CN101503414A - Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof - Google Patents
Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof Download PDFInfo
- Publication number
- CN101503414A CN101503414A CNA200910010552XA CN200910010552A CN101503414A CN 101503414 A CN101503414 A CN 101503414A CN A200910010552X A CNA200910010552X A CN A200910010552XA CN 200910010552 A CN200910010552 A CN 200910010552A CN 101503414 A CN101503414 A CN 101503414A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- triazine
- ketone
- thiazole
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine, and relates to a thiazolo(3,2-b)-1,2,4-triazine derivative and applications thereof. The thiazolo(3,2-b)-1,2,4-triazine derivative includes stereoisomers and pharmaceutically applicable salts of the compound, and has a general structural formula as shown above. The thiazolo(3,2-b)-1,2,4-triazine derivative and the salts added by pharmaceutically applicable acids of the compound can be used by combining with the existing medicaments or separately as acetylcholinesterase inhibitors for enhancing the memory of patients suffering from dementia and alzheimer.
Description
Technical field:
The invention belongs to medical technical field, relate to also [3,2-b]-1 of thiazole, 2,4-triazine derivative and application thereof are specifically related to thiazole also [3,2-b]-1,2, the steric isomer of 4-triazine derivative and this compounds and the salt and the application thereof that pharmaceutically are suitable for.This compounds is an acetylcholinesterase depressant, can be used for improving the memory of suffering from dull-witted and Alzheimer's patient.
Background technology:
The degeneration of the cholinergic neuron in Alzheimer's and the basal forebrain is relevant, and cholinergic neuron plays an important role in recognition function (comprising memory).Because the result of described degeneration, the patient who suffers from this disease is synthetic at vagusstoff, show tangible decay aspect choline acetyltransferase activity, acetylcholine esterase active and the choline absorption.
Therefore known acetylcholinesterase depressant can be used for improving person with Alzheimer's disease's memory being effectively aspect the raising cholinergic activity.By acetylcholine esterase inhibition, described compound can improve the level of neurotransmission mediator vagusstoff in the brain, but so hypermnesis.
Existing acetylcholinesterase depressant such as tacrine, this bright, lycoremines etc. still exist resistance or pharmacokinetics defective.Compound of the present invention has the structure type novelty as the acetylcholinesterase depressant of brand new type, and drug action and existing medicine quite or be better than the characteristics of existing medicine have excellent application value and development prospect.
Summary of the invention:
The invention provides a kind of acetylcholinesterase depressant of new texture type, this compound and derivative thereof can merge with existing medicine or use separately to improve dull-witted and Alzheimer's patient's memory.
The present invention relates to the salt of formula I compound, its steric isomer or its sour addition that pharmaceutically is suitable for, its prodrug and pharmaceutical activity metabolite, and the acceptable salt of the medicine of above-claimed cpd:
Wherein
R
1Can selectively be independently selected from H, halogen ,-OH ,-OCH arbitrarily by 1,2 or 3
3,-CH
3,-NO
2,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6
R
2Can selectively be independently selected from H, halogen ,-OH ,-OCH arbitrarily by 1,2 or 3
3,-CH
3,-NO
2,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6
n
1And n
2Be 0 to 1 integer:
R wherein
3R
4Independently be selected from methyl or ethyl, or R
3R
4Form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring with the nitrogen-atoms that they link to each other;
n
3It is 2 to 4 integer;
R
5R
6Independently be selected from methyl or ethyl, or R
5R
6Form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring with the nitrogen-atoms that they link to each other; Or independently be selected from hydrogen and replacement or unsubstituted phenyl ring group respectively: and
n
4It is 1 to 3 integer.
" the acceptable salt of medicine " has referred to keep the biopotency and the character of formula I compound, and the conventional acid additive salt or the base addition salt that form with suitable non-toxicity organic or inorganic acid or organic or inorganic alkali.The example of acid salt comprises acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cipionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrogen chlorate, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecylate.Alkali salt comprises ammonium salt, an alkali metal salt, for example sodium and sylvite, alkaline earth salt, for example calcium and magnesium salts, the salt of organic bases, dicyclohexyl amine salt for example, N-methyl-D-glucamine salt and amino acid whose salt, arginine for example, Methionin etc., and, the alkalescence nitrogen-containing group can be quaternized with such reagent, and elementary alkyl halide for example is as methyl, ethyl, the chlorine of propyl group and butyl, bromine and iodide; The sulfuric acid dialkyl, as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide, as decyl, lauryl, the chlorine of myristyl and stearyl-, bromine and iodide; Aralkyl halide is as bromide of benzyl and styroyl etc.The acid that is preferred for generating acid salt comprises hydrochloric acid and acetic acid.
" pharmaceutically acceptable " as pharmaceutically acceptable ground carrier, excipient, prodrug etc., refers on the pharmacology acceptable and to the essentially no toxicity of the patient of administration particular compound.
" pharmaceutical active metabolite " refers to the meta-bolites of pharmaceutically acceptable and effective formula I compound.
The present invention also relates to the medicinal compositions of acetylcholine esterase inhibition, said composition contains acid salt and the pharmaceutically suitable carrier that formula I compound or its steric isomer or its pharmaceutically are suitable for.
The invention still further relates to the method that suppresses acetylcholinesterase in the Mammals, this method comprises formula I compound or its steric isomer or its acid salt that pharmaceutically is suitable for of taking the acetylcholine esterase inhibition effective dose to Mammals.
The present invention also relates to the method for formula I hypermnesis or treatment or prevention Alzheimer's, this method comprises formula I compound or its steric isomer or its acid salt that pharmaceutically is suitable for of taking hypermnesis or treatment or prevention Alzheimer's effective dose.
The term of using among the present invention " halogen " comprises chlorine, bromine or fluorine.
" replacement " unless otherwise indicated, refers to that substituting group can exist in one or more positions, and substituting group is independently selected from option particularly.
The present invention more preferably compound is a following formula: compound
Wherein, R
1Can selectively be independently selected from H, halogen ,-OH ,-OCH arbitrarily by 1,2 or 3
3,-CH
3,-NO
2,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6
R
2Can selectively be independently selected from H, halogen ,-OH ,-OCH arbitrarily by 1,2 or 3
3,-CH
3,-NO
2,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6
R wherein
3R
4Independently be selected from methyl or ethyl, or R
3R
4Form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring with the nitrogen-atoms that they link to each other;
n
3It is 2 to 4 integer;
R
5R
6Independently be selected from methyl or ethyl, or R
5R
6Form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring with the nitrogen-atoms that they link to each other; Or independently be selected from hydrogen and replacement or unsubstituted phenyl ring group respectively: and
n
4It is 1 to 3 integer.
The compounds of this invention can be taken to the patient by diverse ways, and is for example oral with capsule or tablet, with sterile solution agent or suspensoid administration, and in some cases, can be with the intravenous injection of solution form.Free alkali compound of the present invention can be prepared and taken with the acid salt form that it pharmaceutically is suitable for.
For general adult, the dosage of The compounds of this invention every day is generally about 1-300 milligram/kilogram, and can or divide equally dosed administration by single dose.For administration, if take solution or suspensoid, the concentration of The compounds of this invention is at least 1% (weight) so, and is better with 4-70% (weight) (based on the gross weight of unit).Non-dose unit through gastrointestinal administration generally contains the 5-100 milligram active compound of having an appointment.
The compounds of this invention can be with inert diluent or edible carrier oral administration, and perhaps they can be encapsulated in the gelatine capsule, perhaps are pressed into tablet.Described preparation should contain at least 0.5% active compound, but according to concrete formulation, concentration can change, and can be 4-70% (weight) (based on the gross weight of unit).Oral dosage units generally contains 1.0 milligrams of-300 milligrams of active compounds.
Use for pharmacology, formula I compound is preferably with the form administration of its medicinal acid addition salt.Certainly the effective dose of compound will be according to the effectiveness of used each compound, to treat severity of disease and character, the particular patient that will treat changes.Generally, with the dosage of about 0.01mg to about 20mg/kg body weight/day, the system of compounds administration can obtain effective result.Should be with than the low dosage begin treatment.Subsequently can solid dosage such as capsule, tablet or pulvis, or with liquid form such as solution or suspension oral administration.These compounds can also sterile solution or the form of suspension outside intestines, inject.
In the embodiment of method of the present invention, preferably activeconstituents is incorporated in the composition that contains pharmaceutical carrier, wherein contain The compounds of this invention or its pharmaceutical salts of have an appointment 5% to 90% (weight)." pharmaceutical carrier " refers to be used to prepare the known pharmaceutical excipients of the pharmaceutical active compounds that takes orally to animal, and they are nontoxic substantially and non-teratogenesis under working conditions.Can prepare this composition with the known technology of preparation tablet, capsule, elixir, syrup, emulsion, dispersion and wetting properties and pulvis foamy, it can contain known in preparation particular type composition useful suitable vehicle.Preferred route of administration is an oral administration.Be oral administration, can be mixed with formula I compound solid-state or liquid formulation such as capsule, pill, tablet, lozenge, lozenge, melt, pulvis, solution, outstanding agent or emulsion.Solid unit dose forms can be a capsule, and it can be common duricrust or soft-shelled gelatin type, wherein contains for example tensio-active agent, lubricant and inert filler such as lactose, sucrose, calcium phosphate and W-Gum.In another embodiment, The compounds of this invention can add tackiness agent such as gum arabic, W-Gum or gelatin with matrix such as lactose, sucrose and the W-Gum compressing tablet of routine; Be used for helping disintegration of tablet and dissolved disintegrating agent such as yam starch, alginic acid, W-Gum and guar gum; The flowability that is used to improve tablet and powder prevents that tablet material from sticking to the lubricant on tablet die and the punch press, as talcum powder, stearic acid or Magnesium Stearate, calcium or zinc; Make them to patient more acceptant coating material, tinting material and seasonings with the outward appearance that is used to improve tablet.The suitable vehicle that is used for oral liquid formulation comprises that water and alcohol as ethanol, phenylcarbinol and polyvinyl alcohol, add or do not add medicinal surfactant, suspension agent or floating agent.But formula I compound of the present invention is the intestines external administration also; promptly subcutaneous; intravenously; intramuscular; or intraperitoneal; injectable dosage formulations administration with the compound in the physiology acceptable diluent; wherein also contain pharmaceutical carrier; can be sterile liquid or liquid and close mixture such as water; salt solution; D/W and relevant sugar soln; alcohol is as ethanol; Virahol; or cetyl alcohol; glycol such as propylene glycol or polyoxyethylene glycol; glycerol ketals is as 2,2-dimethyl-1,3-dioxolane-4-methyl alcohol; ether such as poly(oxyethylene glycol) 400; oil, lipid acid, fatty acid ester or glyceryl ester; or acetylize glycerin fatty acid ester; add or do not add pharmaceutically acceptable surfactant such as soap or washing composition, suspension agent such as pectin; carbomer; methylcellulose gum; the isopropyl methyl Mierocrystalline cellulose; or acid methyl cellulose, or emulsifying agent and other pharmaceutically acceptable additive.Can be used for intestines external preparation of the present invention oil example for those from oil, animal, plant or synthetic oil, for example peanut oil, soya-bean oil, sesame oil, Oleum Gossypii semen, Semen Maydis oil, sweet oil, oil and mineral oil.Suitable lipid acid comprises oleic acid, stearic acid and Unimac 5680.The fatty acid ester that is fit to for example is ethyl oleate and Isopropyl myristate.Suitable soap comprises fatty acid alkali metal salt, and amine salt and triethanolamine salt, suitable tensio-active agent comprise cats product such as dimethyl dialkyl halogeno-amine, alkyl, alkyl pyridine halogenide; Anion surfactant such as alkyl, aryl, sulfonate, alkyl, ether and direactive glyceride vitriol and sulfosuccinate; Nonionogenic tenside such as fatty amine oxide, fatty acid alkyl amide and polyoxyethylene polytrimethylene multipolymer; With amphoterics such as alanine alkyl ester and alkyl imidazoline quaternary ammonium salt, and composition thereof.Intestines topical composition of the present invention generally contains the 0.5 formula I compound to about 25% (weight) of having an appointment in solution.Can use sanitas and buffer reagent.For with the stimulation of injection site to minimum or with its elimination, this composition can contain hydrophil lipophil balance value (HLB) and be about 12 to about 17 nonionogenic tenside.The amount of this tensio-active agent is about 5% to about 15% (weight) in this preparation.This tensio-active agent can be to have the single component of above HLB value or the mixture with required HLB of two or more compositions.The example that is used for the tensio-active agent of intestines external preparation is poly-alkene fatty acid esters of sorbitan class, and for example the high molecular weight adducts of polyoxyethylene-sorbitan mono-oleate and oxyethane and a hydrophobic group forms by propylene oxide and propylene glycol condensation.Mixture of the present invention can also percutaneous dosing.This can be undertaken by the solution for preparing required compound simply, preferably uses the solvent of known promotion Transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO) (DMSO) to add or do not add other vehicle and prepares solution.Preferred percutaneous dosing uses the medicine of storage and porous membranous type or has the medicine that solid substrate changes and carries out.These devices generally contain the backing that limits an one outside surface, one can be through another surperficial viscous layer of qualification of active medicine and at least one storage that contains active medicine between outside surface.Perhaps, active medicine is included in the many tiny capsule and pills that are distributed in the whole transmissibility viscous layer.Which kind of situation no matter, active medicine is transported to the viscous layer that can see through active medicine from storage or microcapsule continuously by a film, and the latter contacts with patient's skin or mucous membrane.If active medicine sees through skin and is absorbed, active medicine then controllable and predetermined flow velocity is applied to the patient.When using microcapsule, coating agent also plays the effect of film.In another device with the The compounds of this invention transdermal administration, pharmaceutical active compounds is included in the matrix, it from matrix with expection progressively, constant and controllable speed discharges.Matrix is permeability to compound by the release that diffusion or micropore flow.It is possible having at least two classes to discharge in these systems.Discharge when diffusion takes place during for imporosity matrix.Pharmaceutical active compounds is dissolved in the matrix and diffusion sees through matrix itself.When transporting by liquid phase in the aperture of pharmaceutical active compounds in matrix, micropore stream takes place discharge.
The compounds of this invention can be measured by the biological test or the pharmacology test of many standards as the activity of acetylcholinesterase depressant.
The active determination test of acetylcholinesterase depressant.
Materials and methods:
Preparation for test agent: positive control drug is set at Hydrogen bromide prostigmin(e) (SigmaN-2001), is formulated as 0.1M solution.
Acetylcholinesterase (people source) is 0.5 unit (SigmaC-1682).
Buffered soln is 100mM PBS solution (pH7.4), 10mM two sulphur dinitrobenzoic acid DTNB (D-8130) (with 100mM PBS preparation), and-20 ℃ keep in Dark Place now-making-now-using.
12.5mM acetylthiocholine ATCh (A-5751) is dissolved in the water ,-20 ℃ keep in Dark Place now-making-now-using.
Be prepared into 10 μ M solution after being subjected to the reagent thing with the DMSO dissolving.
Method and result
Operation steps:
(1) handles sample as follows.
The sample contrast
Enzyme 5 μ L
Sample 1 μ L blank solution 1 μ L
Damping fluid 894 μ L damping fluids 899 μ L
Amount to 900 μ L
(2) 37 ℃ of jolting preheatings 15 minutes gently continuously.
(3) add 50mL ATCh and 50mL DTNB.
(4) 37 ℃ of about 20 minutes of joltings gently continuously occur yellow up to reaction solution.
(5) measure the OD value at its 412nm place.
(6) calculate inhibiting rate.
The sample segment inhibiting rate is listed as follows (n=2):
Sample name inhibiting rate (%)
6-benzyl-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-72.83
Thiazole is [3,2-b]-1,2 also, 4-triazine-7-ketone
6-benzyl-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-48.86
Thiazole is [3,2-b]-1,2 also, 4-triazine-7-ketone
6-benzyl-3-[4-(piperidino) ethoxyl phenenyl]-7H-thiazole and 68.74
[3,2-b]-1,2,4-triazine-7-ketone
6-benzyl-3-[3-methyl-4-(piperidino) ethoxyl phenenyl]-7H-thiophene 89.82
Azoles is [3,2-b]-1,2 also, 4-triazine-7-ketone
6-benzyl-3-[3-methyl-4-(4-morpholinyl) ethoxyl phenenyl]-7H-thiophene 58.86
Azoles is [3,2-b]-1,2 also, 4-triazine-7-ketone
6-benzyl-3-[3-methyl-4-(N, N dimethylamine base) phenetole 42.23
Base]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone
6-benzyl-3-[4-(4-morpholinyl) ethoxyl phenenyl]-7H-thiazole and 46.74
[3,2-b]-1,2,4-triazine-7-ketone
6-benzyl-3-[4-(N, N dimethylamine base) ethoxyl phenenyl]-7H-thiazole 63.89
And [3,2-b]-1,2,4-triazine-7-ketone
6-(4-methoxy-benzyl)-3-[4-(N, N dimethylamine base) phenetole 50.59
Base]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone
6-(4-methoxy-benzyl)-3-[4-(N, N dimethylamine base) formyl methoxyl group 79.36
Phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone
6-(4-methoxy-benzyl)-3-[4-(N, N dimethylamine amido) formyl methoxy 78.87
The base phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone
6-(4-methoxy-benzyl)-3-[4-(piperidino) ethoxyl phenenyl]-7H-54.67
Thiazole is [3,2-b]-1,2 also, 4-triazine-7-ketone
6-(4-methoxy-benzyl)-3-[4-(piperidino) formyl anisole 71.09
Base]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone
6-benzyl-3-(4-hydroxybenzyl)-7H-thiazole is [3,2-b]-1,2 also, and 4-3 62.2
Piperazine-7-ketone
6-(4-methoxy-benzyl)-3-(2-hydroxy phenyl)-7H-thiazole and 64.36
[3,2-b]-1,2,4-triazine-7-ketone
6-(3-methoxy-benzyl)-3-(2-hydroxy phenyl)-7H-thiazole and 33.32
[3,2-b]-1,2,4-triazine-7-ketone
6-(4-hydroxybenzyl)-3-(4-aminomethyl phenyl)-7H-thiazole and 62.98
[3,2-b]-1,2,4-triazine-7-ketone
6-(4-methoxy-benzyl)-3-(4-aminomethyl phenyl)-7H-thiazole and 38.84
[3,2-b]-1,2,4-triazine-7-ketone
6-(4-methoxy-benzyl)-3-(4-chloro-phenyl-)-7H-thiazole and 78.08
[3,2-b]-1,2,4-triazine-7-ketone
6-(4-methoxy-benzyl)-3-(4-bromophenyl)-7H-thiazole and 56.02
[3,2-b]-1,2,4-triazine-7-ketone
6-phenyl-3-[4-(piperidino) ethoxyl phenenyl]-7H-thiazole and 69.85
[3,2-b]-1,2,4-triazine-7-ketone
6-phenyl-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-48.86
Thiazole is [3,2-b]-1,2 also, 4-triazine-7-ketone
6-phenyl-3-(2-hydroxy phenyl)-7H-thiazole is [3,2-b]-1,2 also, and 4-3 39.59
Piperazine-7-ketone
6-phenyl-3-(4-p-methoxy-phenyl)-7H-thiazole is [3,2-b]-1,2 also, and 4-83.56
Triazine-7-ketone
6-phenyl-3-(4-aminomethyl phenyl)-7H-thiazole is [3,2-b]-1,2 also, and 4-3 43.52
Piperazine-7-ketone
6-phenyl-3-(4-chloro-phenyl-)-7H-thiazole is [3,2-b]-1,2 also, 4-triazine 83.02
-7-ketone
Hydrogen bromide prostigmin(e) 0.1M 100
Embodiment:
Schema 1 has been summarized the synthesis step of preparation The compounds of this invention.
Schema 1
Wherein
R
1Can be arbitrarily selectively by 1,2 or 3 are independently selected from H, halogen ,-OH ,-OCH
3,-CH
3,-NO
2,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6
R
2Can be arbitrarily selectively by 1,2 or 3 are independently selected from H, halogen ,-OH ,-OCH
3,-CH
3,-NO
2,-O (CH
2) n
2NR
3R
4,-O (CH
2) n
3CONR
5R
6
n
1Be 0 to 1 integer:
R wherein
3R
4Independently be selected from methyl or ethyl, or R
3R
4Form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring with the nitrogen-atoms that they link to each other;
n
3It is 2 to 4 integer;
R
5R
6Independently be selected from methyl or ethyl, or R
5R
6Form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring with the nitrogen-atoms that they link to each other; Or independently be selected from hydrogen and replacement or unsubstituted phenyl ring group respectively: and
n
4It is 1 to 3 integer.
Be described in detail the present invention with following example.But, should be understood that the following example that the invention is not restricted to concrete narration.
Embodiment 1:6-(4-methoxy-benzyl)-3-(4-hydroxy phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
With aubepine 0.1mol, acetyl glycine 0.12mol, sodium acetate, anhydrous 0.12mol and aceticanhydride 50 grams join in the 100mL three-necked bottle reflux stirring reaction 5 hours successively, after being chilled to room temperature, solution becomes solid, suction filtration, filter cake cold water washing, use acetone recrystallization, get 2-methyl-4-(4-methoxyl group benzylidene) azolactone yellow crystal powder 21.7 grams, yield 100%, MS m/z (M) 217.
With 2-methyl-4-(4-methoxyl group benzylidene) azolactone 0.1mol, water 100ml, acetone 80ml join in the 100ml round-bottomed flask successively, reflux stirring reaction 3 hours, cool to room temperature, separate out a large amount of yellow solids, suction filtration, filter cake washes with cold water and small amount of acetone, use acetone recrystallization, get β-(4-p-methoxy-phenyl) pyruvic acid yellow crystals 23.5 grams, yield 100%, MS m/z (M) 194.
With β-(4-p-methoxy-phenyl) pyruvic acid 0.01mol, thiosemicarbazide 0.01mol, ethanol 30ml, water 30ml joins in the 250ml round-bottomed flask successively, stirs, and heating reflux reaction is after 8 hours, cool to room temperature, underpressure distillation boils off solvent, obtains a large amount of Off-white solid, suction filtration, ethyl alcohol recrystallization is used in oven dry, obtain 6-(4-methoxy-benzyl)-3-sulfo--(2H, 4H)-1,2,4-triazine-5-ketone white crystal 2.24 grams, yield 90%, MS m/z (M) 249.
In 0 ℃, adding 10 mmole 6-(4-methoxy-benzyl)-3-sulfo-in 15 milliliters of glacial acetic acid solutions of 5 mmole sodium-acetates-(2H, 4H)-1,2,4-triazine-5-ketone and 10 mmoles 4 '-hydroxyl-alpha-chloro acetophenone.Stirring at room 30 minutes slowly is warming up to the back of refluxing and continues reaction 2 hours, TLC monitoring reaction process, and reaction finishes postcooling to room temperature, reaction solution is concentrated into dried, adds the saturated common salt aqueous solution, stirs 30 minutes under the room temperature, and uses ethyl acetate extraction.The organic layer drying obtains thick product with concentrating, and ethyl alcohol recrystallization obtains required product yellow crystals 2.19 grams, yield 60%, MS m/z (M) 365;
1HNMR (DMSO): δ 3.70 (3H, s), 4.00 (2H, s), 6.65 (2H, d, J=8.4Hz), 6.72 (2H, d, J=8.7Hz), 6.95 (2H, d, J=8.4Hz), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 8.00 (1H, s).
Embodiment 2:6-benzyl-3-(4-hydroxy phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 1 method, obtain also [3,2-b]-1,2 of 6-benzyl-3-(4-hydroxy phenyl)-7H-thiazole, 4-triazine-7-ketone yellow crystals 2.01 grams, yield 60%, MS m/z (M) 335;
1HNMR (DMSO): δ 4.00 (2H, s), 6.72 (2H, d, J=8.7Hz), 7.06-7.14 (5H, m), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 8.00 (1H, s).
Embodiment 3:6-(3-methoxy-benzyl)-3-(4-hydroxy phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 1 method, obtain also [3,2-b]-1,2 of 6-(3-methoxy-benzyl)-3-(4-hydroxy phenyl)-7H-thiazole, 4-triazine-7-ketone yellow crystals 2.19 grams, yield 60%, MS m/z (M) 365;
1HNMR (DMSO): δ 3.70 (3H, s), 4.00 (2H, s), 6.57 (1H, s), 6.65 (2H, d, J=8.7Hz), 6.72-6.95 (3H, m), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 8.00 (1H, s).
Embodiment 4:6-(4-methoxy-benzyl)-3-(4-aminomethyl phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 1 method, obtain also [3,2-b]-1,2 of 6-(4-methoxy-benzyl)-3-(4-aminomethyl phenyl)-7H-thiazole, 4-triazine-7-ketone 2.17 grams, yield 60%, MS m/z (M) 363;
1HNMR (DMSO): δ 2.30 (3H, s), 3.70 (3H, s), 4.00 (2H, s), 6.65 (2H, d, J=8.4Hz), 6.72 (2H, d, J=8.7Hz), 6.95 (2H, d, J=8.4Hz), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 8.00 (1H, s).
Embodiment 5:6-(4-methoxy-benzyl)-3-(4-chloro-phenyl-)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 1 method, obtain also [3,2-b]-1,2 of 6-(4-methoxy-benzyl)-3-(4-chloro-phenyl-)-7H-thiazole, 4-triazine-7-ketone 2.29 grams, yield 60%, MS m/z (M) 383;
1HNMR (DMSO): δ 3.70 (3H, s), 4.00 (2H, s), 6.65 (2H, d, J=8.4Hz), 6.95 (2H, d, J=8.4Hz), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 7.29 (2H, d, J=8.7Hz), 8.00 (1H, s).
Embodiment 6:6-(4-methoxy-benzyl)-3-(4-bromophenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 1 method, obtain also [3,2-b]-1,2 of 6-(4-methoxy-benzyl)-3-(4-bromophenyl)-7H-thiazole, 4-triazine-7-ketone 2.56 grams, yield 60%, MS m/z (M) 427;
1HNMR (DMSO): δ 3.70 (3H, s), 4.00 (2H, s), 6.65 (2H, d, J=8.4Hz), 6.95 (2H, d, J=8.4Hz), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 7.29 (2H, d, J=8.7Hz), 8.00 (1H, s).
Embodiment 7:6-(4-methoxy-benzyl)-3-(3-methyl-4-hydroxy phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 1 method, obtain also [3,2-b]-1,2 of 6-(4-methoxy-benzyl)-3-(3-methyl-4-hydroxy phenyl)-7H-thiazole, 4-triazine-7-ketone 2.27 grams, yield 60%, MS m/z (M) 379;
1HNMR (DMSO): δ 2.30 (3H, s), 3.70 (3H, s), 4.00 (2H, s), 6.65 (2H, d, J=8.7Hz), 6.8 (1H, d), 7.20 (2H, d, J=8.7Hz), 7.24 (1H, d), 7.25 (1H, s), 7.28 (1H, s).
Embodiment 8:6-benzyl-3-(3-methyl-4-hydroxy phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 1 method, obtain also [3,2-b]-1,2 of 6-benzyl-3-(3-methyl-4-hydroxy phenyl)-7H-thiazole, 4-triazine-7-ketone 2.09 grams, yield 60%, MS m/z (M) 349;
1HNMR (DMSO): δ 2.30 (3H, s), 3.70 (3H, s), 4.00 (2H, s), 6.80 (1H, d), 7.06-7.14 (7H, m), 7.28 (1H, s).
Embodiment 9:6-(4-methoxy-benzyl)-3-{4-[2-(piperidino) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
Under the stirring at room condition, to 1 mmole 6-(4-methoxy-benzyl)-3-(4-hydroxy phenyl)-7H-thiazole also [3,2-b]-1,2, add corresponding 1 mmole chloroethyl piperidine hydrochlorate in the acetone or alcohol solution of 4-triazine-7-ketone, and after adding 1 mmole acid binding agent (Anhydrous potassium carbonate or triethylamine) and 0.1 mmole potassium iodide catalyst, back flow reaction, TLC follows the tracks of reaction process, question response finishes postcooling to room temperature, reaction solution is concentrated into dried, adds 30 milliliters of saturated aqueous common salts, extracted with diethyl ether.The organic layer drying obtains thick product with concentrating, and ethyl alcohol recrystallization obtains required product 0.24 gram, yield 50%.MS?m/z(M)476.19；
1HNMR(CDCl
3)：δ?1.50(6H，m)，2.24(4H，m)，2.78(2H，t)，3.73(3H，s)，3.80(2H，s)，4.04(2H，t)，6.60(1H，s)，6.65(2H，d，J＝8.4Hz)，6.72(2H，d，J＝8.7Hz)，6.95(2H，d，J＝8.4Hz)，7.20(2H，d，J＝8.7Hz)。
Embodiment 10:6-(4-methoxy-benzyl)-3-{4-[2-(N, N dimethylamine base) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-(4-methoxy-benzyl)-3-{4-[2-(N, N dimethylamine base) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.23 gram, yield 50%.MS?m/z(M)464.19；
1HNMR(CDCl
3)：δ?1.20(6H，t)，2.40(4H，q)，2.78(2H，t)，3.73(3H，s)，4.00(2H，s)，4.04(2H，t)，6.60(1H，s)，6.65(2H，d，J＝8.4Hz)，6.72(2H，d，J＝8.7Hz)，6.95(2H，d，J＝8.4Hz)，7.20(2H，d，J＝8.7Hz)。
Embodiment 11:6-benzyl-3-[4-(2-amino ethoxy) phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-benzyl-3-[4-(2-amino ethoxy) phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone.
Embodiment 12:6-benzyl-3-{4-[2-(piperidino) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone compounds
According to embodiment 9 methods, obtain 6-benzyl-3-{4-[2-(piperidino) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.22 gram, yield 49%.MS?m/z(M)446.18；
1HNMR(CDCl
3)：δ?1.50(6H，m)，2.24(4H，m)，2.78(2H，t)，3.80(2H，s)，4.04(2H，t)，6.60(1H，s)，6.72(2H，d，J＝8.7Hz)，7.06-7.14(5H，m)，7.20(2H，d，J＝8.7Hz)。
Embodiment 13:6-benzyl-3-{4-[2-(N, N dimethylamine base) oxyethyl group) phenyl }-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-benzyl-3-{4-[2-(N, N dimethylamine base) oxyethyl group) phenyl }-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.22 gram, yield 51%.MS?m/z(M)434.18；
1HNMR(CDCl
3)：δ?1.20(6H，t)，2.40(4H，q)，2.78(2H，t)，4.00(2H，s)，4.04(2H，t)，6.60(1H，s)，6.72(2H，d，J＝8.7Hz)，7.06-7.14(5H，m)，7.20(2H，d，J＝8.7Hz)。
Embodiment 14:6-benzyl-3-[3-methyl-4-(2-amino ethoxy) phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-benzyl-3-[3-methyl-4-(2-amino ethoxy) phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone.
Embodiment 15:6-benzyl-3-{3-methyl-4-[2-(piperidino) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-benzyl-3-{3-methyl-4-[2-(piperidino) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.23 gram, yield 50%.MS?m/z(M)460.18；
1HNMR(CDCl
3)：δ?1.50(6H，m)，2.24(4H，m)，2.30(3H，s)，2.78(2H，t)，3.80(2H，s)，4.04(2H，t)，6.60(1H，s)，6.80(1H，d)，7.06-7.14(7H，m)。
Embodiment 16:6-benzyl-3-{3-methyl-4-[2-(N, N dimethylamine base) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-benzyl-3-{3-methyl-4-[2-(N, N dimethylamine base) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.23 gram, yield 51%.MS?m/z(M)448.18；
1HNMR(CDCl
3)：δ?1.20(6H，t)，2.30(3H，s)，2.40(4H，q)，2.78(2H，t)，4.00(2H，s)，4.04(2H，t)，6.60(1H，s)，6.80(1H，d)，7.06-7.14(7H，m)。
Embodiment 17:6-benzyl-3-[4-(carbamyl methoxyl group) phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-benzyl-3-[4-(carbamyl methoxyl group) phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone.
Embodiment 18:6-benzyl-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-benzyl-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.22 gram, yield 49%.MS?m/z(M)448.16；
1HNMR(CDCl
3)：δ?1.20(6H，t)，3.42(4H，q)，4.00(2H，s)，4.83(2H，s)，6.60(1H，s)，6.72(2H，d，J＝8.7Hz)，7.06-7.14(5H，m)，7.20(2H，d，J＝8.7Hz)。
Embodiment 19:6-benzyl-3-[4-(piperidino) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-benzyl-3-[4-(piperidino) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.23 gram, yield 50%.MS?m/z(M)460.12；
1HNMR(CDCl
3)：δ?1.50(6H，m)，2.24(4H，m)，4.00(2H，s)，4.83(2H，s)，6.60(1H，s)，6.72(2H，d，J＝8.7Hz)，7.06-7.14(5H，m)，7.20(2H，d，J＝8.7Hz)。
Embodiment 20:6-(4-methoxy-benzyl)-3-[4-(carbamyl methoxyl group) phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-(4-methoxy-benzyl)-3-[4-(carbamyl methoxyl group) phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone.
Embodiment 21:6-(4-methoxy-benzyl)-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-(4-methoxy-benzyl)-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.24 gram, yield 50%.MS?m/z(M)478.17；
1HNMR(CDCl
3)：δ?1.20(6H，t)，3.42(4H，q)，3.73(3H，s)，4.00(2H，s)，4.83(2H，s)，6.60(1H，s)，6.65(2H，d，J＝8.4Hz)，6.72(2H，d，J＝8.7Hz)，6.95(2H，d，J＝8.4Hz)，7.20(2H，d，J＝8.7Hz)。
Embodiment 22:6-(4-methoxy-benzyl)-3-[4-(piperidino) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-(4-methoxy-benzyl)-3-[4-(piperidino) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.23 gram, yield 47%.MS?m/z(M)490.17；
1HNMR(CDCl
3)：δ?1.50(6H，m)，2.24(4H，m)，3.73(3H，s)，4.00(2H，s)，4.83(2H，s)，6.60(1H，s)，6.65(2H，d，J＝8.4Hz)，6.72(2H，d，J＝8.7Hz)，6.95(2H，d，J＝8.4Hz)，7.20(2H，d，J＝8.7Hz)。
Embodiment 23:6-(4-methoxy-benzyl)-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 9 methods, obtain 6-(4-methoxy-benzyl)-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 0.22g, yield 59%.MS?m/z(M)450.14；
1HNMR(CDCl
3)：δ?2.90(6H，s)，3.73(3H，s)，4.00(2H，s)，4.83(2H，s)，6.60(1H，s)，6.65(2H，d，J＝8.7Hz)，6.72(2H，d，J＝8.7Hz)，6.95(2H，d，J＝8.7Hz)，7.20(2H，d，J＝8.7Hz)。
Embodiment 24:6-phenyl-3-(4-hydroxy phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
With vinylbenzene 0.2mol, sodium hydroxide 0.4mol, water 80mL joins in the 1000mL round-bottomed flask, be heated to 70 ℃, potassium permanganate 0.5mol was added within half an hour in batches, with ethanol 50mL unreacted potassium permanganate is destroyed again behind the reaction 10min, reaction solution is carried out suction filtration, keep filtrate, most of water is removed in underpressure distillation, with concentrated hydrochloric acid spissated filtrate is carried out acidifying, use dichloromethane extraction again, remove and desolvate, cooling obtains faint yellow solid, obtain benzoylformic acid white crystalline powder 30 grams, yield 100%, MS m/z (M) 150.2 with ethyl alcohol recrystallization again.
With benzoylformic acid 0.01mol, thiosemicarbazide 0.01mol, ethanol 40ml, water 40ml joins in the 250ml round-bottomed flask successively, stirs, and heating reflux reaction is after 12 hours, cool to room temperature, underpressure distillation boils off solvent, obtains a large amount of Off-white solid, suction filtration, ethyl alcohol recrystallization is used in oven dry, obtain 6-phenyl-3-sulfo--(2H, 4H)-1,2,4-triazine-5-ketone white crystal 2.01 grams, yield 98%, MS m/z (M) 205.
In 0 ℃, adding 10 mmole 6-phenyl-3-sulfo-s in 15 milliliters of glacial acetic acid solutions of 5 mmole sodium-acetates-(2H, 4H)-1,2,4-triazine-5-ketone and 10 mmoles 4 '-hydroxyl-alpha-chloro acetophenone.Stirring at room 30 minutes slowly is warming up to the back of refluxing and continues reaction 2 hours, TLC monitoring reaction process, and reaction finishes postcooling to room temperature, reaction solution is concentrated into dried, adds the saturated common salt aqueous solution, stirs 30 minutes under the room temperature, and uses ethyl acetate extraction.The organic layer drying obtains thick product with concentrating, and ethyl alcohol recrystallization obtains required product yellow crystals 2.24 grams, yield 70%, MS m/z (M) 321;
1HNMR (CDCl
3): δ 4.00 (2H, s), 6.72 (2H, d, J=8.7Hz), 7.06-7.14 (5H, m), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 9.95 (1H, s).
Embodiment 25:6-(4-chloro-phenyl-)-3-(4-hydroxy phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-chloro-phenyl-)-3-(4-hydroxy phenyl)-7H-thiazole, 4-triazine-7-ketone 2.24 grams, yield 70%, MS m/z (M) 321;
1HNMR (CDCl
3): δ 6.72 (2H, d, J=8.7Hz), 7.06-7.14 (7H, m), 9.90 (1H, s).
Embodiment 26:6-(4-p-methoxy-phenyl)-3-(4-bromophenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-p-methoxy-phenyl)-3-(4-bromophenyl)-7H-thiazole, 4-triazine-7-ketone 2.56 grams, yield 60%, MS m/z (M) 427;
1HNMR (DMSO): δ 3.70 (3H, s), 4.00 (2H, s), 6.65 (2H, d, J=8.4Hz), 6.95 (2H, d, J=8.4Hz), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 7.29 (2H, d, J=8.7Hz), 8.00 (1H, s).
Embodiment 27:6-phenyl-3-(4-aminomethyl phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-phenyl-3-(4-aminomethyl phenyl)-7H-thiazole, 4-triazine-7-ketone 2.41g, yield 75%, MS m/z (M) 320.39;
1HNMR (CDCl
3): δ 2.46 (3H, s), 6.84 (1H, d, J=8.7Hz), 7.27-7.76 (7H, m), 8.21-8.24 (2H, s).
Embodiment 28:6-(4-chloro-phenyl-)-3-(4-aminomethyl phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-chloro-phenyl-)-3-(4-aminomethyl phenyl)-7H-thiazole, 4-triazine-7-ketone 2.68g, yield 76%, MS m/z (M) 353.83;
1HNMR (CDCl
3): δ 2.56 (3H, s), 6.94 (1H, d, J=8.7Hz), 7.27-7.76 (7H, m), 8.21-8.24 (1H, s).
Embodiment 29:6-phenyl-3-(4-chloro-phenyl-)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-phenyl-3-(4-chloro-phenyl-)-7H-thiazole, 4-triazine-7-ketone 2.62g, yield 77%, MS m/z (M) 340.81;
1HNMR (CDCl
3): δ 6.72 (1H, s, J=8.7Hz), 7.20-7.53 (5H, m), 7.67 (2H, d, J=8.7Hz), 8.19-8.21 (2H, s).
Embodiment 30:6-(4-chloro-phenyl-)-3-(4-chloro-phenyl-)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-chloro-phenyl-)-3-(4-chloro-phenyl-)-7H-thiazole, 4-triazine-7-ketone 2.99g, yield 80%, MS m/z (M) 374.24;
1HNMR (CDCl
3): δ 6.82 (1H, s, J=8.7Hz), 7.25-7.59 (5H, m), 7.77 (2H, d, J=8.7Hz), 8.19 (1H, s).
Embodiment 31:6-phenyl-3-(4-tert-butyl-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-phenyl-3-(4-tert-butyl-phenyl)-7H-thiazole, 4-triazine-7-ketone 2.67g, yield 74%, MS m/z (M) 361.46;
1HNMR (CDCl
3): δ 1.58 (9H, s), 6.84 (1H, s, J=8.7Hz), 7.26-7.66 (7H, m), 8.21 (2H, m).
Embodiment 32:6-(4-chloro-phenyl-)-3-(4-tert-butyl-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-chloro-phenyl-)-3-(4-tert-butyl-phenyl)-7H-thiazole, 4-triazine-7-ketone 3.01g, yield 76%, MS m/z (M) 395.91;
1HNMR (CDCl
3): δ 1.68 (9H, s), 6.94 (1H, s, J=8.7Hz), 7.20-7.76 (7H, m), 8.21 (1H, s).
Embodiment 33:6-phenyl-3-(3-methyl-4-p-methoxy-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-phenyl-3-(3-methyl-4-p-methoxy-phenyl)-7H-thiazole, 4-triazine-7-ketone 2.44g, yield 70%, MS m/z (M) 349.41;
1HNMR (CDCl
3): δ 2.29 (3H, s), 3.91 (3H, s), 6.84 (1H, s, J=8.7Hz), 7.26-7.66 (6H, m), 8.21 (2H, m).
Embodiment 34:6-(4-chloro-phenyl-)-3-(3-methyl-4-p-methoxy-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-chloro-phenyl-)-3-(3-methyl-4-p-methoxy-phenyl)-7H-thiazole, 4-triazine-7-ketone 2.91g, yield 76%, MS m/z (M) 383.85;
1HNMR (CDCl
3): δ 2.39 (3H, s), 3.99 (3H, s), 6.89 (1H, s, J=8.7Hz), 7.36-7.86 (6H, m), 8.21 (1H, s).
Embodiment 35:6-phenyl-3-(2-methyl-4-p-methoxy-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-phenyl-3-(2-methyl-4-p-methoxy-phenyl)-7H-thiazole, 4-triazine-7-ketone 2.44g, yield 70%, MS m/z (M) 349.41;
1HNMR (CDCl
3): δ 2.24 (3H, s), 3.88 (3H, s), 6.74 (1H, s, J=8.7Hz), 7.16-7.66 (6H, m), 8.23 (2H, m).
Embodiment 36:6-(4-chloro-phenyl-)-3-(2-methyl-4-p-methoxy-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-chloro-phenyl-)-3-(2-methyl-4-p-methoxy-phenyl)-7H-thiazole, 4-triazine-7-ketone 3.07g, yield 80%, MS m/z (M) 383.85;
1HNMR (CDCl
3): δ 2.20 (3H, s), 3.98 (3H, s), 6.84 (1H, s, J=8.7Hz), 7.26-7.86 (6H, m), 8.23 (1H, s).
Embodiment 37:6-phenyl-3-(2-hydroxyl-4-p-methoxy-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-phenyl-3-(2-hydroxyl-4-p-methoxy-phenyl)-7H-thiazole, 4-triazine-7-ketone 2.68g, yield 80%, MS m/z (M) 335.38;
1HNMR (CDCl
3): δ 3.94 (3H, s), 6.74 (1H, s, J=8.7Hz), 7.16-7.66 (6H, m), 8.23 (2H, m), 9.95 (1H, s).
Embodiment 38:6-(4-chloro-phenyl-)-3-(2-hydroxyl-4-p-methoxy-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-chloro-phenyl-)-3-(2-hydroxyl-4-p-methoxy-phenyl)-7H-thiazole, 4-triazine-7-ketone 2.88g, yield 75%, MS m/z (M) 384.85;
1HNMR (CDCl
3): δ 4.01 (3H, s), 6.84 (1H, s, J=8.7Hz), 7.26-7.86 (6H, m), 8.23 (1H, s), 9.95 (1H, s).
Embodiment 39:6-phenyl-3-(2, the 4-3,5-dimethylphenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-phenyl-3-(2, the 4-3,5-dimethylphenyl)-7H-thiazole, 4-triazine-7-ketone 2.50g, yield 75%, MS m/z (M) 333.41;
1HNMR (CDCl
3): δ 2.21 (3H, s), 2.31 (3H, s), 6.84 (1H, s, J=8.7Hz), 7.26-7.86 (6H, m), 8.23 (2H, s).
Embodiment 40:6-(4-chloro-phenyl-)-3-(2, the 4-3,5-dimethylphenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-chloro-phenyl-)-3-(2, the 4-3,5-dimethylphenyl)-7H-thiazole, 4-triazine-7-ketone 2.50g, yield 75%, MS m/z (M) 367.85;
1HNMR (CDCl
3): δ 2.31 (3H, s), 2.51 (3H, s), 6.89 (1H, s, J=8.7Hz), 7.36-7.86 (6H, m), 8.83 (1H, s).
Embodiment 41:6-phenyl-3-(4-p-methoxy-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-phenyl-3-(4-p-methoxy-phenyl)-7H-thiazole, 4-triazine-7-ketone 2.68g, yield 80%, MS m/z (M) 335.38;
1HNMR (CDCl
3): δ 3.94 (3H, s), 6.74 (1H, s, J=8.7Hz), 7.16-7.66 (7H, m), 8.23 (2H, m).
Embodiment 42:6-(4-chloro-phenyl-)-3-(4-p-methoxy-phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-chloro-phenyl-)-3-(4-p-methoxy-phenyl)-7H-thiazole, 4-triazine-7-ketone 3.03g, yield 82%, MS m/z (M) 369.83;
1HNMR (CDCl
3): δ 3.99 (3H, s), 6.74 (1H, s, J=8.7Hz), 7.26-7.86 (7H, m), 8.43 (1H, s).
Embodiment 43:6-(4-ethoxyl phenenyl)-3-phenyl-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-ethoxyl phenenyl)-3-phenyl-7H-thiazole, 4-triazine-7-ketone 2.79g, yield 80%, MS m/z (M) 349.15;
1HNMR (CDCl
3): δ 2.44 (3H, t), 3.94 (2H, s), 6.84 (1H, s, J=8.7Hz), 7.16-7.66 (7H, m), 8.23 (2H, m).
Embodiment 44:6-(4-p-methoxy-phenyl)-3-phenyl-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-p-methoxy-phenyl)-3-phenyl-7H-thiazole, 4-triazine-7-ketone 2.68g, yield 80%, MS m/z (M) 335.38;
1HNMR (CDCl
3): δ 4.04 (3H, s), 6.74 (1H, s, J=8.7Hz), 7.16-7.66 (7H, m), 8.23 (2H, m).
Embodiment 45:6-(4-hydroxy phenyl)-3-phenyl-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-hydroxy phenyl)-3-phenyl-7H-thiazole, 4-triazine-7-ketone 2.57g, yield 80%, MS m/z (M) 321.35;
1HNMR (CDCl
3): δ 6.72 (2H, d, J=8.7Hz), 7.06-7.14 (5H, m), 7.20 (2H, d, J=8.7Hz), 7.28 (2H, m), 9.95 (1H, s).
Embodiment 46:6-(4-aminomethyl phenyl)-3-phenyl-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 24 methods, obtain also [3,2-b]-1,2 of 6-(4-aminomethyl phenyl)-3-phenyl-7H-thiazole, 4-triazine-7-ketone 2.41g, yield 75%, MS m/z (M) 320.39;
1HNMR (CDCl
3): δ 2.46 (3H, s), 6.84 (1H, d, J=8.7Hz), 7.27-7.76 (7H, m), 8.21-8.24 (2H, s).
Embodiment 47:6-phenyl-3-[4-(piperidino) ethoxyl phenenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 9 methods, obtain 6-phenyl-3-[4-(piperidino) ethoxyl phenenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 3.24g, yield 75%, MS m/z (M) 432.99;
1HNMR (CDCl
3): δ 1.50 (6H, t), 2.24 (4H, t), 2.64 (2H, t), 4.06 (4H, t), 6.94 (1H, d, J=8.7Hz), 7.07-7.76 (7H, m), 8.21-8.24 (2H, s).
Embodiment 48:6-(4-chloro-phenyl-)-3-[4-(piperidino) ethoxyl phenenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 9 methods, obtain 6-(4-chloro-phenyl-)-3-[4-(piperidino) ethoxyl phenenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 3.74g, yield 80%, MS m/z (M) 466.99;
1HNMR (CDCl
3): δ 1.56 (6H, t), 2.25 (4H, t), 2.74 (2H, t), 4.16 (4H, t), 6.99 (1H, d, J=8.7Hz), 7.17-7.96 (6H, m), 8.21-8.24 (2H, s).
Embodiment 49:6-phenyl-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 9 methods, obtain 6-phenyl-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 3.47g, yield 80%, MS m/z (M) 434.41;
1HNMR (CDCl
3): δ 1.20 (6H, t), 3.24 (4H, q), 4.82 (2H, s), 6.89 (1H, d, J=8.7Hz), 7.07-7.86 (6H, m), 8.21-8.24 (2H, s).
Embodiment 50:6-(4-chloro-phenyl-)-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 9 methods, obtain 6-(4-chloro-phenyl-)-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 3.84g, yield 82%, MS m/z (M) 468.96;
1HNMR (CDCl
3): δ 1.22 (6H, t), 3.25 (4H, q), 4.84 (2H, s), 6.99 (1H, d, J=8.7Hz), 7.27-7.89 (6H, m), 8.21-8.24 (1H, s).
Embodiment 51:6-phenyl-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 9 methods, obtain 6-phenyl-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 3.04g, yield 75%, MS m/z (M) 406.4;
1HNMR (CDCl
3): δ 2.90 (6H, s), 4.84 (2H, s), 6.99 (1H, d, J=8.7Hz), 7.27-7.89 (7H, m), 8.21-8.24 (2H, s).
Embodiment 52:6-(4-chloro-phenyl-)-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 9 methods, obtain 6-(4-chloro-phenyl-)-3-[4-(N, N dimethylamine base) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 3.30g, yield 75%, MS m/z (M) 440.9;
1HNMR (CDCl
3): δ 2.93 (6H, s), 4.82 (2H, s), 6.80 (1H, d, J=8.7Hz), 7.07-7.89 (6H, m), 8.22-8.24 (2H, s).
Embodiment 53:6-phenyl-3-[4-(N, N-morpholinyl) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 9 methods, obtain 6-phenyl-3-[4-(N, N-morpholinyl) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 3.58g, yield 80%, MS m/z (M) 448.44;
1HNMR (CDCl
3): δ 3.61 (4H, t), 3.47 (4H, t),, 4.82 (4H, s), 6.99 (1H, d, J=8.7Hz), 7.17-7.96 (7H, m), 8.21-8.24 (2H, s).
Embodiment 54:6-(4-chloro-phenyl-)-3-[4-(N, N-morpholinyl) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone.
According to embodiment 9 methods, obtain 6-(4-chloro-phenyl-)-3-[4-(N, N-morpholinyl) formyl p-methoxy-phenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone 3.86g, yield 80%, MS m/z (M) 482.94;
1HNMR (CDCl
3): δ 3.61 (4H, t), 3.47 (4H, t),, 4.82 (4H, s), 6.99 (1H, d, J=8.7Hz), 7.17-7.96 (6H, m), 8.21-8.24 (2H, s).
Example of formulations
Pharmaceutical composition
In following preparation, " activeconstituents " is meant formula I compound, or its salt or solvate.
Example of formulations 1: tablet formulation
Project ingredient m g/ sheet
1 activeconstituents 5 25 100 250 500 750
2 lactose hydrouses 103 83 35 19 38 57
3 croscarmellose sodiums 668 16 32 48
4 PovidoneK30 5 5 6 12 24 36
5 Magnesium Stearates 111369
Gross weight 120 120 150 300 600 900
Production technique: mix project 1,2 and 3 15 minutes in suitable mixing tank (1).(2) powdered mixture of step 1 is granulated with 20%PovidoneK30 solution.(3) at the particle of 50 ℃ of drying step 2.(4) particle with step 3 passes through suitable whole grain device.(5) project 5 is added in the particle of the step 4 after grinding, and mixed 3 minutes.(6) with particle compressing tablet on suitable tabletting machine of step 5.
Example of formulations 2: capsule formula
Project ingredient m g/ capsule
1 activeconstituents 5 25 100 250 500
2 lactose hydrouses 159 123 148
3 W-Gums 25 35 40 35 70
4 talcums 10 15 10 12 24
5 Magnesium Stearates 12236
Gross weight 200 200 300 300 600
Production technique: mix project 1,2 and 3 15 minutes in suitable mixing tank (1).
(2) adding project 4 and 5 and mixed 3 minutes.(3) be filled in the capsule.
Example of formulations 3: injection liquid/emulsion
Project ingredient m g/ml
1 activeconstituents 1mg
2 PGE400 10-50mg
3 phosphatidase 12 0-50mg
4 soya-bean oil 1-5mg
5 glycerine 8-12mg
6 water add to 1ml
Production technique: (1) is dissolved in project 1 in the project 2.(2) with project 3,4 and 5 adding projects 6 and be mixed to dispersion, homogenizing then.(3) solution with step 1 adds in the mixture of step 2, and homogenizing is transparent to dispersion liquid.(4) aseptic filtration 0.2 μ m filter paper and being filled in the bottle.Example of formulations 4: injection liquid/emulsion
Project ingredient m g/ml
1 activeconstituents 1mg
2 Glycofurol 10-50mg
3 phosphatidase 12 0-50mg
4 soya-bean oil 1-5mg
5 glycerine 8-12mg
6 water add to 1ml
Production technique: (1) is dissolved in project 1 in the project 2.(2) with project 3,4 and 5 adding projects 6 and be mixed to dispersion, homogenizing then.(3) solution with step 1 adds in the mixture of step 2, and homogenizing is transparent to dispersion liquid.(4) aseptic filtration 0.2 μ m filter paper and being filled in the bottle.
Embodiment 5: the prescription prescription that contains liposome
A. the preparation of instiling and filling a prescription
In a Glass tubing, mix synthetic two palmitoyl Yelkin TTS (45mg), two myristoyl Yelkin TTS (7mg), DPPG (1mg) and active compound (5mg) are dissolved in all components in the chloroform, use N
2Evaporate most of solvent, decompression then thus, forms lipid membrane on the Glass tubing surface.Add the aqueous solution (0.9%NaCl) in this lipid, form liposome being higher than under the phase inversion temperature of lipid, the gained suspension contains the liposome that magnitude range is minimum vesica to 2 μ m.
B. suck preparation with prescription
Prepare liposome by embodiment A, the aqueous solution wherein contains 10% lactose, and lactose is 7:3 with the ratio of lipid.This liposome suspension is freezing with dry ice, and carry out lyophilize, with the desciccate micronization, the equal aerodynamic diameter of gained particulate matter (MMAD) is about 2 μ m.
Claims (9)
1. the compound of a formula I, its prodrug and pharmaceutical activity metabolite, and the acceptable salt of above-claimed cpd:
Wherein
R
1Can selectively be independently selected from H, halogen ,-OH ,-OCH arbitrarily by 1,2 or 3
3,-CH
3,-NO
2,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6
R
2Can selectively be independently selected from H, halogen ,-OH ,-OCH arbitrarily by 1,2 or 3
3,-CH
3,-NO
2,-O (CH2) n
3NR
3R
4,-O (CH2) n
4CONR
5R
6
n
1And n
2Be 0 to 1 integer:
R wherein
3R
4Independently be selected from methyl or ethyl, or R
3R
4Form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring with the nitrogen-atoms that they link to each other;
n
3It is 2 to 4 integer;
R
5R
6Independently be selected from methyl or ethyl, or R
5R
6Form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring with the nitrogen-atoms that they link to each other; Or independently be selected from hydrogen and replacement or unsubstituted phenyl ring group respectively;
n
4It is 1 to 3 integer.
2, compound according to claim 1 is characterized in that: this compound is preferred:
R
1, R
2With claim 1.
3. a pharmaceutical composition comprises as any one compound in the claim 1 of activeconstituents and medicine acceptable carrier or excipient.
4. compound according to claim 1 is characterized in that: R wherein
1Preferred 3-methyl-4-[(1-piperidines) formyl methoxyl group].
5. compound according to claim 1 is characterized in that: R wherein
1Preferred 3-methyl-4-[2-(1-piperidines) oxyethyl group].
6. compound according to claim 1 is characterized in that: R wherein
1Preferred 3-methyl-4-[(N, the N dimethylamine base) the formyl methoxyl group].
7. compound according to claim 1 is characterized in that: R wherein
1Preferred chlorine.
8. compound according to claim 1 is characterized in that: R wherein
2Preferred hydroxyl.
9. any one compound and composition thereof the application in preparation treatment degenerative dementia disease drug among the claim 1-7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910010552 CN101503414B (en) | 2009-03-04 | 2009-03-04 | Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910010552 CN101503414B (en) | 2009-03-04 | 2009-03-04 | Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101503414A true CN101503414A (en) | 2009-08-12 |
| CN101503414B CN101503414B (en) | 2013-10-30 |
Family
ID=40975806
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910010552 Expired - Fee Related CN101503414B (en) | 2009-03-04 | 2009-03-04 | Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101503414B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102807575A (en) * | 2012-08-09 | 2012-12-05 | 石家庄学院 | 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative and application thereof |
| CN103012439A (en) * | 2012-11-15 | 2013-04-03 | 沈阳药科大学 | Benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and application thereof |
| CN103012438A (en) * | 2012-11-15 | 2013-04-03 | 沈阳药科大学 | Alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives and application thereof |
| CN104788473A (en) * | 2015-03-25 | 2015-07-22 | 石家庄学院 | Antibacterial compound as well as preparation method and application thereof |
| CN104926838A (en) * | 2015-05-31 | 2015-09-23 | 石家庄学院 | 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative and application |
| CN105949220A (en) * | 2016-05-10 | 2016-09-21 | 沈阳药科大学 | Thiazole[3,2-b]-1,2,4-thiazole derivatives and application thereof |
| CN110003244A (en) * | 2019-04-23 | 2019-07-12 | 沈阳药科大学 | Thiazole triazin compound and its application containing trifluoromethyl benzyl |
| CN112047962A (en) * | 2020-10-18 | 2020-12-08 | 石家庄学院 | 2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivative and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5574046A (en) * | 1991-10-03 | 1996-11-12 | Pfizer Inc. | Heteroaryl amines as novel acetylcholinesterase inhibitors |
| EP0891978A2 (en) * | 1997-07-18 | 1999-01-20 | F. Hoffmann-La Roche Ag | 5H-Thiazolo (3,2-a) pyrimidine derivatives |
| CN101220043A (en) * | 2008-01-24 | 2008-07-16 | 沈阳药科大学 | Benzothiazolo [3, 2,-a]-miazine derivant and uses thereof |
-
2009
- 2009-03-04 CN CN 200910010552 patent/CN101503414B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5574046A (en) * | 1991-10-03 | 1996-11-12 | Pfizer Inc. | Heteroaryl amines as novel acetylcholinesterase inhibitors |
| EP0891978A2 (en) * | 1997-07-18 | 1999-01-20 | F. Hoffmann-La Roche Ag | 5H-Thiazolo (3,2-a) pyrimidine derivatives |
| CN101220043A (en) * | 2008-01-24 | 2008-07-16 | 沈阳药科大学 | Benzothiazolo [3, 2,-a]-miazine derivant and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| HUI ZHI等: "design,synthesis, and biological evaluation of 5H-thiazolo[3,2-a]pyrimidine derivatives as a new type of acetylcholinesterase inhibitors]", 《ARKIVOC》 * |
| 胡春等: "7H-噻唑[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及其生物活性研究", 《中国化工学会精细化工专业委员会全国第93次学术会议》 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102807575B (en) * | 2012-08-09 | 2015-03-25 | 石家庄学院 | 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative and application thereof |
| CN102807575A (en) * | 2012-08-09 | 2012-12-05 | 石家庄学院 | 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative and application thereof |
| CN103012438B (en) * | 2012-11-15 | 2015-10-14 | 沈阳药科大学 | The thiazole that alkoxyl group replaces is [3,2-b]-1,2,4-pyrrolotriazine derivatives and application thereof also |
| CN103012439A (en) * | 2012-11-15 | 2013-04-03 | 沈阳药科大学 | Benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and application thereof |
| CN103012438A (en) * | 2012-11-15 | 2013-04-03 | 沈阳药科大学 | Alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives and application thereof |
| CN103012439B (en) * | 2012-11-15 | 2015-03-11 | 沈阳药科大学 | Benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and application thereof |
| CN104788473A (en) * | 2015-03-25 | 2015-07-22 | 石家庄学院 | Antibacterial compound as well as preparation method and application thereof |
| CN104926838A (en) * | 2015-05-31 | 2015-09-23 | 石家庄学院 | 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative and application |
| CN104926838B (en) * | 2015-05-31 | 2017-04-12 | 石家庄学院 | 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative and application |
| CN105949220A (en) * | 2016-05-10 | 2016-09-21 | 沈阳药科大学 | Thiazole[3,2-b]-1,2,4-thiazole derivatives and application thereof |
| CN105949220B (en) * | 2016-05-10 | 2018-05-25 | 沈阳药科大学 | Thiazole simultaneously [3,2-b] -1,2,4- pyrrolotriazine derivatives and its application |
| CN110003244A (en) * | 2019-04-23 | 2019-07-12 | 沈阳药科大学 | Thiazole triazin compound and its application containing trifluoromethyl benzyl |
| CN112047962A (en) * | 2020-10-18 | 2020-12-08 | 石家庄学院 | 2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivative and application thereof |
| CN112047962B (en) * | 2020-10-18 | 2022-04-29 | 石家庄学院 | 2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivative and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101503414B (en) | 2013-10-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101503414B (en) | Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof | |
| ES2239395T3 (en) | NEW PROCEDURE FOR MANUFACTURING SOLID DISPERSIONS OF PAROXETINE. | |
| EP2582697B1 (en) | Nanostructured aprepitant compositions, process for the preparation thereof and pharmaceutical compositions containing them | |
| US20200078295A1 (en) | Low Dose Doxepin Formulations, Including Buccal, Sublingual And Fastmelt Formulations, And Uses Of The Same To Treat Insomnia | |
| TWI387465B (en) | Drug formulations having improved pharmacokinetic properties | |
| CN101456872B (en) | Thiazole[3,2-alpha] miazine derivates and use thereof | |
| TW201204413A (en) | Controlled release sterile injectable aripiprazole formulation and method | |
| EP1104297B1 (en) | Compositions for the treatment of chronic lymphocytic leukemia | |
| MX2007009812A (en) | Orally bioavailable cci-779 tablet formulations. | |
| CN101835472A (en) | Methods of administering N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea to treat proliferative disease | |
| JP2018035162A (en) | Methods for treatment of diseases | |
| CN105168218A (en) | Therapeutic Agent For Spinal Canal Stenosis | |
| EP2000139A1 (en) | Stabilized amorphous forms of imatinib mesylate | |
| CN102459177B (en) | The dibasic Arylsulfonamide ccr 3 antagonists of 2,5- | |
| US20100324018A1 (en) | Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs | |
| AU2010208270B2 (en) | Solid oral formulations of a pyridopyrimidinone | |
| CN103012438B (en) | The thiazole that alkoxyl group replaces is [3,2-b]-1,2,4-pyrrolotriazine derivatives and application thereof also | |
| CN1950346A (en) | N-desmethylclozapine crystalline forms | |
| CN109431966A (en) | Edaravone pharmaceutical composition | |
| CN102892754A (en) | Arylsulfonamide ccr3 antagonists | |
| RU2238726C2 (en) | Employment of saredutant and pharmaceutically acceptable salts thereof for preparing therapeutic products useful in treatment and prevention of extensive depressive disorders | |
| CN103298786A (en) | Salts of arylsulfonamide ccr3 antagonists | |
| US20050147629A1 (en) | Pharmaceutical formulation comprising non-peptide renin inhibitor and surfactant | |
| JPH01128924A (en) | Preparation composition of piperidinoalkanol derivative | |
| CN102796121B (en) | 3-aryl-7H-thiazol[3,2-b]-1,2,4-triazinyl-7-one derivatives and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20131030 Termination date: 20180304 |