CN103012439B - 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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- CN103012439B CN103012439B CN201210459462.0A CN201210459462A CN103012439B CN 103012439 B CN103012439 B CN 103012439B CN 201210459462 A CN201210459462 A CN 201210459462A CN 103012439 B CN103012439 B CN 103012439B
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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 art, relate to thiazole also [3, the 2-that benzoyl replaces
b]-1,2,4-triazine derivatives and application thereof, be specifically related to thiazole also [3, the 2-that benzoyl replaces
b] steric isomer of-1,2,4-triazine derivatives and this compounds and the salt be pharmaceutically suitable for and application thereof.This compounds is acetylcholinesterase depressant, can be used for raising and suffers from the dull-witted and sick man memory of Alzheimer's disease.
Background technology
Alzheimer's disease is relevant with the degeneration of the cholinergic neuron in basal forebrain, and cholinergic neuron plays an important role in recognition function (comprising memory).Due to the result of described degeneration, the patient suffering from this disease shows obvious decay in vagusstoff synthesis, choline acetyltransferase activity, acetylcholine esterase active and choline absorption.
Known acetylcholinesterase depressant is effective in raising cholinergic activity, therefore can be used for the memory improving Alzheimer's disease patient.Described compound, by acetylcholine esterase inhibition activity, delays the speed of acetylcholine hydrolyzation, improves the level as neurotransmission transmitter acetylcholine in brain, thus hypermnesis.
Existing acetylcholinesterase depressant, as tacrine, this bright of profit, all there is resistance or pharmacokinetic deficits in lycoremine etc.
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 be used alone to improve the dull-witted and sick man memory of Alzheimer's disease.
The present invention relates to formula I, its steric isomer or its salt of sour addition be pharmaceutically suitable for, its prodrug and pharmaceutical active metabolite, and the acceptable salt of the medicine of above-claimed cpd:
（I）
Wherein
N
1it is the integer of 0 to 1; n
2it is the integer of 1 to 2; I.e. n
1be 0 or 1; n
2be 1 or 2;
R
1can optionally by 1,2 or 3 independently selected from H, 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 optionally by 1,2 or 3 independently selected from H, 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 2,3 or 4, n
4be 1,2 or 3, n
5be 1,2,3,4 or 5;
Wherein R
3r
4independently selected from methyl or ethyl, or R
3r
4pyrrolidyl is formed, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring together with the nitrogen-atoms that they are connected; Or be separately selected from hydrogen, methyl, hydroxyl, methoxyl group, oxyethyl group, nitro, fluorine, the substituted or unsubstituted benzene radicals of chlorine or bromine;
R
5r
6independently be selected from methyl or ethyl, or R
5r
6pyrrolidyl is formed, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring together with the nitrogen-atoms that they are connected; Or be separately selected from hydrogen, methyl, hydroxyl, methoxyl group, oxyethyl group, nitro, fluorine, the substituted or unsubstituted benzene radicals of chlorine or bromine.
" the acceptable salt of medicine " refers to the biopotency and the character that remain formula I, and with the acid of suitable non-toxic organic or inorganic or the conventional acid addition salts that formed of organic or inorganic alkali or base addition salt.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, 2-isethionate, lactic acid salt, maleate, mesylate, 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, such as sodium and sylvite, alkaline earth salt, such as calcium and magnesium salts, the salt of organic bases, such as dicyclohexyl amine salt,
n-methyl-D-glucamine salt, and amino acid whose salt, such as arginine, Methionin etc., and also Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, as methyl, and ethyl, the chlorine of propyl group and butyl, bromine and iodide; Dialkyl sulfate, as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long chain halide, as decyl, lauryl, the chlorine of myristyl and stearyl-, bromine and iodide; Aralkyl halide, as the bromide etc. of benzyl and styroyl.The acid being preferred for generating acid salt comprises hydrochloric acid and acetic acid.
" pharmaceutically acceptable ", as pharmaceutically acceptable ground carrier, excipient, prodrug etc., refers to pharmacologically 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.
The present invention also relates to the medicinal compositions of acetylcholine esterase inhibition, the carrier that said composition contains formula I compound or its steric isomer or its acid salt be pharmaceutically suitable for and is pharmaceutically suitable for.
The invention still further relates to the method suppressing acetylcholinesterase in Mammals, the method comprises takes the formula I of acetylcholine esterase inhibition effective dose or its steric isomer or its acid salt be pharmaceutically suitable for Mammals.
The present invention also relates to the method for formula I hypermnesis or treatment or prevention Alzheimer's disease, the method comprises the formula I or its steric isomer or its acid salt be pharmaceutically suitable for of taking hypermnesis or treatment or prevention Alzheimer's disease effective dose.
The term " halogen " applied in the present invention comprises chlorine, bromine or fluorine.
" replacement ", unless otherwise indicated, refers to that substituting group can exist in one or more position, and substituting group is independently selected from option particularly.
The compounds of this invention can be taken to patient by diverse ways, such as with capsule or tablet oral, with sterile solution agent or suspensoid administration, and in some cases, can with solution form intravenous injection.Free alkali compound of the present invention can be carried out preparing and taking with its acid addition salt form thereof be pharmaceutically 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 by single dose or divided doses administration.For administration, if take solution or suspensoid, so the concentration of the compounds of this invention is at least 1% (massfraction), better by 4-70% (massfraction) (based on the total mass of unit).The non-dose unit through gastrointestinal administration is generally containing 5 mg-100 mg active compounds of having an appointment.
The compounds of this invention can together with inert diluent or edible carrier oral administration, or they can be encapsulated in gelatine capsule, or 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% (massfraction) (based on the total mass of unit).Oral dosage units is generally containing 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.The effective dose of certain compound by the effect according to each compound used, want the seriousness of disease therapy and character, the particular patient that will treat and changing.Generally, with the dosage of about 0.01 mg to about 20 mg/kg body weight/day, system of compounds administration can obtain effective result.Should with comparatively low dosage begin treatment.Subsequently can solid dosage as capsule, tablet or pulvis, or in liquid form as solution or suspensions for oral administration.These compounds can also the form of sterile solution or suspension be injected outward through intestines.
In the embodiment of method of the present invention, preferably activeconstituents is incorporated in the composition containing pharmaceutical carrier, wherein containing the compounds of this invention or its pharmaceutical salts of the 5%-90 % (massfraction) that has an appointment." pharmaceutical carrier " refers to the known pharmaceutical excipients for preparing the pharmaceutical active compounds taken orally to animal, and they are substantially nontoxic and non-teratogenesis under conditions of use.Can prepare this composition with the known technology preparing tablet, capsule, elixir, syrup, emulsion, dispersion and wetting properties and pulvis foamy, it can containing known suitable vehicle useful in preparation particular type composition.Preferred route of administration is oral administration.For oral administration, formula I can be mixed with solid-state or liquid formulation 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 such as tensio-active agent, lubricant and inert filler as lactose, sucrose, calcium phosphate and W-Gum.In another embodiment, the compounds of this invention with the matrix of routine as lactose, sucrose compressing tablet together with W-Gum, can add tackiness agent as gum arabic, W-Gum or gelatin; For helping the disintegrating agent of disintegration of tablet and dissolving as yam starch, alginic acid, W-Gum and guar gum; Mobility for improving tablet and powder prevents tablet material from sticking to lubricant on tablet die and 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 for improving tablet.Suitable vehicle for Oral liquid dosage forms comprises water and alcohol as ethanol, phenylcarbinol and polyvinyl alcohol, adds or does not add medicinal surfactant, suspension agent or floating agent.Formula I also can intestines external administration, namely subcutaneous, intravenously, intramuscular, or intraperitoneal, with the injectable dosage formulations administration of the compound in the acceptable thinner of physiology, wherein also containing pharmaceutical carrier, can be sterile liquid or liquid and close mixture as water, salt solution, D/W and relevant sugar soln, alcohol is as ethanol, Virahol, or cetyl alcohol, glycol is as propylene glycol or polyoxyethylene glycol, glycerol ketals is as 2, 2-dimethyl-l, 3-dioxolane-4-methyl alcohol, ether is as poly(oxyethylene glycol) 400, oil, lipid acid, fatty acid ester or glyceryl ester, or acetylated fatty acid glyceride, add or do not add pharmaceutically acceptable tensio-active agent as soap or washing composition, suspension agent is as pectin, carbomer, methylcellulose gum, isopropyl methyl Mierocrystalline cellulose, or acid methyl cellulose, or emulsifying agent and other pharmaceutically acceptable additive.The example of the oil of intestines external preparation used in the present invention is those from the oil of oil, animal, plant or synthesis, such as 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 be applicable to is such as ethyl oleate and Isopropyl myristate.Suitable soap comprises fatty acid alkali metal salt, amine salt and triethanolamine salt, suitable tensio-active agent, comprises cats product as dimethyl dialkyl halogeno-amine, alkyl, alky pyridinium halides; Anion surfactant as alkyl, aryl, sulfonate, alkyl, ether and monoglyceride sulfates and sulfosuccinate; Nonionogenic tenside as fatty amine oxide, fatty acid alkyl amide, and polyoxyethylene polytrimethylene multipolymer; With amphoterics as alanine alkyl ester and alkyl imidazoline quaternary ammonium salt, and composition thereof.Intestines topical composition of the present invention is generally in the solution containing the formula I compound of have an appointment 0.5 to about 25% (massfraction).Sanitas and buffer reagent can be used.In order to by the stimulation of injection site to minimum or is eliminated, this composition can contain the nonionogenic tenside that hydrophilic-lipophilic balance number (HLB) be about 12 to about 17.In this preparation, the amount of this tensio-active agent is about 5% to about 15% (massfraction).This tensio-active agent can be have the single component of above HLB value or the mixture with required HLB of two or more compositions.Example for the tensio-active agent of intestines external preparation is polyhexene fatty acid esters of sorbitan class, and the high molecular weight adducts of such as polyoxyethylene-sorbitan mono-oleate and oxyethane and a hydrophobic group is formed by propylene oxide and propylene glycol condensation.Mixture of the present invention can also percutaneous dosing.This is undertaken by the solution preparing required compound simply, preferably prepares solution with the solvent of known promotion Transdermal absorption as ethanol or dimethyl sulfoxide (DMSO) (DMSO) add or do not add other vehicle.The medicine that preferred percutaneous dosing uses the medicine of storage and porous membranous type or has a solid substrate change carries out.These devices generally containing limit an one outside surface backing, one can pass through the viscous layer on another surface of restriction of active medicine and at least one storage containing active medicine between outside surface.Or active medicine is included in the many tiny capsule and pills be distributed in whole transmissibility viscous layer.No matter which kind of situation, active medicine is transported to from storage or microcapsule the viscous layer that can pass through active medicine continuously by a film, the skin of the latter and patient or mucosal contact.If active medicine is absorbed through skin, then active medicine that is controllable and predetermined flow velocity is applied to patient.When using microcapsule, coating agent also plays the effect of film.By in another device of the compounds of this invention transdermal administration, pharmaceutical active compounds is included in matrix, it from matrix with expection progressively, constant and controllable speed release.Matrix is permeability to compound by diffusion or the release of micropore stream.Two class releases are had at least to be possible in such systems.Dispersal events is there is when matrix is imporosity.Pharmaceutical active compounds to be dissolved in matrix and diffuse transmission matrix itself.When being transported by liquid phase in the aperture of pharmaceutical active compounds in matrix, there is the release of micropore stream.
The compounds of this invention can measure by the biological test of many standards or pharmacology test 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) (SigmaC-1682) 0.5 unit.
Buffered soln is 100 mM PBS solution (pH7.4), 10 mM bis-sulphur dinitrobenzoic acid DTNB(D-8130) (prepare) ， – 20 ° of C with 100 mM PBS to keep in Dark Place, now-making-now-using.
12.5 mM acetylthiocholine ATCh (A-5751) the ， – 20 ° of C that are dissolved in the water keep in Dark Place, now-making-now-using.
Test medicine DMSO is prepared into 10 μMs of solution after dissolving.
Method and result
Operation steps:
(1) processing sample as follows.
(2) 37 ° of continuous jolting preheating 15 min gently of C.
(3) 50 mL ATCh and 50 mL DTNB are added.
(4) 37 ° of continuous jolting about 20 min gently of C, until reaction solution occurs yellow.
(5) the OD value at its 412 nm place is measured.
(6) inhibiting rate is calculated.
Sample segment inhibiting rate is listed as follows (n=3):
| 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 |
| 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, as the new acetylcholinesterase depressant of a class, has structure type novelty, and drug action and existing medicine are quite or be better than the feature of existing medicine.Relative to prior art, containing thiazole also [3, the 2-that benzoyl replaces
b]-1,2,4-triazin-6 position side chains have had obvious change, and the inhibiting rate of sample to acetylcholinesterase has had significant raising, has good using value and development prospect.
Embodiment
Reaction formula 1 summarises the synthesis step preparing the compounds of this invention.
The thiazole that reaction formula 1 benzoyl replaces is [3,2-b]-1,2,4-preparation of pyrrolotriazine derivatives also
Wherein
N
1it is the integer of 0 to 1; n
2it is the integer of 1 to 2;
R
1can optionally by 1,2 or 3 independently selected from H, 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 optionally by 1,2 or 3 independently selected from H, 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 the integer of 2 to 4, n
4be the integer of 1 to 3, n
5it is the integer of 1 to 5;
Wherein R
3r
4independently selected from methyl or ethyl, or R
3r
4pyrrolidyl is formed, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring together with the nitrogen-atoms that they are connected; Or be separately selected from hydrogen and substituted or unsubstituted benzene radicals;
R
5r
6independently be selected from methyl or ethyl, or R
5r
6pyrrolidyl is formed, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, benzamido group, 4-chloroanilino, 4-toluidine or hexamethylene imine basic ring together with the nitrogen-atoms that they are connected; Or be separately selected from hydrogen and substituted or unsubstituted benzene radicals.
The present invention is described in detail with following example.But, it should be understood that and the invention is not restricted to the concrete following example described.
Embodiment 1:3-(4-hydroxy phenyl)-6-[2-oxo-2-phenylethyl]-7
h-thiazole is [3,2-also
b] preparation of-1,2,4-triazine-7-ketone
By 50 mL toluene, 0.1 mol sodium ethylate and 0.05 mol oxalic acid diethyl ester join in 500 mL round-bottomed flasks, and reflux 5 min adds 0.02 mol methyl phenyl ketone, room temperature reaction 10 h.After completion of the reaction, will pour 100mL water into, separatory in reaction solution, water intaking layer, by water layer 20 mL washed with diethylether, 1 mol/L hcl acidifying, has solid to separate out.Cooling, suction filtration, washing, dry.Obtain faint yellow solid, ethyl alcohol recrystallization, obtain white crystal 9.2 g, yield 90%.
By 2,4-dioxo-4-phenylbutyrate ethyl ester 1.0 g (0.004mol), thiosemicarbazide 0.37g (0.004mol), ethanol 20 mL, water 20 mL joins in 250 mL round-bottomed flasks successively, then with 40% aqueous sodium hydroxide solution, the pH value of reaction solution is adjusted to 11, stirs, heating reflux reaction 4 h, cool to room temperature.With concentrated hydrochloric acid, the pH value of reaction solution is adjusted to 2, has a large amount of Off-white solid to separate out, suction filtration, 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)。
6-[2-oxo-2-phenylethyl]-3-sulfo--2, the 4-dihydro-3 that upper step is obtained
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 100 mL round-bottomed flasks, and heating reflux reaction 10 h, TLC monitoring reaction is to reacting completely.After cooling, suction filtration, 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 ):
δ13.26 (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] preparation of-1,2,4-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 ):
δ7.96 (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] preparation of-1,2,4-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 ):
δ8.08 (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] preparation of-1,2,4-triazine-7-ketone.
Under stirring at room temperature condition, to 3-(4-the hydroxy phenyl)-6-[2-oxo-2-(4-ethoxyl phenenyl) ethyl]-7 of 0.002 mol
h-thiazole is [3,2-also
b]-1,2,4-triazine-7-ketone acetone or alcohol solution in add corresponding 0.002 mol
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, room temperature is cooled to after question response, reaction solution is concentrated into dry, adds saturated aqueous common salt 30 mL, extracted with diethyl ether.Organic layer drying obtains thick product, ethyl alcohol recrystallization with concentrated, 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 ):
δ8.04 (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] preparation of-1,2,4-triazine-7-ketone.
According to embodiment 4 method, 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 ):
δ9.78 (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] preparation of-1,2,4-triazine-7-ketone.
According to embodiment 4 method, 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 ):
δ8.98 (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] preparation of-1,2,4-triazine-7-ketone.
According to embodiment 4 method, 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 ):
δ10.21 (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] preparation of-1,2,4-triazine-7-ketone.
According to embodiment 1 method, obtain 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 ):
δ10.12 (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] preparation of-1,2,4-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 ):
δ9.07 (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] preparation of-1,2,4-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 ):
δ10.10 (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] preparation of-1,2,4-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 ):
δ9.87 (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] preparation of-1,2,4-triazine-7-ketone.
According to embodiment 4 method, 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 ):
δ7.96 (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] preparation of-1,2,4-triazine-7-ketone.
According to embodiment 4 method, 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 ):
δ8.15 (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 is only preferred embodiment of the present invention, and be not restriction the present invention being made to other form, any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the Equivalent embodiments of equivalent variations.But everyly do not depart from technical solution of the present invention content, any simple modification, equivalent variations and the remodeling done above embodiment according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Claims (3)
1. thiazole also [3,2-b]-1,2,4-pyrrolotriazine derivatives of replacing of benzoyl, 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
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.
2. a pharmaceutical composition, comprises as the compound according to claim 1 of activeconstituents and pharmaceutically acceptable carrier or excipient.
3. compound according to claim 1 or the application of composition according to claim 2 in preparation treatment degenerative dementia disease drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002040486A2 (en) * | 2000-11-17 | 2002-05-23 | Bristol-Myers Squibb Company | METHODS OF TREATING p38 KINASE-ASSOCIATED CONDITIONS AND PYRROLOTRIAZINE COMPOUNDS USEFUL AS KINASE INHIBITORS |
| CN101456872A (en) * | 2008-01-24 | 2009-06-17 | 沈阳药科大学 | Thiazole[3,2-a] miazine derivates and use thereof |
| 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 CN201210459462.0A patent/CN103012439B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002040486A2 (en) * | 2000-11-17 | 2002-05-23 | Bristol-Myers Squibb Company | METHODS OF TREATING p38 KINASE-ASSOCIATED CONDITIONS AND PYRROLOTRIAZINE COMPOUNDS USEFUL AS KINASE INHIBITORS |
| CN101456872A (en) * | 2008-01-24 | 2009-06-17 | 沈阳药科大学 | Thiazole[3,2-a] miazine derivates and use thereof |
| 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,等.Design, synthesis, and biological evaluation of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives as novel acetylcholinesterase inhibitors.《ARKIVOC》.2009,第10卷第333-338页,尤其Scheme 1,Table 2. * |
| Zhe Jin,等.Synthesis and Biological Evaluation of 3,6-diaryl-7H-thiazolo[3,2-b][1,2,4]triazin-7-one Derivatives as Acetylcholinesterase Inhibitors.《Arch. Pharm. Res.》.2010,第33卷(第10期),第1641-1649页,尤其摘要,Scheme 1. * |
| 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》.2009,第19卷(第4期),第251-256页,尤其参见Figure 3,Table 1. * |
| 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》.2011,第21卷(第1期),第25-31页,尤其参见Figure 2-3,Table 3. * |
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