CN107383068B - Thiazole and triazole -6- acetamide derivative and application - Google Patents
Thiazole and triazole -6- acetamide derivative and application Download PDFInfo
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- CN107383068B CN107383068B CN201710693223.4A CN201710693223A CN107383068B CN 107383068 B CN107383068 B CN 107383068B CN 201710693223 A CN201710693223 A CN 201710693223A CN 107383068 B CN107383068 B CN 107383068B
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- 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
R the invention discloses the thiazole of general formula I simultaneously [3,2-b] [1,2,4]-triazole -6- acetamide derivative derivative or its pharmaceutically acceptable hydrate, salt, including its stereoisomer or tautomer, in Formulas I1For hydrogen, methyl, halogen, hydroxyl, methoxyl group, acetyl group, propiono, nitro or alkoxy.Pyrrole radicals, piperidyl, morpholinyl, N methyl piperazine, N- phenylpiperazine are formed together with the nitrogen-atoms that the independent alkyl or R2 and R3 selected from C1-C6 of R2 and R3 is connected with them.Simultaneously [3,2-b] [1,2,4]-triazole -6- acetamide derivative has apparent inhibiting effect to acetylcholinesterase to thiazole of the invention, for enhancing the memory for suffering from dull-witted and Alzheimer's disease patient.The invention further relates to the preparation method of such compound and be used to prepare treatment senile dementia purposes.
Description
Technical field
Invention belongs to pharmaceutical technology field more particularly to thiazole simultaneously [3,2-b] [1,2,4]-triazole -6- second
Amide derivatives and preparation method thereof suffer from dull-witted and Alzheimer for improving with as acetylcholinesterase inhibitor
The application of family name disease patient memory.
Background technique
Alzheimer's disease is related with the degeneration of the cholinergic neuron in basal forebrain.Due to the knot of the degeneration
Fruit, the patient with the disease is in acetylcholine synthesis, choline acetyltransferase activity, acetylcholine esterase active and choline
Absorption aspects show significantly to decay.
Known acetylcholinesterase inhibitor is effective in terms of improving cholinergic activity, therefore can be used for improving A Er
The memory of thatch sea Mo's disease patient.By acetylcholine esterase inhibition, neurotransmission mediator in brain is can be improved in the compound
The level of acetylcholine, therefore memory can be enhanced.
Existing acetylcholinesterase inhibitor such as Tacrine, this bright, galanthamine etc. still remains drug resistance or medicine
Object dynamics defect.Acetylcholinesterase inhibitor of the compound of the present invention as brand new type has structure class
The characteristics of type is novel, and drug action is suitable with existing drug or is better than existing drug, there is good application value and exploitation to answer
Use prospect.
Summary of the invention
The purpose of the present invention is to provide a kind of thiazole simultaneously [3,2-b] [1,2,4]-triazole -6- acetamide derivative,
It is with good inhibiting activity of acetylcholinesterase.
Above-mentioned purpose of the invention is achieved by the following technical solution:
A kind of acetylcholinesterase inhibitor has the function of enhancing dementia and Alzheimer's disease memory in patients,
It is characterized by: the compound is simultaneously [3,2-b] [1,2,4]-triazole -6- acetamide derivative of the thiazole with general formula I
Or its pharmaceutically acceptable hydrate, salt, including its stereoisomer or tautomer；
Wherein, the R1 in Formulas I is hydrogen, methyl, halogen, hydroxyl, methoxyl group, acetyl group, propiono, nitro or alkoxy；
Form pyrrole radicals together with the nitrogen-atoms that the independent alkyl or R2 and R3 selected from C1-C6 of R2 and R3 is connected with them, piperidyl,
Morpholinyl, N methyl piperazine, N- phenylpiperazine.
The term " halogen " applied in the present invention includes fluorine, chlorine or bromine.
The present invention also provides the purposes that above compound is used to prepare treatment senile dementia.
" pharmaceutically acceptable salt " refers to the biopotency and property for remaining type I compound, and with suitable non-toxic
The 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, alginates, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphor
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 sulfonate, 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 sylvite, alkali salt,
Such as calcium and magnesium salts, the salt of organic base, such as dicyclohexyl amine salt, the salt of N- methyl-D-glucamine salt and amino acid, such as essence
Propylhomoserin, lysine etc., moreover, Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, such as first
The chlorine of base, ethyl, propyl and butyl, bromine and iodide；Dialkyl sulfate, such as dimethyl suflfate, 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,
The bromide of such as benzyl and phenethyl.It is preferred for generating the acid of acid-addition salts including hydrochloric acid and acetic acid.
The present invention also provides the preparation method of above-mentioned compound of Formula I, this method sees below formula.
Present system is studied and illustrates the structure and preparation of the compound, and the compound is as a new class of second
Acetylcholinesterase inhibitor, structure type are novel, provide completely new direction and wide to develop novel anti-senile dementia disease drug
Wealthy platform.
Specific embodiment
Embodiment 1
The preparation of 2- { 2- (4- chlorphenyl) thiazole [3,2-b] [1,2,4] triazole -6- base } acetic acid
Addition 0.1 mo1 of thiosemicarbazide in 250 mL there-necked flasks, 100 mL of methylene chloride, ice-water bath stirring and dissolving,
Add 0.13 mo1 pyridine.4- chlorobenzoyl chloride 0.13mo1 is slowly added dropwise at 0-5 DEG C, 20 min are added dropwise, 15 DEG C of reactions
2 h, reaction was completed.System has a large amount of white solids to occur, filtering.Gained white solid is dissolved in 80 mL mass fractions 5%
Sodium hydroxide solution in, be heated to reflux 2h, be down to room temperature, with the dilute hydrochloric acid tune pH to 5-6 of mass fraction 3.65%, have a large amount of
Light yellow solid is precipitated, and filters, and recrystallization obtains 5- (4- chlorphenyl) -3- sulfydryl -1,2,4- triazole 18.3g, yield
86.7%, ESI-MS (m/z): 212.3 (M+H)+.
By 0.6mol5- (4- chlorphenyl) -3- sulfydryl -1,2,4- triazole is added in the KOH solution of 10mL10%, then
It is added dropwise 0.01mol4- chloroacetyl acetacetic ester, after heating reaction 1h, ice water dilution there are a large amount of crystal to be precipitated, dry 4- [3-
(4- chlorphenyl) -1H-1,2,4- triazole -5- sulfenyls]-ethyl 3-oxobutanoate, yield 40%.
0.2mol4- [3- (4- chlorphenyl) -1H-1,2,4- triazole -5- sulfenyl]-ethyl 3-oxobutanoate is added to
In 120 DEG C of 85%PPA, 1h is reacted, is cooled to room temperature after reaction, ice water is added, there are a large amount of solids to be precipitated, filtered, anhydrous second
Alcohol is recrystallized to give 2- { 2- (4- chlorphenyl) thiazole simultaneously [3,2-b] [1,2,4] triazole -6- base } ethyl acetate, yield 42%.
0.1mol2- [2- (4- chlorphenyl) thiazole simultaneously [3,2-b] [1,2,4] triazole -6- base] ethyl acetate is added to
In the NaOH of 2mol/L, 20mL methanol is added, 2h is reacted at room temperature, methanol is removed under reduced pressure, with concentrated hydrochloric acid tune pH=2, is had a large amount of solid
Body is precipitated, and filters, and dehydrated alcohol recrystallizes to obtain buff powder 2- { 2- (4- chlorphenyl) thiazole [3,2-b] [1,2,4] three nitrogen
Azoles -6- base } acetic acid, yield 66%, ESI-MS (m/z): 294.3 (M+H)+.
Embodiment 2
N, N- dimethyl -2- { 2- (4- chlorphenyl) thiazole simultaneously [3,2-b] [1,2,4] triazole -6- base }-acetamide (
L1 preparation)
10mmol dimethylamine hydrochloride, 10mmol2- { 2- (4- chlorphenyl) thiazole [3,2-b] [1,2,4] triazole -6-
Base } acetic acid, 20mL methylene chloride is added in round-bottomed flask, then adds 12mmolEDCI, 12mmolHOBt and triethylamine
10mmol, after reacting at room temperature 12h, reaction solution successively uses 5%HCl, 5%NaHCO3, and saturation NaCl solution is washed, dry rear pillar chromatography point
From white solid, yield 32%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.50 (2H, d, J=8.4Hz), 7.41 (1H, s),
7.38 (2H, d, J=8.4Hz), 4.89 (2H, s), 3.96 (3H, s), 3.02 (3H, s)； ESI-MS (m/
Z): 321.4 (M+H)+.
Embodiment 3
N, N- diethyl -2- { 2- (4- chlorphenyl) thiazole simultaneously [3,2-b] [1,2,4] triazole -6- base }-acetamide (
L2 preparation)
Dimethylamine hydrochloride is replaced with diethylamine, synthetic method is referring to embodiment 2, yield 34%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.52 (2H, d, J=9.0Hz), 7.42 (1H, s),
7.37 (2H, d, J = 9.0Hz), 4.86 (2H, s), 3.98 (2H, m), 3.32 (2H, m), 1.18 (3H,
t), 1.05 (3H, t); ESI-MS (m/z): 349.0 (M+H)+。
Embodiment 4
2- (4- chlorphenyl) -6- [(1- oxo -1- piperidines) ethyl]-thiazole simultaneously [3,2-b] [1,2,4] triazole (L3)
Preparation
Dimethylamine hydrochloride is replaced with piperidines, synthetic method is referring to embodiment 2, yield 35%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.52 (2H, d, J=8.4Hz), 7.42 (1H, s),
7.37 (2H, d, J = 8.4Hz), 4.88 (2H, s), 3.44 (2H, m), 3.41 (2H, m), 1.60 (2H,
m), 1.55 (2H, m), 1.45 (2H, m); ESI-MS (m/z): 361.2 (M+H)+。
Embodiment 5
2- (4- chlorphenyl) -6- [(1- oxo -1- morpholine) ethyl]-thiazole simultaneously [3,2-b] [1,2,4] triazole (L4)
Preparation
Dimethylamine hydrochloride is replaced with morpholine, synthetic method is referring to embodiment 2, yield 36%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.51 (2H, d, J=8.4Hz), 7.41 (1H, s),
7.38 (2H, d, J = 8.4Hz), 4.78 (2H, s), 3.67 (4H, m), 3.37 (4H, m); ESI-MS (m/
z): 363.1(M+H)+。
Embodiment 6
2- (4- chlorphenyl) -6- [(1- oxo -1- (4- methyl piperazine)) ethyl]-thiazole simultaneously [3,2-b] [1,2,4] three nitrogen
The preparation of azoles (L5)
Dimethylamine hydrochloride is replaced with N methyl piperazine, synthetic method is referring to embodiment 2, yield 32%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.50 (2H, d, J=8.4Hz), 7.42 (1H, s), 7.31
(2H, d, J = 8.4Hz), 4.78 (2H, s), 3.66 (4H, dt), 3.44 (4H, t), 2.36 (3H, s);
ESI-MS (m/z): 376.0(M+H)+。
Embodiment 7
2- (4- chlorphenyl) -6- [(1- oxo-1-pyrrolidine) ethyl]-thiazole simultaneously [3,2-b] [1,2,4] triazole (
L6 preparation)
Dimethylamine hydrochloride is replaced with nafoxidine, synthetic method is referring to embodiment 2, yield 29%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.52 (2H, d, J=8.4Hz), 7.39 (1H, s), 7.28
(2H, d, J = 8.4Hz), 4.28 (2H, s), 3.63 (2H, t), 3.54 (2H, t), 2.07 (2H, m),
1.99 (2H, m); ESI-MS (m/z): 347.0(M+H)+。
Embodiment 8
N, N- di-n-butyl -2- { 2- (4- chlorphenyl) thiazole simultaneously [3,2-b] [1,2,4] triazole -6- base }-acetamide (
L7 preparation)
Dimethylamine hydrochloride is replaced with di-n-butyl, synthetic method is referring to embodiment 2, yield 47%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.52 (2H, d, J=9.0Hz), 7.38 (1H, s), 7.30
(2H, d, J = 9.0Hz), 4.06 (2H, s), 3.98 (2H, m), 3.38 (2H, m), 1.69 (2H, m),
1.55 (2H, m), 1.42 (2H, m), 1.30 (2H, m), 1.05 (6H, m); ESI-MS (m/z): 405.1
(M+H)+。
Embodiment 9
2- (4- chlorphenyl) -6- [(1- oxo -1- (4- phenylpiperazine)) ethyl]-thiazole simultaneously [1,2,4] three [3,2-b]
The preparation of nitrogen azoles (L8)
Dimethylamine hydrochloride N- phenylpiperazine is replaced, synthetic method is referring to embodiment 2, yield 32%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.48 (2H, d, J=8.4Hz), 7.42 (1H, s), 7.34
(2H, m), 7.30 (2H, d, J = 8.4Hz), 6.97 (5H, m), 3.95 (2H, s), 3.57(4H, dt),
3.35 (4H, dt); ESI-MS (m/z): 438.0(M+H)+。
Embodiment 10
The active determination test of acetylcholinesterase inhibitor
1. the preparation of material: positive control drug is set as hydrobromic acid neostigmine (SigmaN-2001), is formulated as 0.1M
Solution；0.5 unit of acetylcholinesterase (source of people) (SigmaC-1682)；Buffer solution is 100mM PBS solution (pH7.4),
Bis- sulphur dinitrobenzoic acid DTNB(D-8130 of 10mM) (being prepared with 100mM PBS), -20 DEG C are kept in dark place, now-making-now-using；
12.5mM acetylthiocholine ATCh(A-5751) it is dissolved in the water, -20 DEG C are kept in dark place, now-making-now-using；Test medicine is used
10 μM of solution are prepared into after DMSO dissolution.
2. method:
(1) sample is handled by such as following table method；
(2) 37 DEG C of continuous gently shakings preheat 15 minutes；
(3) 50mL ATCh and 50mL DTNB is added；
(4) 37 DEG C continuously gently shake about 20 minutes, until yellow occurs in reaction solution；
(5) the OD value at its 412nm is measured；
(6) inhibiting rate, acetylcholine ester enzyme inhibition rate=1- (OD experimental group-OD blank group)/(OD experiment contrast are calculated
Group-OD blank group) × 100%.The results are shown in Table 1.
(7) IC50 of acetylcholine esterase inhibition inhibitory activity is measured, the results are shown in Table 2.
3. result:
Compound L 1, L2, L3, L4, L5, L6, L7 and L8 have preferable inhibitory activity to acetylcholinesterase.
Claims (3)
1. a kind of acetylcholinesterase inhibitor has the function of enhancing dementia and Alzheimer's disease memory in patients,
Be characterized in that: the compound is simultaneously [3,2-b] [1,2,4]-triazole -6- acetamide derivative of the thiazole with general formula I；
Specifically:
N, N- dimethyl -2- { 2- (4- chlorphenyl) thiazole simultaneously [3,2-b] [1,2,4] triazole -6- base }-acetamide；
2- (4- chlorphenyl) -6- [(1- oxo -1- morpholine) ethyl]-thiazole simultaneously [3,2-b] [1,2,4] triazole；
2- (4- chlorphenyl) -6- [(1- oxo-1-pyrrolidine) ethyl]-thiazole simultaneously [3,2-b] [1,2,4] triazole；
2- (4- chlorphenyl) -6- [(1- oxo -1- (4- phenylpiperazine)) ethyl]-thiazole simultaneously [3,2-b] [1,2,4] triazole.
2. the preparation method of compound described in claim 1, it is characterised in that: its synthetic route is shown below:
。
3. the purposes that compound described in claim 1 is used to prepare anti senile dementia drug.
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Effective date of registration: 20220629 Address after: 051530 No. 18, Huangguan Road, xinzhaidian Industrial Zone, Zhao county, Shijiazhuang City, Hebei Province Patentee after: SHIJIAZHUANG POLEE PHARMACEUTICAL Co.,Ltd. Address before: 050035 Shijiazhuang University, No. 6, Changjiang Avenue, high tech Development Zone, Shijiazhuang City, Hebei Province Patentee before: SHIJIAZHUANG University |