz);
[965] 7.48 (2H, doublet, J = 8 Hz);
[966] 7.60 (2H, doublet, J = 8 Hz);
[967] 7.79 (2 H, s).
[968] IR spectrum _max (KBr) cm ⁻¹ : 2225, 1617, 1603, 1500, 1140.
[969] Mass spectrum m / z (FAB): 525 (M ⁺ +1).
[970] Specific rotation: [α] _D ²⁵ -73.4。 (c = 1.30, CHCl ₃ ).
[971] Analytical calcd. For C ₂₇ H ₂₆ F ₂ N ₄ O ₃ S: C, 61.82; H, 5.00; N, 10.68
[972] Found: C, 62.00; H, 5.01; N, 10.56.
[973] Reference Example 2
[974] (2R, 3R) -4-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] -2- (2,4-difluorophenyl) -3-methyl-1- (1H-1,2,4-triazol-1-yl) -2-butanol (comparative Compound C)
[975] 3-Fluoro-4-[(1E, 3E) -5-oxo-1,3-pentadienyl] benzonitrile [repared in Example 1 (ii)], in the manner of Example 1 (iii) above 708 mg (3.51 mmol) and (4S, 5R) -5- (2,4-difluorophenyl) -2- (hydroxymethyl) -4-methyl-6- (1H-1,2,4-tria The reaction was carried out using 1000 mg (2.93 mmol) of sol-1-yl) -1,5-hexanediol (manufactured in Japanese Patent Laid-Open No. 11-80135). The crude extract was purified by silica gel (20 g) column chromatography using a 1: 1 mixture of ethyl acetate and hexane as eluent to afford 1.18 g (yield 77%) of the title compound as a pale non-crystalline solid. It was.
[976] ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) ppm:
[977] 0.83 (3H, doublet, J = 7 Hz);
[978] 1.09 (1 H, m);
[979] 1.43 (1 H, m);
[980] 1.95-2.20 (2H, m);
[981] 3.45 (1H, t, J = 11 Hz);
[982] 3.47 (1H, t, J = 11 Hz);
[983] 4.11 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[984] 4.23 (1H, double doublet of doublets, J = 11, 5, 2 Hz);
[985] 4.48 (1H, doublet, J = 14 Hz);
[986] 4.86 (1 H, s);
[987] 4.94 (1H, doublet, J = 14 Hz);
[988] 5.03 (1H, doublet, J = 4 Hz);
[989] 5.91 (1H, doublet of doublets, J = 15, 4 Hz);
[990] 6.61 (1H, doublet of doublets, J = 15, 10 Hz);
[991] 6.65-6.80 (3H, m);
[992] 6.95 (1H, doublet of doublets, J = 15, 10 Hz);
[993] 7.33 (1H, doublet of doublets, J = 10, 1 Hz);
[994] 7.35-7.45 (1 H, m);
[995] 7.39 (1H, doublet of doublets, J = 8, 1 Hz);
[996] 7.57 (1H, t, J = 8 Hz);
[997] 7.77 (1 H, s);
[998] 7.87 (1 H, s).
[999] IR spectrum _max (KBr) cm ⁻¹ : 2231, 1615, 1499, 1141.
[1000] Mass spectrum m / z (EI): 524 (M ⁺ , 100%) 368, 224.
[1001] Specific rotation: [α] _D ²⁵ -66。 (c = 0.5, CHCl ₃ ).
[1002] Formulation example
[1003] Formulation Example 1
[1004] Hard capsule
[1005] A composition was prepared by mixing the components set forth below in the amounts set forth below, which were filled in standard two-component hard gelatin capsules, and then the capsules were washed and dried to give the desired hard capsules.
[1006] Powder Compound (Ib) 100 mg
[1007] Lactose 150 mg
[1008] 50 mg of cellulose
[1009] Magnesium Stearate 6mg
[1010] 306 mg
[1011] Formulation Example 2
[1012] Soft capsule
[1013] Mixtures of compounds (Ib) in digestible oils such as soybean oil, cottonseed oil or olive oil are prepared and injected into gelatin to give a soft capsule containing 100 mg of the active ingredient, which is then washed and dried to obtain the desired soft capsule. Obtained.
[1014] Formulation Example 3
[1015] refine
[1016] According to a conventional method, tablets having the composition shown below were prepared.
[1017] 100 mg of compound (Ib)
[1018] Colloidal silicon dioxide 0.2 mg
[1019] Magnesium Stearate 5mg
[1020] Microcrystalline Cellulose 275 mg
[1021] Starch 11 mg
[1022] Lactose 98.8 mg
[1023] 490 mg
[1024] If desired, tablets may be coated with a suitable formulation coating.
[1025] Test Example
[1026] Test Example 1
[1027] In vitro antifungal activity
[1028] Antifungal activity of the test compounds was evaluated according to their minimum inhibitory concentrations (MICs) measured by the method described below.
[1029] 1 (i) Candida ( CandidaMeasurement method for species
[1030] Using a modified method of the method described in Japanese Journal of Medical Mycology, 32 , 62 (1995), MICs were obtained by the broth microdilution method. Each test compound was dissolved in dimethyl sulfoxide (DMSO). Sequential two-fold dilutions of each test compound were prepared in DMSO, and the final dilutions were prepared in RPMI1640 medium (manufactured by Dainippon Pharmaceutical) with pH 7.0 buffer of 0.615 M 3- (morpholino) propanesulfonic acid (MOPS). It was. The final concentration of DMSO did not exceed 1%. Colonies of the test bacteria were suspended in physiological salt solution of 0.615 M MOPS pH 7.0 buffer in RPMI1640 medium to adjust to 5.0 × 10 ² to 2.5 × 10 ³ cells / ml. 100: 1 bacterial suspension is placed in each well of a microtitre plate, and then 100: 1 of each test compound is added to the wells and mixed with the bacterial suspension and incubated at 35 ° C. for 24 to 72 hours. It was. When no marked growth was observed in control wells in which no compound was present, the MICs of each test compound were measured. MICs are defined as the lowest compound concentrations that show growth inhibition of at least 80% when compared to the control.
[1031] 1 (ii) Cryptococcus neoformans ( Cryptococcus neoformansMeasurement method for
[1032] See Broth Dilution Antifungal Susceptibility Testing of Yeast; Using the modified method of Approved Standard M27-A (Vol. 17, No. 9, June 1997, NCCLS)], MICs were obtained by the broth microdilution method. Each test compound was dissolved in DMSO. Sequential two-fold dilutions of each test compound were prepared in DMSO, and the final dilutions were made in East Nitrogen based medium (manufactured by Difco Laboratories) buffered with a pH 7.0 buffer of 0.615 M MOPS. The final concentration of DMSO did not exceed 1%. Colonies of the test bacteria were suspended in physiological salt solution of 0.615 M MOPS pH 7.0 buffer in yeast nitrogen based medium to adjust to 5.0 x 10 ³ to 2.5 x 10 ⁴ cells / ml. A 100: 1 bacterial suspension was placed in each well of a microtitre plate, and then 100: 1 of each test compound was added to the wells, mixed with the bacterial suspension, and incubated at 35 ° C. for 48-72 hours. When no marked growth was observed in control wells in which no compound was present, the MICs of each test compound were measured. MICs are defined as the lowest compound concentrations that show 50% or more growth inhibition when measured by light absorption at 485 nm and compared with the control.
[1033] 1 (iii) aspergillus ( AspergillusMeasurement method for species
[1034] Using the modification of the protocol of Antimicrob Agents Chemother., 39 , 314 (1995), MICs were obtained by the broth microdilution method. Each test compound was dissolved in DMSO. Sequential two-fold dilutions of each test compound were prepared in DMSO, and the final dilutions were prepared in RPMI1640 medium (manufactured by Dainippon Pharmaceutical) with pH 7.0 buffer of 0.615M 3- (morpholino) propanesulfonic acid (MOPS). It was. The final concentration of DMSO did not exceed 1%. Colonies of the test bacteria were suspended with physiological salt solution of 0.615 M MOPS pH 7.0 buffer in RPMI1640 medium to adjust to about 1.0 × 10 ⁴ cells / ml. A 100: 1 bacterial suspension was placed in each well of a microtitre plate, and then 100: 1 of each test compound was added to the wells, mixed with the bacterial suspension, and incubated at 30 ° C. for 24 to 72 hours. When no marked growth was observed in control wells in which no compound was present, the MICs of each test compound were measured. MICs are defined as the lowest compound concentrations that show growth inhibition of at least 80% when compared to the control.
[1035] The in vitro activity of the compound of formula 2c of the present invention was measured using the above test, and the activity was compared with Comparative Compound A (prepared by the method described in Reference Example 1) and Comparative Compound B (Japan) Compared to Example 27 of Japanese Patent Application Laid-Open No. 8-333350. Comparative compounds A and B are compounds disclosed in Japanese Patent Application Laid-open No. Hei 8-333350 and European Laid-Open Patent Application 0841327. The results are shown in Table 1.
[1036] Comparative compounds A and B are represented by the following formulas.
[1037] Compound A
[1038]
[1039] Compound B
[1040]
[1041] In vitro antifungal activityMIC value (µg / mL) compoundCa (1) ^b) Ca (2) ^c) Ca (3) ^d) Cn ^e) Af ^f)Compound (2c) Comparative Compound (A) Comparative Compound (B)0.250.5-10.5≤0.0080.0160.031-0.0630.0630.125 to 0.250.125 to 0.25≤0.0080.016≤0.0080.0310.0310.125 The test microorganisms of b) to f) show the following: b) C.a. (1): Candida albicans ATCC 64550c) C.a. (2): Candida albicans TIMM 3164d) C.a. (3): Candida albicans TIMM 3165e) C.n. : Cryptococcus neoformans TIMM 0362f) A.f. Aspergillus pumigatus SANK 10569
[1042] As can be seen from Table 1, the in vitro antifungal activity of the compound of formula 2c of the present invention is the same as that of the comparative compounds A and B described in Japanese Patent Application Laid-Open No. 8-333350 and European Patent Application No. 0841327. Or excellent.
[1043] Test Example 2
[1044] Acid stability test
[1045] The stability of the compounds of the present invention in the presence of an acid was evaluated according to the _half- life (t _1/2 ) in the acidic solution measured by the method described below.
[1046] 700 μl of 0.01 N (pH 2) hydrochloric acid was added to a solution of the test compound in 300 μl of acetonitrile (the concentration of the test compound was 167 μg / ml) so that the initial concentration of the test compound was 50 μg / ml and the acetonitrile content was A 30% phosphorus mixture was obtained which was incubated at 37 ° C. A small amount of solution was taken from the reaction solution for a predetermined time interval and neutralized with aqueous sodium hydroxide solution to stop the reaction in the sample. Quantitative determination of the residual rate of the test compound in solution was determined by HPLC.
[1047] The half-life (t _1/2 ) of the test compound in 0.01 N HCl is determined using a degradation rate constant (k _deg ) measured by semi-logarithmic regression analysis of the residual rate in the solution. It measured according to the following formula.
[1048] t _1/2 = (ln2) / k _deg
[1049] The larger the t _1/2 value of the compound, the greater the acid stability.
[1050] Results obtained from the compound of formula 2c of the present invention, results obtained from comparative compound A, comparative compound B and comparative compound C (which are disclosed in Japanese Patent Laid-Open Nos. 11-80135 and WO-A-99 / 02524, supra. Prepared as described in Example 2).
[1051] Compound C
[1052]
[1053] Stability in Acidic Solutionscompoundt _1/2 (min) Compound (2c) Comparative Compound (A) Comparative Compound (B) Comparative Compound (C)6.403.121.542.42
[1054] Compounds of formula (2c) of the present invention showed superior stability in the presence of acids compared to Comparative Compounds A, B and C.
[1055] Test Example 3
[1056] Oral absorption
[1057] The oral absorption rate of the compound of the present invention was evaluated according to the biocompatibility (BA) of the compound of the present invention measured by the method described below.
[1058] Test compounds in polyethylene glycol 400 (PEG 400) were administered orally (4) or intravenously (3) to the tail vein in overnight fasted SD rats (7 weeks of age). The oral dose of test compound was 20 mg per kg body weight of rat. The intravenous dose of test compound injected into the tail vein was 2 mg per kg of rat body weight. The amount of PEG 400 used was 1 ml per kg of rat body weight for both oral and intravenous administration. Integral value of blood concentration of test compound [AUCpo (0-48h)] up to 48 hours after oral administration, and extrapolated blood concentration from 0 to infinity time after intravenous administration to caudal vein [AUCiv (0 -∞)] was used to calculate the biocompatibility (BA) value according to the following equation.
[1059] BA (%) = {[(AUCpo (0-48)) / (dose po)] / [(AUCiv (0-∞)) / (dose iv)]} × 100
[1060] The larger the BA value, the greater the oral absorption rate. The results for the compounds of formula 2c of the invention and the results for comparative examples A, B and C are shown in Table 3.
[1061] Biocompatibility compoundBA (%) Compound (2c) Comparative Compound (A) Comparative Compound (B) Comparative Compound (C)12350.76.2457.8
[1062] The compound of formula 2c of the present invention showed better oral absorption than Comparative Examples A, B and C.
[1063] The results indicate that the compound of formula 1a of the present invention and its pharmaceutically acceptable salts and ester derivatives are superior in vivo to the compounds described in Japanese Patent Application Laid-Open Nos. 8-333350 and 11-80135. It shows in vitro antifungal activity, acid safety and oral absorption. The compounds of the present invention also exhibit low toxicity.
[1064] Accordingly, the compounds of formula 1a and pharmaceutically acceptable salts and ester derivatives thereof of the present invention are particularly useful as antifungal agents against a wide range of fungi.

权利要求:
Claims (14)
[1" claim-type="Currently amended] A compound of Formula 1a or a pharmaceutically acceptable salt or ester derivative thereof:
[Formula 1a]
[Wherein Ar is a phenyl group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a trifluoromethyl group].
[2" claim-type="Currently amended] The compound of formula 1a or a pharmaceutically acceptable salt or ester derivative thereof according to claim 1, wherein Ar is a 2,4-difluorophenyl group or 2-fluorophenyl group.
[3" claim-type="Currently amended] The compound of formula 1a or a pharmaceutically acceptable salt or ester derivative thereof according to claim 1, wherein Ar is a 2,4-difluorophenyl group.
[4" claim-type="Currently amended] The compound of formula 1a, or a pharmaceutically acceptable salt or ester derivative thereof, according to claim 1, wherein the compound of formula 1a is a compound of formula 1b:
[Formula 1b]
[Wherein Ar is a phenyl group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a trifluoromethyl group].
[5" claim-type="Currently amended] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] -1,3 -Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol or its Pharmaceutically acceptable salts or ester derivatives.
[6" claim-type="Currently amended] (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadien-1-yl] in crystalline form -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol .
[7" claim-type="Currently amended] 7. The method of claim 6, determined by X-ray diffraction by powder method using copper K _α -ray, 3.14, 3.39, 3.71, 3.75, 4.21, 4.88, 5.28, 5.42, 5.89, 5.95, 6.79, 6.86, 8.03 And (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) in crystalline form having a major peak at a lattice distance of 8.41 GHz ) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4 -Triazol-1-yl) -2-butanol.
[8" claim-type="Currently amended] The lattice distance of claim 6, determined by X-ray diffraction by powder method using copper K _α -rays, 3.62, 3.96, 4.54, 4.59, 4.79, 4.91, 5.32, 5.48, 6.18, 7.99, and 15.93 kV (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene in crystalline form having a major peak at -1-yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl ) -2-butanol.
[9" claim-type="Currently amended] A pharmaceutical composition comprising an effective amount of a pharmacologically active compound, and a pharmaceutically acceptable carrier or diluent for the active compound, wherein the pharmacologically active compound is any one of claims 1-8. A pharmaceutical composition, which is a compound of Formula 1a or a pharmaceutically acceptable salt or ester derivative thereof.
[10" claim-type="Currently amended] The compound of formula 1a or a pharmaceutically acceptable salt or ester derivative thereof according to any one of claims 1 to 8 for use as a medicament.
[11" claim-type="Currently amended] The compound of formula 1a or a pharmaceutically acceptable salt or ester derivative thereof according to any one of claims 1 to 8 for use as an antifungal agent.
[12" claim-type="Currently amended] Use of a compound of formula 1a according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or ester derivative thereof, in the manufacture of a medicament for the prevention or treatment of a fungal infection.
[13" claim-type="Currently amended] A compound of formula (2a) or an acetal derivative thereof:
[Formula 2a]
[14" claim-type="Currently amended] The compound of formula 2a according to claim 13 having the formula
[Formula 2b]

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-09-09|Priority to JP99-255702

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1999-09-09|Priority to JP25570299

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2000-04-05|Priority to JP2000-103826

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2000-04-05|Priority to JP2000103826

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2000-09-08|Application filed by 가와무라 요시부미, 상꾜 가부시키가이샤

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2001-07-12|Publication of KR20010067169A

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2006-06-23|Application granted

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2006-06-23|Publication of KR100592201B1

优先权:

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申请号 | 申请日 | 专利标题

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JP99-255702|1999-09-09|

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JP25570299|1999-09-09|

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JP2000-103826|2000-04-05|

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JP2000103826|2000-04-05|