CN112939943B - Benzimidazole compound, preparation method thereof and application of benzimidazole compound in preparation of iron death inhibitor - Google Patents
Benzimidazole compound, preparation method thereof and application of benzimidazole compound in preparation of iron death inhibitor Download PDFInfo
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Abstract
The invention discloses a benzimidazole compound, a preparation method thereof and application thereof in preparing an iron death inhibitor. The benzimidazole compound has a structure shown as a formula (I) or a formula (II):
the benzimidazole compound provided by the invention is prepared by reacting at R 1 Introduction of a lipophilic group at position R 2 The position is introduced with a specific group, and the obtained compound has better iron death inhibition activity and can be used as a lead compound for preventing and treating nervous system diseases such as apoplexy.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to a benzimidazole compound, a preparation method thereof and application thereof in preparation of an iron death inhibitor.
Background
Iron death (ferroptosis) was discovered in recent yearsA novel non-apoptotic, regulatable cell death class characterized by iron-dependent lipid ROS stacking. Glutathione peroxidase 4(Glutathione peroxidase 4, GPX4), a key iron death inhibitory protein in the iron death pathway, reduces toxic lipid hydroperoxides to non-toxic lipid alcohols using reduced Glutathione as a cofactor. However, when GPX4 is inactivated, intracellular lipid hydroperoxides accumulate in large quantities, thereby inducing iron death. Cysteine is a key material for the synthesis of reduced glutathione, and the source of intracellular cysteine depends on the glutamate/cystine antiporter system x c - . Extracellular cystine in system x c - Mediated, taken up by the cell into the cell, which is then reduced to cysteine. Suppression system x c - Can cause cysteine exhaustion and inhibit the synthesis of glutathione, thereby indirectly inhibiting the enzyme activity of GPX4 and finally inducing iron death. Thus, direct inhibition of GPX4 enzyme activity, knockout of GPX4, or inhibition of system x c - Iron death can be induced.
More and more researches show that iron death is closely related to the occurrence and development of various nervous system diseases (such as neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Huntington's chorea and the like) and stroke and the like), and the inhibition of iron death is expected to be an effective strategy for preventing or treating the diseases; and the iron death inhibitor is reported to be capable of remarkably inhibiting cell damage and death in pathological models such as Parkinson's disease, Huntington's disease, ischemic cerebral apoplexy and hemorrhagic cerebral apoplexy. However, there are few types of iron death inhibitors available at present, and there are only five major classes of radical-scavenging antioxidants (RTAs), lipoxygenase inhibitors, acyl-coa synthetase long chain family member 4 (ACSL 4) inhibitors, iron chelators, and deuterated polyunsaturated fatty acids. Therefore, the development of novel iron death inhibitors is urgently required.
Studies have been made (Y.Fang, H.Zhou, Q.Gu, J.xu, Synthesis and evaluation of tetrahydroisoquinoline as multifunctionality agents for the purpose of the treatment ofAlzheimer's disease, European journal of medical chemistry 167(2019)133-145, earlier work by the present inventors) found that 10 benzimidazole derivatives were able to inhibit high concentration glutamate-induced iron death on mouse hippocampal neurons HT22 cells, and subsequently we found that these compounds also block system x c - The inhibitor Erastin induces iron death, but the benzimidazole derivative has poor inhibitory activity on iron death.
Therefore, the development of a novel iron death inhibitor with better inhibitory activity has important research significance and application value.
Disclosure of Invention
The invention aims to overcome the defects or shortcomings of few types and poor activity of the existing iron death inhibitors and provides a benzimidazole compound. The benzimidazole compound provided by the invention is prepared by reacting R 1 Introduction of a lipophilic group at position R 2 The position is introduced with a specific group, and the obtained compound has better iron death inhibition activity and can be used as a lead compound for preventing and treating nervous system diseases such as apoplexy.
Another object of the present invention is to provide a process for producing the above benzimidazole compound.
The invention also aims to provide application of the benzimidazole compound in preparing an iron death inhibitor.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
a benzimidazole compound has a structure shown as a formula (I) or a formula (II):
wherein R is 1 Is composed of
R 2 Is composed of
R is halogen, methyl, alkoxy, alkynyloxy or hydroxy;
x is C or N.
In our previous work, 10 benzimidazole derivatives were found to inhibit glutamate-induced iron death at high concentrations in mouse hippocampal neurons HT22 cells, and we subsequently found that these compounds also block system x c - Inhibitor Erastin induced iron death. However, the benzimidazole derivative has poor inhibitory activity on iron death, so that the benzimidazole compound with more excellent iron death inhibitory activity is obtained by structural modification, and can be applied to prevention or treatment of nervous system diseases.
Specifically, the invention is provided by the reaction of a compound at R 1 Lipophilic groups are introduced at the positions to synthesize a series of benzimidazole compounds (formula (I)). Wherein R is 1 The lipophilic groups at the positions include the following four different cyclic fatty amine-based side chains: n-methyl piperazine, methyl piperidine, piperidine and morpholine, wherein the middle aromatic ring is a benzene ring or pyridine; the determination of the inhibitory activity of the series of benzimidazole compounds on iron death shows that R 1 Is composed of
When X is C, the inhibition activity is optimal; based thereon, at R 2 Different groups are introduced into the positions of the benzimidazole derivatives to obtain a series of benzimidazole compounds (shown as a formula (II)).
The benzimidazole compound provided by the invention has good iron death inhibition activity, and can be used as a lead compound for preventing and treating nervous system diseases such as apoplexy.
Preferably, the halogen is F or Cl.
Preferably, the alkoxy group is-OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 or-OCH (CH) 3 ) 2 。
Preferably, the alkynyloxy is-OCH 2 C≡CH。
Preferably, R is substituted at one or two of positions 6,7 or 8.
More preferably, when R is substituted at the 6-position, R is-F, -Cl, -OCH 3 、-OH、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-OCH(CH 3 ) 2 or-OCH 2 C≡CH；
R is-CH when R is substituted at the 7-position 3 ；
When R is substituted at the 8-position, R is-OCH 3 or-OH;
when R is substituted at 6-position and 7-position, R is-OH or-OCH 3 。
When the R is substituted at the 6-position and the 8-position, the R is-OH or-OCH 3 。
The invention also provides a preparation method of the benzimidazole compound.
When the benzimidazole compound has the structure shown in the formula (I), the method comprises the following steps:
s11: 2-nitro-5-chloroaniline and cyclic aliphatic amines R 1 -H is subjected to a coupling reaction to obtain
S12：
Reduction to nickel and hydrazine hydrate
S13：
Reacting to obtain the benzimidazole compound with the structure shown in the formula (I)
The preparation method of the benzimidazole compound comprises the following steps:
s11: 2-nitro-5-chlorobenzeneAmines and cyclic aliphatic amines R 1 -H is subjected to a coupling reaction to obtain
S12：
Reduction to nickel and hydrazine hydrate
S13：
Reacting to obtain the benzimidazole compound with the structure shown in the formula (I)
More preferably, the conditions of the coupling reaction in S11 are: and (3) reacting for 16h under alkaline conditions at 110 ℃.
More preferably, the temperature of the reduction in S12 is 60 ℃ and the time is 2 h.
More preferably, the amide reaction in S13 is stirred for 6h at normal temperature, and the subsequent ring closing reaction is reflux reaction under glacial acetic acid overnight.
When R is 2 Is composed of
The method comprises the following steps:
s21: indanone derivatives
Under the acidic condition, the sodium azide and the sodium azide carry out Aube-Schmidt rearrangement reaction to obtain
S22：
Reducing to obtain the tetrahydroisoquinoline derivative
S23: tetrahydroisoquinoline derivatives
And 3-iodobenzoic acid ethyl ester
Through coupling reaction to obtain
S24：
Hydrolyzing under alkaline condition to obtain
S25：
And o-phenylenediamine derivatives
Obtaining the benzimidazole compound with the structure shown in the formula (II) through an amide reaction and a ring closure reaction
More preferably, a mixed solution of dichloromethane and methanesulfonic acid is used as the solvent in S21.
More preferably, the reduction in S22 is performed using lithium aluminum hydride.
More preferably, the coupling reaction in S23 is performed under the conditions: and reacting for 24 hours at 80 ℃ under an inert atmosphere.
More preferably, the conditions for the amide reaction and the ring-closing reaction in S25 are the same as those in S13.
When R is 2 Is composed of
The method comprises the following steps:
s31: 3-Iodobenzoic acid ethyl ester
Or 3-ethoxycarbonylphenylboronic acid
And R 2 -H or R 2 Coupling reaction of-Br to obtain
S32：
Hydrolyzing under alkaline condition to obtain
S33：
And intermediate o-phenylenediamine derivatives
Through amide reaction and ring closure reaction, the benzimidazole compound with the structure shown in the formula (II) is obtained
More preferably, the conditions of the coupling reaction in S31 are: and reacting for 24 hours or 16 hours at 80 ℃ under an inert atmosphere.
More preferably, the conditions for the amide reaction and the ring-closing reaction in S33 are the same as those in S13.
The application of the benzimidazole compound in preparing the iron death inhibitor is also within the protection scope of the invention.
Preferably, the benzimidazole compound is applied to the preparation of the ischemic cerebral apoplexy medicine.
The compound provided by the invention is tested for the activity of inhibiting iron death by using Erastin cell iron death induction experiments on HT22 cells, the best activity of the compound 9a is found, and the compound is subjected to deep evaluation of the activity of inhibiting iron death, so that research shows that the compound 9a has remarkable inhibitory activity on iron death induced by different types of iron death inducers and has inhibitory effects on two characteristic characteristics of iron death (lipid peroxidation and upregulation of PTGS2 mRNA).
Compared with the prior art, the invention has the following advantages and effects:
(1) the benzimidazole compound provided by the invention has remarkable iron death inhibition activity, and the benzimidazole iron death inhibitor has great application prospect in preventing and treating nervous system diseases such as apoplexy and the like;
(2) the preparation method has the advantages of easily available raw materials and simple preparation.
Drawings
FIG. 1 is a graph of the inhibitory effect of Compound 9a on two characteristics of iron death (RSL 3-induced lipid peroxidation and upregulation of PTGS2 mRNA);
fig. 2 shows TTC detection results.
Detailed Description
The present invention will be further explained with reference to the following examples and drawings, but the examples are not intended to limit the present invention in any manner. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
The benzimidazole compound provided by the embodiment of the invention has a structure shown in a chemical general formula A or B:
EXAMPLE 1 Synthesis of Compounds 4a-4h (formula A), 9a-9k, 14a-14d and 17a-17c (formula B)
The synthesis of compounds 4a-4h, 9a-9k, 14a-14d and 17a-17c is shown in equations 1,2,3 and 4, respectively.
The synthesis of compounds 4a-4h was carried out according to the synthetic route shown in scheme 1. 2-Nitro-5-chloroaniline was coupled with four different cyclic aliphatic amines (N-methylpiperazine, methylpiperidine, piperidine and morpholine) under alkaline conditions to give intermediates 1a to 1d, followed by reduction of the nitro group to amino group under nickel and hydrazine hydrate conditions to give intermediates 2a to 2 d. The intermediates 3a-3b are synthesized according to the conditions in earlier work, and the two organic carboxylic acids respectively react with the intermediates 2a-2d to obtain final products 4a-4 h.
In reaction formula 1: (a) potassium carbonate, N, N-dimethylformamide at 110 ℃ for 16 h; (b) nickel, hydrazine hydrate, methanol, 60 ℃,2 h; (c) O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate, N, N-diisopropylethylamine and N, N-dimethylformamide at room temperature for 6 hours; 2. glacial acetic acid, reflux, overnight.
The method comprises the following specific steps:
(1) synthesis of intermediates 1a-1 d: 2-Nitro-5-chloroaniline (997.6mg,5.8mmol), cyclic aliphatic amine (6.9mmol) and potassium carbonate (1.28g,9.3mmol) were added in this order to a pressure-resistant tube, and then dried N, N-dimethylformamide (10mL) was added, and the reaction was carried out by magnetic stirring at 110 ℃ in an oil bath for 16 hours. After completion of the reaction, an appropriate amount of water was added to the reaction system, followed by extraction with ethyl acetate (3X 150mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solid obtained by spin-drying was purified by column chromatography (dichloromethane: ethyl acetate: 2:1) to give intermediates 1a to 1 d.
Intermediate 1a was synthesized from 2-nitro-5-chloroaniline and N-methylpiperazine as described above to give a yellow solid (0.97g, 71%).
Intermediate 1b was synthesized from 2-nitro-5-chloroaniline and 4-methylpiperidine as described above to give a yellow solid (1.03g, 76%).
Intermediate 1c was synthesized from 2-nitro-5-chloroaniline and piperidine as described above to give a yellow solid (1.06g, 83%).
Intermediate 1d was synthesized from 2-nitro-5-chloroaniline and morpholine as described above to give a yellow solid (1.02g, 79%).
(2) Synthesis of the final products 4a-4 h: intermediate 1a-1d (5.0mmol) was dissolved in methanol (30mL), hydrazine hydrate (5mL) and a catalytic amount of nickel were added, and the reaction was magnetically stirred at 60 ℃ for 2 hours. After the reaction was complete, it was cooled to room temperature, filtered, and the filtrate was concentrated to give intermediates 2a-2d (black solid, 90-95%). Subsequently, the organic acid 3a-3b (1mmol) was dissolved in 5mL of N, N-dimethylformamide, N-diisopropylethylamine (0.21mL,1.2mmol) and O-benzotriazole-N, N' -tetramethyluronyltetrafluoroborate (385mg,1.2mmol) were added under ice-bath, and after stirring for 30 minutes, the O-phenylenediamine derivative 2a-2d (1.1mmol) was added, and the reaction was carried out at room temperature for 6 hours. Then quenching the reaction by ice water, extracting by ethyl acetate, drying the organic layer by anhydrous sodium sulfate, and carrying out decompression spin drying; the solid obtained by spin-drying was dissolved in 10mL of glacial acetic acid and reacted at reflux overnight. After the reaction is finished, cooling to room temperature, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, extracting by using ethyl acetate, drying an organic layer, then decompressing, spin-drying, and separating and purifying by using column chromatography to obtain a corresponding final product.
The structure, appearance and nmr spectrum data of compounds 4a-4h are shown below.
4a was synthesized from 2a and 3a as above and as a white solid (43%). 1 H NMR(400MHz,CDCl 3 )δ7.74(s,1H),7.41-7.28(m,3H),7.21-7.10(m,4H),7.07-6.88(m,3H),4.47(s,2H),3.62(t,J＝5.4Hz,2H),3.23(s,4H),2.98(t,J＝5.2Hz,2H),2.65(s,4H),2.39(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ150.6,150.4,148.0,137.9,135.8,134.7,134.3,131.2,129.5,128.4,126.6,126.3,125.9,118.8,115.7,115.5,113.5,111.7,97.1,54.9(2C),50.2,49.7,49.7,45.8,45.6,28.2.HRMS(ESI):calcd for C 27 H 29 N 5 [M+H] + 424.2496,found 424.2521.
4b was synthesized from 2b and 3a as above and as a white solid (50%). 1 H NMR(500MHz,DMSO-d 6 )δ7.72(s,1H),7.53-7.43(m,2H),7.35(t,J＝7.3Hz,1H),7.27-7.16(m,4H),7.06(d,J＝5.8Hz,1H),6.99-6.85(m,2H),4.47(s,2H),3.66-3.52(m,4H),2.96(s,2H),2.69-2.56(m,2H),1.75-1.66(m,2H),1.52-1.42(m,1H),1.35-1.24(m,2H),0.94(d,J＝6.3Hz,3H). 13 C NMR(125MHz,DMSO-d 6 )δ150.4,148.5,143.7,139.1,137.8,134.7,134.4,131.1,129.6,128.4,126.6,126.3,126.0,123.4,123.1,115.7,115.6,111.8,99.6,50.9,49.7(2C),45.6,34.0(2C),30.2,28.2,21.9.HRMS(ESI):calcd for C 28 H 30 N 4 [M+H] + 423.2543,found 423.2548.
4c was synthesized from 2c and 3a as above and as a white solid (48%). 1 H NMR(500MHz,DMSO-d 6 )δ7.60(s,1H),7.35(d,J＝6.2Hz,2H),7.23(t,J＝6.4Hz,1H),7.17-6.92(m,6H),6.80(s,1H),4.36(s,2H),3.50(s,6H),2.84(s,2H),1.59-1.51(m,4H),1.44-1.40(m,2H). 13 C NMR(125MHz,DMSO-d 6 )δ150.6,150.5,149.1,137.8,135.8,134.8,134.4,131.2,129.7,128.5,126.7,126.4,126.1,118.9,115.9,115.6,114.5,111.8,97.7,52.1,51.6,49.8,45.7,28.3,25.9,25.7,24.0.HRMS(ESI):calcd for C 27 H 28 N 4 [M+H] + 409.2387,found 409.2390.
4d was synthesized as above from 2d and 3a as a white solid (43%). 1 H NMR(400MHz,DMSO-d 6 )δ7.71(s,1H),7.48(t,J＝8.1Hz,1H),7.34(t,J＝8.0Hz,1H),7.27-7.23(m,1H),7.21-7.11(m,5H),6.99-6.88(m,2H),4.47(s,2H),3.79-3.71(m,4H),3.61(t,J＝5.8Hz,2H),3.12-3.04(m,4H),2.95(t,J＝5.7Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ150.9,150.1,147.5,138.7,134.4,134.1,131.7,131.0,129.3,129.1,128.7,127.9,127.0,126.1,125.9,125.5,115.6,115.2,111.8,66.0(2C),50.1(2C),49.5,45.3,27.9.HRMS(ESI):calcd for C 26 H 26 N 4 O[M+H] + 411.2179,found 411.2196.
4e was synthesized from 2a and 3b as above and as a white solid (45%). 1 H NMR(400MHz,CD 3 OD)δ7.63-7.56(m,2H),7.36-7.31(m,2H),7.26-7.21(m,4H),7.13(d,J＝8.9Hz,1H),6.93(d,J＝8.5Hz,1H),4.88(s,2H),4.03(t,J＝5.2Hz,2H),3.44-3.37(m,4H),3.09-3.02(m,6H),2.70(s,3H). 13 C NMR(100MHz,CD 3 OD)δ159.7,153.0,149.2,147.1,139.5,136.6,135.7,129.4,127.6,127.4,127.2,125.3,125.2,118.7,117.0,112.4,110.8,108.8,55.6(2C),50.8(2C),48.0,45.0,43.6,29.9.HRMS(ESI):calcd for C 26 H 28 N 6 [M+H] + 425.2448,found 425.2450.
4f was synthesized as above from 2b and 3b as a white solid (50%). 1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝7.3Hz,1H),7.60-7.52(m,2H),7.24-7.13(m,5H),7.05(d,J＝8.3Hz,1H),6.69(d,J＝8.5Hz,1H),4.76(s,2H),3.89(t,J＝5.8Hz,2H),3.60(d,J＝12.0Hz,2H),2.95(t,J＝5.7Hz,2H),2.73(t,J＝11.2Hz,2H),1.75(d,J＝11.2Hz,2H),1.55-1.37(m,3H),0.98(d,J＝5.8Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ158.0,150.0,149.3,144.4,138.5,135.3,134.2,128.4,126.7,126.5,126.3,116.7,116.4,116.3,110.8,108.2,101.1,101.1,51.8,47.2,42.6,34.1(2C),30.6,29.8,29.0,21.9.HRMS(ESI):calcd for C 27 H 29 N 5 [M+H] + 424.2496,found 424.2516.
4g of white solid (48%) synthesized from 2c and 3b as described above. 1 H NMR(500MHz,CD 3 OD)δ7.64(t,1H),7.54-7.47(m,2H),7.28-7.10(m,5H),7.09-7.02(m,1H),6.86-6.80(m,1H),4.80(s,2H),3.95(t,J＝5.8Hz,2H),3.11(s,4H),2.96(t,J＝5.5Hz,2H),1.80-1.69(m,4H),1.62-1.53(m,2H). 13 C NMR(100MHz,DMSO-d 6 )δ157.8,150.0,149.1,146.6,146.6,138.4,138.0,135.5,135.1,134.5,128.4,126.5,126.2,125.9,119.2,114.7,109.2,106.9,97.8,51.3(2C),46.6,41.9,28.1,25.6(2C),23.9.HRMS(ESI):calcd for C 26 H 27 N 5 [M+H] + 410.2339,found 410.2349.
4h from 2d and 3b as above, white solid (56%). 1 H NMR(400MHz,CDCl 3 )δ7.74-7.61(m,3H),7.25-7.18(m,4H),7.01(d,J＝7.9Hz,2H),6.75(d,J＝8.4Hz,1H),4.79(s,2H),3.95(t,J＝5.9Hz,2H),3.91(t,J＝4.6Hz,4H),3.19(t,J＝4.4Hz,4H),3.02(t,J＝5.8Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ157.9,150.3,148.3,146.6,138.5,138.4,135.5,135.1,134.6,128.5,126.6,126.3,126.0,119.3,113.5,109.3,107.1,97.3,66.3(2C),50.5,50.0(2C),46.5,28.1.HRMS(ESI):calcd for C 25 H 25 N 5 O[M+H] + 412.2132,found 412.2151.
The synthesis of compounds 9a-9k was performed according to the synthetic route shown in scheme 2. Indanone derivatives and sodium azide are subjected to Aube-Schmidt rearrangement reaction under acidic conditions to obtain intermediates 5a-5d, and then the intermediates are reduced by lithium aluminum hydride to obtain tetrahydroisoquinoline derivatives 6a-6 d. The synthesized and commercially available tetrahydroisoquinoline derivatives and 3-iodoethyl benzoate undergo a coupling reaction to obtain intermediates 7a-7 i. Then the intermediate 7a-7i is hydrolyzed under alkaline condition to obtain an intermediate 8a-8i, and then the intermediate 8a-8i and the intermediate o-phenylenediamine derivative 2a are subjected to amide reaction and ring closure reaction to finally obtain a final product 9a-9 k. Wherein intermediates 5a-5b, 6a-6b, 7a and 7c were synthesized according to the conditions in our earlier work.
In reaction formula 2: (a) methanesulfonic acid, sodium azide and dichloromethane at room temperature overnight; (b) lithium aluminum hydride and tetrahydrofuran are refluxed for 4 hours; (c) potassium carbonate, cuprous iodide, L-proline, dimethyl sulfoxide, 80 ℃, 24 hours and nitrogen protection; (d) lithium hydroxide and tetrahydrofuran at 90 ℃ for 3 h; (e) O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, N, N-diisopropylethylamine and N, N-dimethylformamide at room temperature for 6 hours; 2. glacial acetic acid, reflux, overnight. Wherein the compounds 9j and 9k are demethylated from the compounds 9h and 9i, respectively, under boron tribromide conditions.
The method comprises the following specific steps:
(1) synthesis of intermediates 5a-5 d: the starting material, 7-methoxy-1-indanone (4.31g,26.6mmol), was dissolved in a mixture of 40mL methylene chloride and 40mL methanesulfonic acid, cooled to 0 deg.C, and sodium azide (3.46g,53.2mmol) was slowly added to the reaction flask and stirred at room temperature overnight. After the reaction was completed, 20% sodium hydroxide solution was slowly added in ice bath to adjust pH to neutral, followed by extraction with dichloromethane, drying of the organic layer over anhydrous sodium sulfate, concentration under reduced pressure, and separation and purification by column chromatography (petroleum ether: ethyl acetate 1:2) to obtain intermediate 5c (2.87g, 61%) as a white solid. Synthesis of intermediate 5d starting material 5, 7-dimethoxyindanone (5.11g,26.6mmol) was synthesized as described above to give a white solid (3.47g, 63%).
(2) Synthesis of intermediates 6a-6 d: intermediate 5c (1.77g,10mmol) was dissolved in dry tetrahydrofuran (50mL), and a 1mol/L suspension of lithium aluminum hydride in tetrahydrofuran (20mL) was added slowly at 0 deg.C and the reaction was refluxed for 4 hours. After the reaction was completed, the reaction was quenched with 30% sodium hydroxide solution under ice bath, filtered through celite, washed with methanol, and the filtrate was concentrated under reduced pressure and then purified by column chromatography (ethyl acetate: methanol 10:1) to obtain 6c (0.83g, 51%) as a white oil. Synthesis of intermediate 6d from intermediate 5d (2.07g,10mmol) as described above a white oil (1.04g, 54%) was obtained.
(3) Synthesis of intermediates 7a-7 i: 1,2,3, 4-tetrahydroisoquinoline derivatives (30mmol), ethyl 3-iodobenzoate (5.52g,20mmol), potassium carbonate (8.34g,60mmol), cuprous iodide (0.8g,4mmol) and L-proline (0.92g,8mmol) were added to a pressure tube, followed by addition of dimethyl sulfoxide (25mL) as a reaction solvent, nitrogen blanket, oil bath heating to 80 deg.C, magnetic stirring, and reaction for 24 hours. After completion of the reaction, an appropriate amount of an ice-water mixture was added to the reaction system, followed by extraction with ethyl acetate (3 × 150mL), concentration of the organic layer under reduced pressure, and separation and purification of the residue by column chromatography (petroleum ether: ethyl acetate 5:1) to give 7a-7 i.
Synthesis of intermediate 7b from 6-chloro-1, 2,3, 4-tetrahydroisoquinoline (5.03g,30mmol) and ethyl 3-iodobenzoate (5.52g,20mmol), synthesized as described above to give a white oil (3.72g, 59%).
Synthesis of intermediate 7d from 1,2,3, 4-tetrahydroisoquinolin-6-ol (4.48g,30mmol) and ethyl 3-iodobenzoate (5.52g,20mmol) as described above gave a white oil (3.33g, 56%).
Synthesis of intermediate 7e from 7-methyl-1, 2,3, 4-tetrahydro-isoquinoline (4.42g,30mmol) and ethyl 3-iodobenzoate (5.52g,20mmol) was synthesized as above to give a white oil (3.25g, 55%).
Synthesis of intermediate 7f from intermediate 6c (4.90g,30mmol) and ethyl 3-iodobenzoate (5.52g,20mmol) as described above gave a white oil (3.86g, 62%).
Synthesis of intermediate 7g from 1,2,3, 4-tetrahydroisoquinolin-8-ol (4.48g,30mmol) and ethyl 3-iodobenzoate (5.52g,20mmol) as described above gave a white oil (3.98g, 67%).
Synthesis of intermediate 7h from intermediate 6d (5.80g,30mmol) and ethyl 3-iodobenzoate (5.52g,20mmol) as described above gave a white oil (3.68g, 54%).
Synthesis of intermediate 7i from 6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline (5.80g,30mmol) and ethyl 3-iodobenzoate (5.52g,20mmol), synthesized as above to give a white oil (4.09g, 60%).
(4) Synthesis of the end products 9a-9 k: intermediate 7a-7i (10mmol) was added to 50mL of tetrahydrofuran, and lithium hydroxide (1.19g,50mmol) was added to the mixture in ethanol: after dissolving in water (5:1, 5mL), the mixture was added and reacted at 90 ℃ for 3 hours. After the reaction is finished, the reaction solution is dried in vacuum, a small amount of ice water is added for dissolution, and then the pH is slowly adjusted to be neutral by using dilute hydrochloric acid under ice bath until a solid is separated out. The precipitated solid was filtered with suction and dried to obtain intermediate 8a-8 i. 8a-8i and 2a were reacted as described above for 4a-4h to give the final product 9a-9 i. 9j and 9k were demethylated from 9h and 9i, respectively, under boron tribromide conditions, i.e.: 9h or 9i (0.12mmol) was added to dry dichloromethane (15mL), boron tribromide (0.11mL,1.2mmol) was added dropwise at-20 ℃ under nitrogen blanket, and the reaction was carried out at room temperature for 4 hours. After the reaction, saturated sodium bicarbonate solution was slowly added in ice bath to adjust the pH to neutral. Then, the mixture was extracted with ethyl acetate, the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol ═ 6:1) to obtain the final product.
The structure, appearance and nmr spectrum data of compounds 9a-9k are shown below.
9a was synthesized from 8a and 2a as above as a yellow solid (48%). 1 H NMR(400MHz,CD 3 OD)δ7.65(t,J＝1.8Hz,1H),7.42(d,J＝8.8Hz,1H),7.37(m,1H),7.31(t,J＝7.9Hz,1H),7.15(dd,J＝9.4,5.6Hz,1H),7.07-7.03(m,2H),6.98(dd,J＝8.8,2.2Hz,1H),6.87-6.80(m,2H),4.39(s,2H),3.57(t,J＝6.0Hz,2H),2.94(m,6H),2.85(s,4H),2.48(s,3H). 13 C NMR(100MHz,CD 3 OD)δ162.8(d,J＝242.8Hz),153.7,152.3,149.1,138.4(d,J＝7.7Hz),131.7,131.4(d,J＝2.6Hz),130.9(2C),130.6,129.3(d,J＝8.1Hz),117.9,117.7,116.7,115.6(d,J＝21.1Hz),114.1(2C),114.0(d,J＝21.8Hz),102.7,55.7(2C),51.0,50.9,47.3,45.1,43.5,30.0.HRMS(ESI):calcd for C 27 H 28 N 5 F[M+H] + 442.2402,found 442.2412.
9b was synthesized from 8b and 2a as above and as a yellow solid (50%). 1 H NMR(400MHz,CD 3 OD)δ7.71(s,1H),7.52(d,J＝8.8Hz,1H),7.46(d,J＝7.6Hz,1H),7.38(t,J＝8.0Hz,1H),7.32-7.26(m,1H),7.18-7.14(m,3H),7.11(dd,J＝8.2,2.2Hz,1H),7.05(dd,J＝8.8,1.7Hz,1H),4.42(s,2H),3.61(t,J＝5.8Hz,2H),3.34(s,4H),3.14(s,4H),2.97(t,J＝5.7Hz,2H),2.73(s,3H). 13 C NMR(125MHz,CD 3 OD)δ159.7,156.5,152.4,146.6,142.9,140.6,140.1,139.1,138.0,137.5,135.4,134.9,133.1,128.2,125.6,125.3,121.6,119.8,109.0,63.2(2C),58.7,58.2(2C),54.7,53.5,37.4.HRMS(ESI):calcd for C 27 H 28 N 5 Cl[M+H] + 458.2106,found 458.2098.
9c was synthesized from 8c and 2a as above as a yellow solid (52%). 1 H NMR(400MHz,CD 3 OD)δ7.75(s,1H),7.55(d,J＝8.8Hz,1H),7.49-7.39(m,2H),7.21(d,J＝2.0Hz,1H),7.16(d,J＝8.2Hz,2H),7.11(dd,J＝8.8,2.2Hz,1H),6.82-6.75(m,2H),4.46(s,2H),3.80(s,3H),3.67(t,J＝5.9Hz,2H),3.41(brs,4H),3.29-3.24(m,4H),3.02(t,J＝5.8Hz,2H),2.84(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ157.9,157.7,150.4,146.9,135.9,132.2,131.0,129.6,127.6,126.3,124.4,121.1,119.1,115.7,113.0,112.3,111.8,106.9,104.5,56.0,55.0(2C),53.6,49.1,48.6,48.6,45.5,28.4.HRMS(ESI):calcd for C 28 H 31 N 5 O[M+H] + 454.2601,found 454.2604.
9d was synthesized from 8d and 2a as above as a yellow solid (47%). 1 H NMR(500MHz,CD 3 OD)δ7.70(s,1H),7.49(d,J＝8.8Hz,1H),7.43(d,J＝7.6Hz,1H),7.37(t,J＝7.9Hz,1H),7.14-7.08(m,2H),7.06-7.01(m,2H),6.63(dd,J＝8.3,2.1Hz,1H),6.60(s,1H),4.38(s,2H),3.60(t,J＝5.9Hz,2H),3.25(t,J＝3.9Hz,4H),2.93(t,J＝5.7Hz,2H),2.79(t,J＝4.1Hz,4H),2.45(s,3H). 13 C NMR(125MHz,DMSO-d 6 )δ155.8,151.1,150.4,147.8,135.7,131.1,129.5,127.5,124.5,123.2,122.7,118.2,115.6,115.4,114.6,113.9,113.4,111.7,111.2,54.8(2C),49.8(2C),49.2,45.7,45.5,28.4.HRMS(ESI):calcd for C 27 H 29 N 5 O[M+H] + 440.2445,found 440.2458.
9e was synthesized from 8e and 2a as above as a yellow solid (58%). 1 H NMR(400MHz,CD 3 OD)δ7.74(s,1H),7.53(d,J＝8.8Hz,1H),7.47(d,J＝7.6Hz,1H),7.40(t,J＝7.9Hz,1H),7.32-7.26(m,1H),7.17(d,J＝1.5Hz,1H),7.13(dd,J＝8.2,1.9Hz,1H),7.09-7.05(m,1H),7.04-6.97(m,2H),4.44(s,2H),3.63(t,J＝5.8Hz,2H),3.38-3.34(m,4H),3.11(t,J＝4.4Hz,4H),2.95(t,J＝5.8Hz,2H),2.71(s,3H),2.31(s,3H). 13 C NMR(125MHz,CDCl 3 )δ152.2,150.8,147.7,135.6,133.9,131.7,130.1,129.9,128.2,127.2,127.1,125.1,124.4,118.6,116.3,116.2,115.2,112.6,111.1,54.5(2C),50.0,49.5(2C),46.0,45.0,28.6,21.1.HRMS(ESI):calcd for C 28 H 31 N 5 [M+H] + 438.2652,found 438.2662.
9f was synthesized from 8f and 2a as above as a yellow solid (53%). 1 H NMR(400MHz,CDCl 3 )δ7.84(s,1H),7.49(d,J＝7.7Hz,2H),7.29(t,J＝8.0Hz,1H),7.09(t,J＝7.9Hz,1H),7.04-6.87(m,2H),6.90(d,J＝8.7Hz,1H),6.71-6.63(m,2H),4.31(s,2H),3.77(s,3H),3.40(t,J＝5.5Hz,2H),3.12(t,J＝4.0Hz,4H),2.78(t,J＝5.2Hz,2H),2.58(t,J＝4.0Hz,4H),2.33(s,3H). 13 C NMR(100MHz,CDCl 3 )δ156.1,152.3,151.2,147.9,136.1,133.7,132.5,130.8,129.9,129.9,126.9,122.9,120.8,116.5,116.4,115.2,113.1,107.3,101.9,56.0,55.3(2C),54.9(2C),50.2,45.9,45.7,29.2.HRMS(ESI):calcd for C 28 H 31 N 5 O[M+H] + 454.2601,found 454.2602.
9g of a yellow solid (49%) synthesized from 8g and 2a as described above. 1 H NMR(500MHz,CD 3 OD)δ8.22(s,1H),7.97(d,J＝8.8Hz,1H),7.93(d,J＝7.7Hz,1H),7.84(t,J＝7.7Hz,1H),7.63-7.57(m,2H),7.51-7.44(m,2H),7.19(d,J＝7.7Hz,1H),7.13(d,J＝8.0Hz,1H),4.91(s,2H),4.11(t,J＝6.0Hz,2H),3.69(t,J＝4.5Hz,4H),3.38(t,J＝6.0Hz,2H),3.12(t,J＝4.5Hz,4H),2.83(s,3H). 13 C NMR(125MHz,DMSO-d 6 )δ155.7,151.0,150.4,147.6,135.6,131.0,129.4,127.3,124.4,123.2,122.7,118.1,115.7,115.5,114.7,113.9,113.3,111.8,111.1,54.4(2C),50.0(2C),49.4,45.7,45.6,28.6.HRMS(ESI):calcd for C 27 H 29 N 5 O[M+H] + 440.2445,found 440.2473.
9h was synthesized as above from 8h and 2a as a yellow solid (50%). 1 H NMR(400MHz,DMSO-d 6 )δ7.78(s,1H),7.55(d,J＝6.0Hz,1H),7.46(d,J＝8.5Hz,1H),7.35(t,J＝7.7Hz,1H),7.30-7.18(m,1H),7.07-6.92(m,2H),6.44(s,1H),6.38(s,1H),4.25(s,2H),3.83(s,3H),3.74(s,3H),3.57(s,2H),3.19(s,4H),2.90(s,2H),2.71(s,4H),2.38(s,3H). 13 C NMR(125MHz,DMSO-d 6 )δ158.7,156.7,150.7,147.4,142.9,136.4,131.1,129.6,127.6,124.4,123.3,118.5,116.0,115.7,114.6,112.0,110.8,104.3,96.2,55.4(2C),55.2(2C),54.3(2C),49.3,45.2,44.8,28.9.HRMS(ESI):calcd for C 29 H 33 N 5 O 2 [M+H] + 484.2707,found 484.2706.
9i was synthesized from 8i and 2a as above and as a yellow solid (51%). 1 H NMR(400MHz,CD 3 OD)δ7.65(s,1H),7.43(d,J＝8.8Hz,1H),7.37-7.33(m,1H),7.30(t,J＝7.9Hz,1H),7.08-7.03(m,2H),6.98(dd,J＝8.8,2.2Hz,1H),6.73(s,1H),6.67(s,1H),4.33(s,2H),3.74(s,3H),3.71(s,3H),3.56(t,J＝5.8Hz,2H),3.27-3.22(m,4H),2.95-2.90(m,4H),2.85(t,J＝5.8Hz,2H),2.54(s,3H). 13 C NMR(100MHz,CD 3 OD)δ153.8,152.5,149.2,149.1,149.1,131.7,130.9,130.9,128.2,127.8,127.7,118.1,117.7,116.7,114.3,113.1,111.3,103.0,95.3,56.6,56.5,55.7(2C),51.3,51.0(2C),47.9,43.5,29.4.HRMS(ESI):calcd for C 29 H 33 N 5 O 2 [M+H] + 484.2707,found 484.2727.
9 j: yellow solid (73%). 1 H NMR(400MHz,CD 3 OD)δ7.75(s,1H),7.53(d,J＝8.8Hz,1H),7.47(d,J＝7.7Hz,1H),7.41(t,J＝7.9Hz,1H),7.18(d,J＝2.0Hz,1H),7.14(dd,J＝8.2,1.8Hz,1H),7.07(dd,J＝8.8,2.2Hz,1H),6.23(d,J＝2.2Hz,1H),6.18(d,J＝2.1Hz,1H),4.32(s,2H),3.60(t,J＝5.7Hz,2H),3.37(t,J＝4.4Hz,4H),3.14(t,J＝4.8Hz,4H),2.90(t,J＝5.6Hz,2H),2.73(s,3H). 13 C NMR(125MHz,CD 3 OD)δ157.3,155.9,153.8,152.8,148.7,140.1,137.8,136.0,131.5,130.8,117.8,117.6,116.7,116.6,114.1,113.9,107.2,103.0,101.3,55.5(2C),50.4(2C),47.4,46.9,44.6,30.3.HRMS(ESI):calcd for C 27 H 29 N 5 O 2 [M+H] + 456.2394,found 456.2433.
9 k: yellow solid (75%). 1 H NMR(400MHz,DMSO-d 6 )δ7.72(s,1H),7.50(d,J＝7.4Hz,2H),7.36(t,J＝7.9Hz,1H),7.06(d,J＝7.5Hz,1H),7.01-6.89(m,2H),6.64(s,1H),6.56(s,1H),4.32(s,2H),3.58(t,J＝5.8Hz,2H),3.15(brs,4H),2.79(t,J＝5.7Hz,2H),2.27(s,4H),1.92(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ151.1,150.5,147.8,143.9,143.7,131.1,129.7,129.5,124.8,124.5,115.6,115.5,115.2,114.0,114.0,113.9,113.5,111.8,54.8(2C),49.9,49.3(2C),45.9,45.7,27.5.HRMS(ESI):calcd for C 27 H 29 N 5 O 2 [M+H] + 456.2394,found 456.2421.
The synthesis of compounds 14a-14d was performed according to the synthetic route shown in scheme 3. 1,2,3, 4-tetrahydroisoquinoline-6-alcohol is taken as a starting material to obtain 14a-14d through 5 steps.
In reaction formula 3: (a) di-tert-butyl dicarbonate, 4-dimethylaminopyridine and tetrahydrofuran are used for 0.5h at room temperature; (b) sodium hydride, acetonitrile, 60 ℃, 24 h; (c)1, hydrochloric acid, 1, 4-dioxane, room temperature, 3 h; 2. potassium carbonate, cuprous iodide, L-proline, dimethyl sulfoxide, 80 ℃, 24 hours and nitrogen protection; (d) lithium hydroxide and tetrahydrofuran at 90 ℃ for 3 h; (e) O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, N, N-diisopropylethylamine and N, N-dimethylformamide at room temperature for 6 hours; 2. glacial acetic acid, reflux, overnight.
The method comprises the following specific steps:
(1) synthesis of intermediate 10 a: 1,2,3, 4-tetrahydroisoquinolin-6-ol (2.0g,13.4mmol) and 4-dimethylaminopyridine (24mg) were added to tetrahydrofuran (60mL), and di-tert-butyl dicarbonate (3.07mL,13.4mmol) was added dropwise while cooling on ice, followed by stirring at room temperature for half an hour. After completion of the reaction, the solvent was dried under reduced pressure, diluted with dichloromethane, washed with saturated sodium bicarbonate solution, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate 5:1) to obtain 10a (2.34g, 70%) as a white oil.
(2) Synthesis of intermediates 11a-11 d: intermediate 10a (373.5mg,1.5mmol) was dissolved in acetonitrile (10mL), sodium hydride (60% dispersed in mineral oil, 72.9mg,1.8mmol) was added under ice-bath, after stirring at room temperature for 1 hour, the corresponding aromatic bromide (1.8mmol) was added, and the reaction was heated to 60 ℃ for 24 hours. After the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain intermediates 11a to 11 d.
Intermediate 11a was synthesized from 10a and bromoethane (135 μ L,1.8mmol) as described above to give a white oil (0.33g, 79%).
Intermediate 11b was synthesized from 10a and n-propyl bromide (164. mu.L, 1.8mmol) as described above to give a white oil (0.31g, 72%).
Intermediate 11c was synthesized from 10a and 2-bromopropane (169. mu.L, 1.8mmol) as described above to give a yellow oil (0.28g, 65%).
Intermediate 11d was synthesized from 10a and 3-bromopropyne (141. mu.L, 1.8mmol) as described above to give a white oil (0.31g, 71%).
(3) Synthesis of intermediates 12a-12 d: boc derivative 11a-11d (1mmol) was added to 1, 4-dioxane (5mL), 4M hydrochloric acid solution (1.25mL in 1, 4-dioxane) was added and after 3 hours reaction at room temperature, the crude product was rotary dried under reduced pressure and used directly in the next reaction. The crude product was put into a pressure resistant tube, and potassium carbonate (553mg,4mmol), cuprous iodide (38mg,0.2mmol), L-proline (46mg,0.4mmol), ethyl 3-iodobenzoate (276mg,1mmol) and dimethyl sulfoxide (10mL) were added thereto, and the mixture was heated to 80 ℃ in an oil bath under nitrogen protection, and reacted for 24 hours with magnetic stirring. After the reaction is finished, a proper amount of ice-water mixture is added into the reaction system, then ethyl acetate is used for extraction, an organic layer is decompressed and concentrated, and the residual liquid is separated and purified by column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain 12a-12 d.
Intermediate 12a was synthesized from 11a and ethyl 3-iodobenzoate as described above to give a yellow oil (0.21g, 65%).
Intermediate 12b was synthesized from 11b and ethyl 3-iodobenzoate as described above to give a yellow oil (0.23g, 67%).
Intermediate 12c was synthesized from 11c and ethyl 3-iodobenzoate as described above to give a yellow oil (0.19g, 55%).
Intermediate 12d was synthesized from 11d and ethyl 3-iodobenzoate as described above to give a yellow oil (0.20g, 61%).
(4) Synthesis of the end products 14a-14 d: the synthesis of 14a-14d was carried out according to the synthesis method of 9a-9 i.
The structure, appearance and nmr spectrum data of compounds 14a-14d are shown below.
14a was synthesized from 13a and 2a as above as a yellow solid (40%). 1 H NMR(400MHz,DMSO-d 6 )δ7.80(s,1H),7.53(d,J＝7.3Hz,1H),7.46(d,J＝8.6Hz,1H),7.32(t,J＝7.8Hz,1H),7.15(d,J＝7.9Hz,1H),7.08-6.92(m,3H),6.76-6.66(m,2H),4.41(s,2H),3.97(q,J＝7.0Hz,2H),3.39-3.24(m,6H),2.97-2.87(m,6H),2.53(s,3H),1.28(t,J＝6.7Hz,3H). 13 C NMR(125MHz,DMSO-d 6 )δ157.1,151.4,150.5,147.1,136.0,131.1,129.7,127.8,126.4,124.5,123.5,118.5,115.9,115.7,114.2,113.7,112.9,112.1,111.1,63.1,53.8(2C),49.3,48.7(2C),45.6,44.1,28.5,14.9.HRMS(ESI):calcd for C 29 H 33 N 5 O[M+H] + 468.2758,found 468.2767.
14b was synthesized from 13b and 2a as above and as a yellow solid (41%). 1 H NMR(400MHz,CD 3 OD)δ7.74(s,1H),7.54(d,J＝8.7Hz,1H),7.47(d,J＝7.4Hz,1H),7.41(t,J＝7.9Hz,1H),7.18(s,1H),7.14(dd,J＝8.3,3.6Hz,2H),7.08(dd,J＝8.8,2.0Hz,1H),6.79-6.73(m,2H),4.44(s,2H),3.92(t,J＝6.5Hz,2H),3.64(t,J＝5.8Hz,2H),3.38-3.33(m,4H),3.07-2.97(m,6H),2.66(s,3H),1.82-1.74(m,2H),1.05(t,J＝7.4Hz,3H). 13 C NMR(125MHz,CD 3 OD)δ163.7,162.1,157.6,150.8,136.3,131.5,130.5,130.1,130.0,128.0,126.7,122.2,116.2,115.9,114.1,113.8,113.2,112.9,112.3,69.3,54.9(2C),49.9,49.9,49.6,45.9,45.6,28.9,22.5,10.9.HRMS(ESI):calcd for C 30 H 35 N 5 O[M+H] + 482.2914,found 482.2921.
14c was synthesized as yellow solid (37%) from 13c and 2a as described above. 1 H NMR(400MHz,CD 3 OD)δ7.71(s,1H),7.51(d,J＝8.7Hz,1H),7.45(d,J＝7.6Hz,1H),7.37(t,J＝7.9Hz,1H),7.29-7.25(m,1H),7.13(s,1H),7.10-7.06(m,1H),7.03(dd,J＝8.8,2.0Hz,1H),6.76-6.65(m,2H),4.58-4.49(m,1H),4.38(s,2H),3.59(t,J＝5.5Hz,2H),3.36-3.32(m,2H),3.30-3.26(m,2H),3.11-3.05(m,4H),2.94(t,J＝5.7Hz,2H),2.68(s,3H),1.28(d,J＝6.0Hz,6H). 13 C NMR(125MHz,CD 3 OD)δ156.4,152.3,151.0,147.5,135.8,130.2,129.5,127.5,127.2,126.2,124.0,117.4,116.4,116.1,115.1,114.0,112.5,111.0,101.4,69.6,54.1(2C),49.5,49.2(2C),46.1,43.4,28.8,21.0(2C).HRMS(ESI):calcd for C 30 H 35 N 5 O[M+H] + 482.2914,found 482.2926.
14d was synthesized from 13d and 2a as above as a yellow solid (39%). 1 H NMR(400MHz,DMSO-d 6 )δ7.74(s,1H),7.51(d,J＝7.6Hz,1H),7.46(d,J＝8.8Hz,1H),7.41-7.35(m,1H),7.20(d,J＝8.1Hz,1H),7.07(dd,J＝8.2,2.0Hz,1H),7.02(s,1H),6.96(dd,J＝8.8,2.2Hz,1H),6.88-6.80(m,2H),4.77(d,J＝2.3Hz,2H),4.42(s,2H),3.61(t,J＝5.6Hz,2H),3.54(t,J＝2.3Hz,1H),3.23-3.15(m,4H),2.94(t,J＝5.6Hz,2H),2.81-2.71(m,4H),2.44(s,3H). 13 C NMR(125MHz,DMSO-d 6 )δ156.1,151.7,150.8,147.7,136.4,131.5,130.0,128.1,127.6,125.8,124.1,119.1,116.2,116.1,114.6,114.6,113.5,112.2,110.7,79.9,78.6,55.8,54.5(2C),49.6,49.5(2C),45.9,45.0,28.9.HRMS(ESI):calcd for C 30 H 31 N 5 O[M+H] + 478.2601,found 478.2577.
The synthesis of compounds 17a-17c was performed according to the synthetic route shown in scheme 4. 3-iodobenzoic acid ethyl ester or 3-ethoxycarbonylphenylboronic acid is subjected to coupling reaction to obtain intermediates 15a-15c, then the intermediates 16a-16c are obtained by hydrolyzing the intermediates 15a-15c under alkaline conditions, and then the intermediates and the o-phenylenediamine derivative 2a are subjected to amide reaction and ring closing reaction to finally obtain final products 17a-17 c.
In reaction formula 4: (a) potassium carbonate, cuprous iodide, L-proline, dimethyl sulfoxide, 80 ℃ and 24 hours; or sodium carbonate, tetratriphenylphosphine palladium, 1, 4-dioxane/water, 80 ℃,16 h and nitrogen protection; (b) lithium hydroxide and tetrahydrofuran at 90 ℃ for 3 h; (c) O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, N, N-diisopropylethylamine and N, N-dimethylformamide at room temperature for 6 hours; 2. glacial acetic acid, reflux, overnight.
The method comprises the following specific steps:
(1) synthesis of intermediates 15a-15 c: reaction of 1- (2-pyrimidinyl) piperazine or morpholine with ethyl 3-iodobenzoate was carried out under the synthesis conditions of 7a-7i to give intermediates 15a (white oil, 73%) and 15b (white oil, 78%), respectively. For the synthesis of 15c, 4-bromo-1, 2-methylenedioxybenzene (400mg,2mmol) and 3-ethoxycarbonylphenylboronic acid (388mg,2mmol) were added to a mixed solvent of 1, 4-dioxane/water (4:1,15mL), followed by addition of sodium carbonate (424mg,4mmol) and tetrakistriphenylphosphine palladium (115.5mg,0.1mmol), and the reaction was heated to 80 ℃ in an oil bath under nitrogen, and magnetically stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was washed with 1N sodium hydroxide solution, extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain 15c (white oil, 76%).
(2) Synthesis of the end products 17a-17 c: the synthesis of 17a-17c was carried out according to the synthesis method of 9a-9 i.
The structure, appearance and nmr spectrum data of compounds 17a-17c are shown below.
17a was synthesized as above from 16a and 2a as a white solid (45%). 1 H NMR(400MHz,CD 3 OD)δ8.33(d,J＝4.8Hz,2H),7.69(s,1H),7.53-7.47(m,2H),7.37(t,J＝7.8Hz,1H),7.13-7.08(m,2H),7.03(dd,J＝8.8,2.1Hz,1H),6.59(t,J＝4.8Hz,1H),3.95(t,J＝5.2Hz,4H),3.34-3.30(m,4H),3.24(t,J＝4.8Hz,4H),2.77(t,J＝4.8Hz,4H),2.44(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ161.7,158.5(3C),151.8,148.2,131.6(2C),130.0(2C),117.5,117.2,113.6(2C),110.9(3C),55.1(2C),50.1,48.6(2C),45.9,43.7(2C),41.8.HRMS(ESI):calcd for C 26 H 30 N 8 [M+H] + 455.2666,found 455.2701.
17b was synthesized from 16b and 2a as above and as a white solid (40%). 1 H NMR(400MHz,CD 3 OD)δ7.64(s,1H),7.53-7.43(m,2H),7.34(t,J＝8.0Hz,1H),7.09(s,1H),7.00(d,J＝8.7Hz,2H),3.79(t,J＝4.8Hz,4H),3.20-3.13(m,8H),2.64(t,J＝4.8Hz,4H),2.33(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ151.4,150.8,147.8,131.1,129.5,129.1,118.0,117.0,116.1,113.9,113.7,112.4,110.7,66.1(2C),54.8(2C),49.9(2C),48.4(2C),45.7.HRMS(ESI):calcd for C 22 H 27 N 5 O[M+H] + 378.2288,found 378.2289.
17c was synthesized from 16c and 2a as above and as a tan solid (44%). 1 H NMR(400MHz,CD 3 OD)δ8.24(s,1H),7.95(d,J＝7.7Hz,1H),7.62(d,J＝7.8Hz,1H),7.54-7.49(m,2H),7.19(s,1H),7.18-7.16(m,1H),7.11(s,1H),7.04(dd,J＝8.8,2.0Hz,1H),6.90(d,J＝7.8Hz,1H),5.99(s,2H),3.21(t,J＝4.8Hz,4H),2.67(t,J＝4.8Hz,4H),2.37(s,3H). 13 C NMR(100MHz,CD 3 OD)δ152.7,149.7,149.7,148.9,142.9,135.8,131.5,130.5,129.1,125.8,125.7,121.7,116.6,109.5,108.3,102.6,56.1(2C),51.6(2C),46.0.HRMS(ESI):calcd for C 25 H 24 N 4 O 2 [M+H] + 413.1972,found 413.1998.
In order to research the target of a compound in a cell, Biotin is connected to the structure of an alkynyl compound 14d, and a probe Biotin-14d is synthesized, wherein the specific reaction steps are as follows: mixing Biotin-PEG 3 -N 3 (22mg, 0.05mmol) and 14d (24mg, 0.05mmol) were added to a methanol/water (4:1, 2.5mL) mixed solution, followed by addition of 1M copper sulfate pentahydrate solution (20. mu.L) and freshly prepared 1M sodium ascorbate solution (20. mu.L), under nitrogen, and reacted at room temperature overnight. After the reaction is finished, decompressing and concentrating, and performing gradient elution on the crude product by preparative high performance liquid chromatography and purifying to obtain Biotin-14 d. The mobile phase is 0.1 percent of formic acid water containing 10 to 75 percent of acetonitrile, and the flow rate is 3mL/min for 30 minutes. HRMS (ESI) calcd for C 48 H 63 N 11 O 6 S[M+2H] 2+ 461.7415,found 461.7418.
Example 2 test of iron death inhibitory Activity of the Compound obtained in example 1
(1) And (3) cell culture: HT22 cells (mouse hippocampal neuronal cells) were routinely cultured and passaged at 37 ℃ under 5% carbon dioxide concentration in DMEM high-sugar medium containing 10% fetal bovine serum and 1% diabody.
(2) And (3) medicine intervention: cells were seeded at 3000 cells/well in 96-well plates, cultured for 24 hours, and the stock culture was aspirated off, and 1. mu.M Erastin + -compound was added for 24 hours.
(3) And (3) detection: cell viability was measured using Cell Counting Kit-8(CCK-8) Kit, 10. mu.l of CCK-8 solution was added to each well, and after incubation at 37 ℃ for 4 hours, the OD value of absorbance was measured at 450nm wavelength.
(4) Data processing: calculated according to the following formula: cell survival (%) ═ (OD) Sample (I) -OD Blank space )/(OD Control of -OD Blank space ) X 100%, plotting the survival rate of cells as ordinate and the concentration of the compound as abscissa, and calculating the EC of each compound 50 Values were evaluated for the inhibitory activity of each compound on Erastin-induced iron death.
The inhibitory activity of the compounds on Erastin-induced iron death is shown in Table 1. Of these, Ferrostatin-1(Fer-1) and Deferoxamine (DFO) are known iron death inhibitors and were used as positive drugs in this experiment. In addition to the poor activity of compounds 4g-4h, 9d, 9h, 9j-9k and 17a-17c, the EC of the other compounds 50 Values were all in the μ M range and compound 9a was the most active of all compounds, EC 50 0.29 μ M. Therefore, we have conducted a more intensive evaluation of the iron death inhibitory activity of compound 9 a.
Inhibitory Activity of the Compounds of Table 1 on Erastin-induced iron death on HT22 cells
n.d. 1.0. mu.M compound and Erastin treated cells together, cell viability was less than 50%.
Example 3 evaluation of iron-death suppressing Activity of Compound 9a obtained in example 1
To evaluate the iron death inhibitory activity of compound 9a more deeply, the inhibitory activity of compound 9a on the induction of iron death by GPX4 covalent inhibitor RSL3 on HT22 cells, respectively, was examined; inhibitory activity of compound 9a on knockdown of GPX4 induced iron death on HT1080 cells. And the inhibitory effect of compound 9a on two characteristics of iron death (RSL 3-induced lipid peroxidation and PTGS2 mRNA upregulation) was examined, and the results are shown in figure 1.
(1) RSL3 induces iron death
HT22 cells were plated at 3000 cells/well in a 96-well plate, and after 24 hours of culture, the stock culture was aspirated, and after 24 hours of action by adding 1. mu.M RSL 3. + -. compound, 10. mu.l CCK-8 solution was added to each well, and after 4 hours of incubation at 37 ℃, the OD value of absorbance was measured at a wavelength of 450 nm.
(2) Knock-out of GPX4 induces iron death
HT1080 cells (human fibrosarcoma cells) were cultured and passaged routinely at 37 ℃ under 5% carbon dioxide concentration in MEM medium containing 10% fetal bovine serum and 1% diabody. 50nM siRNA scramblel and GPX4 were treated with Lipofectamine TM 3000 reagent is transferred into HT1080 cells, compound is added after 12 hours, cells are harvested after continuous incubation for 36 hours for qPCR and CCK-8 experiments. The qPCR experiment specifically comprises the following steps: the cells to be treated were washed twice with PBS, total RNA was extracted with RNAiso plus reagent, 1. mu.g of total RNA was reverse transcribed into cDNA using ReverTra Ace qPCR RT Master Mix, and PCR amplification was performed using SYBR Green real PCR Master Mix.
(3) Detection of lipid ROS
Flow detection: HT22 cells at 3X 10 4 After 24 hours of culture in 6-well plates, 1. mu.M RSL3 + -compound was added for 3 hours, followed by incubation with 5. mu.M BODIPY-C11 probe at 37 ℃ for half an hour, cells were washed once with PBS, trypsinized, centrifuged, and collected in 1ml PBS, and then the fluorescence intensity of FL1 channel was measured by flow-assay at 488 nm. At least 10,000 cells were detected per sample.
Imaging detection: HT22 cells were seeded at 3000 cells/well in 96-well plates for 24 hours, and 1. mu.M RSL 3. + -. compound was added for 3 hours, followed by incubation with 5. mu.M BODIPY-C11 probe and Hoechst 33342 (1. mu.g/ml) at 37 ℃ for half an hour, and after washing the cells once with PBS, the cells were photographed directly with FV3000 confocal microscope (60X).
(4) Detection of PTGS2 mRNA levels
HT22 cells at 3X 10 4 After 24 hours incubation in 6-well plates, 1 μ M RSL3 + -compound was added for 12 hours, washed twice with PBS, total RNA extracted with RNAiso plus reagent, 1 μ g total RNA was reverse transcribed to cDNA using ReverTra Ace qPCR RT Master Mix, and PCR amplified using SYBR Green real polymerase PCR Master Mix.
As shown in figure 1, compound 9a dose-dependently inhibited RSL 3-induced HT22 cell iron death, similar to the positive compounds Fer-1 and DFO; compound 9a also has inhibitory activity in a model in which GPX4 knockout induces iron death in HT1080 cells; live cell imaging results showed that compound 9a was able to significantly inhibit RSL 3-induced increase in lipid ROS, consistent with flow-type results, and in addition compound 9a also had inhibitory activity against RSL 3-induced increase in cytoplasmic ROS; finally, compound 9a also inhibited RSL 3-induced upregulation of PTGS2 mRNA concentration-dependently.
Example 4 relieving Effect of Compound 9a obtained in example 1 on ischemia-reperfusion injury in vivo
Ischemic stroke is the most common form of stroke and is one of the major diseases leading to death and permanent disability. To date, there is no effective treatment. The research shows that the iron death is involved in the damage and death of neurons in the pathological process of ischemic stroke, and the inhibition of the iron death can reduce the brain damage in vivo. Since compound 9a has significant iron death inhibitory activity on HT22 cells, we investigated whether this compound can protect SD rats from neural injury caused by ischemia/reperfusion on the Middle Cerebral Artery Occlusion (MCAO) model.
(1) Grouping of test animals
Animals were randomly divided into 4 groups, blank control, model control, positive control, and test sample 9a, 12 animals per group. Administration dose: the test sample 9a is 10mg/kg, and the positive control medicament edaravone is 10 mg/kg; the blank control group and model control group animals were given physiological saline in the same manner. The administration frequency is as follows: the medicine is taken once half an hour before operation and once 2 hours after operation; the administration route is as follows: the medicine is administered by intraperitoneal injection, and the volume is 5 ml/kg.
(2) Molding die
Rats were anesthetized with 5ml/kg i.p. injection of 7% chloral hydrate, the neck was opened, the left common carotid artery and external carotid artery were isolated, ligated, and the frontal pterygoid artery was isolated. An artery clamp is placed at the proximal end and the distal end of an internal carotid artery, a 4-0 nylon wire is inserted into a bifurcation of a common carotid artery, the depth of the nylon wire is 17-20 mm, a thrombus wire enters the internal carotid artery and enters the skull to reach the anterior cerebral artery, all blood flow sources of the middle cerebral artery are blocked, the blood is ischemic for 1.5 hours, and then the thrombus wire is pulled out for about 1cm, so that reperfusion is realized. The wound was sterilized with iodophor and the skin was sutured. Then returning to cages for breeding. The blank control group was performed as above except that no plug was used.
(3) TTC detection
After 24 hours of operation, the behavioral tests are carried out, and the model success is determined when the patient has obvious operation side (namely left side) Horner symptoms (left side eyelid droop and eyeball depression) and operation side (namely left side) hemiplegic symptoms (the left forelimb can not be fully extended and the patient falls or turns to the left side during walking), and the degrees of all the animal models are scored. And (3) after the behavioral detection is finished, the animals are sacrificed, brain slices are taken for TTC staining, white is a cerebral infarction area, red is a normal area, and the cerebral infarction volume of the animals is calculated.
As shown in fig. 2, TTC staining results show that, compared with the model group, the volume of cerebral infarction is significantly reduced and the behavior is more normal after 9a treatment, which indicates that compound 9a can significantly alleviate ischemia/reperfusion-induced brain injury in vivo and is expected to be a lead compound for treating ischemic stroke.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A benzimidazole compound, which is characterized by having a structure shown as a formula (I):
wherein R is 1 Is composed of
X is C or N.
2. A benzimidazole compound, which is characterized by having a structure shown as a formula (II):
R 2 is composed of
Wherein R is 6-F, 6-Cl or 6-OCH 3 、6-OCH 2 CH 3 、6-OCH 2 CH 2 CH 3 、6-OCH(CH 3 ) 2 、6-OCH 2 C≡CH、7-CH 3 Or 8-OCH 3 。
3. A benzimidazole compound having the structure shown in 9 i:
4. a process for preparing the benzimidazole compounds of claim 1, which comprises the steps of:
s11: 2-nitro-5-chloroaniline and cyclic aliphatic amine R 1 -H is subjected to a coupling reaction to obtain
S12：
Reduction to form
S13：
Through amide reaction and ring closure reaction, the benzimidazole compound with the structure shown in the formula (I) is obtained
5. The preparation method according to claim 4, wherein the coupling reaction in S11 is carried out under alkaline conditions at 110 ℃ for 16 h; the reduction temperature in S12 is 60 ℃, and the time is 2 h; the amide reaction in S13 is stirred for 6h at normal temperature, and the subsequent ring closing reaction is reflux reaction under glacial acetic acid overnight.
6. A process for preparing the benzimidazole compounds of claim 2, which comprises the steps of:
s21: indanone derivatives
Under the acidic condition, the Aube-Schmidt rearrangement reaction is carried out with sodium azide to obtain
S22：
After reduction, the mixture is obtainedTetrahydroisoquinoline derivatives
S23: tetrahydroisoquinoline derivatives
And 3-iodobenzoic acid ethyl ester
Through coupling reaction to obtain
S24：
Hydrolyzing under alkaline condition to obtain
S25：
And o-phenylenediamine derivatives
Obtaining the benzimidazole compound with the structure shown in the formula (II) through an amide reaction and a ring closure reaction
7. The method according to claim 6, wherein a mixture of dichloromethane and methanesulfonic acid is used as the solvent in S21; reducing by using lithium aluminum hydride in S22; the conditions of the coupling reaction in S23 were: and reacting for 24 hours at 80 ℃ under an inert atmosphere.
8. The preparation method of claim 6, wherein the amide reaction in S25 is stirring for 6h at normal temperature, and the subsequent ring closure reaction is reflux reaction under glacial acetic acid overnight.
9. Use of the benzimidazoles of claims 1,2, or 3 for the preparation of iron death inhibitors.
10. The use of claim 9, wherein the iron death inhibitor is an inhibitor for the treatment of ischemic brain stroke.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232533A (en) * | 2017-09-28 | 2019-01-18 | 北京越之康泰生物医药科技有限公司 | Nitrogen heterocycles derivative, preparation method and its medical usage |
| CN109879856A (en) * | 2018-12-17 | 2019-06-14 | 中山大学 | A kind of benzimidizole derivatives and its preparation method and application of multi-functional anti-Alzheimer disease |
| CN111574474A (en) * | 2019-02-19 | 2020-08-25 | 成都恒昊投资有限公司 | Micromolecular compound for inhibiting iron death and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Inhibiting Ferroptosis through Disrupting the NCOA4-FTH1 Interaction: A New Mechanism of Action;Yuying Fang et al.;《ACS Cent. Sci.》;20210506;第7卷;第980-989页 * |
| Synthesis and evaluation of tetrahydroisoquinoline-benzimidazole hybrids as multifunctional agents for the treatment of Alzheimer"s disease;Yuying Fang et al.;《European Journal of Medicinal Chemistry》;20190204;第167卷;第133-145页 * |
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