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CN106977474B - Substituted 2-cyano-3-phenyl furan-acrylamide derivative and preparation method and application thereof - Google Patents

Substituted 2-cyano-3-phenyl furan-acrylamide derivative and preparation method and application thereof Download PDF

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CN106977474B
CN106977474B CN201710327630.3A CN201710327630A CN106977474B CN 106977474 B CN106977474 B CN 106977474B CN 201710327630 A CN201710327630 A CN 201710327630A CN 106977474 B CN106977474 B CN 106977474B
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CN106977474A (en
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李国菠
吴勇
海俐
王乾韬
刘莎
于竹君
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Sichuan University
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Abstract

本发明提供了一种取代2‑氰基‑3‑苯基呋喃‑丙烯酰胺衍生物，结构式如式I所示：

Figure DDA0001291209770000011
本发明还提供了取代2‑氰基‑3‑苯基呋喃‑丙烯酰胺衍生物的制备工艺和用途。药效试验证明，本发明化合物对SIRT5有较好的抑制活性，尤其是化合物17抑制活性最佳，显著优于目前报道的一些SIRT5小分子抑制剂，如烟酰胺，本发明取代2‑氰基‑3‑苯基呋喃‑丙烯酰胺衍生物药效明确，为临床提供了一种新的用药选择。

Figure 201710327630

The invention provides a kind of substituted 2-cyano-3-phenylfuran-acrylamide derivative, the structural formula is as shown in formula I:

Figure DDA0001291209770000011
The invention also provides the preparation process and application of the substituted 2-cyano-3-phenylfuran-acrylamide derivative. Pharmacodynamic test proves that the compound of the present invention has good inhibitory activity to SIRT5, especially compound 17 has the best inhibitory activity, which is significantly better than some SIRT5 small molecule inhibitors reported at present, such as nicotinamide, the present invention replaces 2-cyano group ‑3‑phenylfuran‑acrylamide derivatives have clear efficacy, providing a new drug option for clinical use.

Figure 201710327630

Description

Substituted 2-cyano-3-phenyl furan-acrylamide derivative and preparation method and application thereof
Technical Field
The invention relates to a substituted 2-cyano-3-phenyl furan-acrylamide derivative, belonging to the field of medicaments.
Background
Sirtuins are a class of Nicotinamide Adenine Dinucleotide (NAD) -dependent protein lysine deacetylases and a single ADP-ribosyltransferase. From bacteria to humans, the amino acid sequence of Sirtuin proteins is highly conserved and is expressed in a variety of tissues and organs, such as the liver, heart, brain and pancreas. The seven currently discovered human Sirtuin proteins, SIRT1-SIRT7, are divided into four subtypes based on their function and subcellular localization. Wherein, the SIRT1-SIRT3 belongs to the first class, has stronger deacetylation and a certain long-chain fat deacetylation; SIRT4 and SIRT5 belong to the second and third classes, respectively, and SIRT6-SIRT7 belong together to the fourth class, and they have little or weak deacetylation. Nevertheless, a great deal of research in recent years has shown that SIRT5 has strong dehydrosuccinylation, dehydromalonylation, and dehydroglutarylation effects, and thus has received much attention from researchers.
Since SIRT5 is mainly localized to mitochondria, it regulates deacylation of various mitochondrial proteins and plays an important role in metabolism. For example, it regulates the degradation of ammonia in vivo by the enzyme succinylated carbamyl phosphate synthetase 1(CPS 1); regulating active oxygen (ROS) enzyme by succinylating copper zinc superoxide dismutase (SOD1) to eliminate active oxygen; glycolysis and the like can also be regulated by demalonylated glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In addition, acyl donor molecules of SIRT5, including acetyl coenzyme A, malonyl coenzyme A, succinyl coenzyme A and the like, are important components in energy metabolism, and the regulation of the amount of the acyl donor can directly affect the metabolism. In view of the wide range of physiological actions, in recent years, more and more researches show that SIRT5 is highly expressed in pathological tissues including tumors, metabolic diseases, central nervous system diseases and the like, and the expression level of SIRT5 has a certain relation with the adverse prognosis of related diseases. Therefore, SIRT5 is considered to be a potential new therapeutic target for various diseases, and the development of inhibitors thereof is highly valued by various pharmaceutical companies and research institutions. At present, the reported SIRT5 inhibitors are mainly divided into substrate analogs and small molecule inhibitors, and the substrate analog inhibitors have the defects of poor selectivity, poor cell permeability and the like, so that the further development of the SIRT5 inhibitors as medicines is limited. On the contrary, small molecule inhibitors may have better development potential, but the SIRT5 small molecule inhibitors reported up to now are very limited, and the activity and selectivity of only a few inhibitors are also poor, so that the development of novel SIRT5 small molecule inhibitors with high activity is urgently needed to provide candidate compounds for the development of SIRT 5-targeted drugs.
Disclosure of Invention
The invention provides a substituted 2-cyano-3-phenyl furan-acrylamide derivative, and also provides a preparation method and application of the derivative.
The invention provides a substituted 2-cyano-3-phenyl furan-acrylamide derivative, the structural formula of which is shown as formula I:
Figure BDA0001291209750000021
wherein A is
Figure BDA0001291209750000022
Figure BDA0001291209750000023
B is
Figure BDA0001291209750000024
R21Is H, halogen or methyl, R22Is carboxyl, nitryl, cyano-group, methyl formate;
further preferably, B is
Figure BDA0001291209750000025
Figure BDA0001291209750000026
Wherein, the derivative is:
Figure BDA0001291209750000027
Figure BDA0001291209750000031
further preferably, the derivative is:
Figure BDA0001291209750000032
the invention also provides a method for synthesizing the derivative, which comprises the following process flow:
Figure BDA0001291209750000033
specifically, it comprises the following steps:
a. synthesis of Compound-substituted 2-cyano-N-phenylacrylamide (22)
Dissolving cyanoacetic acid with dichloromethane, adding phosphorus pentachloride in ice-water bath, reacting at 40 deg.C for half an hour, cooling to room temperature, adding corresponding substituted aniline, slowly heating to 40 deg.C, reacting for 2 hr, stopping reaction, concentrating solvent under reduced pressure, adding water, directly filtering after solid appears, sequentially filtering with saturated NaHCO3Washing the solution with anhydrous ether to obtain a compound substituted 2-cyano-N-phenyl acrylamide;
b. synthesis of compound substituted 5-phenyl furan-2-aldehyde furan (25)
Mixing different substituted iodobenzenes, (5-aldehyde furan-2-yl) phenylboronic acid and Na2CO3And Pd (PPh)3)2Cl2With MeCN/H2Dissolving O1: 1(5 ml/mmol); wherein iodobenzene, (5-aldehyde furan-2-yl) phenylboronic acid and Na2CO3(2.0 equiv.) and Pd (PPh)3)2Cl2The equivalent ratio of (A) to (B) is: 1: 1.5: 2.0: 0.1; after dissolving, replacing nitrogen, moving to 60 ℃ for reaction, after 1h, monitoring whether the reaction is complete by TLC, filtering after the reaction is complete, concentrating the filtrate under reduced pressure, and then separating by column chromatography to obtain a compound substituted 5-phenylfuran-2-aldehyde furan (25);
c. condensation reaction of Compounds 22 and 25
Mixing compound 22 and compound 25 in an equivalent ratio: 1: 1; dissolving with EtOH (5ml/mmol), adding a catalytic amount of piperidine, heating to 80 ℃ for reaction, reacting completely after 2h, filtering the solid, and separating a filter cake by column chromatography to obtain a condensation product;
d. hydrolysis reaction
After a compound (1.0 equivalent) of which the benzene ring substituent is ester is dissolved by THF/MeOH (1: 6ml/mmol), NaOH (1.0 equivalent) is added, the mixture is moved to 60 ℃ for reaction, the reaction is completed after about 0.5h, then the pH is adjusted to 5-7, and then the solid is directly filtered and dried to obtain the target compound of which the benzene ring substituent is carboxyl.
The invention also provides application of the substituted 2-cyano-3-phenyl furan-acrylamide derivative in preparing a SIRT5 protein inhibitor.
The invention provides a SIRT5 protein inhibitor, which is a pharmaceutically common preparation prepared by taking a substituted 2-cyano-3-phenyl furan-acrylamide derivative or a pharmaceutically acceptable salt or hydrate as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
Wherein, the preparation is oral preparation and injection preparation.
The present invention also provides prodrugs of the compounds of the invention, which are derivatives of the above-mentioned compounds which may themselves have weak or even no activity, but which, upon administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The pharmacodynamic test proves that the compound has better inhibitory activity to SIRT5, particularly the compound 17 has the best inhibitory activity, and is obviously superior to some SIRT5 small-molecule inhibitors reported at present, such as nicotinamide, the substituted 2-cyano-3-phenyl furan-acrylamide derivative has definite efficacy, and a new drug choice is provided for clinic.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 Compound 17 with different cofactors NAD+(a) And a substrateIC measured at Subka (b) concentration50Curve line
Detailed Description
EXAMPLE 1 Synthesis of Compounds of the invention
Step a Synthesis of Compound-substituted 2-cyano-N-phenylacrylamide (22)
Dissolving cyanoacetic acid (1.0g) with dichloromethane (20ml), adding phosphorus pentachloride (2.5g) under the condition of ice-water bath, moving to 40 ℃ for reaction for about half an hour, cooling to room temperature, adding corresponding substituted aniline (40), slowly heating to 40 ℃ for continuous reaction, stopping reaction after 2 hours, concentrating the solvent under reduced pressure, adding 50ml of water, allowing a large amount of solid to appear, directly filtering, and sequentially using 10ml of saturated NaHCO for a filter cake3The solution is washed with anhydrous ether to obtain the target compound substituted 2-cyano-N-phenyl acrylamide (22) without further treatment, and the yield is about 83-95%.
Step b, synthesis of compound substituted 5-phenyl furan-2-aldehyde furan (25)
Different substituted iodobenzenes (1.0 equivalent), 5-aldehyde furan-2-yl) phenylboronic acid (1.5 equivalent), Na2CO3(2.0 equiv.) and Pd (PPh)3)2Cl2(0.1 equiv.) with MeCN/H2Dissolving O-1: 1(5ml/mmol), replacing nitrogen for 3 times, moving to 60 ℃ for reaction, after 1h, monitoring whether the reaction is complete by TLC, filtering after the reaction is complete, concentrating the filtrate under reduced pressure, and separating by column chromatography to obtain the compound substituted 5-phenyl furan-2-aldehyde furan (25), wherein the yield is about 68-87%.
Step c condensation reaction of Compounds 22 and 25
Dissolving compound 22(1.0 equivalent) and compound 25(1.0 equivalent) in EtOH (5ml/mmol), adding a catalytic amount of piperidine, heating to 80 deg.C for reaction, reacting completely after 2h, filtering the solid, and separating the filter cake by column chromatography to obtain the condensation product with a yield of 75-90%.
Step d hydrolysis reaction
The compound is prepared by dissolving the compound (1.0 equivalent) with the benzene ring substituent as the ester of the condensation product with THF/MeOH (1: 1) (6ml/mmol), adding NaOH (1.0 equivalent), transferring to 60 ℃ for reaction, reacting completely after about 0.5h, adjusting pH to 5-7, directly filtering the solid, and drying to obtain the target compound with the benzene ring substituent as the carboxyl, wherein the yield is about 65-78% without further purification.
Synthesis of Compound (E) -2-cyano-N- (3, 4-xylyl) -3- (5- (4-methylformate phenyl) furan-2-yl) acrylamide (1)
Figure BDA0001291209750000051
The light yellow target compound 1 is synthesized through the steps a-c, the total yield of the three steps is 59 percent, and the purity is 96.9 percent.1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.42(s,1H),7.99-7.85(m,6H),7.36-7.32(m,2H),7.04(d,J＝5.2Hz,1H),3.81(s,3H),2.13(d,J＝6.0Hz,1H)ppm.13C NMR(100MHz,DMSO-d6)δ160.4,158.3,149.8,144.9,143.7,140.1,137.1,136.8,136.6,136.4,130.7,130.1,127.1,126.8,122.3,118.7,117.0,103.5,100.0,52.8,20.1,19.3ppm.LCMS m/z:401.1[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3, 4-xylyl) -3- (5- (4-cyanophenyl) furan-2-yl) acrylamide (2)
Figure BDA0001291209750000061
The light yellow target compound 2 is synthesized through the steps a-c, the total yield of the three steps is 67%, and the purity is 97.5%.1H NMR(400MHz,DMSO-d6)δ10.14(br s,1H),8.11(s,1H),8.07(d,J＝8.4Hz,2H),8.02(d,J＝8.4Hz,2H),7.61(d,J＝3.6Hz,1H),7.51(d,J＝3.6Hz,1H),7.44(s,1H),7.40(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),2.21(d,J＝9.6Hz,6H)ppm.13C NMR(100MHz,DMSO-d6)δ160.4,156.1,149.3,136.8,136.4,135.5,133.7,133.0,132.7,130.0,125.6,124.9,122.33(s),119.1,118.7,117.0,113.1,111.8,103.1,20.1,19.3ppm.LCMS m/z:368.2[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3, 4-xylyl) -3- (5- (4-nitrophenyl) furan-2-yl) acrylamide (3)
Figure BDA0001291209750000062
The light yellow target compound 3 is synthesized through the steps a-c, the total yield of the three steps is 71%, and the purity is 98.5%.1H NMR(400The title compound was obtained by the general procedures as above,71％for four steps,yellow solid,98.5％HPLC purity.MHz,DMSO-d6)δ10.16(s,1H),8.39(d,J＝8.8Hz,2H),8.14(d,J＝8.8Hz,3H),7.67(d,J＝3.6Hz,1H),7.54(d,J＝3.6Hz,1H),7.44(s,1H),7.40(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),2.21(d,J＝9.6Hz,6H)ppm.13CNMR(100MHz,DMSO-d6)δ160.3,155.6,149.6,147.6,136.8,136.4,135.5,134.8,132.7,130.0,125.9,125.1,124.8,122.3,118.6,116.9,113.8,103.4,20.1,19.3ppm.LCMS m/z:388.2[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3, 4-xylyl) -3- (5- (3-carboxyphenyl) furan-2-yl) acrylamide (4)
Figure BDA0001291209750000071
The light yellow target compound 4 is synthesized through the steps a-d, the total yield of the four steps is 58%, and the purity is 98.0%.1H NMR(400MHz,DMSO-d6)δ13.22(br s,1H),10.24(s,1H),8.49(s,1H),8.23(d,J＝2.0Hz,1H),8.16(d,J＝8.0Hz,1H),7.99(d,J＝7.6Hz,1H),7.68(t,J＝7.6Hz,1H),7.54-7.49(m,3H),7.45(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),2.22(d,J＝11.6Hz,6H)ppm.13C NMR(100MHz,DMSO-d6)δ167.2,160.7,157.3,148.5,136.7,136.6,135.6,132.5,132.4,130.5,130.1,130.0,129.6,129.1,125.9,124.9,122.3,118.6,117.1,111.1,102.1,20.1,19.3ppm.LCMS m/z:387.2[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3, 4-xylyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (5)
Figure BDA0001291209750000072
Through the stepsThe light yellow target compound 5 is synthesized in the four steps, the total yield is 52 percent, and the purity is 97.1 percent.1H NMR(400MHz,DMSO-d6)δ13.10(br s,1H),10.37(s,1H),8.30(s,1H),8.08-8.03(m,4H),7.55(d,J＝4.0Hz,1H),7.51-7.49(m,2H),7.46(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),2.21(d,J＝8.8Hz,6H)ppm.13C NMR(100MHz,DMSO-d6)δ167.1,160.7,157.00,148.9,136.7,136.6,135.6,132.8,132.5,131.6,130.6,130.0,125.11,124.9,122.3,118.6,117.1,112.2,102.6,20.1,19.3ppm.LCMS m/z:387.2[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3, 4-xylyl) -3- (5- (2-fluoro-4-carboxyphenyl) furan-2-yl) acrylamide (6)
Figure BDA0001291209750000073
The light yellow target compound 6 is synthesized through the steps a-d, the total yield of the four steps is 52%, and the purity is 97.1%.1H NMR(400MHz,DMSO-d6)δ13.35(br s,1H),10.27(s,1H),8.22(s,1H),8.10-7.99(m,1H),7.86-7.84(m,1H),7.78(d,J＝11.6Hz,1H),7.46(d,J＝3.8Hz,1H),7.46-7.42(m,2H),7.38(d,J＝8.0Hz,1H),7.25(t,J＝3.6Hz,1H),7.04(d,J＝8.4Hz,1H),2.14(d,J＝8.4Hz,6H)ppm.13CNMR(100MHz,DMSO-d6)δ166.1,163.9,160.5,151.1,148.8,136.8,136.5,135.5,133.5,132.6,130.0,127.0,126.5,124.6,122.3,121.0,118.6,117.6,116.9,115.9,103.6,20.1,19.3ppm.LCMS m/z:405.1[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3, 4-xylyl) -3- (5- (2-methyl-4-carboxyphenyl) furan-2-yl) acrylamide (7)
Figure BDA0001291209750000081
The light yellow target compound 7 is synthesized through the steps a-d, the total yield of the four steps is 52%, and the purity is 97.8%.1H NMR(400MHz,DMSO-d6)δ13.03(br s,1H),10.28(s,1H),8.24(s,1H),7.94(d,J＝8.0Hz,1H),7.85(s,1H),7.79(q,J＝8.0Hz,2H),7.44-7.36(m,2H),7.21(t,J＝3.6Hz,1H),7.02(d,J＝8.4Hz,1H),2.54(d,J＝5.6Hz,3H),2.12(d,J＝9.2Hz,3H)ppm.13C NMR(100MHz,DMSO-d6)δ167.2,160.7,156.9,148.5,136.7,136.6,136.2,135.6,132.9,132.5,132.2,131.3,120.0,127.9,127.6,124.6,122.3,118.6,116.9,115.0,102.5,22.3,20.1,19.3ppm.LCMSm/z:401.2[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3, 5-xylyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (8)
Figure BDA0001291209750000082
The light yellow target compound 8 is synthesized through the steps a-d, the total yield of the four steps is 53 percent, and the purity is 97.8 percent.1H NMR(400MHz,DMSO-d6)δ13.14(br s,1H),10.17(s,1H),8.16(s,1H),8.05(q,J＝8.4Hz,4H),7.54(d,J＝3.6Hz,1H),7.51(d,J＝3.6Hz,1H),7.32(s,2H),6.78(s,1H),2.27(s,6H)ppm.13C NMR(100MHz,DMSO-d6)δ167.2,160.7,157.1,148.9,138.6,138.2,135.6,132.8,131.6,130.6,126.3,125.2,125.1,118.8,117.0,112.2,102.6,21.6ppm.LCMS m/z:387.1[M+H]+.
Synthesis of the Compound (E) -2-cyano-N- (3, 4-dimethoxyphenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (9)
Figure BDA0001291209750000083
The light yellow target compound 9 is synthesized through the steps a-d, the total yield of the four steps is 65%, and the purity is 97.0%.1H NMR(400MHz,DMSO-d6)δ13.14(br s,1H),10.36(s,1H),8.30(s,1H),8.06(q,J＝8.4Hz,4H),7.55(d,J＝3.6Hz,1H),7.50(d,J＝3.6Hz,1H),7.45(s,1H),7.33(d,J＝8.4Hz,1H),6.95(d,J＝8.8Hz,1H),3.76(d,J＝3.6Hz,6H)ppm.13C NMR(100MHz,DMSO-d6)δ167.2,160.5,157.0,148.9,148.8,146.0,135.5,132.8,132.3,131.6,130.6,125.1,124.9,117.0,113.1,112.2,121.1,106.2,102.5,56.2,55.9ppm.LCMS m/z:419.1[M+H]+.
Synthesis of the Compound (E) -2-cyano-N- (3, 4-dioxapentanophenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (10)
Figure BDA0001291209750000091
The light yellow target compound 10 is synthesized through the steps a-d, the total yield of the four steps is 50%, and the purity is 98.8%.1HNMR(400MHz,DMSO-d6)δ13.12(br s,1H),10.40(s,1H),8.27(s,1H),8.04(q,J＝8.4Hz,4H),7.53(d,J＝3.6Hz,1H),7.49(d,J＝3.6Hz,1H),7.38(d,J＝1.6Hz,1H),7.17(dd,J＝8.4,1.6Hz,1H),6.90(d,J＝8.4Hz,1H),6.02(s,2H)ppm.13C NMR(100MHz,DMSO-d6)δ167.2,160.7,157.1,148.9,147.4,144.2,135.6,133.1,132.8,131.6,130.6,125.1,124.9,117.0,114.3,112.2,108.4,103.2,102.4,101.6ppm.LCMS m/z:403.1[M+H]+.
Synthesis of the Compound (E) -2-cyano-N- (3, 4-dioxanophenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (11)
Figure BDA0001291209750000092
The light yellow target compound 11 was synthesized by the above steps a-d with a total yield of 67% and a purity of 97.1% in four steps.1HNMR(400MHz,DMSO-d6)δ13.18(br s,1H),10.26(s,1H),8.21(s,1H),8.05(q,J＝8.8Hz,4H),7.54(d,J＝4.0Hz,1H),7.50(d,J＝4.0Hz,1H),7.32(d,J＝2.4Hz,1H),7.16(dd,J＝8.8,2.4Hz,1H),6.84(d,J＝8.4Hz,1H),4.24(d,J＝2.0Hz,4H)ppm.13C NMR(100MHz,DMSO-d6)δ167.2,160.5,157.0,148.9,143.3,140.6,135.6,132.8,132.4,131.6,130.6,125.1,124.9,117.2,117.0,114.4,112.2,110.2,102.4,64.6,64.5ppm.LCMS m/z:417.1[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3,4, 5-trimethoxyphenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (12)
Figure BDA0001291209750000093
Synthesizing a light yellow target compound 12 through the steps a-d, wherein the total yield of the four steps is 60 percentThe purity is 97.4%.1HNMR(400MHz,DMSO-d6)δ13.09(br s,1H),10.40(s,1H),8.28(s,1H),8.01-7.96(m,4H),7.48(d,J＝3.6Hz,1H),7.44(d,J＝3.6Hz,1H),7.15(s,2H),3.71(s,6H),3.59(s,3H)ppm.13C NMR(100MHz,DMSO-d6)δ167.1,160.8,157.8,157.1,153.0,148.8,135.6,135.0,134.5,132.8,131.6,130.6,125.2,117.0,112.2,102.4,98.9,60.6,56.2ppm.LCMS m/z:449.2[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (4-acetylaminophenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (13)
Figure BDA0001291209750000101
The light yellow target compound 13 is synthesized through the steps a-d, the total yield of the four steps is 59 percent, and the purity is 97.9 percent.1HNMR(400MHz,DMSO-d6)δ13.0(br s,1H),10.29(s,1H),9.99(s,1H),8.10(s,1H),8.04-7.96(m,5H),7.44(d,J＝3.6Hz,2H),7.31(d,J＝7.6Hz,1H),7.26(d,J＝7.6Hz,1H),7.18(t,J＝7.6Hz,1H),1.98(s,3H)ppm.13C NMR(100MHz,DMSO-d6)δ168.9,167.2,160.9,157.1,148.9,140.1,139.1,135.7,132.8,131.6,130.6,129.2,125.2,125.0,117.0,115.9,115.5,112.2,111.9,102.5,24.5ppm.LCMS m/z:416.1[M+H]+.
Synthesis of the compound (E) -2-cyano-N- (4-methyl-carbamoylphenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (14)
Figure BDA0001291209750000102
The light yellow target compound 14 was synthesized by the above steps a-d in 53% overall yield and 97.1% purity over four steps.1HNMR(400MHz,DMSO-d6)δ13.13(br s,1H),10.60(s,1H),8.42(d,J＝3.6Hz,1H),8.26(s,1H),8.08-8.02(m,4H),7.86(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.53(d,J＝2.0Hz,2H),2.78(d,J＝3.6Hz,3H)ppm.13C NMR(100MHz,DMSO-d6)δ167.2,166.5,161.2,157.3,148.8,141.3,136.0,132.8,131.6,130.6,130.4,128.3,125.4,125.2,120.2,116.9,112.3,102.2,26.7ppm.LCMS m/z:416.1[M+H]+.
The compound (E) -2-cyano-N- (3-carboxy-phenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide
(15) Synthesis of (2)
Figure BDA0001291209750000103
The light yellow target compound 15 is synthesized through the steps a-d, the total yield of the four steps is 55%, and the purity is 97.5%.1HNMR(400MHz,DMSO-d6)δ13.03(s,2H),10.92(s,1H),8.44(s,1H),8.09-8.04(m,4H),7.94(q,J＝8.8Hz,4H),7.56(d,J＝3.6Hz,1H),7.53(d,J＝3.6Hz,1H)ppm.13C NMR(100MHz,DMSO-d6)δ167.3,167.1,161.5,157.3,148.8,143.1,138.3,136.2,132.7,131.6,130.6,130.5,126.4,125.4,125.3,125.2,120.2,116.9,112.3,102.2ppm.LCMS m/z:401.1[M-H]-.
Synthesis of Compound (E) -2-cyano-N- (3-trifluoromethyl-4-chlorophenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (16)
Figure BDA0001291209750000111
The light yellow target compound 16 is synthesized through the steps a-d, the total yield of the four steps is 51 percent, and the purity is 97.9 percent.1HNMR(400MHz,DMSO-d6)δ13.16(br s,1H),11.02(d,J＝16.8Hz,1H),8.42(d,J＝10.4Hz,1H),8.34(s,1H),8.10(d,J＝8.4Hz,1H),8.03(q,J＝8.4Hz,4H),7.69(d,J＝8.8Hz,1H),7.52(d,J＝1.6Hz,2H)ppm.13C NMR(100MHz,DMSO-d6)δ167.2,161.5,157.5,148.7,138.5,136.4,132.7,132.4,131.7,130.6,127.2,126.9,125.7(d,J＝6.1Hz),125.2,124.5,121.8,119.8(d,J＝5.6Hz),116.7,112.23,101.6ppm.LCMS m/z:461.1[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3-fluoro-4-cyanophenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (17)
Figure BDA0001291209750000112
The light yellow target compound 17 was synthesized by the above steps a-d in a total yield of 59% and a purity of 97.7% over four steps.1HNMR(400MHz,DMSO-d6)δ13.16(br s,1H),11.22(s,1H),8.44(s,1H),8.04-7.97(m,5H),7.89(t,J＝7.6Hz,1H),7.78(d,J＝8.4Hz,1H),7.55(s,2H)ppm.13C NMR(100MHz,DMSO-d6)δ167.1,164.4,162.0,157.7,148.6,145.6(d,J＝11.4HZ),136.74,134.6,132.6,131.7,130.6,126.1,125.3,117.0,116.7,114.7,112.4,107.7,107.4,101.5ppm.LCMS m/z:402.1[M+H]+.
Synthesis of Compound (E) -2-cyano-N- (3-trifluoromethyl-4-cyanophenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide (18)
Figure BDA0001291209750000113
The light yellow target compound 18 is synthesized through the steps a-d, the total yield of the four steps is 53%, and the purity is 97.2%.1HNMR(400MHz,DMSO-d6)δ13.21(br s,1H),11.08(s,1H),8.38(s,1H),8.30(s,1H),8.23(d,J＝8.0Hz,1H),8.14(d,J＝8.4Hz,1H),8.09-8.02(m,5H),7.58-7.55(m,2H)ppm.13C NMR(100MHz,DMSO-d6)δ167.1,161.9,157.8,148.6,143.7,136.9,136.8,132.6,131.8,130.6,126.3,125.3,124.3,123.7,118.3,116.6,116.2,112.5,112.2,102.9,101.2ppm.LCMS m/z:452.1[M+H]+.
The compound (E) -2-cyano-N- (3, 5-dichlorophenyl) -3- (5- (4-carboxyphenyl) furan-2-yl) acrylamide
(19) Synthesis of (2)
Figure BDA0001291209750000121
The light yellow target compound 19 was synthesized by the above steps a-d in a total yield of 54% and a purity of 97.0% over four steps.1HNMR(400MHz,DMSO-d6)δ13.16(br s,1H),10.56(s,1H),8.18(s,1H),8.05(q,J＝7.6Hz,4H),7.80(d,J＝1.6Hz,2H),7.55(q,J＝4.0Hz,2H),7.34(t,J＝1.6Hz,1H)ppm.13C NMR(100MHz,DMSO-d6)δ167.2,161.3,157.6,148.7,141.2,136.4,134.4,132.7,131.7,130.6,125.8,125.2,123.9,119.1,116.6,112.3,101.5ppm.LCMS m/z:427.0[M+H]+.
The beneficial effects of the present invention are demonstrated by specific activity tests below.
The invention also provides the 2-cyano-3-phenyl furan-acrylamide derivative, the salt or the hydrate thereof as an inhibitor of SIRT5 protein. The specific test method for the inhibitory activity of the compound of the invention on the SIRT5 protein in vitro is as follows:
1) experimental materials:
nicotinamide (product No. 72340) purchased from Sigma-Aldrich; trypsin (product number: T8003) from Sigma-Aldrich; nicotinamide adenine dinucleotide (product number: N7004) available from Sigma-Aldrich Co; a 96-well black transparent-bottom ELISA plate (No. 3603) of Corning company; the SIRT buffer solution is: 50mM Tris,137mM NaCl,2.7mM KCl, pH8.0; the SIRT termination reaction solution is Trysin (5U/. mu.L) and nicotinamide (8 mM/L); sirtuin 5, Sirtuin 2 and Sirtuin 6 proteins were obtained by purification in the laboratory of the inventors; the SIRT enzyme substrate and the tested compound are obtained by synthesis.
2) The experimental method comprises the following steps:
firstly, SIRT5 is cloned, expressed and purified by PCR amplification of a human-derived SIRT5 gene (34-269) and cloning into a PET28 vector having a His tag and a TEV protease cleavage site at the N-terminus, protein is expressed in E.coli (DE3), shaken overnight at 16 ℃, and when OD600 reaches 0.6-0.8, a final concentration of 0.3mM isopropyl β -D-1-thiogalactopyranoside (IPTG) is added to induce overexpression, centrifuged and resuspended in lysis buffer (20mM Tris-HCl, 250mM NaCl, pH8.0), then lysed with an ultra-high pressure homogenizer, and centrifuged at 15,000r/min for 30 minutes to remove cell debris, the supernatant is applied to a Ni-NTA column (Roche), washed extensively with 20mL 10mM imidazole, 20mM Tris-pHHCl 8.0,250mM NaCl to remove non-specifically bound protein, finally purified with 250mM imidazole, 20mM NaCl-pH5-8.0,250 mM NaCl, purified with a protein exchange spectrometer (SIRT-250 mM NaCl, 10mM NaCl, 80, 250mM NaCl, 250mM protein, 80 mM NaCl, 80 mM protein, 250mM protein, 80.
Then, the activity test procedure: add 6. mu.L of Nicotinamide Adenine Dinucleotide (NAD) to each test well+2mM/L), 36. mu.L of SIRT buffer solution, and 6. mu.l of diluted SIRT substrate (100. mu.M/L). Then, all test compounds and positive control compounds nicotinamide were dissolved in 100% DMSO to prepare 10mM/L solution, which was diluted to 3.6mM/L, 1.2mM/L, 400. mu.M/L, and three times diluted compound working solution with 10% DMSO-containing SIRT buffer solution. Then, taking 6 mu l of the prepared compound solution, and adding the compound solution into different test holes; mu.L of Sirtuin 5 protein (2. mu.M/L) was added to each test well, and the reaction was carried out at 37 ℃ for 2 hours. Next, 50. mu.l of SIRT stop reaction solution was added to each well and incubated at 37 ℃ for 30 min. Finally, the fluorescence intensity of the above reaction solution was measured at an excitation wavelength of 390nM and an emission wavelength of 460nM using a BioTek staining 3 microplate reader. Compound concentrations from 600. mu.M to 0.03. mu.M 3-fold dilution for IC determination503 parallel groups were set for each concentration. The inhibition rate was calculated using the following formula:
Figure BDA0001291209750000131
wherein FacFluorescence intensity of reaction System containing test Compound, FaAs fluorescence intensity without test compound, FcThe fluorescence intensity of the test compound itself, F0Fluorescence intensity without SIRT protein. IC was obtained using Graphpad Prism software (La Jolla, Calif.)50/pIC50/s.e.pIC50The value is obtained.
Then, NAD+Determination procedure for substrate competition assay: to investigate the inhibitory mechanism of 17 on SIRT5, different concentrations of SuBKA or NAD were tested+Influence on the inhibitory effect. NAD at different concentrations+IC was measured under the conditions of (800. mu.M, 400. mu.M, 200. mu.M, 100. mu.M and 50. mu.M), SIRT5 (0.2. mu.M), SuBKA (200. mu.M) and 17 (600. mu.M-0.03. mu.M), respectively50The value is obtained. At different concentrations of SuBKA (300. mu.M, 100. mu.M, 33. mu.M and 11. mu.M), with SIRT5 (0.2. mu.M), NAD + (20. mu.M)0 μ M) and 17(600 μ M to 0.03 μ M) were used for the determination of IC50The value is obtained.
Finally, selective test procedure for SIRT2 and SIRT 6: to test 17 for selectivity to sirtuin proteins of the same type, SIRT2 and SIRT6 were tested. The substrates benzyl-acetyl-AMC (AcBKA) and benzyl-tetradecanoyl-AMC (MyBKA) were used for SIRT2 and SIRT6 activity assays, respectively. SIRT2 protein (0.5. mu.M) was mixed with AcBKA (0.2. mu.M), NAD + (200. mu.M) or/and compounds (600. mu.M-0.03. mu.M) at different concentrations. The SIRT6 protein (0.5. mu.M) was mixed with MyBKA (0.2. mu.M), NAD + (200. mu.M) or/and compounds (600. mu.M-0.03. mu.M) at different concentrations. The activity test method of SIRT2 and SIRT6 is similar to the SIRT 5.
3) The experimental results are as follows:
by the above experimental methods, the half-maximal effective Inhibitory Concentration (IC) of the compounds of the present invention against SIRT5 was tested50) See table 1 and fig. 1.
TABLE 1 inhibitory Activity of test Compounds on SIRT5
Figure BDA0001291209750000141
Figure BDA0001291209750000151
As can be seen from Table 1, the compounds of the invention have better inhibitory activity to SIRT5, wherein the inhibitory activity of compound 17 is the best, and is significantly better than that of some SIRT5 small-molecule inhibitors such as nicotinamide reported at present. Further on compound 17 at different concentrations of NAD+And the activity of the SIRT5 inhibitor under the substrate is tested, and the compound 17 is a substrate competitive SIRT5 inhibitor and not NAD+A competitive SIRT5 inhibitor.

Claims (8)

1. A substituted 2-cyano-3-phenylfuran-acrylamide derivative characterized by: the structural formula is shown in formula I:
Figure DEST_PATH_IMAGE001
Ⅰ
wherein A is
Figure DEST_PATH_IMAGE002
；
B is
Figure DEST_PATH_IMAGE003
；
And the compounds of the formula I are not
Figure DEST_PATH_IMAGE004
。
2. A substituted 2-cyano-3-phenylfuran-acrylamide derivative characterized by: the structural formula of the derivative is shown as a formula I-1:
Figure 665051DEST_PATH_IMAGE001
I-1
formula I-1 is selected from the following compounds:
Figure DEST_PATH_IMAGE005
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE007
。
3. a substituted 2-cyano-3-phenylfuran-acrylamide derivative characterized by: the structural formula of the derivative is shown as a formula I-2:
Figure 237983DEST_PATH_IMAGE001
I-2
formula I-2 is the following compound:
Figure DEST_PATH_IMAGE008
。
4. a process for the preparation of a derivative according to any one of claims 1 to 3, comprising the following process scheme:
Figure 220983DEST_PATH_IMAGE009
。
5. a process for the preparation of a derivative according to any one of claims 1 to 3, comprising the following process scheme:
Figure DEST_PATH_IMAGE011
a. synthesis of Compound 22
Dissolving cyanoacetic acid with dichloromethane, adding phosphorus pentachloride in ice-water bath, reacting at 40 deg.C for half an hour, cooling to room temperature, adding corresponding substituted aniline, slowly heating to 40 deg.C, reacting for 2 hr, stopping reaction, concentrating solvent under reduced pressure, adding water, directly filtering after solid appears, sequentially filtering with saturated NaHCO3Washing the solution with anhydrous ether to obtain a compound 22;
b. synthesis of Compound 25
Mixing different substituted iodobenzene, compound 23 and Na2CO3And Pd (PPh)3)2Cl2With MeCN/H2Dissolving a mixed solvent with O =1: 1; differently substituted iodobenzenes, compound 23, Na2CO3And Pd (PPh)3)2Cl2The equivalent ratio of (A) to (B) is: 1: 1.5: 2.0: 0.1; after dissolving, replacing nitrogen, moving to 60 ℃ for reaction, monitoring whether the reaction is complete or not by TLC (thin layer chromatography), filtering after the reaction is complete, concentrating the filtrate under reduced pressure, and separating by column chromatography to obtain a compound 25;
c. condensation reaction of Compounds 22 and 25
Mixing compound 22 and compound 25 in an equivalent ratio: 1: 1; dissolving with EtOH, adding a catalytic amount of piperidine, heating to 80 ℃ for reaction, reacting completely after 2h, filtering the solid, and separating a filter cake by column chromatography to obtain a condensation product.
6. Use of a substituted 2-cyano-3-phenylfuran-acrylamide derivative as claimed in any one of claims 1-3 in the preparation of a SIRT5 protein inhibitor.
7. An SIRT5 protein inhibitor, characterized in that: the substituted 2-cyano-3-phenyl furan-acrylamide derivative or the pharmaceutically acceptable salt thereof as an active ingredient is added with pharmaceutically commonly used auxiliary ingredients to prepare a pharmaceutically commonly used preparation.
8. The SIRT5 protein inhibitor of claim 7, which is characterized by: the preparation is oral preparation and injection preparation.
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