CN104926838B - 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative and application - Google Patents
5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative and application Download PDFInfo
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- CN104926838B CN104926838B CN201510286939.3A CN201510286939A CN104926838B CN 104926838 B CN104926838 B CN 104926838B CN 201510286939 A CN201510286939 A CN 201510286939A CN 104926838 B CN104926838 B CN 104926838B
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- C07—ORGANIC CHEMISTRY
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative with a general formula I, or a pharmaceutically acceptable aquo-complex and salts of the derivative; the derivative comprises a stereisomer or a tautomer, wherein R1 and R2 in the formula I are respectively independent hydrogen, methyl, halogen, hydroxyl, methoxyl, acetyl, propiono, nitro or alkoxy. The 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative has an obvious inhibiting effect on acetylcholin esterase, and is used for improving the memory of a patient suffering from dementia and Alzheimer's disease. The invention also relates to a preparation method of the compound and an application in preparation of a drug for treating Senile Dementia.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to 5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazide spreads out
Biology and preparation method thereof suffers from dull-witted and Alzheimer's disease patient for improving with as acetylcholinesteraseinhibitors inhibitors
The application of memory.
Background technology
Alzheimer is relevant with the degeneration of the cholinergic neuron in basal forebrain.Due to the knot of the degeneration
Really, the patient with the disease is in acetylcholine synthesis, choline acetyltransferase activity, acetylcholine esterase active and choline
Significantly decay is shown in terms of absorption.
Known acetylcholinesteraseinhibitors inhibitors are effective in terms of cholinergic activity is improved, therefore can be used to improve A Er
The memory of thatch sea Mo's disease patient.By acetylcholine esterase inhibition, the compound can improve neurotransmission mediator in brain
The level of acetylcholine, therefore can hypermnesis.
, still there is drug resistance or medicine in existing acetylcholinesteraseinhibitors inhibitors such as tacrine, this bright, galantamine etc.
Thing kinetics defect.Acetylcholinesteraseinhibitors inhibitors of the compound of the present invention as brand new type, with structure class
Type is novel, and drug action is suitable with existing medicine or the characteristics of better than existing medicine, answers with good using value and exploitation
Use prospect.
The content of the invention
It is an object of the invention to provide a kind of 5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazide analog derivative,
Which has good inhibiting activity of acetylcholinesterase.
The above-mentioned purpose of the present invention is achieved by the following technical solution：
A kind of acetylcholinesteraseinhibitors inhibitors, with the effect for strengthening dull-witted and Alzheimer's disease memory in patients,
It is characterized in that：The compound be the 5H- with formula I [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazide derivative or
Its pharmaceutically acceptable hydrate, salt, including its stereoisomer or tautomer；
Wherein, the R in Formulas I1, R2Independently for hydrogen, methyl, halogen, hydroxyl, methoxyl group, acetyl group, propiono, nitre
Base or alkoxyl.
Compound according to claim 1, it is characterised in that：The R1For fluorine.
Compound according to claim 1, it is characterised in that：The R2For chlorine.
Compound according to claim 1, it is characterised in that：The R2For 2- (piperidino) ethyoxyl.
The term " halogen " applied in the present invention is including fluorine, chlorine or bromine.
Present invention also offers above-claimed cpd is used for the purposes for preparing treatment senile dementia.
" pharmaceutically acceptable salt " refers to the biopotency and property for remaining type I compound, and with suitable non-toxic
Conventional acid addition salts or base addition salts that organic or inorganic acid or organic or inorganic alkali are formed.The example of acid-addition salts includes acetic acid
Salt, adipate, alginate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, Camphora
Hydrochlorate, camsilate, cipionate, digluconate, lauryl sulfate, esilate, fumarate, Portugal heptan
Sugar lime, glycerophosphate, Hemisulphate, enanthate, caproate, hydrogen chlorate, hydrobromate, hydriodate, 2- hydroxyl second
Sulfonate, lactate, maleate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oxalates, pamoate, pectin ester
Hydrochlorate, persulfate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate,
Rhodanate, toluene fulfonate and undecylate.Alkali salt includes ammonium salt, alkali metal salt, such as sodium and potassium salt, alkali salt,
Such as calcium and magnesium salt, such as salt of organic base, hexanamine salt, N- methyl-D-glucamine salts, and the salt of aminoacid, such as essence
Propylhomoserin, lysine etc., and, Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, such as first
The chlorine of base, ethyl, propyl group and butyl, bromine and iodide；Dialkyl sulfate, such as dimethyl sulfate, diethylester, dibutyl ester and two
Pentyl ester；The chlorine of long chain halide, such as decyl, lauryl, myristyl and stearyl, bromine and iodide；Aralkyl halide,
Such as bromide of benzyl and phenethyl etc..The acid for being preferred for generating acid-addition salts includes hydrochloric acid and acetic acid.
Present invention also offers the preparation method of above-mentioned compound of Formula I, the method sees below formula.
Structure and the preparation of the compound is studied and illustrated to present system, and the compound is used as the new second of a class
Acetylcholinesterase inhibitor, structure type are novel, provide brand-new direction and extensively to develop new anti-senile dementia disease drug
Wealthy platform.
Specific embodiment
Embodiment 1
The preparation of 5- (4- fluorophenyls) -3- sulfydryl -1,2,4- triazoles
Thiosemicarbazide 9.1g (0.1 mo1), 100 mL of dichloromethane, ice-water bath stirring are added in 250 mL there-necked flasks
Dissolving, adds pyridine 10.3g (0.13 mo1).It is slowly added dropwise 4- fluorobenzoyl chloride 20.6g (0.13mo1) at 0-5 DEG C, 20
Min completion of dropping, 15 DEG C of 2 h of reaction, terminates reaction.System has a large amount of white solids to occur, and filters.Will be gained white solid molten
Solution in the sodium hydroxide solution of 80 mL mass fractions 5% is heated to reflux 2h, is down to room temperature, with the dilute of mass fraction 3.65%
Hydrochloric acid adjusts pH to 5-6, has a large amount of light yellow solids to separate out, filters, recrystallization, obtains 5- (4- fluorophenyls) -3- sulfydryl -1, and 2,4- tri-
17.2 g of nitrogen azoles, yield 88.2%, ESI-MS (m/z): 196.2(M+H)+。
Embodiment 2
5- (4- chlorphenyls) -3- sulfydryl -1, the preparation of 2,4- triazoles
Thiosemicarbazide 9.1g (0.1 mo1), 100 mL of dichloromethane, pyridine 10.3g (0.13 mo1) and 4- chlorobenzene first
Acyl chlorides 22.75g (0.13mo1) obtains 5- (4- chlorphenyls) -3- sulfydryl -1 according to 1 method of embodiment, 2,4- triazole 18.3g,
Yield 86.7%, ESI-MS (m/z): 212.3(M+H)+。
Embodiment 3
2- (4- fluorophenyls) -7- (4 chlorphenyl) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L1）Preparation
By 5- (4- fluorophenyls) -3- sulfydryls -1,2,4- triazole 1.95g (0.01 mol) and 4 '-chloro- 3- brom-acetophenones
2.47g (0.01mol), adds 50 mL acetic acids, back flow reaction 3h after the completion of TLC monitoring reactions, to be cooled to room temperature, react
Liquid separates out solid gradually, sucking filtration, and after water washing, ethyl alcohol recrystallization obtains 2.15 grams of white crystal, yield 62.73%.1H-NMR
(300MHz, DMSO), δ (ppm)：3.61 (H, d), 6.40 (H, t), 7.30 (2H, d,J=8.4Hz), 7.34 (2H, d,J=
8.4Hz), 7.44 (2H, d,J=8.4Hz), 7.77 (2H, d,J=8.4Hz)； ESI-MS (m/z)：344.1 (M+H)+。
Embodiment 4
2- (4- fluorophenyls) -7- (4- fluorophenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L2）System
It is standby
By 5- (4- fluorophenyls) -3- sulfydryls -1,2,4- triazole 1.95g (0.01 mol) and 4 '-fluoro- 3- brom-acetophenones
2.31g (0.01mol), adds 50 mL acetic acids, back flow reaction 3h after the completion of TLC monitoring reactions, to be cooled to room temperature, react
Liquid separates out solid gradually, sucking filtration, and after water washing, ethyl alcohol recrystallization obtains 2.08 grams of white crystal, yield 63.41%.1H-NMR
(300MHz, DMSO), δ (ppm)：3.60 (H, d), 6.41 (H, t), 7.19 (2H, d,J=8.4Hz), 7.30 (2H, d,J=
8.4Hz), 7.36 (2H, d,J=8.4Hz), 7.76 (2H, d,J=8.4Hz)； ESI-MS (m/z)：328.1 (M+H)+。
Embodiment 5
2- (4- fluorophenyls) -7- (4- methoxyphenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L3）
Preparation
By 5- (4- fluorophenyls) -3- sulfydryls -1,2,4- triazole 1.95g (0.01 mol) and 4 '-methoxyl group -3- bromobenzenes third
Ketone 2.43g (0.01mol), adds 50 mL acetic acids, back flow reaction 3h after the completion of TLC monitoring reactions, to be cooled to room temperature, instead
Liquid is answered to separate out gradually solid, sucking filtration, after water washing, ethyl alcohol recrystallization obtains 2.11 grams of white crystal, yield 62.05%.1H-
NMR (300MHz, DMSO), δ (ppm)：3.60 (H, d), 3.83 (3H, s), 6.41 (H, t), 6.84 (2H, d,J=8.4Hz),
7.27 (2H, d,J=8.4Hz), 7.32 (2H, d,J=8.4Hz), 7.76 (2H, d,J=8.4Hz)； ESI-MS (m/z)：340.2
(M+H)+。
Embodiment 6
2- (4- fluorophenyls) -7- (4- hydroxy phenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L4）'s
Prepare
By 5- (4- fluorophenyls) -3- sulfydryls -1,2,4- triazole 1.95g (0.01 mol) and 4 '-hydroxyl -3- brom-acetophenones
2.29g (0.01mol), adds 50 mL acetic acids, back flow reaction 3h after the completion of TLC monitoring reactions, to be cooled to room temperature, react
Liquid separates out solid gradually, sucking filtration, and after water washing, ethyl alcohol recrystallization obtains 2.29 grams of white crystal, yield 70.46%.1H-NMR
(300MHz, DMSO), δ (ppm)：3.60 (H, d), 6.41 (H, t), 6.68 (2H, d,J=8.4Hz), 7.21 (2H, d,J=
8.4Hz), 7.36 (2H, d,J=8.4Hz), 7.78 (2H, d,J=8.4Hz), 8.60 (H, s)； ESI-MS (m/z)：326.1 (M
+H)+。
Embodiment 7
- 5H- [1,2,4] triazole is simultaneously [5,1-b] for 2- (4- fluorophenyls) -7- { 4- [2- (piperidino) ethyoxyl] phenyl }
[1,3] thiazine（L5）Preparation
By 5- (4- fluorophenyls) -3- sulfydryls -1,2,4- triazole 1.95g (0.01 mol) and 4 '-[2- (piperidino) second
Epoxide] -3- brom-acetophenone 3.40g (0.01mol), add 50 mL acetic acids, back flow reaction 3h, TLC monitoring reactions to complete
Afterwards, it is cooled to room temperature, reactant liquor separates out solid gradually, sucking filtration, and after water washing, ethyl alcohol recrystallization obtains 2.69 grams of white crystal,
Yield 61.70%.1H-NMR (300MHz, DMSO), δ (ppm)：1.48 (2H, m), 1.65 (4H, t), 2.46 (4H, t),
2.70 (2H, t), 3.60 (H, d), 4.13 (2H, t), 6.41 (H, t), 6.94 (2H, d,J=8.4Hz), 7.27 (2H, d,J=
8.4Hz), 7.36 (2H, d,J=8.4Hz), 7.77 (2H, d,J=8.4Hz)； ESI-MS (m/z)：436.1 (M+H)+。
Embodiment 8
2- (4- chlorphenyls) -7- (4 chlorphenyl) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L6）Preparation
By 5- (4- chlorphenyls) -3- sulfydryls -1,2,4- triazole 2.11g (0.01 mol) and 4 '-chloro- 3- brom-acetophenones
2.47g (0.01mol), adds 50 mL acetic acids, back flow reaction 3h after the completion of TLC monitoring reactions, to be cooled to room temperature, react
Liquid separates out solid gradually, sucking filtration, and after water washing, ethyl alcohol recrystallization obtains 2.45 grams of white crystal, yield 68.06%.1H-NMR
(300MHz, DMSO), δ (ppm)：3.60 (H, d), 6.42 (H, t), 7.32 (2H, d,J=8.4Hz), 7.44 (2H, d,J=
8.4Hz), 7.56 (2H, d,J=8.4Hz), 8.12 (2H, d,J=8.4Hz)； ESI-MS (m/z)：360.3 (M+H)+。
Embodiment 9
2- (4- chlorphenyls) -7- (4- fluorophenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L7）System
It is standby
By 5- (4- chlorphenyls) -3- sulfydryls -1,2,4- triazole 2.11g (0.01 mol) and 4 '-fluoro- 3- brom-acetophenones
2.31g (0.01mol), adds 50 mL acetic acids, back flow reaction 3h after the completion of TLC monitoring reactions, to be cooled to room temperature, react
Liquid separates out solid gradually, sucking filtration, and after water washing, ethyl alcohol recrystallization obtains 2.27 grams of white crystal, yield 65.99%.1H-NMR
(300MHz, DMSO), δ (ppm)：3.60 (H, d), 6.41 (H, t), 7.20 (2H, d,J=8.4Hz), 7.36 (2H, d,J=
8.4Hz), 7.56 (2H, d,J=8.4Hz), 8.14 (2H, d,J=8.4Hz)； ESI-MS (m/z)：344.2 (M+H)+。
Embodiment 10
2- (4- chlorphenyls) -7- (4- methoxyphenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L8）
Preparation
By 5- (4- chlorphenyls) -3- sulfydryls -1,2,4- triazole 2.11g (0.01 mol) and 4 '-methoxyl group -3- bromobenzenes third
Ketone 2.43g (0.01mol), adds 50 mL acetic acids, back flow reaction 3h after the completion of TLC monitoring reactions, to be cooled to room temperature, instead
Liquid is answered to separate out gradually solid, sucking filtration, after water washing, ethyl alcohol recrystallization obtains 2.17 grams of white crystal, yield 60.95%.1H-
NMR (300MHz, DMSO), δ (ppm)：3.60 (H, d), 3.83 (3H, s), 6.41 (H, t), 6.74 (2H, d,J=8.4Hz),
7.27 (2H, d,J=8.4Hz), 7.55 (2H, d,J=8.4Hz), 8.12 (2H, d,J=8.4Hz)；ESI-MS (m/z)：356.2
(M+H)+。
Embodiment 11
2- (4- chlorphenyls) -7- (4- hydroxy phenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L9）'s
Prepare
By 5- (4- chlorphenyls) -3- sulfydryls -1,2,4- triazole 2.11g (0.01 mol) and 4 '-hydroxyl -3- brom-acetophenones
2.29g (0.01mol), adds 50 mL acetic acids, back flow reaction 3h after the completion of TLC monitoring reactions, to be cooled to room temperature, react
Liquid separates out solid gradually, sucking filtration, and after water washing, ethyl alcohol recrystallization obtains 2.54 grams of white crystal, yield 74.27%.1H-NMR
(300MHz, DMSO), δ (ppm)：3.60 (H, d), 6.41 (H, t), 6.85 (2H, d,J=8.4Hz), 7.26 (2H, d,J=
8.4Hz), 7.56 (2H, d,J=8.4Hz), 8.13 (2H, d,J=8.4Hz), 8.61 (H, s)； ESI-MS (m/z)：342.3 (M
+H)+。
Embodiment 12
- 5H- [1,2,4] triazole is simultaneously [5,1-b] for 2- (4- chlorphenyls) -7- { 4- [2- (piperidino) ethyoxyl] phenyl }
[1,3] thiazine（L10）Preparation
By 5- (4- chlorphenyls) -3- sulfydryls -1,2,4- triazole 2.11g (0.01 mol) and 4 '-[2- (piperidino) second
Epoxide] -3- brom-acetophenone 3.40g (0.01mol), add 50 mL acetic acids, back flow reaction 3h, TLC monitoring reactions to complete
Afterwards, it is cooled to room temperature, reactant liquor separates out solid gradually, sucking filtration, and after water washing, ethyl alcohol recrystallization obtains 2.87 grams of white crystal,
Yield 63.36%.1H-NMR (300MHz, DMSO), δ (ppm)：1.48 (2H, m), 1.64 (4H, t), 2.45 (4H, t),
2.70 (2H, t), 3.62 (H, d), 4.12 (2H, t), 6.41 (H, t), 6.92 (2H, d,J=8.4Hz), 7.28 (2H, d,J=
8.4Hz), 7.56 (2H, d,J=8.4Hz), 8.10 (2H, d,J=8.4Hz)； ESI-MS (m/z)：453.1 (M+H)+。
Embodiment 13
The active determination test of acetylcholinesteraseinhibitors inhibitors
1. the preparation of material：Positive control drug is set as hydrobromic acid neostigmine（SigmaN-2001）, it is formulated as 0.1M
Solution；Acetylcholinesterase（People source）（SigmaC-1682）0.5 unit；Buffer solution is 100mM PBS solutions（pH7.4）,
Bis- sulfur dinitrobenzoic acid DTNB of 10mM（D-8130）（Prepared with 100mM PBS）, -20 DEG C keep in dark place, now-making-now-using；
12.5mM acetylthiocholine ATCh（A-5751）It is dissolved in the water, -20 DEG C keep in dark place, now-making-now-using；Test medicine is used
10 μM of solution are prepared into after DMSO dissolvings.
2. method：
(1) sample is processed by such as following table method；
(2) 37 DEG C of continuous gently shakings are preheated 15 minutes；
(3) 50mL ATCh and 50mL DTNB are added；
(4) 37 DEG C continuously gently shake about 20 minutes, until yellow occurs in reactant liquor；
(5) the OD values at its 412nm are determined；
(6) suppression ratio, acetylcholine ester enzyme inhibition rate=1- (OD experimental group-OD blank groups)/(OD experiment contrasts are calculated
Group-OD blank groups) × 100%, sample segment suppression ratio is as shown in table 1；
(7) measure the IC of acetylcholine esterase inhibition inhibitory activity50, as a result as shown in table 2.
3. result：
Compound L 1, L2, L3, L4, L5, L6, L7, L8, L9 and L10 has to acetylcholinesterase preferably suppress work
Property.
Claims (3)
1. a kind of acetylcholinesteraseinhibitors inhibitors, it is characterised in that：The compound is the 5H- with formula I [1,2,4] triazole
And [5,1-b] [1,3] thiazide derivative；
The compound is specially：
2- (4- fluorophenyls) -7- (4 chlorphenyl) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L1）；2- (4- fluorobenzene
Base) -7- (4- fluorophenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L2）；
2- (4- fluorophenyls) -7- (4- methoxyphenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L3）；
2- (4- fluorophenyls) -7- (4- hydroxy phenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L4）；
2- (4- fluorophenyls) -7- { 4- [2- (piperidino) ethyoxyl] phenyl } -5H- [1,2,4] triazole simultaneously [5,1-b] [1,
3] thiazine（L5）；
2- (4- chlorphenyls) -7- (4 chlorphenyl) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L6）；
2- (4- chlorphenyls) -7- (4- fluorophenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L7）；
2- (4- chlorphenyls) -7- (4- methoxyphenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L8）；
2- (4- chlorphenyls) -7- (4- hydroxy phenyls) -5H- [1,2,4] triazole simultaneously [5,1-b] [1,3] thiazine（L9）；
2- (4- chlorphenyls) -7- { 4- [2- (piperidino) ethyoxyl] phenyl } -5H- [1,2,4] triazole simultaneously [5,1-b] [1,
3] thiazine（L10）.
2. the preparation method of the compound described in claim 1, it is characterised in that：Its synthetic route is shown below：
。
3. the compound described in claim 1 is used for the purposes for preparing treatment senile dementia.
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| CN102807575A (en) * | 2012-08-09 | 2012-12-05 | 石家庄学院 | 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative and application thereof |
| CN103012438A (en) * | 2012-11-15 | 2013-04-03 | 沈阳药科大学 | Alkoxy substituted thiazolo [3,2-b]-1,2,4-triazine derivatives and application thereof |
| CN103012439A (en) * | 2012-11-15 | 2013-04-03 | 沈阳药科大学 | Benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and application thereof |
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