CN1143962A - Triazole compound and processes for preparation thereof - Google Patents

Triazole compound and processes for preparation thereof Download PDF

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CN1143962A
CN1143962A CN 95192082 CN95192082A CN1143962A CN 1143962 A CN1143962 A CN 1143962A CN 95192082 CN95192082 CN 95192082 CN 95192082 A CN95192082 A CN 95192082A CN 1143962 A CN1143962 A CN 1143962A
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butanols
triazol
sulfo
thiadiazoles
difluorophenyl
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李钟郁
蔡正锡
姜熙日
李春浩
朴秀奉
李元熙
金哲
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Yuhan Corp
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Yuhan Corp
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Priority claimed from KR1019940004917A external-priority patent/KR950026874A/en
Priority claimed from KR1019940004918A external-priority patent/KR950026875A/en
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Abstract

Novel triazole compounds of formula (I), and pharmacologically acceptable salts thereof, possess potent antifungal activities, and are useful for the treatment of fungal infections.

Description

Triazole class compounds and preparation method thereof
Invention field
The present invention relates to have the novel triazole antifungal agents of antifungic action, its preparation method and contain the pharmaceutical composition of this compound as activeconstituents.
The description of prior art
Up to now, comprise human fungi infestation, carried out a lot of research work and developed various compounds with anti-mycotic activity in order to treat Mammals.Recently, reported hypotoxic oral triazole derivative, as Fluconazole (GB 2099818) and Itraconazole (USP 4,276,179).
As known anti-mycotic agent, the triazole derivative with following general formula has been disclosed among EP 0322800A1 and the EP 0178533: Wherein, A represents the sulfone (SO that alkyl replaces 2-), sulphur oxygen (SO-) or thioether (S-) group,
Further, EP Nos.47338 and 100193 discloses the compound with above-mentioned general formula, wherein, and the methylthio group (S-CH that the A representative replaces 2-).Similarly, A is provided respectively is disulfide base (S-SO for JP3-258764 and EP 0421210 n-) compound and A representative-S-C-or-S-SO nThe compound of-Ji.Thio group (EP 0061835, EP 0095828 and EP 0552974) with a replacement or a dithiocarbamate groups (EP 0446877) compound as group A is also disclosed.But, still constantly exist the demand that exploitation has the more effective compound of higher anti-mycotic activity and low toxicity.
Summary of the invention
Therefore, primary and foremost purpose of the present invention provides the novel triazole compounds with excellent anti-mycotic activity.
Another object of the present invention provides the pharmaceutical composition that contains described compound.
Further aim of the present invention provides the method for the described novel cpd of preparation.
According to a first aspect of the invention, provide acceptable salt on the novel triazole compounds of general formula (I) and the pharmacology thereof:
Figure A9519208200141
Wherein, X and Y are hydrogen atom or halogen atom independently; And R is selected from by (I-a), (I-b), and (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i) and (I-j) group of the general formula of forming: Wherein, Z is nitrogen-atoms or carbon atom; R 1Represent one can with the C of a nitrogen-atoms Cheng Huan 1-4Alkoxyl group, C 1-4Alkoxyl-methyl, C 1-4Alkyl thio-base, C 1-4Alkylthiomethyl, amino, C 1-4Alkylamino, or a C who is optionally substituted 1-4Alkyl, styryl, phenyl or heteroaryl; R 2Represent a hydrogen atom or a C 1-3Alkyl, phenyl, phenyl, morpholinyl, pyrrolidyl, thio-morpholinyl or piperidines (piperidinyl) base of replacement; And R 3Represent a hydrogen atom or halogen atom or a C 1-3Alkyl, C 1-3Alkoxyl group or nitro.The detailed description of invention
The triazole compounds of general formula of the present invention (I) be with the 3-position on be feature as the five-ring of the sulphur atom coupling of substituent or condensed heterocycle.
In the compound of general formula (I), preferably has the compound of following general formula (I-A)
Figure A9519208200143
Wherein, X, Y, Z and R 1Have and the identical definition of general formula (I).
Wherein Z is that the compound of the general formula (I-A) of nitrogen-atoms is that those R are one 1,2,4-thiadiazolyl group (1,2, the compound of general formula 4-thiadiazol group) (I), Z are that the compound of the general formula (I-A) of carbon atom is that those R are the compound of the general formula (I) of thiazolyl (thiazol group).
Its representational compound is shown in the following table 1.
Table 1
Compound ????X ????Y ????Z ??R 1
Embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 9 embodiment 10 embodiment 13 embodiment 19 embodiment 20 embodiment 21 embodiment 22 embodiment 34 embodiment 41 embodiment 47 embodiment 55 embodiment 57 embodiment 60 embodiment 63 embodiment 64 embodiment 69 embodiment 70 embodiment 71 embodiment 72 embodiment 73 embodiment 77 embodiment 80 embodiment 83 embodiment 84 ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????F ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????N ????C ????C ????C ????C The amino amino ethoxy ethyl of cyclopropyl sec.-propyl methoxychlor methyl dimethoxy 4-fluorostyrene base 4-(2,2,3,3-tetrafluoro propoxy-) styryl fluoro methylenedioxy phenoxy methyl 4-chlorophenyl 2-pyrazinyl styryl pyrimidine-5-base 4-(2,2,3,3-tetrafluoro propoxy-) phenylpyridine-N-oxygen-4-base 3-nitrophenyl 2,5-difluorophenyl pyrazine-3-base 2-methoxyl group-1-chloromethyl methoxymethyl styryl (enantiomorph) methoxyl group (enantiomorph) 2,4-difluorophenyl ethyl 4-methoxyl-styrene 2,3-dichlorostyrene base
In these compounds of general formula (I), still preferred compound is that R is 1,2, and the compound of 5-thiadiazolyl group promptly, has the compound of following general formula (I-B): Wherein, X, Y and R 2Identical with the definition in the general formula (I).Its representational compound is shown in the following table 2.
Table 2
Compound ????X ????Y ????R 2
Embodiment 85 embodiment 86 embodiment 87 embodiment 88 embodiment 89 embodiment 90 embodiment 91 ????F ????H ????Cl ????F ????F ????F ????F ????F ????Cl ????Cl ????F ????F ????F ????F H H H aminomethyl phenyl 2,4 difluorobenzene base (oxalate) H (oxalate)
The similar preferred compound of the present invention is that those R are 1,2, and the compound of the general formula of 3-thiadiazolyl group (I) promptly, has the compound of following general formula (I-C):
Figure A9519208200162
Wherein, X, Y and R 2Identical with the definition in the general formula (I).Its representational compound is shown in the following table 3.
Table 3
Compound ????X ????Y ??????R 2
Embodiment 92 embodiment 93 embodiment 94 embodiment 95 embodiment 96 ????H ????F ????F ????F ????F ????F ????F ????F ????F ????F N-morpholinyl N-thiomorpholine phenylpiperidines-1-base (HCl) tetramethyleneimine-1-base N-thio-morpholinyl (enantiomorph)
Further, triazole compounds of the present invention comprises those R for to be selected from (I-d) compound to the general formula (I) of the annelated heterocycles of (I-j),, has the compound of general formula (I-D) to (I-J) that is: Wherein, X, Y and R 3Identical with the definition in the general formula (I).Its representational compound is shown in the following table 4.
Table 4
Compound ????X ????Y ???????????????R 3
Embodiment 97 embodiment 98 embodiment 99 embodiment 100 embodiment 101 embodiment 102 embodiment 103 embodiment 104 embodiment 105 embodiment 106 embodiment 107 embodiment 108 embodiment 109 ????F ????F ????H ????H ????F ????H ????F ????F ????F ????F ????F ????F ????F ????F ????F ????Cl ????F ????F ????Cl ????F ????F ????F ????F ????F ????F ????F 1,2-benzisothiazole-3-base 1,2-benzisothiazole-3-base (enantiomorph) 1,2-benzisothiazole-3-base 1,2-benzisothiazole-3-base 5-chloro-1,2-benzisothiazole-3-base 5-chloro-1,2-benzisothiazole-3-base 5,6-dimethoxy-1,2-benzisothiazole-3-base 5-methyl isophthalic acid, 2-benzisothiazole-3-base 7-chloro-1,2-benzisothiazole-3-base thieno-[3,4-d] isothiazole-3-base 1,2-benzisothiazole-1,1-two oxa-s-3-base thieno-[3,4-d] isothiazole-1,1-two oxa-s-3-base 2,1-benzisothiazole-3-base
Embodiment 110 embodiment 111 embodiment 112 embodiment 113 ????F ????F ????F ????F ????F ????F ????F ????F 5-nitro-2,1-benzisothiazole-3-base isothiazole also [3,4-d] pyridin-3-yl 1,2-benzisothiazole-3-base thieno-[3,4-d] isothiazole-3-base (enantiomorph)
The triazole compounds of the present invention's general formula (I) is included in two asymmetric carbon atoms on 2 and 3; And therefore, the present invention comprises (2R in its scope *, 3R *) form and (what these can be total represents with general formula (I) for 2R, the 3R) racemic mixture of the enantiomorph of form, and each diastereomer.
Further, the present invention also comprises acceptable salt on the pharmacology of compound of those general formulas (I) in its scope.Acceptable salt can comprise inorganic and organic acid salt on the suitable pharmacology of triazole compounds (I), example hydrochloric acid salt, nitrate, oxalate and mesylate; With, other salt that are known in the art in addition.Acceptable salt can be prepared by ordinary method on the pharmacology of the compound of these general formulas (I).
Triazole compounds of the present invention (I) can be prepared according to following method.Method A
The triazole compounds of general formula of the present invention (I) can pass through the compound of the compound of general formula (II) and general formula (III) or its an alkali metal salt at lithium perchlorate (LiClO 4) reaction under existing prepares. Wherein, X, Y and R are identical with above-mentioned definition.
The compound that is used for general formula of the present invention (II) can for example prepare according to the described method of EP Patent No.421210.
In addition, the compound of general formula (III) can prepare by the method that is disclosed in the various reference, as according to Adv.Heterocycl.Chem., and 5,119 (1965) the described methods that prepare general formula (III-a) compound; J.Heterocycl.Chem., 15,1295 (1978) the described methods that prepare general formula (III-c) compound; And Adv.Heterocycl.Chem., 14,43 (1972) and J.Org.Chem., 47,5255 (1982) the described methods that prepare general formula (III-d)-(III-j) compound; Perhaps, alternatively, the reaction by corresponding isothiazole-3-thioketones (isothiazol-3-thione) derivative and mercaptan (thiol) prepares. Wherein, R 1, R 2And R 3Have definition as hereinbefore, M represents basic metal.
In aforesaid method, compound (II), compound (III) and LiClO 4Preferably with 1: 1-5: 1-5, more preferably with 1: 1-2: the mole of 1-2 recently uses.
Above-mentioned reaction can be carried out in a kind of polar organic solvent, as methyl alcohol, and acetonitrile, dimethyl formamides etc. are reflected at 50-130 ℃, preferably carry out preferred 4 to 10 hours in 80-110 ℃ temperature range 4 to 18 hours.Method B
Perhaps, the triazole compounds of general formula of the present invention (I) can prepare in the reaction in the presence of the alkali by the compound of general formula (IV) with logical formula V.
Figure A9519208200192
Wherein, X, Y and R have definition same as described above, and L represents halogen.
The compound of general formula (IV) can prepare according to for example method described in the EP Patent No.421210.
In addition, the compound of logical formula V can prepare by the method that is disclosed in the various reference, as according to Adv.Heterocycl.Chem., and 5,119 (1965) the described methods that prepare general formula (V-a) compound; Adv.Heterocycl.Chem., 14,43 (1972), J.Org.Chem., 45,617 (1980), Aust.J.Chem., 24,2405 (1971), Can.J.Chem., 51,1741 (1973) and Chem.Ber., 100,3326 (1967) the described methods that prepare general formula (V-d)-(V-j) compound; And, by corresponding 3,4-two chloro-1,2,5-thiadiazoles (3,4-dichloro-1,2, the 5-thiadiazole)) substitution reaction of derivative prepares the compound of general formula (V-b).
Figure A9519208200201
Wherein, R 1, R 2, R 3Has identical definition with L with above-mentioned.
The alkali that is used for above-mentioned reaction comprises mineral alkali, as sodium hydride (NaH), salt of wormwood (K 2CO 3) or sodium methylate (MeONa), and organic bases, as triethylamine or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU, 1,8-diazabicyclo[5.4.0] undec-7-ene).
Above-mentioned reaction can be carried out in a kind of polar organic solvent, as methyl alcohol, and acetonitrile, glycol dimethyl ether, dimethyl formamides etc. are reflected at 0-25 ℃, preferably carry out preferred 15 to 30 minutes in 0-5 ℃ temperature range 15 minutes to 2 hours.
The present invention provides also that acceptable salt is as active ingredient on the compound that contains general formula (I) and its pharmacology, and if necessary, bound drug is learned and gone up acceptable carrier, the pharmaceutical composition of vehicle and other additives.
Pharmaceutical composition of the present invention can pass through oral or drug administration by injection.Be used for oral pharmaceutical composition and can adopt various form,, can contain conventional additive in these formulations as tablet, granule, oral liquid and gelatine capsule, as thinner, lubricant, absorption agent, tinting material, spices (favour), sweeting agent etc.The composition that is used to inject can be isotonic solution or suspension, and can be through sterilising treatment and/or contain adjuvant, as sanitas, stablizer, wetting agent, emulsifying agent, a kind of salt that is used to control osmotic pressure and/or buffered soln, and other drug is learned upward effective raw material.
When being used for the treatment of fungi infestation, though dosage is along with the kind and the severity of disease are different, based on route of administration and administration frequency, the dosage of this pharmaceutical composition is at 0.05-10mg/kg/ days, preferably in 1.0-5mg/kg/ days scope.
Following examples only are used to illustrate the present invention, rather than will limit scope of the present invention.Embodiment 1: synthetic (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-t-butyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under 90 ± 3 ℃, be stirred in 6 milliliters of 0.502g (0.002mol) (2R in the acetonitrile *, 3S *)-2-(2,4 difluorobenzene base)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane, 0.523g (0.003mol) 3-t-butyl-1,2, the mixture of 4-thiadiazoles-5-mercaptan and 0.319g (0.003mol) lithium perchlorate 10 hours.Reaction mixture is with the dilution of 100ml ethyl acetate, the aqueous solution of the sodium hydroxide with 5% (30ml * 2), uses salt solution (30ml * 1) to wash then.The organic layer anhydrous magnesium sulfate drying, reduction vaporization produces residue again, this residue silica gel chromatography, and, obtain title compound by isopropyl ether/normal hexane recrystallization.M.p.:138-141 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.30 (d, 3H), 1.43 (s, 9H), 4.50 (q, 1H), 4.84 and 5.05 (dd, 2H), 6.27 (s, 1H), (m, 3H), 7.71 and 7.88 (ss, 2H) embodiment 2: synthetic (2R for 6.74-7.47 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-methylthio group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.502g (0.002mol) (2R *, 3S *)-2-(2,4 difluorobenzene base)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane, 0.523g (0.003mol) 3-methylthio group-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 obtains title compound.M.p.:149-154 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.24 (d, 3H), 2.65 (s, 3H), 4.57 (q, 1H), 4.79 (s, 2H), 6.62 (s, 1H), (m, 3H), 7.67 and 8.21 (ss, 2H) embodiment 3: synthetic (2R for 6.98-7.27 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-cyclopropyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under 20 ± 2 ℃, be stirred in 6 milliliters of 0.571g (0.002mol) (2R in the acetonitrile *, 3S *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols, 0.48g (0.003mol) 5-chloro-3-cyclopropyl-1,2, the mixture of 4-thiadiazoles and 1.012g (0.010mol) triethylamine 30 minutes.Reaction mixture is through reduction vaporization, with the dilution of 100ml ethyl acetate, the aqueous solution of the sodium hydroxide with 5% (30ml * 2), uses salt solution (30ml * 1) to wash then.The organic layer anhydrous magnesium sulfate drying, reduction vaporization produces residue again, and this residue silica gel chromatography obtains title compound.M.p.:159-161 ℃ 1H-NMR (CDCl 3, δ, ppm) (m, 4H), 1.26 (d, 3H), 2.35 (s, 1H), 4.51 (q, 1H), 4.88 and 5.00 (dd, 2H), 6.18 (s, 1H), (m, 3H), 7.77 and 7.88 (ss, 2H) embodiment 4: synthetic (2R for 6.77-7.50 for 1.13-1.32 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-sec.-propyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.488g (0.003mol) 5-chloro-3-sec.-propyl-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:147-149 ℃ 1H-NMR (CDCl 3, δ, ppm) (m, 9H), 3.32 (m, 1H), 4.53 (q, 1H), 4.90 and 5.05 (dd, 2H), (m, 3H), 7.77 and 7.90 (ss, 2H) embodiment 5: synthetic (2R for 6.75-7.50 for 1.26-1.42 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-methoxyl group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.452g (0.003mol) 5-chloro-3-methoxyl group-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:155-158 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.29 (d, 3H), 4.11 (s, 3H), 4.61 (q, 1H), 4.90 and 5.02 (dd, 2H), (m, 3H), 7.77 and 7.83 (ss, 2H) embodiment 6: synthetic (2R for 6.70-7.50 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-chloromethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.507g (0.003mol) 5-chloro-3-chloromethyl-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:110-113 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.36 (d, 3H), 4.78 (q, 1H), 4.81 (s, 2H), 4.92 and 5.12 (dd, 2H), (m, 3H), 7.83 and 7.90 (ss, 2H) embodiment 7: synthetic (2R for 6.85-7.60 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-dimethylamino-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.491g (0.003mol) 5-chloro-3-dimethylamino-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:120-123 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.32 (d, 3H), 3.22 (d, 6H), 4.51 (q, 1H), 4.93 and 5.03 (dd, 2H), 6.00 (s, 1H), (m, 3H), 7.76 and 7.88 (ss, 2H) embodiment 8: synthetic (2R for 6.75-7.55 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(tetramethyleneimine-1-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate
Adopt 0.569g (0.003mol) 5-chloro-3-(tetramethyleneimine-1-yl)-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:91-95 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.19 (d, 3H), 2.90 (m, 4H), 3.49 (m, 4H), 4.68 (q, 1H), 4.77 and 4.93 (dd, 2H), (m, 3H), 7.65 and 8.29 (ss, 2H) embodiment 9: synthetic (2R for 6.80-7.30 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-amino-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.407g (0.003mol) 5-chloro-3-amino-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:130-132 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.32 (d, 3H), 4.50 (q, 1H), (m, 4H), 5.14 (s, 1H), (m, 3H), 7.81 and 7.97 (ss, 2H) embodiment 10: synthetic (2R for 6.76-7.50 for 4.90-5.20 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-oxyethyl group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.494g (0.003mol) 5-chloro-3-oxyethyl group-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:154-158 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.27 (d, 3H), 1.49 (t, 3H), 4.49 (q, 2H), 4.60 (q, 1H), 4.95 (dd, 2H), 5.64 (s, 1H), (m, 3H), 7.79 and 7.83 (ss, 2H) embodiment 11: synthetic (2R for 6.65-7.48 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-methacryloyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.482g (0.003mol) 5-chloro-3-methacryloyl-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:116-118 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.25 (d, 3H), 2.18 (s, 3H), 4.84 (m, 3H), 5.65 and 6.27 (d, 2H), 6.58 (s, 1H), (m, 3H), 7.67 and 8.29 (ss, 2H) embodiment 12: synthetic (2R for 7.00-7.29 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-methylthiomethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.542g (0.003mol) 5-chloro-3-methylthiomethyl-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:129-132 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.25 (d, 3H), 2.17 (s, 3H), 3.92 (s, 2H), 4.70 (q, 1H), 4.82 (dd, 2H), 6.62 (s, 1H), (m, 3H), 7.68 and 8.28 (ss, 2H) embodiment 13: synthetic (2R for 7 00-7.25 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-ethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.446g (0.003mol) 5-chloro-3-ethyl-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:130-132 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.34 (d, 3H), 1.45 (t, 3H), 3.02 (q, 2H), 4.60 (q, 1H), 5.00 (dd, 2H), 6.10 (s, 1H), (m, 3H), 7.78 and 7.91 (ss, 2H) embodiment 14: synthetic (2R for 6.80-7.50 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(1-chloroethyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.549g (0.003mol) 5-chloro-3-(1-chloroethyl)-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:140-143 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.32 (d, 3H), 2.00 (s, 3H), 4.70 (q, 2H), 4.85 and 5.08 (dd, 2H), 5.27 (m, 2H), 5.70 (s, 1H), (m, 3H), 7.77 and 7.83 (ss, 2H) embodiment 15: synthetic (2R for 6.74-7.45 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-methoxymethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.494g (0.003mol) 5-chloro-3-methoxymethyl-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:73-76 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.20 (d, 3H), 3.50 (q, 1H), 3.93 (s, 2H), 4.22 (s, 2H), 4.75 and 5.03 (dd, 2H), 5.15 (s, 1H), (m, 3H), 7.75 and 7.82 (ss, 2H) embodiment 16: synthetic (2R for 6.69-7.45 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-methoxyl-styrene)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.758g (0.003mol) 5-chloro-3-(4-methoxyl-styrene)-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:129-131 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.34 (d, 3H), 3.86 (s, 3H), 4.75 (m, 3H), 5.01 (dd, 2H), 5.85 (s, 1H), (m, 7H), 7.07 and 7.79 (dd, 2H), 7.78 and 7.82 (ss, 2H) embodiment 17: synthetic (2R for 6.71-7.54 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3-1-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.644g (0.003mol) 5-chloro-3-(3-1-yl)-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:178-181 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.35 (d, 3H), 2.35 and 2.67 (ss, 6H), 4.70 and 5.01 (dd, 2H), 5.70 (s, 1H), 6.06 (s, 1H), (m, 3H), 7.79 and 7.91 (ss, 2H) embodiment 18: synthetic (2R for 6.80-7.45 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-crot(on)yl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.482g (0.003mol) 5-chloro-3-crot(on)yl-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:95-97 ℃ 1H-NMR (CDCl 3, δ, and ppm) 1.32 (d, 3H), (2.01 dd, 3H * 0.75), 2.18 (dd, 3H * 0.25), 4.64 (q, 1H), 4.97 (dd, 2H), (5.78 brs, 1H * 0.25), 9.57 (brs, 1H * 0.75), (6.17-6.35 m, 1H * 0.25), 6.60 (d, 1H), 6.70-7.55 (m, 3H), 7.77 and 7.87 (ss, 2H) embodiment 19: synthetic (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-fluorostyrene base)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.722g (0.003mol) 5-chloro-3-(4-fluorostyrene base)-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:167-169 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.35 (d, 3H), 4.76 (q, 1H), 5.03 (dd, 2H), 5.81 (s, 1H), (m, 7H), (m, 2H), 7.79 and 7.86 (ss, 2H) embodiment 20: synthetic (2R for 6.08-7.80 for 6.73-7.65 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-(2,2,3, the 3-tetrafluoro is for propoxy-) styryl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 1.058g (0.003mol) 5-chloro-3-[4-(2,2,3, the 3-tetrafluoro is for propoxy-) styryl]-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, the same steps as of repetition embodiment 3 obtains title compound.M.p.:109-111 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.35 (d, 3H), 4.40 (t, 2H), 4.74 (q, 1H), 5.11 (dd, 2H), 5.82 (s, 1H), 5.52,6.08 and 6.38 (t, 1H), (m, 7H), 7.10 and 7.79 (dd, 2H), 7.79 and 7.87 (ss, 2H) embodiment 21: synthetic (2R for 6 73-7 59 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-fluoro methyl isophthalic acid, 2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.458g (0.003mol) 5-chloro-3-fluoro methyl isophthalic acid, 2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, the same steps as of repetition embodiment 3 obtains title compound.M.p.:106-108 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.31 (d, 3H), 4.68 (q, 1H), 4.91 and 5.03 (dd, 2H), 5.44 and 5.67 (dd, 2H), 5.65 (s, 1H), (m, 3H), 7.80 and 7.84 (ss, 2H) embodiment 22: synthetic (2R for 6.78-7.50 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-phenoxymethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols HCl
Adopt 0.680g (0.003mol) 5-chloro-3-phenoxymethyl-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2,4-thiadiazoles, the same steps as of repetition embodiment 3, add the saturated ether of 5ml HCl-then therein, the product of gained by the ether recrystallization, is obtained title compound.M.p.:143-146 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.25 (d, 3H), 4.07 (m, 2H), 4.87 (s, 2H), 5.35 (s, 2H), (m, 3H), 8.04 and 8.85 (ss, 2H) embodiment 23: synthetic (2R for 6.60-7.40 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(2-fluoro phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.637g (0.003mol) 3-(2-fluoro phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2, and 4-thiadiazoles-5-mercaptan repeats the same steps as of embodiment 1, then with the product of gained by the diethyl ether recrystallization, obtain title compound.M.p.:133-136 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.00 (d, 3H), 4.57 (m, 3H), 6.34 (s, 1H), (m, 7H), 7.37 and 7.99 (ss, 2H) embodiment 24: synthetic (2R for 6.68-7.30 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(2, the 6-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.691g (0.003mol) 3-(2, the 6-difluorophenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:175-179 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.27 (d, 3H), 4.85 (m, 3H), 6.63 (s, 1H), (m, 6H), 7.67 and 8.27 (ss, 2H) embodiment 25: synthetic (2R for 6.90-7.70 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-fluoro phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.637g (0.003mol) 3-(4-fluoro phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:133-138 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.30 (d, 3H), 4.90 (m, 3H), 6.65 (s, 1H), (m, 7H), 7.70 and 8.25 (ss, 2H) embodiment 26: synthetic (2R for 7.02-8.40 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(2-pyridyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.586g (0.003mol) 3-(2-pyridyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:174-176.5 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.37 (d, 3H), 4.75 (q, 1H), 4.95 and 5.09 (dd, 2H), 5.90 (s, 1H), (m, 7H), 7.77 and 7.91 (ss, 2H) embodiment 27: synthetic (2R for 7.40-8.84 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(2-chlorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.686g (0.003mol) 3-(2-chloro-phenyl-)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:125-127.5 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.20 (d, 3H), 4.88 (m, 3H), 6.65 (s, 1H), (m, 6H), 7.70 and 8.30 (ss, 2H) embodiment 28: synthetic (2R for 7.00-7.90 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-phenyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.583g (0.003mol) 3-phenyl-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:135-138 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.31 (d, 3H), 4.82 (m, 3H), 6.63 (s, 1H), (m, 8H), 7.68 and 8.29 (ss, 2H) embodiment 29: synthetic (2R for 7.02-8.21 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3-pyridyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.586g (0.003mol) 3-(3-pyridyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p:146-149 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.36 (d, 3H), 4.90 (m, 1H), 4.95 and 5.11 (dd, 2H), 5.66 (s, 1H), (m, 6H), 7.80 and 7.81 (ss, 2H) embodiment 30: synthetic (2R for 6.78-9.56 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-pyridyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.586g (0.003mol) 3-(4-pyridyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:178-180 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.37 (d, 3H), 4.90 (m, 1H), 4.95 and 5.09 (dd, 2H), 5.66 (s, 1H), (m, 3H), 7.81 and 7.81 (ss, 2H), (m, 4H) embodiment 31: synthetic (2R for 8.13-8.80 for 6.80-7.46 *, 3R *)-2-(2,4 difluorobenzene base)-3-[4-(1-(N-oximido ethyl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.754g (0.003mol) 4-(1-(N-oximido ethyl) phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:177-180 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.37 (d, 3H), 4.88 (m, 1H), 4.96 and 5.12 (dd, 2H), 5.84 (s, 1H), (m, 7H), 8.30 and 8.37 (ss, 2H), 9.33 (s, 1H) embodiment 32: synthetic (2R for 6.80-7.87 *, 3R *)-2-(4-chlorophenyl)-3-[3-(3, the 5-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.499g (0.002mol) (2R respectively *, 3S *)-2-(4-chlorophenyl)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 0.691g (0.003mol) 3-(3, the 5-difluorophenyl)-1,2,4-thiadiazoles-5-mercaptan replaces (2R *, 3S *)-2-(2,4 difluorobenzene base)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 obtains title compound.M.p.:104-106 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.34 (d, 3H), 4.50 (m, 1H), 4.90 (dd, 2H), 6.44 (s, 1H), (m, 6H), 7.87 and 8.24 (ss, 2H) embodiment 33: synthetic (2R for 7.44-7.85 *, 3R *)-2-(2,4 dichloro benzene base)-3-[3-(4-pyridyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.499g (0.002mol) (2R respectively *, 3S *)-2-(2,4 dichloro benzene base)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 0.586g (0.003mol) 3-(4-pyridyl)-1,2,4-thiadiazoles-5-mercaptan replaces (2R *, 3S *)-2-(2,4 difluorobenzene base)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 obtains title compound.M.p.:142-144 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.32 (d, 3H), 4.90 and 5.63 (dd, 2H), 5.45 (q, 1H), 5.70 (s, 1H), (m, 3H), 7.81 (s, 2H), (m, 4H) embodiment 34: synthetic (2R for 8.15-8.18 for 7.15-7.60 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-chlorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.686g (0.003mol) 3-(4-chlorophenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:156-159 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.30 (d, 3H), 4.85 (m, 3H), 6.64 (s, 1H), (m, 7H), 7.68 and 8.27 (ss, 2H) embodiment 35: synthetic (2R for 6.95-8.23 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3-fluoro phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.637g (0.003mol) 3-(3-fluoro phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:123-125 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.36 (d, 3H), 4.88 (m, 1H), 5.10 (dd, 1H), 5.68 (s, 1H), (m, 7H), 7.79 and 7.82 (ss, 2H) embodiment 36: synthetic (2R for 6.70-8.20 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3, the 4-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.691g (0.003mol) 3-(3, the 4-difluorophenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:137-139.5 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.35 (d, 3H), 4.88 (q, 1H), 5.01 (dd, 2H), 5.65 (s, 1H), (m, 6H), 7.80 (s, 2H) embodiment 37: synthetic (2R for 6.70-8.20 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(2, the 6-dichlorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.790g (0.003mol) 3-(2, the 6-dichlorophenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:138-140 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.29 (d, 3H), 4.85 (m, 3H), 5.71 (s, 1H), (m, 6H), 7.70 and 8.32 (ss, 2H) embodiment 38: synthetic (2R for 6.95-7.80 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3-trifluoromethyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.787g (0.003mol) 3-(3-trifluoromethyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:144-146 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.35 (d, 3H), 4.90 (q, 3H), 5.08 (dd, 2H), 5.59 (s, 1H), (m, 7H), 7.77 and 7.82 (ss, 2H) embodiment 39: synthetic (2R for 6.70-8.65 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3-chlorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.686g (0.003mol) 3-(3-chlorophenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:118-120 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.35 (d, 3H), 4.87 (q, 1H), 5.02 (dd, 2H), 5.64 (s, 1H), (m, 7H), 7.79 and 7.82 (ss, 2H) embodiment 40: synthetic (2R for 6.72-8.32 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-(1H-imidazoles-1-yl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.781g (0.003mol) 3-(4-(1H-imidazoles-1-yl) phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:227-230 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.38 (d, 3H), 4.90 (m, 1H), 4.97 and 5.09 (dd, 2H), 5.75 (s, 1H), (m, 7H), 7.27 and 7.99 (ss, 2H), 8.40 and 8.45 (ss, 2H) embodiment 41: synthetic (2R for 6.80-7.83 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(2-pyrazinyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.589g (0.003mol) 3-(2-pyrazinyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:157-160 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.36 (d, 3H), 4.86 (m, 3H), 4.95 and 5.10 (dd, 2H), 5.72 (s, 1H), (m, 3H), 7.80 and 8.33 (ss, 2H), 8.73 and 9.60 (m, 3H) embodiment 42: synthetic (2R for 6.70-7.50 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(2-chloro-6-fluoro phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.740g (0.003mol) 3-(2-chloro-6-fluoro phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:117-119 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.32 (d, 3H), 4.70 (q, 1H), 5.16 (dd, 2H), 5.73 (s, 1H), (m, 6H), 7.76 and 7.84 (ss, 2H) embodiment 43: synthetic (2R for 6.67-7.55 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-bromo phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.820g (0.003mol) 3-(4-bromo phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:163-165 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.29 (d, 3H), 4.85 (m, 3H), 6.64 (s, 1H), (m, 7H), 7.68 and 8.28 (ss, 2H) embodiment 44: synthetic (2R for 7.00-8.10 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-(1H-1,2,4-triazol-1-yl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.784g (0.003mol) 3-(4-(1H-1,2,4-triazol-1-yl) phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:193-196 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.38 (d, 3H), 4.90 (H, 1H), 4.96 and 5.10 (dd, 2H), 5.70 (s, 1H), (m, 7H), 8.17 and 8.43 (ss, 2H), 8.47 and 8.69 (ss, 2H) embodiment 45: synthetic (2R for 6.80-7.90 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-azido-phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.706g (0.003mol) 3-(4-azido-phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:123-125 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.35 (d, 3H), 4.86 (q, 1H), 4.94 and 5.08 (dd, 2H), 5.77 (s, 1H), (m, 7H), 7.78 and 7.83 (ss, 2H) embodiment 46: synthetic (2R for 6.80-8.33 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3, the 5-bis trifluoromethyl phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.991g (0.003mol) 3-(3, the 5-bis trifluoromethyl phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:123-125 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.29 (d, 3H), 4.90 (m, 3H), 6.63 (s, 1H), (m, 6H), 8.60 and 8.70 (ss, 2H) embodiment 47: synthetic (2R for 7.00-8.40 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-styryl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.661g (0.003mol) 3-styryl-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:151-153 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.36 (d, 3H), 4.68 (q, 1H), 4.96 and 5.05 (dd, 2H), 5.50 (s, 1H), (m, 8H), 7.08 and 7.68 (dd, 2H), 7.82 (ss, 2H) embodiment 48: synthetic (2R for 6.78-7.63 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-morpholine-1-yl) phenyl-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.838g (0.003mol) 3-(4-morpholine-1-yl) phenyl-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:169-171 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.35 (d, 3H), 3.31 and 3.90 (m, 8H), 4.75 (q, 1H), 4.93 and 5.09 (dd, 2H), 6.05 (s, 1H), 6.79 (s, 1H), (m, 7H), 7.76 and 7.87 (ss, 2H) embodiment 49: synthetic (2R for 6.79-8.02 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3-trifluoromethyl-4-kharophen) phenyl-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.958g (0.003mol) 3-(3-trifluoromethyl-4-kharophen) phenyl-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:123-125 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.29 (d, 3H), 2.11 (s, 3H), 4.88 (m, 3H), 6.63 (s, 1H), (m, 6H), 7.67 and 8.28 (ss, 2H), 9.72 (s, 1H) embodiment 50: synthetic (2R for 7.00-8.40 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-(1,3,4-oxadiazole-2-yl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
(4-(1,3,4-oxadiazole-2-yl) phenyl-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1, acquisition title compound to adopt 0.787g (0.003mol) 3-.M.p:122-125 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.35 (d, 3H), 4.90 (m, 3H), 6 68 (s, 1H), (m, 7H), 7.72 and 8.32 (ss, 2H), 9.46 (s, 1H) embodiment 51: synthetic (2R for 7.00-8.42 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-(1,3-dioxolane-2-yl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.799g (0.003mol) 3-(4-(1,3-dioxolane-2-yl) phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:138-140 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.31 (d, 3H), (m, 4H), 4.83 (m, 1H), 4.89 and 5.06 (dd, 2H), 5.74 (s, 1H), 5.86 (s, 1H), (m, 7H), 7.74 and 7.78 (ss, 2H) embodiment 52: synthetic (2R for 6.70-8.30 for 4.04-4.14 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-cyano-phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.658g (0.003mol) 3-(4-cyano-phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:195-197 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.37 (d, 3H), 4.88 (m, 1H), 4.96 and 5.07 (dd, 2H), 5.60 (s, 1H), (m, 7H), 7.81 and 7.84 (ss, 2H) embodiment 53: synthetic (2R for 6.75-8.44 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(benzene sulphur-2-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.601g (0.003mol) 3-(benzene sulphur-2-yl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:122-125 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.28 (d, 3H), 4.83 (m, 3H), 6.60 (s, 1H), (m, 6H), 7.67 and 8.29 (ss, 2H) embodiment 54: synthetic (2R for 7.00-7.82 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-nitrophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate
Adopt 0.718g (0.003mol) 3-(4-nitrophenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 is in the presence of ethyl acetate/normal hexane, in the compound that obtains thus, add 0.18g (0.002mol) oxalic acid, obtain title compound.M.p.:169-172 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.29 (d, 3H), 4.87 (m, 3H), 6.58 (s, 1H), (m, 7H), 7.67 and 8.30 (ss, 2H) embodiment 55: synthetic (2R for 6.67-7.91 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(pyrimidine-5-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.589g (0.003mol) 3-(pyrimidine-5-yl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:140-143 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.30 (d, 3H), 4.90 (m, 3H), 6.61 (s, 1H), (m, 3H), 7.88 and 8.28 (ss, 2H), 9.35 and 9.41 (d, 3H) embodiment 56: synthetic (2R for 7.00-7.30 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-dibiphenylyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.811g (0.003mol) 3-(4-dibiphenylyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:127-129 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.40 (d, 3H), 4.84 (q, 1H), 5.01 (dd, 2H), 5.82 (s, 1H), (m, 12H), 8.38 and 8.41 (ss, 2H) embodiment 57: synthetic (2R for 6.70-7.85 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-(2,2,3,3-tetrafluoro propoxy-) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.973g (0.003mol) 3-(4-(2,2,3,3-tetrafluoro propoxy-) phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:140-142 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.39 (d, 3H), 4.48 (q, 1H), 5.09 (dd, 2H), 5.82 (s, 1H), 5.83,6.15 and 6.40 (t, 1H), (m, 7H), 8.27 and 8.32 (ss, 2H) embodiment 58: synthetic (2R for 6.75-7.83 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-(4-pyridone-1-yl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.862g (0.003mol) 3-(4-(4-pyridone-1-yl) phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:235-238 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.32 (d, 3H), 4.90 (q, 3H), 6.33 and 8.11 (dd, 4H), 6.66 (s, 1H), (m, 7H), 7.69 and 8.30 (ss, 2H) embodiment 59: synthetic (2R for 6.88-8.37 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-methylpyrimidine-2-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.631g (0.003mol) 3-(4-methylpyrimidine-2-yl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:235-238 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.38 (d, 3H), 2 65 (s, 3H), 4 80 (m, 1H), 4.93 (s, 2H), 6.77 (s, 1H), (m, 3H), 7.61 and 8.91 (dd, 2H), 7.69 and 8.30 (ss, 2H) embodiment 60: synthetic (2R for 7.07-7.38 *, 3R *)-2-(2 ,-difluorophenyl)-3-[3-(pyridine-N-oxygen-4-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.634g (0.003mol) 3-(pyridine-N-oxygen 4-yl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:201-204 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.33 (d, 3H), (m, 3H), 6.67 (s, 4H), (m, 3H), 7.72 and 8.31 (ss, 2H), (m, 4H) embodiment 61: synthetic (2R for 8.10-8.40 for 6.90-7.10 for 4.70-5.00 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-methylthio group phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.721g (0.003m0l) 3-(4-methylthio group phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:140-143 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.30 (d, 3H), 2.67 (s, 3H), 4.80 (m, 3H), 6.61 (s, 1H), (m, 7H), 7.00 and 8.30 (ss, 2H) embodiment 62: synthetic (2R for 7.00-8.15 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-methylsulfonyl phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.817g (0.003mol) 3-(4-methylsulfonyl phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:172-174 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.33 (d, 3H), 3.31 (s, 3H), 4.90 (m, 3H), 6.64 (s, 1H), (m, 7H), 7.70 and 8.29 (ss, 2H) embodiment 63: synthetic (2R for 7.00-8.45 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3-nitrophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.718g (0.003mol) 3-(3-nitrophenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:115-118 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.32 (d, 3H), 4.88 (m, 3H), 6.66 (s, 1H), 7.05 (m, 1H), 7.32 (m, 2H), 7.69 (s, 1H), 7.90 (t, 1H), 8.29 (s, 1H), 8.40 and 8.55 (d, 2H) embodiment 64: synthetic (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(2, the 5-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.691g (0.003mol) 3-(2, the 5-difluorophenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:151-153 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.31 (d, 3H), 4.89 (m, 3H), 6.64 (s, 1H), (m, 3H), 7.70 and 8.31 (ss, 2H) embodiment 65: synthetic (2R for 7.05-7.90 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-dimethylamino phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.712g (0.003mol) 3-(4-dimethylamino phenyl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:160-163 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.31 (d, 3H), 3.03 (s, 6H), 4.89 (m, 3H), 6.61 (s, 1H), (m, 3H), 7.69 and 8.32 (ss, 2H) embodiment 66: synthetic (2R for 6.84-8.05 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(1H-1,2,4-triazol-1-yl) methyl isophthalic acid, 2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.640g (0.003mol) 5-chloro-3-bromomethyl-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles repeats the same steps as of embodiment 3, and adds 0.364g (0.004mol) triazole sodium salt acquisition title compound in the reaction mixture that stirs.M.p.:136-140 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.23 (d, 3H), 3.60 (q, 1H), 4.16 (q, 2H), 4.78 and 5.06 (dd, 2H), 5.10 (s, 1H), (m, 3H), 7.41,7.78,8.19 and 9.14 (q, 4H) embodiment 67: synthetic (2R for 6.71-7.50 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(4-methoxyl-styrene)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.758g (0.003mol) 5-chloro-3-(4-methoxyl-styrene)-1,2, the 4-thiadiazoles replaces 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, and the same steps as of repetition embodiment 3 obtains title compound.M.p.:129-131 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.06 (d, 3H), 3.70 (q, 1H), 4.63 and 4.83 (dd, 2H), 6.03 (s, 1H), (dd, 2H), (m, 3H), 7.62 and 8.23 (ss, 2H) embodiment 68: synthetic (2R for 6.90-7.24 for 6.38-8.37 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(3-pyrroles-1-yl) phenyl-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.778g (0.003mol) 3-(3-pyrroles-1-yl) phenyl-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:84-86 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.38 (d, 3H), 5.02 (m, 3H), 6.44 (s, 2H), 6.71 (s, 1H), (m, 11H), 7.75 and 8.38 (ss, 2H) embodiment 69: synthetic (2R for 7.10-8.41 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(pyridazine-3-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.589g (0.003mol) 3-(pyridazine-3-yl)-1,2,4-thiadiazoles-5-mercaptan replaces 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, and the same steps as of repetition embodiment 1 obtains title compound.M.p.:168-170 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.38 (d, 3H), 4.80 (q, 1H), 4.90 and 5.12 (dd, 2H), 5.80 (s, 2H), (m, 3H), (m, 3H), 7.78 and 7.90 (ss, 2H) embodiment 70: synthetic (2R for 7.65-9.35 for 6.75-7.55 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(1-chloro-2-methoxy ethyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols HCl
Under 0 ℃, be stirred in 0.571g (the 0.002mol) (2R in 5 ml methanol *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols, 0.636g (0.003mol) 5-chloro-3-(1-chloro-2-methoxy ethyl)-1,2, about 15 minutes of the mixture of 4-thiadiazoles and 0.108g (0.002mol) sodium methylate.Reaction mixture is handled by the foregoing description 3, and by adding the saturated ether of HCl-by carrying out recrystallization in the ether, obtains title compound.M.p.:178-180 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.27 (d, 3H), 3.31 (s, 3H), 4.00 (m, 2H), 4.74 (q, 1H), 4.89 (s, 2H), 5.44 (m, 1H), (m, 3H), 8.00 and 8.82 (ss, 2H) embodiment 71: synthetic (2R for 6.90-7.40 *, 3R *)-2-(2,4 difluorobenzene base)-3-(3-methoxymethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under 0 ℃, be stirred in 0.571g (the 0.002mol) (2R in 5 ml methanol *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols, 0.640g (0.003mol) 5-chloro-3-bromomethyl-1,2, about 15 minutes of the mixture of 4-thiadiazoles and 0.324g (0.006mol) sodium methylate.Reaction mixture is handled by the foregoing description 3, obtains title compound.M.p.:73-76 ℃ 1H-NMR (CDCl 3, δ, and ppm) 1.20 (d, 3H), 3.55 (q, 1H), 3.93 (q, 2H), 4.22 (s, 3H), 4.72 and 5.03 (dd, 2H), 5.15 (s, 1H), 6.69-7.45 (m, 3H), 7.75 and 7.82 (ss, 2H) embodiment 72: synthetic (2R, 3R)-2-(2,4 difluorobenzene base)-3-(3-styryl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
(2R, 3R)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.668g (0.003mol) 5-chloro-3-styryl-1,2, the 4-thiadiazoles replaces (2R to adopt 0.571g (0.002mol) respectively *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles obtains title compound.In the presence of ethyl acetate/normal hexane,, obtain the oxalate of title compound to wherein adding 0.18g (0.002mol) oxalic acid.In the presence of ether, in title compound, add 0.192g (0.002mol) methylsulfonic acid, obtain the mesylate of title compound.M.p.:125 ℃ (oxalate) M.p.:88-91 ℃ (mesylate) 1H-NMR (CDCl 3, δ, and ppm) 1.35 (d, 3H), 4.77 (q, 1H), 5.05 (dd, 2H), 6.73-7.68 (dd, 3H), 7.20 and 7.85 (dd, 2H), 7.85 and 8.21 (ss, 2H) embodiment 73: synthetic (2R, 3R)-2-(2,4 difluorobenzene base)-3-(3-methoxyl group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Employing 0.571g (0.002mol) (2R, 3R)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols replacement (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols, the same steps as of repetition embodiment 5 obtains title compound.In the presence of ethyl acetate/normal hexane,, obtain the oxalate of title compound to wherein adding 0.18g (0.002mol) oxalic acid.M.p.:77-79 ℃ M.p.:107-110 ℃ (oxalate) 1H-NMR (DMSO-d 6, δ, ppm) 1.21 (d, 3H), 4.78 (s, 3H), 4.62 (q, 1H), 4.78 (s, 2H), 6.66 (s, 1H), (m, 3H), 7.66 and 8.26 (ss, 2H) embodiment 74: synthetic (2R for 6.82-7.38 *, 3R *)-2-(4-chlorophenyl)-3-(3-methoxyl group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.568g (0.002mol) (2R *, 3R *)-2-(4-chlorophenyl)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols replaces (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols, the same steps as of repetition embodiment 5 obtains title compound.M.p.:93-95 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.25 (d, 3H), 3.98 (s, 3H), 4.30 (q, 1H), 4.82 (d, 2H), 6.35 (s, 1H), 7.33 (s, 4H), 7.82 and 8.17 (ss, 2H) embodiment 75: synthetic (2R *, 3R *)-2-(4-fluoro phenyl)-3-(3-methoxyl group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.535g (0.002mol) (2R *, 3R *)-2-(4-fluoro phenyl)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols replaces (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols, the same steps as of repetition embodiment 5 obtains title compound.M.p.:111-113 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1 29 (d, 3H), 4.00 (s, 3H), 4.43 (q, 1H), 4.83 (d, 2H), 6.36 (s, 1H), (m, 4H), 7.86 and 8.19 (ss, 2H) embodiment 76: synthetic (2R for 7.17-7.43 *, 3R *)-2-(4-fluoro phenyl)-3-(3-styryl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.535g (0.002mol) (2R respectively *, 3R *)-2-(4-fluoro phenyl)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.668g (0.003mol) 5-chloro-3-styryl-1,2, the 4-thiadiazoles replaces (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-2-(1H-1,2,4-triazol-1-yl)-2-butanols and 5-chloro-3-cyclopropyl-1,2, the 4-thiadiazoles, the same steps as of repetition embodiment 3 obtains title compound.M.p.:126-129 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.35 (d, 3H), 4.40 (m, 1H), 4.90 (dd, 2H), 6.30 (s, 1H), (m, 11H), 7.89 and 8.24 (ss, 2H) embodiment 77: synthetic (2R for 7.20-7.80 *, 3R *)-2-(2,4 difluorobenzene base)-3-[4-(2, the 6-difluorophenyl)-thiazol-2-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.688g (0.003mol) 4-(2, the 6-difluorophenyl)-thiazol-2-thiol to replace 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 obtains title compound.M.p.:131-133 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.30 (d, 3H), 4.25 (q, 1H), 5.02 (dd, 2H), (m, 7H), 7.66 and 8.12 (ss, 2H) embodiment 78: synthetic (2R for 6.62-7.56 *, 3R *)-2-(2,4 difluorobenzene base)-3-[4-(2,4 dichloro benzene base)-thiazol-2-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.787g (0.003mol) 4-(2,4 dichloro benzene base)-thiazol-2-thiol to replace 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 obtains title compound.M.p.:138-140 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.24 (d, 3H), 4.78 (q, 1H), 4.89 (s, 2H), 6.49 (s, 1H), (m, 6H), 8.10 and 8.30 (ss, 2H) embodiment 79: synthetic (2R for 6.80-7.92 *, 3R *)-2-(2,4 difluorobenzene base)-3-[4-(4-chlorophenyl)-thiazol-2-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.683g (0.003mol) 4-(4-chlorophenyl)-thiazol-2-thiol to replace 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 obtains title compound.M p.:115-117 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.30 (d, 3H), 4.44 (q, 1H), 5.01 (dd, 2H), 6.59 (s, 1H), (m, 8H), 7.95 (s, 1H) embodiment 80: synthetic (2R for 6.65-7.85 *, 3R *)-2-(2,4 difluorobenzene base)-3-(4-ethyl thiazole-2-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate
Adopt 0.436g (0.003mol) 4-ethyl thiazole-2-mercaptan to replace 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, repeat the same steps as of embodiment 1, in the presence of ethyl acetate/normal hexane, in the compound that obtains thus, add 0.18g (0.002mol) oxalic acid, obtain title compound.M.p.:108-110 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.24 (d, 3H), 1.34 (t, 3H), 2.85 (q, 2H), 4.03 (q, 1H), 5.03 (dd, 2H), (m, 3H), 7.88 and 8.63 (ss, 2H) embodiment 81: synthetic (2R for 6.70-7.60 *, 3R *)-2-(2,4 difluorobenzene base)-3-[4-(1-hydroxyl-1-methylethyl) thiazol-2-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate
Adopt 0.526g (0.003mol) 4-(1-hydroxyl-1-methylethyl) thiazol-2-thiol to replace 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, repeat the same steps as of embodiment 1, in the presence of ethyl acetate/normal hexane, in the compound that obtains thus, add 0.18g (0.002mol) oxalic acid, obtain title compound.M.p.:106-108 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.17 (d, 3H), 1.47 (t, 3H), 4.67 (q, 1H), 4.83 (dd, 2H), 6.50 (s, 1H), (m, 3H), 7.32 (s, 1H), 7.63 and 8.31 (ss, 2H) embodiment 82: synthetic (2R for 6.87-7.31 *, 3R *)-2-(2,4 difluorobenzene base)-3-(4-styryl thiazol-2-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.658g (0.003mol) 4-styryl thiazol-2-thiol to replace 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 obtains title compound.M.p.:98-100 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.31 (d, 3H), 4.40 (q, 1H), 5.07 (dd, 2H), (m, 11H), 7.72 and 8.05 (ss, 2H) embodiment 83: synthetic (2R for 6.70-7.60 *, 3R *)-2-(2,4 difluorobenzene base)-3-[4-(4-methoxyl-styrene)-thiazol-2-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.748g (0.003mol) 4-(4-methoxyl-styrene)-thiazol-2-thiol to replace 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 obtains title compound.M.p.:138-140 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.31 (d, 3H), 3.85 (s, 3H), 4.38 (q, 1H), 5.02 (dd, 2H), (m, 10H), 7.71 and 8.05 (ss, 2H) embodiment 84: synthetic (2R for 6.70-7.60 *, 3R *)-2-(2,4 difluorobenzene base)-3-[4-(2,3-dichlorostyrene base)-thiazol-2-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.865g (0.003mol) 4-(2,3-dichlorostyrene base)-thiazol-2-thiol to replace 3-t-butyl-1,2,4-thiadiazoles-5-mercaptan, the same steps as of repetition embodiment 1 obtains title compound.M.p.:135-137 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.33 (d, 3H), 4.05 (q, 1H), 5.07 (dd, 2H), 6.60 (s, 1H), (m, 7H), 7.91 and 8.01 (ss, 2H) embodiment 85: synthetic (2R for 6.65-7.70 *, 3R *)-2-(2,4 difluorobenzene base)-3-(1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under 100 ℃, be stirred in 6 milliliters of 0.502g (0.002mol) (2R in the acetonitrile *, 3S *)-2-(2,4 difluorobenzene base)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane, 0.420g (0.003mol) 1,2, the mixture of 3-thiadiazoles-5-mercaptan Na salt and 0.319g (0.003mol) lithium perchlorate 12 hours.Reaction mixture is with the dilution of 100ml ethyl acetate, the aqueous solution of the sodium hydroxide with 5% (30ml * 2), uses salt solution (30ml * 1) to wash then.The organic layer anhydrous magnesium sulfate drying, reduction vaporization produces residue again, and this residue silica gel chromatography obtains title compound.M.p.:129-131.5 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.26 (d, 3H), 4.20 (q, 1H), 4.94 (s, 2H), 6.73 (s, 1H), (m, 3H), 7.82 and 8.35 (ss, 2H), 9.05 (s, 1H) embodiment 86: synthetic (2R for 7.08-7.44 *, 3R *)-2-(4-chlorophenyl)-3-(1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.499g (0.002mol) (2R *, 3S *)-2-(4-chlorophenyl)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 0.420g (0.003mol) 1,2,3-thiadiazoles-5-mercaptan Na salt, the same steps as of repetition embodiment 85 obtains title compound.M.p.:151-153 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.27 (d, 3H), 4.20 (q, 1H), 4.96 (s, 2H), 6.46 (s, 1H), 7.48 (m, 4H), 7.96 and 8.28 (ss, 2H), 9.04 (s, 1H) embodiment 87: synthetic (2R *, 3R *)-2-(2,4 dichloro benzene base)-3-(1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.568g (0.002mol) (2R *, 3S *)-2-(2,4 dichloro benzene base)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 0.420g (0.003mol) 1,2,3-thiadiazoles-5-mercaptan Na salt, the same steps as of repetition embodiment 85 obtains title compound.M.p.:158-160 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.18 (d, 3H), 4.65 (q, 1H), 5.10 (dd, 2H), 6.78 (s, 1H), (m, 3H), 7.67 and 8.34 (ss, 2H), 9.01 (s, 1H) embodiment 88: synthetic (2R for 7.36-7.60 *, 3R *)-2-(2,4 difluorobenzene base)-3-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.502g (0.002mol) (2R *, 3S *)-2-(2,4 difluorobenzene base)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 0.463g (0.003mol) 4-methyl isophthalic acid, 2,3-thiadiazoles-5-mercaptan Na salt, the same steps as of repetition embodiment 85 obtains title compound.M.p.:135-137 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.14 (d, 3H), 2.61 (s, 3H), 4.00 (q, 1H), 4.95 (m, 2H), 6.63 (s, 1H), (m, 3H), 7.72 and 8.26 (ss, 2H) embodiment 89: synthetic (2R for 7.00-7.30 *, 3R *)-2-(2,4 difluorobenzene base)-3-(4-phenyl-1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Adopt 0.502g (0.002mol) (2R *, 3S *)-2-(2,4 difluorobenzene base)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 0.649g (0.003mol) 4-phenyl-1,2,3-thiadiazoles-5-mercaptan Na salt, the same steps as of repetition embodiment 85 obtains title compound.M.p.:96-98 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.19 (d, 3H), 4.10 (m, 1H), 4.82 (m, 2H), 6.73 (s, 1H), (m, 6H), 7.74 and 8.27 (ss, 2H), 7.90 (s, 2H) embodiment 90: synthetic (2R for 7.05-7.50 *, 3R *)-2-(2,4 difluorobenzene base)-3-[4-(2,4 difluorobenzene base)-1,2,3-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate
Adopt 0.502g (0.002mol) (2R *, 3S *)-2-(2, the 4-difluorophenyl)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 0.753g (0.003mol) 4-(2,4 difluorobenzene base)-1,2,3-thiadiazoles-5-mercaptan Na salt, the same steps as of repetition embodiment 85 is in the presence of ethyl acetate/normal hexane, to wherein adding 0.19g (0.002mol) oxalic acid, obtain title compound.M.p.:111-113 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.34 (d, 3H), 4.05 (q, 1H), 4.76 (s, 2H), 6.65 (s, 1H), (m, 6H), 7.73 and 8.25 (ss, 2H) embodiment 91: synthetic (2R for 7.00-7.80 *, 3R *)-2-(4-fluoro phenyl)-3-(1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate
Adopt 0.467g (0.002mol) (2R *, 3S *)-2-(4-fluoro phenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxyethane and (0.003mol) 1,2 O.463g, 3-thiadiazoles-5-mercaptan Na salt repeats the same steps as of embodiment 90, obtains title compound.M.p.:138-140 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.80 (d, 3H), 4.00 (q, 1H), 4 83 (dd, 2H), 6.30 (s, 1H), (m, 4H), 7.85 and 8.16 (ss, 2H), 8.89 (s, 1H) embodiment 92: synthetic (2R for 7.10-7.30 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(N-morpholinyl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under 25 ℃, be stirred in 6 milliliters of 0.571g (0.002mol) (2R in the glycol dimethyl ether *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols, 0.617g (0.003mol) 4-chloro-3-(N-morpholinyl)-1,2, the mixture of 5-thiadiazoles and 0.072g (0.003mol) NaH 1 hour.Reaction mixture is with the dilution of 100m1 ethyl acetate, the aqueous solution of the sodium hydroxide with 5% (30ml * 2), uses salt solution (30m1 * 1) to wash then.The organic layer anhydrous magnesium sulfate drying, reduction vaporization produces residue again, this residue silica gel chromatography, and, obtain title compound by the isopropyl ether recrystallization.M.p.:155-158 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.25 (d, 3H), 3.45 (m, 4H), 3.87 (m, 4H), 4.75 (q, 1H), 5.00 (dd, 2H), 5.40 (s, 1H), (m, 3H), 7.80 (s, 2H) embodiment 93: synthetic (2R for 6.80-7.40 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(N-thio-morpholinyl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
0.571g (the 0.002mol) (2R of employing in the 6ml glycol dimethyl ether *, 3R *)-2-(2, the 4-difluorophenyl)-3-sulfydryl-1-(1H-1,2, the 4-triazol-1-yl)-the 2-butanols, 0.665g (0.003mol) 4-chloro-3-(N-thio-morpholinyl)-1,2, the mixture of 5-thiadiazoles and 0.072g (0.003mol) NaH, repeat the same steps as of embodiment 92, obtain title compound.M.p.:133-135 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.25 (d, 3H), 3.81 (m, 4H), 3.71 (m, 4H), 4.70 (m, 1H), 4.95 (dd, 2H), 5.39 (s, 1H), (m, 3H), 7.77 (s, 2H) embodiment 94: synthetic (2R for 6.75-7.35 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(piperidines-1-yl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols HCl
0.571g (the 0.002mol) (2R of employing in 6ml methyl alcohol *, 3R *)-2-(2, the 4-difluorophenyl)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols, 0.611g (0.003mol) 4-chloro-3-(piperidines-1-yl)-1,2, the mixture of 5-thiadiazoles and 0.162g (0.003mol) MeONa, the same steps as of repetition embodiment 92, then, in the product of gained, add the saturated ether of 5ml HCl-,, obtain title compound by the ether recrystallization.M.p.:70-73 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.25 (d, 3H), 1.65 (m, 6H), 3 40 (m, 2H), 3.50 (dd, 2H), 4.70 (dd, 1H), 5.00 (dd, 2H), 5.50 (s, 1H), (m, 3H), 7.77 and 7.82 (ss, 2H) embodiment 95: synthetic (2R for 6.80-7.40 *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(tetramethyleneimine-1-yl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
0.571g (the 0.002mol) (2R of employing in the 6ml acetonitrile *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2, the 4-triazol-1-yl)-and the 2-butanols, 0.569g (0.003mol) 4-chloro-3-(tetramethyleneimine-1-yl)-1,2, the mixture of 5-thiadiazoles and 0.072g (0.003mol) NaH, the same steps as of repetition embodiment 92 obtains title compound.M.p.:139-141 ℃ 1H-NMR (CDCl 3, δ, and ppm) 1.25 (d, 3H), 1.99 (m, 4H), 3.75 (m, 4H), 4.65 (dd, 1H), 5.00 (dd, 2H), 5.30 (s, 1H), 6.75-7.40 (m, 3H), 7.77 and 7.82 (ss, 2H) embodiment 96: synthetic (2R, 3R)-2-(2,4 difluorobenzene base)-3-[3-(N-thio-morpholinyl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
0.571g (the 0.002mol) (2R of employing in 6ml methyl alcohol, 3R)-2-(2, the 4-difluorophenyl)-3-sulfydryl-1-(1H-1,2, the 4-triazol-1-yl)-the 2-butanols, 0.665g (0.003mol) 4-chloro-3-(N-thio-morpholinyl)-1,2, the mixture of 5-thiadiazoles and 0.162g (0.003mol) MeONa, the same steps as of repetition embodiment 92 obtains title compound.M.p.:83-86 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.27 (d, 3H), 2.83 (m, 4H), 3.73 (m, 4H), 4.73 (q, 1H), 5.00 (dd, 2H), 5.41 (s, 1H), (m, 3H), 7.81 and 7.84 (ss, 2H) embodiment 97: synthetic (2R for 6.70-7.50 *, 3R *)-2-(2,4 difluorobenzene base)-3-(1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
At room temperature, 1 milliliter of triethylamine is added drop-wise to 0.50g (0.00175mol) (2R in the 4ml acetonitrile *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.59g (0.0035mol) 3-chloro-1 are in the suspension of 2-benzisothiazole.The mixture of gained stirred 1 hour, and evaporation obtains concentrated solution, and this concentrated solution is with the dilution of 100ml ethyl acetate, the aqueous solution of the sodium hydroxide with 5% (30ml * 2), used salt solution (30ml * 1) to wash then.The organic layer anhydrous magnesium sulfate drying, reduction vaporization produces residue again, and this residue silica gel chromatography obtains title compound.M.p.:133-135 ℃ 1H-NMR (DMSO-d 6, δ, and ppm) 1.13 (d, 3H), 3.71 (q, 4H), 4.81 (dd, 2H), 6.40 (s, 1H), 6.85-8.05 (m, 7H), 7.65 and 8.25 (ss, 2H) embodiment 98: synthetic (2R, 3R)-2-(2,4-two difluorophenyls)-3-(1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under 3 ± 2 ℃, with 1 milliliter of triethylamine be added drop-wise to 0.50g (0.00175mol) in the 6ml acetonitrile (2R, 3R)-2-(2, the 4-difluorophenyl)-3-sulfydryl-1-(1H-1,2, the 4-triazol-1-yl)-2-butanols and 0.36g (0.0021mol) 3-chloro-1, in the suspension of 2-benzisothiazole.The product of gained is handled by the same procedure of embodiment 97, obtains title compound.M.p:128-130 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.18 (d, 3H), 3.58 (q, 1H), 4 90-5.10 (m, 3H), 6.66-7.95 (m, 7H), 7.84 and 8.50 (ss, 2H)
Add 0.11g (0.0012mol) oxalic acid in the solution of the title compound of the 0.42g in the 10ml ethyl acetate (0.001mol), the solution with gained is heated to dissolving fully again.In the solution of gained, drip normal hexane, obtain the oxalate of title compound.M.p.:82-85 ℃ (oxalate)
In the solution of the title compound of the 0.42g in the 10ml ether (0.001mol), add the saturated ether of 10ml HCl-, obtain the hydrochloride of title compound.M.p.:87-90 ℃ of (HCl) embodiment 99: synthetic (2R *, 3R *)-2-(4-chlorophenyl)-3-(1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate
Under 3 ± 2 ℃, 1 milliliter of triethylamine slowly is added drop-wise to 0.60g (0.0021mol) (2R in the 6ml acetonitrile *, 3R *)-2-(4-chlorophenyl)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.36g (0.0021mol) 3-chloro-1 are in the suspension of 2-benzisothiazole.The product of gained stirred 20 minutes, and handled by the same procedure of the foregoing description 97.Thus obtained compound dissolution in ethyl acetate, and is added 0.22g (0.0024mol) oxalic acid in the solution that obtains, again gains are heated to dissolving fully.In the solution of gained, drip normal hexane, obtain title compound.M.p.:80-83 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.10 (d, 3H), 3.70 (q, 1H), 4.80 (dd, 2H), 6.10 (s, 1H), (m, 8H), 7.76 and 8.17 (ss, 2H) embodiment 100: synthetic (2R for 7.32-7.90 *, 3R *)-2-(4-fluoro phenyl)-3-(1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate
Under the cooling of ice bath, 0.5 milliliter of triethylamine slowly is added drop-wise to 0.50g (0.00187mol) (2R in the 6ml acetonitrile *, 3R *)-2-(4-fluoro phenyl)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.32g (0.00187mol) 3-chloro-1 are in the suspension of 2-benzisothiazole.The product of gained at room temperature stirred 20 minutes, and handled by the same procedure of the foregoing description 97.Thus obtained compound dissolution in ethyl acetate, and is added 0.22g (0.0024mol) oxalic acid in the solution that obtains, and be heated to dissolving fully.In the solution of gained, add ether, obtain title compound.M.p.:138-140 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.14 (d, 3H), 3.65 (m, 1H), 4.85 (dd, 2H), 6.10 (s, 1H), (m, 8H), 7.80 and 8.19 (ss, 2H) embodiment 101: synthetic (2R for 7.10-7.91 *, 3R *)-2-(2,4 difluorobenzene base)-3-(5-chloro-1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under the cooling of ice bath, 1.5 milliliters of triethylamines slowly are added drop-wise to 0.70g (0.00245mol) (2R in the 10ml acetonitrile *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.82g (0.0040mol) 3,5-two chloro-1 are in the suspension of 2-benzisothiazole.The product of gained stirred 1 hour, and handled by the same procedure of the foregoing description 97, obtained title compound.M.p.:154-156 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.15 (d, 3H), 3.56 (q, 1H), 4.97 (dd, 2H), 5.21 (s, 1H), (m, 6H), 7.79 and 7.81 (ss, 2H) embodiment 102: synthetic (2R for 6.65-7.78 *, 3R *)-2-(4-chlorophenyl)-3-(5-chloro-1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under the cooling of ice bath, 1 milliliter of triethylamine slowly is added drop-wise to 0.50g (0.00176mol) (2R in the 6ml acetonitrile *, 3R *)-2-(4-chlorophenyl)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.51g (0.0025mol) 3,5-two chloro-1 are in the suspension of 2-benzisothiazole.The product of gained at room temperature stirred 30 minutes, and handled by the same procedure of the foregoing description 97, obtained title compound.M.p.:105-107 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.15 (d, 3H), 3.68 (q, 1H), 4.83 (dd, 2H), 6.13 (s, 1H), (m, 7H), 7.80 and 8.19 (ss, 2H) embodiment 103: synthetic (2R for 7.33-8.10 *, 3R *)-2-(2,4 difluorobenzene base)-3-(5,6-dimethoxy-1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under the cooling of ice bath, 1.5 milliliters of triethylamines slowly are added drop-wise to 0.60g (0.00210mol) (2R in the 10ml acetonitrile *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.69g (0.003mol) 3-chloro-5,6-dimethoxy-1 is in the suspension of 2-benzisothiazole.The product of gained at room temperature stirred 30 minutes, and handled by the same procedure of the foregoing description 97, obtained title compound.M.p.:157-160 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.15 (d, 3H), 3.62 (q, 1H), 3.92 and 3.99 (ss, 6H), 4.95 (s, 2H), (m, 5H), 7.78 (ss, 2H) embodiment 104: synthetic (2R for 6.65-7.36 *, 3R *)-2-(2,4 difluorobenzene base)-3-(5-methyl isophthalic acid, 2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under the cooling of ice bath, 1.5 milliliters of triethylamines slowly are added drop-wise to 0.80g (0.0028mol) (2R in the 10ml acetonitrile *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.64g (0.0035mol) 3-chloro-5-methyl isophthalic acid are in the suspension of 2-benzisothiazole.The product of gained at room temperature stirred 30 minutes, and handled by the same procedure of the foregoing description 97, obtained title compound.M.p:150-153 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.19 (d, 3H), 2.44 (s, 3H), 3.62 (q, 1H), 5.00 (s, 2H), 5.10 (s, 1H), (m+s, 8H) embodiment 105: synthetic (2R for 6.67-7.90 *, 3R *)-2-(2,4 difluorobenzene base)-3-(7-chloro-1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under the cooling of ice bath, 1.5 milliliters of triethylamines slowly are added drop-wise to 0.70g (0.00245mol) (2R in the 10ml acetonitrile *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.82g (0.004mol) 3,7-two chloro-1 are in the suspension of 2-benzisothiazole.The product of gained at room temperature stirred 18 hours, and handled by the same procedure of the foregoing description 97, obtained title compound.M.p.:126-128 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.04 (d, 3H), 3.48 (q, 1H), (m, 3H), (m, 6H), 7.67 (s, 2H) embodiment 106: synthetic (2R for 6.55-7.85 for 4.75-5.10 *, 3R *)-2-(2,4 difluorobenzene base)-3-(thieno-[3,4-d] isothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under the cooling of ice bath, 1.5 milliliters of triethylamines slowly are added drop-wise to 1.0g (0.0035mol) (2R in the 15ml acetonitrile *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 1.23g (0.007mol) 3-chlorothiophene are also in the suspension of [3,4-d] isothiazole.The product of gained at room temperature stirred 1 hour, and handled by the same procedure of the foregoing description 97, obtained title compound.M.p.:82-84 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.13 (d, 3H), 3.64 (q, 1H), 4.88 (s, 2H), 5.05 (s, 1H), (m, 3H), 7.64 and 8.04 (ss, 2H), 7.77 (s, 2H) embodiment 107: synthetic (2R for 6.60-7.40 *, 3R *)-2-(2,4 difluorobenzene base)-3-(1,2-benzisothiazole-1,1-two oxa-s-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under the cooling of ice bath, 1.5 milliliters of triethylamines slowly are added drop-wise to 0.70g (0.00245mol) (2R in the 10ml acetonitrile *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.99g (0.0049mol) 3-chloro-1,2-benzisothiazole-1 is in the suspension of 1-dioxide.The product of gained at room temperature stirred 3 hours, and handled by the same procedure of the foregoing description 97, obtained title compound.M.p.:213-217 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.27 (d, 3H), 4.81 (s, 2H), 4.91 (s, 1H), 6.80 (s, 1H), (m, 7H), 7.67 and 8.22 (ss, 2H) embodiment 108: synthetic (2R for 6.90-8.21 *, 3R *)-2-(2,4 difluorobenzene base)-3-(thieno-[3,4-d] isothiazole-1,1-two oxa-s-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under 120 ℃, with the 0.50g in the 6ml acetonitrile (0.002mol) (2R *, 3S *)-2-(2, the 4-difluorophenyl)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane and 0.57g (0.003mol) 3-sulfydryl-thieno-[3,4-d] isothiazole-1, the vlil of 1-dioxide and 0.42g (0.004mol) lithium perchlorate 16 hours stirs simultaneously, and handle by the same procedure of the foregoing description 97, obtain title compound.M.p:149-151 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.27 (d, 3H), 4.94 (dd+q, 3H), 5.54 (s, 1H), (m, 3H), (m, 4H) embodiment 109: synthetic (2R for 7.62-7.88 for 6.67-7.40 *, 3R *)-2-(2,4 difluorobenzene base)-3-(2,1-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols＜method 1 〉
0.27g (0.005mol) sodium methylate is joined 0.57g (0.002mol) (2R in the 6ml methyl alcohol *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.47g (0.0022mol) 3-bromo-2 are in the solution of 1-benzisothiazole.Gains are reflux 10 minutes under agitation, and handles by the same procedure of the foregoing description 97, obtains title compound.M.p.:91-93 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.19 (d, 3H), 4.10 (q, 1H), 4.95 and 5.06 (dd, 2H), 6.65 (s, 1H), 7.00-7.92 (m, 7H), 7.74 and 8.34 (ss, 2H)＜method 2 〉
Under 100 ℃, with the 0.50g in the 6ml acetonitrile (0.002mol) (2R *, 3S *)-2-(2, the 4-difluorophenyl)-3-methyl-2-[(1H-1,2, the 4-triazol-1-yl) methyl] oxyethane, 0.50g (0.003mol) 3 ,-sulfydryl-2, the solution of 1-benzisothiazole and 0.42g (0.004mol) lithium perchlorate be reflux 15 hours under agitation, and handle by the same procedure of the foregoing description 97, obtain title compound.Embodiment 110: synthetic (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(5-nitro-2,1-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
With 0.57g (the 0.002mol) (2R in 0.27g (0.005mol) the sodium methylate adding 6ml methyl alcohol *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.57g (0.0022mol) 3-bromine 5-nitro-2 are in the solution of 1-benzisothiazole.The product of gained at room temperature stirred 30 minutes, and handled by the same procedure of the foregoing description 97, obtained title compound.M p.:142-144 ℃ 1H-NMR (MDSO-d 6, δ, ppm) 1.28 (d, 3H), 4.40 (m, 1H), 4.94 (m, 2H), 6.83 (s, 1H), (m, 6H), 7.77 and 8.74 (ss, 2H) embodiment 111: synthetic (2R for 7.00-8.31 *, 3R *)-2-(2,4 difluorobenzene base)-3-(isothiazole is [3,4-b] pyridin-3-yl also) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols
Under the cooling of ice bath, 15 milliliters of triethylamines slowly are added drop-wise to 0.57g (0.002mol) (2R in the 10ml acetonitrile *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.43g (0.002mol) 3-bromo-isothiazole are also in the solution of [3,4-b] pyridine.The product of gained stirred 15 minutes, and handled by the same procedure of the foregoing description 97, obtained title compound.M.p.:148-150 ℃ 1(ppm) 1.26 (d, 3H), 3.91 (q, 1H), 5.05 and 5.18 (dd, 2H), 5.55 (s, 1H), (m, 7H), 7.85 (s, 2H) embodiment 112: synthetic (2R for 6.73-8.96 for CDCl3, δ for H-NMR *, 3R *)-2-(2,4 difluorobenzene base)-3-(1,2-benzoisoxazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate
With 0.60g (the 0.0023mol) (2R in 0.1g potassiumiodide and 0.27g (0.005mol) the sodium methylate adding 10ml methyl alcohol *, 3R *)-2-(2,4 difluorobenzene base)-3-sulfydryl-1-(1H-1,2,4-triazol-1-yl)-2-butanols and 0.70g (0.00464mol) 3-chloro-1, (3-chloro-1 is in solution 2-benzoisoxazole) for the 2-benzoisoxazole.The product of gained is reflux 15 hours under agitation, and handles by the same procedure of the foregoing description 97, obtains title compound.M.p.:80-82 ℃ 1H-NMR (DMSO-d 6, δ, ppm) 1.25 (d, 3H), 4.84 (m, 3H), 6.60 (s, 1H), 7.00-7.50 (m, 7H), 7.65 and 8.29 (ss, 2H) embodiment 113: synthetic (2R, 3R)-2-(2,4 difluorobenzene base)-3-(thieno-[3,4-d] isothiazole-3-yl) sulfo--1-(1H-1,2, the 4-triazol-1-yl)-the 2-butanols
Under the cooling of ice bath, 1 milliliter of triethylamine slowly is added drop-wise to 0.5g (0.00175mol) (2R in the 15ml acetonitrile, 3R)-2-(2, the 4-difluorophenyl)-3-sulfydryl-1-(1H-1,2, the 4-triazol-1-yl)-2-butanols and 0.6g (0.0035mol) 3-chlorothiophene be also in the solution of [3,4-d] isothiazole.The product of gained at room temperature stirred 1 hour, and handled by the same procedure of the foregoing description 97, obtained title compound.M.p.:129-131 ℃ 1H-NMR (CDCl 3, δ, ppm) 1.13 (d, 3H), 3.64 (q, 1H), 4.88 (s, 2H), 5.05 (s, 1H), 6.60-7.40 (m, 3H), 7.64 and 8.04 (s, 2H)
Activity test
Compound to general formula of the present invention (I) is tested, by the following anti-mycotic activity of measuring them.1. the candidid of mouse whole body (candidosis)
Male ICR mouse (22-25g) is divided into 48 groups, is made up of 10 mouse for every group.The 1st group is contrast, use-testing compound not, and the 2nd group of control group that has been to use Fluconazole, Fluconazole is the triazole antifungal agent that can buy, and the 3rd to the 48th group has been used compound of the present invention.B02630 cultivated 24 hours in the SDA substratum with Candida albicans (Candida albicans), then, and with 4.0 * 10 7The concentration of CFU/ml is suspended in the salt solution of sterilization.
All experimental animals all pass through to tail vein injection 0.2ml fungi suspension and infected.After the infection, will be dissolved in Fluconazole in the Macrogol 200 and compound of the present invention immediately and give the 2nd group and 3-48 group consumption oral administration respectively with 2mg/kg.Test compound served as administration at interval 3 times with 24 hours.And 24 hours to serve as the counting that carries out survival mice at interval, the results are shown in Table 5.
Table 5
Group Compound Survival rate (%)
1 day 4 days 7 days
????1 ????2 ????3 ????4 ????5 ????6 ????7 ????8 ????9 ????10 ????11 ????12 ????13 ????14 ????15 ????16 ????17 ????18 ????19 ????20 ????21 ????22 ????23 ????24 ????25 ????26 ????27 ????28 ????29 ????30 ????31 ????32 ????33 ????34 ????35 ????36 ????37 ????38 ????39 ????40 -Fluconazole embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 9 embodiment 10 embodiment 13 embodiment 19 embodiment 20 embodiment 21 embodiment 22 embodiment 34 embodiment 41 embodiment 47 embodiment 55 embodiment 57 embodiment 60 embodiment 63 embodiment 64 embodiment 69 embodiment 70 embodiment 71 embodiment 72 embodiment 73 embodiment 77 embodiment 80 embodiment 83 embodiment 84 embodiment 85 embodiment 92 embodiment 93 embodiment 94 embodiment 95 embodiment 96 embodiment 97 embodiment 98 embodiment 99 ????0-100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????0-20 ????90-100 ????100 ????100 ????100 ????90 ????100 ????100 ????80 ????100 ????100 ????100 ????100 ????100 ????90 ????100 ????80 ????100 ????100 ????100 ????100 ????90 ????100 ????90 ????100 ????100 ????100 ????80 ????90 ????80 ????80 ????90 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????90 ????0 ????80-90 ????100 ????100 ????100 ????90 ????100 ????100 ????80 ????100 ????100 ????100 ????70 ????90 ????90 ????100 ????80 ????90 ????100 ????100 ????100 ????90 ????90 ????90 ????100 ????100 ????100 ????80 ????90 ????80 ????80 ????90 ????100 ????80 ????100 ????100 ????100 ????90 ????100 ????90
????41 ????42 ????43 ????44 ????45 ????46 ????47 ????48 Embodiment 101 embodiment 102 embodiment 103 embodiment 104 embodiment 106 embodiment 107 embodiment 108 embodiment 111 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????100 ????80 ????100 ????80 ????100 ????90 ????90 ????100
2. antimycotic validity
A. the ED of anti-candida albicans (candida albicans) 50
36 groups of male ICR mouses (22-25g) are made up of 8 mouse for every group, according to aforementioned identical step, make mouse infection Candida albicans (Candida albicans).After the infection, will be dissolved in compound of the present invention in the Macrogol 200 (by embodiments of the invention 5 preparations) immediately with the in the 2nd to 6 group of oral form administration, consumption be each 20,10,5,2.5 and 1.25mg/kg, with 24 hours be the interval, totally 5 times.The 1st group of not administration.By embodiment 47,72, in remaining the 7th to 36 group, each consumption is 20,10,5,2.5 and 1.25 to the The compounds of this invention of 73,93,97 and 98 preparations with oral form administration.With 24 hours served as at interval survival mice to be counted.
Adopt Fluconazole to repeat above-mentioned steps individually.After 14 days,, calculate ED by the number of mice of survival according to the Litchfield-Wilconxon method 50Value, the results are shown in Table 6.
B. the ED of anti-Cryptococcus neoformans (cryptococcus neoformans) 50
Male ICR mouse (22-25g) is divided into 36 groups, is made up of 8 mouse for every group.IFM 40092 cultivated 24 hours in the SDA substratum with Cryptococcus neoformans (Cryptococcus neoformans), then, and with 2.0 * 10 8The concentration of CFU/ml is suspended in the salt solution of sterilization.The endoxan of giving a mouse of every group of peritoneal injection 2mg/ is as immunosuppressor.Inject after 24 hours, every group by tail vein injection 0.2ml fungi suspension, makes every group of infection.Infect after 2 hours, will be by embodiment 5,47, the compounds of the present invention of 72,73,93,97 and 98 preparations deliver medicine to experimental animal in aforesaid mode, and each consumption is 20,10,5,2.5 and 1.25mg/kg.The ED that records 50List in the table 6.
C. the ED of anti-aspergillus fumigatus (Aspergillus fumigatus) 50
Male ICR mouse (22-25g) is divided into 36 groups, is made up of 8 mouse for every group.Give the endoxan (immunosuppressor) of a mouse of every group of peritoneal injection 2mg/.Inject after 24 hours, (concentration in sterile saline is 2.0 * 10 to every group of suspension by tail vein injection 0.2ml Aspergillus fumigatus (Aspergillus fumigatus) B19119 spore 6CFU/ml), make it to infect.Infect after 48 hours, will be by embodiment 5,47, the compounds of the present invention of 72,73,93,97 and 98 preparations deliver medicine to experimental animal in aforesaid mode, and each consumption is 100,50,25,12 5 and 6.25mg/kg.The ED that records 50List in the table 6.
Table 6
Compound ????????????????????????ED 50(mg/kg)
Test A Test B Test C
Fluconazole embodiment 5 embodiment 47 embodiment 72 embodiment 73 embodiment 93 embodiment 97 embodiment 98 ????13.15 ????5.83 ????4.95 ????4.65 ????2.62 ????5.42 ????5.83 ????2.62 ????＞50.00 ????8.64 ????9.10 ????5.06 ????4.29 ????7.28 ????8.64 ????0.96 ????＞100.00 ????20.32 ????＞80 ????22.10 ????10.43 ????64.60 ????20.32 ????10.43
As mentioned above, acceptable salt has the anti-various fungies of potential on the compound of general formula of the present invention (I) and the pharmacology thereof, as Candida albicans (Candida albicans), the activity of Cryptococcus neoformans (Cryptococcusneoformans) and Aspergillus fumigatus (Aspergillus fumigatus), therefore, can be used for Mammals and comprise the human therapy anti-fungal infection.
Though the present invention describes by above-mentioned certain embodiments, should recognize and to make various improvement and variation that these also fall into the present invention with within the defined scope of following claim to the present invention.

Claims (10)

1, acceptable salt on the triazole compounds of following general formula (I) and the pharmacology thereof:
Figure A9519208200021
Wherein, X and Y are hydrogen atom or halogen atom independently of one another; And R is selected from by (I-a), (I-b), and (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i) and (I-j) group of the general formula of forming: Wherein, Z is nitrogen-atoms or carbon atom; R 1Represent one can with the C of a nitrogen-atoms Cheng Huan 1-4Alkoxyl group, C 1-4Alkoxyl-methyl, C 1-4Alkyl thio-base, C 1-4Alkylthiomethyl, amino, C 1-4Alkylamino, or a C who is optionally substituted 1-4Alkyl, styryl, phenyl or heteroaryl; R 2Represent a hydrogen atom or a C 1-3Alkyl, phenyl, phenyl, morpholinyl, pyrrolidyl, thio-morpholinyl or the piperidyl of replacement; And R 3Represent a hydrogen atom or halogen atom or a C 1-3Alkyl, C 1-3Alkoxyl group or nitro.
2, compound as claimed in claim 1, wherein, R is the group of following general formula (I-a):
Figure A9519208200023
Wherein, R 1Identical with the definition of claim 1.
3, the group of the freely following compound composition of compound choosing as claimed in claim 2: (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-t-butyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-methyl mercapto-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-cyclopropyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-isopropyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-methoxyl group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-chloromethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-dimethylamino-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(pyrrolidin-1-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-amino-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazole-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-ethyoxyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-methacryl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-methylthiomethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-ethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazole-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(1-vinyl chloride)-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-methoxy-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-methoxyl-styrene)-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3,5-dimethyl pyrazole-1-yl)-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-crotyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-fluorostyrene base)-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-(2,2,3,3-tetrafluoro propoxyl group) styryl-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-fluoro methyl isophthalic acid, 2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-phenoxymethyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(2-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(2,6-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(2-pyridine radicals)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(2-chlorophenyl)-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-phenyl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazole-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3-pyridine radicals)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-pyridine radicals)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[4-(1-(N-oximido ethyl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(4-chlorophenyl)-3-[3-(3,5-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-dichlorophenyl)-3-[3-(4-pyridine radicals)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-chlorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3,4-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(2,6-dichlorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3-trifluoromethyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3-chlorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-(1H-imidazoles-1-yl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(2-pyrazinyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(2-chloro-6-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-bromo phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-(1H-1,2,4-triazol-1-yl) phenyl-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-azido phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3,5-dual-trifluoromethyl benzene base)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-styryl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-morpholine-1-yl) phenyl-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3-trifluoromethyl-4-acetylamino) phenyl-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-(1,3,4-oxadiazole-2-yl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-(DOX-2-yl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-cyano group phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(benzene sulphur-2-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-nitrobenzophenone)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(pyrimidine-5-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-xenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-(2,2,3,3-tetrafluoro propoxyl group) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-(4-pyridone-1-yl) phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-methylpyrimidine-2-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(pyridine-N-oxygen-4-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-methyl mercapto phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-methylsulfonyl phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3-nitrobenzophenone)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(2,5-difluorophenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-dimethylamino phenyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(1H-1,2,4-triazol-1-yl) methyl isophthalic acid, 2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(4-methoxybenzene vinyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(3-pyrroles-1-yl) phenyl-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(pyridazine-3-yl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[3-(1-chloro-2-methoxyl group ethyl)-1,2,4-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(3-methoxyl group methyl isophthalic acid, 2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R, 3R)-2-(2,4-difluorophenyl)-3-(3-styryl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R, 3R)-2-(2,4-difluorophenyl)-3-(3-methoxyl group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazole-1-yl)-2-butanols; (2R*，3R *)-2-(4-chloro phenyl)-3-(3-methoxyl group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazole-1-yl)-2-butanols; (2R*，3R *)-2-(4-difluorophenyl)-3-(3-methoxyl group-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazole-1-yl)-2-butanols; (2R*，3R *)-2-(4-difluorophenyl)-3-(3-styryl-1,2,4-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[4-(2,6-difluorophenyl)-thiazole-2-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[4-(2,4-dichlorophenyl)-thiazole-2-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[4-(4-chlorophenyl)-thiazol-2-yl] sulfo--1-(1H-1,2,4-triazole-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(4-ethyl thiazole-2-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[4-(1-hydroxyl-1-Methylethyl) thiazol-2-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-(4-styryl thiazol-2-yl) sulfo--1-(1H-1,2,4-triazole-1-yl)-2-butanols; (2R*，3R *)-2-(2,4-difluorophenyl)-3-[4-(4-methoxyl-styrene)-thiazol-2-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols, and (2R*，3R *)-2-(2,4-difluorophenyl)-3-[4-(2,3-dichlorostyrene base)-thiazol-2-yl] sulfo--1-(1H-1,2, the 4-triazol-1-yl)-2-butanols.
4, compound as claimed in claim 1, wherein R has general formula (I-b) or group (I-c):
Figure A9519208200081
R wherein 2Have with claim 1 in identical definition.
5, compound as claimed in claim 4 is selected from the group that following compound is formed: (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(4-chlorophenyl)-3-(1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 dichloro benzene base)-3-(1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(4-phenyl-1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-[4-(2,4 difluorobenzene base)-1,2,3-thiadiazoles-5-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(4-fluoro phenyl)-3-(1,2,3-thiadiazoles-5-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(N-morpholinyl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(N-thio-morpholinyl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(piperidines-1-yl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-[3-(tetramethyleneimine-1-yl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; And (2R, 3R)-2-(2,4 difluorobenzene base)-3-[3-(N-thio-morpholinyl)-1,2,5-thiadiazoles-4-yl] sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols.
6, compound as claimed in claim 1, wherein R is the group that is selected from the group of being made up of general formula (I-d), (I-e), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i) and group (I-j): R wherein 3Have with claim 1 in identical definition.
7, compound as claimed in claim 6 is selected from the group that following compound is formed: (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R, 3R)-2-(2,4 difluorobenzene base)-3-(1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(4-chlorophenyl)-3-(1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(4-fluoro phenyl)-3-(1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(5-chloro-1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(4-chlorophenyl)-3-(5-chloro-1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(5,6-dimethoxy-1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(5-methyl isophthalic acid, 2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(7-chloro-1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(thieno-[3,4-d] isothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(1,2-benzisothiazole-1,1-two oxa-s-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(thieno-[3,4-d] isothiazole-1,1-two oxa-s-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(2,1-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(5-nitro-2,1-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(isothiazole is [3,4-b] pyridin-3-yl also) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols; (2R *, 3R *)-2-(2,4 difluorobenzene base)-3-(1,2-benzisothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols oxalate; And (2R, 3R)-2-(2,4 difluorobenzene base)-3-(thieno-[3,4-d] isothiazole-3-yl) sulfo--1-(1H-1,2,4-triazol-1-yl)-2-butanols.
8, the method for the triazole compounds of a kind of preparation general formula (I) comprises the compound of general formula (II) and compound or its an alkali metal salt of general formula (III) is reacted in the presence of lithium perchlorate: HS-R (III) is wherein: X, Y has the definition identical with claim 1 with R.
9, the method for the triazole compounds of a kind of preparation general formula (I) comprises the compound of general formula (IV) and the compound of logical formula V is reacted in the presence of alkali: L-R (V) is wherein: X, and Y has the definition identical with claim 1 with R; L is a halogen.
10, a kind of pharmaceutical composition, comprise significant quantity on the pharmacology by the triazole compounds of claim 1 definition as active ingredient, and acceptable carrier or adjuvant on the pharmacology.
CN 95192082 1994-03-12 1995-03-13 Triazole compound and processes for preparation thereof Pending CN1143962A (en)

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KR1019940004917A KR950026874A (en) 1994-03-12 1994-03-12 Triazole derivatives and preparation method thereof
KR1019940004918A KR950026875A (en) 1994-03-12 1994-03-12 Triazole derivatives and preparation method thereof
KR94-12285 1994-06-01
KR94-4917 1994-06-01
KR94-4918 1994-06-01

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102947282A (en) * 2010-05-27 2013-02-27 拜耳知识产权有限责任公司 Heterocyclic alkanol derivatives as fungicides
CN105237513A (en) * 2015-11-26 2016-01-13 上海倚诺升生物医药科技有限公司 Triazole aromatic alcohol heterocyclic ether derivative and preparing method and application thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102947282A (en) * 2010-05-27 2013-02-27 拜耳知识产权有限责任公司 Heterocyclic alkanol derivatives as fungicides
CN102947282B (en) * 2010-05-27 2016-06-01 拜耳知识产权有限责任公司 Heterocycle alkanol derivatives as antifungal
CN105237513A (en) * 2015-11-26 2016-01-13 上海倚诺升生物医药科技有限公司 Triazole aromatic alcohol heterocyclic ether derivative and preparing method and application thereof
CN105237513B (en) * 2015-11-26 2018-01-23 上海倚诺升生物医药科技有限公司 A kind of trinitrogenazole alcohol heteroaromatic ether derivative and its preparation method and application

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