CN101684103B - Compound with 1,2,4-triazole structure and preparation method and application thereof - Google Patents

Compound with 1,2,4-triazole structure and preparation method and application thereof Download PDF

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CN101684103B
CN101684103B CN200810151500XA CN200810151500A CN101684103B CN 101684103 B CN101684103 B CN 101684103B CN 200810151500X A CN200810151500X A CN 200810151500XA CN 200810151500 A CN200810151500 A CN 200810151500A CN 101684103 B CN101684103 B CN 101684103B
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compound
amino
methyl
triazole
ethanoyl
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CN101684103A (en
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赵桂龙
李袆亮
徐为人
王玉丽
邹美香
汤立达
石玉
战付旭
张士俊
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Abstract

The invention relates to the field of diabetes associated medicaments, in particular to a 1,2,4-triazole derivative with a general formula I, a preparation method thereof, a medical composition containing the same and application thereof in preparing diabetes medicaments, wherein all groups are as defined in the specification.

Description

1,2, the compound of 4-triazole structure, Preparation Method And The Use
Technical field
The present invention relates to the related drugs field of diabetes, particularly, the present invention relates to 1 of general formula I, 2,4-triazole derivative, its preparation method, contain they pharmaceutical composition and they (dipeptidyl peptidase IV, DPP-IV) inhibitor is in the application of preparation in the diabetes medicament as dipeptidyl peptidase-IV.
Background technology
Diabetes are that the absolute or relative deficiency of Regular Insulin causes blood sugar increasing in the human body, and cause complication, finally cause disabling or lethal a kind of disease of patient.According to WHO statistics, global diabetic subject is nearly about 1.7 hundred million, and wherein about 90% is the type ii diabetes patient.Antidiabetic medicine in clinical use mainly contains class medicines such as Regular Insulin, N1,N1-Dimethylbiguanide, sulfonylurea at present, reach the recent thiazolidinediones medicine that goes on the market, alpha-glucosidase inhibitor etc., these medicines have good curative effect, but still there is the medicine life-time service but can not keeps the shortcoming of long-term efficacy, simultaneously can not be at the effective mitigate the disease of the cause of disease, and have poor stability, be easy to generate liver toxicity, many side effects such as weight increase.
DPP IV (dipeptidyl peptidase IV, DPP-IV) can be effectively and the glucagon-like peptide 1 (GLP-1 that can degrade apace, glucagons-like peptide-1), GLP-1 is one of the most effective stimulant of insulin production and secretion, therefore suppress the effect that DPP-IV can strengthen endogenous GLP-1, thereby improve the level (CN 200480017355.6) of Regular Insulin in the blood.Medical science has confirmed that the DPP-IV inhibitor is a kind of novel antidiabetic treatment medicine (Deacon C.F. at present, Holst J.J., DipeptidylPeptidase IV Inhibitors:A Promising New Therapeutic Approach for theManagement of Type 2 Diabetes.The International Journal of Biochemistry﹠amp; Cell Biology, 2006,38 (5-6): 831-844).Clinical effectiveness shows that such medicine has good hypoglycemic effect, untoward reaction things such as common weight increase of simultaneously not finding other diabetes medicaments and being produced and hypoglycemia.The present invention has found to reduce very effectively the novel DPP-IV inhibitor of plasma glucose levels, and these compounds will lay the first stone for the medicine that further discovery can be used for the treatment of diabetes, particularly non insulin dependent diabetes.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, a kind of excellent activity that has is provided, have the compound and the pharmacy acceptable salt thereof of general formula I.
Another object of the present invention provides the method that preparation has the compound and the pharmacy acceptable salt thereof of general formula I.
A further object of the present invention provide contain general formula I compound as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment diabetes.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The compound that the present invention has general formula I has following structural formula:
Figure GSB00000378271100021
Wherein,
R 1=CF 3Or Me,
R ' 2=H, R 3, F, Cl, Br, I, NO 2, NR 4R 5, COOR 6, CONR 4R 5Or R 6CO, and they two replace or trisubstituted combination, wherein R 3Be C 1-C 8Alkyl, R 4, R 5And R 6Be H or C 1-C 8Alkyl.
Preferred following compound of Formula I or its pharmacy acceptable salt,
Wherein,
R 1=CF 3Or Me,
Figure GSB00000378271100031
R ' 2=H, R 3, F, Cl, Br, I, NO 2, NR 4R 5, CONR 4R 5Or R 6CO, and they two replace or trisubstituted combination, wherein R 3Be C 1-C 4Alkyl, R 4, R 5And R 6Be H or C 1-C 4Alkyl.
It is as shown in the table that preferred the present invention has the compound of general formula I:
Figure GSB00000378271100032
Compound of Formula I of the present invention is synthetic by following steps:
Compound of Formula I of the present invention is synthetic by following steps:
Figure GSB00000378271100041
Compound I I and compound III room temperature reaction in the presence of condensing agent obtains compound IV, and wherein, PG is amino acid whose amino protecting group (as Boc and Cbz etc.), R 1Described as defined above.
Compound IV obtains compound V through behind the deprotection method deprotection corresponding to protecting group PG.
Compound VI and compound V are at mineral alkali, as Na 2CO 3And K 2CO 3, existing down, reaction obtains Compound I, wherein R 2Described as defined above.
Compound III is at mineral alkali, as NaOH and Na by compound VI I 2CO 3Deng, exist and to use methylating reagent down, as methyl iodide and methyl-sulfate etc., methylating obtains.Compound VI I reference method is synthetic, and (two kinds contain the synthetic of two fused heterocyclic compounds, Qingtao Chemical Engineering College's journal: natural science edition, 2001,22 (1): 47-49) for Li Ming, Wen Lirong etc.
The pharmacy acceptable salt of formula I compound of the present invention comprises, but be not limited to and various mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, for example pharmacy acceptable salt that generated such as formic acid, acetate, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid.
Formula I compound of the present invention or its pharmacy acceptable salt can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention can be accepted auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or the bromatology.
Composition of the present invention can be accepted auxiliary material on described pharmacy or the bromatology.Weighting agent is one or more the composition that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, lime carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Compound of Formula I of the present invention or its salt have the restraining effect of DPP-IV, can be used as the medicine that effective constituent is used to prepare the diabetes aspect.The activity of compound of Formula I of the present invention is by hypoglycemic modelling verification in the body.
Compound of Formula I of the present invention is effective in quite wide dosage range.For example the dosage of taking every day is divided into once or administration for several times in 1mg-1000mg/ people's scope.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by the doctor.These situations comprise: by curer's physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.Need to prove that following embodiment is used for explanation, and is not to be used to limit the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Instrument and reagent, unless specified otherwise, agents useful for same all is commercially available analytical pure level reagent, infrared spectra is by U.S. Thermo Nicolet AVATAR FT370 type Fourier transformation infrared spectrometer (KBr compressing tablet or pure product membrane process are measured).
Embodiment 1
The 1-{2-[(tertbutyloxycarbonyl) amino] ethanoyl } amino-3-methyl-5-methylthio group-1,2,4-triazole (IV-a) synthetic
Figure GSB00000378271100061
The glycine II-a that adds 1.75g (10mmol) Boc protection in the round-bottomed flask of 100mL; with the anhydrous THF dissolving of 20mL, then add 2.06g (10mmol) DCC, stirred 1 hour under the room temperature; then add 1.44g (10mmol) compound III-a, stir under the gained system room temperature and spend the night.Remove by filter the solid in the reaction mixture, gained filtrate boils off solvent on Rotary Evaporators, obtains a resistates, and column chromatography obtains product I V-a, 2.41g, productive rate 80%, clear crystal.IR(thin?film)，3321，3217，1684cm -1.
Compound I I-a is one that has in the compound of general formula I I, and compound III-a is one that has in the compound of general formula III, and same compound IV-a also is one that has in the compound IV of general formula.
Embodiment 2
With the operation of embodiment 1, difference is that remaining is operated with embodiment 1, obtains following compound IV-b with the III-a among the following III-b replacement embodiment 1.
Figure GSB00000378271100062
Product IV-b, the 1-{2-[(tertbutyloxycarbonyl) amino] ethanoyl } amino-3-trifluoromethyl-5-methylthio group-1,2,4-triazole, clear crystal, IR (thin film), 3324,3219,1687cm -1.
Compound III-b is one that has in the compound of general formula III, and same compound IV-b also is one that has in the compound IV of general formula.
Embodiment 3
1-[2-(amino) ethanoyl] amino-3-methyl-5-methylthio group-1,2,4-triazole (V-a) synthetic
Figure GSB00000378271100071
Add 3.01g (10mmol) compound IV-a in the reaction flask of 100mL, with 20mL CH 2Cl 2Dissolving adds 1mL trifluoroacetic acid (TFA) under the stirring at room, then continue under the room temperature to stir 2 hours.Reaction system is poured the Na of 100mL 2% into 2CO 3In the solution, stir, with the CH of 50mL * 3 2Cl 2Extraction merges extracted organic phase, with the saturated common salt water washing once, and dry (Na 2SO 4), on Rotary Evaporators, boil off solvent, obtain the pure product of compound V-a, colourless oil liquid, 1.89g, productive rate 94%.IR (thin film), 3331,3311.1686cm -1.
Compound V-a is one that has in the compound of general formula V.
Embodiment 4
With the operation of embodiment 3, difference is that remaining is operated with embodiment 3, obtains following compound V-b with the IV-a among the following IV-b replacement embodiment 3.
Product V-b, 1-[2-(amino) ethanoyl] amino-3-trifluoromethyl-5-methylthio group-1,2,4-triazole, clear crystal, IR (thin film), 3325,3212,1682cm -1.
Compound V-b is one that has in the compound of general formula V.
Embodiment 5
4-{[2-(benzamido group) ethanoyl] amino }-3-methyl-5-methylthio group-1,2,4-triazole (I-1) synthetic
Figure GSB00000378271100072
Add 1.71g (10mmol) compound VI-1 in the round-bottomed flask of a 100mL, 2.01g (10mmol) compound V-a and 1.06g (10mmol) solid Na 2CO 3, then add 10mL MeOH and 10mLCH 2Cl 2System at room temperature stirs spends the night.Remove by filter the solid that exists in the reaction system, filtrate boils off solvent on Rotary Evaporators, and the resistates that obtains obtains product I-1, colorless oil, 2.68g, productive rate 92% through column chromatography purification.IR(thin?film)，3032，3334，3242，1687cm -1.
Embodiment 6-10
With the operation of embodiment 5, difference is that the VI in the following table replaces the VI-1 among the embodiment 5, has replaced V-a among the embodiment 5 with V-b among the part embodiment, and remaining is operated with embodiment 5, and the Compound I-2 that obtains in the following table arrives I-6.
Figure GSB00000378271100081
Figure GSB00000378271100091
The characterization data of the Compound I in the last table is as follows:
I-2:5-methylthio group-4-{{2-{[(2-nitrophenyl) methyl] amino } ethanoyl } amino }-the 3-Trifluoromethyl-1,2,4-triazole, colorless oil, IR (thin film), 3332,3323,3030,3241,1682cm -1.
The I-3:4-{{2-{[(6-tertiary butyl-1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino }-3-methyl-5-methylthio group-1,2,4-triazole, colorless oil, IR (thin film), 3334,3321,3031,3244,1683,1663cm -1.
I-4:4-{{2-{[(4-amino-3-the tertiary butyl-2-nitrophenyl) methyl] amino } ethanoyl } amino }-5-methylthio group-3-Trifluoromethyl-1,2,4-triazole, colorless oil, IR (thin film), 3331,3225,3028,1685cm -1.
I-5:5-methylthio group-4-{{2-{[(4-aminomethyl phenyl) methyl] amino } ethanoyl } amino }-the 3-Trifluoromethyl-1,2,4-triazole, colorless oil, IR (thin film), 3324,3228,3030,1683cm -1.
I-6:5-methylthio group-4-{{2-{[(3-fluorophenyl) methyl] amino } ethanoyl } amino }-the 3-Trifluoromethyl-1,2,4-triazole, colorless oil, IR (thin film), 3331,3225,3031,1687cm -1.
Embodiment 11
4-amino-3-methyl-6-methylthio group-1,2,4-triazole (III-a) synthetic
Figure GSB00000378271100092
13.0g (0.1mol) compound VI I-a, 14.2g (0.1mol) methyl iodide and 4.0g (0.1mol) NaOH solid are dissolved in the 100mL methyl alcohol, stir 1 hour under the room temperature.Suction filtration is removed the solid in the system, boils off solvent and obtain resistates recrystallization from ethyl acetate on Rotary Evaporators, obtains the pure product of III-a, clear crystal, 12.2g, yield 85%.IR(KBr)，3327，3221cm -1.
Compound VI I-a is one that has in the compound of general formula VII, and same compound III-a also is one that has in the compound of general formula III.
Embodiment 12
With the operation of embodiment 9, difference is that remaining is operated with embodiment 9, obtains following compound III-b with the VII-a among the following VII-b replacement embodiment 9.
Figure GSB00000378271100101
III-b, 4-amino-3-methyl-6-methylthio group-1,2,4-triazole, clear crystal, IR (KBr), 3324,3225cm -1.
Compound VI I-b is one that has in the compound of general formula VII, and same compound III-b also is one that has in the compound of general formula III.
Embodiment 13
The 4-{{2-{[(6-tertiary butyl-1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino }-3-methyl-5-methylthio group-1,2,4-triazole fumarate (I-7)
Figure GSB00000378271100102
2.91g (10mmol) Compound I-3 be dissolved into 20mL exsiccant ethyl acetate in, then add 1.16g (10mmol) fumaric acid, stirred under the room temperature 1 hour.Filter and collect crystal, drying obtains product I-7, clear crystal, 3.70g, productive rate 91%.IR(KBr)，3031，2543，1683，1665，1654cm -1。
Embodiment 14
4-{[2-(benzamido group) ethanoyl] amino }-3-methyl-5-methylthio group-1,2,4-triazole trifluoroacetate (I-8) synthetic
With the operation of embodiment 11, difference is to replace I-3 among the embodiment 11 with I-1, has replaced fumaric acid among the embodiment 11 with trifluoroacetic acid, and remaining is operated with embodiment 11, obtains Compound I-8, clear crystal, productive rate 90%.IR(KBr)，3033，2542，1687，1664cm -1。
Embodiment 15
Consumption/sheet
Embodiment 5 samples (I-1) 100mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 16
With reference to the operation of embodiment 15, with the I-1 among sample (I-3) the replacement embodiment 15 of embodiment 7, all the other are operated with embodiment 15, obtain compressing tablet.
Embodiment 17
Consumption/grain
Embodiment 6 samples (I-2) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes, the system softwood sieves, and the system wet granular is in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly.
Embodiment 18
With reference to the operation of embodiment 17, with the I-2 among sample (I-4) the replacement embodiment 17 of embodiment 8, all the other are operated with embodiment 17, obtain capsule.
Embodiment 19
Consumption/50ml
Embodiment 13 sample 50mg
Citric acid 100mg
NaOH an amount of (transferring pH 4.0-5.0)
Distilled water 50ml
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 20
Sample is mixed with the suspension of 5mg/ml concentration with 1% Xylo-Mucine, and the administration capacity is the 0.4ml/20g body weight, is equivalent to 100mg/kg dosage.The diamicron time spent is mixed with 4mg/ml concentration with 1% Xylo-Mucine, and the administration capacity is the 0.4ml/20g body weight, is equivalent to 80mg/kg dosage.Be mixed with 15mg/ml with fresh physiological saline during the tetraoxypyrimidine injection.0.1ml/20g body weight is equivalent to 75mg/kg.
Healthy ICR mouse, male and female half and half, body weight 20～24g meets primary standard.The animal fasting is the tail vein injection tetraoxypyrimidine after 16 hours.Fasting 6 hours is got blood with kapillary from mouse ball rear vein beard after 48 hours, and centrifugation serum is used the determination of glucose oxidase serum glucose level.Select blood glucose value to be higher than the mouse of 300mg/dl, be divided into 4 groups according to the blood-sugar content that records again, be respectively model, the positive (diamicron 80mg/kg) and administration group.Administration 3 days, fasting in 24 hours was got blood in 1 hour after the last administration, measure blood-sugar content.The results are shown in Table
Tetraoxypyrimidine is caused the influence of hyperglycemia model mouse's blood sugar content
Figure GSB00000378271100131
Annotate: * * compares p＜0.01 with model group

Claims (10)

1. has pharmaceutically acceptable salt of the compound of general formula I or its
Figure FSB00000378271000011
Wherein,
R 1=CF 3Or Me,
Figure FSB00000378271000012
R ' 2=H, R 3, F, Cl, Br, I, NO 2, NR 4R 5, COOR 6, CONR 4R 5Or R 6CO, wherein R 3Be C 1-C 8Alkyl, R 4, R 5And R 6Be H or C 1-C 8Alkyl.
2. the compound of the defined general formula I of claim 1 or its acceptable salt pharmaceutically,
Wherein,
R 1=CF 3Or Me,
Figure FSB00000378271000013
R ' 2=H, R 3, F, Cl, Br, I, NO 2, NR 4R 5, CONR 4R 5Or R 6CO, wherein R 3Be C 1-C 4Alkyl, R 4, R 5And R 6Be H or C 1-C 4Alkyl.
3. the defined compound of Formula I of claim 1 or its pharmacy acceptable salt are selected from
4-{[2-(benzamido group) ethanoyl] amino }-3-methyl-5-methylthio group-1,2, the 4-triazole,
5-methylthio group-4-{{2-{[(2-nitrophenyl) methyl] amino } ethanoyl } amino }-the 3-Trifluoromethyl-1,2, the 4-triazole,
The 4-{{2-{[(6-tertiary butyl-1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino }-3-methyl-5-methylthio group-1,2, the 4-triazole,
5-methylthio group-4-{{2-{[(3-fluorophenyl) methyl] amino } ethanoyl } amino }-the 3-Trifluoromethyl-1,2, the 4-triazole,
5-methylthio group-4-{{2-{[(4-aminomethyl phenyl) methyl] amino } ethanoyl } amino }-the 3-Trifluoromethyl-1,2, the 4-triazole,
The 4-{{2-{[(6-tertiary butyl-1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino }-3-methyl-5-methylthio group-1,2,4-triazole fumarate,
4-{[2-(benzamido group) ethanoyl] amino }-3-methyl-5-methylthio group-1,2,4-triazole trifluoroacetate.
4. the method for the compound of Formula I of synthetic claim 1-3 definition may further comprise the steps:
Compound I I and compound III room temperature reaction in the presence of condensing agent obtains compound IV, and wherein, PG is amino acid whose amino protecting group, R 1Definition according to claim 1;
Compound IV obtains compound V through behind the deprotection method deprotection corresponding to protecting group PG;
Compound VI and compound V react in the presence of mineral alkali and obtain Compound I, wherein R 2Definition according to claim 1;
Compound III is methylated with methylating reagent in the presence of mineral alkali by compound VI and obtains.
5. the defined method of claim 4, compound VI and compound V react in the presence of mineral alkali and obtain Compound I, and wherein mineral alkali is selected from Na 2CO 3, K 2CO 3Any one.
6. the defined method of claim 4, compound III is methylated in the presence of mineral alkali by compound VI and obtains, and wherein mineral alkali is selected from NaOH, Na 2CO 3Any one.
7. the defined method of claim 4, compound III is methylated in the presence of mineral alkali by compound VI and obtains, and wherein methylating reagent is selected from any one of methyl iodide, methyl-sulfate.
8. the defined compound of Formula I of claim 1-7 or its pharmacy acceptable salt application aspect the preparation diabetes medicament.
9. pharmaceutical composition contains compound of Formula I or its pharmacy acceptable salt of one of claim 1-7 and appropriate carriers or vehicle.
10. the described pharmaceutical composition of claim 9, wherein said composition is solid orally ingestible, liquid oral medicine or injection.
CN200810151500XA 2008-09-22 2008-09-22 Compound with 1,2,4-triazole structure and preparation method and application thereof Expired - Fee Related CN101684103B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1258480A1 (en) * 2001-05-18 2002-11-20 Eisai Co., Ltd. Pharmaceutical use of N-Carbamoylazole derivatives
CN1617859A (en) * 2001-11-28 2005-05-18 科学研究和应用咨询公司 5-sulfanyl-4h-1,2,4-triazole derivatives and their use as a medicament
CN101119978A (en) * 2005-02-17 2008-02-06 默克专利有限公司 HSP90-inhibiting triazole derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1258480A1 (en) * 2001-05-18 2002-11-20 Eisai Co., Ltd. Pharmaceutical use of N-Carbamoylazole derivatives
CN1617859A (en) * 2001-11-28 2005-05-18 科学研究和应用咨询公司 5-sulfanyl-4h-1,2,4-triazole derivatives and their use as a medicament
CN101119978A (en) * 2005-02-17 2008-02-06 默克专利有限公司 HSP90-inhibiting triazole derivatives

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