WO2011089995A1 - Dérivé de l'acide hydroxamique et inhibiteur de hdac8 l'utilisant - Google Patents

Dérivé de l'acide hydroxamique et inhibiteur de hdac8 l'utilisant Download PDF

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WO2011089995A1
WO2011089995A1 PCT/JP2011/050647 JP2011050647W WO2011089995A1 WO 2011089995 A1 WO2011089995 A1 WO 2011089995A1 JP 2011050647 W JP2011050647 W JP 2011050647W WO 2011089995 A1 WO2011089995 A1 WO 2011089995A1
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直樹 宮田
孝禎 鈴木
庸介 太田
龍三 上田
真介 飯田
政樹 李
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公立大学法人名古屋市立大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms

Definitions

  • the present invention relates to a hydroxamic acid derivative capable of selectively inhibiting the function of HDAC8 and an HDAC8 inhibitor using the same.
  • Histones are proteins that fold DNA in eukaryotes to form a chromatin structure, and are chemically modified by the action of various enzymes, which are thought to change the chromatin structure and control gene expression. . In recent years, various knowledge about such epigenetic gene regulation has been discovered.
  • Histone Deacetylase catalyzes the reaction of deacetylating lysine residues of acetylated histones and controls the expression of many genes.
  • HDAC Histone Deacetylase
  • HDAC has 11 known isoforms from HDAC1 to HDAC11. According to recent research, inhibition of HDAC8 can suppress the growth of blood cancer cells and induce differentiation of neuroblastoma.
  • Non-Patent Document 1 Non-Patent Document 2.
  • HDAC8 affects the living body. Therefore, if a substance that inhibits the catalytic action of HDAC8 (ie, an HDAC8 inhibitor) is found, it can be used as a bioprobe for investigating the function of HDAC8 or used as a new type of anticancer agent. I can expect.
  • Examples of compounds that inhibit HDAC8 reported so far include SAHA (Non-patent Document 3), PCI-34051 (Non-patent Document 1), and the like.
  • the present invention has been made in view of the above-described conventional circumstances, and it is a problem to be solved to provide a compound capable of inhibiting the function of HDAC8 and an HDAC8 inhibitor capable of inhibiting the function of HDAC8. Yes.
  • the present inventors comprehensively searched for compounds having HDAC8 inhibitory activity using 1,3-dipolar cycloaddition reaction (Huisgen reaction, also known as Click reaction) between azide and alkyne. That is, based on the crystal structure analysis of HDAC8, a plurality of types of alkyne compounds having a hydroxamic acid structure capable of coordinating with zinc, which is the center of enzyme activity, and a plurality of types of azide compounds that will fit in the sub-pocket of HDAC8 Were cyclized by the above click reaction to synthesize various compounds, and their inhibitory activity against HDAC8 was examined. As a result, the present inventors have found a compound that can solve the above problems and have completed the present invention.
  • 1,3-dipolar cycloaddition reaction Huisgen reaction, also known as Click reaction
  • the hydroxamic acid derivative of the present invention has the following general formula (1) (wherein X represents an aromatic substituent or a 3- to 8-membered ring which may have a substituent, and n is an integer of 0 to 20). Or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
  • the aromatic substituent means a benzene ring, a polycyclic aromatic ring such as a naphthyl ring, and a heterocyclic ring, and may have a substituent.
  • the 3- to 8-membered ring which may have a substituent may be a cycloalkane ring or a bridged carbocyclic ring such as an adamantane ring.
  • a benzene ring and a cycloalkane ring are preferable.
  • a hydroxamic acid group bonded to the meta position of the benzene ring is particularly preferred because of its excellent selectivity for inhibiting HDAC8.
  • the hydroxamic acid derivative (1) can inhibit the enzyme activity of HDAC8. Therefore, it can be suitably used as a biological tool for examining the function of HDAC8. It also has cancer cell growth inhibitory action and is expected to be used as an anticancer agent.
  • the prodrug means a compound that is hydrolyzed in vivo to regenerate the hydroxamic acid derivative (1).
  • n is preferably an integer of 1 to 5. More preferably, n is an integer of 1 to 3.
  • X in the hydroxamic acid derivative (1) of the present invention is any one of a phenyl group, a p-methoxybenzyl group, a naphthyl group, a cyclopentyl group, a cyclohexyl group, a thiophene group, a phenylsulfanyl group, a phenylsulfinyl group, and a phenylsulfonyl group. It is preferable that More preferred are hydroxamic acid derivatives represented by the following structural formulas (2) to (7). According to the test results of the present inventors, this compound has particularly high HDAC8 inhibitory activity and excellent selectivity. Examples of the substituent bonded to X include CH 3 , OCH 3 , Cl, F, CF 3 , NO 2 and the like, but preferably no substituent.
  • FIG. 3 is a graph showing the results of HDAC8 fluorescence assay of SAHA, PCI-34051, Examples 1 to 24 and Comparative Examples 1 to 30.
  • 3 is a graph showing the results of HDAC8 fluorescence assay of SAHA, PCI-34051 and Comparative Examples 31 to 90.
  • 3 is a graph showing the results of HDACs fluorescence assays of SAHA, PCI-34051, Examples 1 to 24 and Comparative Examples 1 to 30.
  • 3 is a graph showing the results of HDACs fluorescence assays of SAHA, PCI-34051 and Comparative Examples 31-90.
  • FIG. 6 is a graph showing the results of the HDAC8 fluorescence assay of SAHA, PCI-34051, Example 2 and Examples 25 to 55.
  • FIG. 6 is a graph showing the results of HDACs fluorescence assays of SAHA, PCI-34051, Example 2 and Examples 25 to 55.
  • FIG. 6 is a graph showing the results of HDACs fluorescence assays of SAHA, PCI-34051, Example 2 and Examples 25 to 55.
  • the present inventors proceeded rapidly under mild conditions, and a 1,3-dipolar cycloaddition reaction between azide and alkyne catalyzed by Cu (I) (Huisgen reaction, also known as click reaction)
  • the compounds having HDAC8 inhibitory activity were exhaustively searched using the following specific examples). Since this click reaction does not produce a by-product, there is an advantage that no purification operation is required.
  • the molecular design using the click reaction was performed based on the following policy. That is, the alkyne compound serving as one substrate of the click reaction was selected from alkyne compounds having a hydroxamic acid structure capable of coordinating with zinc, which is the center of enzyme activity, based on the crystal structure analysis of HDAC8.
  • the azide compound as the other substrate of the click reaction was selected from azide compounds that would fit in the HDAC8 subpocket. Specifically, one of a plurality of alkyne compounds represented by the following structural formula and one of a plurality of azide compounds are cyclized by click reaction to synthesize various hydroxamic acid derivatives and inhibit HDAC8. The activity was examined.
  • Alkyne Compound (A-mP-1) and Alkyne Compound (A-mP-2) The alkyne compound (A-mP-1) and alkyne compound (A-mP-2) were synthesized according to the synthesis route of Chemical Formula 6 below. did. Details are described below.
  • Step 2 Synthesis of 3-[(trimethylsilyl) ethynyl] benzoic acid methyl ester (105) 3-Iodobenzoic acid methyl ester (104) (3.04 g) obtained in Step 1 was dissolved in THF (24 mL). PdCl2 (PPh3) 2 (244 mg), CuI (133 mg), triethylamine (6 mL), and trimethylsilylacetylene (1.37 g) were added, and the mixture was stirred at room temperature for 26 hours under an argon atmosphere. The reaction mixture was filtered and the filtrate was concentrated.
  • Step 3 Synthesis of 3-ethynylbenzoic acid (106) 3-[(Trimethylsilyl) ethynyl] benzoic acid methyl ester (105) (2.42 g) obtained in Step 2 was dissolved in methanol (30 mL) and ice-cooled. 2N Aqueous sodium hydroxide solution (10.4 mL) was added, and the mixture was stirred at room temperature for 7 hr. The reaction solution was acidified with 2N hydrochloric acid (pH 3-4) and concentrated under reduced pressure. Water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL).
  • Step 4 Synthesis of 3-ethynyl-N- (2-tetrahydropyranyloxy) benzamide (107) 3-ethynylbenzoic acid (106) (669 mg), EDCI (1.49 g), HOBt ⁇ H 2 O (1.19 g) and NH 2 OTHP (1.07 g) were dissolved in DMF (10 mL) and stirred at room temperature for 31 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step of synthesizing N- (2-aminophenyl) 3-ethynylbenzamide (A-mP-2) 1 Synthesis of N- (2-aminophenyl) 3-ethynylbenzamide (A-mP-2) 3-Ethynylbenzoic acid (106) (526 mg), EDCI (1.52 g) and HOBt ⁇ H 2 O (1.21 g) obtained in Step 3 in the synthesis of 2-N-hydroxybenzamide (A-mP-1) o-Phenylenediamine (3.89 g) and were dissolved in DMF (10 mL) and stirred at room temperature for 32 hours.
  • Step 2 Synthesis of 4-[(trimethylsilyl) ethynyl] benzoic acid methyl ester (110)
  • the compound (109) (2.03 g) obtained in Step 1 above was dissolved in THF (16 mL), and PdCl 2 (PPh 3 ) 2 (267 mg), CuI (145 mg), triethylamine (4 mL), and trimethylsilylacetylene (1.49 g) were added, and the mixture was stirred at 80 ° C. for 18 hours in an argon atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 Synthesis of 4-ethynylbenzoic acid (111)
  • Compound (109) (1.89 g) was treated in the same manner as in the synthesis of compound (105) to give compound (110) (1.10 g, 92% yield).
  • compound (110) (1.10 g, 92% yield).
  • ) was obtained as a brown solid.
  • Step 4 Synthesis of 4-ethynyl-N- (2-tetrahydropyranyloxy) benzamide (112)
  • Compound (112) was synthesized. That is, using 4-ethynylbenzoic acid (111)) (524 mg) instead of 3-ethynylbenzoic acid (106), compound (112) (759 mg, 86% yield) was obtained as a brown solid. . 1 H-NMR data of the obtained compound (112) are shown below.
  • Step 5 Synthesis of 4-ethynyl-N-hydroxybenzamide (A-pP-1) Instead of 3-ethynyl-N- (2-tetrahydropyranyloxy) benzamide (107), 4-ethynyl-N- (2-tetrahydropyranyloxy) benzamide (112) (759 mg) was used. A-pP-1) (128 mg, 26% yield) was obtained as a brown solid. Melting point data, 1 H-NMR data, 13 C-NMR data and MS (EI) data of the obtained compound (A-pP-1) are shown below.
  • Step 2 Synthesis of 5-trimethylsilanylethynylthiophene-2-carboxylic acid methyl ester (115) 5-bromo-2-thiophenecarboxylic acid methyl ester (114) (1.03 g) obtained by the above method was converted to diethylamine ( 16 mL), PdCl 2 (PPh 3 ) 2 (32.7 mg), CuI (13.3 mg) and trimethylsilylacetylene (687 mg) were added, and the mixture was stirred at room temperature for 18 hours under an argon atmosphere.
  • Step 3 Synthesis of 5-ethynylthiophene-2-carboxylic acid (116) 5-Trimethylsilanylethynylthiophene-2-carboxylic acid methyl ester (115) (895 mg) obtained in Step 2 was used as described above. In the same manner as in Step 3 in the synthesis of compound (A-mp-1), 5-ethynylthiophene-2-carboxylic acid (116) (224 mg, yield 90%) was obtained as a white solid.
  • Step 4 Synthesis of 5-ethynylthiophene-2-carboxylic acid (2-tetrahydropyranoxy) amide (117) Using 5-ethynylthiophene-2-carboxylic acid (116) (150 mg), compound (117) (224 mg, (90% yield) was obtained as a white solid. 1 H-NMR data of the obtained compound (117) are shown below.
  • Step 5 Synthesis of 5-ethynylthiophene-2-carboxylic acid hydroxamide (AS-1)
  • AS-1 Compound (117) was synthesized by the same synthesis method as in Step 5 in the synthesis of compound (A-mp-1). That is, instead of 3-ethynyl-N- (2-tetrahydropyranyloxy) benzamide (117), 5-ethynylthiophene-2-carboxylic acid (2-tetrahydropyranoxy) synthesized in the above (Step 5-4) was used.
  • Compound (AS-1) 52 mg, 35% yield
  • Synthesis step of azidomethylcyclopentane (B-6) 1 Synthesis of cyclopentylmethyltosylate (120a) Cyclopentanemethanol (119a) (500 mg) was dissolved in pyridine (5 mL), and TsCl (1.43 g) was added and the reaction was stirred at room temperature for 36 hours. The solvent was concentrated under reduced pressure, ethyl acetate (50 mL) was added to the residue, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate.
  • Step 2 Synthesis of Azidomethylcyclopentane (B-6) To the cyclopentylmethyltosylate (120a) (1.13 g) obtained in Step 1 above, 0.5M sodium azide DMSO solution (26.6 mL) was added, and The mixture was stirred at 80 ° C. for 5 hours. Water (50 mL) was added under ice cooling, and the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give azidomethylcyclopentane (B-6) (147 mg, yield).
  • Synthesis step of 1-azidomethyladamantane (B-8) 1 Synthesis of 1-adamantylmethyltosylate (120b) Compound (1) 120b) was synthesized. That is, 1-adamantane methanol (119b) (320 mg) was used in place of cyclopentanemethanol (119a) to obtain compound (120b) (519 mg, 84% yield) as a white solid. 1 H NMR data of the obtained compound (120b) are shown below.
  • Step 2 Synthesis of 1-azidomethyladamantane (B-8) Compound (B-8) was synthesized by the same synthesis method as in Step 2 in the synthesis of azidomethylcyclopentane (B-6). That is, 1-adamantylmethyl tosylate (120b) (435 mg) was used in place of cyclopentylmethyl tosylate (120a) to obtain compound (B-8) (519 mg, 84% yield) as a colorless oil.
  • the 1 H NMR data, 13 C NMR data, and HRMS (EI) data of the obtained compound (B-8) are shown below.
  • the compound (B-4-p) was synthesized according to the synthesis route of the following chemical formula 11. Details are described below.
  • Step 2 Synthesis of 4-phenoxybenzyl azide (B-4-p) Under an argon atmosphere, 4-phenoxyphenylmethanol (122) (300 mg) and DPPA (495 mg) obtained in Step 1 above were combined with anhydrous DMF ( 2.7 mL). DBU (274 mg) was added under ice cooling, and the mixture was stirred for 2 hours and further stirred at room temperature for 24 hours. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (30 mL). The organic layer was washed with 2N aqueous hydrochloric acid (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • ⁇ Activity test ⁇ (Inhibitory activity test of HDACs and HDAC8) The hydroxamic acid derivatives of Examples 1 to 24 and Comparative Examples 1 to 90 synthesized as described above were directly tested for HDAC inhibition without isolation and purification. Measurement of HDACs and HDAC8 inhibitory activity was performed as follows using an HDAC fluorescence assay kit manufactured by Cyclex.
  • one-step assay buffer buffer containing substrate and lysyl endopeptidase (LEP) or HDAC8-reaction buffer buffer was added to all well plates and incubated at room temperature for 1 hour. Incubated with Finally, trichostatin A (TSA) or (10 ⁇ AStop solution) was added to stop the reaction, and the fluorescence intensity was measured with a plate reader.
  • TSA trichostatin A
  • 10 ⁇ AStop solution 10 ⁇ AStop solution
  • FIG.2 and FIG.3 The result of a HDAC8 inhibitory activity test is shown in FIG.2 and FIG.3. As shown in FIGS. 2 and 3, Examples 1 to 24 showed inhibitory activity against HDAC8, and Examples 1 and 2 were comparable to PCI-34051. Moreover, the inhibitory activity with respect to HDAC8 of Example 1 was considerably higher than SAHA. In addition, the inhibitory activity against HDAC8 in Example 2 was very high compared to SAHA and PCI-34051.
  • Example 1 to 24 had weak inhibitory activity against HDACs.
  • Example 1 and Example 2 were considerably lower than SAHA and comparable to PCI-34051.
  • Examples 1 to 12 had high inhibitory activity against HDAC8, the inhibitory activity against HDACs was weak, and an excellent selective inhibitory action against HDAC8 was observed.
  • L of Cu (I) -L is tris [(1-benzyl-1H-1,2,3-triazolyl-), which is a reaction promoting ligand for click reaction without adding a substrate.
  • the result of the blank test which added only 4-yl) methyl] amine (TBTA) is shown. 2 to 5, it can be seen that Cu (I) and TBTA have little influence on the deacetylation reaction by HDAC.
  • Example 1 3-Ethynyl-N-hydroxybenzamide (A-mP-1) (43.2 mg), benzyl azide (51.8 mg) and TBTA (14.2 mg) were mixed with methanol (5 In addition, copper (II) sulfate pentahydrate (6.69 mg) and sodium ascorbate (26.5 mg) dissolved in water (5 mL) were added, and the mixture was stirred at room temperature for 24 hours. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate (50 mL), and the organic layer was washed with water (50 mL) and concentrated under reduced pressure.
  • Example 2 (2-azidoethyl) benzene (108) (895 mg), benzyl azide (51.8 mg) and TBTA (14.2 mg) were dissolved in methanol (5 mL), and water was added. Copper (II) sulfate pentahydrate (6.69 mg) and sodium ascorbate (26.5 mg) dissolved in (5 mL) were added, and the mixture was stirred at room temperature for 24 hours. Then, it refine
  • HDAC1, HDAC2, HDAC4, HDAC6 and HDAC8 HDAC1, HDAC2, HDAC4, HDAC6 inhibitory activity was measured from BIOMOL SIRT1, HDAC1 fluorescence assay kit, BPS HDAC class2 ⁇ fluorescence assay kit and BIOMOL The following was performed using HDAC2 and HDAC6. 10 ⁇ L of 5-fold inhibitor (final concentration 100 to 0.01 ⁇ M), 15 ⁇ L of HDAC1 (or HDAC2, HDAC4, HDAC6: final concentration) and 25 ⁇ l of 2-fold substrate were mixed and reacted at room temperature or 37 ° C. for 30 minutes.
  • HDAC8 or HDACs diluted 5-10 times, 5-10 ⁇ L of 5-10 times inhibitor solution (final concentration 100-0.01 ⁇ M), 35 ⁇ L of HDAC8 reaction buffer solution or 30 ⁇ L of one-step assay buffer solution Mixed and allowed to react for 1 hour at room temperature.
  • the reaction solution was added to double the stop solution 50 ⁇ L or 5 times the trichostatin A 12 [mu] L, fluorescence intensity using a fluorescence plate reader (fluorescence measurement wavelength: 460 nm) was measured, IC 50 values (enzyme 50 % Inhibitory inhibitor concentration) was calculated.
  • the HDACs used in this inhibition activity test were derived from Hela cells. For comparison, SAHA and PCI-34051 were similarly tested for inhibitory activity of HDACs, HDAC1, HDAC2, HDAC4, HDAC6 and HDAC8.
  • the HDAC8 inhibitory activity of the hydroxamic acid derivatives of Example 1 and Example 2 was higher than the HDAC8 inhibitory activity of SAHA and was similar to that of PCl-34051.
  • the hydroxamic acid derivatives of Example 1 and Example 2 all had a lower inhibitory activity than SAHA.
  • the hydroxamic acid derivative of Example 2 showed an activity as low as that of PCI-34051 with respect to the inhibitory activity of HDAC1 and HDAC4 as compared to PCI-34051.
  • Example 1 The hydroxamic acid derivatives of Example 1 and Example 2 were further subjected to hematopoietic tumor cell growth inhibitory activity test (MTS method).
  • MTS method hematopoietic tumor cell growth inhibitory activity test
  • Cultivation Cultivation was performed for 72 hours in a 37 ° C., 5% CO 2 environment, and then 20 ⁇ l of MTS solution was distributed to each well, followed by further culturing for 2 hours.
  • Example 7 The results are shown in Table 7 below. From this table, the hydroxamic acid derivatives of Examples 1 and 2 have a growth inhibitory effect similar to that of PCI-34051 against hematopoietic tumor cell lines Jurkat, MOLT4F, Hut78, MT2 and MT4, It was found that the hematopoietic tumor cell line HH has a higher inhibitory activity than PCI-34051. From the above results, the hydroxamic acid derivatives of Example 1 and Example 2 can be expected to be used not only as HDAC8 inhibitors but also as anticancer agents.
  • T-ALL T-cell lymphoblastic leukemia, CTCL; primary cutaneous T-cell lymphoma ATLL; adult T-cell leukemia / lymphoma
  • Example 2 As described above, the compound of Example 2 (C17) exhibited an excellent selective inhibitory action against HDAC8. Therefore, in order to find a compound having an excellent selective inhibitory action on HDAC8, various derivatives shown below were synthesized using compound (C17) of Example 2 as a lead compound (see Chemical Formula 12), and the HDAC8 The selective inhibitory action on the activity of selenium was investigated.
  • this alkyne compound and various azide compounds shown in the following chemical formula 13 were synthesized, and a click reaction between these compounds and the alkyne compound (A-mP-1) was carried out. Similar to the compound (C17) of Example 2 The compound was synthesized. Details are as follows.
  • Azide Compound (B-9-1) and Azide Compound (B-10) were synthesized according to the synthesis route of Chemical Formula 15 below. State.
  • Azide Compound (B-9-2) and Azide Compound (B-11 to 17) were synthesized according to the synthesis route of Chemical Formula 16 below. The details will be described below.
  • Table 8 shows the structural formulas of the compounds of Examples 25 to 55 thus synthesized by click reaction on the well plate.
  • ⁇ Activity test ⁇ (Inhibitory activity test of HDACs and HDAC8) The hydroxamic acid derivatives of Examples 25 to 55 synthesized as described above were directly tested for HDAC inhibition without isolation and purification. Measurement of HDACs and HDAC8 inhibitory activity was performed using the HDAC fluorescence assay kit of Cyclex.
  • Measurement of HDACs and HDAC8 inhibitory activity was performed by the same method as the measurement of HDACs and HDAC8 inhibitory activity for the hydroxamic acid derivatives of Examples 1 to 24 and Comparative Examples 1 to 90 described above.
  • FIG. 7 The result of the inhibitory activity test with respect to HDACs is shown in FIG. As shown in FIG. 7, the hydroxamic acid derivatives of Examples 25 to 55 had little inhibitory activity against HDACs, similar to the hydroxamic acid derivative of Example 2 used as the lead compound. As described above, although the hydroxamic acid derivatives of Examples 25 to 55 have high inhibitory activity against HDAC8, they have weak inhibitory activity against HDACs, and an excellent selective inhibitory action against HDAC8 was observed.
  • L of Cu (I) -L represents tris [(1-benzyl-1H-1,2,3-triazolyl) which is a reaction promoting ligand for click reaction without adding a substrate.
  • the result of a blank test in which only -4-yl) methyl] amine (TBTA) was added is shown, and it was confirmed that Cu (I) and TBTA have little influence on the deacetylation reaction by HDAC. .
  • hydroxamic acid derivatives of Examples 1 to 55 from among hydroxamic acid derivatives of Examples 1 to 55, derivatives having a hydroxamic acid group bonded to the meta position (ie, Examples 1 to 12 and Examples 25 to 25) 55) was found to have a more prominent inhibitory effect on HDAC8 than HDACs. Furthermore, the hydroxamic acid derivatives of Examples 25-55 were found to inhibit HDAC8 function particularly selectively. Among them, it was found that the hydroxamic acid derivatives of Example 46 and Example 53 exhibited a particularly excellent selective inhibitory action against HDAC8 as shown in Table 9.
  • Example 46 ⁇ Scale-up synthesis of hydroxamic acid derivatives of Example 46 (C142), Example 53 (C149), Example 56 (C152) and Example 57 (C153)>
  • the hydroxamic acid derivatives of Example 46 and Example 53 were further scaled up, synthesized, isolated and purified.
  • the hydroxamic acid derivative of Example 56 in which Example 53 was oxidized to form a sulfinyl compound as a control since the sulfide bond of the hydroxamic acid derivative of Example 53 was easily oxidized to a sulfinyl compound or a sulfonyl compound, the hydroxamic acid derivative of Example 56 in which Example 53 was oxidized to form a sulfinyl compound as a control.
  • the hydroxamic acid derivative of Example 57 in which Example 53 was further oxidized to a sulfonyl compound was synthesized (Chemical Formula 19).
  • Example 46 Synthesis of Hydroxamic Acid Derivative of Example 46
  • the hydroxamic acid derivative of Example 46 was synthesized according to the following synthesis route of Chemical Formula 20. Details are described below.
  • Example 53 Synthesis of Hydroxamic Acid Derivatives of Example 53, Example 56, and Example 57
  • the hydroxamic acid derivatives of Example 53, Example 56, and Example 57 were synthesized according to the following synthesis route of Chemical Formula 21. Details are described below.
  • Example 53 (C149) Synthesis of (N-hydroxy-3- (1-phenylsulfanylmethyl-1H- [1,2,3] triazol-4-yl) -benzamide) 3- (2-Azidoethyl) thiophene as described above Using azidophenyl methyl sulfide (B-18) (106 mg) in place of (B-11), crude crystals (165 mg, 94%) were obtained in the same manner as in Example 46 (C142). Got. The crude crystals were recrystallized from MeOH to give the title compound (80.3 mg) as a white solid. Melting point data, 1 H NMR data, 13 C NMR data, and MS (FAB) data are shown below.
  • Example 56 (3- (1-Benzenesulfinylmethyl-1H- [1,2,3] triazol-4-yl) -N-hydroxybenzamide) Synthesis Step 1: Preparation of azidomethanesulfinylbenzene (206) Synthesis Azidophenyl methyl sulfide (B-18) (144 mg) synthesized above was dissolved in dichloromethane (5 mL), and mCPBA (214 mg) suspended in dichloromethane (5 mL) was added under ice-cooling. Stir for minutes. A saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL).
  • Step 2 Synthesis of 3- (1-benzenesulfinylmethyl-1H- [1,2,3] triazol-4-yl) -N-hydroxybenzamide (Example 56, C152) 3- (2-Azidoethyl) thiophene ( In place of B-11), azidomethanesulfinylbenzene (206) (89.2 mg) obtained in Step 56 of Example 56 described above was used, and a method similar to that for isolation and purification of Example 46 (C142) was used. Crude crystals (98.3 mg, 70%) were obtained. The crude crystals were recrystallized from MeOH to give the title compound (43.7 mg) as a white solid.
  • Example 57 (C153) (3- (1-Benzenesulfonylmethyl-1H- [1,2,3] triazol-4-yl) -N-hydroxybenzamide) Synthesis Step 1: Azidomethanesulfonylbenzene (207) The title compound (175 mg, yield 97%) was obtained as a white solid in the same manner as in Example 56, Step 1 using 2 equivalents of synthetic mCPBA. 1 H NMR data, 13 C NMR data, FTIR data and MS (EI) data are shown below.
  • Step 2 Synthesis of 3- (1-benzenesulfonylmethyl-1H- [1,2,3] triazo-4-yl) -N-hydroxybenzamide (Example 57, C153) 3- (2-Azidoethyl) thiophene ( B-11) was used in place of the azidomethanesulfonylbenzene (207) (172 mg) obtained in Step 1 of Example 56, and crude crystals were obtained in the same manner as in Example 46 (C142). (114 mg, 54%) was obtained. The crude crystals were recrystallized from MeOH to give the title compound (84.5 mg) as a white solid. Melting point data, 1 H NMR data, 13 C NMR data, and MS (FAB) data are shown below.
  • hydroxamic acid derivative and HDAC8 inhibitor of the present invention are expected to be used as a biological tool for examining the function of HDAC8 or as an anticancer agent.

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Abstract

La présente invention a pour objet : un composé qui est capable d'inhiber la fonction de HDAC8 ; et un inhibiteur de HDAC8. La présente invention concerne spécifiquement un dérivé de l'acide hydroxamique qui est caractérisé en ce qu'il est composé d'un composé représenté par la formule générale (1) (dans laquelle X représente un substituant aromatique ou un cycle de 3 à 8 chaînons facultativement substitué, et n représente un nombre entier de 0 à 20), ou son sel, hydrate, solvate ou promédicament pharmaceutiquement acceptable.
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JP2016514159A (ja) * 2013-03-14 2016-05-19 クオンティセル ファーマシューティカルズ，インク． ヒストンデメチラーゼ阻害剤
US9809588B2 (en) 2014-07-03 2017-11-07 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10087149B2 (en) 2013-01-24 2018-10-02 Trustees Of Boston University Selective histone deacetylase 8 inhibitors
US10125128B2 (en) 2015-06-30 2018-11-13 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10150753B2 (en) 2015-12-22 2018-12-11 Board Of Regents, The University Of Texas System Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyrdin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide
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CN117263936A (zh) * 2023-11-21 2023-12-22 中国中医科学院医学实验中心 一种咪唑并[1, 2-a]吡啶衍生物及其制备方法和在中枢神经系统渗透性HDAC6抑制药物中的应用

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JP2013170164A (ja) * 2012-02-23 2013-09-02 Nagoya City Univ 新規アミド化合物及びその用途
US10087149B2 (en) 2013-01-24 2018-10-02 Trustees Of Boston University Selective histone deacetylase 8 inhibitors
JP2016514159A (ja) * 2013-03-14 2016-05-19 クオンティセル ファーマシューティカルズ，インク． ヒストンデメチラーゼ阻害剤
US11370786B2 (en) 2014-07-03 2022-06-28 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US9809588B2 (en) 2014-07-03 2017-11-07 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10344025B2 (en) 2014-07-03 2019-07-09 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US11958849B2 (en) 2014-07-03 2024-04-16 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10766892B2 (en) 2014-07-03 2020-09-08 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10125128B2 (en) 2015-06-30 2018-11-13 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US11713313B2 (en) 2015-06-30 2023-08-01 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10738043B2 (en) 2015-06-30 2020-08-11 Board Of Regents, The University Of Texas System GLS1 inhibitors for treating disease
US10150753B2 (en) 2015-12-22 2018-12-11 Board Of Regents, The University Of Texas System Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyrdin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide
US10899740B2 (en) 2015-12-22 2021-01-26 Board Of Regents, The University Of Texas System Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide
US11603365B2 (en) 2015-12-22 2023-03-14 Board Of Regents, The University Of Texas System Salt forms and polymorphs of (r)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-n-methyl-1H-1,2,3-triazole-4-carboxamide
US11045443B2 (en) 2017-10-18 2021-06-29 Board Of Regents, The University Of Texas System Glutaminase inhibitor therapy
US10722487B2 (en) 2017-10-18 2020-07-28 Board Of Regents, The University Of Texas System Glutaminase inhibitor therapy
US11786500B2 (en) 2017-10-18 2023-10-17 Board Of Regents, The University Of Texas System Glutaminase inhibitor therapy
WO2019235501A1 (fr) * 2018-06-06 2019-12-12 塩野義製薬株式会社 Inhibiteur d'histone désacétylase
CN112920130A (zh) * 2021-02-01 2021-06-08 河北康泰药业有限公司 一种三氮唑的化合物、制备方法以及其在制备防治癌症药物中的应用
CN117263936A (zh) * 2023-11-21 2023-12-22 中国中医科学院医学实验中心 一种咪唑并[1, 2-a]吡啶衍生物及其制备方法和在中枢神经系统渗透性HDAC6抑制药物中的应用
CN117263936B (zh) * 2023-11-21 2024-02-23 中国中医科学院医学实验中心 一种咪唑并[1, 2-a]吡啶衍生物及其制备方法和在中枢神经系统渗透性HDAC6抑制药物中的应用

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