CN103012439B - Benzoyl substituted thiazolo[3,2-b]-1,2,4-triazine derivative and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to benzoyl-substituted thiazolo[3,2-b]-1,2,4-triazine derivatives and applications thereof. Benzoyl-substituted thiazolo[3,2-b]-1,2,4-triazine derivatives include benzoyl-substituted thiazolo[3,2-b]-1,2,4-triazine Stereoisomers and pharmaceutically applicable salts of azine derivatives, the general structural formula of which is as follows: Benzoyl-substituted thiazolo[3,2-b]-1,2,4-triazine derivatives And the pharmaceutically applicable acid addition salts of the compounds can be combined with existing drugs or used alone as acetylcholinesterase inhibitors to enhance the memory of patients with dementia and Alzheimer's disease. Compared with the existing Chinese patent, the 6-position side chain of thiazolo[3,2- b ]-1,2,4-triazine has changed significantly, and the inhibition rate of the sample to acetylcholinesterase has been significantly improved .

Description

Benzoyl-substituted thiazolo[3,2-b]-1,2,4-triazine derivatives and their applications

technical field

The invention belongs to the technical field of medicine, and relates to benzoyl-substituted thiazolo[3,2- b ]-1,2,4-triazine derivatives and applications thereof, in particular to benzoyl-substituted thiazolo[3, 2- b ]-1,2,4-triazine derivatives, stereoisomers and pharmaceutically applicable salts of the compounds and applications thereof. The compounds are acetylcholinesterase inhibitors that can be used to improve 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, which play an important role in recognition functions, including memory. 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. the

Acetylcholinesterase inhibitors are known to be effective in increasing cholinergic activity and thus may be used to improve memory in Alzheimer's patients. The compound delays the hydrolysis speed of acetylcholine by inhibiting the activity of acetylcholinesterase, and increases the level of acetylcholine as a neurotransmitter in the brain, thereby enhancing memory. the

Existing acetylcholinesterase inhibitors, such as tacrine, rivastigmine, and galantamine, all have drug resistance or pharmacokinetic defects. the

Contents of the invention

The present invention provides a new structural type of acetylcholinesterase inhibitor, the compound and its derivatives can be combined with existing drugs or used alone to improve the memory of dementia and Alzheimer's patients. the

The present invention relates to a compound of formula I, its stereoisomer or its pharmaceutically applicable acid addition salt, its prodrug and pharmaceutically active metabolite, and the pharmaceutically acceptable salt of the above-mentioned compound:

(I)

in

n ₁ is an integer from 0 to 1; n ₂ is an integer from 1 to 2; that is, n ₁ is 0 or 1; n ₂ is 1 or 2;

R ₁ can optionally consist of 1, 2 or 3 independently selected from H, halogen, -OH, -O(CH ₂ )n ₃ NR ₃ R ₄ , -O(CH ₂ )n ₄ CONR ₅ R ₆ , -O(CH ₂ )n ₅ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -NO ₂ ;

R ₂ can optionally consist of 1, 2 or 3 independently selected from H, halogen, -OH, -O(CH ₂ )n ₃ NR ₃ R ₄ , -O(CH ₂ )n ₄ CONR ₅ R ₆ , -O(CH ₂ )n ₅ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -NO ₂ ; n ₃ is 2, 3 or 4, n ₄ is 1, 2 or 3, n ₅ is 1, 2, 3, 4 or 5;

Wherein R ₃ R ₄ is independently selected from methyl or ethyl, or R ₃ R ₄ together with their connected nitrogen atoms form pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, piperidinyl, or Linyl, benzylamino, 4-chloroanilino, 4-methylanilino or hexamethyleneimino ring; or independently selected from hydrogen, methyl, hydroxyl, methoxy, ethoxy, nitro, fluorine, chlorine or bromine substituted or unsubstituted benzene ring groups;

R ₅ R ₆ is independently selected from methyl or ethyl, or R ₅ R ₆ together with the nitrogen atom they are connected to form pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, piperidinyl, morpholine Base, benzylamino, 4-chloroanilino, 4-methylanilino or hexamethyleneimino ring; or independently selected from hydrogen, methyl, hydroxyl, methoxy, ethoxy, nitric radical, fluorine, chlorine or bromine substituted or unsubstituted benzene ring groups.

"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.

"Pharmaceutically acceptable", such as a pharmaceutically acceptable carrier, excipient, prodrug, etc., means pharmacologically acceptable and substantially non-toxic to the patient to whom the particular compound is administered. the

"Pharmaceutically active metabolite" refers to a metabolite of a compound of formula I that is pharmaceutically acceptable and effective. the

The present invention also relates to a pharmaceutical composition for inhibiting acetylcholinesterase, which contains a compound of formula I or its stereoisomer or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. the

The present invention also relates to a method for inhibiting acetylcholinesterase in a mammal, the method comprising administering to the mammal an effective dosage of the compound of formula I or its stereoisomer or a pharmaceutically acceptable acid addition salt thereof.

The present invention also relates to a method for formula I to enhance memory or to treat or prevent Alzheimer's disease, the method comprising taking a compound of formula I or its stereoisomer or an effective dosage for enhancing memory or treating or preventing Alzheimer's disease or Its pharmaceutically acceptable acid addition salts. the

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

"Substituted", unless otherwise stated, means that a substituent may be present at one or more positions, the substituents being independently selected from the specified options. the

The compounds of the present invention can be administered to the patient by various methods, for example, orally as capsules or tablets, as sterile solutions or suspensions and, in some cases, as intravenous solutions. The free base compounds of the present invention may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts. the

For an average adult, the daily dose of the compound of the present invention is usually about 1-300 mg/kg body weight, and can be administered in a single dose or in divided doses. For administration, if a solution or suspension is administered, the concentration of the compound of the invention is at least 1% (mass fraction), preferably 4-70% (mass fraction) (based on the total mass of the unit). Dosage units for parenteral administration will generally contain from about 5 mg to 100 mg of the active compound. the

The compounds of this invention may be administered orally with an inert diluent or an edible carrier, or they may be enclosed in gelatin capsules, or compressed into tablets. The formulation should contain at least 0.5% active compound, but depending on the particular dosage form, the concentration may vary and may range from 4 to 70% (mass fraction) (based on the total mass of the unit). Oral dosage units generally contain 1.0 mg to 300 mg of active compound. the

For pharmacological use, the compounds of formula I are preferably administered in the form of their pharmaceutically acceptable acid addition salts. The effective dosage of the compound will of course vary depending on the potency of each compound employed, the severity and nature of the disease being treated, and the particular patient being treated. In general, effective results are obtained with systemic administration of the compounds at dosages from about 0.01 mg to about 20 mg/kg body weight/day. Treatment should be started at a lower dose. It can then be administered orally in solid dosage forms such as capsules, tablets, or powders, or in liquid forms such as solutions or suspensions. The compounds can also be injected parenterally in the form of sterile solutions or suspensions. the

In the embodiment of the method of the present invention, the active ingredient is preferably incorporated into a composition containing a pharmaceutically acceptable carrier, which contains about 5%-90% (mass fraction) of the compound of the present invention or a pharmaceutically acceptable salt thereof. "Pharmaceutically acceptable carrier" means a known pharmaceutically acceptable excipient for formulating a pharmaceutically active compound for internal administration to an animal which is substantially nontoxic and nonteratogenic under the conditions of use. Such compositions may be prepared by known techniques for the preparation of tablets, capsules, elixirs, syrups, emulsions, dispersions and wettable and foamable powders, which may contain suitable excipients known to be useful in the preparation of particular types of compositions. Forming agent. The preferred route of administration is oral administration. For oral administration, the compounds of formula I can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions. A solid unit dosage form may be a capsule, which may be of the ordinary hard or soft shell gelatin type, containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and cornstarch. In another embodiment, the compounds of the present invention can be compressed into tablets with conventional bases such as lactose, sucrose, and cornstarch, with the addition of binders such as acacia, cornstarch, or gelatin; used to aid in tablet disintegration and Solubilized disintegrants such as potato starch, alginic acid, corn starch, and guar gum; lubricants such as talc, stearic acid, or magnesium stearate, calcium or zinc; and coatings, colorings and flavorings to improve the appearance of the tablets and make them more acceptable to the patient. Suitable excipients for oral liquid dosage forms include water and alcohols such as ethanol, benzyl alcohol, and polyvinyl alcohol, with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or suspending agents. The compound of formula I of the present invention can also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or intraperitoneally, in the form of an injectable formulation of the compound in a physiologically acceptable diluent, which also contains a pharmaceutically acceptable carrier. are sterile liquids or liquid mixtures such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol, or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-Dimethyl-l,3-dioxolane-4-methanol, ethers such as macrogol 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides, with or without pharmacy Acceptable surface active agents such as soap or detergent, suspending agents such as pectin, carbomer, methyl cellulose, isopropyl methyl cellulose, or acid methyl cellulose, or emulsifiers and other pharmaceutically acceptable Accepted additives. Examples of oils that can be used in the parenteral formulations of the invention are those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal salts, amine salts and triethanolamine salts, suitable surfactants, including cationic surfactants such as dimethyldialkylamine halides, alkyl, alkylpyridinium halides; anionic surfactants Active agents such as alkyl, aryl, sulfonates, alkyl, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic surfactants such as fatty amine oxides, fatty acid alkanolamides, and poly oxyethylene polypropylene copolymers; and amphoteric surfactants such as alkyl allanyl esters, and alkyl imidazoline quaternary ammonium salts, and mixtures thereof. The parenteral composition of the present invention generally contains about 0.5 to about 25% (mass fraction) of the compound of formula I in the solution. Preservatives and buffers may be used. To minimize or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of this surfactant in this formulation is from about 5% to about 15% (mass fraction). Such surfactants may be a single ingredient having the above HLB values or a mixture of two or more ingredients having the desired HLB. Examples of surfactants for parenteral formulations are polyhexene sorbitan fatty acid esters such as sorbitan monooleate and high molecular weight adducts of ethylene oxide with a hydrophobic Condensed with propylene glycol. The complexes of the present invention can also be administered transdermally. This can be done by simply preparing a solution of the desired compound, preferably in a solvent known to promote transdermal absorption, such as ethanol or dimethylsulfoxide (DMSO), with or without other excipients. Preferred transdermal administration is performed using a reservoir and porous membrane type of drug or a solid matrix variation of the drug. These devices generally comprise a backing defining one outer surface thereof, an active drug permeable adhesive layer defining another surface, and at least one reservoir containing the active drug between the outer surfaces. Alternatively, the active drug is contained in a number of microcapsules distributed throughout the permeable adhesive layer. In either case, the active drug is continuously transported from the reservoir or microcapsule through a membrane to the active drug permeable adhesive layer, which comes into contact with the patient's skin or mucous membranes. If the active drug is absorbed through the skin, a controlled and predetermined flow rate of the active drug is administered to the patient. When microcapsules are used, the coating also acts as a membrane. In another device for the transdermal administration of the compounds of this invention, the pharmaceutically active compound is contained in a matrix from which it is released at a desired gradual, constant and controllable rate. The matrix is permeable to release of the compound by diffusion or pore flow. At least two types of releases are possible in these systems. Diffusion release occurs when the matrix is non-porous. The pharmaceutically active compound dissolves in the matrix and diffuses through the matrix itself. Micropore flow release occurs when the pharmaceutically active compound is transported through the liquid phase within the pores of the matrix. the

The activity of the compounds of the invention as inhibitors of acetylcholinesterase can be determined in a number of standard biological or pharmacological assays. the

Activity assay for acetylcholinesterase inhibitors. the

Materials and Methods:

Preparation of test samples: The positive control drug was set as neostigmine hydrobromide (SigmaN-2001), prepared as a 0.1 M solution.

Acetylcholinesterase (human source) (SigmaC-1682) 0.5 units. the

The buffer solution is 100 mM PBS solution (pH 7.4), 10 mM dithiodinitrobenzoic acid DTNB (D-8130) (prepared with 100 mM PBS), stored at –20 °C in the dark, prepared and used immediately. the

12.5 mM thioacetylcholine ATCh (A-5751) was dissolved in water, stored at –20 °C in the dark, ready to use. the

The test drug was dissolved in DMSO to prepare a 10 μM solution. the

Method and Results

Steps:

(1) Process the sample as follows.

(2) Preheat at 37 °C for 15 min with continuous gentle shaking. the

(3) Add 50 mL ATCh and 50 mL DTNB. the

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

(5) Measure the OD value at 412 nm. the

(6) Calculate the inhibition rate. the

The inhibition rate of some samples is listed as follows (n = 3): Sample name Inhibition rate(%) 3-(4-Hydroxyphenyl)-6-[2-oxo-2-phenylethyl]-7 H -thiazolo[3,2- b ]-1,2,4-triazine-7- ketone 67.37 3-(4-Bromophenyl)-6-[2-oxo-2-(4-methoxyphenyl)ethyl]-7 H -thiazolo[3,2- b ]-1,2, 4-Triazin-7-one 75.24 3-(4-methoxyphenyl)-6-[2-oxo-2-(4-chlorophenyl)ethyl]-7 H -thiazolo[3,2- b ]-1,2, 4-Triazin-7-one 85.35 3-[4-(Diethylcarbamoylmethoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl] -7H -thiazolo[3 ,2- b ]-1,2,4-triazin-7-one 91.29 3-{[4-(4-morpholinyl)formylmethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-hydroxy)phenyl]ethyl} -7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 69.50 3-[4-(Benzylcarbamoylmethoxy)phenyl]-6-{2-oxo-2-[(3-methyl-4-ethoxy)phenyl]ethyl}-7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 87.73 3-{[4-(4-Chloroanilino)formylmethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-methoxy)phenyl]B Base} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 94.92 3-[(4-Hydroxy-3-methoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl]-7 H -thiazolo[3,2 - b ]-1,2,4-triazin-7-one 84.30 3-(4-ethoxyphenyl)-6-{2-oxo-2-[4-(benzylcarbamoylmethoxy)phenyl]ethyl} -7H -thiazolo[3, 2- b ]-1,2,4-triazin-7-one 88.14 3-[(3-methyl-4-methoxy)phenyl]-6-{2-oxo-2-[4-(4-methylanilino)formylmethoxyphenyl]ethyl }-7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 79.68 3-[(3-methyl-4-hydroxy)phenyl]-6-{2-oxo-2-[4-(4-morpholinyl)formylmethoxyphenyl]ethyl}-7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 93.17 3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-ethoxy)phenyl]ethyl base} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 72.44 3-[4-(2-Diethylaminoethoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl] -7H -thiazolo[3 ,2- b ]-1,2,4-triazin-7-one 83.15 Neostigmine hydrobromide 0.1 M 100

As a new class of acetylcholinesterase inhibitors, the compound of the invention has the characteristics of novel structure type and pharmacodynamic effect comparable to or superior to existing drugs. Compared with the prior art, the 6-position side chain of thiazolo[3,2- b ]-1,2,4-triazine containing benzoyl substitution has obvious changes, and the inhibition rate of the sample to acetylcholinesterase has Significantly improved, with good application value and development and application prospects.

Detailed ways

Scheme 1 outlines the synthetic steps to prepare the compounds of the present invention. the

Reaction Scheme 1 Preparation of benzoyl-substituted thiazolo[3,2-b]-1,2,4-triazine derivatives

in

n ₁ is an integer from 0 to 1; n ₂ is an integer from 1 to 2;

R ₁ can optionally consist of 1, 2 or 3 independently selected from H, halogen, -OH, -O(CH ₂ )n ₃ NR ₃ R ₄ , -O(CH ₂ )n ₄ CONR ₅ R ₆ , -O(CH ₂ )n ₅ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -NO ₂ ;

R ₂ can optionally consist of 1, 2 or 3 independently selected from H, halogen, -OH, -O(CH ₂ )n ₃ NR ₃ R ₄ , -O(CH ₂ )n ₄ CONR ₅ R ₆ , -O(CH ₂ )n ₅ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -NO ₂ ;

n ₃ is an integer from 2 to 4, n ₄ is an integer from 1 to 3, and n ₅ is an integer from 1 to 5;

Wherein R ₃ R ₄ is independently selected from methyl or ethyl, or R ₃ R ₄ together with their connected nitrogen atoms form pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, piperidinyl, or Linyl, benzylamino, 4-chloroanilino, 4-methylanilino or hexamethyleneimino rings; or independently selected from hydrogen and substituted or unsubstituted benzene ring groups;

R ₅ R ₆ is independently selected from methyl or ethyl, or R ₅ R ₆ together with the nitrogen atom they are connected to form pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, piperidinyl, morpholine group, benzylamino group, 4-chloroanilino group, 4-methylanilino group or hexamethyleneimino group; or independently selected from hydrogen and substituted or unsubstituted benzene ring groups.

The present invention is described in detail with the following examples. However, it should be understood that the present invention is not limited to the specific recited examples below. the

Example 1: 3-(4-Hydroxyphenyl)-6-[2-oxo-2-phenylethyl] -7H -thiazolo[3,2- b ]-1,2,4-tri Preparation of oxazin-7-one

Add 50 mL toluene, 0.1 mol sodium ethoxide and 0.05 mol diethyl oxalate into a 500 mL round bottom flask, heat to reflux for 5 min, add 0.02 mol acetophenone, and react at room temperature for 10 h. After the reaction was completed, pour 100 mL of water into the reaction solution, separate the layers, take the water layer, wash the water layer with 20 mL of ether, acidify with 1 mol/L hydrochloric acid, and a solid precipitated out. Cool, filter, wash and dry. A light yellow solid was obtained, which was recrystallized from ethanol to obtain 9.2 g of white crystals, with a yield of 90%.

Add 1.0 g (0.004 mol) of ethyl 2,4-dioxo-4-phenylbutyrate, 0.37 g (0.004 mol) of thiosemicarbazide, 20 mL of ethanol, and 20 mL of water into a 250 mL round bottom flask in sequence 40% aqueous sodium hydroxide solution was used to adjust the pH value of the reaction solution to 11, stirred, heated to reflux for 4 h, and cooled to room temperature. The pH value of the reaction solution was adjusted to 2 with concentrated hydrochloric acid, and a large amount of milky white solids were precipitated. Suction filtration, drying, and ethanol recrystallization gave 6-[2-oxo-2-phenylethyl]-3-thio 1.10 g of white crystals of -2,4-dihydro-3 H , 5 H -1,2,4-triazin-7-one. ESI-MS (m/z): 246.1 (MH).

The 6-[2-oxo-2-phenylethyl]-3-thioxo-2,4-dihydro-3 H , 5 H -1,2,4-triazine-7- Add 1.0 g (0.004 mol) of ketone, 0.004 mol of 4-hydroxychloroacetophenone, and 30 mL of glacial acetic acid into a 100 mL round bottom flask, heat to reflux for 10 h, and monitor the reaction by TLC until the reaction is complete. After cooling, filter with suction and recrystallize from absolute ethanol to obtain 3-(4-hydroxyphenyl)-6-[2-oxo-2-phenylethyl] -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one, light yellow powder 0.84 g, yield 50%. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 13.26 (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) ⁺ .

Example 2: 3-(4-bromophenyl)-6-[2-oxo-2-(4-methoxyphenyl)ethyl]-7 H -thiazolo[3,2- b ]- Preparation of 1,2,4-triazin-7-one.

According to the method of Example 1, 3-(4-bromophenyl)-6-[2-oxo-2-(4-methoxyphenyl)ethyl] -7H -thiazolo[3,2- b ]-1,2,4-Triazin-7-one 1.08 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 7.96 (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) ⁺ .

Example 3: 3-(4-methoxyphenyl)-6-[2-oxo-2-(4-chlorophenyl)ethyl]-7 H -thiazolo[3,2- b ]- Preparation of 1,2,4-triazin-7-one

According to the method of Example 1, 3-(4-methoxyphenyl)-6-[2-oxo-2-(4-chlorophenyl)ethyl] -7H -thiazolo[3,2- b ]-1,2,4-Triazin-7-one 1.24 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.08 (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) ⁺ .

Example 4: 3-[4-(diethylcarbamoylmethoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl]-7 H - Preparation of Thiazolo[3,2- b ]-1,2,4-Triazin-7-one.

Under stirring at room temperature, 0.002 mol of 3-(4-hydroxyphenyl)-6-[2-oxo-2-(4-ethoxyphenyl)ethyl] -7H -thiazolo[3, 2- b ]-1,2,4-Triazin-7-one solution in acetone or ethanol was added corresponding 0.002 mol N , N -diethyl chloroacetamide, and 0.002 mol acid-binding agent (anhydrous carbonic acid Potassium or triethylamine) and 0.0003 mol potassium iodide catalyst, reflux reaction, TLC to track the reaction process, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated to dryness, added 30 mL of saturated saline, and extracted with ether. The organic layer was dried and concentrated to give the crude product, which was recrystallized from ethanol to give 3-[4-(diethylcarbamoylmethoxy)phenyl]-6-[2-oxo-2-(4-ethoxy phenyl)ethyl] -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 0.52 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.04 (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) ⁺ .

Example 5: 3-{[4-(4-morpholinyl)formylmethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-hydroxyl)phenyl Preparation of ]ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one.

According to the method of Example 4, 3-{[4-(4-morpholinyl)formylmethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-hydroxyl ) phenyl] ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 0.42 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.78 (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) ⁺ .

Example 6: 3-[4-(Benzylcarbamoylmethoxy)phenyl]-6-{2-oxo-2-[(3-methyl-4-ethoxy)phenyl]B Preparation of base} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one.

According to the method of Example 4, 3-[4-(benzylcarbamoylmethoxy)phenyl]-6-{2-oxo-2-[(3-methyl-4-ethoxy)benzene was obtained Base] ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 0.58 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 8.98 (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) ⁺ .

Example 7: 3-{[4-(4-chloroanilino)formylmethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-methoxy) Preparation of phenyl]ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one.

According to the method of Example 4, 3-{[4-(4-chloroanilino)formylmethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-methyl) was obtained Oxy)phenyl]ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 0.57. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.21 (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) ⁺ .

Example 8: 3-[(4-Hydroxy-3-methoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl] -7H -thiazolo Preparation of [3,2- b ]-1,2,4-triazin-7-one.

According to the method of Example 1, 3-[(4-hydroxyl-3-methoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl] -7H - Thiazolo[3,2- b ]-1,2,4-triazin-7-one 1.16 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.12 (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) ⁺ .

Example 9: 3-(4-Ethoxyphenyl)-6-{2-oxo-2-[4-(benzylcarbamoylmethoxy)phenyl]ethyl} -7H -thiazole Preparation of [3,2- b ]-1,2,4-triazin-7-one.

According to the method of Example 1, 3-(4-ethoxyphenyl)-6-{2-oxo-2-[4-(benzylcarbamoylmethoxy)phenyl]ethyl}-7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 0.51 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.07 (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) ⁺ .

Example 10: 3-[(3-methyl-4-methoxy)phenyl]-6-{2-oxo-2-[4-(4-methylanilino)formylmethoxybenzene Preparation of base]ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one

According to the method of Example 1, the product 3-[(3-methyl-4-methoxy)phenyl]-6-{2-oxo-2-[4-(4-methylanilino)formyl) was obtained Methoxyphenyl]ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 0.44 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 10.10 (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) ⁺ .

Example 11: 3-[(3-methyl-4-hydroxy)phenyl]-6-{2-oxo-2-[4-(4-morpholinyl)formylmethoxyphenyl]B Preparation of base} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one.

According to the method of Example 1, 3-[(3-methyl-4-hydroxy)phenyl]-6-{2-oxo-2-[4-(4-morpholinyl)formylmethoxybenzene was obtained Base] ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 0.34 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 9.87 (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) ⁺ .

Example 12: 3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-ethoxy) Preparation of phenyl]ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one.

According to the method of Example 4, 3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-ethane) was obtained Oxy)phenyl]ethyl} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 0.40 g. ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ 7.96 (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) ⁺ .

Example 13: 3-[4-(2-Diethylaminoethoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl]-7 H - Preparation of Thiazolo[3,2- b ]-1,2,4-Triazin-7-one.

According to the method of Example 4, 3-[4-(2-diethylaminoethoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl]- 7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 0.36 g. ¹ H-NMR (600 MHz, DMSO- d ₆ ): δ 8.15 (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 a preferred embodiment of the present invention, and is not intended to limit the present invention to other forms. Any skilled person who is familiar with this profession may use the technical content disclosed above to change or remodel it into an equivalent change. Example. However, any simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still belong to the protection scope of the technical solution of the present invention. the

Claims (3)

1. Benzoyl-substituted thiazolo[3,2-b]-1,2,4-triazine derivatives selected from: 3-(4-Hydroxyphenyl)-6-[2-oxo-2-phenylethyl]-7 H -thiazolo[3,2- b ]-1,2,4-triazine-7- ketone 3-(4-Bromophenyl)-6-[2-oxo-2-(4-methoxyphenyl)ethyl]-7 H -thiazolo[3,2- b ]-1,2, 4-Triazin-7-one 3-(4-methoxyphenyl)-6-[2-oxo-2-(4-chlorophenyl)ethyl]-7 H -thiazolo[3,2- b ]-1,2, 4-Triazin-7-one 3-[4-(Diethylcarbamoylmethoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl] -7H -thiazolo[3 ,2- b ]-1,2,4-triazin-7-one 3-{[4-(4-morpholinyl)formylmethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-hydroxy)phenyl]ethyl} -7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 3-[4-(Benzylcarbamoylmethoxy)phenyl]-6-{2-oxo-2-[(3-methyl-4-ethoxy)phenyl]ethyl}-7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 3-{[4-(4-Chloroanilino)formylmethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-methoxy)phenyl]B Base} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 3-[(4-Hydroxy-3-methoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl]-7 H -thiazolo[3,2 - b ]-1,2,4-triazin-7-one 3-(4-ethoxyphenyl)-6-{2-oxo-2-[4-(benzylcarbamoylmethoxy)phenyl]ethyl} -7H -thiazolo[3, 2- b ]-1,2,4-triazin-7-one 3-[(3-methyl-4-methoxy)phenyl]-6-{2-oxo-2-[4-(4-methylanilino)formylmethoxyphenyl]ethyl }-7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 3-[(3-methyl-4-hydroxy)phenyl]-6-{2-oxo-2-[4-(4-morpholinyl)formylmethoxyphenyl]ethyl}-7 H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-6-{2-oxo-2-[(3-methyl-4-ethoxy)phenyl]ethyl base} -7H -thiazolo[3,2- b ]-1,2,4-triazin-7-one 3-[4-(2-Diethylaminoethoxy)phenyl]-6-[2-oxo-2-(4-ethoxyphenyl)ethyl] -7H -thiazolo[3 ,2- b ]-1,2,4-triazin-7-one. 2. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient and a pharmaceutically acceptable carrier or excipient. 3. Application of the compound according to claim 1 or the composition according to claim 2 in the preparation of a medicament for the treatment of degenerative dementia.