CN103012438A - Alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives and application thereof - Google Patents
Alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives and application thereof Download PDFInfo
- Publication number
- CN103012438A CN103012438A CN2012104592786A CN201210459278A CN103012438A CN 103012438 A CN103012438 A CN 103012438A CN 2012104592786 A CN2012104592786 A CN 2012104592786A CN 201210459278 A CN201210459278 A CN 201210459278A CN 103012438 A CN103012438 A CN 103012438A
- Authority
- CN
- China
- Prior art keywords
- triazine
- ketone
- thiazole
- phenyl
- methoxyl group
- 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 medicines and relates to alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives and application thereof. The alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives include alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives, stereisomers of the derivatives, and pharmaceutically applicable salts of the derivatives, and have a structural general formula shown in the specification. The alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives and salts prepared by addition of pharmaceutically applicable acid of the derivatives can be mixed with the existing medicine or are singly used as an acetylcholin esterase inhibitor, and are used for enhancing memory of a patient suffering from dementia and Alzheimer's disease. Compared with the existing Chinese patient, samples of the alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives are remarkably increased in the inhibition of acetylcholin esterase.
Description
Technical field
The invention belongs to medical technical field, relate to thiazole that alkoxyl group replaces also [3,2-b]-1,2,4-pyrrolotriazine derivatives and application thereof are specifically related to also [3,2-b]-1 of thiazole that alkoxyl group replaces, the steric isomer of 2,4-pyrrolotriazine derivatives and this compounds and the salt and the application thereof that pharmaceutically are suitable for.This compounds is acetylcholinesterase depressant, can be used for improving the memory of suffering from dull-witted and Alzheimer's disease patient.
Background technology
The degeneration of the cholinergic neuron in Alzheimer's disease 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 obvious decay aspect choline acetyltransferase activity, acetylcholine esterase active and the choline absorption.
Therefore known acetylcholinesterase depressant can be used for improving Alzheimer's disease patient's memory being effectively aspect the raising cholinergic activity.Described compound delays the speed of acetylcholine hydrolyzation by acetylcholine esterase inhibition activity, improves in the brain level as neurotransmission mediator vagusstoff, thus hypermnesis.
Existing acetylcholinesterase depressant, such as tacrine, rivastigamine, lycoremines etc. all exist resistance or pharmacokinetics defective.
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 disease 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:
（I）
Wherein
n
1And n
2It is 0 to 1 integer; Be n
1And n
2Be 0 or 1;
R
1Can selectively be independently selected from H, halogen ,-OH ,-OCH by 1,2 or 3 arbitrarily
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-O (CH by 1,2 or 3 arbitrarily
2) n
5CH
3
n
3Be 2 to 4 integer, n
4Be 1 to 3 integer, n
5It is 1 to 5 integer;
Be n
3Be 2,3 or 4, n
4Be 1,2 or 3, n
5Be 1,2,3,4 or 5;
R wherein
3R
4Be independently selected from methyl or ethyl, or R
3R
4The nitrogen-atoms that links to each other with them forms pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring; Or be independently selected from respectively hydrogen, methyl, hydroxyl, methoxyl group, oxyethyl group, nitro, fluorine, chlorine or bromine and replace or unsubstituted phenyl group;
R
5R
6Independently be selected from methyl or ethyl, or R
5R
6The nitrogen-atoms that links to each other with them forms pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring; Or be independently selected from respectively hydrogen, methyl, hydroxyl, methoxyl group, oxyethyl group, nitro, fluorine, chlorine or bromine and replace or unsubstituted phenyl group.
" the acceptable salt of medicine " has referred to keep 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, and 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 alkaline nitrogen-containing group can be quaternized with such reagent, elementary alkyl halide for example, such as methyl, ethyl, the chlorine of propyl group and butyl, bromine and iodide; The sulfuric acid dialkyl, such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide, such as decyl, lauryl, the chlorine of myristyl and stearyl-, bromine and iodide; Aralkyl halide is such as bromide of benzyl and styroyl etc.The acid that is preferred for generating acid salt comprises hydrochloric acid and acetic acid.
" pharmaceutically acceptable " such as pharmaceutically acceptable ground carrier, excipient, prodrug etc., refers to acceptable on the pharmacology 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 formula I compound or its steric isomer or its pharmaceutically applicable acid salt and applicable carrier pharmaceutically.
The invention still further relates to the method that suppresses acetylcholinesterase in the Mammals, the 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 disease, the 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 disease 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 particularly option.
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 mg/kg body weight, 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% (massfraction) so, with 4-70% (massfraction) (take the total mass of unit as the basis) better.Non-dose unit through gastrointestinal administration generally contains the 5 mg-100 mg active compounds 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, and concentration can change, and can be 4-70% (massfraction) (take the total mass of unit as the basis).Oral dosage units generally contains 1.0 mg-300 mg active compounds.
For pharmacology action, formula I compound is preferably with the form administration of its medicinal acid addition salt.Certainly the effective dose of compound will change according to the effectiveness of used each compound, the seriousness that will treat disease and character, the particular patient that will treat.Generally, with the dosage of about 0.01 mg to about 20 mg/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 the 5%-90 % (massfraction) that has an appointment." pharmaceutical carrier " refers to that they are substantially nontoxic and non-teratogenesis for the known pharmaceutical excipients of preparation to animal pharmaceutical active compounds for oral administration 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 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 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 with matrix such as lactose, sucrose and the W-Gum compressing tablet of routine, add tackiness agent such as gum arabic, W-Gum or gelatin; Be used at the disintegrating agent such as yam starch, alginic acid, W-Gum and the guar gum that help disintegration of tablet and dissolving; The flowability that is used for the raising tablet and powder prevents that tablet material from sticking to the lubricant on tablet die and the punch press, such 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 for the raising tablet.The suitable vehicle that is used for oral liquid formulation comprises that water and alcohol such 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; namely subcutaneous; intravenously; intramuscular; or intraperitoneal; injectable dosage formulations administration with the compound in the acceptable thinner of physiology; 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 such as ethanol; Virahol; or cetyl alcohol; glycol such as propylene glycol or polyoxyethylene glycol; glycerol ketals is such as 2,2-dimethyl-l, 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 tensio-active agent 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.The example that can be used for the oil of intestines external preparation of the present invention is that those are from oil, animal, plant or synthetic oil, for example peanut oil, soya-bean oil, sesame oil, Oleum Gossypii semen, Semen Maydis oil, sweet 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, amine salt and triethanolamine salt, and suitable tensio-active agent comprises 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% (massfraction) 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, hydrophilic-lipophile balance value (HLB) that this composition can contain is about 12 to about 17 nonionogenic tenside.The amount of this tensio-active agent is about 5% to about 15% (massfraction) 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 polyhexene 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 simply required compound, 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 carries out with the medicine of storage and porous membranous type or medicine with solid substrate variation.These devices generally contain the backing that limits an one outside surface, one can be through another surperficial viscous layer of restriction 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, then active medicine 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 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.Diffusion occurs when matrix is imporosity to be discharged.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 occurs discharge.
The compounds of this invention can be measured by 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:
The preparation of test sample: positive control drug is set as Hydrogen bromide prostigmin(e) (SigmaN-2001), is formulated as 0.1 M solution.
Acetylcholinesterase (people source) is 0.5 unit (SigmaC-1682).
Buffered soln is 100 mM PBS solution (pH7.4), 10 mM, two sulphur dinitrobenzoic acid DTNB(D-8130) (keep in Dark Place now-making-now-using with 20 ° of C of 100 mM PBS preparation) ， –.
20 ° of C of ， – keep in Dark Place now-making-now-using 12.5 mM acetylthiocholine ATCh (A-5751) is dissolved in the water.
Tested medicine is prepared into 10 μ M solution after dissolving with DMSO.
Method and result
Operation steps:
(1) processes as follows sample.
(2) 37 ° of C are jolting preheating 15 min gently continuously.
(3) add 50 mL ATCh and 50 mL DTNB.
(4) 37 ° of C are about 20 min of jolting gently continuously, until that reaction solution occurs is yellow.
(5) measure the OD value at its 412 nm place.
(6) calculate inhibiting rate.
The sample segment inhibiting rate is listed as follows (n=3):
| The sample name | Inhibiting rate (%) |
| 3-(4-aminomethyl phenyl)-6-(4-ethoxyl phenenyl)-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 86.30 |
| 6-(4-ethoxyl phenenyl)-3-(4-bromophenyl)-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 79.65 |
| 3-(4-p-methoxy-phenyl)-6-(4-ethoxyl phenenyl)-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 84.73 |
| 6-(4-ethoxyl phenenyl)-3-[4-(diethylin formyl radical methoxyl group) phenyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 73.49 |
| 6-(4-ethoxyl phenenyl)-3-{[4-(4-morpholinyl) formyl radical methoxyl group] phenyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 89.58 |
| 6-(4-ethoxyl phenenyl)-3-[4-(benzamido group formyl radical methoxyl group) phenyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 94.67 |
| 6-(4-ethoxyl phenenyl)-3-{[4-(4-chloroanilino) formyl radical methoxyl group] phenyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 91.26 |
| The 3-[(4-hydroxy-3-methoxy) phenyl]-6-(4-ethoxyl phenenyl)-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 81.04 |
| 6-(4-ethoxyl phenenyl)-3-[3-methoxyl group-4-(benzamido group formyl radical methoxyl group) phenyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 93.41 |
| 6-(4-ethoxy benzyl)-3-[4-(2-diethylin oxyethyl group) phenyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 73.95 |
| 6-(4-ethoxy benzyl)-3-{4-[2-(piperidino) oxyethyl group] phenyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 89.76 |
| 6-(4-ethoxy benzyl)-3-[4-(dimethylin formyl radical methoxyl group) phenyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 97.60 |
| 6-(4-ethoxy benzyl)-3-{[4-(4-toluidine) formyl radical methoxyl group] phenyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 76.20 |
| 6-(4-ethoxy benzyl)-3-{2-[(4-morpholinyl) formyl radical methoxyl group] phenyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 63.29 |
| 6-(4-ethoxy benzyl)-3-[2-(dimethylin formyl radical methoxyl group) phenyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 84.73 |
| Hydrogen bromide prostigmin(e) 0.1 M | 100 |
Compound of the present invention has the structure type novelty as the acetylcholinesterase depressant of brand new type, and drug action and existing medicine are quite or be better than the characteristics of existing medicine.Compared with prior art, sample is significantly improved to the inhibiting rate of acetylcholinesterase, has good using value and development prospect.
Embodiment
Reaction formula 1 has been summarized the synthesis step of preparation the compounds of this invention.
Reaction formula 1
Wherein
n
1And n
2It is 0 to 1 integer;
R
1Can selectively be independently selected from H, halogen ,-OH ,-OCH by 1,2 or 3 arbitrarily
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-O (CH by 1,2 or 3 arbitrarily
2) n
5CH
3
n
3Be 2 to 4 integer, n
4Be 1 to 3 integer, n
5It is 1 to 5 integer;
R wherein
3R
4Be independently selected from methyl or ethyl, or R
3R
4The nitrogen-atoms that links to each other with them forms pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring; Or be independently selected from respectively hydrogen, methyl, hydroxyl, methoxyl group, oxyethyl group, nitro, fluorine, chlorine or bromine and replace or unsubstituted phenyl ring group;
R
5R
6Independently be selected from methyl or ethyl, or R
5R
6The nitrogen-atoms that links to each other with them forms pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring; Or be independently selected from respectively hydrogen, methyl, hydroxyl, methoxyl group, oxyethyl group, nitro, fluorine, chlorine or bromine and replace or unsubstituted phenyl ring group.
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 1:3-(4-aminomethyl phenyl)-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone
With 4 '-phenetole ethene, 0.2 mol, sodium hydroxide 0.4 mol, water 80 mL join in the 500 mL round-bottomed flasks, be heated to 70 ° of C, potassium permanganate 0.5 mol is added within 0.5 h in batches, with ethanol 50 mL unreacted potassium permanganate is destroyed again after reacting 10 min, reaction solution is carried out suction filtration, keep filtrate, most of water is removed in underpressure distillation, with concentrated hydrochloric acid concentrated filtrate is carried out acidifying, uses dichloromethane extraction again, desolventizing, cooling obtains faint yellow solid, and ethyl alcohol recrystallization obtains 2-(4-ethoxyl phenenyl)-2-oxo acetic acid white crystalline powder 36.90 g, yield 95 %, ESI-MS (m/z): 193.2 (M – H)
–
With 2-(4-ethoxyl phenenyl)-2-oxo acetic acid 0.01 mol, thiosemicarbazide 0.01 mol, ethanol 40 mL, water 40 mL join in the 250 mL round-bottomed flasks successively, stir heating reflux reaction 12 h, cool to room temperature, underpressure distillation, steaming desolventizes, obtain a large amount of Off-white solid, suction filtration, oven dry, ethyl alcohol recrystallization obtains 3,4-dihydro-6-(4-phenelyl)-3-sulfo--1,2,4-triazine-5 (2
H)-ketone white crystal 2.39 g, yield 96 %, ESI-MS (m/z): 247.6 (M-H).
Under 0 ° of C condition, in 15 mL glacial acetic acid solution of 0.005 mol sodium-acetate, add 3 of 0.010 mol, 4-dihydro-6-(4-phenelyl)-3-sulfo--1,2,4-triazine-5 (2
H4 '-methyl of)-ketone and 0.011 mol-
α-chloroacetophenone.Stirring at room 30 min slowly are warming up to and continue reaction 2 h after refluxing, and TLC monitoring reaction process react and is cooled to room temperature after complete, reaction solution are concentrated into dried, add the saturated common salt aqueous solution, stirring 30 min under the room temperature, and use ethyl acetate extraction.The organic layer drying obtains thick product with concentrated, and ethyl alcohol recrystallization obtains required product yellow crystals 0.98 g, yield 35 %,
1H-NMR (600 MHz, DMSO-
d 6 ):
δ(8.11 2H, d), 7.68 (2H, d,
J=7.8 Hz), 7.50 (1H, s), 7.37 (2H, d,
J=8.4 Hz), 7.02 (2H, d), 4.09 (2H, q), 2.40 (3H, s), 1.34 (3H, t); ESI-MS (m/z): 364.1 (M+H)
+, 386.1 (M+Na)
+, 402.1 (M+K)
+, 749.3 (2M+Na)
+
Embodiment 2:6-(4-ethoxyl phenenyl)-3-(4-bromophenyl)-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 1 method, obtain 6-(4-ethoxyl phenenyl)-3-(4-bromophenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 2.06 g, yield 48 %,
1H-NMR (600 MHz, DMSO-
d 6 ):
δ8.11 (2H, d,
J=9.0 Hz), 7.79 (2H, d,
J=8.4 Hz), 7.75 (2H, d,
J=8.4 Hz), 7.62 (1H, s), 7.02 (2H, d,
J=9.0 Hz), 4.09 (2H, q), 1.35 (3H, t); ESI-MS (m/z): 428.2 (M+H)
+, 430.2 (M+2+H)
+, 450.2 (M+Na)
+, 452.2 (M+2+Na)
+, 466.2 (M+K)
+, 468.2 (M+2+K)
+
Embodiment 3:3-(4-p-methoxy-phenyl)-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone
According to embodiment 1 method, obtain 3-(4-p-methoxy-phenyl)-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 1.38 g, yield 37 %,
1H-NMR (600 MHz, DMSO-
d 6 ):
δ8.11 (2H, d,
J=8.4 Hz), 7.73 (2H, d,
J=9.0 Hz), 7.44 (1H, s), 7.11 (2H, d,
J=9.0 Hz), 7.02 (2H, d,
J=9.0 Hz), 4.09 (2H, q), 3.84 (3H, s), 1.35 (3H, t); ESI-MS (m/z): 380.1 (M+H)
+, 402.1 (M+Na)
+, 418.0 (M+K)
+
Embodiment 4:6-(4-ethoxyl phenenyl)-3-[4-(diethylin formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 1 method, obtain 3-(4-hydroxy phenyl)-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 1.56 g, yield 43 %.
1H-NMR (600 MHz, DMSO-
d 6 ):
δ 8.12 (2H, d,
J = 9.0 Hz), 7.60 (2H, d,
J = 9.0 Hz), 7.38 (1H, s), 7.02 (2H, d,
J = 9.0 Hz), 6.92 (2H, d,
J = 9.0 Hz), 4.09 (2H, q), 1.35 (3H, t); ESI-MS (m/z): 366.1 (M+H)
+, 388.1 (M+Na)
+, 404.1 (M+K)
+。
Under the stirring at room condition, to the 3-(4-hydroxy phenyl) of 0.002 mol-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2 adds corresponding 0.002 mol in the acetone or alcohol solution of 4-triazine-7-ketone
N,
N-diethylchloro-acetamide, and after adding 0.002 mol acid binding agent (Anhydrous potassium carbonate or triethylamine) and 0.0003 mol potassium iodide catalyst, back flow reaction, TLC follows the tracks of reaction process, be cooled to room temperature after question response is complete, reaction solution is concentrated into dried, adds saturated aqueous common salt 30 mL, extracted with diethyl ether.The organic layer drying obtains thick product with concentrated, and ethyl alcohol recrystallization obtains required product 6-(4-ethoxyl phenenyl)-3-[4-(diethylin formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.33 g, yield 35 %.
1H-NMR (600 MHz, DMSO-
d 6 ):
δ 8.11 (2H, d,
J = 7.8 Hz), 7.71 (2H, d,
J = 8.4 Hz), 7.44 (1H, s), 7.07 (2H, d,
J = 8.4 Hz), 7.00 (2H, d,
J = 9.0 Hz), 4.90 (2H, s), 4.09 (2H, q), 3.30 (4H, q), 1.34 (3H, t), 1.17 (3H, t), 1.05 (3H, t); ESI-MS (m/z): 479.3 (M+H)
+, 501.3 (M+Na)
+, 517.0 (M+K)
+。
Embodiment 5:6-(4-ethoxyl phenenyl)-3-{[4-(4-morpholinyl) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 4 methods, obtain 6-(4-ethoxyl phenenyl)-3-{[4-(4-morpholinyl) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.38 g, yield 39 %.
1H-NMR (600 MHz, DMSO-
d 6 ):
δ 8.10 (2H, d), 7.71 (2H, d), 7.44 (1H, s), 7.09 (2H, d,
J = 7.2 Hz), 7.01 (2H, d,
J = 7.2 Hz), 4.95 (2H, s), 4.09 (2H, q), 3.60 (4H, t), 3.48 (4H, t), 1.34 (3H, t); ESI-MS (m/z): 493.4 (M+H)
+, 515.4 (M+Na)
+。
Embodiment 6:6-(4-ethoxyl phenenyl)-3-[4-(benzamido group formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 4 methods, obtain 6-(4-ethoxyl phenenyl)-3-[4-(benzamido group formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.45 g, yield 44 %.
1H-NMR (600 MHz, DMSO-
d 6 ):
δ 8.73 (1H, t), 8.11 (2H, d,
J = 8.4 Hz), 7.74 (2H, d,
J = 8.4 Hz), 7.46 (1H, s), 7.21~7.32 (5H, m), 7.15 (2H, d,
J = 8.4 Hz), 7.00 (2H, d), 4.67 (2H, s), 4.36 (2H, s), 4.08 (2H, q), 1.34 (3H, t); ESI-MS (m/z): 510.9 (M-H), 546.9 (M+Cl), 556.9 (M+COO)。
Embodiment 7:6-(4-ethoxyl phenenyl)-3-{[4-(4-chloroanilino) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 4 methods, obtain 6-(4-ethoxyl phenenyl)-3-{[4-(4-chloroanilino) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.61 g, yield 57 %.
1H-NMR (600 MHz, DMSO-
d 6 ):
δ 10.32 (1H, s), 8.11 (2H, d,
J = 8.4 Hz), 7.75 (2H, d,
J = 8.4 Hz), 7.69 (2H, d,
J = 8.4 Hz), 7.46 (1H, s), 7.40 (2H, d,
J = 8.4 Hz), 7.17 (2H, d,
J = 8.4 Hz), 7.00 (2H, d,
J = 8.4 Hz), 4.82 (2H, s), 4.08 (2H, q), 1.35 (3H, t); ESI-MS (m/z): 533.2 (M+H)
+, 555.2 (M+Na)
+, 557.2 (M+2+Na)
+, 571.1 (M+K)
+, 573.1 (M+2+K)
+。
Embodiment 8:3-[(4-hydroxy-3-methoxy) phenyl]-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 1 method, obtain the 3-[(4-hydroxy-3-methoxy) phenyl]-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 2.39 g, yield 61 %.
1H-NMR (600 MHz, DMSO-
d 6 ):
δ 10.75 (1H, br), 8.15 (2H, d,
J = 8.4 Hz), 7.43 (1H, s), 7.41 (1H, d), 7.21 (1H, s), 7.03 (2H, d,
J = 7.8 Hz), 6.95 (1H, d), 4.09 (2H, q), 3.83 (3H, s), 1.35 (3H, t); ESI-MS (m/z): 393.9 (M-H)。
Embodiment 9:6-(4-ethoxyl phenenyl)-3-[3-methoxyl group-4-(benzamido group formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 4 methods, obtain 6-(4-ethoxyl phenenyl)-3-[3-methoxyl group-4-(benzamido group formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.73 g, yield 67 %.
1H-NMR (600 MHz, DMSO-
d 6 ):
δ 8.54 (1H, s), 8.14 (2H, d,
J = 9.0 Hz), 7.50 (1H, s), 7.26~7.33 (5H, m), 7.23~7.24 (2H, m), 7.07 (1H, d), 7.02 (2H, d,
J = 8.4 Hz), 4.65 (2H, s), 4.36 (2H, d), 4.09 (2H, q), 3.83 (3H, s), 1.34 (3H, t); ESI-MS (m/z): 543.3 (M+H)
+, 565.2 (M+Na)
+, 581.2 (M+K)
+。
Embodiment 10:6-(4-ethoxy benzyl)-3-[4-(2-diethylin oxyethyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone
With 4-ethoxy-benzaldehyde 0.1 mol, acetyl glycine 0.12 mol, sodium acetate, anhydrous 0.12 mol and diacetyl oxide 50 g join in the 100 mL three-necked bottles successively, reflux stirring reaction 5 h, after being cooled to room temperature, solution becomes solid, suction filtration, filter cake cold water washing, use acetone recrystallization, get 2-methyl-4-(4-oxyethyl group benzylidene) azolactone yellow crystal powder 23.0 g, yield 99 %, ESI-MS (m/z): 232.1 (M+H)
+
(4-oxyethyl group benzylidene) azolactone 0.1 mol, water 100 mL, acetone 80 mL join in the 100 mL round-bottomed flasks successively, reflux stirring reaction 3 h, cool to room temperature with 2-methyl-4-.Product is transferred in the 500 mL round-bottomed flasks, added HCl solution 200 mL of 1mol/L, be heated to backflow, react 5 h, after the TLC monitoring reaction is finished, stopped reaction, a large amount of yellow solids are separated out in cooling, suction filtration, filter cake cold water and a small amount of acetone rinsing, acetone recrystallization,
β-(4-ethoxyl phenenyl) pyruvic acid yellow crystals 19.8 g, yield 95%, ESI-MS (m/z): 207.1 (M-H).
Will
β-(4-ethoxyl phenenyl) pyruvic acid 0.01 mol, thiosemicarbazide 0.011 mol, ethanol 30 mL, water 30 mL join in the 250 mL round-bottomed flasks successively, stir, behind heating reflux reaction 8 h, cool to room temperature, underpressure distillation boils off solvent, obtain a large amount of Off-white solid, suction filtration, oven dry, use ethyl alcohol recrystallization, obtain 6-(4-ethoxy benzyl)-3-sulfo--(2
H, 4
H)-1,2,4-triazine-5-ketone white crystal 2.37 g, yield 90 %, ESI-MS (m/z): 262.1 (M-H).
Under 0 ° of C condition, add the 6-(4-ethoxy benzyl) of 0.01 mol-3-sulfo--(2 in the 15 mL glacial acetic acid solutions of 0.005 mol sodium acetate
H, 4
H)-1,2,4 '-hydroxyl of 4-triazine-5-ketone and 0.01 mol-
α-chloroacetophenone.Stirring at room 30 min heat up 2 h that reflux, TLC monitoring reaction process.React complete after, be cooled to room temperature, reaction solution is concentrated into dried, add the saturated common salt aqueous solution, stir 30 min, ethyl acetate extraction under the room temperature, the organic layer drying obtains thick product with concentrated, and ethyl alcohol recrystallization obtains 6-(4-ethoxy benzyl)-3-(4-hydroxy phenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 2.38 g, yield 63 %.
1H-NMR (600 MHz, DMSO-
d 6 ):
δ 10.0 (1H, s), 7.48 (2H, d,
J = 8.4 Hz), 7.33 (1H, s), 7.21 (2H, d,
J = 8.4 Hz), 6.87 (2H, d,
J = 8.4 Hz), 6.80 (2H, d,
J = 8.4 Hz), 4.02 (2H, q), 3.91 (2H, s), 1.31 (3H, t); ESI-MS (m/z): 380.0 (M+H)
+, 780.8 (2M+Na)
+。
With 6-(4-ethoxy benzyl)-3-(4-hydroxy phenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.002 mol with
N,
N-diethyl chloroethylamine hydrochloride 0.002 mol is dissolved in the 50 mL acetone, and adds K
2CO
30.02 mol, KI 0.0002 mol stirs lower back flow reaction 8 h, and the TLC monitoring reaction is to reacting completely, and suction filtration, concentration of reaction solution are extremely dried, and ethyl alcohol recrystallization obtains product 6-(4-ethoxy benzyl)-3-[4-(2-diethylin oxyethyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.47 g, yield 49 %.
1H-NMR (300 MHz, CDCl
3):
δ 7.47 (2H, d,
J = 8.7 Hz), 7.26 (2H, d,
J = 8.5 Hz), 6.93(2H, d,
J = 8.7 Hz), 6.82 (2H, d,
J = 8.5 Hz), 6.70 (1H, s), 4.13 (2H, t), 4.05 (2H, s), 4.01 (2H, q), 2.95 (2H, t), 2.61~2.73 (4H, m), 1.31 (3H, t), 1.04~1.13 (6H, m); ESI-MS (m/z): 479.0 (M+H)
+。
Embodiment 11:6-(4-ethoxy benzyl)-3-{4-[2-(piperidino) oxyethyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 10 methods, obtain 6-(4-ethoxy benzyl)-3-{4-[2-(piperidino) oxyethyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.36 g, yield 36 %,
1H-NMR (300 MHz, CDCl
3):
δ7.47 (2H, d,
J=8.7 Hz), 7.27 (2H, d,
J=8.4 Hz), 6.94 (2H, d,
J=8.7 Hz), 6.83 (2H, d,
J=8.4 Hz), 6.72 (1H, s), 4.20 (2H, t), 4.05 (2H, s), (4.00 2H, q), 2.86 (2H, t), 2.59 (4H, s), (1.64 4H, s), 1.49 (2H, s), 1.32 (3H, t); ESI-MS (m/z): 491.7 (M+H)
+
Embodiment 12:6-(4-ethoxy benzyl)-3-[4-(dimethylin formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 10 methods, obtain 6-(4-ethoxy benzyl)-3-[4-(dimethylin formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.37 g, yield 40 %,
1H-NMR (300 MHz, CDCl
3):
δ7.49 (2H, d,
J=8.6Hz), 7.27 (2H, d,
J=8.4Hz), 7.00 (2H, d,
J=8.6Hz), 6.84 (2H, d,
J=8.4Hz), 6.71 (1H, s), 4.78 (2H, s), 4.05 (2H, s), 3.98 (2H, q), 3.79 (3H, s), 3.13 (3H, s), 3.02 (3H, s), 1.31 (3H, t); ESI-MS (m/z): 465.1 (M+H)
+
Embodiment 13:6-(4-ethoxy benzyl)-3-{[4-(4-toluidine) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 10 methods, obtain 6-(4-ethoxy benzyl)-3-{[4-(4-toluidine) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.40 g, yield 38 %,
1H-NMR (600 MHz, DMSO-
d 6 ):
δ(10.06 1H, s), 7.61 (2H, d,
J=8.4 Hz), 7.53 (2H, d,
J=8.4 Hz), 7.42 (1H, s), 7.40 (2H, d,
J=8.4 Hz), 7.13 (2H, d,
J=8.4 Hz), 7.05 (2H, d,
J=8.4 Hz), 6.86 (2H, d,
J=8.4 Hz), 4.77 (2H, s), 4.03 (2H, q), 3.89 (2H, s), 2.26 (3H, s), 1.32 (3H, t); ESI-MS (m/z): 527.3 (M+H)
+, 549.2 (M+Na)
+
Embodiment 14:6-(4-ethoxy benzyl)-3-{2-[(4-morpholinyl) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 10 methods, obtain 6-(4-ethoxy benzyl)-3-{2-[(4-morpholinyl) the formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.35 g, yield 35 %,
1H-NMR (600 MHz, DMSO-
d 6 ):
δ(7.48 1H, t), 7.45 (2H, d), 7.12 (2H, d,
J=9.0 Hz), 7.06 (2H, m), 6.79 (2H, d,
J=9.0 Hz), 4.80 (2H, s), 4.01 (2H, q), 3.80 (2H, s), 3.50 (4H, s), 3.32 (4H, s), 1.32 (3H, t); ESI-MS (m/z): 507.0 (M+H)
+
Embodiment 15:6-(4-ethoxy benzyl)-3-[2-(dimethylin formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 10 methods, obtain 6-(4-ethoxy benzyl)-3-[2-(dimethylin formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.39 g, yield 42 %,
1H-NMR (600 MHz, DMSO-
d 6 ):
δ7.34 ~ 7.48 (3H, m), 7.12 (2H, d,
J=8.4 Hz), 7.05 (2H, m), 6.79 (2H, d,
J=8.4 Hz), 4.77 (2H, s), 4.02 (2H, q), 3.80 (2H, s), 2.89 (3H, s), 2.78 (3H, s), 1.31 (3H, t); ESI-MS (m/z): 465.0 (M+H)
+, 486.9 (M+Na)
+
Example of formulations
Pharmaceutical composition
In following preparation, " activeconstituents " refers to formula I compound, or its salt or its solvate.
Example of formulations 1: tablet formulation
Production technique: (1) mixes 15 min with project 1,2 and 3 in suitable mixing tank.(2) powdered mixture of step 1 is granulated with 20%Povidone K30 solution.(3) at the particle of 50 ° of C 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 mix 3 min.(6) with particle compressing tablet on suitable tabletting machine of step 5.
Example of formulations 2: capsule formula
Production technique: (1) mixes 15 min with project 1,2 and 3 in suitable mixing tank.(2) adding project 4 and 5 and mix 3 min.(3) be filled in the capsule.
Example of formulations 3: injection liquid/emulsion
| Project | Composition | mg/mL |
| 1 | Activeconstituents | 1 mg |
| 2 | PGE 400 | 10-50 mg |
| 3 | Phosphatide | 20-50 mg |
| 4 | Soya-bean oil | 1-5 mg |
| 5 | Glycerine | 8-12 mg |
| 6 | Water adds to | 1 mL |
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 | Composition | mg/mL |
| 1 | Activeconstituents | 1 mg |
| 2 | Glycofurol | 10-50 mg |
| 3 | Phosphatide | 20-50 mg |
| 4 | Soya-bean oil | 1-5 mg |
| 5 | Glycerine | 8-12 mg |
| 6 | Water adds to | 1 mL |
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
The preparation of A. instiling and filling a prescription
In a Glass tubing, mix synthetic DPPC (45 mg), two myristoyl Yelkin TTS (7 mg), DPPG (1 mg) and active compound (5 mg) are dissolved in all components in the chloroform, use N
2Evaporate most of solvent, then decompression thus, forms lipid membrane on the Glass tubing surface. in this lipid, add the aqueous solution (0.9 % NaCl), 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 the 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 the matter of gained particle (MMAD) is about 2 μ m.
The above only is preferred embodiment of the present invention, is not to be the restriction of the present invention being made other form, and any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the equivalent embodiment of equivalent variations.But every technical solution of the present invention content that do not break away to any simple modification, equivalent variations and remodeling that above embodiment does, still belongs to the protection domain of technical solution of the present invention according to technical spirit of the present invention.
Claims (4)
1. the compound of a formula I, its prodrug and pharmaceutical activity metabolite, and the acceptable salt of above-claimed cpd:
(I)
Wherein
n
1And n
2It is 0 to 1 integer;
R
1Can selectively be independently selected from H, halogen ,-OH ,-OCH by 1,2 or 3 arbitrarily
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-O (CH by 1,2 or 3 arbitrarily
2) n
5CH
3
n
3Be 2 to 4 integer, n
4Be 1 to 3 integer, n
5It is 1 to 5 integer;
R wherein
3R
4Be independently selected from methyl or ethyl, or R
3R
4The nitrogen-atoms that links to each other with them forms pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring; Or be independently selected from respectively hydrogen, methyl, hydroxyl, methoxyl group, oxyethyl group, nitro, fluorine, chlorine or bromine and replace or unsubstituted phenyl group;
R
5R
6Independently be selected from methyl or ethyl, or R
5R
6The nitrogen-atoms that links to each other with them forms pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring; Or be independently selected from respectively hydrogen, methyl, hydroxyl, methoxyl group, oxyethyl group, nitro, fluorine, chlorine or bromine and replace or unsubstituted phenyl group.
2. the compound of claim 1 comprises:
3-(4-aminomethyl phenyl)-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxyl phenenyl)-3-(4-bromophenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-(4-p-methoxy-phenyl)-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxyl phenenyl)-3-[4-(diethylin formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxyl phenenyl)-3-{[4-(4-morpholinyl) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxyl phenenyl)-3-[4-(benzamido group formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxyl phenenyl)-3-{[4-(4-chloroanilino) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
The 3-[(4-hydroxy-3-methoxy) phenyl]-6-(4-ethoxyl phenenyl)-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxyl phenenyl)-3-[3-methoxyl group-4-(benzamido group formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxy benzyl)-3-[4-(2-diethylin oxyethyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxy benzyl)-3-{4-[2-(piperidino) oxyethyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxy benzyl)-3-[4-(dimethylin formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxy benzyl)-3-{[4-(4-toluidine) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxy benzyl)-3-{2-[(4-morpholinyl) formyl radical methoxyl group] phenyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
6-(4-ethoxy benzyl)-3-[2-(dimethylin formyl radical methoxyl group) phenyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone.
3. a pharmaceutical composition comprises claim 1 or 2 described compounds and pharmaceutically acceptable carrier or excipient as activeconstituents.
4. claim 1 or 2 described compounds or composition claimed in claim 3 application in preparation treatment degenerative dementia disease drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210459278.6A CN103012438B (en) | 2012-11-15 | 2012-11-15 | The thiazole that alkoxyl group replaces is [3,2-b]-1,2,4-pyrrolotriazine derivatives and application thereof also |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210459278.6A CN103012438B (en) | 2012-11-15 | 2012-11-15 | The thiazole that alkoxyl group replaces is [3,2-b]-1,2,4-pyrrolotriazine derivatives and application thereof also |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103012438A true CN103012438A (en) | 2013-04-03 |
| CN103012438B CN103012438B (en) | 2015-10-14 |
Family
ID=47961590
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210459278.6A Expired - Fee Related CN103012438B (en) | 2012-11-15 | 2012-11-15 | The thiazole that alkoxyl group replaces is [3,2-b]-1,2,4-pyrrolotriazine derivatives and application thereof also |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103012438B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN115197244A (en) * | 2022-09-03 | 2022-10-18 | 石家庄学院 | [1,2,4] triazino [3,2-b ] [1,3,5] thiadiazine derivative and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101503414A (en) * | 2009-03-04 | 2009-08-12 | 沈阳药科大学 | Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof |
-
2012
- 2012-11-15 CN CN201210459278.6A patent/CN103012438B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101503414A (en) * | 2009-03-04 | 2009-08-12 | 沈阳药科大学 | Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof |
Non-Patent Citations (4)
| Title |
|---|
| SI-JIE LIU ET AL.: "Design, synthesis, and biological evaluation of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives as novel acetylcholinesterase inhibitors", 《ARKIVOC》 * |
| ZHE JIN ET AL.: "Synthesis and Biological Evaluation of 3,6-diaryl-7H-thiazolo[3,2-b] [1,2,4]triazin-7-one Derivatives as Acetylcholinesterase Inhibitors", 《ARCHIVES OF PHARMACAL RESEARCH》 * |
| 刘斯婕 等: "新型乙酰胆碱酯酶抑制剂7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与生物活性", 《中国药物化学杂志》 * |
| 金辄 等: "乙酰胆碱酯酶抑制剂3, 6-二芳基-7H-噻唑并[ 3, 2-b]-1, 2, 4-三嗪-7-酮类化合物的设计、合成与生物活性", 《中国药物化学杂志》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN115197244A (en) * | 2022-09-03 | 2022-10-18 | 石家庄学院 | [1,2,4] triazino [3,2-b ] [1,3,5] thiadiazine derivative and application thereof |
| CN115197244B (en) * | 2022-09-03 | 2023-07-07 | 石家庄学院 | [1,2,4] triazino [3,2-b ] [1,3,5] thiadiazine derivatives and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103012438B (en) | 2015-10-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101503414B (en) | Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof | |
| CA2623237C (en) | Novel dosage formulation | |
| CN101456872B (en) | Thiazole[3,2-alpha] miazine derivates and use thereof | |
| EP3984528B1 (en) | Pharmaceutical compositions comprising nilotinib | |
| EP3182962B1 (en) | Compositions and uses of amidine derivatives | |
| EP2305263B1 (en) | Stabilized amorphous forms of imatinib mesylate | |
| TWI246921B (en) | Stabilized pharmaceutical composition with calcium blocker | |
| CN1646538A (en) | Topiramate salts and compositions comprising and methods of making and using the same | |
| CN105408324A (en) | Substituted benzylpyrazoles | |
| CN105168218A (en) | Therapeutic Agent For Spinal Canal Stenosis | |
| CN103012438B (en) | The thiazole that alkoxyl group replaces is [3,2-b]-1,2,4-pyrrolotriazine derivatives and application thereof also | |
| CN101304731A (en) | Bazedoxifene acetate formulations and preparation method | |
| CN102459177B (en) | The dibasic Arylsulfonamide ccr 3 antagonists of 2,5- | |
| WO2007142811A2 (en) | Low dose doxepin formulations, including buccal, sublingual and fastmelt formulations, and uses of the same to treat insomnia | |
| JP2002520282A (en) | Methods and compositions for the treatment of chronic lymphocytic leukemia | |
| CN100430383C (en) | Benzimidazoles that are useful in treating sexual dysfunction | |
| AU2021228622A1 (en) | Hot melt extruded solid dispersions containing a BCL2 inhibitor | |
| TW202019414A (en) | Bioavailable oral dosage forms | |
| CN102892754A (en) | Arylsulfonamide ccr3 antagonists | |
| CN103298786B (en) | Arylsulfonyl amine salt CCR3 antagonist | |
| CN103012439B (en) | Benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and application thereof | |
| BR112016016021B1 (en) | PHARMACEUTICAL COMPOSITION, ITS USE, ORAL DOSAGE FORMULATION AND METHOD FOR PREPARING TABLETS BY DIRECT COMPRESSION IN SINGLE DOSAGE FORMULATION | |
| CN103694233B (en) | Benzisoxa azole compounds and application thereof | |
| JPH01128924A (en) | Preparation composition of piperidinoalkanol derivative | |
| EP4355326A1 (en) | Therapeutically effective oral administration of a 2 arylbenzimidazole |
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: 20151014 Termination date: 20201115 |