CN104926838A - 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative and application - Google Patents

Abstract

The invention discloses 5H-[1,2,4]triazolo[5,1-b][1,3]thiazine derivatives of general formula I or pharmaceutically acceptable hydrates and salts thereof, including Its stereoisomers or tautomers, wherein R ₁ and R ₂ in formula I are independently hydrogen, methyl, halogen, hydroxyl, methoxy, acetyl, propionyl, nitro or alkoxy base. The 5H-[1,2,4]triazolo[5,1-b][1,3]thiazine derivatives of the present invention have obvious inhibitory effect on acetylcholinesterase, and are used to enhance the Memory in Alzheimer's patients. The invention also relates to a preparation method of the compound and its application in the preparation of a medicine for treating senile dementia.

Description

5H-[1,2,4]triazolo[5,1-b][1,3]thiazide derivatives and their application

technical field

The invention belongs to the technical field of medicine, in particular to 5H-[1,2,4]triazolo[5,1-b][1,3]thiazine derivatives and their preparation methods and as acetylcholinesterase inhibitors , an application for improving memory in patients with dementia and Alzheimer's disease.

Background technique

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 exhibit marked attenuations 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 disease patients. By inhibiting acetylcholinesterase, the compound increases levels of the neurotransmitter acetylcholine in the brain, thereby enhancing memory.

The existing acetylcholinesterase inhibitors, such as tacrine, stigmine, galantamine, etc., still have drug resistance or pharmacokinetic defects. As an acetylcholinesterase inhibitor of a new structure type, the compound of the invention has the characteristics of novel structure type, pharmacodynamic effect equivalent to or better than the existing drugs, and has good application value and development and application prospect.

Contents of the invention

The object of the present invention is to provide a 5H-[1,2,4]triazolo[5,1-b][1,3]thiazide derivative, which has good acetylcholinesterase inhibitory activity.

Above-mentioned purpose of the present invention is achieved by following technical scheme:

An acetylcholinesterase inhibitor, which has the effect of enhancing the memory of patients with dementia and Alzheimer's disease, is characterized in that: the compound is 5H-[1,2,4]triazolo[5 ,1-b][1,3]thiazide derivatives or their pharmaceutically acceptable hydrates and salts, including their stereoisomers or tautomers;

Wherein, R ₁ and R ₂ in formula I are independently hydrogen, methyl, halogen, hydroxyl, methoxy, acetyl, propionyl, nitro or alkoxy.

The compound according to claim 1, wherein said R ₁ is fluorine.

The compound according to claim ₁ , wherein said R is chlorine.

The compound according to claim 1, wherein said R ₂ is 2-(1-piperidinyl)ethoxy.

The term "halogen" as used herein includes fluorine, chlorine or bromine.

The present invention also provides the application of the above-mentioned compound in the preparation of medicament for treating senile dementia.

"Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases while retaining the biological efficacy and properties of the compounds of formula I. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphoric acid Salt, camphorsulfonate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanate salt, hexanoate, hydrochlorate, 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 of organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine salts, and salts of amino acids such as arginine, lysine, etc. Also, basic nitrogen-containing groups can be quaternized with such reagents as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorine, bromine and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl and dipentyl; long-chain halides such as decyl, lauryl, myristyl and hard Acyl chlorine, bromine and iodide; aralkyl halides, such as benzyl and phenethyl bromide, etc. Preferred acids for the formation of acid addition salts include hydrochloric acid and acetic acid.

The present invention also provides a preparation method of the compound of the above general formula I, the method is shown in the following formula.

The present invention systematically studies and explains the structure and preparation of the compound. As a new class of acetylcholinesterase inhibitors, the compound has a novel structure type and provides a new direction and a broad platform for the development of new anti-senile dementia drugs .

Detailed ways

Example 1

Preparation of 5-(4-fluorophenyl)-3-mercapto-1,2,4-triazole

Add 9.1 g (0.1 mol) of thiosemicarbazide and 100 mL of dichloromethane into a 250 mL three-necked flask, stir and dissolve in an ice-water bath, and then add 10.3 g (0.13 mol) of pyridine. 20.6g (0.13mol) of 4-fluorobenzoyl chloride was slowly added dropwise at 0-5°C, and the dropwise addition was completed within 20 minutes. After 2 hours of reaction at 15°C, the reaction was terminated. A large amount of white solid appeared in the system and was filtered. Dissolve the obtained white solid in 80 mL of 5% sodium hydroxide solution by mass fraction, heat to reflux for 2 hours, cool down to room temperature, adjust the pH to 5-6 with dilute hydrochloric acid with a mass fraction of 3.65%, a large amount of light yellow solid precipitates, filter , recrystallized to obtain 17.2 g of 5-(4-fluorophenyl)-3-mercapto-1,2,4-triazole, yield 88.2%, ESI-MS (m/z): 196.2(M +H) ⁺ .

Example 2

Preparation of 5-(4-chlorophenyl)-3-mercapto-1,2,4-triazole

Thiosemicarbazide 9.1g (0.1 mol), dichloromethane 100 mL, pyridine 10.3g (0.13 mol) and 4-chlorobenzoyl chloride 22.75g (0.13mol) According to the method of Example 1, 5-(4-chloro Phenyl)-3-mercapto-1,2,4-triazole 18.3g, yield 86.7%, ESI-MS (m/z): 212.3(M+H) ⁺ .

Example 3

2-(4-fluorophenyl)-7-(4chlorophenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L1) preparation

Add 1.95g (0.01mol) of 5-(4-fluorophenyl)-3-mercapto-1,2,4-triazole and 2.47g (0.01mol) of 4'-chloro-3-bromopropiophenone in 50 mL of acetic acid was dissolved and refluxed for 3 hours. After the reaction was monitored by TLC, it was cooled to room temperature. The reaction solution gradually precipitated solids. After suction filtration, washing with water, and ethanol recrystallization, 2.15 g of white crystals were obtained, with a yield of 62.73%. ¹ H-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 =8.4 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.4 Hz); ESI-MS (m/z): 344.1 (M+H) ⁺ .

Example 4

2-(4-fluorophenyl)-7-(4-fluorophenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L2) preparation of

Add 1.95g (0.01mol) of 5-(4-fluorophenyl)-3-mercapto-1,2,4-triazole and 2.31g (0.01mol) of 4'-fluoro-3-bromopropiophenone in 50 mL of acetic acid was dissolved and refluxed for 3 hours. After the reaction was monitored by TLC, it was cooled to room temperature. Solids gradually precipitated from the reaction liquid. After suction filtration, washing with water, and ethanol recrystallization, 2.08 g of white crystals were obtained, with a yield of 63.41%. ¹ H-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 =8.4 Hz), 7.36 (2H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8.4 Hz); ESI-MS (m/z): 328.1 (M+H) ⁺ .

Example 5

2-(4-fluorophenyl)-7-(4-methoxyphenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine ( L3) Preparation

1.95g (0.01mol) of 5-(4-fluorophenyl)-3-mercapto-1,2,4-triazole and 2.43g (0.01mol) of 4'-methoxy-3-bromopropiophenone, Add 50 mL of acetic acid to dissolve, and reflux for 3 hours. After the reaction is monitored by TLC, it is cooled to room temperature. The reaction solution gradually precipitates solids. After suction filtration, washing with water, and ethanol recrystallization, 2.11 g of white crystals are obtained, with a yield of 62.05%. ¹ H-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) ⁺ .

Example 6

2-(4-fluorophenyl)-7-(4-hydroxyphenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L4) preparation of

Add 1.95 g (0.01 mol) of 5-(4-fluorophenyl)-3-mercapto-1,2,4-triazole and 2.29 g (0.01 mol) of 4'-hydroxy-3-bromopropiophenone in 50 mL of acetic acid was dissolved and refluxed for 3 hours. After the reaction was monitored by TLC, it was cooled to room temperature. The reaction solution gradually precipitated solids. After suction filtration, washing with water, and ethanol recrystallization, 2.29 g of white crystals were obtained, with a yield of 70.46%. ¹ H-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 =8.4 Hz), 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) ⁺ .

Example 7

2-(4-fluorophenyl)-7-{4-[2-(1-piperidinyl)ethoxy]phenyl}-5H-[1,2,4]triazolo[5,1 -b] Preparation of [1,3]thiazine (L5)

1.95 g (0.01 mol) of 5-(4-fluorophenyl)-3-mercapto-1,2,4-triazole and 4'-[2-(1-piperidinyl)ethoxy]-3 -Bromopropiophenone 3.40g (0.01mol), add 50 mL of acetic acid to dissolve, reflux reaction for 3h, TLC monitors the completion of the reaction, cools to room temperature, the reaction solution gradually precipitates solid, suction filtration, after washing with water, ethanol recrystallization to obtain white Crystal 2.69 g, yield 61.70%. ¹ H-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 = 8.4 Hz); ESI-MS (m/z): 436.1 (M+H) ⁺ .

Example 8

2-(4-Chlorophenyl)-7-(4-chlorophenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L6) preparation

Add 2.11 g (0.01 mol) of 5-(4-chlorophenyl)-3-mercapto-1,2,4-triazole and 2.47 g (0.01 mol) of 4'-chloro-3-bromopropiophenone in 50 mL of acetic acid was dissolved and refluxed for 3 hours. After the reaction was monitored by TLC, it was cooled to room temperature. The reaction solution gradually precipitated solids. After suction filtration, washing with water, and ethanol recrystallization, 2.45 g of white crystals were obtained, with a yield of 68.06%. ¹ H-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 =8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 8.12 (2H, d, J = 8.4 Hz); ESI-MS (m/z): 360.3 (M+H) ⁺ .

Example 9

2-(4-Chlorophenyl)-7-(4-fluorophenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L7) preparation of

Add 2.11 g (0.01 mol) of 5-(4-chlorophenyl)-3-mercapto-1,2,4-triazole and 2.31 g (0.01 mol) of 4'-fluoro-3-bromopropiophenone in 50 mL of acetic acid was dissolved and refluxed for 3 hours. After the reaction was monitored by TLC, it was cooled to room temperature. Solids gradually precipitated from the reaction solution, filtered with suction, washed with water, and recrystallized with ethanol to obtain 2.27 g of white crystals with a yield of 65.99%. ¹ H-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 =8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 8.14 (2H, d, J = 8.4 Hz); ESI-MS (m/z): 344.2 (M+H) ⁺ .

Example 10

2-(4-chlorophenyl)-7-(4-methoxyphenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine ( L8) Preparation

2.11 g (0.01 mol) of 5-(4-chlorophenyl)-3-mercapto-1,2,4-triazole and 2.43 g (0.01 mol) of 4'-methoxy-3-bromopropiophenone, Add 50 mL of acetic acid to dissolve, reflux for 3 hours, TLC monitors the completion of the reaction, cool to room temperature, the reaction solution gradually precipitates a solid, suction filtration, washing with water, ethanol recrystallization to obtain 2.17 g of white crystals, yield 60.95%. ¹ H-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) ⁺ .

Example 11

2-(4-Chlorophenyl)-7-(4-hydroxyphenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L9) preparation of

Add 2.11 g (0.01 mol) of 5-(4-chlorophenyl)-3-mercapto-1,2,4-triazole and 2.29 g (0.01 mol) of 4'-hydroxy-3-bromopropiophenone in 50 mL of acetic acid was dissolved and refluxed for 3 hours. After the reaction was monitored by TLC, it was cooled to room temperature. The reaction solution gradually precipitated solids. After suction filtration, washing with water, and ethanol recrystallization, 2.54 g of white crystals were obtained, with a yield of 74.27%. ¹ H-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 =8.4 Hz), 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) ⁺ .

Example 12

2-(4-Chlorophenyl)-7-{4-[2-(1-piperidinyl)ethoxy]phenyl}-5H-[1,2,4]triazolo[5,1 -b] Preparation of [1,3]thiazine (L10)

2.11 g (0.01 mol) of 5-(4-chlorophenyl)-3-mercapto-1,2,4-triazole and 4'-[2-(1-piperidinyl)ethoxy]-3 -Bromopropiophenone 3.40g (0.01mol), add 50 mL of acetic acid to dissolve, reflux reaction for 3h, TLC monitors the completion of the reaction, cools to room temperature, the reaction solution gradually precipitates solid, suction filtration, after washing with water, ethanol recrystallization to obtain white Crystal 2.87 g, yield 63.36%. ¹ H-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 = 8.4 Hz); ESI-MS (m/z): 453.1 (M+H) ⁺ .

Example 13

Activity Assay of Acetylcholinesterase Inhibitors

1. Preparation of materials: The positive control drug was set as neostigmine hydrobromide (SigmaN-2001), prepared as a 0.1M solution; 0.5 units of acetylcholinesterase (human source) (SigmaC-1682); the buffer solution was 100mM PBS solution (pH7.4), 10mM dithiodinitrobenzoic acid DTNB (D-8130) (prepared with 100mM PBS), stored at -20°C in the dark, ready to use; 12.5mM Thioacetylcholine ATCh (A- 5751) was dissolved in water, stored at -20°C in the dark, and used immediately after preparation; the test drug was dissolved in DMSO to prepare a 10 μM solution.

2. Method:

(1) Process the samples according to the method in the table below;

(2) Preheat at 37°C for 15 minutes with continuous gentle shaking;

(3) Add 50mL ATCh and 50mL DTNB;

(4) Shake gently at 37°C for about 20 minutes until the reaction solution turns yellow;

(5) Measure its OD value at 412nm;

(6) Calculation of inhibition rate, acetylcholinesterase inhibition rate=1-(OD experimental group-OD blank group)/(OD experimental control group-OD blank group)×100%, some sample inhibition rates are shown in Table 1;

(7) Measure the IC ₅₀ for inhibiting the inhibitory activity of acetylcholinesterase, and the results are shown in Table 2.

3. Results:

Compounds L1, L2, L3, L4, L5, L6, L7, L8, L9 and L10 all have good inhibitory activity on acetylcholinesterase.

Claims (7)

1. An acetylcholinesterase inhibitor has the effect of enhancing the memory of dementia and Alzheimer's disease patients, and is characterized in that: the compound is 5H-[1,2,4]triazolo with general formula I [5,1-b][1,3]thiazide derivatives or their pharmaceutically acceptable hydrates and salts, including their stereoisomers or tautomers; Wherein, R ₁ and R ₂ in formula I are independently hydrogen, methyl, halogen, hydroxyl, methoxy, acetyl, propionyl, nitro or alkoxy. 2. The compound according to claim ₁ , wherein said R is fluorine. 3. The compound according to claim 1, characterized in that: said R ₂ is chlorine. 4. The compound according to claim 1, characterized in that: said R ₂ is 2-(1-piperidinyl)ethoxy. 5. The compound according to claim 1, comprising: 2-(4-fluorophenyl)-7-(4chlorophenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L1); 2-(4-fluorophenyl)-7-(4-fluorophenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L2) ; 2-(4-fluorophenyl)-7-(4-methoxyphenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine ( L3); 2-(4-fluorophenyl)-7-(4-hydroxyphenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L4) ; 2-(4-fluorophenyl)-7-{4-[2-(1-piperidinyl)ethoxy]phenyl}-5H-[1,2,4]triazolo[5,1 -b][1,3]thiazine (L5); 2-(4-chlorophenyl)-7-(4-chlorophenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L6); 2-(4-Chlorophenyl)-7-(4-fluorophenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L7) ; 2-(4-chlorophenyl)-7-(4-methoxyphenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine ( L8); 2-(4-Chlorophenyl)-7-(4-hydroxyphenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (L9) ; 2-(4-Chlorophenyl)-7-{4-[2-(1-piperidinyl)ethoxy]phenyl}-5H-[1,2,4]triazolo[5,1 -b][1,3]thiazine (L10). 6. The preparation method of the compound described in claim 1, characterized in that: its synthetic route is shown in the following formula. 7. The compound of claim 1 is used for the preparation of the purposes of medicament for treating Alzheimer's disease.