CN103012439A - Benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and application thereof - Google Patents
Benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medical technology, and relates to a benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and an application thereof. The benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative comprises a stereoisomer and pharmaceutically acceptable salt of the benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative, wherein the structural general formula is shown in the specification; and the benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and the pharmaceutically acceptable acid-added salt of the compound can be combined with the existing medicine or independently used as an acetylcholin esterase inhibitor and used for improving the memory of the patients suffering from dementia and Alzheimer disease. Compared with the existing Chinese patent, the 6-site side chain of thiazolo[3,2-b]-1,2,4-triazine is obviously changed, and the inhibition ratio of a sample against acetylcholin esterase is obviously improved.
Description
Technical field
The invention belongs to medical technical field, relate to also [3,2-of thiazole that benzoyl replaces
b]-1,2,4-triazine derivative and application thereof are specifically related to also [3,2-of thiazole that benzoyl replaces
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 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
1It is 0 to 1 integer; n
2It is 1 to 2 integer; Be n
1Be 0 or 1; n
2Be 1 or 2;
R
1Can selectively be independently selected from H by 1,2 or 3 arbitrarily, halogen ,-OH ,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6,-O (CH
2) n
5CH
3,-CH
3,-CH
2CH
3,-NO
2
R
2Can selectively be independently selected from H by 1,2 or 3 arbitrarily, halogen ,-OH ,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6,-O (CH
2) n
5CH
3,-CH
3,-CH
2CH
3,-NO
2n
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 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.
" 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-hydroxy phenyl)-6-[2-oxo-2-phenylethyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 67.37 |
| 3-(4-bromophenyl)-6-[2-oxo-2-(4-p-methoxy-phenyl) ethyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 75.24 |
| 3-(4-p-methoxy-phenyl)-6-[2-oxo-2-(4-chloro-phenyl-) ethyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 85.35 |
| 3-[4-(diethylin formyl radical methoxyl group) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 91.29 |
| 3-{[4-(4-morpholinyl) formyl radical methoxyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-hydroxyl) phenyl] ethyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 69.50 |
| 3-[4-(benzamido group formyl radical methoxyl group) phenyl]-6-{2-oxo-2-[(3-methyl-4-oxyethyl group) phenyl] ethyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 87.73 |
| 3-{[4-(4-chloroanilino) formyl radical methoxyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-methoxyl group) phenyl] ethyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 94.92 |
| The 3-[(4-hydroxy-3-methoxy) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 84.30 |
| 3-(4-ethoxyl phenenyl)-6-{2-oxo-2-[4-(benzamido group formyl radical methoxyl group) phenyl] ethyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 88.14 |
| 3-[(3-methyl-4-methoxyl group) phenyl]-6-{2-oxo-2-[4-(4-toluidine) formyl radical p-methoxy-phenyl] ethyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 79.68 |
| 3-[(3-methyl-4-hydroxyl) phenyl]-6-{2-oxo-2-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl] ethyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 93.17 |
| 3-{4-[2-(piperidino) oxyethyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-oxyethyl group) phenyl] ethyl }-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 72.44 |
| 3-[4-(2-diethylin oxyethyl group) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7 H-thiazole is [3,2-also b]-1,2,4-triazine-7-ketone | 83.15 |
| Hydrogen bromide prostigmin(e) 0.1 M | 100 |
Compound of the present invention has the structure type novelty as the new acetylcholinesterase depressant of a class, and drug action and existing medicine are quite or be better than the characteristics of existing medicine.With respect to prior art, contain also [3,2-of thiazole that benzoyl replaces
b]-1,2,4-triazin-6 position side chain has had obvious variation, and sample had significant raising 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.
The thiazole that reaction formula 1 benzoyl replaces is [3,2-b]-1,2 also, the preparation of 4-pyrrolotriazine derivatives
Wherein
n
1It is 0 to 1 integer; n
2It is 1 to 2 integer;
R
1Can selectively be independently selected from H by 1,2 or 3 arbitrarily, halogen ,-OH ,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6,-O (CH
2) n
5CH
3,-CH
3,-CH
2CH
3,-NO
2
R
2Can selectively be independently selected from H by 1,2 or 3 arbitrarily, halogen ,-OH ,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6,-O (CH
2) n
5CH
3,-CH
3,-CH
2CH
3,-NO
2
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 and replacement 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 and replacement 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-hydroxy phenyl)-6-[2-oxo-2-phenylethyl]-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone
With 50 mL toluene, 0.1 mol sodium ethylate and 0.05 mol oxalic acid diethyl ester join in the 500 mL round-bottomed flasks, and reflux 5 min add 0.02 mol methyl phenyl ketone, room temperature reaction 10 h.React complete after, will pour 100mL water in the reaction solution into, separatory, water intaking layer washs water layer with 20 mL ether, 1 mol/L hcl acidifying has solid to separate out.Cooling, suction filtration, washing, drying.Obtain faint yellow solid, ethyl alcohol recrystallization obtains white crystal 9.2 g, yield 90%.
With 2,4-dioxo-4-phenylbutyrate ethyl ester 1.0 g (0.004mol), thiosemicarbazide 0.37g (0.004mol), ethanol 20 mL, water 20 mL join in the 250 mL round-bottomed flasks successively, with 40% aqueous sodium hydroxide solution the pH value of reaction solution are transferred to 11 again, stir, heating reflux reaction 4 h, cool to room temperature.With concentrated hydrochloric acid the pH value of reaction solution is transferred to 2, have a large amount of Off-white solid to separate out, suction filtration, oven dry, ethyl alcohol recrystallization obtains 6-[2-oxo-2-phenylethyl]-3-sulfo--2,4-dihydro-3
H, 5
H-1,2,4-triazine-7-ketone white crystal 1.10 g.ESI-MS (m/z): 246.1 (M-H)。
The 6-[2-oxo that the upper step was obtained-2-phenylethyl]-3-sulfo--2,4-dihydro-3
H, 5
H-1,2,4-triazine-7-ketone 1.0 g (0.004 mol), 4-hydroxyl chloroacetophenone 0.004 mol, glacial acetic acid 30 mL join in the 100 mL round-bottomed flasks, heating reflux reaction 10 h, the TLC monitoring reaction is to reacting completely.After the cooling, suction filtration, the dehydrated alcohol recrystallization obtains 3-(4-hydroxy phenyl)-6-[2-oxo-2-phenylethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone, pale yellow powder 0.84 g, yield 50 %.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 13.26 (1H, s), 8.01 (4H, m), 7.70 (2H, m), 7.57 (4H, m), 4.32 (2H, s)。ESI-MS (m/z): 364.0 (M+H)
+。
Embodiment 2:3-(4-bromophenyl)-6-[2-oxo-2-(4-p-methoxy-phenyl) ethyl]-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-bromophenyl)-6-[2-oxo-2-(4-p-methoxy-phenyl) ethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 1.08 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 7.96 (2H, d,
J = 9.0 Hz), 7.72 (2H, d,
J = 8.4 Hz), 7.48 (2H, d,
J = 8.4 Hz), 7.34 (1H, s), 7.04 (2H, d,
J = 9.0 Hz), 3.85 (3H, s), 2.72 (2H, s); ESI-MS (m/z): 455.9 (M+H)
+, 457.9 (M+2+H)
+。
Embodiment 3:3-(4-p-methoxy-phenyl)-6-[2-oxo-2-(4-chloro-phenyl-) ethyl]-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-[2-oxo-2-(4-chloro-phenyl-) ethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 1.24 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 8.08 (2H, d,
J = 8.4 Hz), 7.76 (2H, d,
J = 9.0 Hz), 7.64 (2H, d,
J = 9.0 Hz), 7.56 (2H, d,
J = 8.4 Hz), 7.32 (1H, s), 3.82 (3H, s), 2.67 (2H, s); ESI-MS (m/z): 412.0 (M+H)
+, 414.1 (M+2+H)
+, 434.0 (M+Na)
+。
Embodiment 4:3-[4-(diethylin formyl radical methoxyl group) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
Under the stirring at room condition, to the 3-(4-hydroxy phenyl) of 0.002 mol-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-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 3-[4-(diethylin formyl radical methoxyl group) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.52 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 8.04 (2H, d,
J = 7.2 Hz), 7.64 (2H, d,
J = 8.4 Hz), 7.44 (2H, d,
J = 8.4 Hz), 7.36 (1H, s), 6.98 (2H, d,
J = 7.2 Hz), 4.84(2H, s), 4.15 (2H, q), 3.28 (4H, q), 2.72 (2H, s), 1.38 (3H, t), 1.22 (6H, t); ESI-MS (m/z): 521.2 (M+H)
+, 543.2 (M+Na)
+。
Embodiment 5:3-{[4-(4-morpholinyl) formyl radical methoxyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-hydroxyl) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 4 methods, obtain 3-{[4-(4-morpholinyl) formyl radical methoxyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-hydroxyl) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.42 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 9.78 (1H, s), 7.96 (1H, d), 7.80 (2H, d), 7.62 (1H, s), 7.32 (1H, s), 6.95 (2H, d), 6.90 (1H, s), 4.90 (2H, s), 3.75 (4H, t), 3.52 (4H, t), 2.83 (2H, s), 2.32 (3H, s); ESI-MS (m/z): 521.1 (M+H)
+, 543.1 (M+Na)
+。
Embodiment 6:3-[4-(benzamido group formyl radical methoxyl group) phenyl]-6-{2-oxo-2-[(3-methyl-4-oxyethyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 4 methods, obtain 3-[4-(benzamido group formyl radical methoxyl group) phenyl]-6-{2-oxo-2-[(3-methyl-4-oxyethyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.58 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 8.98 (1H, q), 8.12 (1H, d), 7.94 (2H, d,
J = 9.0 Hz), 7.88 (1H, s), 7.36 (1H, s), 7.24~7.32 (5H, m), 7.08 (2H, d), 6.96 (1H, d), 4.88 (2H, s), 4.45 (2H, d), 4.04 (2H, q), 2.72 (2H, s), 2.24(3H, d), 1.36 (3H, t); ESI-MS (m/z): 569.2 (M+H)
+, 591.2 (M+Na)
+。
Embodiment 7:3-{[4-(4-chloroanilino) formyl radical methoxyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-methoxyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 4 methods, obtain 3-{[4-(4-chloroanilino) formyl radical methoxyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-methoxyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.57.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 10.21 (1H, s), 8.04 (1H, d), 7.82 (2H, d,
J = 8.4 Hz), 7.70 (2H, d,
J = 7.2 Hz), 7.64 (1H, s), 7.54 (2H, d), 7.37 (1H, s), 7.16 (1H, d), 7.07 (2H, d,
J = 7.2 Hz), 4.64 (2H, s), 3.85 (3H, s), 2.71 (2H, s), 2.14 (3H, s); ESI-MS (m/z): 575.1 (M+H)
+, 577.1 (M+2+H)
+, 597.1 (M+Na)
+, 599.1 (M+2+Na)
+。
Embodiment 8:3-[(4-hydroxy-3-methoxy) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-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-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 1.16 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 10.12 (1H, s), 8.07 (2H, d,
J = 8.4 Hz), 7.62 (1H, s), 7.40 (1H, s), 7.25 (1H, d), 7.17 (2H, d,
J = 8.4 Hz), 6.86 (1H, d), 4.22 (2H, q), 3.88 (3H, s), 2.68 (2H, s), 1.37 (3H, t); ESI-MS (m/z): 438.1 (M+H)
+, 460.1 (M+Na)
+。
Embodiment 9:3-(4-ethoxyl phenenyl)-6-{2-oxo-2-[4-(benzamido group formyl radical methoxyl group) phenyl] ethyl }-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-ethoxyl phenenyl)-6-{2-oxo-2-[4-(benzamido group formyl radical methoxyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.51 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 9.07 (1H, s), 7.98 (2H, d), 7.74 (2H, d), 7.44 (1H, s), 7.18~7.26 (5H, m), 7.05 (2H, d), 6.92 (2H, d), 4.92 (2H, s), 4.48 (2H, d), 4.15 (2H, q), 2.71 (2H, s), 1.38 (3H, t); ESI-MS (m/z): 555.1 (M+H)
+, 577.1 (M+Na)
+。
Embodiment 10:3-[(3-methyl-4-methoxyl group) phenyl]-6-{2-oxo-2-[4-(4-toluidine) formyl radical p-methoxy-phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone
According to embodiment 1 method, obtain product 3-[(3-methyl-4-methoxyl group) phenyl]-6-{2-oxo-2-[4-(4-toluidine) formyl radical p-methoxy-phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.44 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 10.10 (1H, s), 8.05 (2H, d,
J = 8.4 Hz), 7.78 (2H, d,
J = 7.2 Hz), 7.60 (2H, d,
J = 7.2 Hz), 7.57 (1H, d), 7.36 (1H, s), 7.30 (1H, s), 7.22 (2H, d,
J = 8.4 Hz), 7.11 (1H, d), 4.68 (2H, s), 3.78 (3H, s), 2.68 (2H, s), 2.35 (3H, s), 2.17 (3H, s); ESI-MS (m/z): 555.2 (M+H)
+, 577.2 (M+Na)
+。
Embodiment 11:3-[(3-methyl-4-hydroxyl) phenyl]-6-{2-oxo-2-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 1 method, obtain 3-[(3-methyl-4-hydroxyl) phenyl]-6-{2-oxo-2-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.34 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 9.87 (1H, s), 8.08 (2H, d,
J = 7.2 Hz), 7.65 (1H, s), 7.37 (1H, s), 7.12 (1H, s), 6.99 (2H, d,
J = 7.2 Hz), 6.64 (1H, d), 4.87 (2H, s), 3.71 (4H, t), 3.54 (4H, t), 2.76 (2H, s), 2.38 (3H, s); ESI-MS (m/z): 521.1 (M+H)
+ , 543.1 (M+Na)
+。
Embodiment 12:3-{4-[2-(piperidino) oxyethyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-oxyethyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 4 methods, obtain 3-{4-[2-(piperidino) oxyethyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-oxyethyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.40 g.
1H-NMR (300 MHz, DMSO-
d 6 ):
δ 7.96 (1H, d), 7.67 (2H, d,
J = 9.0 Hz), 7.61 (1H, s), 7.38 (1H, s), 7.24 (2H, d,
J = 9.0 Hz), 6.95 (1H, d), 4.32 (2H, t), 4.08 (2H, q), 2.85 (2H, t), 2.68 (2H, s), 2.28~2.36 (4H, m), 2.12 (3H, s), 1.46~1.57 (6H, m), 1.35 (3H, t); ESI-MS (m/z): 533.2 (M+H)
+ , 555.2 (M+Na)
+。
Embodiment 13:3-[4-(2-diethylin oxyethyl group) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7
H-thiazole is [3,2-also
b]-1,2, the preparation of 4-triazine-7-ketone.
According to embodiment 4 methods, obtain 3-[4-(2-diethylin oxyethyl group) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone 0.36 g.
1H-NMR (600 MHz, DMSO-
d 6 ):
δ 8.15 (2H, d,
J = 8.4 Hz), 7.72 (2H, d,
J = 7.2 Hz), 7.48 (2H, d,
J = 7.2 Hz), 7.38 (1H, s), 7.05 (2H, d,
J = 8.4 Hz), 4.32 (2H, q), 4.12 (2H, t), 2.94 (2H, t), 2.70 (2H, s), 2.42 (4H, q), 1.34 (3H, t), 1.10 (6H, t); ESI-MS (m/z): 507.2 (M+H)
+, 529.2 (M+Na)
+。
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:
Wherein
n
1Be 0 or 1; n
2Be 1 or 2;
R
1Can selectively be independently selected from H by 1,2 or 3 arbitrarily, halogen ,-OH ,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6,-O (CH
2) n
5CH
3,-CH
3,-CH
2CH
3,-NO
2
R
2Can selectively be independently selected from H by 1,2 or 3 arbitrarily, halogen ,-OH ,-O (CH
2) n
3NR
3R
4,-O (CH
2) n
4CONR
5R
6,-O (CH
2) n
5CH
3,-CH
3,-CH
2CH
3,-NO
2n
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; Hydrogen, methyl, hydroxyl, methoxyl group, oxyethyl group, nitro, fluorine, chlorine or bromine replace or unsubstituted phenyl group.
2. compound claimed in claim 1 is selected from:
3-(4-hydroxy phenyl)-6-[2-oxo-2-phenylethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-(4-bromophenyl)-6-[2-oxo-2-(4-p-methoxy-phenyl) ethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-(4-p-methoxy-phenyl)-6-[2-oxo-2-(4-chloro-phenyl-) ethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-[4-(diethylin formyl radical methoxyl group) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-{[4-(4-morpholinyl) formyl radical methoxyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-hydroxyl) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-[4-(benzamido group formyl radical methoxyl group) phenyl]-6-{2-oxo-2-[(3-methyl-4-oxyethyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-{[4-(4-chloroanilino) formyl radical methoxyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-methoxyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
The 3-[(4-hydroxy-3-methoxy) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-(4-ethoxyl phenenyl)-6-{2-oxo-2-[4-(benzamido group formyl radical methoxyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-[(3-methyl-4-methoxyl group) phenyl]-6-{2-oxo-2-[4-(4-toluidine) formyl radical p-methoxy-phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-[(3-methyl-4-hydroxyl) phenyl]-6-{2-oxo-2-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-{4-[2-(piperidino) oxyethyl group] phenyl }-6-{2-oxo-2-[(3-methyl-4-oxyethyl group) phenyl] ethyl }-7
H-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone
3-[4-(2-diethylin oxyethyl group) phenyl]-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-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.
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