CN112047962A - 2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivative and application thereof - Google Patents
2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivative and application thereof Download PDFInfo
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Abstract
The invention discloses 2H-thiazolo [3,2-b ] of a general formula I]-1,2, 4-triazine-3, 7-dione derivatives or pharmaceutically acceptable hydrates, salts thereof, including stereoisomers or tautomers thereof, R in formula I1And R2Optionally 1,2 or 3 independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, acetyl, propionyl, nitro or trifluoromethyl. 2H-thiazolo [3,2-b ]]The (E) -1,2, 4-triazine-3, 7-diketone derivatives have obvious inhibitory effect on acetylcholinesterase and are used for enhancing the memory of patients suffering from dementia and Alzheimer's disease. The invention also relates to a preparation method of the compound and application of the compound in preparing a medicament for treating senile dementia.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to 2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivatives, a preparation method thereof and application of the derivatives as acetylcholinesterase inhibitors for improving memory of patients suffering from dementia and Alzheimer's disease.
Background
Alzheimer's disease is associated with the degeneration of cholinergic neurons in the basal forebrain. As a result of said degeneration, patients suffering from this disease show a marked attenuation in acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity and choline absorption.
Acetylcholinesterase inhibitors are known to be effective in increasing cholinergic activity and thus may be used to improve memory in alzheimer's patients. By inhibiting acetylcholinesterase, the compounds can increase the level of the neurotransmitter acetylcholine in the brain, thereby enhancing memory.
The existing acetylcholinesterase inhibitors such as tacrine, strychnine, galanthamine and the like still have drug resistance or pharmacokinetic defects. The compound of the invention is used as an acetylcholinesterase inhibitor with a brand new structure type, has the characteristics of novel structure type, equivalent or superior drug effect to the existing drug, and has good application value and development and application prospects.
Disclosure of Invention
The invention aims to provide a 2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivative which has good acetylcholinesterase inhibition activity.
The above object of the present invention is achieved by the following technical solutions:
an acetylcholinesterase inhibitor having the ability to enhance memory in patients with dementia and alzheimer's disease, characterized by: the compound is a 2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivative with a general formula I or pharmaceutically acceptable hydrate and salt thereof, including a stereoisomer or a tautomer thereof;
wherein R in the formula I1And R2Optionally 1,2 or 3 independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, acetyl, propionyl, nitro or trifluoromethyl.
The term "halogen" as used in the present invention includes fluorine, chlorine or bromine.
The invention also provides the application of the compound in preparing a medicament for treating senile dementia.
"pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts which retain the biological potency and properties of the compounds of formula I and which are formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids, such as arginine, lysine, and the like, and basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides and the like. Preferred acids for forming acid addition salts include hydrochloric acid and acetic acid.
The present invention also provides a process for the preparation of a compound of formula I as described above, which process is represented by the following formula:
the invention systematically researches and explains the structure and preparation of the compound, the compound is used as a novel acetylcholinesterase inhibitor, the structure type is novel, and a brand new direction and a wide platform are provided for developing novel anti-senile dementia drugs.
Detailed Description
Example 1
Preparation of 3, 4-dihydro-6-benzyl-3-thio-1, 2, 4-triazin-5 (2H) -one
0.1mol of benzaldehyde, 0.13 mol of acetylglycine, 0.12mol of anhydrous sodium acetate and 50 g of acetic anhydride are sequentially added into a 100 mL three-necked bottle, the temperature is controlled at 90 ℃, the mixture is stirred and reacts for 5 hours, after the mixture is cooled to room temperature, the solution becomes solid, the solution is filtered and filtered, and filter cakes are washed by cold water to obtain the 2-methyl-4-benzylidene oxazolone with the yield of 100 percent.
Adding 0.1mol of 2-methyl-4-benzylidene oxazolone, 150 mL of water and 170 mL of acetone into a round-bottom flask in sequence, heating, refluxing, stirring and reacting for 12 h, cooling to room temperature after TLC monitoring reaction is finished, precipitating a large amount of solid, performing suction filtration, washing a filter cake with cold water and a small amount of acetone, and drying to obtain the alpha-acetamido-beta-phenylacrylic acid with the yield of 90%.
And (2) sequentially adding 0.1mol of alpha-acetamido-beta-phenylacrylic acid and 220 mL of 1mol/L HCl solution into a 500mL round-bottom flask, heating and refluxing for reaction for 7 h, stopping the reaction after TLC monitoring reaction is finished, cooling, precipitating a large amount of solid, performing suction filtration, and drying a filter cake to obtain the beta-phenylpyruvic acid with the yield of 85%.
Adding 0.1mol of beta-phenylpyruvic acid, 0.1mol of thiosemicarbazide, 60 mL of ethanol and 60 mL of H2O 60 into a 250 mL round-bottom flask, adjusting the pH to be about 11 by using 1mol/L NaOH solution, heating and refluxing for 2H, cooling to room temperature, adjusting the pH to be about 2 by using concentrated hydrochloric acid, precipitating a large amount of milk solid, carrying out suction filtration, drying, and recrystallizing by using ethanol to obtain the 3, 4-dihydro-6-benzyl-3-thio-1, 2, 4-triazine-5 (2H) -ketone with the yield of 75%.
Example 2
(E) Preparation of (E) -6-benzyl-2-benzylidene-2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione (L1)
Adding 1mmol of 3, 4-dihydro-6-benzyl-3-thio-1, 2, 4-triazine-5 (2H) -ketone, 1mmol of bromoacetonitrile, 1mmol of benzaldehyde and 5mL of glacial vinegar into a round-bottom flask, carrying out reflux reaction for 10H, cooling, neutralizing with ammonia water, carrying out suction filtration, and recrystallizing a solid with absolute ethyl alcohol to obtain the yield of 68%. Mp 180 ℃ 182 ℃; ESI-MS (M/z): 347.7 (M + H) +, 369.6 (M + Na) +, 718.3 (2M + Na) +;1H NMR (600 MHz, DMSO) 8.25 (s, 1H), 7.77 (d, J = 6.8 Hz, 2H), 7.64-7.55 (M, 3H), 7.24-7.34 (M, 5H), 4.01 (s, 2H); 13C NMR (151 MHz, DMSO) 165.49, 159.90, 154.19, 138.48, 136.04, 132.96, 132.22, 131.25, 130.14, 129.67, 128.89, 127.28, 117.48, 36.95).
Example 3
(E) Preparation of (E) -6-benzyl-2- (4-methoxybenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione (L2)
Benzaldehyde was replaced with p-methoxybenzaldehyde, and the synthesis method was referenced to example 2, yield 60%. Mp 190 ℃; ESI-MS (M/z):400.3 (M + Na) +;1H NMR (600 MHz, DMSO) 8.20 (s, 1H), 7.75 (d, J = 9 Hz, 2H), 7.36-7.21 (M, 5H), 7.17 (d, J = 9 Hz, 2H), 4.01 (s, 2H), 3.86 (s, 3H); 13C NMR (151 MHz, DMSO) 165.37, 162.63, 159.96, 154.21, 138.70, 136.10, 133.71, 129.67, 128.87, 127.25, 125.51, 115.79, 113.80, 56.21, 36.86.
Example 4
(E) Preparation of (E) -6-benzyl-2- (4-fluorobenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione (L3)
Benzaldehyde was replaced with p-fluorobenzaldehyde, and the synthesis method was according to example 2 with a yield of 72%.1H NMR (600 MHz, DMSO), (ppm): 8.27 (s, 1H), 7.86 (dd, J = 9.0, 6.0 Hz, 2H), 7.46 (t, J = 8.4 Hz, 2H), 7.36-7.22 (m, 5H), 4.02 (s, 2H); ESI-MS (m/z): 378.6 (M+H)+, 777.8 (M+Na)+。
Example 5
(E) Preparation of (E) -6-benzyl-2- (4-chlorobenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione (L4)
Benzaldehyde was synthesized from p-chlorobenzaldehyde in a yield of 73% according to example 2. Mp: 220 ℃; ESI-MS (M/z): 404.1 (M + Na) +;1H NMR (600 MHz, DMSO) 8.26 (s, 1H), 7.79 (d, J = 9 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.35-7.22 (M, 5H), 4.01 (s, 2H); 13C NMR (151 MHz, DMSO) 165.47, 159.87, 154.29, 137.08, 136.85, 136.01, 133.06, 132.86, 131.85, 130.22, 129.67, 128.89, 127.28, 118.22, 36.95.
Example 6
(E) Preparation of (E) -6-benzyl-2- (3-trifluoromethylbenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione (L5)
Benzaldehyde was replaced with 3-trifluoromethylbenzaldehyde and the synthesis was performed according to example 2 in a yield of 75%. Mp: 216 ℃ 218 ℃; ESI-MS (M/z): 416.2 (M + H) +, 438.3 (M + Na) +;1H NMR (600 MHz, DMSO) 8.38 (s, 1H), 8.17 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.36-7.21 (M, 5H), 4.02 (s, 2H); 13C NMR (151 MHz, DMSO) 165.24, 159.82, 159.74, 154.27, 136.65, 135.98, 134.03, 133.53, 131.35, 129.64, 128.96, 128.57, 128.18, 127.38, 119.76, 36.87.
Example 7
(E) Preparation of (E) -6-benzyl-2- (4-isopropoxybenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione (L6)
Benzaldehyde was replaced with 4-isopropoxybenzaldehyde, and the synthesis was as described in example 2 with a yield of 60%. And Mp: 212 ℃ 214 ℃, ESI-MS (m/z): 420.4 (M + H) +, 442.3 (M + Na) +;1H NMR (600 MHz, DMSO) 8.20 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.37-7.21 (m, 5H), 7.16 (d, J = 8.4 Hz, 2H), 4.01 (s, 2H), 3.87 (d, J = 6 Hz, 2H), 2.09-2.00 (m, 1H), 0.99 (d, J = 6.6 Hz, 6H); 13C NMR (151 MHz, DMSO) 165.37, 162.20, 160.04, 159.97, 154.12, 138.87, 136.11, 133.73, 129.66, 128.87, 127.25, 125.38, 116.23, 113.83, 74.61, 36.96, 28.08, 19.23.
Example 8
(E) Preparation of (E) -6-benzyl-2- (benzo [ D ] [1,3] dioxol-4-ylmethylene) -2H-thiazol [3,2-b ] -1,2, 4-triazine-3, 7-dione (L7)
Benzaldehyde was replaced with 2, 3-dihydroxybenzo [ b ] [1,4] dioxin-5-carbaldehyde and synthesized in 56% yield according to example 2. Mp: 232 ℃; ESI-MS (M/z): 392.2 (M + H) +, 414.2 (M + Na) +;1H NMR (600 MHz, DMSO) 8.02 (s, 1H), 7.35-7.23 (M, 5H), 7.14 (M, 2H), 7.04 (t, J = 7.8 Hz, 1H), 6.22 (s, 2H), 4.01 (s, 2H); 13C NMR (151 MHz, DMSO) 165.45, 159.82, 154.28, 148.40, 147.76, 136.01, 130.94, 129.69, 128.88, 127.28, 123.39, 121.68, 118.59, 114.90, 112.06, 102.61, 36.93.
Example 10
Activity assay for acetylcholinesterase inhibitors
The acetylcholinesterase inhibitory activity was determined by the modified Ellman method. After 140. mu.L of LBuffer B, 20. mu.L of 0.05U/mL AChE and 20. mu.L of the test compound were added in this order, mixed well and incubated in an incubator at 25 ℃ for 15 minutes, 10. mu.L of 10.0mM DNTB and 10. mu.L of 7.5 mM ATCI were added and incubated in the incubator at 37 ℃ for 30 minutes, and the absorbance (OD) at 412nm of the solution was measured. The control was negative with a DMSO concentration of 20 μ L, positive with 20 μ L donepezil instead of test compound, and the blank was tested by adding 20 μ LBuffer B instead of test compound, with inhibition =100 × (a test-a empty)/(a standard-a empty)%.
Claims (5)
1. An acetylcholinesterase inhibitor having the ability to enhance memory in patients with dementia and alzheimer's disease, characterized by: the compound is a 2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivative with a general formula I or pharmaceutically acceptable hydrate and salt thereof, including a stereoisomer or a tautomer thereof;
wherein R in the formula I1And R2Can be optionally selected from 1,2 or 3 independently selected from hydrogen, alkyl, alkoxy, halogenHydroxyl, acetyl, propionyl, nitro or trifluoromethyl.
2. The compound of claim 1, wherein: the R is1Are hydrogen and methoxy.
3. A process for the preparation of a compound according to claim 1, characterized in that: the synthetic route is shown as the following formula:
4. the compound of claim 1, comprising:
(E) -6-benzyl-2-benzylidene-2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione;
(E) -6-benzyl-2- (4-methoxybenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione;
(E) -6-benzyl-2- (4-fluorobenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione;
(E) -6-benzyl-2- (4-chlorobenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione;
(E) -6-benzyl-2- (3-trifluoromethylbenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione;
(E) -6-benzyl-2- (4-isopropoxybenzylidene) -2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-dione;
(E) -6-benzyl-2- (benzo [ D ] [1,3] dioxol-4-ylmethylene) -2H-thiazole [3,2-b ] -1,2, 4-triazine-3, 7-dione.
5. The use of a compound according to claim 1 for the preparation of a medicament for the treatment of alzheimer's disease.
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| CN115197244A (en) * | 2022-09-03 | 2022-10-18 | 石家庄学院 | [1,2,4] triazino [3,2-b ] [1,3,5] thiadiazine derivative and application thereof |
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| 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 |
| CN102796121A (en) * | 2012-08-09 | 2012-11-28 | 石家庄学院 | 3-aryl-7H-thiazol[3,2-b]-1,2,4-triazinyl-7-one derivatives and application thereof |
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| 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 |
| CN102796121A (en) * | 2012-08-09 | 2012-11-28 | 石家庄学院 | 3-aryl-7H-thiazol[3,2-b]-1,2,4-triazinyl-7-one derivatives and application thereof |
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| CN115197244A (en) * | 2022-09-03 | 2022-10-18 | 石家庄学院 | [1,2,4] triazino [3,2-b ] [1,3,5] thiadiazine derivative and application thereof |
| CN115197244B (en) * | 2022-09-03 | 2023-07-07 | 石家庄学院 | [1,2,4] triazino [3,2-b ] [1,3,5] thiadiazine derivatives and application thereof |
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