CN102690264B - 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
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- CN102690264B CN102690264B CN201210203694.XA CN201210203694A CN102690264B CN 102690264 B CN102690264 B CN 102690264B CN 201210203694 A CN201210203694 A CN 201210203694A CN 102690264 B CN102690264 B CN 102690264B
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- pyridine
- imidazo
- gyq
- phenyl
- isoxazole
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- CUMCMYMKECWGHO-UHFFFAOYSA-N 3-methyl-1,2-oxazole Chemical compound CC=1C=CON=1 CUMCMYMKECWGHO-UHFFFAOYSA-N 0.000 claims description 27
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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 2-phenyl-3-substituted imidazole that a class has 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, the pharmacologically active such as anticancer, antiviral, for example: imidazo [1, the 2-a] pyridine derivate of describing in patent CN87106804, CN200980148444.7, CN201010256861.8 has the pharmacologically active of prevention and treatment gastrointestinal tract disease; Imidazo [1, the 2-a] pyridine that the related 8-alkoxyl group base of patent CN88106859.4 and CN87108027 replaces has antiulcer activity; The patent No. is that related polysubstituted imidazo [1, the 2-a] pyridine of the patent of CN200880122184.1 has anti-inflammatory, Pycnorus cinnabarius; The tropane derivatives that related imidazo [1, the 2-a] pyridine of patent CN200910146182.2 replaces has antiviral activity.In addition, pyrazole derivatives can also be served as the inhibitor of cell and enzyme, in patent CN200480008491.9, CN200480024041.9, CN200480027819.1, CN200580018762.3, CN200980122215.8, CN201080008839.X, all has and relates to.In other respects, the imidazo [1 that patent CN200710193642.8 and CN200910023047.9 are related, 2-a] pyridine derivate can be for the manufacture of Organic Light Emitting Diode and organic electro-phosphorescent luminescent device, and in patent CN90100789.7, its derivative can be used as weedicide and applies:.
Tumour and virus infection are the serious problems of facing mankind always, in the urgent need to researching and developing new medicine.Some medicine can be to the certain effect of antitumor and antiviral generation, but antitumor and viral inhibiting rate is not high.
Three, summary of the invention
The object of the invention is for the deficiencies in the prior art, find a kind of antitumor and effective compound of influenza virus, compound and the pharmacy acceptable salt thereof with general formula I structure are provided.
The technical scheme that the present invention takes is: also [1,2-a] pyridine derivatives of 2-phenyl-3-substituted imidazole, is characterized in that: have formula
the compound of structure or its pharmacy acceptable salt:
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 multiple substituting groups, and be in respectively contraposition, ortho position or the position on aromatic ring;
X is N-R
3or O;
R
3be-OH or C
1-C
4straight chain, branched-chain alkyl or monosubstituted, polysubstituted phenyl.
Tool the present invention of the present invention has formula
the compound of structure or its pharmacy acceptable salt:
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 multiple substituting groups, and be in respectively contraposition, ortho position or the position on aromatic ring;
X is N-R
3or O;
R
3be-OH or C
1-C
4straight chain, branched-chain alkyl or monosubstituted, polysubstituted phenyl.
General formula of the present invention
compound or pharmacy acceptable salt, be selected from
GYQ-1:2-phenyl-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-2:2-(4-fluorophenyl)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-3:2-(4-chloro-phenyl-)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-4:2-(4-bromophenyl)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-5:2-(4-p-methoxy-phenyl)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-6:2-(4-nitrophenyl)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
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) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-14:2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-15:2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-16:2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-17:2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-18:2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
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 20-40 degree, and the reaction times is 8-24 hour; Compound
withoxammonium hydrochloride or phenylhydrazine reaction, solvent is ethanol, and temperature of reaction is 50-80 degree, and the reaction times is 12-48 hour, generates compound
or
; Compound
or
with
nCSprocess, under alkaline condition, with the alkene replacing or alkynes, 1,3 dipolar addition reaction occurs and generate final compound
aor
b,solvent is methylene dichloride, and temperature of reaction is 20-50 degree, and the reaction times is 3-8 hour,
The defined general formula of the claims in the present invention 1
the application aspect the antitumor or antiviral of preparation of compound or pharmacy acceptable salt.
A kind of pharmaceutical composition, the general formula that contains one of claim 1-3
compound or pharmacy acceptable salt, and suitable carrier or vehicle.
Composition of the present invention is solid orally ingestible, liquid oral medicine or injection.
Formula of the present invention
the pharmacy acceptable salt of compound, can contain carboxyl or amido according to different derivatives, carboxyl can react with alkaline matter (as the oxyhydroxide of basic metal or alkaline-earth metal, carbonate and supercarbonate), they include, but are not limited to: sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate etc. form pharmacy acceptable salt, as corresponding sodium salt, and sylvite or calcium salt etc.Also can adopt nontoxic organic bases as generation salt such as methylamine, triethylamine, meglumines; 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, acetic acid, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid etc., but being not limited only to this).
Formula of the present invention
the pharmacy acceptable salt of compound, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, thinner or vehicle.This pharmaceutical composition can be made the formulation such as solid orally ingestible, liquid oral medicine, and 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 lactose, starch or N.F,USP MANNITOL as thinner, uses gelatin, and 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, micropowder silica gel, stearin, calcium stearate or magnesium etc. as antiadhesives and lubricant.
The preparation method of described solid orally ingestible comprises the following steps: by activeconstituents and auxiliary material comprise thinner, tackiness agent, optionally with one or both disintegration additive composition mixtures; adopt dry granulation maybe by the aqueous solution of this mixture and tackiness agent; alcohol or aqueous alcohol solution carry out wet method in suitable equipment; or dried particles, add subsequently other disintegrating agent, lubricant and antiadhesives or capsule, granule etc. to be applicable to clinical formulation.
Described liquid oral medicine adopts lactose, N.F,USP MANNITOL as thinner; Methylcellulose gum, hypromellose, polyvinylpyrrolidone, carboxymethyl cellulose etc. are as thickening material or suspensoid; Sorbic Acid, hydrochloric acid, lactic acid, sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC etc. are as PH conditioning agent; Pool Luo Samu, sodium lauryl sulphate, poly(oxyethylene glycol) 400, Polyethylene Glycol-600, cetomacrogol 1000 etc. are as solubilizing agent; Aspartame, Steviosin, Sodium Glutamate, fructose, lemon flavour, orange taste essence etc. are correctives; Tegosept E, phenylcarbinol etc. are as sanitas.
The preparation method of described liquid oral medicine comprises the following steps: get distilled water appropriate, add water-soluble filler, PH conditioning agent, thickening material or suspensoid, solubilizing agent, correctives etc. to be stirred to dissolve, add again thing of the present invention, add after sanitas, filling 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 injection administration.
Described injecting and administering preparations comprises freeze-dried powder, small injection and primary infusion.Its feature comprises water-soluble filler N.F,USP MANNITOL, low molecular dextran, sorbyl alcohol, polyoxyethylene glycol, tween, glucose.Lactose or semi-lactosi; The acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry of physiology and the salt such as PH conditioning agent phosphoric acid, hydrochloric acid, potassium hydroxide, sodium hydroxide, sodium carbonate or potassium or ammonium salt, sodium bicarbonate or potassium or ammonium 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 as follows:
Freeze-dried
Get the compounds of this invention and salt thereof and water-soluble filler, stablizer, osmotic pressure agent etc., add water for injection appropriate, regulate pH value to 4-8 make its dissolve, add water to scale, add 0.1-0.5% gac, under 20-50 degree, stir 10-60 minute, decarburization, adopts filtering with microporous membrane degerming, filtrate is carried out packing, adopt freeze-drying, make white loose block, sealing is.
Small injection
Get the compounds of this invention and salt thereof and water-soluble filler, stablizer, osmotic pressure agent etc., add water for injection appropriate, regulate pH value to make its dissolving to 4-8, add water to scale, add 0.1-0.5% gac, under 20-50 degree, stir 10-60 minute, decarburization, smart filter, embedding, sterilizing.
Primary infusion
Get the compounds of this invention and salt thereof and water-soluble filler, stablizer, osmotic pressure agent etc., add water for injection appropriate approximately 30%, regulate pH value to make its dissolving to 4-8, add 0.1-0.5% gac, under 20-50 degree, stir 10-60 minute, decarburization, add water to scale, smart filter, embedding, sterilizing.
The actual dosage of taking compound of series compound of the present invention should be decided according to relevant situation by doctor, these situations comprise the person's of being treated physical state, patient's route of administration, age, body weight, individual reaction to medicine and severity of symptom etc.
Formula of the present invention
the biological activity of compound is measured in the following manner:
(1) anti-tumor activity
Sample is with DMSO hydrotropy, and serum-free DMEM substratum is diluted to desired concn, and sample segment solution is suspension.
Cell strain: human acute promyelocytic leukemia HL-60 cells; People's gastric cancer SGC-7901 cell line; Human colon carcinoma SW-480 cell.
The cell of taking the logarithm vegetative period, after 0.25% tryptic digestion, (suspension cell is without digestion), is suspended in containing in the DMEM nutrient solution of 10% calf serum, blows and beats into gently single cell suspension with Glass tubing, uses blood cell counting plate living cell counting under microscope.The 96 every hole of well culture plate inoculating cell suspension 90 μ L(cell concns are 5-10 × 10
4individual/mL), at 37 degree, 100% relative humidity, containing 5%CO
2, 95% air incubator in cultivate after 24h, every hole adds 10 μ L liquids (final concentration is made as 10 μ g/mL).Separately establish negative control (isoconcentration DMSO) and blank background (not adding cell), all establish 3 multiple holes for each group.Cultured continuously 24h again, then every hole adds the MTT solution of 10 μ L 5mg/mL, continues to cultivate after 4h, carefully sucks supernatant liquor (suspension cell, need to be first centrifugal, then suck supernatant liquid).Every hole adds 100 μ LDMSO, is placed in micro oscillator concussion 5min so that crystal dissolves completely, in the mono-wavelength colorimetric of microplate reader 492nm, measures 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, after 0.25% tryptic digestion (suspension cell is without digestion), be suspended in containing in the DMEM nutrient solution of 10% calf serum, blow and beat into gently single cell suspension with Glass tubing, under microscope, use blood cell counting plate living cell counting.The 96 every hole of well culture plate inoculating cell suspension 90 μ L(cell concns are 5-10 × 10
4individual/mL), at 37 degree, 100% relative humidity, containing 5%CO
2, 95% air incubator in cultivate after 24h, every hole adds 10 μ L liquids (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, separately establishes negative control (isoconcentration DMSO) and blank background (not adding cell), all establishes 3 multiple holes for each group.Cultured continuously 24h again, then every hole adds the MTT solution of 10 μ L 5mg/mL, continues to cultivate after 4h, carefully sucks supernatant liquor (suspension cell, need to be first centrifugal, then suck supernatant liquid).Every hole adds 100 μ LDMSO, is placed in micro oscillator concussion 5min so that crystal dissolves completely, in the mono-wavelength colorimetric of microplate reader 492nm, measures 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 measures and has certain resisiting influenza virus and antineoplastic biological activity through pharmacology:
| ? | Human leukemia HL-60 cell's inhibiting rate (%) | People's gastric cancer SGC-7901 cell line inhibiting 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 |
From above experimental data: the inhibiting rate of infected by influenza of the present invention, on average up to more than 50%, has also played certain restraining effect to gastric cancer SGC-7901 cell line.
The invention has the beneficial effects as follows: the compounds of this invention compared with prior art, owing to having formula I structure, improves at the successful of resisiting influenza virus, also can play certain restraining effect to gastric adenocarcinoma cells.
embodiment:
Below in conjunction with embodiment, the present invention is further illustrated, and the compound of invention detects through thin-layer chromatography, uses subsequently
1h NMR confirms its structure.
Also [1,2-a] pyridine-3-formaldehyde of embodiment 1 7-methyl-2-phenylimidazole
Under ice bath, by phosphorus oxychloride 1.38 mL(15mmol) be slowly added drop-wise in 10 mLDMF, dropwise rear stirring at room temperature 1h, in system, drip the also DMF solution of [1,2-a] pyridine (2.08g, 10 mmol) of 7-methyl-2-phenylimidazole, dropwise rear stirring at room temperature 24h, pour in frozen water, stir after 1h, dichloromethane extraction three times, merge organic phase, washing, dry, concentrate to obtain crude product, methylene dichloride recrystallization obtains sterling.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 is prepared 7-methyl-2-(4-fluorophenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (89%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-bromophenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (80%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-p-methoxy-phenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (84%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-nitrophenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (78%).
1h NMR (CDCl
3, TMS) and 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 is prepared also [1,2-a] pyridine-7-acetoacetic ester of 2-phenyl-3-formyl imidazoles, productive rate (76%)
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-fluorophenyl) also [1,2-a] pyridine-7-acetoacetic ester of-3-formyl imidazoles, productive rate (70%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-chloro-phenyl-) also [1,2-a] pyridine-7-acetoacetic ester of-3-formyl imidazoles, productive rate (79%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-bromophenyl) also [1,2-a] pyridine-7-acetoacetic ester of-3-formyl imidazoles, productive rate (70%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-p-methoxy-phenyl) also [1,2-a] pyridine-7-acetoacetic ester of-3-formyl imidazoles, productive rate (74%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-nitrophenyl) also [1,2-a] pyridine-7-acetoacetic ester of-3-formyl imidazoles, productive rate (72%).
1h NMR (CDCl
3, TMS) and 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..
Also [1,2-a] pyridine-3-formoxime of embodiment 12 7-methyl-2-phenylimidazoles
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, after stirring, add oxammonium hydrochloride (0.42g, 6 mmol), after dissolving completely, slowly add sodium carbonate (0.318g, 3 mmol), stirring at room temperature 4h, after TLC detection reaction finishes, add 50 mL water, dichloromethane extraction three times, merges organic phase, washing, dry, concentrate to obtain white solid, product is directly used in the next step.Productive rate 92%.
Embodiment 13
Reference example 12 is prepared 7-methyl-2-(4-fluorophenyl) imidazo [1,2-a] pyridine-3-formoxime, productive rate (89%)..
Embodiment 14
Reference example 12 is prepared 7-methyl-2-(4-chloro-phenyl-) imidazo [1,2-a] pyridine-3-formoxime, productive rate (91%)..
Embodiment 15
Reference example 12 is prepared 7-methyl-2-(4-bromophenyl) imidazo [1,2-a] pyridine-3-formoxime, productive rate (86%)..
Embodiment 16
Reference example 12 is prepared 7-methyl-2-(4-p-methoxy-phenyl) imidazo [1,2-a] pyridine-3-formaldehyde, productive rate (87%)..
Embodiment 17
Reference example 12 is prepared 7-methyl-2-(4-nitrophenyl) imidazo [1,2-a] pyridine-3-formoxime, productive rate (84%)..
Embodiment 18
Reference example 12 is prepared 2-phenyl-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (71%).
Embodiment 19
Reference example 12 is prepared 2-(4-fluorophenyl)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (70%)..
Embodiment 20
Reference example 12 is prepared 2-(4-chloro-phenyl-)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (69%)..
Embodiment 21
Reference example 12 is prepared 2-(4-bromophenyl)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (67%).
Embodiment 22
Reference example 12 is prepared 2-(4-p-methoxy-phenyl)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (66%)..
Embodiment 23
Reference example 12 is prepared 2-(4-nitrophenyl)-3-hydroxyl formimino imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (61%)..
Embodiment 24 7-methyl-2-phenyl-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridines
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, after stirring, add phenylhydrazine (0.65g, 6 mmol), room temperature reaction 12h, after TLC detection reaction finishes, add 50 mL water, dichloromethane extraction three times, merges organic phase, washing, dry, concentrate to obtain white solid, product is directly used in the next step.Productive rate 88%.
Embodiment 25
Reference example 24 is prepared 7-methyl-2-(4-fluorophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine, productive rate (80%)..
Embodiment 26
Reference example 24 is prepared 7-methyl-2-(4-chloro-phenyl-)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine, productive rate (81%)..
Embodiment 27
Reference example 24 is prepared 7-methyl-2-(4-bromophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine, productive rate (81%)..
Embodiment 28
Reference example 24 is prepared 7-methyl-2-(4-p-methoxy-phenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine, productive rate (78%)..
Embodiment 29
Reference example 23 is prepared 7-methyl-2-(4-nitrophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine, productive rate (80%)..
Embodiment 30
Reference example 24 is prepared 2-phenyl-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (61%).
Embodiment 31
Reference example 24 is prepared 2-(4-fluorophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (60%)..
Embodiment 32
Reference example 24 is prepared 2-(4-chloro-phenyl-)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (64%)..
Embodiment 33
Reference example 24 is prepared 2-(4-bromophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (63%)..
Embodiment 34
Reference example 24 is prepared 2-(4-p-methoxy-phenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (65%)..
Embodiment 35
Reference example 24 is prepared 2-(4-nitrophenyl)-3-aldehyde radical phenylhydrazone imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (61%).
Embodiment 36 7-methyl-2-phenyl-3-(5-Qiang methyl-isoxazoles) imidazo [1,2-a] pyridine
In 50 mL round-bottomed flasks, add 20 mL methylene dichloride and 7-methyl-2-phenylimidazole also [1,2-a] pyridine-3-formoxime (1.26g, 5 mmol), after stirring, add NCS(0.85g, 6 mmol), reflux 30min, add propargyl alcohol (0.28g, 5 mmol), drip triethylamine (0.60g, 6 mmol), reflux 3h.After TLC detection reaction finishes, concentrated, 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 is prepared 7-methyl-2-(4-fluorophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine, productive rate (69%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-chloro-phenyl-)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine, productive rate (68%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-bromophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine, productive rate (60%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-p-methoxy-phenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine, productive rate (64%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-nitrophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine, productive rate (78%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-phenyl-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (63%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-fluorophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (66%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-chloro-phenyl-)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (67%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-bromophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (62%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-p-methoxy-phenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (64%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-nitrophenyl)-3-(5-hydroxyl methyl-isoxazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (60%).
1h NMR (CDCl
3, TMS) and 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-phenylpyrazoles) 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), after stirring, add NCS(0.85g, 6 mmol), reflux 30min, add propargyl alcohol (0.28g, 5 mmol), drip triethylamine (0.60g, 6 mmol), reflux 3h.After TLC detection reaction finishes, concentrated, 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 is prepared 7-methyl-2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine, productive rate (61%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine, productive rate (61%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine, productive rate (60%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine, productive rate (64%).
1h NMR (CDCl
3, TMS) and 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 is prepared 7-methyl-2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine, productive rate (56%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-phenyl-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (62%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (60%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (60%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (62%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (64%).
1h NMR (CDCl
3, TMS) and 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 is prepared 2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole) imidazo [1,2-a] pyridine-7-acetoacetic ester, productive rate (60%).
1h NMR (CDCl
3, TMS) and 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, adds the NaOH solution of 0.2M appropriate, is heated to 50 degree and dissolves, and the lower sufficient crystallising of refrigeration, had both obtained 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, add the NaOH solution of 0.2M appropriate, be heated to 50 degree and dissolve, adding hydrochloric acid tune pH is 2 left and right, precipitation is fully separated out, after static a few hours, suction filtration obtains solid, and solid adds appropriate dissolve with methanol, add appropriate triethylamine, stir after 1h, the lower sufficient crystallising of refrigeration, had both obtained triethylamine salt.
Embodiment 62
Method for preparing tablet thereof is as follows:
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
Technique: activeconstituents auxiliary material is crossed respectively to 100 mesh sieves; the main ingredient and the auxiliary material (half sodium starch glycolate) that take recipe quantity fully mix; add the polyvinylpyrrolidone aqueous solution appropriate; cross 20 mesh sieves, make wet granular and be dried 2 hours in 50-60 degree baking oven, by remaining sodium starch glycolate; Magnesium Stearate mixes with particle; whole grain, measures intermediate content, uses special-shaped stamping.
Embodiment 63
The preparation method of capsule is as follows:
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
Technique: activeconstituents auxiliary material is crossed respectively to 100 mesh sieves; the main ingredient and the auxiliary material that take recipe quantity fully mix; add hypromellose appropriate; cross 24 mesh sieves; make wet granular and be dried 2 hours in 50-60 degree baking oven, micropowder silica gel, talcum powder are mixed with particle, whole grain; measure intermediate content, filling with No. 3 capsules.
Embodiment 64
The preparation (every bottle of amount) of oral solution
Prescription consumption/sheet
Embodiment 56 product 30mg
N.F,USP MANNITOL 100mg
Citric acid 20mg
Orange taste essence 10mg
Aspartame 10mg
Distilled water 100ml
Tegosept E qs
Technique: get distilled water 100ml, take N.F,USP MANNITOL, citric acid, orange taste essence, aspartame and the medicine stirring and dissolving of recipe quantity, add after sanitas, filling in bottle.
Embodiment 65(dispersible tablet) (every amount)
Embodiment 57 product 50mg
Lactose 120mg
Microcrystalline Cellulose 30mg
In sodium starch glycolate, add the additional 10mg of 10mg
Aspartame 3mg
Orange essence 3mg
2% hypromellose qs
Silicon-dioxide qs
Calcium stearate qs
Technique: major ingredient and auxiliary material are crossed respectively to 100 mesh sieves, fully mix, then take prescription auxiliary material and fully mix with main ingredient.Add again tackiness agent softwood processed, 20 wooden sieve series grains, 55 is dry, the whole grain of 18 mesh sieves.Finally add lubricant and remaining carboxymethylstach sodium to mix compressing tablet.
Embodiment 66(orally disintegrating tablet) (every amount)
Embodiment 58 70mg
N.F,USP MANNITOL 120mg
Microcrystalline Cellulose 40mg
Croscarmellose sodium 15mg
Magnesium Stearate qs
Technique: major ingredient and auxiliary material are crossed respectively to 100 mesh sieves, fully mix, adopt Kun press cake of press, then cross the whole grain of 18 mesh sieves with whole grain, finally add the even compressing tablet of mix lubricant.
Embodiment 67(effervescent tablet) (every amount)
Embodiment 59 100mg
Tartrate 100mg
Sodium bicarbonate 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
Stearic acid qs
Preparation technology is with embodiment 62
Every bag of embodiment 69(granule)
Embodiment 49 200mg
Lactose 600mg
N.F,USP MANNITOL 180mg
Steviosin 5mg
Essence 5mg
2% hypromellose (water) qs
Technique: main ingredient and auxiliary material are crossed respectively to 100 mesh sieves, fully mix, then take recipe quantity auxiliary material and fully mix with main ingredient.
Add tackiness agent softwood processed, 14 mesh sieves are granulated again, and 55 ℃ dry, and the whole grain of 16 mesh sieves is measured heavily packing of bag.
Embodiment 70(enteric coated tablet) (every amount)
Element tablet recipe
Embodiment 50 100mg
Secondary calcium phosphate 80mg
Lactose 40mg
Sodium cellulose glycolate 10mg
Polyvinylpolypyrrolidone 10mg
2% hypromellose qs
Magnesium Stearate qs
Preparation technology is with embodiment 65.
Dressing prescription:
Element 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 are dissolved in 95% ethanol, fully mix;
Recipe quantity element sheet is placed in coating pan by b, starts air blast, and making sheet temperature is 40 ℃ of left and right, sprays into enteric coating with spray gun, and spray speed is 5ml/ minute, sprayed to enteric coating, is dried 1h, packing.
Embodiment 71
The preparation of small injection
The product 0.5g of embodiment 52
SODIUM PHOSPHATE, MONOBASIC 10mg
Citric acid 20mg
Sodium-chlor 450mg
Water for injection 50ml
Technique: get water for injection 50ml, the citric acid, SODIUM PHOSPHATE, MONOBASIC, the sodium-chlor that take recipe quantity are stirred to dissolve, and add sample stirring and dissolving, with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L be 5.0-8.0, add 0.1% charcoal absorption 20 minutes.First filter with 0.45 μ m filter membrane, then filter with 0.22 μ m is smart.Cut open 2ml by every peace filling, 105 ℃ of high-temperature sterilizations obtain injection liquid for 30 minutes.
Embodiment 72
The preparation of freeze-drying injection liquid
Embodiment 52 product 1.0g
N.F,USP MANNITOL 200mg
Citric acid 5mg
Poloxamer 10mg
Water for injection 100ml
Technique: get water for injection 50ml, the citric acid, the poloxamer that take recipe quantity are stirred to dissolve, and add sample stirring and dissolving, with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L be 4.0-6.0, mend and add water to 100ml.Add the gac of 0.5g at 30 ℃, to adsorb 20 minutes.First filter with 0.45 μ m filter membrane, then filter with 0.22 μ m is smart.Filtrate is carried out packing by every 2ml, and pre-freeze is after 2 hours, freezing lower drying under reduced pressure 18 hours, to sample temperature after room temperature, drier 5 hours, make white loose block, seal and obtain freeze-dried powder.
Embodiment 73
The preparation of primary infusion
The product 0.1g of embodiment 52
SODIUM PHOSPHATE, MONOBASIC 0.1g
Citric acid 0.2g
Sodium-chlor 9g
Water for injection 1000ml
Technique: get water for injection 500ml, the citric acid, SODIUM PHOSPHATE, MONOBASIC, the sodium-chlor that take recipe quantity are stirred to dissolve, and add sample stirring and dissolving, with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L be 4.0-8.0, add 0.1% charcoal absorption 20 minutes.Benefit adds water to 1000ml, first filters with 0.45 μ m filter membrane, then filters with 0.22 μ m is smart.Every bottle of 100ml of embedding, sterilizing, obtains invention compound sodium chloride injection.
Embodiment 74
General formula
the synthetic 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 ethanol, and temperature of reaction is 50 degree, and the reaction times is 12 hours, generates compound
or
; Compound
or
with
nCSprocess, under alkaline condition, with the alkene replacing or alkynes, 1,3 dipolar addition reaction occurs and generate final compound
aor
b,solvent is 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 ethanol, and temperature of reaction is 80 degree, and the reaction times is 48 hours, generates compound
or
; Compound
or
with
nCSprocess, under alkaline condition, with the alkene replacing or alkynes, 1,3 dipolar addition reaction occurs and generate final compound
aor
b,solvent is 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 ethanol, and temperature of reaction is 65 degree, and the reaction times is 24 hours, generates compound
or
; Compound
or
with
nCSprocess, under alkaline condition, with the alkene replacing or alkynes, 1,3 dipolar addition reaction occurs and generate final compound
aor
b,solvent is 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 ethanol, and temperature of reaction is 70 degree, and the reaction times is 33 hours, generates compound
or
; Compound
or
with
nCSprocess, under alkaline condition, with the alkene replacing or alkynes, 1,3 dipolar addition reaction occurs and generate final compound
aor
b,solvent is methylene dichloride, and temperature of reaction is 40 degree, and the reaction times is 6 hours.
Claims (5)
1. also [1,2-a] pyridine derivatives of 2-phenyl-3-substituted imidazole, is characterized in that: compound or its pharmacy acceptable salt with formula I structure:
Wherein:
R
1and R
2for: – H ,-F ,-Cl ,-Br ,-O CH
3,-NO
2,-CH
3,-CH
2cH
3,-CH
2cH
2cH
3,-CH
2cH
2cH
2cH
3,-OH ,-CN or-CO (CH
2)
0-3cH
3in one of them substituting group;
X is O.
2. also [1,2-a] pyridine derivatives of 2-phenyl-3-substituted imidazole, is characterized in that: be selected from following compound:
GYQ-1:2-phenyl-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-2:2-(4-fluorophenyl)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-3:2-(4-chloro-phenyl-)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-4:2-(4-bromophenyl)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-5:2-(4-p-methoxy-phenyl)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-6:2-(4-nitrophenyl)-3-(5-Qiang methyl-isoxazole) also [1,2-a] pyridine of-7-Methylimidazole
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) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-14:2-(4-fluorophenyl)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-15:2-(4-chloro-phenyl-)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-16:2-(4-bromophenyl)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-17:2-(4-p-methoxy-phenyl)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
GYQ-18:2-(4-nitrophenyl)-3-(5-methylol-1-phenylpyrazole) also [1,2-a] pyridine of-7-Methylimidazole
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.
3. a pharmaceutical composition, the compound of Formula I that it contains claim 1 or pharmacy acceptable salt, and suitable vehicle.
4. a pharmaceutical composition, the compound that it contains claim 2, and suitable vehicle.
5. the pharmaceutical composition described in claim 3 or 4, is characterized in that: described composition is solid orally ingestible, liquid oral medicine or injection.
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