Medicine for treating Alzheimer's disease and preparation method thereof

Abstract

The invention relates to a medicine for treating Alzheimer's disease and a preparation method thereof. The medicine for treating the Alzheimer's disease is an osthole derivative, has the structure shown in the formula I, and has excellent activity for preventing and treating the Alzheimer's disease, and particularly, the activity far exceeds that of osthole. The compound is simple to prepare and easy to industrially apply. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a drug for treating Alzheimer's disease and a preparation method thereof. Background Art

[0002] Alzheimer's disease (AD) is the most common dementia in clinical practice, commonly known as senile dementia. There are more than 400 million people with Alzheimer's disease worldwide, accounting for 22% of people aged 50 and above. In the early stages of Alzheimer's disease, it affects the patient's memory, language and thinking ability. As the disease progresses, it gradually reduces the patient's ability to take care of themselves. Some patients will experience changes in mood, personality or behavior, which seriously affects the patient's quality of life. The pathogenesis of Alzheimer's disease is still inconclusive. Currently, the main hypotheses are Aβ amyloid degeneration, tau protein phosphorylation, oxidative stress, and cholinergic damage hypothesis. The main pathological characteristics of AD are the formation of senile plaques and neurofibrillary tangles in the brain, which are composed of beta amyloid protein (Betaamyloid protein, Aβ) and hyperphosphorylated tau protein, respectively. The amyloid cascade hypothesis holds that the core of senile plaque formation is Aβ deposition in the brain, which in turn leads to inflammatory cascade reactions, energy metabolism disorders, and cell apoptosis. By activating protein kinases, it promotes abnormal phosphorylation of tau protein, damages neurons, and ultimately leads to neuron reduction, triggering the occurrence of Alzheimer's disease. Neurofibrillary tangles are mainly composed of abnormally phosphorylated tau protein, which, through neurotoxicity, leads to microtubule collapse, axon degeneration, and neuronal death.

[0003] Currently, the expected goal of treating Alzheimer's disease is to delay and limit the development of cognitive symptoms and improve the behavioral and psychological symptoms of dementia. It is based on improving clinical symptoms rather than curing. The main therapeutic drugs are galantamine, donepezil, memantine, and rivastigmine, which are mainly administered orally or transdermally. Due to the limitation of the blood-brain barrier, the therapeutic effect is not ideal.

[0004] Most of the active monomer compounds of traditional Chinese medicine have multiple pharmacological effects and biological activities, multiple targets and few side effects, and are rich resources for discovering and developing new drugs for treating neuronal diseases. Literature has reported that a variety of active monomers of traditional Chinese medicine have preventive and therapeutic effects on Alzheimer's disease, including okra polysaccharides, wolfberry polysaccharides, yew polysaccharides, resveratrol, crocin, schisandrae alcohol A, tetrahydroschefflerine, berberine, curcumin, aloe-emodin, arctidin, osthole, quercetin, luteolin, tanshinone IIA, cryptotanshinone, asiatic acid, ellagic acid, scutellariae glycosides, astragaloside A, hyperoside, etc. However, the active monomers of traditional Chinese medicine often have the problem of insufficient activity. Therefore, it is a common research and development strategy to use active monomers of traditional Chinese medicine as lead compounds to develop more and more effective drugs. Summary of the invention

[0005] The present invention develops a novel osthole derivative based on osthole, which has excellent activity in preventing and treating Alzheimer's disease.

[0006] The osthole derivative for preventing and / or treating Alzheimer's disease of the present invention has a structure shown in Formula I:

[0007]

[0008] Wherein, R1 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0009] M is selected from N or CR5;

[0010] R2-R5 are independently selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, cyano, nitro, and hydroxyl.

[0011] In one embodiment, R1 is selected from hydrogen, methyl, ethyl, preferably methyl.

[0012] In one embodiment, M is selected from N.

[0013] In one embodiment, R2-R4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, 2,2,2-trifluoroethyl.

[0014] In one embodiment, R2-R4 are all selected from hydrogen.

[0015] In one embodiment, two of R2-R4 are selected from hydrogen, and the remaining are selected from fluorine, chlorine, bromine, methyl, trifluoromethyl.

[0016] In one embodiment, R2 and R4 are selected from hydrogen, and R3 is selected from fluorine, trifluoromethyl; or R3 and R4 are selected from hydrogen, and R2 is selected from fluorine, trifluoromethyl.

[0017] In one embodiment, the compound is selected from:

[0018]

[0019] The present invention also relates to pharmaceutically acceptable salts, solvates and prodrugs of the compound of formula I.

[0020] In the present invention, the "pharmaceutically acceptable salt" includes all inorganic and organic acid addition salts, especially all pharmaceutically acceptable inorganic and organic acid addition salts, especially all pharmaceutically acceptable inorganic and organic acid addition salts commonly used in pharmacy. Another aspect of the present invention is the salt formed with dicarboxylic acids and tricarboxylic acids.

[0021] Examples of acid addition salts include, but are not limited to, hydrochloride, hydrobromide, phosphate, nitrate, sulfate, sulfamate, formate, acetate, propionate, citrate, D-gluconate, benzoate, butyrate, salicylate, sulfosalicylate, lactate, maleate, laurate, malate, fumarate, succinate, oxalate, malonate, pyruvate, acetoacetate, tartrate, stearate, benzenesulfonate, toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, 3-hydroxy-naphthoate, naphthalene disulfonate, and trifluoroacetate.

[0022] Examples of salts formed with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine, ammonium, salts optionally derived from NH3 or an organic amine having 1 to 16 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and guanidine salts.

[0023] In the present invention, the "solvate" refers to a crystalline form containing one or more solvent molecules in a periodic three-dimensional arrangement.

[0024] In the present invention, the "prodrug" means any compound that is converted into any compound of the present invention under physiological conditions. The prodrug may be, but is not necessarily, pharmacologically inactive until converted into an active compound. The prodrug can be obtained by derivatizing one or more functional groups in the active compound with a prodrug group, i.e., a group that masks the functional group in the active compound and undergoes conversion to release the functional group under specific conditions of use, such as in vivo.

[0025] The present invention also relates to a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0026] In one embodiment, the pharmaceutical composition may further include one or more any conventional pharmaceutically acceptable excipients and / or carriers, such as solvents, fillers, diluents, adhesives, lubricants, glidants, viscosity modifiers, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickeners, buffers, pH modifiers, absorption delay agents, stabilizers, antioxidants, preservatives, antimicrobials, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, aromatics and coloring agents. Conventional formulation techniques known in the art, such as conventional mixing, dissolving, suspending, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or compression methods, can be used to prepare the composition.

[0027] Depending on the purpose of treatment, the pharmaceutical composition can be prepared into various types of dosage unit forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc., preferably liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions), etc.

[0028] In order to shape the pharmaceutical composition in tablet form, any excipient known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride of stearic acid, starch and lactose, etc.; disintegration inhibitors such as white sugar, tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium base and sodium lauryl sulfate, etc.; wetting agents such as glycerol and starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, etc.; and lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol, etc. Ordinary coating materials can be selected as needed to make sugar-coated tablets, gelatin-film-coated tablets, enteric-coated tablets, film-coated tablets, double-layer film tablets and multi-layer tablets.

[0029] In order to shape the pharmaceutical composition in the form of pills, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrants such as agar and kelp powder, etc.

[0030] In order to prepare the pharmaceutical composition in the form of injection, the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerol, etc.) to prepare an injection with an osmotic pressure equal to that of blood. When preparing the injection, any commonly used carrier in the art can also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan, etc. In addition, common solvents, buffers and analgesics, etc. can also be added.

[0031] In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited and can be selected within a wide range, usually 1 to 99% by mass, preferably 5 to 80% by mass, and most preferably 10 to 40% by mass.

[0032] In the present invention, the administration method of the pharmaceutical composition is not particularly limited. Various dosage forms of preparations can be selected for administration according to the patient's age, gender, and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules can be administered orally; injections can be administered alone or mixed with an injection delivery fluid (such as a glucose solution and an amino acid solution) for intravenous injection.

[0033] The present invention also provides the use of the compound of formula I or its pharmaceutically acceptable salt, solvate, prodrug or the pharmaceutical composition in the preparation of a drug for preventing and / or treating Alzheimer's disease.

[0034] The present invention also provides a method for preparing the compound of formula I, which comprises:

[0035]

[0036] Reacting a compound of formula II with a compound of formula III to produce a compound of formula I;

[0037] Wherein, M, R1-R4 are as described in the present invention.

[0038] Preferably, the reaction is carried out under the catalysis of boron trifluoride etherate.

[0039] Beneficial Effects

[0040] The present invention provides a drug for treating Alzheimer's disease and a preparation method thereof. The drug for treating Alzheimer's disease is an osthole derivative, which has excellent activity in preventing and treating Alzheimer's disease, especially far exceeding the lead compound osthole. The compound is simple to prepare and easy to industrialize and apply. DETAILED DESCRIPTION

[0041] The present invention is described in more detail hereinafter to facilitate understanding of the present invention.

[0042] It should be understood that the terms or words used in the specification and claims should not be understood as having the meaning defined in the dictionary, but should be understood as having the meaning consistent with their meaning in the context of the present invention based on the following principle: the concept of the term can be appropriately defined by the inventor for the best explanation of the present invention.

[0043] Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention.The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0044] Example 1: Preparation of Compound 1

[0045]

[0046] Under magnetic stirring, osthole (1.22 g, 5 mmol) and 2-cyanopyrimidine (0.53 g, 5 mmol) were dissolved in 80 ml of toluene, and then 5 ml of boron trifluoride etherate (BF3·O(C2H5)2) was added dropwise thereto, stirred at room temperature, and the reaction was monitored by TLC. After 2 hours, the raw material disappeared, and after stirring for 1 hour, 100 ml of a saturated solution of sodium bicarbonate was added to quench, and then 100 ml of chloroform was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and recrystallized with methanol to obtain compound 1, 1.52 g, HPLC purity 99.4%, yield 82.5%.

[0047] HRMS(ESI)C 20 H 21 N3O4+H + :Theoretical value 368.1610; measured value 368.1626.

[0048] Elemental Analysis C 20 H 21 N3O4: Theoretical value C, 65.38; H, 5.76; N, 11.44; O, 17.42; Actual value: C, 65.42; H, 5.79; N, 11.45; O, 17.40.

[0049] 1 H NMR (400MHz, DMSO-d6) δ8.88(d,J=8.3Hz,2H),7.90(d,J=9.5Hz,1H),7.59(s,1H),7.50(d,J=8.7Hz,1H),7.42(t,J=8. 3Hz, 1H), 6.86 (d, J = 8.7Hz, 1H), 6.29 (d, J = 9.5Hz, 1H), 3.84 (s, 3H), 2.85-2.68 (m, 2H), 1.99-1.80 (m, 2H), 1.38 (s, 6H).

[0050] Example 2: Preparation of Compound 2

[0051]

[0052] Under magnetic stirring, osthole (1.22g, 5mmol) and 2-cyano-5-fluoropyrimidine (0.62g, 5mmol) were dissolved in 80ml of toluene, and then 5ml of boron trifluoride ether (BF3·O(C2H5)2) was added dropwise thereto, stirred at room temperature, and the reaction was monitored by TLC. After 1.5h, the raw material disappeared, and after stirring for 1h, 100ml of a saturated solution of sodium bicarbonate was added to quench, and then 100ml of chloroform was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and recrystallized from ethanol to obtain compound 2, 1.63g, HPLC purity 99.2%, yield 84.7%.

[0053] HRMS(ESI)C 20 H 20 FN3O4+H + :Theoretical value 386.1516; measured value 386.1502.

[0054] 1 H NMR (400MHz, DMSO-d6) δ8.54(s,2H),7.90(d,J=9.5Hz,1H),7.58(s,1H),7.50(d,J=8.7Hz,1H),6.86(d ,J=8.7Hz,1H),6.29(d,J=9.5Hz,1H),3.84(s,3H),2.85-2.68(m,2H),1.99-1.80(m,2H),1.38(s,6H).

[0055] Example 3: Preparation of Compound 3

[0056]

[0057] Under magnetic stirring, osthole (1.22 g, 5 mmol) and 2-cyano-3-trifluoromethylpyrimidine (0.87 g, 5 mmol) were dissolved in 70 ml of xylene, and then 5 ml of boron trifluoride ether (BF3·O(C2H5)2) was added dropwise thereto, stirred at room temperature, and the reaction was monitored by TLC. After 2.5 h, the raw material disappeared, and after stirring for 1 h, 100 ml of a saturated solution of sodium bicarbonate was added to quench, and then 120 ml of dichloromethane was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and recrystallized from tetrahydrofuran to obtain compound 3, 1.73 g, HPLC purity 99.3%, yield 79.6%.

[0058] HRMS(ESI)C 21 H 20 F3N3O4+H + :Theoretical value 386.1516; measured value 386.1502.

[0059] 1 H NMR (400MHz, DMSO-d6) δ8.87(d,J=8.3Hz,1H),7.90(d,J=9.5Hz,1H),7.71(d,J=8.3Hz,1H),7.64(s,1H),7.50(d,J=8. 7Hz, 1H), 6.86 (d, J = 8.7Hz, 1H), 6.29 (d, J = 9.5Hz, 1H), 3.84 (s, 3H), 2.87-2.68 (m, 2H), 1.99-1.80 (m, 2H), 1.38 (s, 6H).

[0060] Example 4: Pharmacodynamics test

[0061] Modeling and drug administration: 48 SPF male ICR mice with a body weight of (20±2) g (purchased from Chengdu Dashuo Experimental Animal Co., Ltd.) were housed in an animal room with alternating light and dark every 12 hours. The indoor temperature was controlled at 23.0±2.0℃ and the relative humidity was 50±10%, and standard feed and drinking water were given. They were randomly divided into 6 groups, including blank group, model group, compound 1 group, compound 2 group, compound 3 group and osthole group, with 8 mice in each group. Except for the blank group, the other groups used intraperitoneal injection of D-galactose combined with oral gavage of AlCl3 to establish a rapid aging AD mouse model. D-galactose was dissolved in sterile saline to obtain 12g·L -1 Solution, dose 60 mg kg -1 ·d -1 Intraperitoneal injection to create a rapid aging model. Dissolve AlCl3 in sterile saline to obtain 20 g·L -1 AlCl3 solution, at a dosage of 100 mg kg -1 ·d -1 The model was established for 8 weeks. After 4 weeks of model establishment, compound 1, compound 2, compound 3 and osthole groups were given oral administration at 20 mg kg -1 ·d -1 The blank group and the model group were intraperitoneally injected or gavaged with the same volume of saline.

[0062] Morris water maze experiment: The water maze is divided into 4 quadrants, and one of the 4 quadrants is randomly selected as the position for the mouse to enter the water. The platform is placed 1 cm below the horizontal plane in one of the quadrants. The time (s) the mouse takes to find the underwater platform is recorded, which is the escape latency. If the mouse fails to find the platform within 120s, the experimenter will pull it to the platform and stay there for 10s. The escape latency is recorded as 120s. Each animal is trained 4 times a day for 5 consecutive days. The platform is removed and a 120s spatial exploration experiment is started. The mouse is placed in the water from the opposite side of the original platform quadrant. The time the animal spends in the target quadrant (the quadrant where the platform was originally placed) and the number of times it enters the quadrant are recorded as indicators of spatial memory. The experimental data are expressed as GraphPad Prism 7 was used for data analysis, and one-way ANOVA was used to compare differences between groups. P < 0.05 indicated that the difference was statistically significant. The results are shown in the following table:

[0063]

[0064] Note: Compared with the blank group, aP<0.05; compared with the model group, bP<0.05; compared with osthole, cP<0.05.

[0065] It can be seen from the above results that the compound of the present invention has excellent AD prevention and treatment effects and is superior to the lead compound osthole.

[0066] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof: in, R1 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl; M is selected from N or CR5; R2-R5 are independently selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, cyano, nitro, and hydroxyl.

2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that: R1 is selected from hydrogen, methyl, ethyl, preferably methyl.

3. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that: M is selected from N.

4. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, characterized in that: R2-R4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, 2,2,2-trifluoroethyl.

5. The compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1, characterized in that: R2-R4 are all selected from hydrogen; or two of R2-R4 are selected from hydrogen, and the rest are selected from fluorine, chlorine, bromine, methyl, trifluoromethyl.

6. The compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1, characterized in that: R2 and R4 are selected from hydrogen, and R3 is selected from fluorine and trifluoromethyl; or R3 and R4 are selected from hydrogen, and R2 is selected from fluorine and trifluoromethyl.

7. The compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1, characterized in that: The compound is selected from:

8. A pharmaceutical composition comprising at least one compound of formula I according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate or prodrug thereof.

9. Use of the compound of formula I according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate, prodrug thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating Alzheimer's disease.

10. A method for preparing a compound of formula I as claimed in claim 1, comprising: Reacting a compound of formula II with a compound of formula III to produce a compound of formula I; Wherein, M, R1-R4 are as described in claim 1.

Images