CN114560813B - Benzimidazole MK2 allosteric inhibitor and preparation method and application thereof - Google Patents

Benzimidazole MK2 allosteric inhibitor and preparation method and application thereof Download PDF

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CN114560813B
CN114560813B CN202210223566.5A CN202210223566A CN114560813B CN 114560813 B CN114560813 B CN 114560813B CN 202210223566 A CN202210223566 A CN 202210223566A CN 114560813 B CN114560813 B CN 114560813B
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杨烨
李念光
羊丽金
孙善亮
顾春艳
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Nanjing University of Chinese Medicine
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Abstract

The invention relates to a benzimidazole compound, in particular to a benzimidazole compound which can be used as a novel MK2 allosteric inhibitor, and a preparation method and application thereof. The compound is a compound shown in a general formula (I), wherein: r in the general formula (I) 1 Is phenyl or a five-membered or six-membered aromatic heterocyclic ring containing 1 to 2 nitrogen atoms or 1 sulfur atom or 1 oxygen atom and other hetero atoms. R is R 2 May be hydrogen, methyl, methoxy, trifluoromethyl or halogen. R is R 3 Is piperazinyl or substituted piperazinyl, and the substituent of the substituted piperazinyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl and the like; five-membered or six-membered rings containing 1 or 2 hetero atoms among nitrogen atom, sulfur atom, oxygen atom; may also be- (CH) 2 )n‑OH、‑(CH 2 )n‑NH 2 N=3 to 5. The benzimidazole MK2 allosteric inhibitor (I) provided by the invention can be used for preparing an anti-multiple myeloma drug.

Description

Benzimidazole MK2 allosteric inhibitor and preparation method and application thereof
Technical Field
The invention relates to a benzimidazole compound, in particular to a benzimidazole compound which can be used as a novel MK2 allosteric inhibitor, and a preparation method and application thereof.
Background
Multiple Myeloma (MM) is a single-clone plasma cell malignancy, accounting for about 1% of all tumors, accounting for 13% of all hematological malignancies [ Rajkumar SV. Tree of Multiple myela. Nat Rev Clin Oncol.2011,8 (8): 479-91.Siegel R,Ma J,Zou Z,Jemal A.Cancer statistics,2014.CA Cancer J Clin.2014,64 (1): 9-29 ]. It is characterized by proliferation of cloned plasma cells both intramedullary and extramedullary, in most cases secreting a monoclonal protein, and is clinically manifested as end organ damage, as determined by four major disease symptoms, namely "CRAB signature", including hypercalcemia, renal insufficiency, anemia and bone diseases [ Kyle RA, rajkumar sv. About 28000 new diagnosed patients exist in China each year, and the incidence rate of the new patients exceeds that of acute leukemia, and the patients are located on the second position (second to the first lymphoma) of the malignant tumors of the blood system. With the trend of aging population in China, the number of patients with multiple myeloma increases at a rate of 1% per year.
Over the past twenty years, survival of MM patients has increased significantly with the introduction of Proteasome Inhibitors (PIs) bortezomib and carfilzomib, and immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide [ Murray MY, auger MJ, bowles km. Overhanging bortezomib resistance in multiple mychem Soc trans.2014,42 (4): 804-8.Kumar SK,Lee JH,Lahuerta JJ,Morgan G,Richardson PG,Crowley J,et al.Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib:amulticenter international myeloma working group study.Leukemia.2012,26 (1): 149-57 ]. Although proteasome inhibitors and immunomodulatory drugs have had good clinical results in primary treatment of patients, almost all MM patients eventually become resistant and relapse, requiring further treatment. Relapsed MM patients, particularly those resistant to proteasome inhibitors and IMiDs, have a poor prognosis (median overall survival of 9 months, no event survival of 5 months), with only 22% of patients responding to subsequent treatment. Thus, there is a need for ongoing innovations in therapeutic approaches, such as the development of new inhibitors with different mechanisms of action.
MAPK-activated protein kinase 2 (MK 2) is a serine/threonine protein kinase, a downstream protein called p38MAP kinase, involved in many cellular processes such as stress and inflammatory responses, nuclear export, cell proliferation and invasion. Tumor gene chip database studies showed that MK2 was expressed relatively higher in MM compared to normal plasma cells, high expression of MK2 triggered resistance and recurrence of MM, while MK2 increased stability of nuclear RNA by blocking RNA exosome targeting [ Tiedje C, lubas M, tehrani M, menon MB, ronkina N, rousseau S, cohen P, kotlyarov A, gaestel M.p38MAPK/MK2-mediated phosphorylation of RBM7 regulates the human nuclear exosome targeting complex. RNA.2015,21 (2): 262-78 ]. Thus, MK2 may be considered a powerful marker for cancer cells, and inhibition of MK2 may disrupt tumor growth [ Kotlyarov A, yannon Y, fritz S, laass K, telliez JB, pitman D, et al Distinct cellular functions of MK2.Mol Cell biol. (2002) 22:4827-4835 ], which provides a new approach and treatment for exploring drugs for the treatment of MM.
Earlier work in this group studied MK2 expression in MM patients by Gene Expression Profiling (GEP) and array-based comparative genomic hybridization (aCGH) and determined MK2 function in MM by MTT, western blot and flow cytometry. In addition, MK2 activity in MM was demonstrated by mouse survival experiments. The mRNA levels of MK2 and chromosomes at MK2 sites in MM cells were significantly increased compared to normal cells [ Guo M, sun D, fan Z, yuan Y, shao M, hou J, zhu Y, wei R, zhu Y, qian J, li F, yang Y, gu C.targeting MK2 Is a novel approach to interfere in multiple myeloma.front Oncol.2019,9:722 ].
Whereas the p 38/MAPK-activated kinase 2 (MK 2) signaling pathway is involved in a range of pathological states (inflammatory diseases and tumor metastasis) and in the drug resistance mechanism of antitumor drugs. p38 inhibitors have not entered clinical trials because of their systemic side effects. MK2 can avoid the side effects of p38 inhibitors, and is identified as an alternative target to block this pathway.
Over the past several years, potential MK2 inhibitors may block MK2 activity by either an ATP-competitive or an ATP-noncompetitive mechanism of action [ Fiore M, forli S, manetti F. Targeting mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK 2, MK 2): medicinal chemistry efforts to lead small molecule inhibitors to clinical trials. J. Med. Chem.2016,59,3609-3634]. ATP-competitive MK2 inhibitors suffer from low solubility, poor cell permeability, poor kinase selectivity, and the like. Whereas MK2 non-ATP-competitive inhibitors (i.e., allosteric inhibitors) do not interact with ATP binding sites, thus avoiding selectivity issues between kinases. In addition, MK2 allosteric inhibitors do not need to compete with intracellular high concentrations of ATP, nor do they need to compete with ATP for high affinity for inactive and active forms of MK2. Thus, MK2 allosteric inhibitors also have the additional advantage of being effective at lower concentrations, with fewer side effects, than ATP-competitive inhibitors.
Disclosure of Invention
The invention aims to provide a benzimidazole compound which can be used as an MK2 allosteric inhibitor.
Another problem to be solved by the present invention is to provide a method for preparing the benzimidazole compound.
The invention also aims to provide an application of the benzimidazole compound in preparing anti-myeloma medicaments.
In order to solve the problems, the invention adopts the following technical scheme:
a benzimidazole compound is shown in a formula (I):
or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt or prodrug thereof;
wherein:
R 1 selected from phenyl, five-membered or six-membered aromatic heterocyclic rings containing 1 to 2 nitrogen atoms or 1 sulfur atom or 1 oxygen atom;
R 2 selected from-H, methyl, methoxy, trifluoromethyl or halogen;
R 3 selected from piperazinyl or substituted piperazinyl, the substituents of the substituted piperazinyl being selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl; alternatively, R 3 A five-membered ring or a six-membered ring selected from 1 or 2 hetero atoms containing nitrogen atom, sulfur atom, oxygen atom; alternatively, R 3 Selected from- (CH) 2 )n-OH、-(CH 2 )n-NH 2 ，n＝3～5。
Preferably, the compound is selected from:
the invention also relates to a process for the preparation of a compound of formula (I), comprising the steps of:
adding substituted formaldehyde and substituted o-phenylenediamine into DMF, adding sodium bisulfite, stirring and refluxing for full reaction; cooling to room temperature, diluting with ice water, extracting with dichloromethane, mixing organic layers, drying, concentrating, and performing column chromatography to obtain substituted benzimidazole V-A;
b. adding the substituted benzimidazole V-A and the potassium carbonate into anhydrous DMF, fully stirring and uniformly mixing, adding the 3-bromobenzyl bromide, refluxing and fully stirring for reaction; cooling to room temperature, diluting with ice water, extracting with ethyl acetate, mixing organic layers, drying, concentrating, and performing column chromatography to obtain intermediate V-B;
c. the intermediate V-B is added into dioxane, and then Pd is added respectively 2 (dba) 3 Charging nitrogen into Xphos and tertiary sodium butoxide, stirring at room temperature for full reaction; adding substituted piperazine, stirring and refluxing for full reaction; cooling to room temperature, concentrating, and performing column chromatography.
In one embodiment, if the substituted piperazine is 1- (tert-butoxycarbonyl) piperazine, after the reaction to obtain an intermediate, dichloromethane and trifluoroacetic acid (TFA) are added, and the mixture is stirred at room temperature to fully react for 1h; diluting the reaction solution with ethyl acetate, extracting with water for 3 times, mixing the water layers, and regulating pH to 10 in ice bath; extracting with ethyl acetate for 3 times, mixing organic layers, and noDrying with sodium sulfate hydrate, concentrating to obtain R 3 Is piperazine substituted target compound (I).
The invention also relates to a pharmaceutical composition, which is characterized in that the composition contains the benzimidazole compound according to claim 1 or 2.
The invention also relates to application of the benzimidazole compound in preparation of medicines for resisting multiple myeloma.
Further, the benzimidazole compound and a pharmaceutically acceptable carrier are prepared into a tablet, a capsule, a granule, a spray, an injection, a microcapsule, an ointment or a transdermal controlled release patch.
In one embodiment, when the benzimidazole compound provided by the invention is prepared into tablets, the benzimidazole compound and carrier lactose or corn starch are added with lubricant magnesium stearate when needed, uniformly mixed, and then pressed into tablets.
In one embodiment, the benzimidazole compound provided by the invention is uniformly mixed with carrier lactose or corn starch when being prepared into capsules, and then the capsules are prepared after the mixture is granulated.
In one embodiment, when the benzimidazole compound provided by the invention is prepared into granules, the composition and the diluent lactose or corn starch are uniformly mixed, granulated, dried and prepared into granules.
Compared with the prior art, the invention has the following beneficial technical effects:
(1) The benzimidazole compound can be used as an MK2 allosteric inhibitor for preparing medicines for resisting multiple myeloma.
(2) The synthesis method provided by the invention is simple and convenient to operate and high in yield.
The following test examples are described in detail with respect to the advantageous technical effects of the present invention.
Definition of the definition
The term "halogen" or prefix "halo" refers to F, cl, br or I.
As described in the present invention, the substituents describe a ring formed by a bond to the central ringThe system (shown as formula I) represents R 2 May be substituted at any substitutable position on the ring.
The term "pharmaceutically acceptable" as used herein is meant to include any material which does not interfere with the effectiveness of the biological activity of the active ingredient and which is not toxic to the host to which it is administered.
The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula I. Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be esters, and in the prior invention, the esters can be phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters serving as the prodrugs. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent.
All tautomeric forms of the compounds of the invention are included within the scope of the invention unless otherwise indicated. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms. The term "tautomer" or "tautomeric form" refers to isomers of structures of different energies that can be interconverted by a low energy barrier. Examples include, but are not limited to, proton tautomers (i.e., proton-mobile tautomers) including tautomers by proton transport, such as keto-enol and imine-enamine isomerisation. Valency (valence) tautomers include the recombinant interconversion of some of the bond-forming electrons.
The compounds of the invention may contain asymmetric or chiral centers and thus exist as different stereoisomers. All stereoisomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the invention. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to denote the absolute configuration of the chiral center of the molecule. The prefix d, l or (+), (-) is used to name the sign of the compound plane polarized light rotation, the prefix (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereoisomers are different. The particular stereoisomer may be an enantiomer, and the mixture of isomers is commonly referred to as an enantiomeric mixture. The 50:50 enantiomeric mixture is known as a racemic mixture or racemate, which may result in the absence of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
Pharmaceutically acceptable carrier for use in the present invention means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the co-formulated contents.
Drawings
FIG. 1 is a structural general formula diagram of the compound.
FIG. 2 is a reaction scheme of a method for synthesizing the compounds of the present invention.
FIG. 3 is a graph showing the interaction results of the binding of the compound I-1 of the present invention with MK2 protein.
FIG. 4 is a graph showing the interaction results of the binding of Compound I-2 of the present invention to MK2 protein.
FIG. 5 is a graph showing the interaction results of the binding of Compound I-3 of the present invention to MK2 protein.
FIG. 6 is a graph showing the interaction results of the binding of Compound I-4 of the present invention to MK2 protein.
FIG. 7 is a graph showing the interaction results of the binding of Compound I-5 of the present invention to MK2 protein.
FIG. 8 is a graph showing the interaction results of the binding of Compound I-6 of the present invention to MK2 protein.
Detailed Description
The invention will be better understood from the following examples. However, it will be readily understood by those skilled in the art that the specific material ratios, process conditions and results thereof described in the examples are illustrative of the present invention and should not be construed as limiting the invention described in detail in the claims.
In the present invention, the structure of the compounds is determined by Mass Spectrometry (MS) and/or nuclear magnetic resonance (1 HNMR) equipment. The chemical abbreviations have the following meanings: DMF: n, N-dimethylformamide; TFA: trifluoroacetic acid. Xphos is a commercially available biphosphine ligand with large steric hindrance, pd 2 (dba) 3 Is a commercial palladium catalyst, and the two are often used together.
The compounds of the present invention may be prepared according to methods conventional in the art, using suitable reagents, starting materials and purification methods known to those skilled in the art. The following more specifically describes the preparation method of the compound of the present invention, but these specific methods do not limit the present invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Example 12 preparation of phenyl-1- (3- (1-piperazinyl) benzyl) -1H-benzimidazole (I-1)
(1) Synthesis of intermediate 2-phenyl-1H-benzimidazole: a250 mL round bottom flask was taken at room temperature, o-phenylenediamine (1.0814 mg,10 mmol), benzaldehyde (1.0612 g,10 mmol) and DMF (100 mL) were added sequentially, sodium bisulphite (312.18 mg,3 mmol) was added and the reaction stirred at 80℃for 6h. After the reaction, cooling to room temperature, diluting the reaction solution with ice water, extracting with dichloromethane for 3 times, combining organic layers, drying with anhydrous sodium sulfate, and concentrating; separating and purifying by silica gel column chromatography, and eluting with mixed solvent (4:1) of petroleum ether and ethyl acetate to obtain pale yellow solid (2-phenyl-1H-benzimidazole) with yield of 67.3% and about 1.3056 g.
(2) Synthesis of intermediate 1- (3-bromophenyl) -2-phenyl-1H-benzimidazole: a100 mL round bottom flask was taken at room temperature, and 2-phenyl-1H-benzimidazole (1.240 g,6.26 mmol) prepared above, potassium carbonate (863.88 mg,6.26 mmol) and anhydrous DMF (30 mL) were added in sequence, and stirred well, and then 3-bromobenzyl bromide (1.560 mg,6.26 mmol) was added to the mixture, and stirred at 85℃for 5H. After the reaction, cooling to room temperature, diluting the reaction solution with ice water, extracting with ethyl acetate for 3 times, combining organic layers, drying with anhydrous sodium sulfate, and concentrating; separating and purifying by silica gel column chromatography, eluting with mixed solvent (6:1) of petroleum ether and ethyl acetate to obtain pale yellow solid (1- (3-bromophenyl) -2-phenyl-1H-benzimidazole) with yield of 27.8% and about 631.7 mg.
(3) Synthesis of tert-butyl 4- (3- ((2-phenyl-1H-benzimidazol-1-yl) methyl) phenyl) piperazine-1-carboxylate: a50 mL round bottom flask was taken at room temperature and 1- (3-bromophenyl) -2-phenyl-1H-benzimidazole (338.8 mg,0.924 mmol) prepared above, pd, were added sequentially 2 (dba) 3 (33.88 mg,0.037 mmol), xphos (35.25 mg,0.074 mmol), sodium t-butoxide (248.6 mg,2.59 mmol) and dioxane (28 mL), and after charging nitrogen, stirring at room temperature for 30min, 1- (t-butoxycarbonyl) piperazine (838.15 mg,4.5 mmol) was added and reacted at 105℃for 12h under nitrogen. After the reaction is finished, cooling to room temperature, spin-drying the reaction liquid, and concentrating; separating and purifying by silica gel column chromatography, and eluting with mixed solvent (6:1) of petroleum ether and ethyl acetate to obtain light yellow oily substance (4- (3- ((2-phenyl-1H-benzimidazole-1-yl) methyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester) with a yield of 23.1%.
(4) Synthesis of the title compound (I-1): a25 mL round bottom flask was taken at room temperature, and tert-butyl 4- (3- ((2-phenyl-1H-benzimidazol-1-yl) methyl) phenyl) piperazine-1-carboxylate (145 mg), dichloromethane (4 mL) and trifluoroacetic acid (TFA) (1 mL) prepared as described above were added sequentially and the reaction was stirred at room temperature for 1H. After the reaction was completed, the reaction solution was diluted with ethyl acetate, extracted 3 times with water, the aqueous layers were combined, and the pH was adjusted to 10 with 1M NaOH solution under ice-bath conditions; extraction with ethyl acetate was repeated 3 times, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil, about 25mg, and a yield of 21.9%. 1 H NMR(500MHz,DMSO-d 6 )δ7.79–7.74(m,1H),7.72(ddd,J＝7.8,5.2,2.8Hz,1H),7.59–7.53(m,2H),7.53–7.49(m,1H),7.29–7.21(m,1H),7.07(t,J＝7.9Hz,1H),6.77(dd,J＝8.3,2.1Hz,1H),6.62(d,J＝21.1Hz,1H),6.34(d,J＝7.6Hz,1H),5.51(s,1H),2.96–2.86(m,2H),2.80–2.72(m,2H). 13 C NMR(126MHz,DMSO-d 6 )δ153.70,152.25,143.10,138.03,136.38,130.76,130.26,129.79,129.57,129.28,123.09,122.63,119.68,116.65,114.83,113.52,111.64,49.45,48.20,45.87。
Example 21 preparation of- (3- (4-methylpiperazin-1-yl) benzyl) -2-phenyl-1H-benzimidazole (I-2)
The title compound was obtained as a pale yellow oil, about 26.7mg, and a yield of 25.3% by the method of step (3) in example 1, using N-methylpiperazine instead of 1- (t-butoxycarbonyl) piperazine, and reacting with 1- (3-bromophenyl) -2-phenyl-1H-benzimidazole (prepared according to steps (1) to (3) in example 1). 1 H NMR(500MHz,CDCl 3 )δ7.88(d,J＝8.0Hz,1H),7.76–7.71(m,2H),7.51–7.44(m,3H),7.33(ddd,J＝8.1,5.8,2.5Hz,1H),7.29–7.25(m,2H),7.22(t,J＝7.9Hz,1H),6.87(dd,J＝8.3,2.2Hz,1H),6.67(s,1H),6.60(d,J＝7.6Hz,1H),5.43(s,2H),3.21–3.08(m,4H),2.59–2.50(m,4H),2.35(s,3H). 13 C NMR(126MHz,CDCl 3 )δ157.95,157.06,156.80,154.70,150.74,143.95,138.63,134.60,133.62,133.09,131.47,129.75,128.49,127.94,127.30,115.30,114.68,80.00,49.12,39.63,28.43。
Example 32 preparation of- (2-furyl) -1- (3- (1-piperazinyl) benzyl) -1H-benzimidazole (I-3)
(1) Synthesis of intermediate 2- (2-furyl) -1H-benzimidazole: a250 mL round bottom flask was taken at room temperature, o-phenylenediamine (1.0814 g,10 mmol), furfural (960.8 mg,10 mmol) and DMF (100 mL) were added in this order, sodium bisulphite (312.18 mg,3 mmol) was added, and the reaction was stirred at 80℃for 6h. After the reaction, cooling to room temperature, diluting the reaction solution with ice water, extracting with dichloromethane for 3 times, combining organic layers, drying with anhydrous sodium sulfate, and concentrating; separating and purifying by silica gel column chromatography, eluting with mixed solvent (4:1) of petroleum ether and ethyl acetate to obtain pale yellow solid (about 879.8 mg) with a yield of 47.8%.
(2) Synthesis of intermediate 1- (3-bromophenyl) -2- (2-furyl) -1H-benzimidazole: a100 mL round bottom flask was taken at room temperature, and 2- (2-furyl) -1H-benzimidazole (284 mg,4.48 mmol), potassium carbonate (618.24 mg,4.48 mmol) and anhydrous DMF (60 mL) prepared above were added in sequence and mixed well, and 3-bromobenzyl bromide (1.120 g,4.48 mmol) was added to the mixture and reacted at 85℃for 5H with stirring. After the reaction, cooling to room temperature, diluting the reaction solution with ice water, extracting with ethyl acetate for 3 times, combining organic layers, drying with anhydrous sodium sulfate, and concentrating; separating and purifying by silica gel column chromatography, and eluting with mixed solvent (6:1) of petroleum ether and ethyl acetate to obtain pale yellow solid, about 1.291g, and 81.9% yield.
(3) Synthesis of intermediate 4- (3- ((2- (2-furyl) -1H-benzimidazol-1-yl) methyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester: a100 mL round bottom flask was taken at room temperature and 1- (3-bromophenyl) -2- (2-furyl) -1H-benzimidazole (803 mg,2.3 mmol) prepared as described above, pd, were added sequentially 2 (dba) 3 (84.2 mg,0.092 mmol), xphos (88 mg,0.184 mmol), sodium t-butoxide (618.9 mg,6.44 mmol) and dioxane (40 mL), and after charging nitrogen, stirring at room temperature for 30min, 1- (t-butoxycarbonyl) piperazine (1.2852 g,6.9 mmol) was added and reacted at 105℃under nitrogen for 12h. After the reaction is finished, cooling to room temperature, spin-drying the reaction liquid, and concentrating; separating and purifying by silica gel column chromatography, eluting with mixed solvent (2:1) of petroleum ether and ethyl acetate to obtain pale yellow oily substance, about 226.59mg, and yield 21.5%.
(4) Synthesis of the title compound (I-3): a25 mL round bottom flask was taken at room temperature, and tert-butyl 4- (3- ((2- (2-furyl) -1H-benzimidazol-1-yl) methyl) phenyl) piperazine-1-carboxylate (180 mg) prepared above, dichloromethane (6 mL) and trifluoroacetic acid (TFA) (1.5 mL) were added sequentially and the reaction was stirred at room temperature for 1H. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, extracted 3 times with water, the aqueous layers were combined, and p was extracted with 1M NaOH solution under ice-bath conditionsH is adjusted to 10; extraction with ethyl acetate was repeated 3 times, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil, about 63mg, in 44.8% yield. 1 H NMR(500MHz,CDCl 3 )δ7.88–7.78(m,1H),7.57(d,J＝1.1Hz,1H),7.29(ddd,J＝7.2,4.0,1.9Hz,2H),7.25–7.21(m,1H),7.16(t,J＝7.9Hz,1H),7.05(d,J＝3.4Hz,1H),6.80(dd,J＝8.2,2.2Hz,1H),6.68(s,1H),6.59(d,J＝7.6Hz,1H),6.54(dd,J＝3.5,1.8Hz,1H),5.62(s,2H),3.03(dd,J＝6.2,3.6Hz,4H),2.95(dd,J＝6.2,3.6Hz,4H),2.10(d,J＝47.2Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ152.19,145.15,144.53,144.09,143.06,137.25,135.82,129.67,123.25,122.88,119.81,117.36,115.14,113.53,112.69,111.96,110.12,49.92,48.52,45.92。
Example 42 preparation of- (2-furyl) -1- (3- (4-methylpiperazin-1-yl) benzyl) -1H-benzimidazole (I-4)
Following the procedure of step (3) of example 3 substituting N-methylpiperazine for 1- (t-butoxycarbonyl) piperazine was reacted with 1- (3-bromophenyl) -2- (2-furyl) -1H-benzimidazole (prepared according to example 3 steps (1) to (3)) to give the title compound as a pale yellow oil, about 32mg, yield 30.3%. 1 H NMR(500MHz,CDCl 3 )δ7.97(dd,J＝1.6,0.6Hz,1H),7.71–7.65(m,1H),7.64–7.57(m,1H),7.30–7.22(m,2H),7.15(dd,J＝3.5,0.6Hz,1H),7.08(t,J＝7.9Hz,1H),6.83(s,1H),6.82–6.78(m,1H),6.74(dd,J＝3.5,1.8Hz,1H),6.37(d,J＝7.6Hz,1H),5.72(s,2H),3.07(d,J＝4.5Hz,4H),2.26(s,3H). 13 C NMR(126MHz,CDCl 3 )δ151.68,145.21,144.55,144.08,143.10,137.30,135.83,129.70,123.25,122.88,119.86,117.38,115.12,113.55,112.70,111.95,110.11,54.92,48.71,48.55,46.02。
Example 52 preparation of- (2-furyl) -1- (3- (1-piperazinyl) benzyl) -1H-benzimidazole (I-5)
(1) Synthesis of intermediate 2- (2-thienyl) -1H-benzimidazole: a150 mL round bottom flask was taken at room temperature, and o-phenylenediamine (1.292 g,11.98 mmol), thiophene 2-carbaldehyde (1.344 g,11.98 mmol) and DMF (80 mL) were added in this order, followed by sodium bisulfite (264 mg,3.594 mmol) and reacted for 6h with stirring at 80 ℃. After the reaction, cooling to room temperature, diluting the reaction solution with ice water, extracting with dichloromethane for 3 times, combining organic layers, drying with anhydrous sodium sulfate, and concentrating; separating and purifying by silica gel column chromatography, eluting with mixed solvent (2:1) of petroleum ether and ethyl acetate to obtain 2- (2-thienyl) -1H-benzimidazole, wherein the yield is about 498mg as pale yellow solid, and 20.8%.
(2) Synthesis of intermediate 1- (3-bromophenyl) -2- (2-thienyl) -1H-benzimidazole: a100 mL round bottom flask was taken at room temperature, and 2- (2-thienyl) -1H-benzimidazole (4638 mg,2.34 mmol) prepared above, potassium carbonate (324 mg,2.34 mmol) and anhydrous DMF (40 mL) were added in sequence, and stirred well, and then 3-bromobenzyl bromide (585 mg,2.34 mmol) was added to the mixture, and reacted at 85℃for 5H with stirring. After the reaction, cooling to room temperature, diluting the reaction solution with ice water, extracting with ethyl acetate for 3 times, combining organic layers, drying with anhydrous sodium sulfate, and concentrating; separating and purifying by silica gel column chromatography, eluting with mixed solvent (2:1) of petroleum ether and ethyl acetate to obtain 1- (3-bromophenyl) -2- (2-thienyl) -1H-benzimidazole, wherein about 311.08mg is pale yellow solid, and the yield is 36.0%.
(3) Synthesis of intermediate 4- (3- ((2- (2-thienyl) -1H-benzimidazol-1-yl) methyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester: a100 mL round bottom flask was taken at room temperature and 1- (3-bromophenyl) -2- (2-thienyl) -1H-benzimidazole (214.5 mg,0.585 mmol) prepared as described above, pd, were added sequentially 2 (dba) 3 (21.42 mg,0.0234 mmol), xphos (22.35 mg,0.0468 mmol), sodium t-butoxide (157.5 mg, 1.428 mmol) and dioxane (30 mL), and after charging nitrogen, stirring at room temperature for 30min, 1- (t-butoxycarbonyl) piperazine (327 mg,1.75 mmol) was added and reacted at 105℃for 12h under nitrogen. After the reaction is finished, cooling to room temperature, spin-drying the reaction liquid, and concentrating; separating and purifying by silica gel column chromatography, and eluting with mixed solvent (2:1) of petroleum ether and ethyl acetate to obtain 4- (3- ((2- (2-thienyl) -1H-benzo)Imidazol-1-yl) methyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester, about 180mg, as a pale yellow oil in 64.8% yield.
(4) Synthesis of the title compound (I-5): a25 mL round bottom flask was taken at room temperature, and tert-butyl 4- (3- ((2- (2-thienyl) -1H-benzimidazol-1-yl) methyl) phenyl) piperazine-1-carboxylate (150 mg), dichloromethane (4 mL) and trifluoroacetic acid (TFA) (1 mL) prepared as described above were added sequentially and the reaction was stirred at room temperature for 1H. After the reaction was completed, the reaction solution was diluted with ethyl acetate, extracted 3 times with water, the aqueous layers were combined, and the pH was adjusted to 10 with 1M NaOH solution under ice-bath conditions; the mixture was extracted 3 times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give the title compound as a pale yellow oil, about 32mg, and yield 27.1%. 1 H NMR(500MHz,CDCl 3 )δ7.86(d,J＝8.0Hz,1H),7.49(dd,J＝5.1,1.0Hz,1H),7.35–7.32(m,1H),7.32–7.29(m,1H),7.28(d,J＝7.3Hz,1H),7.26–7.23(m,1H),7.22(d,J＝7.9Hz,1H),7.09(dd,J＝5.1,3.7Hz,1H),6.86(dd,J＝8.2,2.2Hz,1H),6.68(s,1H),6.60(d,J＝7.7Hz,1H),5.55(s,2H),3.08(dd,J＝6.2,3.8Hz,4H),2.98(dd,J＝6.2,3.7Hz,4H),2.14(s,1H). 13 C NMR(126MHz,CDCl 3 )δ152.37,148.16,143.00,137.05,136.40,132.13,129.92,128.77,127.93,127.87,123.24,122.89,119.79,116.92,115.16,113.04,110.08,49.90,48.45,45.93,29.71。
Example 62 preparation of- (2-furyl) -1- (3- (4-methylpiperazin-1-yl) benzyl) -1H-benzimidazole (I-6)
Following the procedure of step (3) of example 5 substituting N-methylpiperazine for 1- (t-butoxycarbonyl) piperazine was reacted with 1- (3-bromophenyl) -2- (2-thienyl) -1H-benzimidazole (prepared according to example 5 steps (1) to (3)) to give the title compound as a pale yellow oil, about 31mg, yield 29.5%. 1 H NMR(500MHz,CDCl 3 )δ7.87(d,J＝8.0Hz,1H),7.51(d,J＝5.0Hz,1H),7.35(d,J＝4.2Hz,1H),7.32(dd,J＝8.0,1.8Hz,1H),7.29–7.27(m,2H),7.23(d,J＝7.9Hz,1H),7.10(dd,J＝4.8,4.0Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.70(s,1H),6.61(d,J＝7.6Hz,1H),5.57(s,2H),3.19–3.13(m,4H),2.60–2.54(m,4H),2.36(s,3H). 13 C NMR(126MHz,CDCl 3 )δ151.78,148.17,143.00,137.09,136.38,132.10,129.96,128.78,127.93,127.89,123.26,122.91,119.81,117.01,115.16,113.13,110.07,54.76,48.52,48.45,45.82。
Test examples biological Activity assays of the Compounds of the invention
1. Research on interaction of MK2 protein and small molecule
Experiment name: MST (micro thermophoresis) experiment:
MicroScale Thermophoresis (MST, micro-thermophoresis) is a revolutionary technique proposed by the Germany Nano Temper Technologies company for quantitative analysis of biomolecular interactions. The interaction between molecules is precisely quantified by detecting the motion rule (the change of molecular mass, charge number and hydration layer) of the molecules in a microcosmic temperature gradient field. When MST experiments are performed, the sample is heated by infrared laser to generate a microscopic temperature gradient field, and the directional movement of the molecules is monitored and quantified by autofluorescence of covalently bound fluorescent dye or tryptophan. The application range includes: small molecule interaction research, interaction between proteins, polypeptides, nucleic acids, small molecule interaction research, to detect interaction affinity between biomolecules.
The invention uses MST technology to accurately measure the dissociation constant Kd value of MK2 protein and the inhibitor synthesized by the invention in solution, and the higher the Kd value is, the smaller the affinity is, because the Kd value is inversely proportional to the affinity of the nucleotide chain. The magnitude of the affinity between the compound we synthesized and MK2 protein molecules was examined according to the above experimental principles.
Experimental results:
MST results of benzimidazole compounds of examples 1-6 (see FIGS. 3-8) in examples of the present invention.
Wherein the affinity Kd values of the compounds I-3, I-4, I-5 and I-6 with MK2 are 30.123. Mu.M, 11.327. Mu.M, 0.384. Mu.M and 0.195. Mu.M, respectively, which indicate that the compounds have strong binding activity with MK 2; the affinity Kd values of the compounds I-1 and I-2 and MK2 are 166.57 mu M and 191.86 mu M respectively, and the compounds have certain binding activity with MK2. The experimental result provides a basis for subsequent research of MK2 binding sites and exploration of novel MK 2-based targeted medicines for treating multiple myeloma.
2. Cell activity assay: effect of MK2 allosteric inhibitors on MM cell proliferation
Succinate dehydrogenase in the mitochondria of living cells reduces exogenous MTT to water-insoluble blue-violet crystalline Formazan (Formazan) and deposits in cells, whereas dead cells do not. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, an absorption value of the formazan is measured at a wavelength of 570nm by an enzyme-labeled instrument, the amount of MTT crystallization is proportional to the number of cells in a certain cell number range, and the number of living cells is judged according to the measured absorbance value (OD), wherein the larger the OD is, the stronger the cell activity is. The method comprises the following specific steps: 1) ARP1 and CAG wild-type myeloma cells in log phase were seeded in sterile 96-well plates, each group was provided with 3 multiplex wells, 5 concentration gradients of drug were added, 5% CO at 37 °c 2 Incubating for 48 hours in an incubator; 2) Each well was incubated with freshly prepared MTT reagent at 37℃in an incubator with 5% CO2 for 3h; 3) Centrifuging in a centrifuge, and adding 150 mu L of DMSO into each well; 4) The OD of each well was measured at 572nm using a microplate reader, and the growth inhibition ratio of the drug to myeloma cells was calculated according to the following formula, inhibition ratio= (experimental group OD-blank group OD)/(control group OD-blank group OD) ×100% (results are shown in table 1).
Inhibitory Activity of Table 1 Compounds against ARP1 and CAG wild type myeloma cells
Myeloma inhibition results experiments (Table 1) show that compounds I-1, I-3, I-4, I-5, I-6 have IC to ARP1 wild type myeloma cells 50 29.66. Mu.M, 46.73. Mu.M, 50.04. Mu.M, 18.13. Mu.M, 19.45. Mu.M, respectively, IC for CAG wild-type myeloma cells 50 40.26. Mu.M, 52.28. Mu.M, 68.48. Mu.M, 33.49. Mu.M, 35.63. Mu.M, respectively, which indicate that the above compounds are non-myeloma-inhibitingGood development prospect.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (5)

1. A benzimidazole compound is shown in a formula (I):
or a pharmaceutically acceptable salt thereof;
and, the compound is selected from the compounds listed in the following table, the R 1 、R 2 、R 3 The compounds listed in the following table are shown:
2. a process for preparing the compound of claim 1, comprising the steps of:
adding substituted formaldehyde and substituted o-phenylenediamine into DMF, adding sodium bisulfite, stirring and refluxing for full reaction; cooling to room temperature, diluting with ice water, extracting with dichloromethane, mixing organic layers, drying, concentrating, and performing column chromatography to obtain substituted benzimidazole V-A;
b. adding the substituted benzimidazole V-A and the potassium carbonate into anhydrous DMF, fully stirring and uniformly mixing, adding the 3-bromobenzyl bromide, refluxing and fully stirring for reaction; cooling to room temperature, diluting with ice water, extracting with ethyl acetate, mixing organic layers, drying, concentrating, and performing column chromatography to obtain intermediate V-B;
c. the intermediate V-B is added into dioxane, and then Pd is added respectively 2 (dba) 3 Charging nitrogen into the xphos and the sodium tert-butoxide, and stirring at room temperature for full reaction; adding substituted piperazine, stirring and refluxing for full reaction; cooling to room temperature, concentrating, and performing column chromatography.
3. A process for preparing the compound of claim 1, comprising the steps of:
adding substituted formaldehyde and substituted o-phenylenediamine into DMF, adding sodium bisulfite, stirring and refluxing for full reaction; cooling to room temperature, diluting with ice water, extracting with dichloromethane, mixing organic layers, drying, concentrating, and performing column chromatography to obtain substituted benzimidazole V-A;
b. adding the substituted benzimidazole V-A and the potassium carbonate into anhydrous DMF, fully stirring and uniformly mixing, adding the 3-bromobenzyl bromide, refluxing and fully stirring for reaction; cooling to room temperature, diluting with ice water, extracting with ethyl acetate, mixing organic layers, drying, concentrating, and performing column chromatography to obtain intermediate V-B;
c. adding V-B, pd into dioxane 2 (dba) 3 Charging nitrogen into Xphos and sodium tert-butoxide, stirring at room temperature for reaction for 30min, then adding 1- (tert-butoxycarbonyl) piperazine, and then refluxing at 105 ℃ for reaction overnight; cooling to room temperature, concentrating the reaction solution, separating and purifying by column chromatography to obtain an intermediate, adding dichloromethane and trifluoroacetic acid (TFA), and stirring at room temperature for full reaction for 1h; diluting the reaction solution with ethyl acetate, extracting with water for 3 times, mixing the water layers, and regulating pH to 10 in ice bath; extracting with ethyl acetate for 3 times, mixing the organic layers, drying with anhydrous sodium sulfate, and concentrating.
4. A pharmaceutical composition comprising the benzimidazole compound of claim 1.
5. The use of benzimidazole compounds according to claim 1 for the preparation of a medicament against multiple myeloma.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066622A1 (en) * 2002-02-06 2003-08-14 Isis, Pharmaceuticals Novel benzimidazole compounds
WO2004047769A2 (en) * 2002-11-26 2004-06-10 Isis Pharmaceuticals, Inc. Benzimidazoles and analogs thereof as antibacterials

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066622A1 (en) * 2002-02-06 2003-08-14 Isis, Pharmaceuticals Novel benzimidazole compounds
WO2004047769A2 (en) * 2002-11-26 2004-06-10 Isis Pharmaceuticals, Inc. Benzimidazoles and analogs thereof as antibacterials

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Sravanthi, A. ; .Synthesis of 1, 2 disubstituted benzimidazoles using sodium acetate as catalyst.International Research Journal of Pharmacy.2019,第10卷(第3期),181-184. *

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