CN101544634B - 2-phenyl-3-substituted pyrazolo[1,5-a]pyridine derivatives, preparation method and application thereof - Google Patents
2-phenyl-3-substituted pyrazolo[1,5-a]pyridine derivatives, preparation method and application thereof Download PDFInfo
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- CN101544634B CN101544634B CN2008100525362A CN200810052536A CN101544634B CN 101544634 B CN101544634 B CN 101544634B CN 2008100525362 A CN2008100525362 A CN 2008100525362A CN 200810052536 A CN200810052536 A CN 200810052536A CN 101544634 B CN101544634 B CN 101544634B
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- phenyl
- pyridine
- methylol
- acetoacetic ester
- pyrazolo
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Abstract
The invention relates to pharmaceutical compounds (I) for treating diseases such as tumor and viruses, a preparation method and application thereof, wherein the definitions of R1, R2, R3 and R4 are described as description. The invention also discloses pharmaceutical compositions consisting of compounds taken as active ingredients I against tumor and viruses or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, excipients or diluting agents.
Description
Technical field
The present invention relates to the pharmaceutical field of tumour and antiviral therapy, or rather, relate to the also Preparation method and use of [1,5-a] pyridine derivatives of 2-phenyl-3-substituted pyrazolecarboxylic that a class has antitumor or an antivirus action, and the pharmaceutical composition that contains them.
Background technology
In recent years, pyrazolo [1,5-a] pyridine compounds and their has caused people's extensive concern.Gmeiner etc. (J.Med.Chem.2007,50,489-500.) report that this compounds is good dopamine D 2, D3, D4 receptor antagonist.Kuroda etc. (Bioorg.Med.Chem.Let.1999,9,1979-1984.) report that this compounds is the antagonist of xanthine adenosine A l acceptor.After having announced hexa-member heterocycle of 3 introducings of pyrazolo [1,5-a] pyridine compounds and their among the patent EP1385847, have significant herpesvirus resisting activity, but reactions steps is more, total recovery is not high.Also mentioned in other relevant patents, the document similarly at 3 hexa-member heterocycles of introducing other.After having announced 4 introducing oxiranes among the patent US5202334, alkaline condition has serotonin antagonist activation activity with the compound that amine reaction open loop obtains down, reacts simple, easy to operate, but does not further further investigate at 3.Announced the antagonist of pyrazolo [1,5-a] pyridine compounds and their as a CRF acceptor among the patent US7151109, can suppress the various disorders that caused by it effectively, its 3 all is substituted-amino or alkyl, does not see that it introduces five-membered ring.Find among the patent US4578392 that this compounds that 3 alkyl replace also has antiallergic activity.So far, 3 derivatives of introducing isoxazole or pyrazoles five-membered ring do not have systematic study, and do not see any bibliographical information as yet.Tumour and virus infection are another serious problems that the mankind face always, press for the new medicine of research, and this research has been synthesized new pyrazolo [1,5-a] pyridine compounds and their at antitumor and antiviral direction, to seek new medicine.
Summary of the invention
An object of the present invention is at the deficiencies in the prior art, seek the antitumor and antiviral of new texture, compound and pharmacy acceptable salt thereof with general formula I structure are provided.
Another object of the present invention provides the compound with general formula I structure or the preparation method of its pharmacy acceptable salt.
A further object of the present invention provides and contains compound of Formula I or its pharmacy acceptable salt as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application in the disease that prevention and the responsive virus of treatment and tumour cause.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The compound that the present invention relates to general formula (I) has following array structure:
Wherein:
R
1For :-H ,-F ,-Cl ,-Br ,-OCH
3, NO
2,-(CH
2)
0-3CH
3,-OH ,-N (CH
3)
2,-CN ,-CO (CH
2)
0-3CH
3R
1Can be single or multiple substituting groups, and be in contraposition, ortho position or a position on the phenyl ring respectively;
R
2Be :-H ,-CH
3
R
3Be :-OH ,-(CH
2)
0-3CH
3,-OCH
3, O (CH
2)
0-3CH
33,-OCH (CH
3)
2,-OC (CH
3)
3,-NH
2,-NHCH
3,-NHCH
2CH
3,-NHCH (CH
3)
2,-NHCH
2CH
2CH
3
X is N or O;
When X is N, R
4Be C
1-C
4Straight or branched alkyl, the single replacement or polysubstituted phenyl;
When X is O, no R
4
Preferred following compound of Formula I or its pharmacy acceptable salt, wherein,
R
1For-H ,-F ,-Cl ,-Br ,-OR, NO
2,-CH
3,-CH
2CH
3,-CH
2CH
2CH
3The CH of ,-(CH)
3,-CH
2CH
2CH
2CH
3,-OH ,-N (CH
3) ,-CN; R
1Can be single or multiple substituting groups, and be in contraposition, ortho position or a position on the phenyl ring respectively;
R
2Be-H ,-CH
3
R
3Can be-OH ,-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-OCH
3,-OCH
2CH
3,-OCH
2CH
2CH
3,-OCH (CH
3)
2,-OC (CH
3)
3,-NH
2,-NHCH
3,-NHCH
2CH
3,-NHCH (CH
3)
2,-NHCH
2CH
2CH
3
X is N or O;
When X is N, R
4Be-CH
3,-CH
2CH
3,-CH
2CH
2CH
3The CH of ,-(CH)
3,-CH
2CH
2CH
2CH
3-F ,-Cl ,-Br ,-OR, NO
2,-CH
3,-CH
2CH
3,-CH
2CH
2CH
3The CH of ,-(CH)
3,-CH
2CH
2CH
2CH
3,-OH ,-N (CH
3) ,-CN is single to be replaced or polysubstituted phenyl;
When X is O, no R
4
The present invention relates in general formula (I) structure preferred compound and code name thereof is:
W1:2-phenyl-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W2:2-(4-fluorophenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W3:2-(4-chloro-phenyl-)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W4:2-(4-bromophenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W5:2-(4-aminomethyl phenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W6:2-(4-p-methoxy-phenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W7:2-phenyl-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W8:2-(4-fluorophenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W9:2-(4-chloro-phenyl-)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W10:2-(4-bromophenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W11:2-(4-aminomethyl phenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W12:2-(4-p-methoxy-phenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W13:2-phenyl-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W14:2-(4-fluorophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W15:2-(4-chloro-phenyl-)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W16:2-(4-bromophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W17:2-(4-aminomethyl phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W18:2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
W19:2-phenyl-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W20:2-(4-fluorophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W21:2-(4-chloro-phenyl-)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W22:2-(4-bromophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W23:2-(4-aminomethyl phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W24:2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
W25:2-phenyl-3-(5-methylol 3-isoxazole)-pyrazolo [1,5a] pyridine-5-carboxylic acid sodium
Compound of Formula I of the present invention is synthetic by following steps:
The novel preparation method of key intermediate V comprises the steps: compounds X and oxalic acid diethyl ester, and the hydrazine hydrate one pot reaction generates IX; Tetrahydrochysene lithium aluminium reducing IX obtains compound VIII; VIII is obtained compound VI I by the PCC oxidation; γ-bromo crotonate generation cascade reaction that VII and β replace, one go on foot product V.
The method of general formula I (Ia or Ib) compound comprises the steps: compound V and DMF, POCl
3Effect obtains compound IV; Compound IV and oxammonium hydrochloride or phenylhydrazine reacting generating compound II or III; Compound I I or III handle with NCS, under alkaline condition, with alkene that replaces or alkynes the reaction of 1,3 dipolar addition take place and generate final Compound I a or Ib.
The pharmacy acceptable salt of formula I compound of the present invention, can contain carboxyl or amido according to different derivatives, carboxyl can react with alkaline matter (as oxyhydroxide, carbonate and the supercarbonate of basic metal or alkaline-earth metal), they include, but are not limited to: sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash etc. form pharmacy acceptable salt, as corresponding sodium salts, and sylvite or calcium salt or the like.Also can adopt nontoxic organic bases such as methylamine, triethylamine, meglumine etc. to generate salt; Amido can generate salt with various mineral acids (example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., but be not limited only to this) or organic acid (as formic acid, acetate, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid or the like, but being not limited only to this).
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, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, syrup, oral solution, injection.
Described solid orally ingestible adopts the thinner of lactose, starch or N.F,USP MANNITOL conduct; Use gelatin, methylcellulose gum, hypromellose, polyvinylpyrrolidone, starch slurry etc. are as tackiness agent; Use starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose as disintegrating agent; Use talcum powder, little part of silica gel, stearin, calcium stearate or magnesium etc. are as antiadhesives and lubricant.
The preparation method of described solid orally ingestible may further comprise the steps: with activeconstituents and auxiliary material comprise thinner, tackiness agent, optionally with one or both disintegration additive composition mixtures; adopt dry granulation maybe with the aqueous solution of this mixture and tackiness agent; alcohol or aqueous alcohol solution in suitable device, carry out wet method or; dried particles, the disintegrating agent, lubricant and the antisticking agent that add other are subsequently made tablet or suitable clinical formulation such as capsule, granule.
Described liquid oral medicine adopts the thinner of lactose, N.F,USP MANNITOL conduct; Methylcellulose gum, hypromellose, polyvinylpyrrolidone, carboxymethyl cellulose etc. are thickening material or suspensoid; Citric Acid, Sorbic Acid, hydrochloric acid, lactic acid, sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC etc. are the PH conditioning agent; Pool Luo Samu, sodium lauryl sulphate, poly(oxyethylene glycol) 400, Polyethylene Glycol-600, cetomacrogol 1000 etc. are solubilizing agent; Aspartame, Steviosin, Sodium Glutamate, fructose, lemon flavour, orange flavor essence etc. are correctives; Ni Baijin, phenylcarbinol etc. are sanitas.
The preparation method of described liquid oral medicine may further comprise the steps: it is an amount of to get distilled water, add stirrings such as water-soluble filler, PH conditioning agent, thickening material or suspensoid, solubilizing agent, correctives and make dissolving, add thing of the present invention again, after the adding sanitas, can is in bottle.
Series compound of the present invention can also pass through non-enteron aisle form administration, and as externally-applied soft ointment, patch etc., preferred parenterai administration form is the injection administration.
Described injecting and administering preparations comprises freeze-dried powder, small injection and primary infusion.Its feature comprises that water-soluble filler is N.F,USP MANNITOL, low molecular dextran, sorbyl alcohol, polyoxyethylene glycol, tween, glucose, lactose or semi-lactosi; The PH conditioning agent is nonvolatile acid and potassium hydroxide, sodium hydroxide or potassium or ammonium, yellow soda ash or potassium or acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry of ammonium salt, sodium bicarbonate or physiology such as potassium or ammonium salt and salt such as Citric Acid, phosphoric acid, hydrochloric acid; Stablizer is pool Luo Samu, carbomer, sodium lauryl sulphate or Tutofusin tris; It is one or both combination of sodium-chlor, Repone K that Seepage presses conditioning agent thoroughly.
The preparation method of different administrated by injection preparations comprises the following steps
Freeze-dried
Get The compounds of this invention and salt thereof and water-soluble filler, stablizer, Seepage presses agent etc. thoroughly, it is an amount of to add water for injection, regulates pH value and makes its dissolving to 4-8, adds water to scale, add the 0.1-0.5% gac, stirred 10-60 minute down at 20-50 ℃, the filtering with microporous membrane degerming is adopted in decarburization, filtrate is carried out packing, adopt freeze-drying, make the white loose block, seal promptly;
Small injection
Get The compounds of this invention and salt thereof and water-soluble filler, stablizer, Seepage presses agent etc. thoroughly, it is an amount of to add water for injection, regulates pH value and makes its dissolving to 4-8, add water to scale, add the 0.1-0.5% gac, stirred 10-60 minute down at 20-50 ℃, decarburization, smart filter, embedding, sterilization;
Primary infusion
Get its salt of The compounds of this invention and water-soluble filler, stablizer, Seepage presses agent etc. thoroughly, it is an amount of about 20% to add water for injection, regulates pH value and makes its dissolving to 4-8, add the 0.1-0.5% gac, stirred decarburization 10-60 minute down at 20-50 ℃, add water to scale, smart filter, embedding, sterilization.
The actual dosage of taking compound of series compound of the present invention should be decided according to relevant situation by the doctor, these situations comprise by curer's physical state, patient's route of administration, age, body weight, to the individual reaction of medicine and severity of symptom or the like.
The biological activity of compound of Formula I of the present invention is measured in the following manner:
(1) anti-tumor activity
Sample is with the DMSO hydrotropy, and serum-free DMEM substratum is diluted to desired concn, and sample segment solution is suspension.
Cell strain: human promyelocytic leukemia HL-60 cell; People's adenocarcinoma of stomach SGC-7901 cell; Human colon carcinoma SW-480 cell.
The cell of taking the logarithm vegetative period, behind 0.25% tryptic digestion (suspension cell need not digest), be suspended in the DMEM nutrient solution that contains 10% calf serum, blow and beat into single cell suspension gently, microscopically blood cell counts plate numeration viable cell with the glass dropper.(cell concn is 5～10 * 10 to the every hole of 96 well culture plates inoculating cell suspension 90 μ l
4Individual/ml), at 37 ℃, 100% relative humidity, contain 5%CO
2, 95% air incubator cultivate 24h in advance after, every hole adds 10 μ l soups, and (final concentration is made as: 10 μ g/ml μ g/ml).Establish negative control (isoconcentration DMSO) and blank background (not adding cell) in addition, each group is all established 3 multiple holes.Cultured continuously 24h again, every then hole adds the MTT solution of 10 μ l 5mg/ml, and after continuing to cultivate 4h, the careful suction removed supernatant liquor (suspension cell needs earlier centrifugally, removes supernatant in suction).Every hole adds 100 μ l DMSO, puts micro oscillator concussion 5min so that crystallization is dissolved fully, in the single wavelength colorimetric of microplate reader 492nm, measures the OD value.
Inhibiting rate (%)=[1-(experimental group OD average-blank group OD average)/(control group OD average-blank group OD average)] * 100%.
(2) antiviral activity
The mdck cell of taking the logarithm vegetative period, behind 0.25% tryptic digestion (suspension cell need not digest), be suspended in the DMEM nutrient solution that contains 10% calf serum, blow and beat into single cell suspension gently, microscopically blood cell counts plate numeration viable cell with the glass dropper.(cell concn is 5～10 * 10 to the every hole of 96 well culture plates inoculating cell suspension 90 μ l
4Individual/10 μ g/ml μ g/ml) and 10ul influenza A virus liquid (titre 1: 100) ml), after 37 ℃, 100% relative humidity, the incubator that contains 5%CO2,95% air were cultivated 24h in advance, every hole adds 10 μ l soups, and (final concentration was made as:.Model group only adds virus and does not add medicine, and normal group does not add virus, establishes negative control (isoconcentration DMSO) and blank background (not adding cell) in addition, and each group is all established 3 multiple holes.Cultured continuously 24h again, every then hole adds the MTT solution of 10 μ l 5mg/ml, and after continuing to cultivate 4h, the careful suction removed supernatant liquor.Every hole adds 100 μ l DMSO, puts micro oscillator concussion 5min so that crystallization is dissolved fully, in the single wavelength colorimetric of microplate reader 492nm, measures the OD value.
Inhibiting rate (%)=(experimental group OD average-model group OD average)/(normal group OD average-model group OD average) * 100%.
Embodiment:
The present invention is described further below in conjunction with embodiment, embodiment only is indicative, mean that never it limits the scope of the invention by any way, the compound of invention detects through thin-layer chromatography (TLC), adopts nucleus magnetic resonance (1H-NMR) further to prove conclusively its structure subsequently.
The preparation of embodiment 12-phenylpyrazole-5-ethyl formate
Take by weighing 0.42g (18mmol) Na and add and 30ml to be housed newly to steam in the alcoholic acid 100ml bottle with two necks, stir and treat that sodium all after the dissolving, is chilled to room temperature, add 2.10ml (15mmol) oxalic acid diethyl ester, stir.Slowly add methyl phenyl ketone 1.75ml (15mmol), 30min dropwises, in reaction flask, add 1.74ml (18mmol) AcOH after under rt., stirring 1h, dropwise add 1.2ml (18mmol) hydrazine hydrate behind the stirring 30min, dropwise the back and continue stirring at room 12h, concentrate, suction filtration, washing (20ml) successively, sherwood oil is washed (20ml), crude product gets product (white solid) 2.83g, yield 87.3% with the 20ml re-crystallizing in ethyl acetate.
Embodiment 2
Reference example 1 preparation 2-rubigan pyrazoles-5-ethyl formate is a raw material with 2.33g (15mmol) parachloroacetophenone, gets product (white solid) 3.39g, yield 90.0% at last.
Embodiment 3
Reference example 1 preparation 2-is raw material with 2.07g (15mmol) to fluoro acetophenone to fluorophenyl pyrazoles-5-ethyl formate, gets product (white solid) 3.11g, yield 88.6% at last.
Embodiment 4
Reference example 1 preparation 2-is raw material to bromophenyl pyrazoles-5-ethyl formate with 2.99g (15mmol) parabromoacetophenone, gets product (white solid) 3.69g, yield 83.5% at last.
Embodiment 5
Reference example 1 preparation 2-p-methylphenyl pyrazoles-5-ethyl formate is a raw material with 2.01g (15mmol) p-methyl aceto phenone, gets product (white solid) 3.07g, yield 89.0% at last.
Embodiment 6
Reference example 1 preparation 2-p-methoxyphenyl pyrazoles-5-ethyl formate is a raw material with 2.25g (15mmol) p-methoxy-acetophenone, gets product (white solid) 2.99g, yield 81.1% at last.
Synthesizing of embodiment 72-phenylpyrazole-5-methyl alcohol
In the THF of tetrahydrochysene lithium aluminium 0.38g (10mmol) (15ml) solution, drip THF (20ml) solution of 2-phenylpyrazole-5-ethyl formate 2.16g (10mmol), after 30min dropwises, room temperature reaction 3h.Add less water successively, dilute hydrochloric acid, 10%NaOH solution, suction filtration, filter cake is given a baby a bath on the third day after its birth time with the 100ml tetrahydrofuran (THF), filtrate merges, concentrate product (white solid) 1.68g, yield 96.6%.
1H?NMR(CDCl
3，TMS)，δ(ppm)：4.5(s)，2H；5.3(s)，1H；6.6(s)，1H；7.3-7.4(m)，3H；7.8(d)，2H；12.9(s)，1H.
Embodiment 8
Reference example 7 preparation 2-are raw material with 2-to fluorophenyl pyrazoles-5-ethyl formate 2.34g (10mmol) to fluorophenyl pyrazoles-5-methyl alcohol, get product (white solid) 1.67g, yield 87.0% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：4.5(s)，2H；5.3(s)，1H；6.6(s)，1H；7.2(d)，2H；7.8(d)，2H；12.8(s)，1H.
Embodiment 9
Reference example 7 preparation 2-rubigan pyrazoles-5-methyl alcohol are raw material with 2-rubigan pyrazoles-5-ethyl formate 2.51g (10mmol), get product (white solid) 1.83g, yield 87.6% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：4.7(s)，2H；5.4(s)，1H；6.5(s)，1H；7.3(d)，2H；7.7(d)，2H；12.8(s)，1H.
Embodiment 10
Reference example 7 preparation 2-are raw material with 2-to bromochlorophene base pyrazoles-5-ethyl formate 2.95g (10mmol) to bromophenyl pyrazoles-5-methyl alcohol, get product (white solid) 2.12g, yield 83.7% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：4.5(s)，2H；5.3(s)，1H；6.6(s)，1H；7.7-7.8(m)，4H；12.8(s)，1H.
Embodiment 11
Reference example 7 preparation 2-p-methylphenyl pyrazoles-5-methyl alcohol are raw material with 2-p-methylphenyl pyrazoles-5-ethyl formate 2.31g (10mmol), get product (white solid) 1.63g, yield 86.7% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：2.3(s)，3H；4.5(s)，2H；5.3(s)，1H；6.5(s)，1H；7.2(d)，2H；7.7(d)，2H；12.7(s)，1H.
Embodiment 12
Reference example 7 preparation 2-p-methoxyphenyl pyrazoles-5-methyl alcohol are raw material with 2-p-methoxyphenyl pyrazoles-5-ethyl formate 2.46g (10mmol), get product (white solid) 1.65g, yield 80.9% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：3.8(s)，2H；4.5(s)，2H；5.2(s)，1H；6.5(s)，1H；7.0(d)，2H；7.7(d)，2H；12.7(s)，1H.
Synthesizing of embodiment 132-phenylpyrazole-5-formaldehyde
In the DMF (20ml) of 2-phenylpyrazole-5-methyl alcohol 1.74g (10mmol) solution, add PCC 6.47g (30mmol), room temperature reaction 3h, short column chromatography (PE/EA=3: 1) get product (faint yellow solid) 1.05g, yield 61.0%.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：7.0(s)，1H；7.4-7.5(m)，4H；7.8-7.9(s)，3H.
Embodiment 14
Reference example 13 preparation 2-are raw material with 2-to fluorophenyl-pyrazoles-5-ethyl formate 1.92g (10mmol) to fluorophenyl pyrazoles-5-formaldehyde, get product (faint yellow solid) 1.24g, yield 65.3% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：7.1(s)，1H；7.5-7.6(m)，4H；7.9-8.0(s)，3H.
Embodiment 15
Reference example 13 preparation 2-rubigan pyrazoles-5-formaldehyde are raw material with 2-rubigan pyrazoles-5-ethyl formate 2.09g (10mmol), get product (faint yellow solid) 1.33g, yield 64.2% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：7.0(s)，1H；7.5-7.6(m)，4H；7.9-8.0(s)，3H.
Embodiment 16
Reference example 13 preparation 2-are raw material with 2-to bromophenyl pyrazoles-5-ethyl formate 2.53g (10mmol) to bromophenyl pyrazoles-5-formaldehyde, get product (faint yellow solid) 1.58g, yield 62.9% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：7.0(s)，1H；7.4-7.5(m)，4H；7.8-7.9(s)，3H.
Embodiment 17
Reference example 13 preparation 2-p-methylphenyl pyrazoles-5-formaldehyde are raw material with 2-p-methylphenyl pyrazoles-5-ethyl formate 1.88g (10mmol), get product (faint yellow solid) 1.19g, yield 60.2% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：2.3(s)，3H；7.2(s)，1H；7.2-7.3(m)，4H；7.7-7.8(s)，3H.
Embodiment 18
Reference example 13 preparation 2-p-methylphenyl pyrazoles-5-formaldehyde are raw material with 2-p-methylphenyl pyrazoles-5-ethyl formate 2.04g (10mmol), get product (faint yellow solid) 1.22g, yield 60.4% at last.
1H?NMR(DMSO-d
6，TMS)，δ(ppm)：3.8(s)，3H；6.9(s)，1H；6.9-7.0(m)，3H；7.8-7.9(s)，3H.
Embodiment 19 2-phenylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also
In the DMF (20ml) of 2-phenylpyrazole-5-formaldehyde 1.72g (10mmol) solution, add salt of wormwood 2.76g (20mmol) successively, γ-bromo ethyl crotonate 2.12g (11mmol), room temperature reaction 6h, add 100ml water, dichloromethane extraction, methylene dichloride are dry mutually, concentrate, column chromatography (PE/EA=3: 1) get product (white solid) 1.05g, productive rate 78%.
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 4.4 (q), 2H; 7.3 (dd), 1H; 7.4 (s), 1H; 7.5-7.6 (m), 3H; 8.0-8.1 (d), 2H; 8.4 (d), 1H; 8.8 (d), 1H.
13C NMR (75.4MHz, CDCl
3): δ 164.4,153.9,139.8,131.9,128.1,127.5,125.8,124.9,120.1,110.2,96.1,60.9,13.6.
Embodiment 20
Reference example 19 preparation 2-(4-fluorophenyl) pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 80%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 4.4 (q), 2H; 6.9 (s), 1H; 7.1-7.2 (m), 2H; 7.3 (dd), 1H; 7.9-8.0 (m), 2H; 8.3 (d), 1H; 8.5 (d), 1H.
13C NMR (75.4MHz, CDCl
3): δ 165.1,164.9,153.7,140.6,128.9,128.8,128.3,128.2,128.1,125.8.120.8,116.0,115.7,111.0,96.5,61.6,14.3.
Embodiment 21
Reference example 19 preparation 2-(4-chloro-phenyl-) H pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 83%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 4.4 (q), 2H; 7.0 (s), 1H; 7.3 (dd), 1H; 7.4 (d), 2H; 7.9 (d), 2H; 8.3 (d), 1H; 8.5 (d), 1H.
13C NMR (75.4MHz, CDCl
3): δ 164.3,152.9,139.9,133.9,130.4,128.3,128.1,127.4,127.0,125.8,125.1,120.1,110.4,96.0,60.9,13.6.
Embodiment 22
Reference example 19 preparation 2-(4-bromophenyl) pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 78%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 4.4 (q), 2H; 7.0 (s), 1H; 7.4 (dd), 1H; 7.6 (d), 2H; 7.8 (d), 2H; 8.3 (d), 1H; 8.5 (d), 1H.
13C NMR (75.4MHz, CDCl
3): δ 164.3,152.8,140.0,131.3,130.9,128.1,127.5,127.3,125.8,125.1,122.2,120.1,110.4,96.0,60.9,13.6.
Embodiment 23
Reference example 19 preparation 2-(4-aminomethyl phenyl) pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 75%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.4 (s), 3H; 4.4 (q), 2H; 7.2 (dd), 1H; 7.3 (s), 1H; 7.3 (d), 2H; 7.9 (d), 2H; 8.3 (d), 1H; 8.8 (d), 1H.
13C NMR (75.4MHz, CDCl
3): δ 164.5,153.9,139.8,138.0,129.1,128.8,127.4,125.7,124.8,120.0,110.0,95.8,60.8,20.7,13.6.
Embodiment 24
Reference example 19 preparation 2-(4-p-methoxy-phenyl) pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 66%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 3.9 (s), 3H; 4.4 (q), 2H; 6.9 (s), 1H; 7.3 (dd), 1H; 7.0 (d), 2H; 7.9 (d), 2H; 8.3 (d), 1H; 8.5 (d), 1H.
Embodiment 25
In the DMF (20ml) of 2-phenylpyrazole-5-formaldehyde 1.72g (10mmol) solution, add salt of wormwood 2.76g (20mmol) successively, γ-bromo senecioic acid ethyl ester 2.28g (11mmol), room temperature reaction 6h, add 100ml water, dichloromethane extraction, methylene dichloride are dry mutually, concentrate, column chromatography (PE/EA=3: 1) get product (white solid) 1.05g, productive rate 76%.
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 6.9 (s), 1H; 7.4-7.5 (m), 3H; 8.0 (d), 2H; 8.2 (s), 1H; 8.3 (s), 1H.
13C NMR (75.4MHz, CDCl
3): δ 165.3,153.2,138.6,132.2,128.1,127.9,126.9,125.9,125.7,120.7,120.5,95.2,60.6,18.0,13.6.
Embodiment 26
Reference example 25 preparation 2-(4-fluorophenyl)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 76%) also
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.5(s)，3H；4.4(q)，2H；6.9(s)，1H；7.1-7.2(m)，2H；7.9-8.0(d)，2H；8.2(s)，1H；8.3(s)，1H.
13C?NMR(75.4MHz，CDCl
3)：δ165.9，164.7，161.5，139.4，129.2，129.1，128.2，128.1，127.6，126.8，121.3，115.9，115.6，95.6，61.3，18.6，14.3.
Embodiment 27
Reference example 25 preparation 2-(4-chloro-phenyl-)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 78%) also.
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 6.9 (s), 1H; 7.4 (d), 2H; 7.9 (d), 2H; 8.2 (s), 1H; 8.3 (s), 1H.
13C NMR (75.4MHz, CDCl
3): δ 165.2,152.0,138.7,133.7,130.7,128.3,127.0,126.9,126.2,120.8,120.6,95.2,60.6,18.0,13.6.
Embodiment 28
Reference example 25 preparation 2-(4-bromophenyl)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 72%) also
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.6(s)，3H；4.4(q)，2H；6.9(s)，1H；7.6(d)，2H；7.8(d)，2H；8.2(s)，1H；8.4(s)，1H.
13C?NMR(75.4MHz，CDCl
3)：δ165.9，152.8，139.4，131.9，131.8，127.9，127.6，126.8，122.6，121.5，121.4，95.9，61.3，18.7，14.3.
Embodiment 29
Reference example 25 preparation 2-(4-aminomethyl phenyl)-6-methyl H pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 69%)
1HNMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.4 (s), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 6.9 (s), 1H; 7.3 (d), 2H; 7.8 (d), 2H; 8.2 (s), 1H; 8.3 (s), 1H.
13C NMR (75.4MHz, CDCl
3): δ 165.3,153.3,138.6,137.8,129.3,128.8,126.9,125.8,125.6,120.6,120.3,95.0,60.5,20.6,18.0,13.6.
Embodiment 30
Reference example 25 preparation 2-(4-p-methoxy-phenyl)-6-methyl H pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 62%)
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 3.9 (s), 3H; 4.4 (q), 2H; 6.8 (s), 1H; 7.0 (d), 2H; 7.9 (d), 2H; 8.2 (s), 1H; 8.3 (s), 1H.
Embodiment 312-phenyl-3-aldehyde radical pyrazolo [1,5a] pyridine-5-acetoacetic ester
Under the ice bath, phosphorus oxychloride 1.38ml (15mmol) slowly is added drop-wise among the 10ml DMF, dropwises back stirring at room 1h, in system, drip 2-phenylpyrazole also [1,5a] pyridine-5-acetoacetic ester (2.66g, DMF solution 10mmol), stirred overnight at room temperature is poured in the frozen water, precipitation appears, suction filtration, dry product 2.80g, the productive rate 95% of getting.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.3(t)，3H；4.4(q)，2H；7.3(dd)，1H；7.4-7.5(m)，3H；8.0-8.1(d)，2H；8.4(d)，1H；8.8(d)，1H；10.2(s)，1H.
Embodiment 32
Reference example 31 preparation 2-(4-fluorophenyl)-3-aldehyde radical pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 93%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 4.4 (q), 2H; 7.1-7.2 (m), 2H; 7.3 (dd), 1H; 7.9-8.0 (m), 2H; 8.3 (d), 1H; 8.5 (d), 1H; 10.1 (s), 1H.
Embodiment 33
Reference example 31 preparation 2-(4-chloro-phenyl-)-3-aldehyde radical pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 94%)
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 4.4 (q), 2H; 7.4 (dd), 1H; 7.4 (d), 2H; 7.9 (d), 2H; 8.3 (d), 1H; 8.5 (d), 1H; 10.1 (s), 1H.
Embodiment 34
Reference example 31 preparation 2-(4-bromophenyl)-3-aldehyde radical pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 94%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 4.4 (q), 2H; 7.4 (dd), 1H; 7.6 (d), 2H; 7.8 (d), 2H; 8.3 (d), 1H; 8.5 (d), 1H; 10.2 (s), 1H.
Embodiment 35
Reference example 31 preparation 2-(4-aminomethyl phenyl)-3-aldehyde radical pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 92%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.6 (s), 3H; 4.4 (q), 2H; 7.4-7.5 (m), 3H; 8.0 (d), 2H; 8.2 (s), 1H; 8.4 (s), 1H.; 10.1 (s), 1H.
Embodiment 36
Reference example 31 preparation 2-(4-aminomethyl phenyl)-3-aldehyde radical pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 90%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 3.9 (s), 3H; 4.4 (q), 2H; 7.3 (dd), 1H; 7.0 (d), 2H; 7.9 (d), 2H; 8.3 (d), 1H; 8.5 (d), 1H; 10.1 (s), 1H.
Embodiment 37
Reference example 31 preparation 2-(4-aminomethyl phenyl)-3-aldehyde radical pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 95%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.4-7.5 (m), 3H; 8.0 (d), 2H; 8.2 (s), 1H; 8.3 (s), 1H; 10.1 (s), 1H.
Embodiment 38
Reference example 31 preparation 2-(4-fluorophenyl)-3-aldehyde radical-6-methyl H pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 92%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.1-7.2 (m), 2H; 7.9-8.0 (d), 2H; 8.2 (s), 1H; 8.3 (s), 1H; 10.1 (s), 1H.
Embodiment 39
Reference example 31 preparation 2-(4-chloro-phenyl-)-3-aldehyde radical-6-methyl H pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 92%).
1HNMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.4 (d), 2H; 7.9 (d), 2H; 8.2 (s), 1H; 8.3 (s), 1H; 10.1 (s), 1H.
Embodiment 40
Reference example 31 preparation 2-(4-bromophenyl)-3-aldehyde radical 6-methyl H pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 94%).
1HNMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.6 (d), 2H; 7.8 (d), 2H; 8.2 (s), 1H; 8.4 (s), 1H; 10.1 (s), 1H.
Embodiment 41
Reference example 31 preparation 2-(4-aminomethyl phenyl) 3-aldehyde radical-6-methyl H pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 95%)
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.4 (s), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.3 (d), 2H; 7.8 (d), 2H; 8.2 (s), 1H; 8.3 (s), 1H; 10.1 (s), 1H.
Embodiment 42
Reference example 31 preparation 2-(4-p-methoxy-phenyl) 3-aldehyde radical-6-methyl H pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 95%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 3.9 (s), 3H; 4.4 (q), 2H; 7.0 (d), 2H; 7.9 (d), 2H; 8.2 (s), 1H; 8.3 (s), 1H; 10.1 (s), 1H.
Embodiment 43 2-phenyl-3-hydroxyl formimino pyrazolo [1,5a] pyridine-5-acetoacetic ester
(1.47g, 5mmol), the back that stirs adds NH to add methyl alcohol (15mL) and 2-phenyl-3-aldehyde radical pyrazolo [1,5a] pyridine-5-acetoacetic ester in the Erlenmeyer flask of 50mL
2(0.42g, 6mmol), (0.318g, 3mmol), stirring at room 4h adds entry (50mL) after the end of TLC detection reaction to OHHCl, methylene dichloride (20mL * 3) extraction slowly to add yellow soda ash fully after the dissolving.Merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure get white solid (1.33g, yield 86%); Product directly carries out the next step.
Embodiment 44
Reference example 43 preparation 2-(4-fluorophenyl)-3-hydroxyl formimino pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 88%).
Embodiment 45
Reference example 43 preparation 2-(4-chloro-phenyl-)-3-hydroxyl formimino pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 86%)
Embodiment 46
Reference example 43 preparation 2-(4-bromophenyl)-3-hydroxyl formimino pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 85%).
Embodiment 47
Reference example 43 preparation 2-(4-aminomethyl phenyl)-3-hydroxyl formimino pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 89%).
Embodiment 48
Reference example 43 preparation 2-(4-p-methoxy-phenyl)-3-hydroxyl formimino pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 82%).
Embodiment 49
Reference example 43 preparation 2-phenyl-6-methyl-3-hydroxyl formimino pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 88%).
Embodiment 50
Reference example 43 preparation 2-(4-fluorophenyl)-3-hydroxyl formimino-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 83%) also
Embodiment 51
Reference example 43 preparation 2-(4-chloro-phenyl-)-3-hydroxyl formimino-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 85%) also.
Embodiment 52
Reference example 43 preparation 2-(4-bromophenyl)-3-hydroxyl formimino-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 84%) also.
Embodiment 53
Reference example 43 preparation 2-(4-aminomethyl phenyl) 3-hydroxyl formimino-6-methyl H pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 85%)
Embodiment 54
Reference example 43 preparation 2-(4-p-methoxy-phenyl) 3-hydroxyl formimino-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 86%) also.
Embodiment 55 2-phenyl-3-aldehyde radical phenylhydrazone pyrazolo [1,5a] pyridine-5-acetoacetic ester
In the Erlenmeyer flask of 50mL, add methyl alcohol (15mL) and 2-phenyl-3-aldehyde radical pyrazolo [1,5a] pyridine-5-acetoacetic ester (1.47g, 5mmol), back adding phenylhydrazine (0.65g stirs, 6mmol), backflow 2h, the TLC detection reaction finishes the back concentrating under reduced pressure and gets white solid (1.58g, yield 82%); Product directly carries out the next step.
Embodiment 56
Reference example 55 preparation 2-(4-fluorophenyl)-3-aldehyde radical phenylhydrazone pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 84%).
Embodiment 57
Reference example 55 preparation 2-(4-chloro-phenyl-)-3-aldehyde radical phenylhydrazone pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 83%)
Embodiment 58
Reference example 55 preparation 2-(4-bromophenyl)-3-aldehyde radical phenylhydrazone pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 85%).
Embodiment 59
Reference example 55 preparation 2-(4-aminomethyl phenyl)-3-aldehyde radical phenylhydrazone pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 81%).
Embodiment 60
Reference example 55 preparation 2-(4-aminomethyl phenyl)-3-aldehyde radical phenylhydrazone pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 82%).
Embodiment 61
Reference example 55 preparation 2-phenyl-6-methyl-3-aldehyde radical phenylhydrazone pyrazolo [1,5a] pyridine-5-acetoacetic esters (productive rate 87%).
Embodiment 62
Reference example 55 preparation 2-(4-fluorophenyl)-3-aldehyde radical phenylhydrazone-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 83%) also
Embodiment 63
Reference example 55 preparation 2-(4-chloro-phenyl-)-3-aldehyde radical phenylhydrazone-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 85%) also.
Embodiment 64
Reference example 55 preparation 2-(4-bromophenyl)-3-aldehyde radical phenylhydrazone-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 86%) also.
Embodiment 65
Reference example 55 preparation 2-(4-aminomethyl phenyl) 3-aldehyde radical phenylhydrazone-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 83%) also
Embodiment 66
Reference example 55 preparation 2-(4-p-methoxy-phenyl) 3-aldehyde radical phenylhydrazone-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester (productive rate 85%) also.
Embodiment 672-phenyl-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
In the triangular flask of magnetic agitation is housed, 2-phenyl-3-hydroxyl formimino pyrazolo [1,5a] pyridine-5-acetoacetic ester 1.52g (5mmol) is dissolved in the 30ml exsiccant methylene dichloride, adds N-chlorosuccinimide 0.85g (6mmol), stir, after the dissolving, heat 20min a little fully, add propargyl alcohol 0.28g (5mmol), drip triethylamine 0.60g (6mmol), there are a large amount of white smoke to produce, reflux condensing tube are installed, reflux 2h.Silica gel column chromatography separates, and eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (V: V=4: 1), get product (faint yellow solid) 1.29g, yield 71%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；4.4(q)，2H；4.7(s)，2H；6.4(s)，1H；7.3(dd)，1H；7.4-7.5(m)，3H；8.0-8.1(d)，2H；8.4(d)，1H；8.8(d)，1H.
Embodiment 68
Reference example 67 preparation 2-(4-fluorophenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic esters, yield 68%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.1-7.2(m)，2H；7.4(dd)，1H；7.9-8.0(m)，2H；8.3(d)，1H；8.5(d)，1H.
Embodiment 69
Reference example 67 preparation 2-(4-chloro-phenyl-)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic esters, 67%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.8(s)，1H；4.4(q)，2H；4.7(s)，2H；6.4(s)，1H；7.4(dd)，1H；7.4(d)，2H；7.9(d)，2H；8.3(d)，1H；8.5(d)，1H.
Embodiment 70
Reference example 67 preparation 2-(4-bromophenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic esters, 69%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.4(dd)，1H；7.6(d)，2H；7.9(d)，2H；8.3(d)，1H；8.5(d)，1H.
Embodiment 71
Reference example 67 preparation 2-(4-aminomethyl phenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic esters, 67%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.6(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.4-7.5(m)，3H；8.0(d)，2H；8.3(s)，1H；8.4(s)，1H.
Embodiment 72
Reference example 67 preparation 2-(4-p-methoxy-phenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic esters, 69%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；3.9(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.3(dd)，1H；7.0(d)，2H；7.9(d)，2H；8.3(d)，1H；8.5(d)，1H.
Embodiment 73
Reference example 67 preparation 2-phenyl-3-(5-methylol 3-isoxazole)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 67%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.5(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.4-7.5(m)，3H；8.0(d)，2H；8.2(s)，1H；8.3(s)，1H.
Embodiment 74
Reference example 67 preparation 2-(4-fluorophenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 65%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.5(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.1-7.2(m)，2H；7.9-8.0(d)，2H；8.2(s)，1H；8.3(s)，1H.
Embodiment 75
Reference example 67 preparation 2-(4-chloro-phenyl-)-3-(5-methylol 3-isoxazole)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 67%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.6(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.4(d)，2H；7.9(d)，2H；8.2(s)，1H；8.3(s)，1H.
Embodiment 76
Reference example 67 preparation 2-(4-bromophenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 70%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.6(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.6(d)，2H；7.8(d)，2H；8.2(s)，1H；8.4(s)，1H.
Embodiment 77
Reference example 67 preparation 2-(4-aminomethyl phenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 67%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.4(s)，3H；2.6(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.3(d)，2H；7.9(d)，2H；8.2(s)，1H；8.3(s)，1H.
Embodiment 78
Reference example 67 preparation 2-(4-p-methoxy-phenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 65%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.6(s)，3H；3.9(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7，0(d)，2H；7.9(d)，2H；8.2(s)，1H；8.3(s)，1H.
Embodiment 79 2-phenyl-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
In the triangular flask of magnetic agitation is housed, 2-phenyl-3-aldehyde radical phenylhydrazone pyrazolo [1,5a] pyridine-5-acetoacetic ester 1.92g (5mmol) is dissolved in the 30ml exsiccant methylene dichloride, adds N-chlorosuccinimide 0.85g (6mmol), stir, after the dissolving, heat 20min a little fully, add propargyl alcohol 0.28g (5mmol), drip triethylamine 0.60g (6mmol), there are a large amount of white smoke to produce, reflux condensing tube are installed, reflux 2h.Silica gel column chromatography separates, and eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (V: V=4: 1), get product (faint yellow solid) 1.43g, yield 65%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.3(s)，1H；4.4(q)，2H；4.5(s)，2H；6.6(s)，1H；7.3(dd)，1H；7.2-7.3，7.3-7.5(m)，6H；8.0-8.2(d)，4H；8.4(d)，1H；8.8(d)，1H.
Embodiment 80
Reference example 79 preparation 2-(4-fluorophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic esters, yield 65%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.0-7.3(m)，5H；7.4(dd)，1H；7.8-8.0(m)，4H；8.3(d)，1H；8.5(d)，1H.
Embodiment 81
Reference example 79 preparation 2-(4-chloro-phenyl-)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic esters, 63%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.8(s)，1H；4.4(q)，2H；4.7(s)，2H；6.4(s)，1H；7.4(dd)，1H；7.0-7.3(m)，5H；7.7-8.0(m)，4H；8.3(d)，1H；8.5(d)，1H.
Embodiment 82
Reference example 79 preparation 2-(4-bromophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic esters, 63%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.4(dd)，1H；7.4-7.6(m)，5H；7.7-7.9(m)，4H；8.3(d)，1H；8.5(d)，1H.
Embodiment 83
Reference example 79 preparation 2-(4-aminomethyl phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic esters, 65%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.6(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.2-8.0(m)，10H；8.3(s)，1H；8.4(s)，1H.
Embodiment 84
Reference example 67 preparation 2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic esters, 61%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；3.9(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.3(dd)，1H；7.0-7.2(m)，5H；7.6-7.9(m)，4H；8.3(d)，1H；8.5(d)，1H.
Embodiment 85
Reference example 79 preparation 2-phenyl-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 64%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.5(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.1-8.0(m)，10H；8.2(s)，1H；8.3(s)，1H.
Embodiment 86
Reference example 79 preparation 2-(4-fluorophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 63%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.5(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.1-8.0(m)，9H；8.2(s)，1H；8.3(s)，1H.
Embodiment 87
Reference example 79 preparation 2-(4-chloro-phenyl-)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 67%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.6(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.0-8.0(m)，9H；8.2(s)，1H；8.3(s)，1H.
Embodiment 88
Reference example 79 preparation 2-(4-bromophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 63%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.6(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.2-8.0(m)，9H；8.2(s)，1H；8.4(s)，1H.
Embodiment 89
Reference example 79 preparation 2-(4-aminomethyl phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 64%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.4(s)，3H；2.6(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.2-8.0(m)，9H；8.2(s)，1H；8.3(s)，1H.
Embodiment 90
Reference example 79 preparation 2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazoles are [1,5a] pyridine-5-acetoacetic ester also, and 61%.
1H?NMR(CDCl
3，TMS)δ(ppm)：1.4(t)，3H；2.2(s)，1H；2.6(s)，3H；3.9(s)，3H；4.4(q)，2H；4.8(s)，2H；6.5(s)，1H；7.0-7.9(m)，9H；8.2(s)，1H；8.3(s)，1H.
Embodiment 91
The product of embodiment 79, the NaOH solution an amount of (1: 8) of adding 0.2M is heated to 50 degree stirring and dissolving, and refrigeration is abundant crystallization down, has both got sodium salt, yield 55%.
1H?NMR(D
2O，TMS)δ(ppm)：3H；2.5(s)，1H；4.4(s)，2H；6.7(s)，1H；7.4(dd)，1H；7.3-7.4，7.4-7.6(m)，6H；8.0-8.2(d)，4H；8.4(d)，1H；8.8(d)，1H.
Embodiment 92
The product of embodiment 79, the NaOH solution an amount of (1: 10) of adding 0.2M is heated to 50 degree stirring and dissolving, adding hydrochloric acid transfers about pH to 2, precipitation is fully separated out, and after static a few hours, suction filtration gets solid, solid adds an amount of dissolve with ethanol, suitably excessive triethylamine such as add, stirs after 1 hour, cooling, abundant crystallization, both, triethylamine salt.
Embodiment 93
Method for preparing tablet thereof is as follows:
Prescription consumption/sheet
Embodiment 79 product 10mg
Lactose 80mg
Microcrystalline Cellulose 20mg
Pre-paying starch 40mg
Polyvidone 4mg
Sodium starch glycolate 10mg
Magnesium Stearate qs
Technology: the activeconstituents auxiliary material is crossed 100 mesh sieves respectively; take by weighing the main ingredient and auxiliary material (half sodium starch glycolate) thorough mixing of recipe quantity; add the polyvinylpyrrolidone aqueous solution and make softwood in right amount; cross 20 mesh sieves, make wet granular in 50-60 ℃ of baking oven dry about 1-3 hour, will remain sodium starch glycolate; Magnesium Stearate and particle mix; whole grain is measured intermediate content, uses special-shaped stamping.
Embodiment 94
Capsular being prepared as follows:
Prescription consumption/grain
Embodiment 85 product 20mg
Microcrystalline Cellulose 20mg
Lactose 100mg
Sodium starch glycolate 8mg
Hypromellose 5mg
Micropowder silica gel 5mg
Talcum powder qs
Technology: the activeconstituents auxiliary material is crossed 100 mesh sieves respectively; take by weighing the main ingredient and the auxiliary material thorough mixing of recipe quantity; add hypromellose solution and make softwood in right amount; cross 24 mesh sieves; make wet granular in 50-60 ℃ of baking oven dry about 2-3 hour, micropowder silica gel, talcum powder and particle are mixed whole; measure intermediate content, with No. 3 capsule cans.
Embodiment 95
The preparation of oral solution (every bottle of amount)
Embodiment 87 product 30mg
N.F,USP MANNITOL 100mg
Citric acid 20mg
Orange flavor essence 10mg
Aspartame 10mg
Tegosept E qs
Distilled water 100ml
Technology: get distilled water 10ml, the citric acid, N.F,USP MANNITOL, orange flavor essence, aspartame, the sample that take by weighing recipe quantity stir and make dissolving, and after the adding sanitas, can is in bottle.
Embodiment 96 (dispersible tablet) (every amount)
Embodiment 82 product 50mg
Lactose 120mg
Microcrystalline Cellulose 30mg
Add 10mg in the sodium starch glycolate and add 10mg
Aspartame 3mg
Orange essence 3mg
2% hypromellose qs
Silicon-dioxide qs
Calcium stearate qs
Technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing recipe quantity auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 20 mesh sieves are granulated, 55 ℃ of dryings, the whole grain of 18 mesh sieves.Add lubricant at last and remaining carboxymethylstach sodium mixes compressing tablet.
Embodiment 97 (orally disintegrating tablet) (every amount)
Embodiment 90 75mg
N.F,USP MANNITOL 120mg
Microcrystalline Cellulose 40mg
Croscarmellose sodium, 15mg
Magnesium Stearate qs
Technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing adopts the roll squeezer cake of press, crosses the whole grain of 18 mesh sieves with whole granula again, adds the even compressing tablet of mix lubricant at last.
Embodiment 98 (effervescent tablet) (every amount)
Embodiment 87 100mg
Tartrate 100mg
Sodium bicarbonate 100ng
Methylcellulose gum 10mg
Maltose alcohol 10mg
Lemon flavour 5mg
Talcum powder qs
Preparation technology is with embodiment 93.
Embodiment 99 (chewable tablet) (every amount)
Embodiment 84 120mg
N.F,USP MANNITOL 100mg
Sorbyl alcohol 30mg
5% polyethylene glycol 6000 (50% ethanol) qs
Stevioside 5mg
Pericarpium Citri junoris tincture 5mg
Stearic acid qs
Preparation technology is with embodiment 93.
Embodiment 100 (every bag of granule)
Embodiment 87 200mg
Lactose 600mg
N.F,USP MANNITOL 180mg
Steviosin 5mg
Essence 5mg
2% hypromellose (water) qs
Technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing recipe quantity auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 14 mesh sieves are granulated, 55 ℃ of dryings, and the whole grain of 16 mesh sieves is measured heavily packing of bag.
Embodiment 101 (enteric coated tablet) (every amount)
Plain tablet recipe
Embodiment 81 100mg
Secondary calcium phosphate 80mg
Lactose 40mg
Xylo-Mucine 10mg
Polyvinylpolypyrrolidone 10mg
2% hypromellose qs
Magnesium Stearate qs
Preparation technology is with embodiment 96.
The dressing prescription:
Plain sheet 80g
Acrylic resin L100-55 10.0g
Talcum powder 2.5g
Titanium dioxide 2.0g
Triethyl citrate qs
95% ethanol adds to 160ml
Art for coating:
A, acrylic resin L100-55, titanium dioxide, talcum powder, the triethyl citrate of recipe quantity be dissolved in 95% the ethanol, fully mixing.
B, the plain sheet of recipe quantity is placed coating pan, start air blast, making the sheet temperature is about 40 ℃, sprays into enteric coating with spray gun, and spray speed is 5ml/ minute, sprayed to enteric coating, and dry 1h, packing gets final product.
Embodiment 102
The preparation of small injection
Embodiment 91 0.5g
SODIUM PHOSPHATE, MONOBASIC 10mg
Citric acid 20mg
Sodium-chlor 450mg
Water for injection 50ml
Technology: get water for injection 50ml, the citric acid, SODIUM PHOSPHATE, MONOBASIC, sodium-chlor that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, are 5.0-8.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, the charcoal absorption of adding 0.1% 20 minutes.Filter with 045 μ m filter membrane earlier, again with the smart filter of 022 μ m.Cut open the 2ml can by every peace, 105 ℃ of high-temperature sterilizations promptly got injection liquid in 30 minutes.
Embodiment 103
The preparation of freeze-drying injection liquid
Embodiment 91 product 1.0g
N.F,USP MANNITOL 200mg
Citric acid 5mg
Pool Luo Samu 10mg
Water for injection 100ml
Technology: get water for injection 50ml, the citric acid, poloxamer that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, are 4.0-6.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, and benefit adds water to 100ml.The gac that adds 0.5g adsorbed 20 minutes down at 30 ℃.Filter with 045 μ m filter membrane earlier, again with the smart filter of 022 μ m.Filtrate is carried out packing by every 2ml, and pre-freeze is after 2 hours, freezing drying under reduced pressure down 18 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal and promptly get freeze-dried powder.
Embodiment 104
The preparation of primary infusion
Embodiment 91 product 0.1g
SODIUM PHOSPHATE, MONOBASIC 0.1g
Citric acid 0.2g
Sodium-chlor 9g
Water for injection 1000ml
Technology: get water for injection 500ml, the citric acid, SODIUM PHOSPHATE, MONOBASIC, sodium-chlor that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, are 4.0-8.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, the charcoal absorption of adding 0.1% 20 minutes.Benefit adds water to 1000ml, filters with 0.45 μ m filter membrane earlier, again with the smart filter of 0.22 μ m.Every bottle of 100ml of embedding, sterilization promptly gets invention compound sodium chloride injection.
The present invention relates to general formula (I) compound and have certain resisiting influenza virus and anti-tumor bioactivity through pharmacology mensuration.
Claims (8)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein:
R
1For :-H ,-F ,-Cl ,-Br ,-OCH
3,-NO
2,-(CH
2)
0-3CH
3,-OH ,-N (CH
3)
2,-CN ,-CO (CH
2)
0-3CH
3, R
1Can be in contraposition, ortho position or a position on the phenyl ring, and be single replacement or polysubstituted;
R
2Be :-H ,-CH
3
R
3Be :-OH ,-(CH
2)
0-3CH
3,-O (CH
2)
0-3CH
3,-OCH (CH
3)
2,-OC (CH
3)
3,-NH
2,-NHCH
3,-NHCH
2CH
3,-NHCH (CH
3)
2,-NHCH
2CH
2CH
3
X is N or O, wherein,
When X is N, R
4Be C
1-C
4The straight or branched alkyl; Quilt-F ,-Cl ,-Br ,-NO
2,-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH
2CH
2CH
2CH
3,-OH ,-CN is single to be replaced or polysubstituted phenyl;
When X is O, no R
4
2. according to the defined compound of Formula I of claim 1 or its pharmacy acceptable salt, preferentially descend array structure, wherein,
R
1For-H ,-F ,-Cl ,-Br ,-OCH
3,-NO
2,-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH
2CH
2CH
2CH
3,-OH ,-N (CH
3)
2,-CN, R
1Can be in contraposition, ortho position or a position on the phenyl ring, and be single replacement or polysubstituted;
R
2Be-H ,-CH
3
R
3Can be-OH ,-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-OCH
3,-OCH
2CH
3,-OCH
2CH
2CH
3,-OCH (CH
3)
2,-OC (CH
3)
3,-NH
2,-NHCH
3,-NHCH
2CH
3,-NHCH (CH
3)
2,-NHCH
2CH
2CH
3
X is N or O, wherein,
When X is N, R
4Be :-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH
2CH
2CH
2CH
3Quilt-F ,-Cl ,-Br ,-NO
2,-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH
2CH
2CH
2CH
3,-OH ,-CN is single to be replaced or polysubstituted phenyl;
When X is O, no R
4
3. following compound or its pharmacy acceptable salt are selected from
2-phenyl-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-fluorophenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-chloro-phenyl-)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-bromophenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-aminomethyl phenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-p-methoxy-phenyl)-3-(5-methylol 3-isoxazole) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-phenyl-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-fluorophenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-chloro-phenyl-)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-bromophenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-aminomethyl phenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-p-methoxy-phenyl)-3-(5-methylol 3-isoxazole)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-phenyl-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-fluorophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-chloro-phenyl-)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-bromophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-aminomethyl phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles) pyrazolo [1,5a] pyridine-5-acetoacetic ester
2-phenyl-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-fluorophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-chloro-phenyl-)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-bromophenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-aminomethyl phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also
2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenyl-3-pyrazoles)-6-methylpyrazole is [1,5a] pyridine-5-acetoacetic ester also.
4. synthesize the method for each described compound of claim 1-3, the preparation method of key intermediate V comprises the steps: compounds X and oxalic acid diethyl ester, and the hydrazine hydrate one pot reaction generates IX; Tetrahydrochysene lithium aluminium reducing IX obtains compound VIII; VIII is obtained compound VI I by the PCC oxidation; γ-bromo crotonate generation cascade reaction that VII and β replace, one go on foot product V;
5. the method for synthetic each described compound of claim 1-3 comprises the steps: compound V and DMF, POCl
3Effect obtains compound IV; Compound IV and oxammonium hydrochloride or phenylhydrazine reacting generating compound II or III; Compound I I or III handle with NCS, under alkaline condition, with alkene that replaces or alkynes the reaction of 1,3 dipolar addition take place and generate final Compound I a or Ib;
6. the defined compound of Formula I of claim 1 or its pharmacy acceptable salt application aspect the antitumor or antiviral of preparation.
7. a pharmaceutical composition contains each described compound of claim 1-3 or its pharmacy acceptable salt, and appropriate carriers or vehicle.
8. the described pharmaceutical composition of claim 7, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
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| CN1694698A (en) * | 2002-09-06 | 2005-11-09 | 比奥根艾迪克Ma公司 | Pyrazolopyridines and methods of making and using the same |
| US20050282842A1 (en) * | 2002-10-03 | 2005-12-22 | Gudmundsson Kristjan S | Therapeutic compounds based on pyrazolopyridine derivatives |
-
2008
- 2008-03-27 CN CN2008100525362A patent/CN101544634B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1694698A (en) * | 2002-09-06 | 2005-11-09 | 比奥根艾迪克Ma公司 | Pyrazolopyridines and methods of making and using the same |
| US20050282842A1 (en) * | 2002-10-03 | 2005-12-22 | Gudmundsson Kristjan S | Therapeutic compounds based on pyrazolopyridine derivatives |
Non-Patent Citations (3)
| Title |
|---|
| Medicinal Chemistry Letters》.1999,第9卷1979-1984. * |
| Satoru Kuroda et al..Discovery of FR166124,a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist.《Bioorganic & Medicinal Chemistry Letters》.1999,第9卷1979-1984. |
| Satoru Kuroda et al..Discovery of FR166124,a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist.《Bioorganic & * |
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| CN101544634A (en) | 2009-09-30 |
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