CN114516832A - Tubulin inhibitor and preparation method and application thereof - Google Patents

Tubulin inhibitor and preparation method and application thereof Download PDF

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Publication number
CN114516832A
CN114516832A CN202111387237.6A CN202111387237A CN114516832A CN 114516832 A CN114516832 A CN 114516832A CN 202111387237 A CN202111387237 A CN 202111387237A CN 114516832 A CN114516832 A CN 114516832A
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compound
hydroxy
substituent
pharmaceutically acceptable
substituted
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CN114516832B (en
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广兵
阳泰
董韧涵
刘进
覃传军
占伟
黄胜
谢建
赖永新
彭向阳
许庆
彭坚
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Chengdu Benuo Kecheng Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

The invention belongs to the field of chemical medicine, and particularly relates to a tubulin inhibitor, and a preparation method and application thereof. The invention provides a compound shown in formula I. The compound has significant inhibitory effect on cancer cells and HacaT cells, and IC thereof50Is obviously lower than the similar compounds in the prior art, so the compound provided by the invention can be used for preparing the medicine for preventing and treating cancerA medicament for the treatment of conditions, actinic keratosis and psoriasis. In addition, the compounds of the present invention may be used in the preparation of tubulin inhibitors.

Description

Tubulin inhibitor and preparation method and application thereof
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a tubulin inhibitor, and a preparation method and application thereof.
Background
Microtubules are the major component of the cytoskeleton and are present in all eukaryotic cells. Because of the important role that microtubules play in cell mitosis, tubulin is becoming one of the important targets for medical workers to research and develop anticancer drugs. Tubulysins can be classified into 3 types, depending on their site of action on tubulysins: a tubulin inhibitor acting on colchicine sites; ② tubulin inhibitors acting on the vinblastine site; ③ tubulin inhibitors acting on the paclitaxel site. At present, vinblastine and paclitaxel site tubulin inhibitor drugs play an important role in clinical treatment of tumors, and paclitaxel is an important first-line treatment drug for lung cancer, breast cancer and ovarian cancer. However, as with other antineoplastic drugs, the clinical use of tubulin inhibitors has been limited by the development of intolerable side effects and drug resistance following drug administration. Therefore, the development of novel tubulin inhibitors which have stronger activity, lower toxicity and are more effective on multidrug resistant tumor cells has great application prospect.
In Chinese patent application "CN 105263907A N- (3-fluorobenzyl) -2- (5- (4-morpholinophenyl) pyridin-2-yl) acetamide as protein tyrosine kinase regulator" a compound with the following structure is disclosed.
Figure BDA0003367464900000011
The literature indicates that the compound shows an inhibitory effect on tubulin, and thus has therapeutic and prophylactic effects on cancer, precancer, and the like. However, this compound still has a problem of weak inhibitory effect.
Disclosure of Invention
Aiming at the problems of clinical use of a tubulin inhibitor in the prior art, the invention provides the tubulin inhibitor and the preparation method and the application thereof, and the compound has stronger inhibition effect on tubulin, thereby showing stronger inhibition effect on cancer cells and human immortalized epidermal cells.
A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0003367464900000021
wherein X is selected from nitro or
Figure BDA0003367464900000022
R1、R2Each independently selected from H, substituted or unsubstituted C1～C10Alkyl, hydroxy; the substituent is C1-C10Alkoxy, cyano, hydroxy, carboxy, halogen or amino;
or, R1、R2Together with the N atom, form a substituted or unsubstituted ternary or quaternary heterocyclic ring or a seven-to eleven-membered heteroatom-containing spirocyclic ring;
the substituent is C1-C10Alkyl radical, C1-C10Alkoxy, cyano, hydroxy, carboxyl, halogen or amino;
R3selected from H, cyano or halogen.
Preferably, said R is1、R2Each independently selected from H, substituted or unsubstituted C1～C2Alkyl, hydroxy; the substituent is hydroxyl or halogen;
or, R1、R2Together with the N atom, form a substituted or unsubstituted, ternary or quaternary heterocycloalkyl; the substituent is C1-C10Alkyl radical, C1-C10Alkoxy, cyano, hydroxy, carboxyl, halogen or amino.
Preferably, said R is1、R2Each independently selected from H, methyl, ethyl, hydroxyl-substituted ethyl, chlorine-substituted ethyl, hydroxyl;
or, R1、R2Together with the N atom, form a ternary or quaternary heterocyclic ring.
Preferably, said R is3Selected from H or F.
Preferably, the compound of formula I is a compound of formula II:
Figure BDA0003367464900000023
wherein X is selected from nitro or
Figure BDA0003367464900000031
R1、R2Each independently selected from H, substituted or unsubstituted C1～C10Alkyl, hydroxy; the substituent is C1-C10Alkoxy, cyano, hydroxy, carboxy, halogen or amino;
or, R1、R2Together with the N atom, form a substituted or unsubstituted ternary or quaternary heterocyclic ring; the substituent is C1-C10Alkyl radical, C1-C10Alkoxy, cyano, hydroxy, carboxyl, halogen or amino.
Preferably, said R is1、R2Each independently selected from H, substituted or unsubstituted C1～C2Alkyl, hydroxy; the substituent is hydroxyl or halogen;
or, R1、R2Together with the N atom, form a substituted or unsubstituted ternary or quaternary heterocycle; the substituent is C1-C10Alkyl radical, C1-C10Alkoxy, cyano, hydroxy, carboxyl, halogen or amino.
Preferably, said R is1、R2Each independently selected from H, methyl, ethyl, hydroxyl-substituted ethyl, chlorine-substituted ethyl, hydroxyl;
or, R1、R2Together with the N atom forming a ternary or quaternary heterocyclic ring or
Figure BDA0003367464900000032
Preferably, the compound is the following:
Figure BDA0003367464900000033
Figure BDA0003367464900000041
the invention also provides a preparation method of the compound shown in the formula I, which is characterized by comprising the following steps:
Figure BDA0003367464900000042
wherein, X and R3As claimed in claim 1.
Preferably, the reaction is carried out by:
(1) the synthesis steps of the intermediate M-1 are as follows:
mixing and dissolving 5-bromo-2-fluoropyridine and diethyl malonate, heating to react under the action of cesium carbonate, separating, and concentrating to dryness to obtain a residue;
dissolving the obtained residue, adding strong base for reaction, adjusting pH to 4-5, separating out solid, separating, and drying to obtain intermediate M-1;
(2) the synthesis steps of the intermediate M-2 are as follows:
intermediate M-1 and meta have R3Mixing and dissolving substituted benzylamine, reacting under the action of DIPEA and TBTU, and separating to obtain an intermediate M-2;
(3) the synthesis steps of the compound of formula I are:
and mixing and dissolving the intermediate M-2 and phenylboronic acid with the para-position X substituent, heating to react under the action of potassium carbonate and tetrakis (triphenylphosphine) palladium, and separating to obtain the compound shown in the formula I.
The invention also provides a preparation method of the pharmaceutically acceptable salt of the compound shown in the formula I, which comprises the following steps: heating and dissolving the compound shown in the formula I in an organic solvent, adding acid, reacting, cooling and separating to obtain the compound.
Preferably, the organic solvent is one or more of methanol, ethanol, isopropanol, ethyl acetate, butyl acetate, acetone, tetrahydrofuran, dichloromethane, n-hexane and methyl tert-butyl ether;
and/or the acid is selected from hydrochloric acid, sulphuric acid, citric acid, benzenesulphonic acid, hydrobromic acid, hydrofluoric acid, phosphoric acid, acetic acid, propionic acid, succinic acid, oxalic acid, lactic acid, malic acid, succinic acid, fumaric acid, maleic acid, tartaric acid or trifluoroacetic acid;
and/or adding methyl tert-butyl ether to separate out crystals, and filtering.
The invention also provides application of the compound or the stereoisomer or the pharmaceutically acceptable salt thereof in preparing tubulin inhibitors.
Preferably, the tubulin inhibitor is used for the treatment and/or prevention of cancer, skin diseases.
Preferably, the cancer comprises at least one of ovarian cancer, breast cancer, glioma, colon cancer and lymphoma;
and/or, the skin disorder comprises at least one of actinic keratosis and psoriasis.
The invention also provides application of the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in preparing an anti-tumor medicament.
Preferably, the drug is an anti-ovarian, breast, glioma, colon, or lymphoma drug.
The invention also provides application of the compound or the stereoisomer or the pharmaceutically acceptable salt thereof in preparing a medicament for treating and/or preventing skin diseases.
Preferably, the medicament is a medicament for the treatment and/or prevention of actinic keratosis and psoriasis.
The invention also provides a pharmaceutical composition, which is prepared by taking the compound, or the stereoisomer or the pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
Preferably, the adjuvant or auxiliary ingredient is selected from at least one of diluents, fillers, colorants, glidants, lubricants, binders, stabilizers, suspending agents and buffering agents.
Preferably, the pharmaceutical composition is in the form of tablet, capsule, oral liquid, injection, transdermal agent, aerosol solid preparation, liposome or sustained-release preparation.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix Ca-CbAlkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1-C4Alkyl "refers to an alkyl group containing 1 to 4 carbon atoms.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. E.g. C1-C6Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as C1-C6An alkoxy group.
"cycloalkyl" refers to a saturated or partially saturated cyclic group having from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). For polycyclic systems having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
"alkenyl" refers to a straight or branched chain hydrocarbyl group having 2 to 10 carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms, and having at least 1 site of vinyl unsaturation (> C ═ C <). For example, (Ca-Cb) alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1, 3-butadienyl, and the like.
"alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C2-C6) alkynyl is intended to include ethynyl, propynyl, and the like.
"halogen" is fluorine, chlorine, bromine or iodine.
"heterocycle" refers to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom;
“R1、R2taken together with the N atom "means R1And R2At least one atom in the structure is connected by chemical bonds, so that R in the general structure1And R2With the N atom jointly bound as part of the skeleton and R of the ring structure1And R2Together form a heterocyclic ring.
"stereoisomers" include enantiomers and diastereomers.
The term "pharmaceutically acceptable" refers to a carrier, cargo, diluent, excipient, and/or salt formed generally
Chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form, and physiologically compatible with the receptor.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, lactate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
In the present invention, the room temperature is 25. + -. 5 ℃ and the overnight time is 12. + -.2 h.
The compound provided by the invention has stronger inhibition effect on tubulin, thereby showing stronger treatment and prevention effect on diseases related to the activity increase of the tubulin, such as cancer and partial skin diseases. The compound has obvious inhibiting effect on ovarian cancer cells, breast cancer cells, glioma cells, colon cancer cells, lymph cancer cells and immortal keratinocytes, and can be used for preparing the medicines for preventing and treating ovarian cancer, breast cancer, glioma, colon cancer, lymph cancer, actinic keratosis and psoriasis by single or combined application. The compounds provided herein have significantly reduced IC50 for inhibiting tubulin or cancer cells compared to small molecule compounds of similar function in the prior art.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
EXAMPLE 1 Synthesis of Compound I-1
Figure BDA0003367464900000081
Wherein, i: DMSO, Cs2CO3；ii：MeOH，NaOH；iii：DMF，DIPEA，TBTU；iv：1,4-Dioxane，K2CO3，H2O，Pd[P(C6H5)3]4。
Step 1: 50.0 g of 5-bromo-2-fluoropyridine (S-1, 0.28mol) and 113.7 g of diethyl malonate (0.71mol) were dissolved in 1L of DMSO with stirring, 231.3 g of cesium carbonate (0.71mol) was added thereto, and the mixture was heated to 80 ℃ to react for 16 to 20 hours. TLC detection of raw material 5-bromo-2-fluoropyridine basically completely reacts. The reaction solution was cooled to room temperature, diluted with 2L of water, and then extracted 3 times with 500 mL of ethyl acetate. The ethyl acetate was combined, washed twice with 150 ml of water, and concentrated to dryness under reduced pressure.
Adding 300 ml of methanol and 200 g of sodium hydroxide solution with the mass fraction of 30% into the residue, heating to 60 ℃, stirring and reacting for 16-20 hours, and detecting the complete reaction of the raw materials by TLC. Stopping heating, concentrating the reaction solution under reduced pressure to reduce the volume to about 200 ml, cooling, adjusting the pH value to 6 with 4M hydrochloric acid, adjusting the pH value to 4-5 with 1M citric acid aqueous solution, precipitating the product, standing for about 1 hour, filtering, washing the solid with a small amount of water for 2 times, and washing with ethyl acetate for 1 time. Drying to obtain an intermediate M-1.
Step 2: 18.0 g of intermediate M-1(83.3mmol) and 17.8 g of benzylamine (166.6mmol) are taken up, dissolved in 150 ml of DMF, and 21.5 g of DIPEA (166.6mmol) are added with stirring, after which 40.1 g of TBTU (125.0mmol) are added in portions slowly and the reaction is stirred at room temperature overnight. TLC detects that the raw material completely reacts, 500 ml of ethyl acetate and 1L of water are added into the reaction solution, an ethyl acetate layer is taken after standing and layering, the water layer is extracted for 2 times by 150 ml of ethyl acetate, the ethyl acetate layer is combined, washed twice by 90 ml of 5% potassium carbonate solution and washed twice by 50 ml of saturated saline, and then dried for 1 hour by 35 g of anhydrous sodium sulfate. Filtering to remove sodium sulfate, concentrating the filtrate under reduced pressure to dryness, dispersing the oily substance with petroleum ether for crystallization, and filtering to obtain intermediate M-2.
And step 3: dissolving 14.0 g of intermediate M-2(45.9mmol) and 9.2 g of p-nitrobenzeneboronic acid (55.1mmol) in 200 ml of dioxane; dissolving another 12.7 g of potassium carbonate (91.8mmol) in 50 ml of water, dropwise adding the solution into the system, adding 0.5 g of tetrakis (triphenylphosphine) palladium, heating to 80 ℃ for reaction for 10-12 hours, detecting that the raw materials react completely by TLC, cooling the reaction system to room temperature, adding 200 ml of ethyl acetate and 400 ml of water, standing for layering, extracting a water layer for 2 times by using 100 ml of ethyl acetate, combining ethyl acetate layers, washing for 3 times by using 20 ml of 5% sodium hydroxide, washing for once by using 20 ml of 5% diluted saline, washing with 20 ml of saturated saline until the water layer is neutral, adding 15 g of anhydrous sodium sulfate, and drying for 1 hour. Filtering to remove sodium sulfate, concentrating the filtrate under reduced pressure to dryness, dispersing and crystallizing the oily substance with methyl tert-butyl ether, and filtering to obtain compound I-1.
1HNMR(400MHz，DMSO-d6)δ：8.92(d，J＝2.4Hz，1H)，8.68(t，J＝6.0Hz，1H)，8.37-8.29(m，2H)，8.18(dd，J＝8.2，2.5Hz，1H)，8.07-8.00(m，2H)，7.52(d，J＝8.2Hz，1H)，7.37-7.19(m，5H)，4.31(d，J＝5.9Hz，2H)，3.78(s，2H)。
ESI-MS m/z:346.17[M-1]-。
EXAMPLE 2 Synthesis of Compound I-2
Figure BDA0003367464900000091
Taking 2.00 g of compound I-1(5.76mmol) to suspend in a mixed system of 40 ml of ethanol and 10 ml of water, adding 0.97 g of iron powder (17.37mmol) and 0.92 g of ammonium chloride (17.20mmol), heating to 90 ℃, reacting for 4-8 hours, monitoring the complete reaction of raw materials by TLC, cooling to room temperature, adding 40 ml of ethyl acetate, filtering, leaching a filter cake once by 15 ml of ethyl acetate, collecting a filtrate, adding a 40 ml of water layer, taking an ethyl acetate layer, extracting the water layer for 2 times by 15 ml of ethyl acetate, combining the ethyl acetate layers, washing once by saturated saline, adding 10 g of anhydrous sodium sulfate, and drying for one hour. Filtering to remove sodium sulfate, concentrating the filtrate under reduced pressure to dryness, dispersing and crystallizing the oily substance with methyl tert-butyl ether, and filtering to obtain crude compound I-2. And purifying the crude product by column chromatography (eluting system ethyl acetate/petroleum ether) to obtain the compound I-2.
1HNMR(400MHz，DMSO-d6)δ：8.70-8.57(m，2H)，7.78(dd，J＝8.2，2.5Hz，1H)，7.40(d，J＝8.2Hz，2H)，7.37-7.19(m，6H)，6.66(d，J＝8.2Hz，2H)，5.35(brs，2H)，4.30(d，J＝5.9Hz，2H)，3.68(s，2H)。
ESI-MS m/z:316.07[M-1]-。
500 mg of compound I-2(1.58mmol) are suspended in 5 ml of ethyl acetate, dissolved in an oil bath heated to 70 ℃ and 183 mg of fumaric acid (1.58mmol) are slowly added, held at 70 ℃ for 30 minutes and allowed to cool to room temperature. Concentrating ethyl acetate under reduced pressure to about 1ml volume, adding 5 ml methyl tert-butyl ether to gradually separate out crystals, and filtering to obtain fumarate I-2-1 of compound I-2, wherein the structure is as follows:
Figure BDA0003367464900000092
EXAMPLE 3 Synthesis of Compound I-3
Figure BDA0003367464900000101
iv：1,4-Dioxane，K2CO3，H2O，Pd[P(C6H5)3]4。
The intermediate M-2 and 4- (dimethylamino) phenylboronic acid are used as raw materials, and the synthesis method is similar to the step 3 in the example 1, so that the crude compound I-3 is obtained. Purifying by column chromatography (eluting system ethyl acetate petroleum ether) to obtain compound I-3.
1HNMR(400MHz，DMSO-d6)δ：8.73(d，J＝2.4Hz，1H)，8.62(t，J＝6.0Hz，1H)，7.95(dd，J＝8.1，2.5Hz，1H)7.60-7.53(m，2H)，7.41-7.19(m，6H)，6.86-6.79(m，2H)，4.30(d，J＝5.9Hz，2H)，3.70(s，2H)，2.95(s，6H)。
ESI-MS m/z:344.10[M-1]-。
500 mg of compound I-3(1.45mmol) are suspended in 5 ml of ethyl acetate, dissolved in an oil bath heated to 70 ℃ and 168 mg of fumaric acid (1.45mmol) are slowly added, held at 70 ℃ for 30 minutes and allowed to cool to room temperature. Concentrating ethyl acetate under reduced pressure to about 1ml volume, adding 5 ml methyl tert-butyl ether to gradually separate out crystals, and filtering to obtain fumarate I-3-1 of compound I-3, wherein the structure is as follows:
Figure BDA0003367464900000102
EXAMPLE 4 Synthesis of Compound I-4
Figure BDA0003367464900000103
The method comprises the following steps: dissolving 1.00 g of compound I-2(3.15mmol) in 25 ml of DMF, adding 0.64 g of 1, 3-dibromopropane (3.17mmol) and 0.87 g of potassium carbonate (6.29mmol) under stirring, heating to 60 ℃, reacting for 12 hours, detecting the complete reaction of raw materials by TLC, cooling to room temperature, pouring the reaction solution into 100 ml of ice water, extracting for 3 times by 75 ml of ethyl acetate, combining ethyl acetate layers, washing for 2 times by saturated salt water, adding 15 g of anhydrous sodium sulfate, and drying for one hour. Filtering to remove sodium sulfate, and concentrating the filtrate under reduced pressure to obtain crude compound I-4. And purifying by column chromatography (eluting with methanol/dichloromethane) to obtain compound I-4.
The second method comprises the following steps:
Figure BDA0003367464900000111
iv：1,4-Dioxane，K2CO3，H2O，Pd[P(C6H5)3]4。
the intermediate M-2 and 4- (cyclobutylamino) phenylboronic acid are used as raw materials, and the synthesis method is similar to the step 3 in the example 1, so that the crude product of the compound I-4 is obtained. And purifying by column chromatography (eluting with methanol/dichloromethane) to obtain compound I-4.
1HNMR(400MHz，CDCl3)δ：8.71-8.65(m，1H)，7.79(dd，J＝8.0，2.4Hz，1H)，7.51-7.39(m，2H)，7.35-7.16(m，6H)，6.57-6.48(m，2H)，4.52-4.44(m，2H)，3.94(t，J＝7.2Hz，4H)，3.83-3.77(m，2H)，2.40(p，J＝7.2Hz，2H)。
ESI-MS m/z:356.08[M-1]-。
EXAMPLE 5 Synthesis of Compound I-5
Figure BDA0003367464900000112
Wherein, i: DMSO, Cs2CO3；ii：MeOH，NaOH；iii：DMF，DIPEA，TBTU；iv：1,4-Dioxane，K2CO3，H2O，Pd[P(C6H5)3]4。
The synthesis was carried out in analogy to example 1, substituting 3-fluorobenzylamine for benzylamine in step 2 to give compound I-5.
ESI-MS m/z:364.02[M-1]-。
EXAMPLE 6 Synthesis of Compound I-6
Figure BDA0003367464900000113
Using the compound I-5 as a starting material, the synthesis method was similar to example 2 to give the compound I-6
ESI-MS m/z:334.14[M-1]-。
EXAMPLE 7 Synthesis of Compound I-7
Figure BDA0003367464900000114
iv：1,4-Dioxane，K2CO3，H2O，Pd[P(C6H5)3]4。
The intermediate M-3, 4- (dimethylamino) phenylboronic acid was used as a starting material, and the synthesis method was similar to example 3, yielding compound I-7.
ESI-MS m/z:362.15[M-1]-。
EXAMPLE 8 Synthesis of Compound I-8
Figure BDA0003367464900000121
iv：1,4-Dioxane，K2CO3，H2O，Pd[P(C6H5)3]4。
The intermediate M-3 was used as a starting material, and the synthesis was similar to example 3, giving compound I-8.
ESI-MS m/z:374.13[M-1]-。
EXAMPLE 9 Synthesis of Compound I-9
Figure BDA0003367464900000122
iv：1,4-Dioxane，K2CO3，H2O，Pd[P(C6H5)3]4。
Starting from the intermediate M-2, the synthesis was carried out analogously to example 3 to give the compound I-9.
ESI-MS m/z:398.40[M-1]-。
EXAMPLE 10 Synthesis of Compound I-10
Figure BDA0003367464900000123
iii：DMF，DIPEA，TBTU；iv：1,4-Dioxane，K2CO3，H2O，Pd[P(C6H5)3]4。
The intermediate M-1 was used as a starting material, and the synthesis method was similar to example 1, to give compound I-10.
ESI-MS m/z:374.13[M-1]-。
EXAMPLE 11 Synthesis of Compound I-11
Figure BDA0003367464900000124
iii：DMF，DIPEA，TBTU；iv：1,4-Dioxane，K2CO3，H2O，Pd[P(C6H5)3]4。
Starting from the intermediate M-1, the synthesis was carried out analogously to example 1 to give the compound I-11.
ESI-MS m/z:374.13[M-1]-。
The advantageous effects of the present invention are demonstrated by specific test examples below.
Test example 1 Activity test of the Compound of the present invention for blocking human Colon cancer cell HT29 cell cycle
The activity of the compounds of the invention to arrest the cell cycle was tested using human colon cancer cells HT 29. 2ml of cells, 1E 6/well, were added to a 6-well cell culture plate and 12h of adherent culture, the drug of the invention and control compounds 1, 2 were added at final concentrations of 25nM and 50nM, respectively. After the compound acts for 24 hours, the adherent cells are digested by pancreatin, centrifuged for 5min at 300g, and the culture solution is removed. Wash by addition of 1ml of pre-cooled PBS. Centrifuging 300g for 5min, removing supernatant, collecting cells, adding 70% ethanol pre-cooled at-20 deg.C, mixing, and fixing at 4 deg.C overnight. Centrifuge at 1000g for 5min to remove ethanol. Cell cycle is detected by using a cell cycle rapid detection kit RedNucleus dye of UE company. Adding RedNucleus I staining solution, slowly and fully mixing, and incubating for 20min at room temperature in a dark place. The detection wavelength was 660/20nm using a 638nm laser excitation by an eisen flow cytometer. The analysis was performed using flow cytometry-equipped cycle analysis software to compare the G2/M ratio of the cells of the different treatment groups. After the tubulin inhibitor acts on the cell, cell division is blocked, and the ratio of G/2M phase of the cell cycle is increased. HT29 blank group G2/M phase cell ratio was 12.9. + -. 1.3. The results of the ratio of G2/M phase blocking HT29 in the various concentrations of the compound are shown in Table 1 below:
Figure BDA0003367464900000131
TABLE 1 Activity of the Compounds of the invention on cell cycle arrest of human Colon cancer cells HT29 at various concentrations
Figure BDA0003367464900000132
Figure BDA0003367464900000141
The experimental results show that: the activity of the compound of the invention on the HT-29 cell cycle arrest of human colon cancer cells is obviously higher than that of the existing compound, which shows that the compound of the invention has obvious inhibitory activity on the mitosis process of eukaryotic cells.
Test example 2 inhibitory Activity of the Compound of the present invention against human Breast cancer cell MDA-MB-231 and human ovarian cancer cell SKOV-3
Respectively collecting human breast cancer cell MDA-MB-231 and human ovarian cancer cell SKOV-3 in logarithmic growth phase, counting, resuspending the cells with complete culture medium, adjusting cell concentration to 20/mu L to respectively obtain human breast cancer cell suspension and human ovarian cancer cell suspension, inoculating to 96-well plate, and adding 100 mu L of cell suspension to each well. Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2After 24 hours incubation in the incubator, the compounds of the invention and the control compounds were diluted with the medium to the respective effect concentrations set and added to the cells at 25. mu.L/well. The final concentration of the compound was diluted from 0nM to 400nM in 4-fold gradient for 10 concentration points. After addition of the test compoundCells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 72 hours. Absorbing and removing the culture medium, adding 100 mu L of fresh culture medium containing 10% CCK-8 into each well, placing the culture medium in an incubator at 37 ℃ for incubation for 2-4 hours, after slight shaking, measuring the absorbance at the wavelength of 450nm on a SpectraMax M5 Microplate Reader, taking the absorbance at 650nm as a reference, and measuring the inhibitory activity IC of the compound to be measured on human breast cancer cell MDA-MB-231 and human ovarian cancer cell SKOV-350The results are shown in Table 2:
TABLE 2 inhibitory Activity of the Compounds of the present invention against human Breast cancer cell MDA-MB-231 and human ovarian cancer cell SKOV-3
Figure BDA0003367464900000142
The experimental results show that: IC of the inventive Compounds on human Breast cancer cells MDA-MB-231 and human ovarian cancer cells SKOV-350The value is obviously lower than that of the existing compound, which shows that the compound has good inhibition effect on breast cancer cells and ovarian cancer cells, and can be used for preventing and treating breast cancer and ovarian cancer.
Test example 3 inhibitory Activity of the Compound of the present invention against human Colon cancer cell HT-29 and human brain glioma cell T98G
Collecting human colon cancer cells HT-29 and human brain glioma cells T98G in logarithmic growth phase, respectively, counting, resuspending the cells with complete culture medium, adjusting cell concentration to 20/mu L, respectively obtaining human colon cancer cell suspension and human brain glioma cell suspension, inoculating 96-well plates, and adding 100 mu L of cell suspension in each well. Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2After 24 hours incubation in the incubator, the test compounds were diluted with the medium to the set corresponding effect concentration and added to the cells at 25 μ L/well. The final concentration of the compound was diluted in 4-fold gradient from 0nM to 400nM for 10 concentration points. After addition of the candidate compound, the cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 72 hours. The medium was aspirated off, then 100. mu.L of fresh medium containing 10% CCK-8 was added to each well, incubated in an incubator at 37 ℃ for 2-4 hours,after gentle shaking, absorbance at the wavelength of 450nm is measured on a SpectraMax M5 Microplate Reader, and the absorbance at the wavelength of 650nm is taken as reference, so that the inhibitory activity IC of the compound to be measured on human colon cancer cells HT-29 and human brain glioma cells T89G50The results are shown in Table 3:
TABLE 3 inhibitory Activity of the Compounds of the present invention against human Colon cancer cell HT-29 and human brain glioma cell T98G
Figure BDA0003367464900000151
The experimental results show that: IC of the Compounds of the invention on human Colon cancer cells HT-29 and human glioma cell T98G50The value is obviously lower than that of the existing compound, which shows that the compound has good inhibition effect on colon cancer cells and brain glioma cells, and can be used for preventing and treating colon cancer and glioma.
Test example 4 inhibition test of human tissue lymphoma cell U937 by the Compound of the present invention
Human histiocyte lymphoma cells in logarithmic growth phase U937 (purchased from ATCC) were collected, the cells were resuspended in complete medium, the cell concentration was adjusted to 60/μ L to obtain a cell suspension, and 96-well plates were seeded with 100 μ L of cell suspension per plate. Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2After 24 hours incubation in an incubator, the test compounds of the invention were diluted with medium to the respective effect concentrations set and added to 96-well plates at 25. mu.L/well. The final concentration of the compound was diluted from 0nM to 400nM in 4-fold gradient. After addition of test compound, cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 72 hours. Then adding 100 mu L of fresh culture medium containing 10% CCK-8 into each hole, placing the mixture in an incubator at 37 ℃ for incubation for 2-4 hours, after gentle shaking, measuring the absorbance at the wavelength of 450nm on a SpectraMax M5 Microplate Reader, taking the absorbance at 650nm as reference, and calculating the inhibitory activity IC 937 of the compound to be detected on human histiocyte lymphoma cells U93750The results are shown in Table 4:
TABLE 4 inhibitory Activity of the Compounds of the invention against human histiocytic lymphoma cells U937
Compound numbering IC50(nM)
I-1 14.79
I-2 6.31
I-3 5.92
I-4 2.67
Control Compound 1 18.66
Control Compound 2 54.77
The test result shows that: IC for inhibition of human histiocytic lymphoma cells by compounds of the invention50The value is obviously lower than that of the existing compound, which shows that the compound has good inhibition effect on lymphoma cells and can be used for preventing and treating lymphoma.
Test example 5 inhibition test of HacaT cells with Compound of the present invention
Collecting logarithmic growth phase HacaT cells (purchased from ATCC), resuspending the cells in complete medium, adjusting the cell concentration to 20/. mu.l to obtain a cell suspension, inoculating 96-well plates, adding 100. mu.l of each plateL cell suspension. Cells were incubated at 37 ℃ 100% relative humidity, 5% CO2After 24 hours incubation in an incubator, the test compounds of the invention were diluted with medium to the respective effect concentrations set and added to 96-well plates at 25. mu.L/well. The final concentration of the compound was diluted from 0nM to 400nM in 4-fold gradient. After addition of test compound, cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 72 hours. Then adding 100 mu L of fresh culture medium containing 10% CCK-8 into each hole, placing the mixture in an incubator at 37 ℃ for incubation for 2-4 hours, after gentle shaking, measuring the absorbance at the wavelength of 450nm on a SpectraMax M5 Microplate Reader, taking the absorbance at the wavelength of 650nm as reference, and calculating the inhibitory activity IC of the compound to be detected on HacaT cells50The results are shown in Table 5:
TABLE 5 inhibitory Activity of the Compounds of the invention on HacaT cells
Compound numbering IC50(nM)
I-1 39.25
I-2 34.91
I-3 45.42
I-4 28.03
Control Compound 1 163.32
Control Compound 2 111.28
The test result shows that: IC of Compounds of the invention for HacaT cell inhibition50The value is obviously lower than that of the existing compound, which shows that the compound of the invention has good inhibition effect on human immortalized epidermal cells and can be used for preventing and treating actinic keratosis and psoriasis.
In conclusion, the compound has obvious inhibition effect on breast cancer cells, ovarian cancer cells, colon cancer cells, human brain glioma cells and lymph cancer cells, and the IC of the compound is50Is obviously lower than the similar compounds in the prior art, so the compound has extremely high application potential when being used for preparing the medicine for preventing and treating the cancer. The compounds of the invention also have significant inhibitory effects on HacaT cells, the IC thereof50Is obviously lower than the similar compounds in the prior art, so the compound can also be used for preparing the medicine for preventing and treating actinic keratosis and psoriasis. Meanwhile, the compound can be used for preparing a tubulin inhibitor.

Claims (10)

1. A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0003367464890000011
wherein X is selected from nitro or
Figure FDA0003367464890000012
R1、R2Each independently selected from H, substituted or unsubstituted C1～C10Alkyl, hydroxy; the substituent is C1-C10Alkoxy, cyano, hydroxy, carboxy, halogen or amino;
or, R1、R2Together with the N atom forming a substituent or notA substituted tri-or four-membered heterocyclic ring or a seven-to eleven-membered heteroatom-containing spirocyclic ring;
the substituent is C1-C10Alkyl radical, C1-C10Alkoxy, cyano, hydroxy, carboxy, halogen or amino;
R3selected from H, cyano or halogen.
2. A compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
the R is1、R2Each independently selected from H, substituted or unsubstituted C1～C2Alkyl, hydroxy; the substituent is hydroxyl or halogen;
or, R1、R2Together with the N atom, form a substituted or unsubstituted ternary or quaternary heterocyclic ring; the substituent is C1-C10Alkyl radical, C1-C10Alkoxy, cyano, hydroxy, carboxy, halogen or amino;
the R is3Selected from H or F.
3. A compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: the compound of formula I is a compound of formula II:
Figure FDA0003367464890000013
wherein X is selected from nitro or
Figure FDA0003367464890000021
R1、R2Each independently selected from H, substituted or unsubstituted C1～C10Alkyl, hydroxy; the substituent is C1-C10Alkoxy, cyano, hydroxy, carboxy, halogen or amino;
or, R1、R2Together with the N atom, form a substituted or unsubstituted ternary or quaternary heterocyclic ring; the substituent is C1-C10Alkyl radical, C1-C10Alkoxy, cyano, hydroxy, carboxyl, halogen or amino.
4. A compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
said R is1、R2Each independently selected from H, substituted or unsubstituted C1～C2Alkyl, hydroxy; the substituent is hydroxyl or halogen;
or, R1、R2Together with the N atom, form a substituted or unsubstituted ternary or quaternary heterocyclic ring; the substituent is C1-C10Alkyl radical, C1-C10Alkoxy, cyano, hydroxy, carboxyl, halogen or amino.
5. A compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: the compound is the following compound:
Figure FDA0003367464890000022
Figure FDA0003367464890000031
6. a process for the preparation of the compound of claim 1, wherein the reaction is carried out by:
Figure FDA0003367464890000032
wherein, X and R3As claimed in claim 1;
the reaction is carried out by the following steps:
(1) the synthesis steps of the intermediate M-1 are as follows:
mixing and dissolving 5-bromo-2-fluoropyridine and diethyl malonate, heating to react under the action of cesium carbonate, separating, and concentrating to dryness to obtain a residue;
dissolving the obtained residue, adding strong base for reaction, adjusting pH to 4-5, separating out solid, separating, and drying to obtain intermediate M-1;
(2) the synthesis steps of the intermediate M-2 are as follows:
intermediate M-1 and meta have R3Mixing and dissolving substituted benzylamine, reacting under the action of DIPEA and TBTU, and separating to obtain an intermediate M-2;
(3) the synthesis steps of the compound of formula I are:
and mixing and dissolving the intermediate M-2 and phenylboronic acid with the para-position X substituent, heating to react under the action of potassium carbonate and tetrakis (triphenylphosphine) palladium, and separating to obtain the compound shown in the formula I.
7. Use of a compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a tubulin inhibitor.
8. Use of a compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for combating ovarian cancer, breast cancer, glioma, colon cancer, lymphoma.
9. Use of a compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of skin diseases, said medicament being for the treatment and/or prevention of actinic keratosis and psoriasis.
10. A pharmaceutical composition characterized by: the compound is prepared by taking the compound of any one of claims 1 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
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CN115073362A (en) * 2022-08-04 2022-09-20 重庆迈德凯医药有限公司 Synthesis method of tinib bulin
WO2023134753A1 (en) * 2022-01-14 2023-07-20 武汉人福创新药物研发中心有限公司 Tubulin-src dual target inhibitor
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WO2023134753A1 (en) * 2022-01-14 2023-07-20 武汉人福创新药物研发中心有限公司 Tubulin-src dual target inhibitor
WO2024012534A1 (en) * 2022-07-13 2024-01-18 武汉人福创新药物研发中心有限公司 Heterocyclic fused benzene ring compounds, preparation method therefor, and use thereof
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