CN111393372B - Benzimidazole derivative and preparation method and application thereof - Google Patents
Benzimidazole derivative and preparation method and application thereof Download PDFInfo
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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 is 1 Selected 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 CF 3 . Compared with the prior art, the invention discloses benzimidazole derivatives with selective inhibition effect on retinal dehydrogenase (ALDH1A1) and pharmaceutically acceptable salts thereof, and pharmacological experiments prove that the compounds have significant inhibition effect on ALDH1A 1and can be particularly used as drugs for treating diabetes.
Description
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 human genome encodes 19 aldehyde dehydrogenases (ALDHs) which metabolize endogenous and exogenous aldehydes in the human body to corresponding carboxylic acids and derivatives thereof, thereby preventing cytotoxicity and canceration caused by excessive accumulation of aldehydes in the human body. Due to the differences in substrate specificity and gene expression, 19 ALDHs have similar but distinct physiological functions, of which ALDH1a1 is the most studied and widespread member of the ALDHs family, and one important physiological function in vivo is the oxidation of retinal to retinoic acid, and is therefore also known as retinal dehydrogenase (RALDH 1). ALDH1a1 is a highly conserved homo-tetrameric cytoplasmic protein with monomers of about 55 kDa molecular weight, each monomer containing three domains: a catalytic domain, a cofactor (NAD) binding domain, and an oligomerization domain. ALDH1a1 is expressed in various organs or tissues of the human body, such as the brain, testis, liver, kidney, lung, adipose tissue, lens, retina, and the like. The research shows that the change of the biological activity and the metabolic pathway of ALDH1A1 in vivo is related to the occurrence and the development of a series of diseases, such as cancer, inflammation, Parkinson's disease, obesity, diabetes and the like.
Vitamin a is a vitamin essential to the human body, mainly derived from carotenoids in plants and retinyl esters in animals, and has been shown to be involved in visual regulation, embryogenesis, tissue differentiation, immunity, and the like. The physiological functions of retinoids are believed to be mediated primarily by retinoic acid. Retinoic acid is involved in the bidirectional regulation of sugar and fat metabolism by activating the expression of key enzymes and proteins such as retinoid receptors, glucose-6-phosphatase, etc., and the net effect in hepatic glucose metabolism is to increase the production of sugar. Multiple studies have shown that ALDH1A1 is knocked out -/- The gene and the treatment with exogenous retinaldehyde and ALDH1A1 inhibitor citral can obviously improve the sensitivity of diabetic rats and high fat raised mice to insulin, improve the sugar tolerance and reduce fat accumulation. Therefore, inhibitors targeting ALDH1a1 are expected to be a feasible strategy for the treatment of 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:
wherein R is 1 Selected 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 CF 3 。
Preferably, the method comprises the following steps:
the R is 1 Selected 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 CF 3 A substituted benzyl group.
The R is 1 Selected 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 CF 3 A substituted benzyl group.
Most preferably, the benzimidazole derivative of formula I is selected from the following compounds:
the pharmaceutically acceptable salt refers to a compound shown in 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 R 1 -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;
wherein R is 1 As previously mentioned, 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 a selective retinal dehydrogenase inhibitor.
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.
Has the advantages that: compared with the prior art, the invention discloses benzimidazole derivatives with selective inhibition effect on retinal dehydrogenase (ALDH1A1) and pharmaceutically acceptable salts thereof, and pharmacological experiments prove that the compounds have significant inhibition effect on ALDH1A 1and can be particularly used as drugs 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 10mL of DMF at room temperature, and potassium carbonate (0.93g,6.75mmol) was added thereto under stirring to conduct a reaction for 20min with stirring. Then, iodoethane (0.12g,4.05 mmol) was slowly added dropwise, and after the addition, the temperature was raised to 60 ℃ and the reaction was stirred for 10 hours. TLC monitoring, disappearance of the starting material, reaction was stopped, 50mL of water was poured into the reaction mixture, ethyl acetate (40 mL. times.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 suction, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1:10) to obtain 0.40g of a pale yellow oily substance in 68% yield. 1 H NMR(300MHz, CDCl 3 )δ7.65–7.60(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 10mL of DCM at room temperature, followed by slow addition of dessimutan-oxidant (0.61g,1.44mmol) with stirring, and the reaction was continued for 2H after the addition. TLC detection, disappearance of the starting material, reaction stop, 30mL of water was poured into the reaction mixture, dichloromethane (30 mL. times.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 suction, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to obtain 0.18g of pale yellow oil in 88% yield. 1 H NMR(300MHz,CDCl 3 )δ10.10(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-MS m/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) was dissolved in 10mL of DCM at room temperature, glacial acetic acid (0.01g,0.11mmol) and 1-tert-butoxycarbonylpiperazine (0.25g,1.33mmol) were slowly added with stirring, and after completion of the addition, sodium cyanoborohydride (0.14g,2.22mmol) was added in portions and the reaction was continued for 5H at room temperature. TLC monitoring, disappearance of the raw material, reaction stop, 30mL of saturated aqueous ammonium chloride solution was poured into the reaction solution to quench, the organic layer was separated, washed with saturated aqueous saline solution, 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 2:1) to obtain 0.16g of pale yellow oily substance with a yield of 43%. 1 H NMR(300MHz,CDCl 3 )δ7.70–7.64(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 10mL of a 3N methanol hydrochloride solution and stirred for 1H. TLC monitoring, the raw material disappeared, stop the reaction, and concentrate to dryness under reduced pressure for the next reaction. The resulting intermediate (0.14g,0.52mmol) was dissolved in 10mL DCM, triethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol) were slowly added, and the reaction was stirred at room temperature for 16 h. TLC monitoring, disappearance of raw materials, reaction stopping, pouring 20mL of DCM into the reaction solution, washing the organic phase with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl solution and saturated aqueous sodium chloride solution in turn, collecting the organic layer, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, evaporating to remove the organic solvent, purifying by column chromatography (eluent: petroleum ether/ethyl acetate 1:4), and freeze-drying to obtain 73mg of white solid with the yield of 45%. 1 H NMR(300MHz,CDCl 3 )δ7.68–7.62(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). 13 C NMR(75 MHz,CDCl 3 )δ172.01,150.10,142.18,135.12,122.67,121.92,119.61,109.51,55.40,53.15, 53.03,45.27,41.98,38.89,15.11,10.86,7.44.HRMS(ESI-TOF)m/z calc’d for C 18 H 25 N 4 O [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
2-hydroxymethylbenzimidazole (0.50g,3.37mmol) was dissolved in 10mL of DMF at room temperature, and potassium carbonate (0.93g,6.75mmol) was added thereto under stirring to conduct a reaction for 20min under stirring. Then, 1-iodo-2-methylpropane (0.75g,4.05mmol) was slowly added dropwise, after the addition, the temperature was raised to 60 ℃ and the reaction was stirred for 8 hours. TLC detection, disappearance of the starting material, reaction stop, 50mL of water was poured into the reaction mixture, ethyl acetate (40 mL. times.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 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. 1 H NMR (300MHz,CDCl 3 )δ7.93–7.89(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 10mL of DCM at room temperature, followed by slow addition of dessimutan-oxidant (0.61g,1.44mmol) with stirring, and the reaction was continued for 2H after the addition. TLC monitoring, the material disappeared and stoppedAfter the reaction, 30mL of water was poured into the reaction mixture, methylene chloride (30mL × 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 suction, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to obtain 0.22g of a pale yellow oily substance with a yield of 87%. 1 H NMR(300MHz,CDCl 3 )δ10.09(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
1-isobutyl-1H-benzimidazole-2-carbaldehyde (0.22g,1.10mmol) is dissolved in 10mL DCM at room temperature, glacial acetic acid (0.01g,0.11mmol) and 1-tert-butoxycarbonylpiperazine (0.25g,1.33mmol) are slowly added with stirring, after the addition is completed, the reaction is continued for 1H, sodium cyanoborohydride (0.14g,2.22mmol) is added in portions, and the reaction is continued for 5H at room temperature with stirring. TLC monitoring, disappearance of the raw material, reaction stop, 30mL of saturated aqueous ammonium chloride solution was poured into the reaction solution to quench, the organic layer was separated, washed with saturated aqueous saline solution, 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 2:1) to obtain 0.20g of pale yellow oil with a yield of 49%. 1 H NMR(300MHz,CDCl 3 )δ7.1–7.65(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-MS m/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 10mL of a 3N methanol hydrochloride solution and stirred for 1H. TLC monitoring, the raw material disappeared, stop the reaction, and concentrate to dryness under reduced pressure for the next reaction. The resulting intermediate (0.16g,0.52mmol) was dissolved in 10mL DCM and slowly addedTriethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol) were stirred at room temperature for 16 h. TLC monitoring, disappearance of raw materials, reaction stopping, pouring 20mL of DCM into the reaction solution, washing the organic phase with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl solution and saturated aqueous sodium chloride solution in turn, collecting the organic layer, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, evaporating to remove the organic solvent, purifying by column chromatography (eluent: petroleum ether/ethyl acetate 1:4), and freeze-drying to obtain 85mg of white solid with the yield of 48%. 1 H NMR(300MHz,CDCl 3 )δ7.69–7.62(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). 13 C NMR(75MHz, CDCl 3 )δ172.00,150.54,142.04,135.89,122.60,121.89,119.59,110.15,55.55,53.24,53.15, 51.33,45.24,41.95,29.11,20.44,10.86,7.44.HRMS(ESI-TOF)m/z calc’d for C 20 H 29 N 4 O [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 10mL of DMF at room temperature, and potassium carbonate (0.93g,6.75mmol) was added thereto under stirring to conduct a reaction for 20min with stirring. Then, 2-methylbenzyl bromide (0.75g,4.05mmol) was slowly added dropwise, and the reaction was stirred for 2 hours. TLC detection, disappearance of the starting material, reaction stop, 50mL of water was poured into the reaction mixture, ethyl acetate (40 mL. times.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 suction, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1:10) to obtain 0.69g of a pale yellow solid with a yield of 81%. 1 H NMR(300MHz,CDCl 3 ) δ7.80–7.75(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) was dissolved in 10mL of DCM at room temperature, followed by slow addition of dessimutane oxidant (0.61g,1.44mmol) with stirring, and the reaction was continued for 2H after the addition. TLC detection, disappearance of the starting material, reaction stop, 30mL of water was poured into the reaction mixture, dichloromethane (30 mL. times.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 suction, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to obtain 0.26g of a pale yellow solid with a yield of 88%. 1 H NMR(300MHz,CDCl 3 )δ10.13(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 10mL of DCM at room temperature, glacial acetic acid (0.01g,0.11mmol) and 1-tert-butoxycarbonylpiperazine (0.25g,1.33mmol) are slowly added with stirring, after the addition is completed, the reaction is continued for 1H, sodium cyanoborohydride (0.14g,2.22mmol) is added in portions, and the reaction is continued for 5H at room temperature with stirring. TLC monitoring, disappearance of raw material, reaction stop, 30mL of saturated aqueous ammonium chloride solution was poured into the reaction solution for quenching, the organic layer was separated, washed with saturated aqueous sodium chloride solution, 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 2:1) to obtain 0.25g of pale yellow solid with a yield of 53%. 1 H NMR(300MHz,CDCl 3 )δ7.83–7.76(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 10mL of a 3N methanol hydrochloride solution and stirred for 1H. TLC monitoring, disappearance of raw materials, stopping reaction, and concentration under reduced pressure until the raw materials are dried for the next reaction. The resulting intermediate (0.18g,0.52mmol) was dissolved in 10mL DCM, triethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol) were slowly added, and the reaction was stirred at room temperature for 16 h. TLC monitoring, disappearance of raw materials, reaction stopping, pouring 20mL of DCM into the reaction solution, washing the organic phase with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl solution and saturated aqueous sodium chloride solution in turn, collecting the organic layer, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, evaporating to remove the organic solvent, purifying by column chromatography (eluent: petroleum ether/ethyl acetate 1:4), and freeze-drying to obtain 99mg of white solid with 49% yield. 1 H NMR(300MHz,CDCl 3 )δ7.81–7.74(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). 13 C NMR(75 MHz,CDCl 3 )δ171.94,150.89,142.11,136.26,134.59,134.52,130.46,127.46,126.41, 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 C 24 H 29 N 4 O[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 at room temperature10mL of DMF was added with stirring potassium carbonate (0.93g,6.75mmol) and the reaction was stirred for 20 min. Then, 3-methoxybenzyl bromide (0.81 g,4.05mmol) was slowly added dropwise, and the reaction was stirred for 2 h. TLC monitoring, disappearance of the starting material, reaction was stopped, 50mL of water was poured into the reaction solution, ethyl acetate (40 mL. times.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 suction, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1:10) to obtain 0.74g of a pale yellow solid in 82% yield. 1 H NMR(300MHz,CDCl 3 ) δ7.73–7.67(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
1- (3-methoxybenzyl) -2-hydroxymethyl-1H-benzimidazole (0.37g,1.20mmol) was dissolved in 10mL DCM at room temperature, followed by slow addition of dessimidine oxidant (0.61g,1.44mmol) with stirring, and the reaction was continued for 2H after the addition. TLC detection, disappearance of the starting material, reaction stop, 30mL of water was poured into the reaction mixture, dichloromethane (30 mL. times.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 suction, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to obtain 0.28g of a pale yellow solid with a yield of 87%. 1 H NMR(300MHz,CDCl 3 )δ10.13(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
Dissolving 1- (3-methoxybenzyl) -1H-benzimidazole-2-carbaldehyde (0.29g,1.10mmol) in 10mL of 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 after the addition is finished, adding sodium cyanoborohydride (0.14g,2.22mmol) in batches, and standingThe reaction was stirred for further 5h at room temperature. TLC monitoring, disappearance of raw material, reaction stop, 30mL of saturated aqueous ammonium chloride solution was poured into the reaction solution for quenching, the organic layer was separated, washed with saturated aqueous sodium chloride solution, 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 2:1) to obtain 0.24g of pale yellow solid with a yield of 54%. 1 H NMR(300MHz,CDCl 3 )δ7.75–7.70(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)
1- (3-methoxybenzyl) -2- ((tert-butoxycarbonylpiperazin-1-yl) methyl) -1H-benzimidazole (0.23g,0.52mmol) was weighed at room temperature into 10mL of a 3N methanol hydrochloride solution and stirred for 1H. TLC monitoring, disappearance of raw materials, stopping reaction, and concentration under reduced pressure until the raw materials are dried for the next reaction. The resulting intermediate (0.20g,0.52mmol) was dissolved in 10mL DCM, triethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol) were slowly added, and the reaction was stirred at room temperature for 16 h. TLC monitoring, disappearance of raw materials, reaction stopping, pouring 20mL of DCM into the reaction solution, washing the organic phase with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl solution and saturated aqueous sodium chloride solution in turn, collecting the organic layer, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, evaporating to remove the organic solvent, purifying by column chromatography (eluent: petroleum ether/ethyl acetate 1:4), and freeze-drying to obtain 104 mg of white solid with 49% yield. 1 H NMR(300MHz,CDCl 3 )δ7.78–7.73(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). 13 C NMR(75MHz,CDCl 3 )δ171.96,160.03,150.70,142.14,138.10,136.09,129.99,123.12, 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 C 24 H 29 N 4 O 2 [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 10mL of DMF at room temperature, and potassium carbonate (0.93g,6.75mmol) was added thereto under stirring to conduct a reaction for 20min with stirring. Then, 2- (trifluoromethyl) benzyl bromide (0.97g,4.05mmol) was slowly added dropwise, and the reaction was stirred for 2 h. TLC monitoring, disappearance of the starting material, reaction was stopped, 50mL of water was poured into the reaction solution, ethyl acetate (40 mL. times.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 suction, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1:10) to obtain 0.84g of a pale yellow solid with a yield of 80%. 1 H NMR(300MHz, CDCl 3 )δ7.73–7.67(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) was dissolved in 10mL DCM at room temperature, followed by slow addition of dessimutane oxidant (0.61g,1.44mmol) with stirring and stirring for 2H. TLC detection showed disappearance of the starting material, and the reaction was stopped by pouring 30mL of water into the reaction mixture, extracting the aqueous layer with dichloromethane (30 mL. times.2), combining the organic layers, washing with a saturated saline solution, drying over anhydrous sodium sulfate, suction-filtering, concentrating under reduced pressure to remove the organic solvent by evaporation, and purifying by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to give 0.31g of pale yellow solid in 85% yield. 1 H NMR(300MHz,CDCl 3 )δ10.15(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-MS m/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) was dissolved in 10mL of DCM at room temperature, glacial acetic acid (0.01g,0.11mmol) and 1-tert-butoxycarbonylpiperazine (0.25g,1.33mmol) were slowly added with stirring, and after 1H of addition, sodium cyanoborohydride (0.14g,2.22mmol) was added in portions and the reaction was further stirred at room temperature for 5H. TLC monitoring, disappearance of raw material, reaction stop, 30mL of saturated aqueous ammonium chloride solution was poured into the reaction solution for quenching, the organic layer was separated, washed with saturated aqueous sodium chloride solution, 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 2:1) to obtain 0.27g of pale yellow solid, yield 52%. 1 H NMR(300MHz,CDCl 3 )δ7.82–7.70(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 into 10mL of a 3N methanol hydrochloride solution and stirred for 1H. TLC monitoring, the raw material disappeared, stop the reaction, and concentrate to dryness under reduced pressure for the next reaction. The resulting intermediate (0.22g,0.52mmol) was dissolved in 10mL DCM, triethylamine (0.07g,0.62mmol), EDCI (0.20g,1.03mmol) and cyclopropanecarboxylic acid (0.05g,0.62mmol) were slowly added, and the reaction was stirred at room temperature for 16 h. TLC monitoring, disappearance of raw material, stopping reaction, pouring 20mL DCM into the reaction solution, washing the organic phase with saturated sodium bicarbonate solution, 2N HCl aqueous solution and saturated sodium chloride aqueous solution in turn, collecting the organic layer, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, evaporating to remove the organic solvent, purifying by column chromatography(eluent: petroleum ether/ethyl acetate 1:4), and freeze-dried to give 109 mg of a white solid in 47% yield. 1 H NMR(300MHz,CDCl 3 )δ7.82–7.71(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). 13 C NMR(75 MHz,CDCl 3 )δ171.87,150.93,142.13,136.16,135.46,132.45,127.54,126.95,126.32, 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 C 24 H 26 F 3 N 4 O[M+H] + 443.2059,found 443.2063.
The following compounds were prepared analogously as in examples 1-5:
experimental example:
test of inhibitory Activity of the benzimidazole Compounds on ALDHs
The experimental method comprises the following steps:
first, the test compound (30. mu.L) was mixed with ALDHs (30. mu.L) and NAD + /NADP + (15. mu.L), incubating the mixture at 25 ℃ for 15 minutes in the absence of light, 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 by using a microplate reader to determine the amount of NADH/NADPH produced. The following four groups were set up (as exemplified by the ALDH1a1 test): positive control (test compound solution + ALDH1A1 enzyme solution + NAD) + + propanal, reading a); negative control (buffer + ALDH1A1 enzyme solution + NAD) + + propanal, 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 was 90. mu.L, and the concentration of each substance was 20mM Tris, 120mM NaCl, 1mM DTT, pH 7.5. The test for the inhibitory activity of the test compound on ALDH1A1, ALDH1A2, ALDH1A3 and ALDH2 specifically comprises pure enzyme (150nM), NAD + (500. mu.M) and propionaldehyde (400. mu.M). The test for the inhibitory activity of the test compound on ALDH1A3 specifically comprises pure enzyme (20nM) and NADP + (300. mu.M) and benzaldehyde (300. mu.M).
TABLE 1 test results of ALDH1A1 inhibitory Activity of the respective Compounds
All 25 compounds in Table 1 showed better inhibitory activity against ALDH1A1, with the most active compound being I-23, IC 50 The value was 0.17. mu.M. The ALDH1A1 isozyme inhibition ability test result shows that the series of compounds have no inhibition ability on ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1 at the concentration of 10 mu M, and show high selective inhibition on ALDH1A 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 3.7g/L NaHCO) 3 ) HepG2 cells were seeded in 24-well plates at a density of 2.5X 10 before the experiment 5 Cells/well, 5% CO at 37 ℃ 2 Culturing 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:
a male clean SD mouse is fed with high-fat feed for 1 month under the conditions that the body weight is 20 +/-5 g, the environmental temperature is 22-24 ℃ and the humidity is 52-58% during the experiment period, and the blood sugar of the male clean SD mouse is measured after 5-hour fasting, and the male clean SD mouse with the blood sugar of more than or equal to 8mmol/L is regarded as a successful animal of a hyperglycemia model. Selecting 30 animals with hyperglycemia, randomly dividing into 1 model control group and 2 model administration groups according to blood sugar level, and continuously feeding the animals in the model control group and the administration groups with high fat feed. Test compound I-23(5, 10mg/kg) was administered to each group by intragastric administration, and the normal mice and model control mice were administered with a blank vehicle 1 time a day, 30 days later, and after the last administration for 6 hours, fasting blood glucose values were measured, and blood glucose values and blood glucose reduction percentages of the animals in each group were compared. Percent of blood glucose decrease (blood glucose value before administration test-blood glucose value after administration test)/blood glucose value before administration test × 100%.
TABLE 2 Effect of test Compounds I-23 on fasting plasma glucose in hyperglycemic model mice
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 ALDH1A1D, and has an application prospect in developing drugs for treating diabetes.
Claims (8)
1. A benzimidazole derivative represented by the general formula I or a pharmaceutically acceptable salt thereof:
I
wherein R is 1 Selected from C2-C8 alkyl, C2-C8 alkenyl, cycloalkylmethyl or substituted benzyl;
the cycloalkyl is 3-6 membered cycloalkyl;
on the substituted benzyl group, halogen, C1-C4 alkyl, C1-C4 alkoxy or CF 3 Substituted with one or more groups;
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 is hydrogen chloride, hydrogen bromide, methanesulfonic acid, acetic acid, benzenesulfonic acid or p-toluenesulfonic acid.
2. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is 1 Is selected from C2-C5 alkyl, C5 alkenyl, cycloalkyl methyl or substituted benzyl, the cycloalkyl is 3-6 membered cycloalkyl, the substituted benzyl is halogen, methyl, methoxy or CF 3 A substituted benzyl group.
3. The benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is 1 Selected from ethyl, propyl, isopropyl, n-butyl, isobutyl, isoamyl, isopentenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or substituted benzyl which is halo, methyl, methoxy or CF 3 A 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:
5. the process for producing the benzimidazole derivative according to claim 1, comprising the steps of:
(1) compound 1and compound R 1 -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;
wherein R is 1 As in claim 1, X is selected from iodine or bromine.
6. A pharmaceutical composition, it is mainly made up of therapeutically effective amount of active ingredient and acceptable supplementary product pharmaceutically; the active ingredient comprising the benzimidazole derivative of any one of claims 1-4, or a pharmaceutically acceptable salt thereof.
7. Use of the benzimidazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, or the pharmaceutical composition according to claim 6, for preparing a selective retinoid dehydrogenase inhibitor.
8. Use of the benzimidazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, or the pharmaceutical composition according to claim 6, for the preparation of a medicament for the treatment of diabetes, obesity or hyperlipidemia.
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