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CN111848454A - Histone deacetylase 6 inhibitor and preparation method and application thereof - Google Patents

Histone deacetylase 6 inhibitor and preparation method and application thereof Download PDF

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CN111848454A
CN111848454A CN201910347227.6A CN201910347227A CN111848454A CN 111848454 A CN111848454 A CN 111848454A CN 201910347227 A CN201910347227 A CN 201910347227A CN 111848454 A CN111848454 A CN 111848454A
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张颖杰
徐文方
高倩文
赵春龙
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Abstract

The invention discloses a histone deacetylase 6 inhibitor, and a preparation method and application thereof. The histone deacetylase 6 inhibitor has a structure shown in the following general formula (I). The invention also provides a preparation method of the compound and application of the compound in preparing a medicament for preventing or treating diseases related to abnormal activity or expression of HDAC 6.

Description

Histone deacetylase 6 inhibitor and preparation method and application thereof
Technical Field
The invention relates to a histone deacetylase 6(HDAC6) inhibitor, and a preparation method and application thereof, and belongs to the technical field of organic compound synthesis and medical application.
Background
Unlike other Histone Deacetylase (HDAC) members, HDAC6 is a histone deacetylase (CD1 and CD2) containing only two catalytic domains, distributed mainly in the cytoplasm rather than the nucleus, and has no significant role in the post-translational modification of histones, but is mainly involved in regulating the acetylation status of non-histones such as α -tubulin (α -tubulin), cortical actin (cortictin), heat shock protein 90(HSP-90) and peroxiredoxins I/II (peroxiredoxins I/II). An increasing number of studies have shown that HDAC6 is a potential therapeutic target for tumors, autoimmune diseases and neurodegenerative diseases (Kalin, j.h.etc. j.med.chem.2013,56, 6297-. In the field of tumor therapy, two reversible inhibitors of HDAC6 (ACY-1215 and ACY-241) have entered clinical research (Rodrigues, D.A.etc. Mini.Rev.Med.chem.2016,16, 1175-1184). However, the selectivity of HDAC6 of the two compounds is not high, and is only about 10 times higher than that of HDAC1/2/3 (Rodrigues, d.a.etc. mini.rev.med.chem.2016,16,1175-1184), so that the toxic and side effects caused by inhibiting other HDAC subtypes cannot be completely avoided.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a histone deacetylase 6(HDAC6) inhibitor, and a preparation method and application thereof.
The technical scheme of the invention is as follows:
inhibitors of histone deacetylase 6(HDAC6)
A histone deacetylase 6(HDAC6) inhibitor having the following structural formula (I), a pharmaceutically acceptable salt, solvate or prodrug thereof:
Figure BDA0002042759220000011
wherein: x is a side chain of various amino acids;
y is
Figure BDA0002042759220000012
Z is
Figure BDA0002042759220000021
R is aliphatic hydrocarbon, aromatic hydrocarbon or hydrogen;
is in the S or R configuration, or a racemate thereof.
Preferred according to the invention, wherein:
x is
Figure BDA0002042759220000022
Y is
Figure BDA0002042759220000023
Z is in para-or meta-position of the benzene ring
Figure BDA0002042759220000024
R is
Figure BDA0002042759220000025
Or H;
is in the S configuration;
further preferably, the compound is one of the following:
Figure BDA0002042759220000026
Figure BDA0002042759220000031
Figure BDA0002042759220000041
Figure BDA0002042759220000051
Figure BDA0002042759220000061
II, preparation method of histone deacetylase 6(HDAC6) inhibitor
The preparation method of the histone deacetylase 6(HDAC6) inhibitor comprises the following steps:
carrying out methyl esterification reaction on an initial raw material L-amino acid 1a-1c in methanol to obtain an intermediate 2a-2c, condensing a Boc-L-amino acid 3a-3c with cyclopentanol, then removing a protecting group to obtain an intermediate 4a-4c, carrying out condensation reaction and oxidation reaction on p-hydroxymethylbenzoic acid or m-hydroxymethylbenzoic acid and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine to obtain a key intermediate 7a-7b, then carrying out reductive amination reaction on the key intermediate and the intermediate 2a-2c,4a-4c, and then removing the protecting group from HCl/EtOAc to obtain a hydroxamic acid target compound 8 a-8L; p-hydroxymethylbenzoic acid or m-hydroxymethylbenzoic acid is taken as a raw material, a key intermediate 9a-9b is obtained through a condensation reaction, (Boc)2O protection and an oxidation reaction with O-phenylenediamine, then the key intermediate and the intermediate 2a-2c,4a-4c are subjected to a reductive amination reaction, then a protective group is removed through HCl/EtOAc to obtain a target compound 10a-10l of the O-phenylenediamine, and a hydrolysis reaction is carried out on the compound 10d-10f to obtain a compound 11a-11 c;
The synthetic route is as follows:
Figure BDA0002042759220000071
reagents and reaction conditions in the above synthetic route: a) thionyl chloride, methanol; b) cyclopentanol, (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, dichloromethane; HCl/EtOAC; c) the method comprises the following steps O- (tetrahydro-2H-pyran-2-yl) hydroxylamine or O-phenylenediamine, (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, triethylamine, dichloromethane; d): manganese dioxide, dichloromethane; e) the method comprises the following steps Di-tert-butyl dicarbonate, triethylamine and dichloromethane; f) the method comprises the following steps Compound 2a-2c or 4a-4c, triethylamine, sodium cyanoborohydride, glacial acetic acid and methanol/tetrahydrofuran with the volume ratio of 1: 1; HCl/EtOAC; g) lithium hydroxide and methanol/water in a volume ratio of 1: 1.
According to a preferred embodiment of the present invention, the preparation of histone deacetylase 6(HDAC6) inhibitor compounds 8a-8l, 10a-10l, 11a-11c, exemplified by compounds 8a,10a,11a, respectively, comprises the following steps:
(1) preparation of intermediate 2a methyl (S) -2-amino-2-phenylacetate hydrochloride
Dissolving 10mmol of L-phenylglycine (1a) in 50mL of anhydrous methanol at 0 ℃, dropwise adding 40mmol of thionyl chloride, after the addition is completed, stirring the solution at 0 ℃ for 0.5 hour, then heating at 75 ℃ for 6 hours, removing the solvent when the completion of the reaction is confirmed by TLC, recrystallizing the residue with ethyl acetate, filtering, and drying to obtain compound 2 a;
Compounds 2b-2c were prepared in analogy to Compound 2 a;
(2) intermediate 4a preparation of cyclopentyl (S) -2-amino-2-phenylacetate hydrochloride
To a solution of Boc-L-phenylglycine 2.0mmol (3a) dissolved in 20mL of anhydrous dichloromethane at 0 deg.C was added 2.4mmol EDCI, 2.4mmol HOBT and 2.4mmol triethylamine; after the addition was complete, the mixture was stirred at 0 ℃ for 0.5 h, then 2.4mmol cyclopentanol was added, then the solution was warmed to 25 ℃ and stirred for 12 h, the solvent was removed and the residue was diluted with ethyl acetate and washed twice with 1M citric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in that order; the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow oil; to the resulting yellow oil was added HCl/EtOAc 5mL and stirred at 25 ℃ for 4 hours, the product precipitated, filtered and dried in vacuo to give compound (4 a);
compounds 4b-4c were prepared in a similar manner to Compound 4 a;
(3) preparation of intermediate 6a 4- (hydroxymethyl) -N- ((tetrahydro-2H-pyran-2-yl) oxy) benzamide
After 5.0mmol of compound 5a (and 6.0mmol of EDCI were dissolved in 50mL of dichloromethane at 25 deg.C, 5.0mmol of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine was added at 0 deg.C, the mixture was stirred at 25 deg.C, and when the reaction was complete, the solvent was removed under vacuum, the resulting residue was diluted with ethyl acetate, washed twice with saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and dried under vacuum to give compound 6 a;
Compound 6b was prepared in analogy to compound 6 a;
(4) intermediate 6c preparation of N- (2-aminophenyl) -4- (hydroxymethyl) benzamide
10mmol of compound 5a are dissolved in 80mL of dichloromethane at 25 ℃ and 12mmol of EDCI and 12mmol of triethylamine are added; the mixture was stirred at 0 ℃ for 0.5 h, then 12mmol of o-phenylenediamine was added to the solution and stirred at 25 ℃ for 15 h; filtering the crude product, and recrystallizing with ethyl acetate to obtain a compound 6 c;
compound 6d was prepared similarly to compound 6 c;
(5) preparation of intermediate 7a 4-formyl-N- ((tetrahydro-2H-pyran-2-yl) oxy) benzamide
3.98mmol of compound 6a are dissolved in 40mL of dichloromethane at 25 ℃ and 59.69mmol of manganese dioxide are slowly added; after the addition was complete, the mixture was stirred for a further 6 hours, after the reaction was complete, the mixture was filtered through celite, concentrated and concentrated by passing PE/EA ═ 1: 1, purifying by column chromatography to obtain a compound 7 a;
compounds 7b,9a-9b were prepared in analogy to Compound 7 a;
(6) preparation of intermediate 7c tert-butyl (2- (4- (hydroxymethyl) benzoylamino) phenyl) carbamate
Dissolving 2.9mmol of compound 6c and 3.5mmol of triethylamine in 10mL of dichloromethane at 0 ℃, dissolving 3.5mmol of BOC anhydride in 10mL of tetrahydrofuran and adding dropwise to dichloromethane, after the addition, stirring the mixture at 25 ℃ for 12 hours, then removing the solvent under reduced pressure, diluting the residue with ethyl acetate, and washing with water, 1M citric acid and saturated aqueous sodium chloride solution in sequence; drying the organic layer over anhydrous magnesium sulfate, filtering, concentrating and purifying by column chromatography to give compound 7 c;
Compound 7d was prepared similarly to compound 7 c;
(7) preparation of Compound 8a cyclopentyl (S) -2- ((4- (hydroxycarbamoyl) benzyl) amino) -2-phenylacetate hydrochloride
At 25 ℃, 0.86mmol of compound 7a and 1.0mmol of compound 4a are added to 20mL of a solution of 1: 1 in a tetrahydrofuran/methanol mixed solvent, then adding 1.0mmol of triethylamine, stirring the mixture at 50 ℃ for 0.5 hour, then adding 1.72mmol of sodium cyanoborohydride and one drop of glacial acetic acid, stirring the solution at 25 ℃ for 6 hours, after the reaction is finished, removing the solvent and diluting the residue with ethyl acetate, and washing the residue twice with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in turn; the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography to give a colorless oil; to the resulting oil was added 4mL HCl/EtOAc and stirred at 25 ℃ for 6 h, the product precipitated and was filtered and dried to give a light red solid as the hydrochloride salt;
compounds 8b-8l were prepared in analogy to Compound 8 a;
(8) preparation of Compound 10a cyclopentyl (S) -2- ((4- ((2-aminophenyl) carbamoyl) benzyl) amino) -2-phenylacetate hydrochloride
At 25 ℃, 0.44mmol of compound 9a and 0.53mmol of compound 4a are added to 20mL of a solution of 1: 1 in tetrahydrofuran/methanol mixed solvent, then 0.53mmol of triethylamine is added, the mixture is stirred at 50 ℃ for 0.5 hour, then 1.1mmol of sodium cyanoborohydride and one drop of glacial acetic acid are added, the solution is stirred at 25 ℃ for 6 hours, after the reaction is finished, the solvent is removed and the residue is diluted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in sequence, the organic layer is dried with anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography to obtain colorless oil, 4mL of HCl/EtOAc is added to the obtained oil and stirred at 25 ℃ for 6 hours, the product is precipitated and filtered, and dried to obtain light red solid as hydrochloride;
Compounds 10b-10l were prepared in analogy to Compound 10 a;
(9) preparation of compound 11a (S) -2- ((4- ((2-aminophenyl) carbamoyl) benzyl) amino) -2-phenylacetic acid
At 25 ℃, dissolving 0.32mmol of compound 8e in 10mL of methanol/water mixed solvent with the volume ratio of 1:1, adding 3.2mmol of lithium hydroxide, refluxing at 65 ℃ for 1 hour after the addition is finished, concentrating the reaction solution after the reaction is finished, adjusting the pH to 6 by using 1M hydrochloric acid, filtering, and drying in vacuum to obtain an off-white solid;
compounds 11b-11c were prepared in a similar manner to compound 11 a.
The above steps can be optimized by those skilled in the art to improve the yield, and they can make synthetic routes according to the basic knowledge in the art, such as selecting reactants, solvents and temperature, and can improve the yield by using various protecting groups to avoid side reactions. These conventional protection methods can be found in t.greene, Protecting Groups in organic Synthesis.
Application of histone deacetylase 6(HDAC6) inhibitor
The invention also provides an application of the histone deacetylase 6(HDAC6) inhibitor in preparing a medicament for preventing or treating diseases related to abnormal activity or expression of HDAC 6;
the diseases related to the abnormal activity or expression of the HDAC6 are various tumors, autoimmune diseases and neurodegenerative diseases.
The tumors comprise melanoma, multiple myeloma and the like, the autoimmune diseases comprise rheumatoid arthritis, inflammation and the like, and the neurodegenerative diseases comprise Alzheimer disease, Parkinson syndrome and the like.
In addition, the invention also includes a pharmaceutical composition suitable for oral or parenteral administration, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention and one or more pharmaceutically acceptable carriers or excipients.
The invention has the beneficial effects that:
the compound has a novel structure, shows a strong HDAC6 inhibition effect, has antiproliferative activity on U266, can remarkably enhance the antiproliferative activity of Bortezomib on U266 cells by combining with a marketed proteasome inhibitor Bortezomib, and shows a strong chemosensitization effect, so that the compound can be used for preparing a medicament for preventing or treating diseases related to abnormal expression or activity of HDAC 6.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
Example 1 preparation of Compounds 8a-8l, exemplified by Compound 8a
The specific synthetic method and steps are as follows:
(1) preparation of intermediate 2a methyl (S) -2-amino-2-phenylacetate hydrochloride
L-phenylglycine (1a, 1.51g, 1.0eq, 10mmol) was dissolved in 50mL of anhydrous methanol at 0 deg.C, sulfoxide chloride (2.9mL, 4.0eq, 40mmol) was added dropwise, and after the addition was complete, the solution was stirred at 0 deg.C for 0.5 h, and then heated at 75 deg.C for 6 h. When the reaction was complete as determined by TLC, the solvent was removed, the residue was recrystallized from ethyl acetate, filtered, and dried to give compound 2a as a white solid (1.71g, 86% yield).1H NMR(400MHz,DMSO-d6)9.32–9.08(m,3H),7.56–7.50(m,2H),7.49-7.43(m,3H),5.26(s,1H),3.71(s,3H).
Compounds 2b-2c were prepared in analogy to Compound 2 a.
(2) Intermediate 4a preparation of cyclopentyl (S) -2-amino-2-phenylacetate hydrochloride
To a solution of Boc-L-phenylglycine (3a, 0.50g, 1.0eq, 2.0mmol) dissolved in 20mL of anhydrous dichloromethane at 0 deg.C were added EDCI (0.48g, 1.2eq, 2.4mmol), HOBT (0.33g, 1.2eq, 2.4mmol) and triethylamine (0.24g, 1.2eq, 2.4 mmol). After the addition was complete, the mixture was stirred at 0 ℃ for 0.5 h, then cyclopentanol (0.21g, 1.2eq, 2.4mmol) was added. The solution was then warmed to 25 ℃ and stirred for an additional 12 hours. The solvent was removed and the residue was diluted with ethyl acetate and washed twice with 1M citric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in that order. Use the organic layer Dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow oil. To the resulting yellow oil was added HCl/EtOAc (5mL) and stirred at 25 ℃ for 4 h. The product was precipitated, filtered and dried in vacuo to give compound (4a) as a white solid (0.28g, 55% yield).1H NMR(400MHz，DMSO-d6)8.94(s，3H)，7.49-7.46(m，5H)，5.26-5.15(m，2H)，1.90-1.30(m，8H)。
Compounds 4b-4c were prepared in a similar manner to compound 4 a.
(3) Preparation of intermediate 6a 4- (hydroxymethyl) -N- ((tetrahydro-2H-pyran-2-yl) oxy) benzamide
Compound 5a (0.75g, 1.0eq, 5.0mmol) and EDCI (1.15g, 1.2eq, 6.0mmol) were dissolved in dichloromethane (50mL) at 25 deg.C, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.59g, 1.0eq, 5.0mmol) was added at 0 deg.C, and the mixture was stirred at 25 deg.C. When the reaction was deemed complete, the solvent was removed under vacuum and the resulting residue was diluted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo to give compound 6a as a colorless oil (1.0g, 80% yield).1H NMR(400MHz，DMSO-d6)11.61(s，1H)，7.73(d，J＝8.0Hz，2H)，7.40(d，J＝8.0Hz，2H)，5.33(t，J＝5.8Hz)，1H)，4.99(t，J＝3.0Hz，1H)，4.55(d，J＝5.6Hz，2H)，4.09-4.03(m，1H)，3.55-3.51(m，1H)，1.75-1.70(m，3H)，1.60-1.51(m，3H)。
Compound 6b was prepared in analogy to compound 6 a.
(4) Preparation of intermediate 7a 4-formyl-N- ((tetrahydro-2H-pyran-2-yl) oxy) benzamide
Compound 6a (1.0g, 1.0eq, 3.98mmol) was dissolved in dichloromethane (40mL) at 25 deg.C and manganese dioxide (5.2g, 15.0eq, 59.69mmol) was added slowly. After the addition was complete, the mixture was stirred for an additional 6 hours. After the reaction was complete, the mixture was filtered through celite, concentrated and purified by column chromatography (PE/EA ═ 1: 1) to give compound 7a as a colorless oil (0.66g, 67% yield). 1H NMR(400MHz，DMSO-d6)11.88(s，1H)，10.08(s，1H)，8.01(d，J＝8.1Hz，2H)，7.96(d，J＝8.1Hz，2H)，5.04(t，J＝3.2Hz，1H)，4.10-4.02(m，1H)，3.57-3.52(m，1H)，1.81-1.68(m，3H)，1.64-1.50(m，3H)。
Compound 7b was prepared in analogy to compound 7 a.
(5) Preparation of Compound 8a cyclopentyl (S) -2- ((4- (hydroxycarbamoyl) benzyl) amino) -2-phenylacetate hydrochloride
Compound 7a (0.22g, 1.0eq, 0.86mmol) and Compound 4a (0.25g, 1.2eq, 1.0mmol) were added to 20mL of a tetrahydrofuran/methanol (1: 1) mixed solvent at 25 deg.C, then triethylamine (0.1g, 1.2eq, 1.0mmol) was added, the mixture was stirred at 50 deg.C for 0.5 hour, then sodium cyanoborohydride (0.11g, 2.0eq, 1.72mmol) and one drop of glacial acetic acid were added, and the solution was stirred at 25 deg.C for 6 hours. After the reaction was completed, the solvent was removed and the residue was diluted with ethyl acetate and washed twice with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography to give a colorless oil. To the resulting oil was added HCl/EtOAc (4mL) and stirred at 25 ℃ for 6 h, the product precipitated and was filtered off and dried to give a pale red solid as the hydrochloride salt (0.15g, 54% yield).1H NMR(400MHz,DMSO-d6)11.33(s,1H),10.54(s,1H),10.31(s,1H),9.10(s,1H),7.79(d,J＝8.0Hz,2H),7.57(d,J＝7.4Hz,4H),7.53–7.46(m,3H),5.24(s,1H),5.15(t,J＝5.8Hz,1H),4.17(d,J＝13.0Hz,1H),4.04–3.94(m,1H),1.85-1.78(m,1H),1.76-1.63(m,2H),1.61–1.34(m,5H).13C NMR(101MHz,DMSO-d6)167.58,164.14,133.57,133.46,130.42,129.98,129.63,129.34,128.97,127.55,79.84,62.67,49.48,32.27,23.56,23.45.HRMS(AP-ESI)m/z calcd for C21H24N2O4[M+H]+369.1814,found 369.1810.
Compounds 8b-8l were prepared in analogy to Compound 8 a.
Example 2 preparation of Compounds 10a-10l, exemplified by Compound 10a
The specific synthetic method and steps are as follows:
(1) intermediate 6c preparation of N- (2-aminophenyl) -4- (hydroxymethyl) benzamide
Compound 5a (1.52g, 1.0eq, 10mmol) was dissolved in 80mL of dichloromethane at 25 deg.C, followed by the addition of EDCI (2.30g, 1.2eq,12mmol) and triethylamine (1.21g, 1.2eq,12 mmol). The mixture was stirred at 0 ℃ for 0.5 h, then o-phenylenediamine (1.3g, 1.2eq,12mmol) was added to the solution and stirred at 25 ℃ for 15 h. The crude product was filtered and recrystallized from ethyl acetate to give compound 6c as a pale yellow solid (0.76g, 31% yield).1H NMR(400MHz,DMSO-d6)9.63(s,1H),7.95(d,J＝7.9Hz,2H),7.44(d,J＝7.9Hz,2H),7.17(d,J＝7.8Hz,1H),6.97(td,J＝7.6,1.5Hz,1H),6.78(dd,J＝8.0,1.4Hz,1H),6.60(td,J＝7.6,1.4Hz,1H),5.33(t,J＝5.7Hz,1H),4.89(s,2H),4.58(d,J＝5.6Hz,2H).
Compound 6d was prepared in analogy to compound 6 c.
(2) Preparation of intermediate 7c tert-butyl (2- (4- (hydroxymethyl) benzoylamino) phenyl) carbamate
Compound 6c (0.70g, 1.0eq, 2.9mmol) and triethylamine (0.36g, 1.2eq, 3.5mmol) were dissolved in 10mL of dichloromethane at 0 ℃, the BOC anhydride (0.76g, 1.2eq, 3.5mmol) was dissolved in 10mL of tetrahydrofuran and added dropwise to dichloromethane, after which the mixture was stirred at 25 ℃ for 12 hours, then the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate and washed with water, 1M citric acid and saturated aqueous sodium chloride solution in that order. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography to give compound 7c as a colorless oil (0.85g, 86% yield). 1H NMR(400MHz,DMSO-d6)9.81(s,1H),8.70(s,1H),7.92(d,J＝8.0Hz,2H),7.56(dd,J＝7.7,1.8Hz,1H),7.52(dd,J＝7.9,1.6Hz,1H),7.47(d,J＝7.9Hz,2H),7.22-7.13(m,2H),5.36(t,J＝5.7Hz,1H),4.59(d,J＝5.5Hz,2H),1.45(s,9H).
Compound 7d was prepared in analogy to compound 7 c.
(3) Intermediate 9a preparation of tert-butyl (2- (4-formylbenzoylamino) phenyl) carbamate
Compounds 9a-9b were prepared in analogy to compound 7 a.
9a, white solid (0.20g, 70% yield).1H NMR(400MHz,DMSO-d6)10.13(s,1H),10.00(s,1H),8.73(s,1H),8.15(d,J＝8.0Hz,2H),8.07(d,J＝8.0Hz,2H),7.59–7.51(m,2H),7.22(td,J＝7.7,1.7Hz,1H),7.16(td,J＝7.6,1.6Hz,1H),1.44(s,9H).
(4) Preparation of Compound 10a cyclopentyl (S) -2- ((4- ((2-aminophenyl) carbamoyl) benzyl) amino) -2-phenylacetate hydrochloride
Compound 9a (0.15g, 1.0eq, 0.44mmol) and compound 4a (0.14g, 1.2eq, 0.53mmol) were added to 20mL of a tetrahydrofuran/methanol (1: 1) mixed solvent at 25 deg.C, then triethylamine (0.05g, 1.2eq, 0.53mmol) was added, the mixture was stirred at 50 deg.C for 0.5 hour, then sodium cyanoborohydride (0.07g, 2.5eq, 1.1mmol) and a drop of glacial acetic acid were added, and the solution was stirred at 25 deg.C for 6 hours. After the reaction was completed, the solvent was removed and the residue was diluted with ethyl acetate and washed twice with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography to give a colorless oil. To the resulting oil was added HCl/EtOAc (4mL) and stirred at 25 ℃ for 6 h, the product precipitated and was filtered off and dried to give a pale red solid as the hydrochloride salt (0.12g, 53% yield). 1H NMR(400MHz,DMSO-d6)10.57(s,1H),8.16(d,J＝8.0Hz,2H),7.66(d,J＝8.0Hz,2H),7.60-7.57(m,3H),7.53-7.51(m,3H),7.47–7.41(m,1H),7.35-7.29(m,,2H),5.27(s,1H),5.19-5.15(m,1H),4.23(d,J＝13.2Hz,1H),4.04(d,J＝13.6Hz,1H),1.89–1.29(m,8H).13C NMR(101MHz,DMSO-d6)167.52,165.56,135.52,134.60,131.56,130.95,130.81,130.47,129.66,129.43,128.66,127.75,126.96,124.09,79.86,62.64,49.06,32.27,23.58,23.47.HRMS(AP-ESI)m/z calcd for C27H29N3O3[M+H]+444.2287,found 444.2285.
Compounds 10b-10l were prepared in analogy to compound 10 a.
Example 3 preparation of Compounds 11a-11c, exemplified by Compound 11a
Preparation of compound 11a (S) -2- ((4- ((2-aminophenyl) carbamoyl) benzyl) amino) -2-phenylacetic acid
Compound 10d (0.15g,1.0eq,0.32mmol) was dissolved in 10mL of methanol/water (1:1) mixed solvent at 25 ℃, lithium hydroxide (0.14g,10eq,3.2mmol) was added, after the addition was completed, reflux was carried out at 65 ℃ for 1 hour, after the reaction was completed, the reaction solution was concentrated, pH was adjusted to 6 with 1M hydrochloric acid, filtered, and dried under vacuum to give an off-white solid (85mg, 71% yield).1H NMR(400MHz,DMSO-d6)9.67(s,1H),7.96(d,J＝7.9Hz,2H),7.47(d,J＝8.0Hz,2H),7.44–7.30(m,5H),7.17(d,J＝7.8Hz,1H),7.00-6.96(m,1H),6.79(dd,J＝8.1,1.4Hz,1H),6.65–6.57(m,1H),4.97(s,2H),4.22(s,1H),3.82(d,J＝3.1Hz,2H).
Compounds 11b-11c were prepared in a similar manner to compound 11 a.
Example 4 evaluation of in vitro HDAC inhibitory Activity of target Compounds
We have measured the inhibitory activity of HDAC6 and HeLa nuclear extracts (mainly containing HDAC1 and HDAC2) of the target compounds using fluorescence analysis, using the approved non-selective HDAC inhibitor SAHA on the market as a positive control.
The experimental results (table 1) show that the compounds 8a-8f of the present invention exhibit strong inhibition of HDAC6, wherein 8a-8d have superior inhibitory activity on HDAC6 than the non-selective HDAC inhibitor SAHA. More importantly, 8a-8f, 8g, 8i and 8l have excellent HDAC6 selectivity compared to SAHA.
TABLE 1 results of evaluation of HDAC inhibitory Activity in vitro
Figure BDA0002042759220000141
Figure BDA0002042759220000151
Figure BDA0002042759220000161
Figure BDA0002042759220000171
aND:Not determined
Example 5 in vitro anti-proliferation assay of human multiple myeloma U266 cells with a Compound of interest
Tumor cells with a certain density are inoculated on a 96-well plate, after the cells are cultured in a cell culture box for 12 hours, test drugs with different concentrations are added, the cells are continuously cultured for 48 hours, 20 mu L of MTT is added into each well, after the cells are incubated for 4 hours, culture solution in the wells is carefully discarded, formazan formed by dissolving DMSO is added, and the absorbance is measured by a microplate reader, so that the cell antiproliferative activity of the test drugs is measured.
From the results in Table 2, it can be seen that compounds 8a-8f all have antiproliferative activity on U266, and although 8a-8f have weaker antiproliferative activity on U266 than the non-selective HDAC inhibitor SAHA, the antiproliferative activity of compounds 8a-8c,8f on U266 is better than that of the reported selective inhibitor Tubastatin A of HDAC 6.
TABLE 2 in vitro antiproliferation of U266 cells by target Compoundsa
Figure BDA0002042759220000172
Figure BDA0002042759220000181
aValues are expressed as the mean of three independent replicates. The SD value is less than 20% of the average value.
Example 6 in vitro anti-proliferative assay of Compounds 8a-8f in combination with the marketed proteasome inhibitor Bortezomib on human multiple myeloma U266 cells
To further investigate the anti-tumor activity of the compounds of interest, we tested the antiproliferative activity of compounds 8a-8f on U266 cells in combination with the marketed proteasome inhibitor Bortezomib. Cells were pretreated with 5. mu.M of 8a-8f followed by 48h of Bortezomib. The experimental results show (table 3) that compounds 8a-8f all significantly enhanced the antiproliferative activity of Bortezomib on U266 cells. Among them, compounds 8a-8c,8f showed very strong chemosensitization. Compared with Tubastatin A, a reported HDAC6 selective inhibitor, the compounds 8a-8c,8f have stronger Bortezomib sensitization.
TABLE 3 antiproliferative test of combination on U266a
Figure BDA0002042759220000182
aValues are expressed as the mean of three independent replicates. The SD value is less than 20% of the average value.
bIC by administration of Bortezomib alone50Divided by the corresponding combination50To calculate the sensitization factor.

Claims (9)

1. A histone deacetylase 6 inhibitor having the following structural formula (I), a pharmaceutically acceptable salt, solvate or prodrug thereof:
Figure FDA0002042759210000011
wherein: x is a side chain of various amino acids;
y is
Figure FDA0002042759210000012
Z is
Figure FDA0002042759210000013
R is aliphatic hydrocarbon, aromatic hydrocarbon or hydrogen;
is in the S or R configuration, or a racemate thereof.
2. The histone deacetylase 6 inhibitor according to claim 1, wherein:
x is
Figure FDA0002042759210000014
Y is
Figure FDA0002042759210000015
Z is in para-or meta-position of the benzene ring
Figure FDA0002042759210000016
R is
Figure FDA0002042759210000017
Or H;
is in the S configuration.
3. A histone deacetylase 6 inhibitor according to claim 1 or 2, which is one of the following compounds:
Figure FDA0002042759210000021
Figure FDA0002042759210000031
Figure FDA0002042759210000041
Figure FDA0002042759210000051
4. the method for preparing the histone deacetylase 6 inhibitor according to claim 1 or 2, comprising the steps of:
carrying out methyl esterification reaction on an initial raw material L-amino acid 1a-1c in methanol to obtain an intermediate 2a-2c, condensing a Boc-L-amino acid 3a-3c with cyclopentanol, then removing a protecting group to obtain an intermediate 4a-4c, carrying out condensation reaction and oxidation reaction on p-hydroxymethylbenzoic acid or m-hydroxymethylbenzoic acid and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine to obtain a key intermediate 7a-7b, then carrying out reductive amination reaction on the key intermediate and the intermediate 2a-2c,4a-4c, and then removing the protecting group from HCl/EtOAc to obtain a hydroxamic acid target compound 8 a-8L; p-hydroxymethylbenzoic acid or m-hydroxymethylbenzoic acid is taken as a raw material, a key intermediate 9a-9b is obtained through a condensation reaction, (Boc)2O protection and an oxidation reaction with O-phenylenediamine, then the key intermediate and the intermediate 2a-2c,4a-4c are subjected to a reductive amination reaction, then a protective group is removed through HCl/EtOAc to obtain a target compound 10a-10l of the O-phenylenediamine, and a hydrolysis reaction is carried out on the compound 10d-10f to obtain a compound 11a-11 c;
The synthetic route is as follows:
Figure FDA0002042759210000061
reagents and reaction conditions in the above synthetic route: a) thionyl chloride, methanol; b) cyclopentanol, (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, dichloromethane; HCl/EtOAC; c) the method comprises the following steps O- (tetrahydro-2H-pyran-2-yl) hydroxylamine or O-phenylenediamine, (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, triethylamine, dichloromethane; d): manganese dioxide, dichloromethane; e) the method comprises the following steps Di-tert-butyl dicarbonate, triethylamine and dichloromethane; f) the method comprises the following steps Compound 2a-2c or 4a-4c, triethylamine, sodium cyanoborohydride, glacial acetic acid and methanol/tetrahydrofuran with the volume ratio of 1: 1; HCl/EtOAC; g) lithium hydroxide and methanol/water in a volume ratio of 1: 1.
5. The preparation of the histone deacetylase 6 inhibitor compound 8a-8l, 10a-10l, 11a-11c according to claim 3, comprising the following steps:
(1) preparation of intermediate 2a methyl (S) -2-amino-2-phenylacetate hydrochloride
Dissolving 10mmol of L-phenylglycine (1a) in 50mL of anhydrous methanol at 0 ℃, dropwise adding 40mmol of thionyl chloride, after the addition is completed, stirring the solution at 0 ℃ for 0.5 hour, then heating at 75 ℃ for 6 hours, removing the solvent when the completion of the reaction is confirmed by TLC, recrystallizing the residue with ethyl acetate, filtering, and drying to obtain compound 2 a;
Compounds 2b-2c were prepared in analogy to Compound 2 a;
(2) intermediate 4a preparation of cyclopentyl (S) -2-amino-2-phenylacetate hydrochloride
To a solution of Boc-L-phenylglycine 2.0mmol (3a) dissolved in 20mL of anhydrous dichloromethane at 0 deg.C was added 2.4mmol EDCI, 2.4mmol HOBT and 2.4mmol triethylamine; after the addition was complete, the mixture was stirred at 0 ℃ for 0.5 h, then 2.4mmol cyclopentanol was added, then the solution was warmed to 25 ℃ and stirred for 12 h, the solvent was removed and the residue was diluted with ethyl acetate and washed twice with 1M citric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in that order; the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow oil; to the resulting yellow oil was added HCl/EtOAc5mL and stirred at 25 ℃ for 4 h, the product precipitated, filtered and dried in vacuo to give compound (4 a);
compounds 4b-4c were prepared in a similar manner to Compound 4 a;
(3) preparation of intermediate 6a 4- (hydroxymethyl) -N- ((tetrahydro-2H-pyran-2-yl) oxy) benzamide
After 5.0mmol of compound 5a (and 6.0mmol of EDCI were dissolved in 50mL of dichloromethane at 25 deg.C, 5.0mmol of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine was added at 0 deg.C, the mixture was stirred at 25 deg.C, and when the reaction was complete, the solvent was removed under vacuum, the resulting residue was diluted with ethyl acetate, washed twice with saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and dried under vacuum to give compound 6 a;
Compound 6b was prepared in analogy to compound 6 a;
(4) intermediate 6c preparation of N- (2-aminophenyl) -4- (hydroxymethyl) benzamide
10mmol of compound 5a are dissolved in 80mL of dichloromethane at 25 ℃ and 12mmol of EDCI and 12mmol of triethylamine are added; the mixture was stirred at 0 ℃ for 0.5 h, then 12mmol of o-phenylenediamine was added to the solution and stirred at 25 ℃ for 15 h; filtering the crude product, and recrystallizing with ethyl acetate to obtain a compound 6 c;
compound 6d was prepared similarly to compound 6 c;
(5) preparation of intermediate 7a 4-formyl-N- ((tetrahydro-2H-pyran-2-yl) oxy) benzamide
3.98mmol of compound 6a are dissolved in 40mL of dichloromethane at 25 ℃ and 59.69mmol of manganese dioxide are slowly added; after the addition was complete, the mixture was stirred for a further 6 hours, after the reaction was complete, the mixture was filtered through celite, concentrated and concentrated by passing PE/EA ═ 1: 1, purifying by column chromatography to obtain a compound 7 a;
compounds 7b,9a-9b were prepared in analogy to Compound 7 a;
(6) preparation of intermediate 7c tert-butyl (2- (4- (hydroxymethyl) benzoylamino) phenyl) carbamate
Dissolving 2.9mmol of compound 6c and 3.5mmol of triethylamine in 10mL of dichloromethane at 0 ℃, dissolving 3.5mmol of BOC anhydride in 10mL of tetrahydrofuran and adding dropwise to dichloromethane, after the addition, stirring the mixture at 25 ℃ for 12 hours, then removing the solvent under reduced pressure, diluting the residue with ethyl acetate, and washing with water, 1M citric acid and saturated aqueous sodium chloride solution in sequence; drying the organic layer over anhydrous magnesium sulfate, filtering, concentrating and purifying by column chromatography to give compound 7 c;
Compound 7d was prepared similarly to compound 7 c;
(7) preparation of Compound 8a cyclopentyl (S) -2- ((4- (hydroxycarbamoyl) benzyl) amino) -2-phenylacetate hydrochloride
At 25 ℃, 0.86mmol of compound 7a and 1.0mmol of compound 4a are added to 20mL of a solution of 1: 1 in a tetrahydrofuran/methanol mixed solvent, then adding 1.0mmol of triethylamine, stirring the mixture at 50 ℃ for 0.5 hour, then adding 1.72mmol of sodium cyanoborohydride and one drop of glacial acetic acid, stirring the solution at 25 ℃ for 6 hours, after the reaction is finished, removing the solvent and diluting the residue with ethyl acetate, and washing the residue twice with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in turn; the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography to give a colorless oil; to the resulting oil was added 4mL HCl/EtOAc and stirred at 25 ℃ for 6 h, the product precipitated and was filtered and dried to give a light red solid as the hydrochloride salt;
compounds 8b-8l were prepared in analogy to Compound 8 a;
(8) preparation of Compound 10a cyclopentyl (S) -2- ((4- ((2-aminophenyl) carbamoyl) benzyl) amino) -2-phenylacetate hydrochloride
At 25 ℃, 0.44mmol of compound 9a and 0.53mmol of compound 4a are added to 20mL of a solution of 1: 1 in tetrahydrofuran/methanol mixed solvent, then 0.53mmol of triethylamine is added, the mixture is stirred at 50 ℃ for 0.5 hour, then 1.1mmol of sodium cyanoborohydride and one drop of glacial acetic acid are added, the solution is stirred at 25 ℃ for 6 hours, after the reaction is finished, the solvent is removed and the residue is diluted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in sequence, the organic layer is dried with anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography to obtain colorless oil, 4mL of HCl/EtOAc is added to the obtained oil and stirred at 25 ℃ for 6 hours, the product is precipitated and filtered, and dried to obtain light red solid as hydrochloride;
Compounds 10b-10l were prepared in analogy to Compound 10 a;
(9) preparation of compound 11a (S) -2- ((4- ((2-aminophenyl) carbamoyl) benzyl) amino) -2-phenylacetic acid
At 25 ℃, dissolving 0.32mmol of compound 8e in 10mL of methanol/water mixed solvent with the volume ratio of 1:1, adding 3.2mmol of lithium hydroxide, refluxing at 65 ℃ for 1 hour after the addition is finished, concentrating the reaction solution after the reaction is finished, adjusting the pH to 6 by using 1M hydrochloric acid, filtering, and drying in vacuum to obtain an off-white solid;
compounds 11b-11c were prepared in a similar manner to compound 11 a.
6. Use of a histone deacetylase 6 inhibitor according to any one of claims 1 to 3 for the manufacture of a medicament for the prevention or treatment of a disease associated with aberrant HDAC6 activity or expression.
7. The use according to claim 5, wherein the disease associated with aberrant HDAC6 activity or expression is a tumor, an autoimmune disease or a neurodegenerative disease.
8. The use of claim 7, wherein the tumors are melanoma, multiple myeloma; the autoimmune disease is rheumatoid arthritis and inflammation; the neurodegenerative disease is Alzheimer disease and Parkinson syndrome.
9. A pharmaceutical composition suitable for oral or parenteral administration comprising a histone deacetylase 6 inhibitor according to any one of claims 1-3 and one or more pharmaceutically acceptable carriers or excipients.
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