CN102002054B - Pyrazole type compound and preparation method and application thereof - Google Patents
Pyrazole type compound and preparation method and application thereof Download PDFInfo
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- CN102002054B CN102002054B CN 201010517703 CN201010517703A CN102002054B CN 102002054 B CN102002054 B CN 102002054B CN 201010517703 CN201010517703 CN 201010517703 CN 201010517703 A CN201010517703 A CN 201010517703A CN 102002054 B CN102002054 B CN 102002054B
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- Prior art keywords
- compound
- acceptable salt
- pharmacy acceptable
- formula
- salt
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 150000003217 pyrazoles Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 150000003839 salts Chemical class 0.000 claims abstract description 65
- 239000003814 drug Substances 0.000 claims abstract description 23
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 8
- 206010017533 Fungal infection Diseases 0.000 claims abstract description 3
- 208000031888 Mycoses Diseases 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- -1 pyridine-5-yl Chemical group 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000543 intermediate Substances 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229960001701 chloroform Drugs 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 7
- 239000003826 tablet Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 235000010755 mineral Nutrition 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- 239000001103 potassium chloride Substances 0.000 claims description 6
- 235000011164 potassium chloride Nutrition 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 5
- 229910052728 basic metal Inorganic materials 0.000 claims description 5
- 150000003818 basic metals Chemical class 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000011968 lewis acid catalyst Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical group [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 150000004648 butanoic acid derivatives Chemical class 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 150000004679 hydroxides Chemical class 0.000 claims description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000003016 phosphoric acids Chemical class 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical class 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- 159000000000 sodium salts Chemical group 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- 229940095064 tartrate Drugs 0.000 claims description 3
- 229940104261 taurate Drugs 0.000 claims description 3
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 3
- 229950004288 tosilate Drugs 0.000 claims description 3
- 239000004246 zinc acetate Substances 0.000 claims description 3
- 239000007910 chewable tablet Substances 0.000 claims description 2
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- 239000007919 dispersible tablet Substances 0.000 claims description 2
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- 239000003978 infusion fluid Substances 0.000 claims description 2
- 229940100688 oral solution Drugs 0.000 claims description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 8
- 229940121375 antifungal agent Drugs 0.000 abstract description 7
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 229960004756 ethanol Drugs 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 9
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- 239000003429 antifungal agent Substances 0.000 description 9
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 6
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- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
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- 150000003852 triazoles Chemical class 0.000 description 4
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Landscapes
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Abstract
The invention discloses a pyrazole type compound with a structure of the formula I and a pharmaceutically acceptable salt thereof. The invention also discloses a preparation method of the compound, a medicinal composition using the compound or the pharmaceutically acceptable salt of the compound as an active ingredient, and application of the compound and the medicinal composition in preparing an antifungal medicament. The compound and the salt of the compound have a function of inhibiting fungal infections, and can be used for preparing the antifungal medicament.
Description
Technical field
The invention belongs to medical technical field, particularly, the present invention relates to pyrazole compound, preparation method, composition and use thereof that a class has anti-mycotic activity.
Background technology
Fungi infestation is larger to the harm that the mankind cause, and skin and first section are more common in part fungi infestation, are a kind of common disease, frequently-occurring disease; And some fungi as Candida albicans and Cryptococcus neoformans, though its sickness rate is low, but infects threat to life when serious.Particularly in recent decades, along with being widely used of broad-spectrum antibiotics, cortin, antitumor drug and immunosuppressor, extensively carrying out of radiotherapy and organ transplantation, generally carrying out of conduit and intubate, and especially AIDS patient's increase rapidly of immune deficiency patient, destroyed the symbiotic relationship of normal flora, human body is reduced the resistibility of fungi, thereby cause fungi infestation significantly to be risen, and become one of major disease main causes of death such as acquired immune deficiency syndrome (AIDS) and tumour.
In existing antifungal drug, azole drug is the class with better prospect, is widely used clinically.The curative effect of nitrogen azole drug is comparatively desirable, so be the focus of studying in antifungal drug always.They can rely on C14-α-demethylase (ERGl1) by Antifungi Cytochrome P450 3A, and this enzyme is lanosterol to be changed into the key enzyme of ergosterol.Its mechanism of action is blocking-up substrate hydroxylation reaction, and the interior methylated sterol of lanosterol 14-of fungus body is accumulated in a large number, and ergosterol is synthetic to be lacked, and causes many enzyme activity changes on membrane permeability and film, thus the growth of Antifungi.
Research of Triazole Antifungal Agents take fluconazole (Fluconazole, FCZ) and itraconazole (Itraconazole, ICZ) as representative is the main choice drug for the treatment of clinically fungi infestation at present.Voriconazole (Voriconazole, VOR) is a kind of novel antifungal drug in triazole class, is the fluconazole derivative.Add 1 methyl in its structure on the propyl group skeleton and replaced 1 triazole ring in the fluconazole with 1 fluorinated pyrimidine ring.Not only wider than former medicine anti-fungus spectra through the voriconazole that the fluconazole structure of modification is obtained, and anti-mycotic activity is also stronger.
Yet also there are some problems in the Research of Triazole Antifungal Agents of present clinical first-selection: the antimicrobial spectrum relative narrower of fluconazole, and very low to the activity of the fungies such as aspergillus tubigensis, and easily produce resistance; Itraconazole exists oral administration biaavailability unstable, the problems such as GI irritation.Although voriconazole toxicity is less, also more easily produce resistance.Have and report from 851 strain Candida albicanss of clinical separation, 37.2% pair of fluconazole resistance is arranged, 47.6% pair of itraconazole resistance.
For the limitation that existing medicine exists, except the preparation of optimizing the existing medicine of improvement, the research of novel antifungal drugs has also become one of hot fields of global new drug development.In addition, the interaction between medicine makes the fungi infestation treatment become more complicated, therefore, and clinical novel antifungal drugs in the urgent need to high-efficiency low-toxicity, has a broad antifungal spectrum, highly selective.
Summary of the invention
For above-mentioned technical problem, one object of the present invention is to provide a kind of novel pyrazole compounds and pharmaceutical salts thereof, to solve the deficiency of existing antifungal drug.
Another object of the present invention is to provide the preparation method of described compound and pharmaceutical salts thereof.
A further object of the present invention is to provide the pharmaceutical composition take described compound and pharmaceutical salts thereof as main active ingredient.
A further object of the invention is to provide described compound and pharmaceutical salts thereof in the purposes aspect antifungal drug.
To achieve these goals, the technical scheme taked of the present invention is as follows:
On the one hand, the invention provides the compound shown in a kind of formula I or its pharmacy acceptable salt:
Wherein:
R
1, R
2, R
3Be independently
1) hydrogen, C
1-C
6Straight or branched alkyl, C
3-C
6Cycloalkyl, this alkyl or cycloalkyl is replaced by following one or more group: halogen, hydroxyl, carboxyl, amino, amide group, cyano group, nitro, phenyl, C
1-C
4Alkoxyl group;
2) five yuan, hexa-member heterocycle base, these five yuan, hexa-member heterocycle base can be replaced by following one or more group: halogen, hydroxyl, carboxyl, amino, amide group, cyano group, nitro, C
1-C
4Alkoxyl group;
R
4Be pyrazolyl, this pyrazolyl can be replaced by following one or more groups: hydrogen, C
1-C
6Straight or branched alkyl, C
3-C
6The C that cycloalkyl, halogen replace
1-C
6The C that alkyl or branched-chain alkyl, cyano group replace
1-C
6Straight or branched alkyl, phenyl, chlorophenyl.
Particularly, the compound shown in formula I can for:
I-1 3-(2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1, the 5-dimethyl pyrazole;
I-2 3-(2-(2-hydroxyl-5-nitrophenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1, the 5-dimethyl pyrazole;
I-3 4-(2-(2-ethoxyl phenenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-methyl-3-trifluoromethyl pyrazol;
I-4 5-(2-(to cyano-phenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-rubigan-4-cyanogen methylpyrazole;
I-5 5-(2-(to carboxyl phenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-rubigan-4-cyanogen methylpyrazole.
In above-mentioned compound or its pharmacy acceptable salt, described pharmacy acceptable salt is preferably the salt that the compound shown in formula I becomes with mineral acid and/or organic acid;
Further preferably; described salt is hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate.
Alternatively, described pharmacy acceptable salt is the salt that the compound shown in formula I becomes with oxide compound and/or the hydroxides of basic metal, alkaline-earth metal; Described salt is preferably sodium salt, sylvite, calcium salt, magnesium salts.
On the other hand, the invention provides the preparation method of above-claimed cpd or its pharmacy acceptable salt, said method comprising the steps of:
Intermediate (
2) with 4,5,6, the 7-tetrahydrothieno pyridines is under triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide and/or potassium hydroxide etc. exist, take methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane and/or toluene etc. as solvent, 25 ~ 120 ℃ of reactions make key intermediate (
3); And
Key intermediate (
3) pyrazole compound amino with band (
4) in methyl alcohol, ethanol, toluene, DMSO and/or DMF equal solvent, under Lewis acid catalyst such as zinc acetate, Lewis alkaline catalysts such as sodium methylate, non-acid base catalysator such as PbO etc. exist ,-5 ~ 200 ℃ of reactions,
Wherein each substituting group is as above-mentioned definition.
Preferably, above-mentioned preparation method also comprises various intermediates or products therefrom and mineral acid and/or organic acid, the step of the oxide compound of basic metal, alkaline-earth metal and/or oxyhydroxide salify.
On the one hand, the present invention also provides a kind of pharmaceutical composition again, and it comprises above-claimed cpd or its pharmacy acceptable salt for the treatment of significant quantity;
Preferably, described compound or the content of its pharmacy acceptable salt in pharmaceutical composition are 0.05%-90%, further preferred 0.05%-70%.
Preferably, described pharmaceutical composition also comprises one or more pharmaceutically acceptable auxiliary materials; And described pharmaceutical composition can be tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coat agent, granule, dry powder doses, oral solution, the little pin of injection, injection freeze-dried powder or infusion solutions.
Another aspect, the present invention also provides above-claimed cpd and the purposes of pharmacy acceptable salt in the medicine of preparation anti-fungal infection thereof.
Below will describe the present invention.
Compound and the pharmacy acceptable salt thereof of general formula I structure involved in the present invention are as follows:
Wherein:
R
1, R
2, R
3Be at the same time or separately
1) hydrogen, C
1-C
6Straight or branched alkyl, C
3-C
6Cycloalkyl, this alkyl or cycloalkyl is replaced by following one or more group: halogen, hydroxyl, carboxyl, amino, amide group, cyano group, nitro, phenyl, C
1-C
4Alkoxyl group;
2) five yuan, hexa-member heterocycle base, these five yuan, hexa-member heterocycle base can be replaced by following one or more group: halogen, hydroxyl, carboxyl, amino, amide group, cyano group, nitro, C
1-C
4Alkoxyl group;
R
4Be pyrazolyl, this pyrazolyl can be replaced by following one or more groups: hydrogen, C
1-C
6Straight or branched alkyl, C
3-C
6The C that cycloalkyl, halogen replace
1-C
6The C that alkyl or branched-chain alkyl, cyano group replace
1-C
6Straight or branched alkyl, phenyl, chlorophenyl.
The compound with general formula I structure that relates in the present invention or its pharmacy acceptable salt, representation compound is:
I-1 3-(2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1, the 5-dimethyl pyrazole;
I-2 3-(2-(2-hydroxyl-5-nitrophenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1, the 5-dimethyl pyrazole;
I-3 4-(2-(2-ethoxyl phenenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-methyl-3-trifluoromethyl pyrazol;
I-4 5-(2-(to cyano-phenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-rubigan-4-cyanogen methylpyrazole;
I-5 5-(2-(to carboxyl phenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-rubigan-4-cyanogen methylpyrazole.
Compound or its pharmacy acceptable salt with formula I structure of the present invention means: the salt that the compounds of this invention becomes with mineral acid, organic acid.Wherein particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate etc.Described salt can also be formula I compound and the oxide compound of basic metal, alkaline-earth metal, the salt that hydroxides becomes.Wherein particularly preferred salt is sodium salt, sylvite, calcium salt, magnesium salts.
The syntheti c route of formula I compound is as follows:
Referenced patent US 5,036, the method for 156 A1, with compound of benzaldehyde category (
1) for starting raw material can prepare alpha-brominated benzoic acid derivative, then take tosic acid as catalyzer, reflux in toluene carry out esterification can make intermediate (
2).Intermediate (
2) with 4,5,6, the 7-tetrahydrothieno pyridines is under the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide exist, take methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene etc. as solvent, 25 ~ 120 ℃ of reactions make key intermediate (
3).(
3) again the pyrazole compound amino with band (
4) in methyl alcohol, ethanol, toluene, DMSO, DMF equal solvent, under Lewis acid catalyst such as zinc acetate, Lewis alkaline catalysts such as sodium methylate, non-acid base catalysator such as PbO etc. exist,-5 ~ 200 ℃ of reactions can get the target compound I, and wherein each substituting group defines as mentioned.
Reaction is made various intermediates or products therefrom be dissolved in a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drip mineral acid or organic acid solution, make pharmacy acceptable salt.
Specifically various compounds are dissolved in a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drip the hydrochloric acid diethyl ether solution to pH=2 under ice-water bath, make hydrochloride; Also each compound can be dissolved in a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, mole toxilic acid such as add, heated and stirred gets its maleate; Or various compounds are dissolved in a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drip the ethanolic soln of potassium hydroxide, transfer pH=9, make its sylvite, etc.
This compounds is effective for treatment mankind fungal infectious disease.Although compound of the present invention can be without the direct administration of any preparation, described various compounds preferably use with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (as vein, muscle administration) and oral administration.
The pharmaceutical composition preparation method of the compounds of this invention is as follows: Application standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension, for example injection, pulvis etc.
The amount of the active ingredient that contains in pharmaceutical composition and unit dosage form (the compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, and the amount of compound used or concentration are regulated in a wider scope.Usually, the scope of active compound amount is 0.05%~90% (weight) of composition, and another preferred scope is 0.05%-70%.
Compared with prior art, the invention provides novel pyrazole compounds or its pharmacy acceptable salt that a class has formula I structure, this compounds and salt pair fungi thereof have obvious restraining effect, can be used as the activeconstituents in antifungal drug, further widened the scope of azole drug in the antifungal drug.
Embodiment
Below in conjunction with specific embodiment, and comparable data describes in further detail the present invention.Should be understood that these embodiment just in order to demonstrate the invention, but not limit by any way scope of invention.
In following embodiment, various processes and the method do not described in detail are ordinary methods as known in the art.
Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1H NMR,
13C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.
Embodiment 1: the preparation of intermediate 2
Intermediate
2Preparation: alpha-brominated o-chlorobenzene acetic acid methyl esters (
2a)
1. referenced patent US 5,036, and the method for 156A1 (Bouisset etc.) prepares alpha-brominated o-chlorobenzene acetic acid by o-chlorobenzaldehyde, gets the white powder product, m.p.107.2~109.3 ℃, yield 45%.
2. add alpha-brominated o-chlorobenzene acetic acid 0.02mol in the reaction flask that agitator, condenser, water trap are housed, with 50ml toluene, it is dissolved, then add tosic acid 1.0g, methyl alcohol 0.11mol is heated to reflux.When time telling to obvious anhydrous generation the moisture in water trap in the back flow reaction process, add a small amount of alcohol, if still anhydrous telling can be thought and react completely.Be cooled to room temperature, with 2 * 50ml saturated sodium bicarbonate solution washing, 2 * 50ml distilled water wash is got the organic layer anhydrous sodium sulfate drying, filter, evaporate to dryness get compound (
2A), yield 91.3%.
With similar method can conveniently prepare 2-bromo-2-(2-hydroxyl-5-nitrophenyl) methyl acetate (
2B), 2-bromo-2-(2-ethoxyl phenenyl) methyl acetate (
2C), 2-bromo-2-(to cyano-phenyl) methyl acetate (
2D), 2-bromo-2-(to carboxyl phenyl) methyl acetate (
2E).
Embodiment 2: the preparation of key intermediate 3
Key intermediate
3Preparation: 2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) methyl acetate (
3a)
Will (
2A) during 0.018mol packs dry single port bottle into, after the dissolving of 20ml toluene, add Anhydrous potassium carbonate 0.036mol.Drip also [3,2-c] pyridine 0.022mol of 4,5,6,7-tetramethylene sulfide under stirring at room, dropwise stirring reaction under rear room temperature.The point plate is controlled reaction process, the rear filtration that reacts completely, the filtrate evaporate to dryness, with combiflash companion separate key intermediate (
3A), yield 89.5%.
Can conveniently prepare with similar method:
2-(2-hydroxyl-5-nitrophenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) methyl acetate (
3B);
2-(2-ethoxyl phenenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) methyl acetate (
3C);
2-(to cyano-phenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) methyl acetate (
3D);
2-(to carboxyl phenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) methyl acetate (
3E).
The preparation of embodiment 3:I-1 and I-2
3-(2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1, the preparation of 5-dimethyl pyrazole (I-1):
With 1 of 0.02mol, 5-dimethyl-3-amino-pyrazol is added in the reaction flask of 250ml, with 50mL ethanol, it is dissolved.Add 30% sodium methylate, control temperature of reaction at 0 ℃, slowly drip intermediate (
3A).Dropwise rear underpressure distillation, the methyl alcohol that reaction is generated steams.The rising temperature of reaction continues reaction to refluxing, the TLC monitoring.Be down to room temperature after reacting completely, add in the vitriol oil and sodium methylate, steaming desolventizes, and post separates to get white powder product (HPLC:99.3%).The Rf=0.38(single-point, developping agent: v (trichloromethane): v (methyl alcohol)=10:1), yield 52.2%.EI-MS(m/z):400.1。
Can conveniently prepare 3-(2-(2-hydroxyl-5-nitrophenyl)-2-(4,5,6 with similar method, 7-tetramethylene sulfide also [3,2-c] pyridine-5-yl) kharophen)-1,5-dimethyl pyrazole (I-2), white powder (HPLC:99.7%).The Rf=0.32(single-point, developping agent: v (trichloromethane): v (methyl alcohol)=10:1), yield 54%.EI-MS(m/z):4271。
The preparation of embodiment 4:I-3
The preparation of 4-(2-(2-ethoxyl phenenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-methyl-3-trifluoromethyl pyrazol (I-3):
The toluene solution of the 1-methyl of 0.02mol-3-trifluoromethyl-4-amino-pyrazol is added in the 250ml reaction flask, drip under 40 ℃ intermediate (
3C), react 30min under microwave oven 600w condition, post separates to get yellow powder shape product (HPLC:98.8%).The Rf=0.41(single-point, developping agent: v (trichloromethane): v (methyl alcohol)=10:1), yield 55.4%.EI-MS(m/z):464.0。
The preparation of embodiment 5:I-4 and I-5
The preparation of 5-(2-(to cyano-phenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-rubigan-4-cyanogen methylpyrazole (I-4):
The 1-rubigan of 0.02mol-4-cyanogen methylpyrazole is added in the reaction flask of 250mL, adds 30mLDMF and appropriate PbO, be warming up to 140 ℃ and slowly drip intermediate (
3D), dropwise rear underpressure distillation, the methyl alcohol that reaction is generated steams.The rising temperature of reaction continues reaction to refluxing, the TLC monitoring.Be down to room temperature after reacting completely, suction filtration, filtrate steaming removal solvent, post separate to get white powder product (HPLC:99.4%).The Rf=0.40(single-point, developping agent: v (trichloromethane): v (methyl alcohol)=10:1), yield 58.6%.EI-MS(m/z):511.9。
Can conveniently synthesize 5-(2-(to carboxyl phenyl)-2-(4 with similar method, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine-5-yl) kharophen)-1-rubigan-4-cyanogen methylpyrazole (I-5), white powder (HPLC:99.0%).The Rf=0.27(single-point, developping agent: v (trichloromethane): v (methyl alcohol)=10:1), yield 57.9%.EI-MS(m/z):5311。
Embodiment 6: Compound I-1 one-tenth hydrochloride
Get I-1 solid product 1.5g, be dissolved in the 10ml anhydrous diethyl ether.Ice-water bath is cooled to 0 ℃, drip 11.1% hydrochloric acid diethyl ether solution to pH be 2, continued under ice-water bath stir about 1 hour.Filter, get light yellow solid.
Embodiment 7: Compound I-2 one-tenth maleate
Get I-2 solid product 2.0g, be dissolved in the 15ml dehydrated alcohol.Add after being heated to reflux and wait mole toxilic acid, continue at time stirring reaction approximately 3 hours of refluxing.React complete, under room temperature standing 24 hours.Filter, get light yellow solid.
Embodiment 8: Compound I-5 one-tenth sylvite
Get I-5 solid product 1.0g, be dissolved in the 40mL anhydrous methanol.Ice-water bath is cooled to 5 ℃, stir lower drip 20% potassium hydroxide aqueous solution to pH be 9, continued under ice-water bath stir about 1 hour.Under room temperature standing 24 hours.Separate out light yellow crystallization, filter.
Embodiment 9: the Antibacterial Activity of compound
(NCCLSM-27A) measure its minimum inhibitory concentration further illustrates the compounds of this invention to the In Vitro Bacteriostatic of clinical several frequently seen fungi to employing standard micro-dilution method.Concentration (the MIC that suppresses selected fungi 90% growth with target compound
90) as the judgement terminal point.
Test strain:
Trichophyton (Trichophyton rubrum, T.rub.), sporotrichum schenckii (Sporothrix schenckii, S.sch.) and fonsecaea pedrosoi (Fonsecaea pedrosoi, F.ped.).Above bacterial strain provides by our unit's pharmacological experiment chamber.
Test drug:
The compounds of this invention (I-1, I-2, I-3, I-4, I-5), miconazole (MCZ) be as positive control drug, dimethyl sulfoxide (DMSO) (DMSO), AR level (Tianjin triumphant letter chemical industry company limited).Microplate reader, BIO-RAD680.
Test method:
Take RPMI-1640 (Sigma) as nutrient solution, it is 1 * 10 that experimental strain is made into concentration
4~1 * 10
5The suspension of/ml.Compound with sterile purified water and DMSO dissolving, is made medicine storage liquid (6400 μ g/m1), and-20 ℃ of preservations are stand-by.Be diluted to 640 μ g/m1 with RPMI-1640 during use, establish simultaneously solvent control and blank.Get the aseptic 96 flat microtest plates in hole, No. 1 hole adds RPMI-1640 100 μ L and makes blank, and No. 2 the hole adds bacteria suspension 180 μ L and liquid 20 μ L, and the 3-12 hole respectively adds bacteria suspension 100 μ L, 10 grades, 2-11 hole doubling dilution, 100 μ L of sucking-off abandon from No. 11 holes at last.Each hole drug level is respectively 64,32,16,8,4,2,1,0.5,0.25,0.125 μ gmL
-1No. 12 the hole does not add liquid, makes the medicine negative control.26 ℃ of constant temperature culture of fungi are observed the growing state in 1 week.Analyze with microplate reader, compare with the medicine negative control hole, suppress corresponding lowest drug concentration as its minimal inhibitory concentration value (MIC take 90%
90).
Extracorporeal antifungal activity (the MIC of table 1 compound
90, μ gmL
-1)
By In Vitro Bacteriostasis test experiments result as seen, all target compounds all have to a certain degree anti-mycotic activity to 3 kinds of pathomycetes, have further further investigation and are worth.
For the pharmaceutical composition of pyrazole compound of the present invention is described more fully, the below provides following FORMULATION EXAMPLE, and described embodiment only is used for explanation, rather than is used for limiting the scope of the invention.Described preparation can use any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in embodiment 3-5.
Embodiment 10: capsule
Prepare hard gelatin capsule with following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.Press recipe quantity with the mentioned component mixing, cross 60 mesh sieve three times, add appropriate 10% polyvidone ethanol (95%) solution softwood processed, cross 18 mesh sieves and granulate, 40 ℃ of dryings are crossed the 16 whole grains of mesh sieve, are packed in hard gelatin capsule.
Embodiment 11: tablet
Prepare tablet with following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.First with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material, cross 20 mesh sieves, drying is 2 hours in 55 ℃ of ventilated drying ovens, and dried particle is crossed 16 mesh sieves and arranged, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 12: injection
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and propylene glycol, add medicinal basic to regulate pH value to 4~8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 13: pulvis
The preparation of injection lyophilized powder:
The sylvite 45mg of Compound I-5
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-80%
Preparation method: get activeconstituents and add water for injection, regulate pH value to 4~8 with medicinal basic and make its dissolving.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, sealing, and get final product.
Claims (15)
1. compound or its pharmacy acceptable salt shown in a formula I, perhaps Compound I-1 ~ I-5 or its pharmacy acceptable salt:
Wherein:
R
1, R
2, R
3Be independently
Hydrogen, C
1-C
6The straight or branched alkyl, this alkyl is replaced by following one or more group: halogen, hydroxyl, carboxyl, amino, cyano group, nitro, C
1-C
4Alkoxyl group;
R
4Be pyrazolyl, this pyrazolyl can be replaced by following one or more groups: hydrogen, C
1-C
6Straight or branched alkyl, C
3-C
6The C that cycloalkyl, halogen replace
1-C
6The C that alkyl, cyano group replace
1-C
6Straight or branched alkyl, phenyl, chlorophenyl;
Wherein, described Compound I-1 ~ I-5 is respectively:
I-1 3-(2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1, the 5-dimethyl pyrazole;
I-2 3-(2-(2-hydroxyl-5-nitrophenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1, the 5-dimethyl pyrazole;
I-3 4-(2-(2-ethoxyl phenenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-methyl-3-trifluoromethyl pyrazol;
I-4 5-(2-(to cyano-phenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-rubigan-4-cyanogen methylpyrazole;
I-5 5-(2-(to carboxyl phenyl)-2-(4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) kharophen)-1-rubigan-4-cyanogen methylpyrazole.
2. the compound shown in formula I as claimed in claim 1 or its pharmacy acceptable salt, perhaps Compound I-1 ~ I-5 or its pharmacy acceptable salt, wherein, the C that described halogen replaces
1-C
6Alkyl is the C that halogen replaces
1-C
6Branched-chain alkyl.
3. the compound shown in formula I as claimed in claim 1 or 2 or its pharmacy acceptable salt, perhaps Compound I-1 ~ I-5 or its pharmacy acceptable salt, wherein, described pharmacy acceptable salt is the salt that the compound shown in formula I or Compound I-1 ~ I-5 become with mineral acid and/or organic acid.
4. the compound shown in formula I as claimed in claim 3 or its pharmacy acceptable salt; perhaps Compound I-1 ~ I-5 or its pharmacy acceptable salt; wherein; described pharmacy acceptable salt is selected from hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate or taurate.
5. the compound shown in formula I as claimed in claim 1 or 2 or its pharmacy acceptable salt, perhaps Compound I-1 ~ I-5 or its pharmacy acceptable salt, wherein, described pharmacy acceptable salt is the salt that the compound shown in formula I or Compound I-1 ~ I-5 become with oxide compound and/or the hydroxides of basic metal, alkaline-earth metal.
6. the compound shown in formula I as claimed in claim 5 or its pharmacy acceptable salt, perhaps Compound I-1 ~ I-5 or its pharmacy acceptable salt, wherein, described pharmacy acceptable salt is selected from sodium salt, sylvite, calcium salt, magnesium salts.
7. compound or its pharmacy acceptable salt as shown in formula I as described in any one in claim 1-6, the perhaps preparation method of Compound I-1 ~ I-5 or its pharmacy acceptable salt,
Wherein, said method comprising the steps of:
Intermediate (
2) with 4,5,6, the 7-tetrahydrothieno pyridines is under triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide and/or potassium hydroxide exist, take methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane and/or toluene as solvent, 25 ~ 120 ℃ of reactions make key intermediate (
3); And
Key intermediate (
3) pyrazole compound amino with band (
4) in methyl alcohol, ethanol, toluene, DMSO and/or DMF solvent, under Lewis acid catalyst, Lewis alkaline catalysts or non-acid base catalysator existed ,-5 ~ 200 ℃ of reactions got the compound shown in formula I,
Wherein each substituting group such as claim 1 or 2 definition;
Randomly, with the above-mentioned various intermediates that make or products therefrom and mineral acid and/or organic acid, the oxide compound of basic metal, alkaline-earth metal and/or oxyhydroxide salify are made pharmacy acceptable salt.
8. the compound shown in formula I as claimed in claim 7 or its pharmacy acceptable salt, the perhaps preparation method of Compound I-1 ~ I-5 or its pharmacy acceptable salt, wherein, the Lewis acid catalyst is zinc acetate, the Lewis alkaline catalysts is sodium methylate, and non-acid base catalysator is PbO.
9. pharmaceutical composition, it comprises the compound shown in the described formula I of any one or its pharmacy acceptable salt in the claim 1-6 that treats significant quantity, perhaps Compound I-1 ~ I-5 or its pharmacy acceptable salt.
10. pharmaceutical composition as claimed in claim 9, wherein, the compound shown in described formula I or its pharmacy acceptable salt, perhaps Compound I-1 ~ I-5 or the content of its pharmacy acceptable salt in pharmaceutical composition are 0.05%-90%.
11. pharmaceutical composition as claimed in claim 9, wherein, the compound shown in described formula I or its pharmacy acceptable salt, perhaps Compound I-1 ~ I-5 or the content of its pharmacy acceptable salt in pharmaceutical composition are 0.05%-70%.
12. as the described pharmaceutical composition of claim 9-11 any one, wherein, described pharmaceutical composition also comprises one or more pharmaceutically acceptable auxiliary materials.
13. pharmaceutical composition as claimed in claim 12, wherein, described pharmaceutical composition is tablet, capsule, sugar-coat agent, granule, dry powder doses, oral solution, the little pin of injection or infusion solutions.
14. pharmaceutical composition as claimed in claim 13, wherein, described pharmaceutical composition is dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet or injection freeze-dried powder.
15. the compound as shown in the formula I of any one in claim 1-6 or its pharmacy acceptable salt, perhaps Compound I-1 ~ I-5 or its pharmacy acceptable salt purposes in the medicine of preparation anti-fungal infection.
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EP0178682A2 (en) * | 1984-10-19 | 1986-04-23 | Schering Corporation | 1,3-Bis(1H-1,2,4-triazol-1-yl)-2-fluoro-2-(2,4-difluorophenyl)propane, antifungal composition containing it, and process for preparation of the compound and the composition |
CN101817834A (en) * | 2010-05-13 | 2010-09-01 | 天津药物研究院 | Pyrazole derivatives and preparation method and application thereof |
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EP0178682A2 (en) * | 1984-10-19 | 1986-04-23 | Schering Corporation | 1,3-Bis(1H-1,2,4-triazol-1-yl)-2-fluoro-2-(2,4-difluorophenyl)propane, antifungal composition containing it, and process for preparation of the compound and the composition |
CN101817834A (en) * | 2010-05-13 | 2010-09-01 | 天津药物研究院 | Pyrazole derivatives and preparation method and application thereof |
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