CN102690264A - 2-phenyl-3-substituted-imidazo[1,2-a]pyridine derivatives and preparation method thereof - Google Patents
2-phenyl-3-substituted-imidazo[1,2-a]pyridine derivatives and preparation method thereof Download PDFInfo
- Publication number
- CN102690264A CN102690264A CN201210203694XA CN201210203694A CN102690264A CN 102690264 A CN102690264 A CN 102690264A CN 201210203694X A CN201210203694X A CN 201210203694XA CN 201210203694 A CN201210203694 A CN 201210203694A CN 102690264 A CN102690264 A CN 102690264A
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- Prior art keywords
- pyridine
- gyq
- phenyl
- imidazo
- compound
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- -1 2-phenyl-3-substituted-imidazo[1,2-a]pyridine Chemical class 0.000 title claims abstract description 14
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- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical class C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 claims description 35
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Abstract
The invention relates to 2-phenyl-3-substituted-imidazo[1,2-a]pyridine derivatives, a pharmaceutical compound I capable of treating tumors, viruses and other diseases, and a preparation method and application thereof. Compared with the prior art, since the 2-phenyl-3-substituted-imidazo[1,2-a]pyridine derivatives have the structure disclosed as Formula I, the anti-influenza virus effect is obviously enhanced, and the 2-phenyl-3-substituted-imidazo[1,2-a]pyridine derivatives can also have a certain inhibiting action on stomach sdenocarcinoma cells. The invention also discloses pharmaceutically acceptable salts containing the compound I, and one or more pharmaceutical compositions composed of pharmaceutically acceptable carrier, excipient or diluter.
Description
One, technical field
The present invention relates to the pharmaceutical field of tumour and antiviral therapy; Or rather; Relate to the also Preparation Method And The Use of [1,2-a] pyridine derivatives of one type of 2-phenyl-3-substituted imidazole with antitumor or antivirus action, and the pharmaceutical composition that contains them.
Two, background technology
In recent years, imidazo [1,2-a] pyridine compounds and their has caused people's extensive concern.This compounds has stomach trouble prevention and treatment, antiulcer agent, anti-inflammatory, pharmacologically active such as anticancer, antiviral; For example: the imidazo of in patent CN87106804, CN200980148444.7, CN201010256861.8, describing [1,2-a] pyridine derivate has the pharmacologically active of prevention and treatment gastrointestinal tract disease; The related substituted imidazo of 8-alkoxyl group base [1, the 2-a] pyridine of patent CN88106859.4 and CN87108027 has antiulcer activity; The patent No. is that the related polysubstituted imidazo of the patent of CN200880122184.1 [1,2-a] pyridine has anti-inflammatory, anticancer pharmacologically active; The related substituted tropane derivatives of imidazo [1,2-a] pyridine of patent CN200910146182.2 has antiviral activity.In addition; Pyrazole derivatives can also all have to relate in patent CN200480008491.9, CN200480024041.9, CN200480027819.1, CN200580018762.3, CN200980122215.8, CN201080008839.X as the suppressor factor of cell and enzyme.In other respects; The imidazo [1 that patent CN200710193642.8 and CN200910023047.9 are related; 2-a] pyridine derivate can be used to make Organic Light Emitting Diode and organic electro-phosphorescent luminescent device, and its verivate can be used as weedicide and uses among the patent CN90100789.7:.
Tumour and virus infection are the serious problems of face of mankind always, press for the new medicine of research and development.Some medicine can be to antitumor and antiviral generation certain function, but antitumor and viral inhibiting rate is not high.
Three, summary of the invention
The objective of the invention is deficiency, seek a kind of antitumor and effective compound of influenza virus, compound and pharmacy acceptable salt thereof with general formula I structure are provided to prior art.
The technical scheme that the present invention takes is: 2-phenyl-3-substituted imidazole also [1; 2-a] pyridine derivatives, it is characterized in that: compound or its pharmacy acceptable salt with formula
structure:
Wherein:
R
1And R
2For: – 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 or-CO (CH
2)
0-3CH
3In single or a plurality of substituting groups, and be in contraposition, ortho position or the position on the aromatic ring respectively;
X is N-R
3Or O;
R
3Be-OH or C
1-C
4Straight chain, branched-chain alkyl or single replace, polysubstituted phenyl.
Tool the present invention of the present invention has compound or its pharmacy acceptable salt of formula
structure:
Wherein:
R
1And R
2For: – H ,-F ,-Cl ,-Br ,-O CH
3, 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 or-CO (CH
2)
0-3CH
3In single or a plurality of substituting groups, and be in contraposition, ortho position or the position on the aromatic ring respectively;
X is N-R
3Or O;
R
3Be-OH or C
1-C
4Straight chain, branched-chain alkyl or single replace, polysubstituted phenyl.
General formula of the present invention
compound or pharmacy acceptable salt are selected from
GYQ-1:2-phenyl-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-2:2-(4-fluorophenyl)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-3:2-(4-chloro-phenyl-)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-4:2-(4-bromophenyl)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-5:2-(4-p-methoxy-phenyl)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-6:2-(4-nitrophenyl)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-7:2-phenyl-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-8:2-(4-fluorophenyl)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-9:2-(4-chloro-phenyl-)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-10:2-(4-bromophenyl)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-11:2-(4-p-methoxy-phenyl)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-12:2-(4-nitrophenyl)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-13:2-phenyl-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-14:2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-15:2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-16:2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-17:2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-18:2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-19:2-phenyl-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-20:2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-21:2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-22:2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-23:2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-24:2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-25:2-phenyl-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-carboxylic acid sodium.
The general formula of the synthetic claim 1-2 of the present invention
The method of compound comprises the steps: compound
With DMF, POCl
3Effect obtains compound
,Solvent is DMF, and temperature of reaction is the 20-40 degree, and the reaction times is 8-24 hour; Compound
WithOxammonium hydrochloride or phenylhydrazine reaction, solvent is an ethanol, and temperature of reaction is the 50-80 degree, and the reaction times is 12-48 hour, generates compound
Or
Compound
Or
Use
NCSHandle, under alkaline condition, with substituted alkene or alkynes the reaction of 1,3 dipolar addition takes place and generate final compound
aOr
B,Solvent is a methylene dichloride, and temperature of reaction is the 20-50 degree, and the reaction times is 3-8 hour,
The application aspect the antitumor or antiviral of preparation of the defined general formula of claim 1 of the present invention
compound or pharmacy acceptable salt.
A kind of pharmaceutical composition; The general formula
compound or the pharmacy acceptable salt that contain one of claim 1-3, and appropriate carriers or vehicle.
Compsn of the present invention is solid orally ingestible, liquid oral medicine or injection.
The pharmacy acceptable salt of formula according to the invention
compound; Can contain carboxyl or amido according to different verivates, carboxyl can react with alkaline matter (like oxyhydroxide, carbonate and the supercarbonate of basic metal or earth alkali metal), and they comprise; But be not limited to: sodium hydroxide; Pottasium Hydroxide, calcium hydroxide, yellow soda ash etc. form pharmacy acceptable salt; Like corresponding sodium salts, 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 (like formic acid, acetate, Hydrocerol A, oxalic acid, fumaric acid, toxilic acid, amino acid or the like, but being not limited only to this).
The pharmacy acceptable salt of formula according to the invention
compound can be processed pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, thinner or vehicle.This pharmaceutical composition can be processed formulations such as solid orally ingestible, liquid oral medicine, and described solid and liquid oral medicine comprise: tablet, dispersible tablet, enteric coated tablet, chewable tablet, oral cavity disintegration tablet, capsule, granule, syrup, oral solution, injection.
Described solid orally ingestible adopts lactose, starch or N.F,USP MANNITOL as thinner, uses gelatin, and methylcellulose gum, hypromellose, Vinylpyrrolidone polymer, starch slurry etc. are as tackiness agent; Use starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, PVPP, Microcrystalline Cellulose as disintegrating agent; Use talcum powder, micropowder silica gel, stearin, calcium stearate or magnesium etc. as antiadhesives and lubricant.
The preparation method of said 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 aqs soln of this mixture and tackiness agent; Alcohol property or aqueous alcohol property solution carry out wet method in suitable device; Or dried particles, disintegrating agent, lubricant and the antiadhesives or capsule, the granule etc. that add other subsequently are fit to clinical formulation.
Said liquid oral medicine adopts lactose, N.F,USP MANNITOL as thinner; Methylcellulose gum, hypromellose, Vinylpyrrolidone polymer, CMC 99.5 etc. are as thickening material or suspensoid; Sorbic Acid, hydrochloric acid, lactic acid, sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC etc. are as the PH regulator; Pool Luo Samu, sodium lauryl sulphate, PEG 400, Polyethylene Glycol-600, cetomacrogol 1000 etc. are as solubilizing agent; ASPARTAME POWDER BP/USP, Steviosin, Sodium Glutamate, fructose, lemon flavour, orange flavor essence etc. are correctives; Tegosept E, phenylcarbinol etc. are as sanitas.
The preparation method of said liquid oral medicine may further comprise the steps: it is an amount of to get zero(ppm) water; Add stirrings such as water-soluble filler, PH regulator, 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 like 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 characteristic comprises water-soluble filler N.F,USP MANNITOL, low molecular dextran, sorbyl alcohol, polyoxyethylene glycol, tween, glucose.Lactose or semi-lactosi; PH regulator phosphoric acid, hydrochloric acid, Pottasium Hydroxide, sodium hydroxide, yellow soda ash or potassium or acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry of ammonium salt, sodium hydrogencarbonate or physiology such as potassium or ammonium salt and salt; Stablizer carbomer, sodium lauryl sulphate or Tutofusin tris; One or both combinations of osmotic pressure regulator sodium-chlor, Repone K.
The preparation method of different administrated by injection preparations is following:
Freeze-dried
Get The compounds of this invention and salt thereof and water-soluble filler, stablizer, osmotic pressure agent etc., 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, under the 20-50 degree, stirred 10-60 minute; The filtering with microporous membrane degerming is adopted in decarburization, and filtrating 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, osmotic pressure agent etc., 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, under the 20-50 degree, stirred 10-60 minute; Decarburization, smart filter, embedding, sterilization.
Primary infusion
Get The compounds of this invention and salt thereof and water-soluble filler, stablizer, osmotic pressure agent etc., it is an amount of about 30% to add water for injection, regulates pH value and makes its dissolving to 4-8; Add the 0.1-0.5% gac, under the 20-50 degree, stirred 10-60 minute decarburization; 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 situation 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 formula according to the invention
compound 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, (suspension cell need not digestion) is suspended in the DMEM nutrient solution that contains 10% calf serum behind 0.25% tryptic digestion, blows and beats into single cell suspension gently with Glass tubing, and microscopically is used the blood cell counting plate living cell counting.(cell concn is 5-10 * 10 to the every hole of 96 well culture plates inoculating cell suspension 90 μ L
4Individual/mL), in 37 degree, 100% relative humidity, contain 5%CO
2, 95% air incubator in cultivate 24h after, every hole adds 10 μ L soups (final concentration is made as 10 μ g/mL).Other establishes negative control (isoconcentration DMSO) and blank background (not adding cell), 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 (suspension cell needs earlier centrifugally, inhales and removes supernatant liquid).Every hole adds 100 μ LDMSO, places micro oscillator concussion 5min so that crystal dissolves fully, in the single wavelength colorimetric of ELIASA 492nm, measures the OD value.
Inhibiting rate (%)=[1-(experimental group OD average-blank control group OD average)/(control group OD average-blank control 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 digestion); Be suspended in the DMEM nutrient solution that contains 10% calf serum, blow and beat into single cell suspension gently with Glass tubing, microscopically is used the blood cell counting plate living cell counting.(cell concn is 5-10 * 10 to the every hole of 96 well culture plates inoculating cell suspension 90 μ L
4Individual/mL), in 37 degree, 100% relative humidity, contain 5%CO
2, 95% air incubator in cultivate 24h after, every hole adds 10 μ L soups (final concentration is made as 10 μ g/mL) and 10 μ L influenza A virus venom (titre 1:100).Model group only adds virus and does not add medicine, and normal group does not add virus, and other establishes negative control (isoconcentration DMSO) and blank background (not adding cell), 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 (suspension cell needs earlier centrifugally, inhales and removes supernatant liquid).Every hole adds 100 μ LDMSO, places micro oscillator concussion 5min so that crystal dissolves fully, in the single wavelength colorimetric of ELIASA 492nm, measures the OD value.
Inhibiting rate (%)=(experimental group OD average-model group OD average)/(normal group OD average-model group OD average) * 100%.
The present invention relates to compound of Formula I and have certain resisiting influenza virus and anti-tumor bioactivity through pharmacology mensuration:
| ? | Human leukemia HL-60 cell's inhibiting rate (%) | People's adenocarcinoma of stomach SGC-7901 cell inhibitory rate (%) | Influenza virus inhibiting rate (%) |
| GYQ-1 | 12.3 | 15.6 | 35.7 |
| GYQ-3 | 48.6 | 54.4 | 55.1 |
| GYQ-7 | 20.3 | 15.3 | 61.1 |
| GYQ-9 | 30.2 | 20.1 | 76.3 |
| GYQ-13 | 30.6 | 23.3 | 40.0 |
| GYQ-17 | 40.1 | 35.5 | 69.1 |
| GYQ-20 | 49.9 | 27.7 | 60.6 |
| GYQ-25 | 53.2 | 42.2 | 77.5 |
Can be known by above experimental data: the present invention on average up to more than 50%, has also played certain restraining effect to adenocarcinoma of stomach SGC-7901 cell to the inhibiting rate of influenza virus.
The invention has the beneficial effects as follows: The compounds of this invention compared with prior art owing to have a formula I structure, obviously improves in the effect of resisiting influenza virus, also can play certain restraining effect to the adenocarcinoma of stomach cell.
Embodiment:
Below in conjunction with embodiment the present invention is further described, the compound of invention detects through thin-layer chromatography, uses subsequently
1H NMR proves conclusively its structure.
Embodiment 1 7-methyl-2-phenylimidazole is [1,2-a] pyridine-3-formaldehyde also
Under the ice bath, POCl3 1.38 mL (15mmol) slowly are added drop-wise among 10 mLDMF, dropwise back stirring at room 1h, in system, drip 7-methyl-2-phenylimidazole also [1; 2-a] the DMF solution of pyridine (2.08g, 10 mmol), dropwise back stirring at room 24h, pour in the frozen water; After stirring 1h, dichloromethane extraction three times merges organic phase, washing; Drying, concentrate bullion, the methylene dichloride recrystallization gets pure article.Productive rate 86%.
1H?NMR(CDCl
3,?TMS)?δ(ppm):?2.5(s),?3H;?7.0(dd),?1H;?7.5-7.6(m),?4H;?7.8(m),?2H;?9.5(d),?1H;?10.0(s),?1H.。
Embodiment 2
Reference example 1 preparation 7-methyl-2-(4-fluorophenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (89%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 7.3 (d), 1H; 7.4 (d), 2H; 7.8 (s), 1H; 8.2 (d), 2H; 9.4 (d), 1H; 10.0 (s), 1H..
Embodiment 3
Reference example 1 preparation 7-methyl-2-(4-bromophenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (80%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 7.1 (d), 1H; 7.6 (s), 1H; 7.7 (d), 2H; 7.8 (d), 2H; 9.4 (d), 1H; 10.0 (s), 1H..
Embodiment 4
Reference example 1 preparation 7-methyl-2-(4-p-methoxy-phenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (84%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 3.9 (s), 3H; 6.9 (d), 1H; 7.0 (d), 2H; 7.5 (s), 1H; 7.8 (d), 2H; 9.5 (d), 1H; 10.0 (s), 1H..
Embodiment 5
Reference example 1 preparation 7-methyl-2-(4-nitrophenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (78%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 7.4 (d), 1H; 7.9 (s), 1H; 8.1 (d), 2H; 8.3 (d), 2H; 9.4 (d), 1H; 10.0 (s), 1H..
Embodiment 6
Reference example 1 preparation 2-phenyl-3-formyl imidazoles is [1,2-a] pyridine-7-acetoacetic ester also, productive rate (76%)
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.0 (dd), 1H; 7.5-7.8 (m), 5H; 8.0 (s), 1H; 9.7 (d), 1H; 10.0 (s), 1H..
Embodiment 7
Reference example 1 preparation 2-(4-fluorophenyl)-3-formyl imidazoles is [1,2-a] pyridine-7-acetoacetic ester also, productive rate (70%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.3 (d), 1H; 7.4 (d), 2H; 8.0 (s), 1H; 8.2 (d), 2H; 9.7 (d), 1H; 10.0 (s), 1H..
Embodiment 8
Reference example 1 preparation 2-(4-chloro-phenyl-)-3-formyl imidazoles is [1,2-a] pyridine-7-acetoacetic ester also, productive rate (79%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.2 (d), 1H; 7.6 (d), 2H; 8.0 (s), 1H; 8.0 (d), 2H; 9.7 (d), 1H; 10.0 (s), 1H..
Embodiment 9
Reference example 1 preparation 2-(4-bromophenyl)-3-formyl imidazoles is [1,2-a] pyridine-7-acetoacetic ester also, productive rate (70%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.1 (d), 1H; 7.6 (s), 1H; 7.7 (d), 2H; 7.8 (d), 2H; 9.6 (d), 1H; 10.0 (s), 1H..
Embodiment 10
Reference example 1 preparation 2-(4-p-methoxy-phenyl)-3-formyl imidazoles is [1,2-a] pyridine-7-acetoacetic ester also, productive rate (74%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 3.9 (s), 3H; 4.4 (q), 2H; 6.9 (d), 1H; 7.0 (d), 2H; 7.6 (s), 1H; 7.8 (d), 2H; 9.6 (d), 1H; 10.0 (s), 1H..
Embodiment 11
Reference example 1 preparation 2-(4-nitrophenyl)-3-formyl imidazoles is [1,2-a] pyridine-7-acetoacetic ester also, productive rate (72%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 7.4 (d), 1H; 8.1 (s), 1H; 8.2 (d), 2H; 8.4 (d), 2H; 9.7 (d), 1H; 10.0 (s), 1H..
Embodiment 12 7-methyl-2-phenylimidazole is [1,2-a] pyridine-3-formoxime also
In 50 mL round-bottomed flasks, add also [1,2-a] pyridine-3-formaldehyde (1.18g, 5 mmol) of 15 mL methyl alcohol and 7-methyl-2-phenylimidazole, the back that stirs adds oxammonium hydrochloride (0.42g; 6 mmol), slowly add yellow soda ash (0.318g, 3 mmol), stirring at room 4h after the dissolving fully; The TLC detection reaction adds 50 mL water after finishing, and dichloromethane extraction three times merges organic phase; Washing, drying, concentrate white solid, product directly is used for step reaction down.Productive rate 92%.
Embodiment 13
Reference example 12 preparation 7-methyl-2-(4-fluorophenyl) imidazo [1,2-a] pyridine-3-formoximes, productive rate (89%)..
Embodiment 14
Reference example 12 preparation 7-methyl-2-(4-chloro-phenyl-) imidazo [1,2-a] pyridine-3-formoximes, productive rate (91%)..
Embodiment 15
Reference example 12 preparation 7-methyl-2-(4-bromophenyl) imidazo [1,2-a] pyridine-3-formoximes, productive rate (86%)..
Embodiment 16
Reference example 12 preparation 7-methyl-2-(4-p-methoxy-phenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (87%)..
Embodiment 17
Reference example 12 preparation 7-methyl-2-(4-nitrophenyl) imidazo [1,2-a] pyridine-3-formoximes, productive rate (84%)..
Embodiment 18
Reference example 12 preparation 2-phenyl-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (71%).
Embodiment 19
Reference example 12 preparation 2-(4-fluorophenyl)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (70%)..
Embodiment 20
Reference example 12 preparation 2-(4-chloro-phenyl-)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (69%)..
Embodiment 21
Reference example 12 preparation 2-(4-bromophenyl)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (67%).
Embodiment 22
Reference example 12 preparation 2-(4-p-methoxy-phenyl)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (66%)..
Embodiment 23
Reference example 12 preparation 2-(4-nitrophenyl)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (61%)..
Embodiment 24 7-methyl-2-phenyl-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine
In 50 mL round-bottomed flasks, add also [1,2-a] pyridine-3-formaldehyde (1.18g, 5 mmol) of 15 mL methyl alcohol and 7-methyl-2-phenylimidazole, the back that stirs adds phenylhydrazine (0.65g; 6 mmol), room temperature reaction 12h, the TLC detection reaction adds 50 mL water after finishing; Dichloromethane extraction three times merges organic phase, washing; Drying, concentrate white solid, product directly is used for step reaction down.Productive rate 88%.
Embodiment 25
Reference example 24 preparation 7-methyl-2-(4-fluorophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridines, productive rate (80%)..
Embodiment 26
Reference example 24 preparation 7-methyl-2-(4-chloro-phenyl-)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridines, productive rate (81%)..
Embodiment 27
Reference example 24 preparation 7-methyl-2-(4-bromophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridines, productive rate (81%)..
Embodiment 28
Reference example 24 preparation 7-methyl-2-(4-p-methoxy-phenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridines, productive rate (78%)..
Embodiment 29
Reference example 23 preparation 7-methyl-2-(4-nitrophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridines, productive rate (80%)..
Embodiment 30
Reference example 24 preparation 2-phenyl-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (61%).
Embodiment 31
Reference example 24 preparation 2-(4-fluorophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (60%)..
Embodiment 32
Reference example 24 preparation 2-(4-chloro-phenyl-)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (64%)..
Embodiment 33
Reference example 24 preparation 2-(4-bromophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (63%)..
Embodiment 34
Reference example 24 preparation 2-(4-p-methoxy-phenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (65%)..
Embodiment 35
Reference example 24 preparation 2-(4-nitrophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (61%).
Embodiment 36 7-methyl-2-phenyl-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine
In 50 mL round-bottomed flasks, add also [1,2-a] pyridine-3-formoxime (1.26g, 5 mmol) of 20 mL methylene dichloride and 7-methyl-2-phenylimidazole; Add NCS (0.85g, 6 mmol), reflux 30min after stirring; Add propynol (0.28g, 5 mmol), drip triethylamine (0.60g; 6 mmol), reflux 3h.After the TLC detection reaction finishes, concentrate, silica gel column chromatography separates, and eluent is petroleum ether-ethyl acetate (5:1).Productive rate 65%.
1H?NMR(CDCl
3,?TMS)?δ(ppm):?2.5(s),?3H;?4.7(s),?2H;?6.4(s),?1H;?7.0(dd),?1H;?7.5-7.6(m),?4H;?7.8(m),?2H;?8.6(d),?1H。
Embodiment 37
Reference example 36 preparation 7-methyl-2-(4-fluorophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridines, productive rate (69%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 4.8 (s), 2H; 6.5 (s), 1H; 7.3 (d), 1H; 7.4 (d), 2H; 7.8 (s), 1H; 8.2 (d), 2H; 8.6 (d), 1H.
Embodiment 38
Reference example 36 preparation 7-methyl-2-(4-chloro-phenyl-)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridines, productive rate (68%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 4.7 (s), 2H; 6.4 (s), 1H; 7.2 (d), 1H; 7.6 (d), 2H; 7.7 (s), 1H; 8.0 (d), 2H; 8.6 (d), 1H.
Embodiment 39
Reference example 36 preparation 7-methyl-2-(4-bromophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridines, productive rate (60%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 4.7 (s), 2H; 6.4 (s), 1H; 7.1 (d), 1H; 7.6 (s), 1H; 7.7 (d), 2H; 7.8 (d), 2H; 8.6 (d), 1H.
Embodiment 40
Reference example 36 preparation 7-methyl-2-(4-p-methoxy-phenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridines, productive rate (64%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 3.9 (s), 3H; 4.7 (s), 2H; 6.4 (s), 1H; 6.9 (d), 1H; 7.0 (d), 2H; 7.5 (s), 1H; 7.8 (d), 2H; 8.5 (d), 1H.
Embodiment 41
Reference example 36 preparation 7-methyl-2-(4-nitrophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridines, productive rate (78%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 4.8 (s), 2H; 6.5 (s), 1H; 7.4 (d), 1H; 7.9 (s), 1H; 8.1 (d), 2H; 8.3 (d), 2H; 8.8 (d), 1H.
Embodiment 42
Reference example 36 preparation 2-phenyl-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (63%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.7 (s), 2H; 6.4 (s), 1H; 7.0 (dd), 1H; 7.5-7.6 (m), 4H; 7.8 (m), 2H; 8.6 (d), 1H.
Embodiment 43
Reference example 36 preparation 2-(4-fluorophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (66%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.8 (s), 2H; 6.5 (s), 1H; 7.3 (d), 1H; 7.4 (d), 2H; 7.8 (s), 1H; 8.2 (d), 2H; 8.6 (d), 1H.
Embodiment 44
Reference example 36 preparation 2-(4-chloro-phenyl-)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (67%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.7 (s), 2H; 6.4 (s), 1H; 7.2 (d), 1H; 7.6 (d), 2H; 7.7 (s), 1H; 8.0 (d), 2H; 8.6 (d), 1H.
Embodiment 45
Reference example 36 preparation 2-(4-bromophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (62%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.7 (s), 2H; 6.4 (s), 1H; 7.1 (d), 1H; 7.6 (s), 1H; 7.7 (d), 2H; 7.8 (d), 2H; 8.6 (d), 1H.
Embodiment 46
Reference example 36 preparation 2-(4-p-methoxy-phenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (64%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 3.9 (s), 3H; 4.4 (q), 2H; 4.7 (s), 2H; 6.4 (s), 1H; 6.9 (d), 1H; 7.0 (d), 2H; 7.5 (s), 1H; 7.8 (d), 2H; 8.5 (d), 1H.
Embodiment 47
Reference example 36 preparation 2-(4-nitrophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (60%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.8 (s), 2H; 6.5 (s), 1H; 7.4 (d), 1H; 7.9 (s), 1H; 8.1 (d), 2H; 8.3 (d), 2H; 8.8 (d), 1H.
Embodiment 48 7-methyl-2-phenyl-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine
In 50 mL round-bottomed flasks, add 20 mL methylene dichloride and 7-methyl-2-phenyl 3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine (1.26g, 5 mmol); Add NCS (0.85g, 6 mmol), reflux 30min after stirring; Add propynol (0.28g, 5 mmol), drip triethylamine (0.60g; 6 mmol), reflux 3h.After the TLC detection reaction finishes, concentrate, silica gel column chromatography separates, and eluent is petroleum ether-ethyl acetate (5:1).Productive rate 59%.
1H?NMR(CDCl
3,?TMS)?δ(ppm):?2.5(s),?3H;?4.8(s),?2H;?6.4(s),?1H;?7.0(dd),?1H;?7.3-7.4,?7.5-7.8(m),?10H;?7.8(s),?1H;?8.6(d),?1H。
Embodiment 49
Reference example 48 preparation 7-methyl-2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridines, productive rate (61%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 4.8 (s), 2H; 6.5 (s), 1H; 7.2 (d), 2H; 7.3 (d), 1H; 7.4-8.0 (m), 8H; 8.6 (d), 1H.
Embodiment 50
Reference example 48 preparation 7-methyl-2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridines, productive rate (61%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 4.8 (s), 2H; 6.5 (s), 1H; 7.2 (d), 2H; 7.3 (d), 1H; 7.4-7.9 (m), 8H; 8.6 (d), 1H.
Embodiment 51
Reference example 48 preparation 7-methyl-2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridines, productive rate (60%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 4.8 (s), 2H; 6.5 (s), 1H; 7.2 (d), 2H; 7.3 (d), 1H; 7.4-7.9 (m), 8H; 8.6 (d), 1H.
Embodiment 52
Reference example 48 preparation 7-methyl-2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridines, productive rate (64%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 4.8 (s), 2H; 6.5 (s), 1H; 6.9 (d), 1H; 7.0 (d), 2H; 7.4-7.8 (m), 8H; 8.5 (d), 1H.
Embodiment 53
Reference example 48 preparation 7-methyl-2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridines, productive rate (56%).
1H NMR (CDCl
3, TMS) δ (ppm): 2.5 (s), 3H; 4.9 (s), 2H; 6.6 (s), 1H; 7.4 (d), 1H; 7.9 (s), 1H; 8.1 (d), 2H; 8.3 (d), 2H; 8.8 (d), 1H.
Embodiment 54
Reference example 48 preparation 2-phenyl-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (62%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.8 (s), 2H; 6.7 (s), 1H; 7.0 (d), 1H; 7.2-8.2 (m), 11H; 8.6 (d), 1H.
Embodiment 55
Reference example 48 preparation 2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (60%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.8 (s), 2H; 6.8 (s), 1H; 7.3 (d), 1H; 7.4-8.2 (m), 11H; 8.6 (d), 1H.
Embodiment 56
Reference example 48 preparation 2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (60%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.7 (s), 2H; 6.7 (s), 1H; 7.2 (d), 1H; 7.4-8.2 (m), 11H; 8.6 (d), 1H.
Embodiment 57
Reference example 48 preparation 2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (62%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.7 (s), 2H; 6.4 (s), 1H; 7.1 (d), 1H; 7.2-8.2 (m), 11H; 8.6 (d), 1H.
Embodiment 58
Reference example 48 preparation 2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (64%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 3.9 (s), 3H; 4.4 (q), 2H; 4.7 (s), 2H; 6.6 (s), 1H; 6.9 (d), 1H; 7.1-8.0 11H; 8.5 (d), 1H.
Embodiment 59
Reference example 48 preparation 2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic esters, productive rate (60%).
1H NMR (CDCl
3, TMS) δ (ppm): 1.4 (t), 3H; 2.5 (s), 3H; 4.4 (q), 2H; 4.8 (s), 2H; 6.8 (s), 1H; 7.4-8.3 (d), 12H; 8.8 (d), 1H.
Embodiment 60
The product of embodiment 54, the NaOH solution of adding 0.2M is an amount of, is heated to 50 degree dissolvings, and refrigeration is sufficient crystallising down, has both got sodium salt, yield 50%.
1H NMR (D
2O, TMS) δ (ppm): 2.5 (s), 3H; 4.8 (s), 2H; 6.7 (s), 1H; 7.0 (d), 1H; 7.2-8.2 (m), 11H; 8.6 (d), 1H.
Embodiment 61
The product of embodiment 55, the NaOH solution that adds 0.2M is an amount of, is heated to 50 degree dissolvings; Adding hydrochloric acid accent pH is about 2, deposition is fully separated out, after static several hours; Suction filtration gets solid, and solid adds an amount of dissolve with methanol, adds an amount of triethylamine; After stirring 1h, refrigeration is sufficient crystallising down, has both got triethylamine salt.
Embodiment 62
Method for preparing tablet thereof is following:
Prescription consumption/sheet
Embodiment 55 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, the adding Vinylpyrrolidone polymer aqueous solution is an amount of; Cross 20 mesh sieves, make wet granular in 50-60 degree baking oven dry 2 hours, remaining sodium starch glycolate; Magnesium Stearate and particle mix; Whole grain is measured midbody content, uses special-shaped stamping.
Embodiment 63
Capsular preparation method is following:
Prescription consumption/grain
Embodiment 56 product 15mg
Lactose 100mg
Microcrystalline Cellulose 20mg
Hypromellose 5mg
Micropowder silica gel 4mg
Sodium starch glycolate 8mg
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, the adding hypromellose is an amount of; Cross 24 mesh sieves; Make wet granular in 50-60 degree baking oven dry 2 hours, micropowder silica gel, talcum powder and particle are mixed whole; Measure midbody content, with No. 3 capsule cans.
Embodiment 64
The preparation of oral solution (every bottle of amount)
Prescription consumption/sheet
Embodiment 56 product 30mg
N.F,USP MANNITOL 100mg
Hydrocerol A 20mg
Orange flavor essence 10mg
ASPARTAME POWDER BP/USP 10mg
Zero(ppm) water 100ml
Tegosept E qs
Technology: get zero(ppm) water 100ml, take by weighing N.F,USP MANNITOL, Hydrocerol A, orange flavor essence, ASPARTAME POWDER BP/USP and the medicine stirring and dissolving of recipe quantity, after the adding sanitas, can is in bottle.
Embodiment 65 (dispersible tablet) (every amount)
Embodiment 57 product 50mg
Lactose 120mg
Microcrystalline Cellulose 30mg
Add 10mg in the sodium starch glycolate and add 10mg
ASPARTAME POWDER BP/USP 3mg
Orange essence 3mg
2% hypromellose qs
Silicon-dioxide qs
Calcium stearate qs
Technology: major ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing prescription auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 20 wooden sieve series grains, 55 dryings, the whole grain of 18 mesh sieves.Add lubricant at last and remaining carboxymethylstach sodium mixes compressing tablet.
Embodiment 66 (oral cavity disintegration tablet) (every amount)
Embodiment 58 70mg
N.F,USP MANNITOL 120mg
Microcrystalline Cellulose 40mg
Sodium Croscarmellose 15mg
Magnesium Stearate qs
Technology: major ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing adopts Kun press cake of press, crosses the whole grain of 18 mesh sieves with whole grain again, adds the even compressing tablet of mix lubricant at last.
Embodiment 67 (effervescent tablet) (every amount)
Embodiment 59 100mg
Tartrate 100mg
Sodium hydrogencarbonate 100mg
Methylcellulose gum 10mg
Maltose alcohol 10mg
Lemon flavour 5mg
Talcum powder qs
Preparation technology is with embodiment 62.
Embodiment 68 (chewable tablet) (every amount)
Embodiment 48 120mg
N.F,USP MANNITOL 100mg
Sorbyl alcohol 30mg
5% polyethylene glycol 6000 (50% ethanol) qs
Stevia rebaudianum 5mg
Pericarpium Citri junoris tincture 5mg
Triple Pressed Stearic Acid qs
Preparation technology is with embodiment 62
Embodiment 69 (every bag of granule)
Embodiment 49 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 70 (enteric coated tablet) (every amount)
Plain tablet recipe
Embodiment 50 100mg
Secondary calcium phosphate 80mg
Lactose 40mg
Sodium cellulose glycolate 10mg
PVPP 10mg
2% hypromellose qs
Magnesium Stearate qs
Preparation technology is with embodiment 65.
The dressing prescription:
Plain sheet 80g
Vinyl resin L100-55 10.0g
Talcum powder 2.5g
Titanium oxide 2.0g
Triethyl citrate qs
95% ethanol adds to 160ml
Art for coating:
A, vinyl resin L100-55, titanium oxide, talcum powder, the triethyl citrate of recipe quantity be dissolved in 95% the ethanol, fully mixing;
B places coating pan with the plain sheet of recipe quantity, starts air blast, and 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 71
The preparation of small injection
The product 0.5g of embodiment 52
SODIUM PHOSPHATE, MONOBASIC 10mg
Hydrocerol A 20mg
Sodium-chlor 450mg
Water for injection 50ml
Technology: get water for injection 50ml, the Hydrocerol A, SODIUM PHOSPHATE, MONOBASIC, the sodium-chlor that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, use the hydrochloric acid of 0.1mol/L or sodium hydroxide adjust pH to be 5.0-8.0, the charcoal absorption of adding 0.1% 20 minutes.Filter with 0.45 μ m filter membrane earlier, again with the smart filter of 0.22 μ m.Cut open the 2ml can by every peace, 105 ℃ of high-temperature sterilizations promptly got injection liquid in 30 minutes.
Embodiment 72
The preparation of freeze-drying injection liquid
Embodiment 52 product 1.0g
N.F,USP MANNITOL 200mg
Hydrocerol A 5mg
Prist 10mg
Water for injection 100ml
Technology: get water for injection 50ml, the Hydrocerol A, the Prist that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, use the hydrochloric acid of 0.1mol/L or sodium hydroxide adjust pH to be 4.0-6.0, mend and add water to 100ml.The gac that adds 0.5g adsorbed 20 minutes down at 30 ℃.Filter with 0.45 μ m filter membrane earlier, again with the smart filter of 0.22 μ m.Filtrating 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 73
The preparation of primary infusion
The product 0.1g of embodiment 52
SODIUM PHOSPHATE, MONOBASIC 0.1g
Hydrocerol A 0.2g
Sodium-chlor 9g
Water for injection 1000ml
Technology: get water for injection 500ml, the Hydrocerol A, SODIUM PHOSPHATE, MONOBASIC, the sodium-chlor that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, use the hydrochloric acid of 0.1mol/L or sodium hydroxide adjust pH to be 4.0-8.0, 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 and invents the compound sodium chloride injection.
Embodiment 74
General formula
The compound method of compound comprises the steps: compound
With DMF, POCl
3Effect obtains compound
,Solvent is DMF, and temperature of reaction is 20 degree, and the reaction times is 8 hours; Compound
WithOxammonium hydrochloride or phenylhydrazine reaction, solvent is an ethanol, and temperature of reaction is 50 degree, and the reaction times is 12 hours, generates compound
Or
Compound
Or
Use
NCSHandle, under alkaline condition, with substituted alkene or alkynes the reaction of 1,3 dipolar addition takes place and generate final compound
aOr
B,Solvent is a methylene dichloride, and temperature of reaction is 20 degree, and the reaction times is 3 hours.
Embodiment 75
The general formula of synthetic claim 1-2
The method of compound comprises the steps: compound
With DMF, POCl
3Effect obtains compound
,Solvent is DMF, and temperature of reaction is 40 degree, and the reaction times is 24 hours; Compound
WithOxammonium hydrochloride or phenylhydrazine reaction, solvent is an ethanol, and temperature of reaction is 80 degree, and the reaction times is 48 hours, generates compound
Or
Compound
Or
Use
NCSHandle, under alkaline condition, with substituted alkene or alkynes the reaction of 1,3 dipolar addition takes place and generate final compound
aOr
B,Solvent is a methylene dichloride, and temperature of reaction is 50 degree, and the reaction times is 8 hours.
Embodiment 76
The general formula of synthetic claim 1-2
The method of compound comprises the steps: compound
With DMF, POCl
3Effect obtains compound
,Solvent is DMF, and temperature of reaction is 30 degree, and the reaction times is 12 hours; Compound
WithOxammonium hydrochloride or phenylhydrazine reaction, solvent is an ethanol, and temperature of reaction is 65 degree, and the reaction times is 24 hours, generates compound
Or
Compound
Or
Use
NCSHandle, under alkaline condition, with substituted alkene or alkynes the reaction of 1,3 dipolar addition takes place and generate final compound
aOr
B,Solvent is a methylene dichloride, and temperature of reaction is 35 degree, and the reaction times is 6 hours.
Embodiment 77
The general formula of synthetic claim 1-2
The method of compound comprises the steps: compound
With DMF, POCl
3Effect obtains compound
,Solvent is DMF, and temperature of reaction is 35 degree, and the reaction times is 20 hours; Compound
WithOxammonium hydrochloride or phenylhydrazine reaction, solvent is an ethanol, and temperature of reaction is 70 degree, and the reaction times is 33 hours, generates compound
Or
Compound
Or
Use
NCSHandle, under alkaline condition, with substituted alkene or alkynes the reaction of 1,3 dipolar addition takes place and generate final compound
aOr
B,Solvent is a methylene dichloride, and temperature of reaction is 40 degree, and the reaction times is 6 hours.
Claims (7)
1.2-phenyl-3-substituted imidazole also [1; 2-a] pyridine derivatives, it is characterized in that: compound or its pharmacy acceptable salt with formula
structure:
Wherein:
R
1And R
2For: – 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 or-CO (CH
2)
0-3CH
3In single or a plurality of substituting groups, and be in contraposition, ortho position or the position on the aromatic ring respectively;
X is N-R
3Or O;
R
3Be-OH or C
1-C
4Straight chain, branched-chain alkyl or single replace, polysubstituted phenyl.
2. 2-phenyl according to claim 1-3-substituted imidazole also [1; 2-a] pyridine derivatives, it is characterized in that: compound or its pharmacy acceptable salt with formula
structure:
Wherein:
R
1And R
2For: – H ,-F ,-Cl ,-Br ,-O CH
3, 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 or-CO (CH
2)
0-3CH
3In single or a plurality of substituting groups, and be in contraposition, ortho position or the position on the aromatic ring respectively;
X is N-R
3Or O;
R
3Be-OH or C
1-C
4Straight chain, branched-chain alkyl or single replace, polysubstituted phenyl.
3. 2-phenyl according to claim 1 and 2-3-substituted imidazole also [1; 2-a] pyridine derivatives; It is characterized in that: general formula
compound or pharmacy acceptable salt are selected from
GYQ-1:2-phenyl-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-2:2-(4-fluorophenyl)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-3:2-(4-chloro-phenyl-)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-4:2-(4-bromophenyl)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-5:2-(4-p-methoxy-phenyl)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-6:2-(4-nitrophenyl)-3-(5-Qiang methyl-isoxazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-7:2-phenyl-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-8:2-(4-fluorophenyl)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-9:2-(4-chloro-phenyl-)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-10:2-(4-bromophenyl)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-11:2-(4-p-methoxy-phenyl)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-12:2-(4-nitrophenyl)-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-13:2-phenyl-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-14:2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-15:2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-16:2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-17:2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-18:2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole)-7-Methylimidazole is [1,2-a] pyridine also
GYQ-19:2-phenyl-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-20:2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-21:2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-22:2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-23:2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-24:2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester
GYQ-25:2-phenyl-3-(5-Qiang methyl-isoxazole) imidazo [1,2-a] pyridine-7-carboxylic acid sodium.
4.2-phenyl-3-substituted imidazole is the preparation method of [1,2-a] pyridine derivatives also, it is characterized in that: the general formula of synthetic claim 1-2
The method of compound comprises the steps: compound
With DMF, POCl
3Effect obtains compound
,Solvent is DMF, and temperature of reaction is the 20-40 degree, and the reaction times is 8-24 hour; Compound
WithOxammonium hydrochloride or phenylhydrazine reaction, solvent is an ethanol, and temperature of reaction is the 50-80 degree, and the reaction times is 12-48 hour, generates compound
Or
Compound
Or
Use
NCSHandle, under alkaline condition, with substituted alkene or alkynes the reaction of 1,3 dipolar addition takes place and generate final compound
aOr
B,Solvent is a methylene dichloride, and temperature of reaction is the 20-50 degree, and the reaction times is 3-8 hour,
5. the defined general formula of claim 1
compound or the pharmacy acceptable salt application aspect the antitumor or antiviral of preparation.
6. pharmaceutical composition; The general formula
compound or the pharmacy acceptable salt that contain one of claim 1-3, and appropriate carriers or vehicle.
7. the described pharmaceutical composition of claim 6, it is characterized in that: described compsn is solid orally ingestible, liquid oral medicine or injection.
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| CN102209711A (en) * | 2008-09-11 | 2011-10-05 | 百时美施贵宝公司 | Compounds for the treatment of hepatitis c |
| US20110257171A1 (en) * | 2008-07-18 | 2011-10-20 | Sanofi-Aventis | Novel imidazo[1,2-a]pyridine derivatives, method for the preparation thereof, use thereof as medicaments, pharmaceutical compositions and novel use in particular as met inhibitors |
-
2012
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|---|---|---|---|---|
| US20110257171A1 (en) * | 2008-07-18 | 2011-10-20 | Sanofi-Aventis | Novel imidazo[1,2-a]pyridine derivatives, method for the preparation thereof, use thereof as medicaments, pharmaceutical compositions and novel use in particular as met inhibitors |
| CN102209711A (en) * | 2008-09-11 | 2011-10-05 | 百时美施贵宝公司 | Compounds for the treatment of hepatitis c |
Non-Patent Citations (1)
| Title |
|---|
| 李文赟等: "抗肿瘤细胞周期蛋白依赖性激酶抑制剂的研究进展", 《国外医药抗生素分册》 * |
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