CN102002054A - Pyrazole type compound and preparation method and application thereof - Google Patents

Pyrazole type compound and preparation method and application thereof Download PDF

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CN102002054A
CN102002054A CN 201010517703 CN201010517703A CN102002054A CN 102002054 A CN102002054 A CN 102002054A CN 201010517703 CN201010517703 CN 201010517703 CN 201010517703 A CN201010517703 A CN 201010517703A CN 102002054 A CN102002054 A CN 102002054A
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compound
salt
acceptable salt
pharmacy acceptable
pyridine
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CN102002054B (en
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刘登科
刘颖
陈继方
刘冰妮
刘默
支爽
龙丽
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Tianjin Institute of Pharmaceutical Research Co Ltd
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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

A kind of pyrazole compound and its production and use
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 bigger to the harm that the mankind cause, and skin and first portion are more common in part fungi infestation, is 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 extensive use of 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 to be risen significantly, and become one of major disease main causes of death such as acquired immune deficiency syndrome (AIDS) and tumour.
In the existing antifungal drug, azole drug is the class with better prospect, has obtained clinically using widely.The curative effect of nitrogen azole drug is comparatively desirable, so be the focus of studying in the antifungal drug always.They can suppress fungal cell's cytochrome p 450 3A and rely on C14-α-demethylase (ERGl1), and this enzyme is the key enzyme that lanosterol is changed into ergosterol.Its mechanism of action is a 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 the film, thereby suppresses fungi growth.
With fluconazole (Fluconazole, FCZ) and itraconazole (Itraconazole is the main choice drug for the treatment of at present fungi infestation clinically for the Research of Triazole Antifungal Agents of representative ICZ).(Voriconazole VOR) is a kind of novel antifungal drug in triazole class to voriconazole, 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 through the voriconazole that the fluconazole structure of modification is obtained than former medicine anti-fungus spectra, and anti-mycotic activity is also stronger.
Figure BSA00000316407900021
The fluconazole voriconazole
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 fungies such as aspergillus tubigensis, and easily produce resistance; Itraconazole exists oral administration biaavailability instability, problems such as GI irritation.Though voriconazole toxicity is less, also more easily produce resistance.Report from clinical isolating 851 strain Candida albicanss 37.2% pair of fluconazole resistance is arranged, 47.6% pair of itraconazole resistance.
At the limitation that existing medicine exists, except the preparation of optimizing the existing medicine of improvement, the research of novel anti fungi-medicine has also become one of hot fields of global new drug development.In addition, the interaction between medicine makes the fungi infestation treatment become complicated more, therefore, and the clinical novel anti fungi-medicine that presses for high-efficiency low-toxicity, has a broad antifungal spectrum, highly selective.
Summary of the invention
At 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.
It is the pharmaceutical composition of main active ingredient that a further object of the present invention is to provide with described compound and pharmaceutical salts thereof.
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:
Figure BSA00000316407900022
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, itrile 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, itrile 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, itrile group replace 1-C 6Straight or branched alkyl, phenyl, chlorophenyl.
Particularly, the compound shown in the formula I can for:
I-1 3-(2-(2-chloro-phenyl-)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1, the 5-dimethyl pyrazole;
I-2 3-(2-(2-hydroxyl-5-nitrophenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1, the 5-dimethyl pyrazole;
I-3 4-(2-(2-ethoxyl phenenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-methyl-3-trifluoromethyl pyrazol;
I-4 5-(2-(to cyano-phenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-rubigan-4-nitrile methylpyrazole;
I-5 5-(2-(to carboxyl phenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-rubigan-4-nitrile methylpyrazole.
In above-mentioned compound or its pharmacy acceptable salt, described pharmacy acceptable salt is preferably the salt that the compound shown in the formula I is become 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 the formula I becomes with the 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 4,5,6,7-tetramethylene sulfide and pyridine are in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide and/or potassium hydroxide etc., with methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane and/or toluene etc. is 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, in the presence of Lewis acid catalyst such as zinc acetate, Lewis alkaline catalysts such as sodium methylate, non-acid base catalysator such as PbO etc. ,-5～200 ℃ of reactions,
Figure BSA00000316407900041
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 salifiable step of the oxide compound of basic metal, alkaline-earth metal and/or oxyhydroxide.
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 acceptable accessories; 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.
The compound and the pharmacy acceptable salt thereof of general formula I structure involved in the present invention are as follows:
Figure BSA00000316407900042
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, itrile 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, itrile 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, itrile group replace 1-C 6Straight or branched alkyl, phenyl, chlorophenyl.
The compound that relates among the present invention or its pharmacy acceptable salt with general formula I structure, representation compound is:
I-1 3-(2-(2-chloro-phenyl-)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1, the 5-dimethyl pyrazole;
I-2 3-(2-(2-hydroxyl-5-nitrophenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1, the 5-dimethyl pyrazole;
I-3 4-(2-(2-ethoxyl phenenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-methyl-3-trifluoromethyl pyrazol;
I-4 5-(2-(to cyano-phenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-rubigan-4-nitrile methylpyrazole;
I-5 5-(2-(to carboxyl phenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-rubigan-4-nitrile methylpyrazole.
Compound or its pharmacy acceptable salt with formula I structure of the present invention means: the salt that The compounds of this invention is become 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 or the like.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 preparation route of formula I compound is as follows:
Referenced patent US 5,036, the method for 156 A1, with the phenyl aldehyde compounds ( 1) for starting raw material can prepare alpha-brominated benzoic acid derivative, be catalyzer then with the tosic acid, reflux in toluene carry out esterification can make intermediate ( 2).Intermediate ( 2) with 4,5,6,7-tetramethylene sulfide and pyridine are in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide or potassium hydroxide, with methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene etc. is solvent, 25～120 ℃ of reactions make key intermediate ( 3).( 3) amino with band again pyrazole compound ( 4) in methyl alcohol, ethanol, toluene, DMSO, DMF equal solvent, in the presence of Lewis acid catalyst such as zinc acetate, Lewis alkaline catalysts such as sodium methylate, non-acid base catalysator such as PbO etc.,-5～200 ℃ of reactions can get target compound I, and wherein each substituting group defines as mentioned.
Figure BSA00000316407900061
Reaction is made various intermediates or products therefrom be dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, dropping inorganic acid or organic acid solution are made pharmacy acceptable salt.
Specifically be that all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, the dripping hydrochloric acid diethyl ether solution is made hydrochloride to pH=2 under ice-water bath; Also each compound can be dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, add and wait a mole toxilic acid, heated and stirred gets its maleate; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, drips the ethanolic soln of potassium hydroxide, transfer pH=9, make its sylvite, or the like.
This compounds is effective for the human fungal infectious disease of treatment.Although compound of the present invention can be without the direct administration of any preparation, described all cpds preferably uses with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (as vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions method of The compounds of this invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.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 for example 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 or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the 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 used compound or concentration are regulated in the scope of a broad.Usually, the scope of active compound amount is 0.05%～90% (weight) of composition, and another preferred range 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 the obvious suppression effect, can be used as the activeconstituents in the 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 scope of invention by any way.
In following embodiment, various processes of Xiang Ximiaoshuing and method are not 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)
Figure BSA00000316407900071
1. referenced patent US 5,036, and the method for 156 A1 (Bouisset etc.) prepares alpha-brominated o-chlorobenzene acetic acid by o-chlorobenzaldehyde, 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, add tosic acid 1.0g again, methyl alcohol 0.11mol is heated to backflow.When in the back flow reaction process moisture in the water trap time being told, add a small amount of alcohol, can think and react completely as if anhydrous telling still to obvious anhydrous generations.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, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) methyl acetate ( 3A)
Figure BSA00000316407900081
Will ( 2A) during 0.018mol packs dry single port bottle into, after the dissolving of 20ml toluene, add Anhydrous potassium carbonate 0.036mol.Drip 4,5,6 under the stirring at room, the 7-tetramethylene sulfide is [3,2-c] pyridine 0.022mol also, dropwises stirring reaction under the room temperature of back.Point plate control reaction process, the after-filtration that reacts completely, the filtrate evaporate to dryness, with quick preparative chromatography separate key intermediate ( 3A), yield 89.5%.
Can conveniently prepare with similar method:
2-(2-hydroxyl-5-nitrophenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) methyl acetate ( 3B);
2-(2-ethoxyl phenenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) methyl acetate ( 3C);
2-(to cyano-phenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) methyl acetate ( 3D);
2-(to carboxyl phenyl)-2-(4,5,6, the 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, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1, the preparation of 5-dimethyl pyrazole (I-1):
Figure BSA00000316407900082
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 reaction temperature is at 0 ℃, slowly drip intermediate ( 3A).Dropwise the back underpressure distillation, the methyl alcohol that reaction is generated steams.The rising temperature of reaction continues reaction to refluxing, the TLC monitoring.Reduce to room temperature after reacting completely, add in the vitriol oil and sodium methylate, steaming desolventizes, post separate white powder product (HPLC:99.3%).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, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1,5-dimethyl pyrazole (I-2), white powder (HPLC:99.7%) with similar method.Rf=0.32 (single-point, developping agent: v (trichloromethane): v (methyl alcohol)=10: 1), yield 54%.EI-MS(m/z)：427.1。
The preparation of embodiment 4:I-3
The preparation of 4-(2-(2-ethoxyl phenenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-methyl-3-trifluoromethyl pyrazol (I-3):
Figure BSA00000316407900091
The toluene solution of 1-methyl-3-trifluoromethyl-4-amino-pyrazol of 0.02mol is added in the 250ml reaction flask, 40 ℃ drip down intermediates ( 3C), under microwave oven 600w condition, react 30min, post separate yellow powder shape product (HPLC:98.8%).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, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-rubigan-4-nitrile methylpyrazole (I-4):
Figure BSA00000316407900092
1-rubigan-4-nitrile methylpyrazole of 0.02mol is added in the reaction flask of 250mL, adds 30mLDMF and an amount of PbO, be warming up to 140 ℃ and slowly drip intermediates ( 3D), dropwise the back underpressure distillation, the methyl alcohol that reaction is generated steams.The rising temperature of reaction continues reaction to refluxing, the TLC monitoring.Reduce to room temperature after reacting completely, suction filtration, filtrate steaming removal solvent, post separate white powder product (HPLC:99.4%).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-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-rubigan-4-nitrile methylpyrazole (I-5), white powder (HPLC:99.0%) with similar method.Rf=0.27 (single-point, developping agent: v (trichloromethane): v (methyl alcohol)=10: 1), yield 57.9%.EI-MS(m/z)：531.1。
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 the 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.Be heated to the back of refluxing and add and wait a mole toxilic acid, continue at about 3 hours of the stirring reaction that refluxes down.Reaction finishes, and leaves standstill under room temperature 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 drip down 20% potassium hydroxide aqueous solution to pH be 9, continued under the ice-water bath stir about 1 hour.Under room temperature, left standstill 24 hours.Separate out light yellow crystallization, filter.
Embodiment 9: the bacteriostatic activity of compound is measured
Employing standard micro-dilution method (NCCLSM-27A) is measured its minimum inhibitory concentration, further specifies the external bacteriostatic activity of The compounds of this invention to clinical several frequently seen fungi.Concentration (the MIC that suppresses selected fungi 90% growth with target compound 90) as judging 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 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 (the triumphant letter chemical industry in Tianjin company limited).Microplate reader, BIO-RAD680.
Test method:
With RPMI-1640 (Sigma) is nutrient solution, and 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/ml), and-20 ℃ of preservations are stand-by.Be diluted to 640 μ g/ml with RPMI-1640 during use, establish solvent control and blank simultaneously.Get the flat microtest plate in aseptic 96 holes, No. 1 hole adds RPMI-1640 100 μ L and makes blank, and No. 2 the hole adds bacteria suspension 180 μ L and soup 20 μ L, and the 3-12 hole respectively adds bacteria suspension 100 μ L, the 10 grades of doubling dilutions in 2-11 hole, 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 soup, 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, suppressing pairing lowest concentration of drug with 90% is its minimal inhibitory concentration value (MIC 90).
Extracorporeal antifungal activity (the MIC of table 1 compound 90, μ gmL -1)
Figure BSA00000316407900111
By external antibacterial 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, following example of formulations is provided below, described embodiment only is used for explanation, rather than is used to limit the scope of the invention.Described preparation can use any active compound and the salt thereof in the The compounds of this invention, preferably uses the compound described in the embodiment 3-5.
Embodiment 10: capsule
Prepare hard gelatin capsule with following compositions:
Consumption/capsule
Compound I-1 40mg
Pregelatinized Starch 100mg
Poloxamer 4mg
Sodium starch glycolate 10mg
Magnesium Stearate 20mg
10% polyvidone ethanolic soln is an amount of
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Press recipe quantity with the mentioned component mixing, cross 60 mesh sieves three times, add an amount of 10% polyvidone ethanol (95%) solution system softwood, cross 18 mesh sieves and granulate, 40 ℃ of dryings are crossed the whole grain of 16 mesh sieves, are packed in the hard gelatin capsule.
Embodiment 11: tablet
Prepare tablet with following compositions:
Consumption/sheet
Compound I-4 60mg
Starch 45mg
Microcrystalline Cellulose 40mg
Carboxymethyl starch sodium salt 4.5mg
Magnesium Stearate 1mg
Talcum powder 1mg
Poloxamer 3mg
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the 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 the arrangement of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 12: injection
The preparation of injection liquid:
The maleate 50mg of Compound I-2
Propylene glycol 100mg
Polysorbate 80 is an amount of
Distilled water 300ml
Preparation method: get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and propylene glycol, add medicinal basic adjusting 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, seals, promptly.

Claims (10)

1. compound or its pharmacy acceptable salt shown in the formula I:
Figure FSA00000316407800011
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, itrile 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, itrile 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, itrile group replace 1-C 6Straight or branched alkyl, phenyl, chlorophenyl.
2. compound as claimed in claim 1 or its pharmacy acceptable salt, wherein, described compound is:
I-1 3-(2-(2-chloro-phenyl-)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1, the 5-dimethyl pyrazole;
I-2 3-(2-(2-hydroxyl-5-nitrophenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1, the 5-dimethyl pyrazole;
I-3 4-(2-(2-ethoxyl phenenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-methyl-3-trifluoromethyl pyrazol;
I-4 5-(2-(to cyano-phenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-rubigan-4-nitrile methylpyrazole;
I-5 5-(2-(to carboxyl phenyl)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetamido)-1-rubigan-4-nitrile methylpyrazole.
3. compound as claimed in claim 1 or 2 or its pharmacy acceptable salt, wherein, described pharmacy acceptable salt is the salt that the compound shown in the formula I is become with mineral acid and/or organic acid;
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.
4. compound as claimed in claim 1 or 2 or its pharmacy acceptable salt, wherein, described pharmacy acceptable salt is the salt that the compound shown in the formula I becomes with the oxide compound and/or the hydroxides of basic metal, alkaline-earth metal;
Preferably, described salt is sodium salt, sylvite, calcium salt, magnesium salts.
5. as the preparation method of each described compound or its pharmacy acceptable salt among the claim 1-4, wherein, said method comprising the steps of:
Intermediate ( 2) with 4,5,6,7-tetramethylene sulfide and pyridine are in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide and/or potassium hydroxide etc., with methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane and/or toluene etc. is 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, in the presence of Lewis acid catalyst such as zinc acetate, Lewis alkaline catalysts such as sodium methylate, non-acid base catalysator such as PbO etc. ,-5～200 ℃ of reactions,
Figure FSA00000316407800021
Wherein each substituting group such as claim 1 or 2 definition.
6. preparation method as claimed in claim 5, wherein, described method also comprises various intermediates or products therefrom and mineral acid and/or organic acid, the salifiable step of the oxide compound of basic metal, alkaline-earth metal and/or oxyhydroxide.
7. pharmaceutical composition, it comprises each described compound or its pharmacy acceptable salt among the claim 1-4 that treats significant quantity.
8. pharmaceutical composition as claimed in claim 7, wherein, described compound or the content of its pharmacy acceptable salt in pharmaceutical composition are 0.05%-90%, preferred 0.05%-70%.
9. as claim 7 or 8 described pharmaceutical compositions, wherein, described pharmaceutical composition also comprises one or more acceptable accessories;
Preferably, described pharmaceutical composition is 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.
As among the claim 1-4 each compound and pharmacy acceptable salt the preparation anti-fungal infection medicine in purposes.
CN 201010517703 2010-10-25 2010-10-25 Pyrazole type compound and preparation method and application thereof Expired - Fee Related CN102002054B (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN103145732A (en) * 2013-03-19 2013-06-12 天津药物研究院 Antifungal derivatives of piperazine, as well as 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

Patent Citations (2)

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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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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103145732A (en) * 2013-03-19 2013-06-12 天津药物研究院 Antifungal derivatives of piperazine, as well as preparation method and application thereof
CN103145732B (en) * 2013-03-19 2015-09-23 天津药物研究院有限公司 Antimycotic derivative, the Preparation Method And The Use of one class piperazine

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