CN115785094B

CN115785094B - Benzyl substituted alpha-carboline compound or medicinal salt thereof, pharmaceutical composition thereof, preparation method and application thereof

Info

Publication number: CN115785094B
Application number: CN202211560104.9A
Authority: CN
Inventors: 代江坤; 张姣月; 刘金易; 曹译丹; 高吉祥; 淡文佳
Original assignee: Weifang Medical University
Current assignee: Weifang Medical University
Priority date: 2022-12-07
Filing date: 2022-12-07
Publication date: 2024-05-07
Anticipated expiration: 2042-12-07
Also published as: CN115785094A

Abstract

The invention discloses a benzyl substituted alpha-carboline compound or a medicinal salt thereof and a pharmaceutical composition thereof, which not only have anti-neuritis activity, but also have low cytotoxicity, can be used for preventing and/or treating neurodegenerative diseases (such as Alzheimer disease), neuroinflammatory diseases and the like, and can make up for the defect that the existing cholinergic drugs only can relieve symptoms of Alzheimer disease.

Description

Benzyl substituted alpha-carboline compound or medicinal salt thereof, pharmaceutical composition thereof, preparation method and application thereof

Technical Field

The invention relates to the field of medicine synthesis, in particular to a benzyl substituted alpha-carboline compound or a medicinal salt thereof, a pharmaceutical composition thereof, a preparation method and application thereof.

Background

Alzheimer's Disease (AD) is one of five diseases that threaten human health, and AD patients need to take comprehensive care for a long time, and bring about a heavy burden to families and society. The etiology of the disease is complex, most of the current drugs are cholinergic drugs such as donepezil, galantamine and the like, and only can relieve symptoms, but the occurrence and the development of the disease are difficult to prevent. There is increasing evidence that cerebral neuroinflammation is not only a pathological feature of AD, but is likely to be an important etiology. Thus, compounds with anti-neuroinflammation have been discovered and have become new targets for the treatment of AD.

Natural products and analogs thereof are important sources for the discovery of anti-neuritic compounds such as quercetin, piperine, sophocarpine and the like. Alpha-carboline alkaloids have been reported to have anti-tumor, anti-microbial and anti-atherosclerosis activities, but have not been reported to have anti-neuritic activity. The research and development of the alpha-carboline analogue capable of resisting the neuroinflammation has important significance for preventing, improving or treating neurodegenerative diseases such as Alzheimer disease and the like.

Disclosure of Invention

Based on the above-mentioned needs of the prior art, the present invention provides a benzyl substituted alpha-carboline compound or its pharmaceutical salts, its pharmaceutical composition, its preparation method and application.

The first aspect of the invention provides a benzyl substituted alpha-carboline compound or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is shown as a general formula (I):

Wherein R ₁ is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a halogen; the substitution positions of R ₁ are any of the positions 2',3',4',5' and 6 '.

Preferably, the alkyl is a C _1-12 alkyl.

Preferably, the haloalkyl is a C _1-12 alkyl.

Preferably, the halogen is selected from fluorine atoms, chlorine atoms and bromine atoms.

Preferably, the R ₁ is selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group, a fluorinated C _1-6 alkyl group, a chlorinated C _1-6 alkyl group, a brominated C _1-6 alkyl group, and a fluorine atom, a chlorine atom, and a bromine atom.

Preferably, the R ₁ is selected from the group consisting of a hydrogen atom, a methyl group, a trifluoromethyl group, a fluorine atom, a chlorine atom, and a bromine atom.

Preferably, the benzyl substituted alpha-carboline compound or the pharmaceutically acceptable salt thereof is selected from the group consisting of:

in a second aspect the present invention provides a pharmaceutical composition comprising an effective amount of a compound as described above, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier.

The third aspect of the invention provides the use of the benzyl substituted alpha-carboline compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a medicament for treating Alzheimer's disease.

The fourth aspect of the invention provides application of the benzyl substituted alpha-carboline compound or the pharmaceutically acceptable salt thereof in preparing anti-neuritis drugs

The beneficial effects of the invention at least comprise:

The features and advantages of the present invention will be described in detail in the detailed description that follows.

Detailed Description

The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein. In the description of the present application, unless otherwise indicated, the meaning of "a", "an", "a plurality" and the like are two or more.

[ PREPARATION ] A method for producing a polypeptide

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary from the recited value to within ±5%.

As used herein, the term "comprising" or "including" can be open, semi-closed, and closed.

As used herein, the definition of standard chemical terms (e.g., groups) can be found in the literature references in the art.

Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left.

The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.

The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. In some preferred embodiments, monovalent or multivalent (e.g., monovalent or divalent) containing 1 to 12 carbon atoms (C _1-12 alkyl groups). In some more preferred embodiments, the alkyl group contains 1 to 6 carbon atoms (C _1-6 alkyl), for example 1, 2, 3, 4, 5 or 6 carbon atoms. In other embodiments, the alkyl group contains 1 to 3 carbon atoms, for example 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2, 2-dimethylpropyl. A particularly preferred but non-limiting example of an alkyl group is methyl.

The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferably, "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br).

The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced with a halogen atom. Preferably, "haloalkyl" refers to an alkyl group wherein 1,2 or 3 hydrogen atoms of the alkyl group have been replaced by halogen atoms, preferably by fluorine, chlorine, bromine. A particularly preferred, but non-limiting, example of a haloalkyl group is trifluoromethyl (CF ₃).

As used herein, the term "compound of the invention" or "active ingredient of the invention" is used interchangeably to refer to stereoisomers, enantiomers, or pharmaceutically acceptable salts thereof, of a compound of formula (la). The term also includes racemates, optical isomers, isotopic compounds (e.g., deuterated compounds) or precursors.

"Stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.

When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both the E-and Z-geometric isomers unless otherwise specified.

"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.

The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may produce enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography.

The present application also includes isotopically-labeled compounds, equivalent to those disclosed herein as original compounds. In practice it will often occur that one or more atoms are replaced by an atom of a different atomic weight or mass number than it is. Examples of isotopes that can be listed as compounds of the application include hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine isotopes. The compounds of the present application, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes of the above-mentioned compounds or other isotopic atoms are included within the scope of the present application. Certain isotopically-labeled compounds of the present application, for example, radioisotopes, are also useful in tissue distribution experiments of drugs and substrates. For example tritium, ³ H and carbon 14, ¹⁴ C, are relatively easy to prepare and detect. Is the first choice in isotopes. In addition, heavier isotopic substitutions such as deuterium, ² H, may be preferred in certain situations because of their good metabolic stability which may be advantageous in certain therapies, such as increasing half-life or reducing dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by substituting a readily available isotopically-labeled reagent with a non-isotopically labeled reagent using the protocols disclosed in the examples. In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts.

"Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; preferred inorganic acids include hydrochloride and sulfate salts. Organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, and the like. Preferred organic acids include formate and acetate salts. These salts can be prepared by methods known in the art.

As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to extend their inclusion. In general, the term "substituted", whether appearing before or after the term "optional", in the formulas of the present invention includes substituents, means that the specified structural substituent is substituted for the hydrogen radical. When multiple of a particular structure are substituted at a position with multiple particular substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible organic compound substitutions. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any of the permissible organic compounds described hereinabove to supplement the valence state thereof. Furthermore, the present invention is not intended to be limited in any way to allow substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds. The term "stable" as used herein refers to a compound that is stable for a period of time sufficient to maintain structural integrity of the compound, preferably for a period of time sufficient to be effective, as used herein for the purposes described above.

Metabolites of the compounds and pharmaceutically acceptable salts thereof of the present application, as well as prodrugs that can be converted in vivo to structures of the compounds and pharmaceutically acceptable salts thereof of the present application are also encompassed by the claims of the present application.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition is used for preventing and/or treating neurodegenerative diseases (such as Alzheimer disease), neuroinflammatory diseases and the like. In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity. The term "pharmaceutically acceptable" as used herein refers to materials (e.g., carriers or diluents) that do not affect the biological activity or properties of the compounds of the application and are relatively non-toxic, i.e., the materials can be administered to an individual without causing an adverse biological reaction or interacting in an undesirable manner with any of the components contained in the composition.

In the present application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers that are approved by the relevant government regulatory agency as acceptable for human or livestock use.

The term "preventing" as used herein includes reducing the likelihood of a patient from developing or worsening a disease or condition.

The term "treatment" and other similar synonyms as used herein include the following meanings:

(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;

(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;

(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively

(Iv) Alleviating symptoms caused by the disease or condition.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. The skilled artisan is familiar with the techniques of administration that can be used with the compounds and methods described herein. In a preferred embodiment, the compounds and compositions of the present invention are administered orally, and formulations of the compounds disclosed herein suitable for oral administration may be presented in discrete units, such as tablets, capsules or cachets, each containing a predetermined amount of the active ingredient. In other preferred embodiments, the compounds and compositions of the present invention are injectable and powder formulations.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.

In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.

The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary. The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals.

When used in pharmaceutical compositions, a safe and effective amount of a compound of the invention is administered to a subject (including mammals, such as humans) in need of treatment. Of course, the particular dosage will also take into account factors such as the route of administration, the health of the subject in need of treatment, and the like, which are within the skill of the skilled practitioner.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: a pharmaceutically acceptable carrier is admixed with a compound of formula (I) according to the invention or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, to form a pharmaceutical composition.

The invention also provides a treatment method, which comprises the following steps: the benzyl substituted alpha-carboline compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of the invention is applied to subjects in need of treatment for resisting neuroinflammation so as to achieve the effect of preventing and/or treating Alzheimer disease.

Process for the preparation of compounds of formula (I)

(I) In a proper solvent (such as toluene), benzotriazole and 2-bromopyridine are taken as raw materials, and the mixture is heated and refluxed to obtain a compound 3;

(ii) In a proper solvent (such as polyphosphoric acid), cyclizing the compound 3 under acid catalysis to generate alpha-carboline, namely the compound 4;

(iii) In a proper solvent (such as acetonitrile), potassium carbonate is added as a base, and the compound 4 and the compound 5 (benzyl halide) undergo substitution reaction under heating condition to obtain the compounds 6a-6l.

In some embodiments, the methods of making the α -carboline compounds of the invention comprise:

(i) 1.19g of benzotriazole was dissolved in 30mL of toluene, then 2.843g of 2-bromopyridine was added, stirred at 120℃and after the reaction was completed, the objective compound 3 was obtained as a white solid in 97% yield by concentration, drying and column chromatography.

The stirring can be uniform stirring, and the rotating speed is 500-700 rpm.

The completion of the reaction can be detected by TLC trace, detecting disappearance of starting material 1.

The column chromatography may be silica gel column chromatography, petroleum ether: ethyl acetate (4:1).

(Ii) 1.96g of Compound 3 was dissolved in 10mL of polyphosphoric acid, then stirred at 170℃and ice water 200mL was added after the reaction was completed, then pH was adjusted to be alkaline by dissolution with 30% potassium hydroxide, and the precipitate was obtained by filtration, and the objective Compound 4 was obtained as a white solid in 46% yield.

The stirring can be uniform stirring, and the rotating speed is 500-700 rpm.

The completion of the reaction can be detected by TLC trace, detecting disappearance of starting material 3.

The pH is adjusted to be alkaline, and the pH range is 9-10.

The column chromatography may be silica gel column chromatography, petroleum ether: ethyl acetate (2:1).

(Iii) 84mg of compound 4 was dissolved in 15mL of acetonitrile, then 0.6mmol of benzyl bromide or benzyl chloride (containing substituents) was added, 138mg of potassium carbonate was added, and the mixture was stirred under heating at 80℃to obtain compounds 6a to 6l by extraction, concentration and column chromatography.

The stirring can be uniform stirring, and the rotating speed is 500-700 rpm.

The completion of the reaction can be detected by TLC trace, detecting disappearance of starting material 4.

Examples

It should be noted that the various materials and reagents used in the examples below are those commonly used in the art and are commercially available in general terms unless otherwise indicated.

Example 1 9-benzyl-alpha-carboline (Compound 6 a)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of bromobenzyl and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9-benzyl-alpha-carboline as yellow solid, wherein the melting point is 107-108 ℃ and the yield is high 88％;¹H NMR(CDCl₃)δ:8.59(dd,J＝5.0Hz,2.5Hz,1H),8.41(dd,J＝5.0Hz,2.5Hz,1H),8.16(d,J＝10.0Hz,1H),7.50(t,J＝7.5Hz,1H),7.43(d,J＝5.0Hz,1H),7.35–7.25(m,7H),5.78(s,2H);¹³C NMR(CDCl₃)δ:151.78,146.22,139.63,137.37,128.68,128.22,127.38,127.01,126.81,121.05,120.69,120.06,115.94,115.37,109.93,45.01.HRMS(ESI)m/z calcd for C₁₈H₁₅N₂[M+H]⁺259.1229,found 259.1228.

Example 2 9- (4-methylbenzyl) -alpha-carboline (Compound 6 b)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 4-methyl bromobenzyl and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (4-methylbenzyl) -alpha-carboline as a yellow solid, wherein the melting point is 87-88 ℃ and the yield is 85％;¹H NMR(CDCl₃)δ:8.58(dd,J＝5.0Hz,2.5Hz,1H),8.36(dd,J＝5.0Hz,2.5Hz,1H),8.12(d,J＝10.0Hz,1H),7.47(t,J＝7.5Hz,1H),7.42(d,J＝10.0Hz,1H),7.30(t,J＝7.5Hz,1H),7.23–7.21(m,1H),7.20(d,J＝5.0Hz,2H),7.10(d,J＝5.0Hz,2H),5.71(s,2H),2.31(s,3H);¹³C NMR(CDCl₃)δ:151.80,146.22,139.67,137.02,134.41,129.38,128.19,127.07,126.80,121.05,120.70,120.02,115.95,115.32,109.99,44.82,21.14.HRMS(ESI)m/z calcd for C₁₉H₁₇N₂[M+H]⁺273.1386,found 273.1386.

Example 3 9- (3-methylbenzyl) -alpha-carboline (Compound 6 c)

84Mg of compound 4 is dissolved in 15mL of acetonitrile, then 0.6mmol of 3-methyl bromobenzyl and 138mg of potassium carbonate are added, heating and stirring are carried out at 80 ℃, and after the reaction is finished, extraction, concentration and column chromatography are carried out, the target product 9- (3-methylbenzyl) -alpha-carboline is obtained as yellow oil, and the yield is high 86％;¹H NMR(CDCl₃)δ:8.56(d,J＝5.0Hz,1H),8.37(d,J＝10.0Hz,1H),8.12(d,J＝10.0Hz,1H),7.47(t,J＝7.5Hz,1H),7.41(d,J＝10.0Hz,1H),7.30(t,J＝7.5Hz,1H),7.23–7.20(m,1H),7.16(t,J＝7.5Hz,1H),7.11(s,1H),7.06(d,J＝5.0Hz,2H),5.70(s,2H),2.28(s,3H);¹³C NMR(CDCl₃)δ:151.82,146.23,139.73,138.37,137.35,128.59,128.22,127.72,126.82,124.11,121.04,120.69,120.04,115.95,115.34,110.00,45.05,21.47.HRMS(ESI)m/z calcd for C₁₉H₁₇N₂[M+H]⁺273.1386,found 273.1385.

Example 4 9- (2-methylbenzyl) -alpha-carboline (Compound 6 d)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 2-methyl bromobenzyl and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (2-methylbenzyl) -alpha-carboline as yellow solid, wherein the melting point is 109-111 ℃ and the yield is 88％;¹H NMR(CDCl₃)δ:8.54(dd,J＝5.0Hz,2.5Hz,1H),8.40(dd,J＝10.0Hz,2.5Hz,1H),8.15(d,J＝10.0Hz,1H),7.44(td,J＝7.5Hz,2.5Hz,1H),7.31(t,J＝7.5Hz,1H),7.20(d,J＝10.0Hz,1H),7.24–7.21(m,2H),7.16(t,J＝7.5Hz,1H),6.98(t,J＝7.5Hz,1H),6.62(d,J＝10.0Hz,1H),5.70(s,2H),2.49(s,3H);¹³C NMR(CDCl₃)δ:151.83,146.23,139.82,135.34,134.89,130.44,128.29,127.18,126.88.126.23,125.80,121.08,120.70,120.14,115.95,115.41,110.08,43.16,19.39.HRMS(ESI)m/z calcd for C₁₉H₁₇N₂[M+H]⁺273.1386,found 273.1386.

Example 5 9- (4-trifluoromethylbenzyl) -alpha-carboline (Compound 6 e)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 4- (trifluoromethyl) bromobenzyl and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (4-trifluoromethyl benzyl) -alpha-carboline which is a yellow solid, the melting point is 90-91 ℃ and the yield is high 75％;¹H NMR(CDCl₃)δ:8.54(dd,J＝5.0Hz,2.5Hz,1H),8.38(dd,J＝10.0Hz,2.5Hz,1H),8.12(d,J＝10.0Hz,1H),7.54(d,J＝10.0Hz,2H),7.47(td,J＝7.5Hz,2.5Hz,1H),7.35–7.30(m,4H),7.24–7.22(m,1H),5.76(s,2H);¹³C NMR(CDCl₃)δ:151.63,146.31,141.45,139.36,130.13(¹J_C-CF3＝32.5Hz),128.40,127.23,127.00,125.76(²J_C-CF3＝3.8Hz),125.22(CF₃,J＝271.3Hz),121.25,120.80,120.40,116.00,115.70,109.59,44.56.HRMS(ESI)m/zcalcd for C₁₉H₁₄F₃N₂[M+H]⁺327.1103,found 327.1104.

Example 6 9- (3-trifluoromethylbenzyl) -alpha-carboline (Compound 6 f)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 3- (trifluoromethyl) bromobenzyl and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (3-trifluoromethyl benzyl) -alpha-carboline which is a white solid with a melting point of 93-94 ℃ and a yield 72％;¹H NMR(CDCl₃)δ:8.60(d,J＝5.0Hz,1H),8.41(d,J＝10.0Hz,1H),8.17(d,J＝10.0Hz,1H),7.7(s,1H),7.56–7.51(m,2H),7.40–7.35(m,4H),7.29–7.26(m,1H),5.79(s,2H);¹³C NMR(CDCl₃)δ:151.66,146.30,139.39,138.50,131.46(¹J_C-CF3＝32.5Hz),130.32,129.27,128.37,127.00,125.17(CF₃,J＝270.0Hz),124.44(²J_C-CF3＝3.8Hz),123.96(²J_C-CF3＝3.8Hz),121.24,120.83,120.39,116.02,115.70,109.57,44.64.HRMS(ESI)m/z calcd for C₁₉H₁₄F₃N₂[M+H]⁺327.1103,found 327.1103.

Example 7 9- (2-Fluorobenzyl) -alpha-carboline (Compound 6 g)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 2-fluorobenzyl and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (2-fluorobenzyl) -alpha-carboline as a yellow solid, wherein the melting point is 52-54 ℃ and the yield is high 87％;¹H NMR(CDCl₃)δ:8.58(dd,J＝5.0Hz,2.5Hz,1H),8.35(dd,J＝5.0Hz,2.5Hz,1H),8.11(dd,J＝10.0Hz,2.5Hz,1H),7.51(td,J＝7.5Hz,2.5Hz,1H),7.45(d,J＝5.0Hz,1H),7.32(td,J＝7.5Hz,2.5Hz,1H),7.23–7.18(m,2H),7.12(td,J＝7.5Hz,2.5Hz,1H),7.01(td,J＝7.5Hz,2.5Hz,1H),6.92(td,J＝7.5Hz,2.5Hz,1H),5.80(s,2H);¹³C NMR(CDCl₃)δ:161.52(¹J_C-F ＝243.8Hz),151.79,146.25,139.48,129.14,129.07,129.04,128.27,126.99,124.47(³J_C-F ＝6.3Hz),121.09,120.70,120.27,116.04,115.53(³J_C-F ＝7.5Hz),115.31,109.74,38.47.HRMS(ESI)m/z calcd forC₁₈H₁₄FN₂[M+H]⁺277.1135,found277.1136.

Example 8 9- (4-chlorobenzyl) -alpha-carboline (Compound 6 h)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 4-chlorobenzyl chloride and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (4-chlorobenzyl) -alpha-carboline as a white solid, wherein the melting point is 135-136 ℃ and the yield is high 77％;¹H NMR(CDCl₃)δ:8.56(dd,J＝5.0Hz,2.5Hz,1H),8.35(dd,J＝10.0Hz,2.5Hz,1H),8.11(d,J＝10.0Hz,1H),7.47(td,J＝7.5Hz,2.5Hz,1H),7.34–7.29(m,2H),7.25–7.18(m,5H),5.66(s,2H);¹³C NMR(CDCl₃)δ:151.64,146.27,139.41,135.93,133.23,128.89,128.47,128.33,126.94,121.20,120.76,120.28,115.97,115.58,109.73,44.38.HRMS(ESI)m/z calcd forC₁₈H₁₄ClN₂[M+H]⁺293.0840,found 293.0840.

Example 9 9- (2-chlorobenzyl) -alpha-carboline (Compound 6 i)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 2-chlorobenzyl chloride and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (2-chlorobenzyl) -alpha-carboline as yellow solid, wherein the melting point is 121-122 ℃ and the yield is high 77％;¹H NMR(CDCl₃)δ:8.54(dd,J＝5.0Hz,2.5Hz,1H),8.38(dd,J＝10.0Hz,2.5Hz,1H),8.13(d,J＝10.0Hz,1H),7.46(t,J＝10.0Hz,2H),7.32(t,J＝7.5Hz,2H),7.24(q,J＝5.0Hz,1H),7.16(t,J＝7.5Hz,1H),6.98(t,J＝7.5Hz,1H),6.62(d,J＝10.0Hz,1H),5.82(s,2H);¹³C NMR(CDCl₃)δ:151.79,146.33,139.52,134.61,132.61,129.56,128.51,128.34,127.48,127.11,127.03,121.14,120.73,120.38,116.02,115.63,109.86,42.64.HRMS(ESI)m/z calcd forC₁₈H₁₄ClN₂[M+H]⁺293.0840,found 293.0841.

Example 10 9- (4-bromobenzyl) -alpha-carboline (Compound 6 j)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 4-bromobenzyl bromide and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (4-bromobenzyl) -alpha-carboline as a white solid, wherein the melting point is 158-159 ℃ and the yield is high 88％;¹H NMR(CDCl₃)δ:8.52(d,J＝5.0Hz,1H),8.37(d,J＝10.0Hz,1H),8.11(d,J＝10.0Hz,1H),7.46(t,J＝7.5Hz,1H),7.38(d,J＝10.0Hz,2H),7.33–7.27(m,2H),7.23–7.21(m,1H),7.12(d,J＝10.0Hz,2H),5.66(s,2H);¹³C NMR(CDCl₃)δ:151.61,146.24,139.36,136.37,131.80,128.74,128.35,126.90,121.29,121.16,120.72,120.25,115.95,115.56,109.70,44.43.HRMS(ESI)m/z calcd forC₁₈H₁₄BrN₂[M+H]⁺337.0334,found 337.0335.

Example 11 9- (3-bromobenzyl) -alpha-carboline (Compound 6 k)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 3-bromobenzyl bromide and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (3-bromobenzyl) -alpha-carboline as a white solid, wherein the melting point is 87-88 ℃ and the yield is 84％;¹H NMR(CDCl₃)δ:8.55(dd,J＝5.0Hz,2.5Hz,1H),8.35(dd,J＝5.0Hz,2.5Hz,1H),8.11(d,J＝10.0Hz,1H),7.49–7.45(m,2H),7.37–7.29(m,3H),7.23–7.20(m,1H),7.16(d,J＝10.0Hz,1H),7.10(t,J＝7.5Hz,1H),5.66(s,2H);¹³C NMR(CDCl₃)δ:151.62,146.25,139.77,139.42,130.65,130.31,130.07,128.36,126.98,125.66,122.86,121.20,120.78,120.33,116.00,115.63,109.70,44.47.HRMS(ESI)m/z calcd forC₁₈H₁₄BrN₂[M+H]⁺337.0334,found 337.0334.

Example 12 9- (2-bromobenzyl) -alpha-carboline (Compound 6 l)

Dissolving 84mg of compound 4 in 15mL of acetonitrile, then adding 0.6mmol of 2-bromobenzyl bromide and 138mg of potassium carbonate, heating and stirring at 80 ℃, extracting, concentrating and performing column chromatography after the reaction is finished to obtain a target product 9- (2-bromobenzyl) -alpha-carboline as a white solid, wherein the melting point is 128-129 ℃ and the yield is 85％;¹H NMR(CDCl₃)δ:8.52(d,J＝5.0Hz,1H),8.39(d,J＝10.0Hz,1H),8.13(d,J＝5.0Hz,1H),7.64(d,J＝10.0Hz,1H),7.46(t,J＝7.5Hz,1H),7.33–7.28(m,2H),7.24–7.22(m,1H),7.09(t,J＝7.5Hz,1H),7.01(t,J＝7.5Hz,1H),6.54(d,J＝10.0Hz,1H),5.77(s,2H);¹³C NMR(CDCl₃)δ:151.73,146.34,139.47,136.03,132.82,128.80,128.39,127.72,127.40,127.04,122.41,121.14,120.70,120.39,116.01,115.66,109.91,45.24.HRMS(ESI)m/z calcd forC₁₈H₁₄BrN₂[M+H]⁺337.0334,found 337.0336.

Example 13 anti-neuritis Activity test

The anti-neuritic activity of the compounds was determined by using mouse microglial cells (BV-2) as a neural cell model, lipopolysaccharide (LPS) as endotoxin to induce cells to produce inflammatory response, to secrete excessive NO, and detecting the release amount of NO in the culture solution using a nitric oxide kit in the experiment. Cells were seeded into 96-well plates (100. Mu.L/well) at a density of 2X 10 ⁵/mL and incubated in a constant temperature incubator at 37℃for 24 hours with 5% CO ₂. The experiment is divided into: control (DMSO), LPS treated (DMSO+1. Mu.g/mL LPS), positive control (1. Mu.g/mL LPS+10. Mu.M quercetin) and compound treated (1. Mu.g/mL LPS+10. Mu.M compound), after treatment, incubated for a further 24 hours, 50. Mu.L of supernatant was removed into a new 96-well plate, then 50. Mu.L of Griess reagent I and II each was added sequentially, and after mixing on a shaker for 5 minutes, absorbance (OD value) at 540nm was scanned on a microplate reader. The inhibition results are shown in Table 1.

EXAMPLE 14 cell viability test

Cells were seeded into 96-well plates at a density of 1X 10 ⁵/mL (100. Mu.L/well), cultured in an incubator at 37℃with 5% CO ₂ for 24 hours, then added with 20. Mu.M compound, and cultured again for 24 hours. Finally, 10. Mu.L of CCK-8 was added to each well, the tinfoil was protected from light, and the mixture was further cultured in a constant temperature incubator containing 5% CO ₂ at 37℃for 4 hours, and the absorbance (OD value) was measured at 450nm using a microplate reader. The cell viability results are shown in table 1.

TABLE 1 anti-neuritic Activity of benzyl substituted alpha-carboline analogs and corresponding cell viability ^a

Numbering of compounds	Inhibition (10. Mu.M,%)	Cell viability (20. Mu.M,%)
			2a	64.47±0.89	87.17±1.26
2b	75.00±1.61	89.35±0.59
			2c	82.89±0.77	92.12±0.84
2d	98.96±1.26	91.18±1.02
			2e	78.95±0.55	86.88±0.66
2f	64.47±0.89	92.93±0.82
			2g	65.79±1.48	91.26±0.83
2h	63.16±1.64	85.47±1.33
			2i	65.79±1.12	53.26±1.45
2j	84.84±0.14	74.67±1.04
			2k	81.58±2.82	77.59±0.73
2l	92.67±1.37	94.85±0.45

Note that: a. all values are expressed as mean ± SD from at least three independent experiments.

The anti-neuritis test result shows that the benzyl substituted alpha-carboline analogues have anti-neuritis activity, the inhibition rate of 10 mu M of 12 compounds is higher than that of positive control quercetin (56.63%), the cell survival rate of 11 compounds at 20 mu M concentration is still higher than 70%, and the anti-neuritis compound has very low cytotoxicity. Based on the 'neuritis hypothesis' of the current anti-Alzheimer disease pathological mechanism, the provided compound has potential application of medicaments for preventing and/or treating Alzheimer disease and other related neurological diseases, and can be used as an effective component for preparing the Alzheimer disease medicaments.

Finally, the above embodiments are only for illustrating the technical solution of the present invention, and do not limit the present invention. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.

Claims

1. A benzyl substituted alpha-carboline compound or a pharmaceutically acceptable salt thereof is characterized in that the structure of the compound is shown as a general formula (I):

Wherein R ₁ is selected from C _1-12 alkyl, chlorinated C _1-6 alkyl, brominated C _1-6 alkyl, chlorine atom or bromine atom; the substitution positions of R ₁ are any of the positions 2',3',4',5' and 6 '.

2. The benzyl substituted α -carboline compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

3. a pharmaceutical composition comprising a therapeutically effective amount of a benzyl-substituted α -carboline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient or carrier.

4. Use of a benzyl-substituted a-carboline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and/or treatment of alzheimer's disease.

5. Use of a benzyl-substituted a-carboline compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the manufacture of an anti-neuritis medicament.