CN111393372A - Benzimidazole derivative and preparation method and application thereof - Google Patents

Benzimidazole derivative and preparation method and application thereof Download PDF

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CN111393372A
CN111393372A CN202010396295.4A CN202010396295A CN111393372A CN 111393372 A CN111393372 A CN 111393372A CN 202010396295 A CN202010396295 A CN 202010396295A CN 111393372 A CN111393372 A CN 111393372A
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benzimidazole derivative
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benzimidazole
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江程
刘李
梁黛琳
刘晓东
李冰艳
蒋玲
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Abstract

The invention discloses a benzimidazole derivative shown in a general formula I or a pharmaceutically acceptable salt thereof, a preparation method thereof and application thereof as a selective retinal dehydrogenase inhibitor. Wherein R is1Selected from C1-C8 alkyl, C2-C8 alkenyl, cycloalkylmethyl or benzyl; the cycloalkyl is 3-6 membered cycloalkyl; the benzyl group may be optionally substituted with one or more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy or CF3In contrast to the prior art, the present invention discloses a class of benzimidazole derivatives having selective inhibitory effect on retinoid dehydrogenase (A L DH1A1)The compounds have obvious inhibition effect on A L DH1A1, and can be especially used as medicaments for treating diabetes.

Description

Benzimidazole derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of new compounds, and particularly relates to a benzimidazole derivative, and a preparation method and application thereof.
Background
The 19A L DHs have similar but different physiological functions due to the differences in substrate specificity and gene expression, among which A L DH1A1 is the most studied and widespread member of the A L DHs family, an important physiological function in vivo is the oxidation of retinal to retinoic acid, and is therefore also known as retinal dehydrogenase (RA L DH 1). A L DH1A1 is a highly conserved homo-tetrameric cytosol protein, the molecular weight of the monomer is about 55kDa, each monomer contains three domains, a catalytic domain, a cofactor (NAD) binding domain and an oligomerization domain.A L DH1A 584 is expressed in various organs or tissues of the human body, e.g., brain, testis, fatty tissue, kidney tissue and liver tissue, and the like, and the metabolic pathways of retinal diseases such as inflammatory diseases, such as Parkinson's disease, diabetic retinopathy, inflammatory disease, diabetic retinopathy, inflammatory disease, diabetic retinopathy related to the development of the human body, and obesity, L.
Vitamin A is an essential vitamin in humans, mainly derived from carotenoids in plants and retinyl esters in animals, and has been shown to be involved in visual regulation, embryogenesis, tissue differentiation and immunity, etc. the physiological functions of retinoids are thought to be mediated primarily by retinoic acid, which, through activation of retinoid receptors, expression of key enzymes and proteins such as glucose-6-phosphatase, is involved in the bidirectional regulation of carbohydrate and fat metabolism, with the net effect in hepatic glucose metabolism being an increase in carbohydrate production-/-Gene and treatment with exogenous retinal, A L DH1A1 inhibitor citralAnd then, the inhibitor can obviously improve the sensitivity of diabetic rats and high-fat fed mice to insulin, improve the sugar tolerance and reduce fat accumulation, so that the inhibitor targeting A L DH1A1 is expected to become a feasible strategy for treating diabetes and obesity.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problems, the invention provides a benzimidazole derivative, a preparation method and application thereof, and provides a basis for developing treatment-related medicaments.
The technical scheme is as follows: in order to achieve the purpose, the technical scheme of the invention is as follows:
a benzimidazole derivative represented by the general formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002487703450000021
wherein R is1Selected from C1-C8 alkyl, C2-C8 alkenyl, cycloalkylmethyl or benzyl;
the cycloalkyl is 3-6 membered cycloalkyl;
the benzyl group may be optionally substituted with one or more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy or CF3
Preferably, the method comprises the following steps:
the R is1Selected from C2-C5 alkyl, C5 alkenyl, cycloalkylmethyl, unsubstituted benzyl or substituted benzyl, the cycloalkyl is 3-6 membered cycloalkyl, the substituted benzyl is halogen, methyl, methoxy or CF3A substituted benzyl group.
The R is1Selected from ethyl, propyl, isopropyl, n-butyl, isobutyl, isoamyl, isopentenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, unsubstituted benzyl or substituted benzyl, said substituted benzyl being halogen, methyl, methoxy or CF3A substituted benzyl group.
Most preferably, the benzimidazole derivative of formula I is selected from the following compounds:
Figure BDA0002487703450000022
the pharmaceutically acceptable salt refers to a compound of the general formula I, which can form an acid addition salt with a pharmaceutically acceptable acid, wherein the acid comprises hydrogen chloride, hydrogen bromide, methanesulfonic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
The alkyl group in the invention represents a straight chain alkyl group or a branched chain alkyl group.
The preparation method of the benzimidazole derivative comprises the following steps:
(1) compound 1and compound R1-X under basic conditions gives compound 2;
(2) oxidizing the compound 2 to obtain a compound 3;
(3) carrying out reductive amination on the compound 3 and the compound 3-1 to obtain a compound 4;
(4) removing the Boc protecting group from the compound 4 under an acidic condition, and carrying out a condensation reaction with cyclopropanecarboxylic acid to obtain a compound 5, namely a compound shown in a formula I;
Figure BDA0002487703450000031
wherein R is1The process of claim 1, wherein X is selected from iodine or bromine.
The invention also provides a pharmaceutical composition which mainly comprises active components with effective dose in treatment and pharmaceutically acceptable auxiliary materials; the active component comprises the benzimidazole derivative or pharmaceutically acceptable salt thereof.
The invention also provides application of the benzimidazole derivative or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of selective retinal dehydrogenase inhibitors.
The invention also provides the application of the benzimidazole derivative or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicines for treating diabetes, obesity or hyperlipidemia.
When the benzimidazole derivative is used as a selective retinal dehydrogenase inhibitor, the benzimidazole derivative can be used alone, can be matched with other medicines for use at the same time, or can be prepared into a compound preparation together with other medicines for use, and the aim of inhibiting selective retinal dehydrogenase can be achieved.
The pharmaceutically acceptable auxiliary materials refer to various conventional auxiliary materials required when preparing different dosage forms, such as diluents, adhesives, disintegrants, glidants, lubricants, flavoring agents, inclusion materials, adsorbing materials and the like, and the pharmaceutically acceptable auxiliary materials are prepared into any one of common oral preparations by a conventional preparation method, such as granules, powder, tablets, capsules, pills, oral liquid, decoction, dropping pills and the like.
Compared with the prior art, the invention discloses benzimidazole derivatives and medicinal salts thereof which have selective inhibition effect on retinal dehydrogenase (A L DH1A1), and pharmacological experiments prove that the compounds have obvious inhibition effect on A L DH1A 1and can be particularly used as medicaments for treating diabetes.
Detailed Description
The present invention will be described in detail with reference to examples.
Example 1
Preparation of 1-ethyl-2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-1)
The preparation of I-1 comprises the following four steps:
the method comprises the following steps: preparation of 1-ethyl-2-hydroxymethyl-1H-benzimidazole
2-hydroxymethylbenzimidazole (0.50g,3.37mmol) was dissolved in 10m L DMF at room temperature, potassium carbonate (0.93g,6.75mmol) was added with stirring, the reaction was stirred for 20min, ethyl iodide (0.12g,4.05mmol) was slowly added dropwise, after the addition was completed, the temperature was raised to 60 ℃ and the reaction was monitored with stirring at 10 h.T L C, the reaction was stopped, 50m L water was poured into the reaction mixture, ethyl acetate (40m L× 2) was added to extract the aqueous layer, the organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered under reduced pressure, concentrated to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1:10) to give 0.40g of pale yellow oil in 68% yield.1H NMR(300MHz,CDCl3)7.65–7.60(m,1H),7.29–7.24(m,1H),7.21–7.10(m,2H),4.81(s,2H),4.21(q,J=7.3Hz,2H),1.38(t,J=7.2Hz,3H).ESI-MS m/z:177.2[M+H]+.
Step two: preparation of 1-ethyl-1H-benzimidazole-2-carbaldehyde
1-ethyl-2-hydroxymethyl-1H-benzimidazole (0.21g,1.20mmol) was dissolved in 10m L DCM at room temperature, dessimutane oxidant (0.61g,1.44mmol) was slowly added with stirring, reaction 2 h.T L C was continued with stirring to monitor that the starting material disappeared and stopped, 30m L water was poured into the reaction solution, dichloromethane (30m L× 2) was added to extract the aqueous layer, the organic layers were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to give a pale yellow oil 0.18g, 88% yield.1H NMR(300MHz,CDCl3)10.10(s,1H),7.79–7.70(m,1H),7.41–7.35(m,1H),7.27–7.20(m,2H),4.27(q,J=7.2Hz,2H),1.38(t,J=7.2Hz,3H).ESI-MSm/z:175.2[M+H]+.
Step three: preparation of 1-ethyl-2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole
1-ethyl-1H-benzimidazole-2-carbaldehyde (0.19g,1.10mmol) is dissolved in 10m L DCM at room temperature, glacial acetic acid (0.01g,0.11mmol) and 1-tert-butoxycarbonylpiperazine (0.25g,1.33mmol) are slowly added under stirring, after the addition is finished, sodium cyanoborohydride (0.14g,2.22mmol) is added in batches, the reaction is continued at room temperature under monitoring of 5 h.T L C, the raw materials disappear and stop reacting, 30m L saturated aqueous ammonium chloride solution is poured into the reaction solution for quenching, an organic layer is separated, an eluent is washed by saturated saline solution, dried by anhydrous sodium sulfate, filtered, evaporated under reduced pressure, an organic solvent is removed by column chromatography (eluent: petroleum ether/ethyl acetate ═ 2:1) to obtain 0.16g of light yellow oily matter with a yield of 43%.1H NMR(300MHz,CDCl3)7.70–7.64(m,1H),7.33–7.29(m,1H),7.25–7.16(m,2H),4.21(q,J=7.3Hz,2H),3.75(s,2H),3.55–3.47(m,4H),2.54–2.43(m,4H),1.44(s,9H),1.35(t,J=7.2Hz,3H).ESI-MS m/z:345.4[M+H]+.
Step four: preparation of 1-ethyl-2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-1)
1-Ethyl-2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole (0.18g,0.52mmol) was weighed at room temperature into 10m L3N methanol hydrochloride solution, and monitored by stirring at 1 h.T L C, the starting material disappeared, the reaction was stopped, and concentrated under reduced pressure to dryness for the next reaction.the resulting intermediate (0.14g,0.52mmol) was dissolved in 10m L DCM, triethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol) were slowly added, reaction 16 h.T L C was stirred at room temperature, the starting material disappeared, the reaction was stopped, 20m L DCM was poured into the reaction solution, the organic phase was washed with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl solution, saturated aqueous sodium chloride solution in this order, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1: 73 mg), and dried to give a white solid.1H NMR(300MHz,CDCl3)7.68–7.62(m,1H),7.30–7.26(m,1H),7.23–7.12(m,2H),4.23(q,J=7.2Hz,2H),3.72(s,2H),3.59–3.49(m,4H),2.50–2.40(m,4H),1.68–1.54(m,1H),1.38(t,J=7.2Hz,3H),0.92–0.84(m,2H),0.69–0.61(m,2H).13C NMR(75MHz,CDCl3)172.01,150.10,142.18,135.12,122.67,121.92,119.61,109.51,55.40,53.15,53.03,45.27,41.98,38.89,15.11,10.86,7.44.HRMS(ESI-TOF)m/zcalc’d for C18H25N4O[M+H]+313.2028,found 313.2025.
Example 2
Preparation of 1-isobutyl-2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-5)
The preparation of I-5 comprises the following four steps:
the method comprises the following steps: preparation of 1-isobutyl-2-hydroxymethyl-1H-benzimidazole
Dissolving 2-hydroxymethyl benzimidazole (0.50g,3.37mmol) in 10m L DMF at room temperature, adding potassium carbonate (0.93g,6.75mmol) under stirring, stirring for reaction for 20min, slowly adding 1-iodine-2-methylpropane (0.75g,4.05mmol) dropwise, heating to 60 deg.C after adding, stirring for reaction at 8 h.T L C, monitoring, stopping the reaction, and stoppingAfter the reaction, 50m L of water was poured into the reaction mixture, ethyl acetate (40m L× 2) was added to extract the aqueous layer, the organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered under suction, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1:10) to obtain 0.47g of a pale yellow oily substance in 68% yield.1H NMR(300MHz,CDCl3)7.93–7.89(m,1H),7.63–7.56(m,1H),7.25–7.20(m,1H),7.18–7.12(m,1H),4.83(s,2H),3.96(d,J=7.5Hz,2H),2.29–2.15(m,1H),0.87(d,J=6.7Hz,6H).ESI-MS m/z:205.2[M+H]+.
Step two: preparation of 1-isobutyl-1H-benzimidazole-2-carbaldehyde
1-isobutyl-2-hydroxymethyl-1H-benzimidazole (0.25g,1.20mmol) was dissolved in 10m L DCM at room temperature, dessimutane oxidant (0.61g,1.44mmol) was slowly added with stirring, reaction 2 h.T L C was continued with stirring to monitor that the starting material disappeared and stopped, 30m L water was poured into the reaction solution, dichloromethane (30m L× 2) was added to extract the aqueous layer, the organic layers were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to give 0.22g of pale yellow oil, 87% yield.1HNMR(300MHz,CDCl3)10.09(s,1H),7.94–7.88(m,1H),7.56–7.50(m,1H),7.41–7.32(m,2H),4.31(d,J=7.7Hz,2H),2.31–2.17(m,1H),0.96(d,J=6.6Hz,6H).ESI-MS m/z:203.2[M+H]+.
Step three: preparation of 1-isobutyl-2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole
Dissolving 1-isobutyl-1H-benzimidazole-2-formaldehyde (0.22g,1.10mmol) in 10m L DCM at room temperature, slowly adding glacial acetic acid (0.01g,0.11mmol) and 1-tert-butoxycarbonylpiperazine (0.25g,1.33mmol) under stirring, continuing to react for 1H, adding sodium cyanoborohydride (0.14g,2.22mmol) in batches, continuing to stir at room temperature for 5 h.T L C, monitoring until the raw materials disappear, stopping reaction, pouring 30m L saturated ammonium chloride aqueous solution into the reaction solution for quenching, separating an organic layer, washing with saturated saline aqueous solution, drying with anhydrous sodium sulfate, pumping out sodium sulfate, and stopping reactionFiltration, concentration under reduced pressure and evaporation of the organic solvent were carried out, and purification was carried out by column chromatography (eluent: petroleum ether/ethyl acetate 2:1) to obtain 0.20g of a pale yellow oil with a yield of 49%.1H NMR(300MHz,CDCl3)7.1–7.65(m,1H),7.34–7.29(m,1H),7.23–7.14(m,2H),4.05(d,J=7.5Hz,2H),3.76(s,2H),3.62–3.54(m,4H),2.53–2.44(m,4H),2.29–2.16(m,1H),1.44(s,9H),0.92(d,J=6.6Hz,6H).ESI-MSm/z:373.4[M+H]+.
Step four: preparation of (E) -isobutyl-2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-5)
1-isobutyl-2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole (0.20g,0.52mmol) was weighed at room temperature into 10m L3N methanolic hydrochloric acid solution, and monitored by stirring at 1 h.T L C, the starting material disappeared, the reaction was stopped, and concentrated under reduced pressure to dryness for the next reaction.the resulting intermediate (0.16g,0.52mmol) was dissolved in 10m L DCM, triethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol) were slowly added, and monitored by stirring at room temperature for 16 h.T L C, the starting material disappeared, the reaction was stopped, 20m L DCM was poured into the reaction solution, the organic phase was washed with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl solution, saturated aqueous sodium chloride solution in this order, the organic layer was collected, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate: 1:4), and dried to give a white solid yield of 48 mg.1H NMR(300MHz,CDCl3)7.69–7.62(m,1H),7.31–7.27(m,1H),7.21–7.12(m,2H),4.03(d,J=7.5Hz,2H),3.75(s,2H),3.60–3.52(m,4H),2.52–2.42(m,4H),2.33–2.17(m,1H),1.67–1.56(m,1H),0.93–0.83(m,8H),0.72–0.59(m,2H).13CNMR(75MHz,CDCl3)172.00,150.54,142.04,135.89,122.60,121.89,119.59,110.15,55.55,53.24,53.15,51.33,45.24,41.95,29.11,20.44,10.86,7.44.HRMS(ESI-TOF)m/zcalc’d for C20H29N4O[M+H]+341.2341,found 341.2341.
Example 3
Preparation of 1- (2-methylbenzyl) -2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-13)
The preparation of I-13 comprises the following four steps:
the method comprises the following steps: preparation of 1- (2-methylbenzyl) -2-hydroxymethyl-1H-benzimidazole
2-hydroxymethylbenzimidazole (0.50g,3.37mmol) was dissolved in 10m L DMF at room temperature, potassium carbonate (0.93g,6.75mmol) was added with stirring, the reaction was stirred for 20min, then 2-methylbenzyl bromide (0.75g,4.05mmol) was slowly added dropwise, after the addition was completed, the reaction was continued with stirring and 2 h.T L C monitoring, the starting material disappeared and the reaction was stopped, 50m L water was poured into the reaction solution, ethyl acetate (40m L× 2) was added to extract the aqueous layer, the organic layers were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered under reduced pressure, concentrated to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate ═ 1:10) to give 0.69g of pale yellow solid at a yield of 81%.1H NMR(300MHz,CDCl3)7.80–7.75(m,1H),7.33–7.27(m,2H),7.25–7.18(m,2H),7.16–7.11(m,1H),7.07–6.99(m,1H),6.51–6.46(m,1H),6.12–5.89(m,1H),5.46(s,2H),4.87(s,2H),2.46(s,3H).ESI-MS m/z:253.3[M+H]+.
Step two: preparation of 1- (2-methylbenzyl) -1H-benzimidazole-2-carbaldehyde
1- (2-methylbenzyl) -2-hydroxymethyl-1H-benzimidazole (0.30g,1.20mmol) is dissolved in 10m L DCM at room temperature, dessimutane oxidant (0.61g,1.44mmol) is slowly added with stirring, reaction 2 h.T L C is continuously stirred to monitor that the raw material disappears and stops the reaction, 30m L water is poured into the reaction solution, dichloromethane (30m L× 2) is added to extract an aqueous layer, organic layers are combined, washed with a saturated saline solution, dried by anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove an organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to obtain a pale yellow solid 0.26g with 88% yield.1HNMR(300MHz,CDCl3)10.13(s,1H),8.03–7.95(m,1H),7.45–7.37(m,2H),7.32–7.26(m,1H),7.24–7.13(m,2H),7.03–6.96(m,1H),6.39–6.33(m,1H),5.86(s,2H),2.44(s,3H).ESI-MS m/z:251.2[M+H]+.
Step three: preparation of 1- (2-methylbenzyl) -2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole
1- (2-methylbenzyl) -1H-benzimidazole-2-carbaldehyde (0.28g,1.10mmol) is dissolved in 10m L DCM at room temperature, glacial acetic acid (0.01g,0.11mmol) and 1-tert-butoxycarbonylpiperazine (0.25g,1.33mmol) are slowly added under stirring, after the addition is completed, sodium cyanoborohydride (0.14g,2.22mmol) is added in portions, reaction is continued at room temperature under monitoring of 5 h.T L C with stirring, the reaction is stopped, 30m L saturated aqueous ammonium chloride solution is poured into the reaction solution for quenching, the organic layer is separated, washed with saturated aqueous saline solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate ═ 2:1) to obtain 0.25g of pale yellow solid, yield: 53%.1H NMR(300MHz,CDCl3)7.83–7.76(m,1H),7.31–7.12(m,5H),7.04–6.94(m,1H),6.46–6.39(m,1H),5.54–5.47(m,2H),3.75–3.68(m,2H),3.25–3.16(m,4H),2.44–2.33(m,7H),1.43(s,9H).ESI-MS m/z:421.5[M+H]+.
Step four: preparation of 1- (2-methylbenzyl) -2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-13)
1- (2-methylbenzyl) -2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole (0.22g,0.52mmol) was weighed at room temperature into 10m L3N methanolic hydrochloric acid solution, and stirred at 1 h.T L C to monitor disappearance of the starting material, stopping the reaction, and concentrated under reduced pressure to dryness for the next reaction the obtained intermediate (0.18g,0.52mmol) was dissolved in 10m L DCM, triethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol) were slowly added, reaction 16 h.T L C was stirred at room temperature to monitor disappearance of the starting material, the reaction was stopped, 20m L DCM was poured into the reaction solution, the organic phase was washed with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl solution, saturated aqueous chlorinated solution in this order, the organic layer was collected, dried without water, sodium sulfate was filtered and concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate: 1: 99mg, yield, and dried to obtain 49 mg of a white solid.1H NMR(300MHz,CDCl3)7.81–7.74(m,1H),7.28–7.10(m,5H),6.96(td,J=7.5,1.5Hz,1H),6.41–6.37(m,1H),5.46(s,2H),3.72(s,2H),3.42–3.31(m,4H),2.45–2.35(m,7H),1.66–1.55(m,1H),0.96–0.86(m,2H),0.73–0.64(m,2H).13CNMR(75MHz,CDCl3)171.94,150.89,142.11,136.26,134.59,134.52,130.46,127.46,126.41,124.99,123.15,122.31,119.81,109.85,55.78,53.20,53.06,45.27,45.04,41.80,19.34,10.87,7.48.HRMS(ESI-TOF)m/z calc’d for C24H29N4O[M+H]+389.2341,found 389.2338.
Example 4
Preparation of 1- (3-methoxybenzyl) -2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-16)
The preparation of I-16 comprises the following four steps:
the method comprises the following steps: preparation of 1- (3-methoxybenzyl) -2-hydroxymethyl-1H-benzimidazole
2-hydroxymethylbenzimidazole (0.50g,3.37mmol) was dissolved in 10m L DMF at room temperature, potassium carbonate (0.93g,6.75mmol) was added with stirring, the reaction was stirred for 20min, then 3-methoxybenzyl bromide (0.81g,4.05mmol) was slowly added dropwise, after the addition was completed, the reaction was continued with stirring and monitoring at 2 h.T L C until the starting material disappeared, the reaction was stopped, 50m L water was poured into the reaction solution, ethyl acetate (40m L× 2) was added to extract the aqueous layer, the organic layers were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered under reduced pressure, concentrated to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1:10) to obtain 0.74g of a pale yellow solid with a yield of 82%.1H NMR(300MHz,CDCl3)7.73–7.67(m,1H),7.24–7.15(m,4H),6.79(dd,J=8.3,2.3Hz,1H),6.69–6.63(m,2H),5.75–5.49(m,1H),5.41(s,2H),4.86(s,2H),3.71(s,3H).ESI-MS m/z:267.2[M+H]+.
Step two: preparation of 1- (3-methoxybenzyl) -1H-benzimidazole-2-carbaldehyde
Dissolving 1- (3-methoxybenzyl) -2-hydroxymethyl-1H-benzimidazole (0.37g,1.20mmol) in 10m L DCM at room temperature, slowly adding dessimidine oxidant (0.61g,1.44mmol) under stirring, continuing to stir for reaction 2 h.T L C, monitoring until the raw material disappears, stopping the reaction, pouring 30m L water into the reaction solution, adding dichloromethane (30m L× 2) to extract the water layer, combining the organic layers, washing with saturated saline solution, and removing impuritiesDrying over sodium sulfate, suction filtering, vacuum concentrating to remove the organic solvent, purifying by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to obtain light yellow solid 0.28g, yield 87%.1HNMR(300MHz,CDCl3)10.13(s,1H),7.96–7.91(m,1H),7.46–7.34(m,3H),7.22–7.14(m,1H),6.80–6.67(m,3H),5.79(s,2H),3.70(s,3H).ESI-MS m/z:267.3[M+H]+.
Step three: preparation of 1- (3-methoxybenzyl) -2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole
1- (3-methoxybenzyl) -1H-benzimidazole-2-carbaldehyde (0.29g,1.10mmol) is dissolved in 10m L DCM at room temperature, glacial acetic acid (0.01g,0.11mmol) and 1-tert-butoxycarbonylpiperazine (0.25g,1.33mmol) are slowly added under stirring, after the addition is completed, sodium cyanoborohydride (0.14g,2.22mmol) is added in portions, reaction is continued at room temperature under monitoring of 5 h.T L C with stirring, the reaction is stopped, 30m L saturated aqueous ammonium chloride solution is poured into the reaction solution for quenching, the organic layer is separated, washed with saturated aqueous saline solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate ═ 2:1) to obtain 0.24g, 54% of pale yellow solid.1H NMR(300MHz,CDCl3)7.75–7.70(m,1H),7.25–7.16(m,4H),6.80–6.76(m,1H),6.63–6.58(m,2H),5.51(s,2H),3.70(s,3H),3.33–3.25(m,4H),2.46–2.37(m,4H),1.42(s,9H).ESI-MS m/z:437.3[M+H]+.
Preparation of 1- (3-methoxybenzyl) -2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-16)
Weighing 1- (3-methoxybenzyl) -2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole (0.23g,0.52mmol) at room temperature, adding 10m L3N methanol hydrochloride solution, monitoring with stirring at 1 h.T L C, allowing the starting material to disappear, stopping the reaction, concentrating under reduced pressure to dryness for the next reaction, dissolving the obtained intermediate (0.20g,0.52mmol) in 10m L DCM, slowly adding triethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol), stirring at room temperature for 16 h.T L C, monitoring with disappearance of the starting material, stopping the reaction, pouring 20m L DCM into the mixtureIn the reaction solution, the organic phase was washed with a saturated aqueous sodium bicarbonate solution, a 2N aqueous HCl solution and a saturated aqueous sodium chloride solution in this order, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, purified by column chromatography (eluent: petroleum ether/ethyl acetate 1:4), and lyophilized to give 104mg of a white solid with a yield of 49%.1H NMR(300MHz,CDCl3)7.78–7.73(m,1H),7.25–7.15(m,4H),6.80–6.75(m,1H),6.64–6.59(m,2H),5.51(s,2H),3.76(s,2H),3.70(s,3H),3.53–3.47(m,4H),2.51–2.42(m,4H),1.70–1.60(m,1H),0.97–0.90(m,2H),0.75–0.67(m,2H).13CNMR(75MHz,CDCl3)171.96,160.03,150.70,142.14,138.10,136.09,129.99,123.12,122.28,119.80,118.48,112.60,112.39,109.86,55.68,55.23,53.25,53.08,47.28,45.14,41.88,10.89,7.47.HRMS(ESI-TOF)m/z calc’d for C24H29N4O2[M+H]+405.2291,found 405.2285.
Example 5
Preparation of 1- (2- (trifluoromethyl) benzyl) -2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-23)
The preparation of I-23 comprises the following four steps:
the method comprises the following steps: preparation of 1- (2- (trifluoromethyl) benzyl) -2-hydroxymethyl-1H-benzimidazole
2-hydroxymethylbenzimidazole (0.50g,3.37mmol) was dissolved in 10m L DMF at room temperature, potassium carbonate (0.93g,6.75mmol) was added with stirring, the reaction was stirred for 20min, then 2- (trifluoromethyl) benzyl bromide (0.97g,4.05mmol) was slowly added dropwise, after the addition was completed, the reaction was continued with stirring 2 h.T L C monitoring, the starting material disappeared and stopped, 50m L water was poured into the reaction solution, ethyl acetate (40m L× 2) was added to extract the aqueous layer, the organic layers were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate ═ 1:10) to obtain 0.84g of a pale yellow solid with a yield of 80%.1H NMR(300MHz,CDCl3)7.73–7.67(m,1H),7.24–7.15(m,4H),6.79(dd,J=8.3,2.3Hz,1H),6.69–6.63(m,2H),5.75–5.49(m,1H),5.41(s,2H),4.86(s,2H),3.71(s,3H).ESI-MS m/z:267.2[M+H]+.
Step two: preparation of 1- (2- (trifluoromethyl) benzyl) -1H-benzimidazole-2-carbaldehyde
1- (2- (trifluoromethyl) benzyl) -2-hydroxymethyl-1H-benzimidazole (0.37g,1.20mmol) is dissolved in 10m L DCM at room temperature, dessimidine oxidant (0.61g,1.44mmol) is slowly added with stirring, reaction 2 h.T L C is continuously stirred to monitor that the raw material disappears and stop the reaction, 30m L water is poured into the reaction solution, dichloromethane (30m L× 2) is added to extract the water layer, the organic layers are combined, washed with saturated saline solution, dried with anhydrous sodium sulfate, filtered, decompressed, concentrated and evaporated to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to obtain light yellow solid 0.31g with 85% yield.1H NMR(300MHz,CDCl3)10.15(s,1H),8.03–7.96(m,1H),7.79–7.72(m,1H),7.47–7.24(m,5H),6.44–6.37(m,1H),6.09(s,2H).ESI-MSm/z:305.2[M+H]+.
Step three: preparation of 1- (2- (trifluoromethyl) benzyl) -2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole
1- (2- (trifluoromethyl) benzyl) -1H-benzimidazole-2-carbaldehyde (0.33g,1.10mmol) is dissolved in 10m L DCM at room temperature, glacial acetic acid (0.01g,0.11mmol) and 1-tert-butoxycarbonylpiperazine (0.25g,1.33mmol) are slowly added under stirring, after the addition is completed, sodium cyanoborohydride (0.14g,2.22mmol) is added in portions, the reaction is further stirred at room temperature for 5 h.T L C to monitor that the raw materials disappear and stop the reaction, 30m L saturated aqueous ammonium chloride solution is poured into the reaction solution for quenching, the organic layer is separated, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered by suction, concentrated by evaporation under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate ═ 2:1) to obtain 0.27g of pale yellow solid with a yield of 52%.1H NMR(300MHz,CDCl3)7.82–7.70(m,2H),7.38–7.27(m,3H),7.25–7.16(m,2H),6.50–6.44(m,1H),5.76(s,2H),3.73(s,2H),3.13–3.03(m,4H),2.39–2.30(m,4H),1.40(s,9H).ESI-MS m/z:475.5[M+H]+.
Preparation of 1- (2- (trifluoromethyl) benzyl) -2- ((cyclopropylformylpiperazin-1-yl) methyl) -1H-benzimidazole (I-23)
1- (2- (trifluoromethyl) benzyl) -2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole (0.25g,0.52mmol) was weighed at room temperature, 10m L3N methanolic hydrochloric acid was added, stirring was monitored at 1 h.T L C, the starting material disappeared, the reaction was stopped, and the reaction was concentrated under reduced pressure to dryness for the next reaction.the resulting intermediate (0.22g,0.52mmol) was dissolved in 10m L DCM, triethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol) were slowly added, reaction was monitored at room temperature by stirring 16 h.T L C, the starting material disappeared, the reaction was stopped, 20m L DCM was poured into the reaction solution, the organic phase was washed with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl, saturated chlorinated solution in this order, the organic layer was collected, dried over anhydrous sodium sulfate, the organic solvent was evaporated under reduced pressure, purified by column chromatography (petroleum ether/ethyl acetate: 1: 47 mg yield, and dried by freezing to obtain a white solid.1H NMR(300MHz,CDCl3)7.82–7.71(m,2H),7.39–7.27(m,4H),7.24–7.18(m,1H),6.52–6.46(m,1H),5.76(s,2H),3.75(s,2H),3.37–3.23(m,4H),2.46–2.33(m,4H),1.67–1.55(m,1H),0.95–0.88(m,2H),0.74–0.64(m,2H).13CNMR(75MHz,CDCl3)171.87,150.93,142.13,136.16,135.46,132.45,127.54,126.95,126.32,126.16,124.76,123.50,122.64,120.05,109.51,55.66,53.22,52.78,44.98,43.91,41.63,10.82,7.44.HRMS(ESI-TOF)m/z calc’d for C24H26F3N4O[M+H]+443.2059,found 443.2063.
The following compounds were prepared analogously as in examples 1-5:
Figure BDA0002487703450000121
Figure BDA0002487703450000131
Figure BDA0002487703450000141
Figure BDA0002487703450000151
Figure BDA0002487703450000161
Figure BDA0002487703450000171
experimental example:
(I) test of inhibitory activity of benzimidazole compounds on A L DHs
The experimental method comprises the following steps:
firstly, a compound to be tested (30 mu L), A L DHs (30 mu L) and NAD (nicotinamide adenine dinucleotide)+/NADP+(15. mu. L), incubating the mixture at 25 ℃ for 15 minutes in the dark, adding propionaldehyde or benzaldehyde (15. mu. L) as a substrate, incubating the mixture continuously, and after 15 minutes, reading the absorbance at a wavelength of 340nm using a microplate reader to determine the amount of NADH/NADPH produced++ propionaldehyde, reading a), negative control (buffer + A L DH1A1 enzyme solution + NAD)++ propionaldehyde, reading b); blank 1 (buffer + NAD)++ propionaldehyde, reading c); blank control 2 (test compound solution + buffer + NAD)++ propionaldehyde, reading d). Each group is provided with 3 multiple holes, the processing methods are consistent, and the calculation of the inhibition rate is carried out according to the following formula:
inhibition (%) - (b-c) - (a-d) ]/(b-c) × 100%
The total volume in the buffer system is 90 mu L, the concentration of each substance is 20mM Tris, 120mM NaCl and 1mM DTT, and the pH is 7.5. the test experiment of the inhibitory activity of the test compound on A L DH1A1, A L DH1A2, A L DH1A3 and A L DH2 specifically comprises pure enzyme (150nM), NAD+The test experiment of the inhibitory activity of the compound to be tested on A L DH1A3 specifically comprises pure enzyme (20nM) and NADP+(300. mu.M) and benzaldehyde (300. mu.M).
TABLE 1 test results for inhibitory Activity of the Compounds on A L DH1A1
Figure BDA0002487703450000181
Figure BDA0002487703450000191
Figure BDA0002487703450000201
Figure BDA0002487703450000211
The 25 compounds in Table 1 all showed better inhibitory activity against A L DH1A1, of which the most active compound was I-23, IC50The value of 0.17 mu M.A L DH1A1 isozyme inhibition ability test result shows that the series of compounds have no inhibition ability on A L DH1A2, A L DH1A3, A L DH2 and A L DH3A1 under the concentration of 10 mu M and show high selectivity inhibition on A L DH1A 1.
(II) test Compounds improve HepG2 cell sugar utilization test
The experimental method comprises the following steps:
HepG2 cell line was cultured in DMEM medium (containing 10% fetal bovine serum, 1% nonessential amino acids, 100U/ml penicillin, 100. mu.g/ml streptomycin, 2mM L-glutamine and 3.7 g/L NaHCO)3) HepG2 cells were seeded in 24-well plates at a density of 2.5 × 10 before the experiment5Cells/well, 5% CO at 37 ℃2Culturing in a cell culture box. When the cells in the cell plates were full to 70%, HepG2 cells were incubated for 24h with media containing different concentrations of test compound (1and 10. mu.M). HepG2 cells were collected to determine glucose consumption, and the cell protein concentration was determined using the BSA protein assay kit.
Test results show that the tested compounds can improve the sugar utilization condition of HepG2 cells, wherein the effects of I-17, I-20 and I-23 are most obvious, and the ideal blood sugar reduction effect is expected to be generated in animals.
Pharmacological experimental test of hypoglycemic Effect of test Compound I-23 on Whole animal level
The experimental method comprises the following steps:
the method comprises the following steps of selecting 30 successful hyperglycemic model animals, randomly dividing the animals into 1 model control group and 2 model administration groups according to blood glucose level, continuously feeding the animals of the model control group and the administration groups with the high fat feed, respectively feeding the animals of the model control group and the administration groups with the test compound I-23(5 and 10mg/kg) by intragastric administration, respectively feeding the normal mice and the model control mice with blank solvents, administering the animals for 1 time every day, measuring fasting blood glucose value after 6 hours of last administration after 30 days, and comparing the blood glucose value of the animals with blood glucose reduction percentage (blood glucose value before administration experiment-blood glucose value after administration experiment)/blood glucose value before administration experiment ×% after 6 hours of last administration.
TABLE 2 Effect of test Compounds I-23 on fasting plasma glucose in hyperglycemic model mice
Figure BDA0002487703450000221
The data in Table 2 are the mean values of fasting plasma glucose. + -. standard deviation of 10 mice, and the one-way anova analysis of variance was performed, and it can be seen from the table that the test compound I-23 significantly reduced fasting plasma glucose in hyperglycemic mice and significantly increased the percentage of blood glucose reduction before and after administration (P < 0.05).
The pharmacological tests show that the benzimidazole compound has the activity of selectively inhibiting A L DH1A1D, and has an application prospect in developing drugs for treating diabetes.

Claims (9)

1. A benzimidazole derivative represented by the general formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0002487703440000011
wherein R is1Selected from C1-C8 alkyl, C2-C8 alkenyl, cycloalkylmethyl or benzyl;
the cycloalkyl is 3-6 membered cycloalkyl;
the benzyl group may be optionally substituted with one or more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy or CF3
2. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is1Selected from C2-C5 alkyl, C5 alkenyl, cycloalkylmethyl, unsubstituted benzyl or substituted benzyl, the cycloalkyl is 3-6 membered cycloalkyl, the substituted benzyl is halogen, methyl, methoxy or CF3A substituted benzyl group.
3. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is1Selected from ethyl, propyl, isopropyl, n-butyl, isobutyl, isoamyl, isopentenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, unsubstituted benzyl or substituted benzyl, said substituted benzyl being halogen, methyl, methoxy or CF3A substituted benzyl group.
4. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the benzimidazole derivative of formula I is selected from the group consisting of:
Figure FDA0002487703440000012
Figure FDA0002487703440000021
5. the benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a compound of formula I, which can form an acid addition salt with a pharmaceutically acceptable acid, and the acid comprises hydrogen chloride, hydrogen bromide, methanesulfonic acid, acetic acid, benzenesulfonic acid or p-toluenesulfonic acid.
6. The process for producing a benzimidazole derivative according to claim 1, which comprises the steps of:
(1) compound 1and compound R1-X under basic conditions gives compound 2;
(2) oxidizing the compound 2 to obtain a compound 3;
(3) carrying out reductive amination on the compound 3 and the compound 3-1 to obtain a compound 4;
(4) removing the Boc protecting group from the compound 4 under an acidic condition, and carrying out a condensation reaction with cyclopropanecarboxylic acid to obtain a compound 5, namely a compound shown in a formula I;
Figure FDA0002487703440000022
wherein R is1The process of claim 1, wherein X is selected from iodine or bromine.
7. A pharmaceutical composition, it is mainly made up of active ingredient and acceptable supplementary product pharmaceutically in effective quantity on the treatment; the active ingredient comprising the benzimidazole derivative of any one of claims 1-5, or a pharmaceutically acceptable salt thereof.
8. Use of the benzimidazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7, for preparing a selective retinoid dehydrogenase inhibitor.
9. Use of the benzimidazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7, for the preparation of a medicament for treating diabetes, obesity or hyperlipidemia.
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