KR101900575B1 - Novel Hydroxamic Acids and Uses Thereof - Google Patents

Abstract

The present invention relates to novel hydroxamic acid based compounds and their use. More particularly, the present invention provides novel hydroxamic acid-based compounds useful as histone deacetylase inhibitors and compositions comprising same, wherein the compounds according to the present invention are useful for the treatment and prevention of cancer It can be used effectively as a medicine.

Description

Novel Hydroxamic Acids and Uses Thereof < RTI ID = 0.0 >

The present invention relates to novel hydroxamic acids and their use.

Histone deacetylases (HDACs) are groups of enzymes that catalyze the removal of acetyl groups from lysine residues in the tail of histone proteins [1-3]. Up to now, 18 different isoforms of HDAC have been identified in eukaryotes [4]. Based on the relative similarity between sequences, these isoforms are classified into four classes. HDAC class I consists of four enzymes including HDAC1, 2, 3 and HDAC8, and HDAC class II consists of six enzymes including HDAC4, 5, 6, 7, 9 and HDAC10. HDAC class III, also known as Sirtuin, has seven enzymes (Sirt1-7). Siruin is an NAD + dependent enzyme. Finally, there is only one enzyme (HDAC11) in HDAC class IV. This isoform is known to have both HDAC2 characteristics of class II and class I [3].

Different HDAC isoforms, particularly isoforms of class I and II, are known to be involved in various cell related processes. For example, HDACs 1, 2, 3 and 8 promote cell proliferation whereas HDACs 1-4, 5 and 8 prevent apoptosis and differentiation. Several other isoforms, including HDACs 4, 6, 7 and 10, have been shown to promote two important processes in cancer cell metastasis, angiogenesis and cell migration [4,5 ]. Inhibition of each HDAC isoform shows effects associated with differentiation, apoptosis and cell cycle arrest in many types of tumor cells. In addition, the selective effect of HDAC inhibition on tumor cell growth has been evident not only in vitro but also in a number of in vivo preclinical models and clinical settings [6,7]. Therefore, inhibition of HDAC has become a very interesting approach in recent cancer treatment methods [8]. Thus, a number of HDAC inhibitors have been reported over the past several years.

The HDAC inhibitors developed so far range from short chain fatty acids such as butyrate, phenylbutyrate or valproic acid to various forms of hydroxamic acid, or benzamide . Of these, vorinostat (Zolinza®) (also known as SAHA or suberoylanilide hydroxamic acid) is the first of its kind approved by the US FDA in October 2006 for the treatment of skin T-cell lymphoma (CTCL) HDAC inhibitors. The second FDA-approved HDAC inhibitor, romidepsin (Istodax®), was approved by the US FDA in 2009. Recently, panobinostat (LBH-589, trade name Farydak®) has been approved by the US FDA in February 2015 for the treatment of multiple myeloma [16] and chidamide (product name: Epidaza® ) Received approval from the FDA of China for relapsed or refractory peripheral T cell lymphoma. In addition, several other HDAC inhibitors, such as PXD-01 (Belinostat) and MS-27-527 (Entinostat), are currently in various stages of clinical trials.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

Nam, N. H .; Parang, K. Current targets for anticancer drugs discovery. Curr. Drugs Targets 2003, 4, 159-179. Witt, O .; Deubzer, H. E .; Milde, T .; Oehme, I. HDAC family: What are cancer relevant targets? Cancer Lett. 2009, 277, 8-21. De Ruijter, A. J. M .; Gennip, A.H.V .; Caron, H. N .; Kemp, S .; Kuilenburg, A.B.P.V. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem. J., 2003, 370, 737-739. Zwergel C, Valente S, Jacob C, Mai A. Emerging approaches forhistonedeacetylaseinhibitor drug discovery. Expert Opin. Drug Discov.2015, 10, 599-613. West, A. C .; Johnstone, R.W. New and emerging HDACinhibitors for cancer treatment. J. Clin. Invest., 2014, 124, 30-39. Hamm, C. A., Costa, F. F. Epinomes as therapeutic targets. Pharmacol Ther., 201, 151, 72-86. Glaser, K.B. HDAC inhibitors: clinical update and mechanism-based potential. Biochem. Pharmacol., 2007, 74, 659-671. Bolden, J. E .; Peart, M.J .; Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 2006, 5, 769-784. Dallavalle, S .; Cincinelli, R .; Nannei, R .; Merlini, L .; Morini, G .; Penco, S .; Pisano, C .; Vesci, L .; Barbarino, M .; Zuco, V .; De Cesare, M .; Zunino, F. Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Eur J. Med. Chem., 2009, 44, 1900-1912. Bracker, TU, Sommer, A., Fichtner, I., Faus, H., Haendler, B., Hess-Stumpp, H. Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, . Int. J. Oncol., 2009, 35, 909-920. Barbarotta L., Hurley K. Romidepsin for the Treatment of Peripheral T-Cell Lymphoma. J. Adv. Pract. Oncol. 2015, 6, 22-36. Valente, S .; Mai, A. Small-molecule inhibitors of histone deacetylasefor the treatment of cancer and non-cancer diseases: a patent review (2011-2013). Expert. Opin. Ther. Pat., 2014, 24, 401-415. Li, J .; Li, G .; Xu, X. Histone deacetylase inhibitors: an attractive strategy for cancer therapy. Curr. Med. Chem. 2013, 20, 1858-1886. Ververis, K .; Hiong, A .; Karagiannis, T. C .; Licciardi, P.V. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents. Biologics 2013, 7, 47-60. Qiu T, Zhou L, Zhu W, Wang T, Wang J, Shu Y, Liu P. Effects of treatment with histone deacetylase inhibitors on solid tumors: a review based on 30 clinical trials. Future Oncol., 2013, 9, 255-269. "FDA approves Farydak for treatment of multiple myeloma" .fda.gov. Retrieved 6 October2015. Malini G. HDAC inhibitors still need a home run, yet recent approval.Nature Reviews Drug Dis. 2015, 14, 225-226. Oanh, D.T.K .; Hai, H. V .; Hue, V.T.M .; Park, S. H.,; Kim, H. J .; Han, B. W .; Kim, H. S .; Hong, J.T .; Han, S.B .; Nam, N.H. Benzothiazole-containing hydroxamic acids such as histone deacetylase inhibitors and antitumor agents. Bioorg. Med. Chem. Lett., 2011, 21, 7509-7512. Tung, T.T .; Oanh, D.T .; Dung, P. T .; Hue, V.T .; Park, S. H .; Han, B. W .; Kim, Y .; Hong, J.T .; Han, S.B .; Nam, N.H. New benzothiazole / thiazole-containing hydroxamic acids as potent histone deacetylase inhibitors and antitumor agents. Med. Chem. 2013, 9, 1051-1057. Nam, N. H .; Huong, T. L .; Dung, D.T.M .; Oanh, D.T.K .; Dung, P. T. P .; Kim, K. R .; Han, B. W .; Kim, Y.S .; Hong, J.T .; Han, S.B. Synthesis, bioevaluation and docking studies of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents. J. Enzyme Inhib. Med. Chem. (2013) (published online, doi: 10.3109 / 14756366.2013.832238). Nam, N. H .; Huong, T. L .; Dung, D.T.M .; Oanh, D.T.K .; Dung, P. T. P .; Quyen, D .; Kim, K. R .; Han, B. W .; Kim, Y.S .; Hong, J.T .; Han, S.B. Novel isatin-based hydroxamic acids such as histone deacetylase inhibitors and antitumor agents. Eur. J. Med. Chem., 2013, 70, 477-486. Skehan, P .; Storeng, R .; Scudiero, D .; Monk, A .; MacMahon, J .; Vistica, D .; Warren, J.T .; Bokesch, H .; Kenney, S .; Boyd. M.R. New colorimetric cytotoxicity assay for anticancer drug screening. J. Natl. Cancer Inst., 1990, 82, 1107-1112. You, Y.J .; Kim, Y .; Nam, N. H .; Bang, S. C .; Ahn, B.Z. Alkyl and carboxylate esters of 4'-demethyl-4-deoxypodophyllotoxin: synthesis, cytotoxic, and antitumor activity. Eur. J. Med. Chem., 2004, 39, 189-193. Kim, Y .; You, Y.J .; Nam, N. H. ;; Ahn, B.Z. Prodrugs of 4'-demethyl-4-deoxypodophyllotoxin: synthesis and evaluation of the antitumor activity. Bioorg. Med. Chem. Lett., 2002, 12, 3435-3438. Wu, L .; Smythe, A. M .; Stinson, S. F .; Mullendore, L.A .; Monks, A .; Scudiero, D.A .; Paull, K. D .; Koutsoukos, A.D .; Rubinstein, L. V .; Boyd, M. R .; Shoemaker, R.H. Multidrug-resistant phenotype of disease-oriented panels of human tumor cell lines used for anticancer drug screening. Cancer Res., 1992, 52, 3029-3034. Trott, O .; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31, 455-461. Lauffer, B. E .; Mintzer, R .; Fong, R .; Mukund, S .; Tam, C .; Zilberleyb, I .; Flicke, B .; Ritscher, A .; Fedorowicz, G .; Vallero, R .; Ortwine, D. F .; Gunzner, J .; Modrusan, Z .; Neumann, L .; Koth, C. M .; Lupardus, P.J .; Kaminker, J. S .; Heise, C. E .; Steiner, P. histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability, J. Biol. Chem., 2013, 288, 26926-26943. Schuttelkopf, A. W .; van Aalten, D.M. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta crystallographica. Section D, Biological crystallography 2004, 60, 1355-1363. Pelzel, H. R .; Schlamp, C. L .; Nickells, R.W. Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis. BMC Neuroscience 2010, 11, 62

The present inventors have made extensive efforts to develop new hydroxamic acid as a potential inhibitor of histone deacetylase (HDAC) and anticancer drugs. As a result, a novel hydroxamic acid containing 1 - ((1 H -1,2,3-triazol-4-yl) methyl) -3-substituted-indolin- acids have not only very strong HDAC inhibitory activity but also cytotoxicity against cancer cells.

Accordingly, an object of the present invention is to provide a hydroxamic acid-based compound represented by the following formula (1).

Another object of the present invention is to provide a pharmaceutical composition for the treatment and prevention of cancer comprising a hydroxamic acid compound represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a histone deacetylase inhibitor comprising a hydroxamic acid compound represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, there is provided a hydroxamic acid-based compound represented by the following Formula 1:

[Chemical Formula 1]

Wherein R is a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a C _1-6 lower alkyl group and a C _1-6 lower alkoxy group, and n is an integer of 0-5.

The compound group represented by Formula 1 may specifically include a group of compounds wherein R is a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a C _1-3 lower alkyl group, and a C _1-3 lower alkoxy group.

More specifically, the group of compounds represented by Formula 1 may include a compound group in which R is a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a methyl group, and a methoxy group.

As the most specific compound among the group of compounds represented by the above formula (1)

N is 0 to the compound is N-hydroxy-3- (4 - ((3- (hydroxyimino) -2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- triazol-1-yl) propanoic amide (4a), 3- (4 - (( 5-fluoro-3- (hydroxyimino) -2-oxo-in turned-1-yl) methyl) -1 H -1 , 2,3-triazol-1-yl) - N - hydroxy-propanoic amide (4b), or 3- (4- (5-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1 H -1,2,3- triazol- -yl) - N-hydroxy-propanoic amide (4c);

In which the n 1 the compound is N-hydroxy-4- (4 - ((3- (hydroxyimino) -1-yl-2-oxo-turned in) methyl) -1 H -1,2,3- triazol-1-yl) butane amide (5a), 4- (4 - ((5-Fluoro-3- ( hydroxyimino) -1-yl) methyl-2-oxo-turned in) -1 H -1, (5-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) - N -hydroxybutanamide ) methyl) -1 H -1,2,3- triazol-1-yl) - N - hydroxy-butane amide (5c), 4- (4 - ((5- bromo-3- (hydroxyimino) 2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- triazol-1-yl) - N - hydroxy-butane amide (5d), N - hydroxy-4- (4 - ((3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) methyl) -1 H -1,2,3- triazol- 1- yl) butanamide (5e) N-hydroxy-4- (4 - ((3- (hydroxyimino) -5-methoxy-2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- triazol- 1- yl) butane amide (5f), or 4- (4 - ((7-chloro-3- (hydroxyimino) -1-yl-2-oxo-turned in) methyl) -1 H -1,2, 3 -Triazol-l-yl) -N -hydroxybutanamide (5 g);

In which the n 2 is the compound N- hydroxy-5- (4 - ((3- (hydroxyimino) -2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- Triazol-1-yl) pentanamide (6a), 5- (4 - ((5- fluoro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1 H -1,2,3- triazol- - yl) -N -hydroxypentanamide (6b), 5- (4 - ((5- chloro-3- (hydroxyimino) -2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- triazol-1- Yl) -N -hydroxypentanamide (6c), 5- (4- (5-bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1 H -1,2,3- triazol- - yl) -N -hydroxypentanamide (6d), N-hydroxy-5- (4 - ((3- (hydroxyimino) -1-yl) methyl-2-oxo-5-turn) -1 H -1,2,3- Triazol-1-yl) pentanamide (6e), N-hydroxy-5- (4 - ((3- (hydroxyimino) -5-methoxy-2-oxo-in turned-1-yl) methyl) -1 H -1,2,3 -Triazol-1-yl) pentanamide (6f), or 5- (4 - ((7-chloro-3- (hydroxyimino) -2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- triazol -1 - yl) -N -hydroxypentanamide (6g).

The compounds of the present invention represented by the above formula (1) can be prepared as pharmaceutically acceptable salts and solvates according to conventional methods in the art.

Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, lactic acid, glycollic acid, gluconic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt in particular, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

The pharmaceutically acceptable salt of the hydroxamic acid compound of the present invention having the structure of the above formula (1), unless otherwise indicated, is an acidic or basic group which may exist in the hydroxamic acid compound having the structure of formula ≪ / RTI > For example, pharmaceutically acceptable salts include the sodium, calcium and potassium salts of hydroxy groups and can be prepared by methods or processes known in the art for the preparation of salts.

All optical isomers and R or S stereoisomers of the hydroxamic acid compound having the structure of Formula 1 and mixtures thereof are also included in the scope of the present invention. The present invention includes the use of racemates, one or more enantiomeric forms, one or more diastereoisomeric forms, or mixtures thereof, and includes methods and processes for the isolation and isomerization of isomers known in the art.

Another object of the present invention is to provide a method for preparing a compound having the structure of Formula 1, which can be chemically synthesized by the method shown in the following reaction formulas, but is not limited thereto.

The following reaction schemes show the preparation of representative compounds of the present invention according to the preparation steps. Various compounds of the present invention can be prepared by a small modification such as changing reagents, solvents and reaction sequence used in the synthesis of Scheme 1.

Some of the compounds of the present invention were synthesized according to procedures not included in the scope of the reaction formulas, and detailed synthesis procedures for these compounds are described in each of these examples.

[Reaction Scheme 1]

1 - ((1 H -1,2,3- Triazole Yl) methyl ) -3-substituted- Indolin -2- On  Of the present invention Of hydroxamic acids  synthesis

The hydroxamic acid compound (4-6) of the present invention was synthesized through a three-step route as illustrated in Scheme 1.

The reaction of the first step is carried out in the presence of a mixture of isatin (1) and ( ₂ ) in basic form (K ₂ CO ₃ ) in dimethylformamide (DMF) containing a catalytic amount of KI to produce 1-propargine- Nucleophilic substitution reaction between propargyl bromide.

In the second step, the propargyl compound (2) and the respective methyl azide alkanoate (methyl 3-azidopropanoate, methyl 4-azidobutanoate, methyl 5-azidovalerate, methyl 6 -Azid hexanoate and methyl 7-azidoheptanoate) yields the intermediate ester (3). This reaction proceeds smoothly using acetonitrile as a solvent and using copper iodide as a catalyst. In most cases, the ester intermediate is precipitated by titration of the reaction residue obtained by evaporating acetonitrile with cold water.

The final third step involves the nucleophilic acyl substitution reaction of the hydroxylamine hydrochloride with the ester (3). This reaction takes place under basic conditions at 0-5 ° C in a solvent mixture comprising tetrahydrofurane and methanol. Through the above reaction, the hydroxamic acid compound (4-6) of the present invention can be obtained . The overall yield of the objective compound (4-6) of the present invention was normal.

Accordingly, the present invention provides a process for preparing the hydroxamic acid compound represented by the above formula (1).

The inventors of the present invention have confirmed that the compounds of the formula (1) obtained by the above-described method exhibit a strong inhibitory action on histone deacetylase (HDAC), thus being useful as therapeutic agents for treating or preventing cancer.

In the present invention, the cancer includes, but is not necessarily limited to, liver cancer, stomach cancer, brain cancer, bladder cancer, cervical cancer, ovarian cancer, colon cancer, prostate cancer, pancreatic cancer and lung cancer.

Accordingly, in accordance with another aspect of the present invention, there is provided a pharmaceutical composition for the treatment and prevention of cancer comprising the hydroxynate compound represented by Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Lt; / RTI >

According to another aspect of the present invention, there is provided a histone deacetylase inhibitor comprising the hydroxamic acid compound represented by Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, to provide.

As used herein, the term " HDAC inhibitor (HDACi), histone deacylase inhibitor " refers to a histone deacylase inhibitor that removes the acetyl group (O = C-CH ₃ ) from the ε- Refers to a compound that inhibits histone deacetylase (HDAC), an enzyme group that allows it to be wrapped more tightly. Histone deacetylase inhibitors have been used for a long time in psychiatric and nervous systems such as neurotransmitters and anticonvulsants, but they have recently been used as possible treatments for cancer, parasitic diseases and inflammatory diseases.

In this regard, many studies have shown a global decrease in single acetylation and triple methylation at the gene genome level in cancer cells, abnormal expression of HDAC in cancerous tumors, and the use of HDAC1, 5, and 7 as tumor biomarkers Respectively. In addition, HDAC overexpression significantly reduced disease-free and overall survival in several types of carcinoma (prostate, colorectal, breast, lung, liver, stomach, etc.) have. Therefore, deacetylation of histone is recognized as an important mechanism for the development of various carcinomas. It is generally recognized that a histone deacetylase inhibitor (HDACi) that inhibits its activity can be used as an anticancer agent for various carcinomas. The exact mechanism by which a histone deacetylase inhibitor compound acts to treat and prevent cancer is not yet clear, but an epigenetic genetic pathway is proposed. Histone deacetylase inhibitors are known to induce the expression of p21 (WAF1), a modulator of p53 tumor suppressor activity. Recent data indicate that chromatin inactivation mediated by HDAC and DNA methylation is an important component of ERα silencing in human breast cancer cells.

&Quot; Classical " histone deacetylase inhibitors act exclusively in Class I, II and Class IV HDACs by binding to the zinc-containing catalytic domain of HDAC. These classical HDIs can be classified into several groups depending on the chemical moiety that binds to the zinc ion (except the cyclic tetrapeptide bound to the zinc ion as a thiol group), and some examples of the order in which the typical zinc binding affinity decreases are as follows: There are the same things:

1. Hydroxyamide acid (or hydroxamic acid), such as tricostatin A

2. Cyclic tetrapeptides (such as tratoxin B) and depsipeptide,

3. Benzamide,

4. Electrophilic ketones and

5. Fatty acid compounds such as phenyl butyrate and valproic acid.

"Second generation" histone deacetylase inhibitors include hydroxamic acids, borinostat (SAHA), verinostat (PXD101), LAQ824 and panovinostat (LBH589); And benzamide, entinostat (MS-275), CI994, and mosetinostat (MGCD0103).

In addition, sirtuin class III HDAC is dependent on NAD + and is inhibited by nicotinamide as well as derivatives of NAD, dihydrocoumarin, naphthopyranone and 2-cydoxynaphthaldehydes It is known.

As used herein, the term " prevention " refers to all actions that inhibit the onset or delay the onset of cancer by administration of a composition containing the hydroxamic acid-based compound of the present invention. It means any act that improves or alters the cancer.

The pharmaceutical compositions containing the hydroxamic acid compound of the present invention can be used not only for humans but also for mammals such as cows, horses, sheep, pigs, goats, camels, nutrition, dogs, cats and the like which can develop cancer.

The compositions comprising the compounds of the present invention may further comprise suitable carriers, excipients or diluents according to conventional methods.

Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The composition containing the compound of the present invention can be formulated in the form of powders, granules, tablets, capsules, oral preparations such as suspensions, emulsions, syrups and aerosols, external preparations, suppositories or sterilized injection solutions, Can be used.

More specifically, when formulating the composition, it can be prepared using a diluent or an excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ), Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. in addition to commonly used diluents such as water and liquid paraffin . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.

The preferred dosage of the compound of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably 0.001 to 100 mg / kg, once or several times a day. In the composition, the compound of the present invention should be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the entire composition.

In addition, the pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds, as well as in suitable aggregates.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

The present invention provides a novel hydroxamic acid compound useful as a histone deacetylase inhibitor and a composition containing the same, and the compound according to the present invention can be used as a medicine for treating and preventing cancer.

FIG. 1 is a view showing the kind of HDAC inhibitors known so far.
Fig. 2 is a diagram showing a three-dimensional shape for the overlapping of the binding modes of the compound 5a-g and the SAHA at the binding site of HDAC2. The compound was expressed as a stick model and the SAHA was expressed as a thick purple stick.
Figure 3 is a diagram showing the actual bonding pose of SAHA and the three-dimensional shape of the simulated docking pose of compounds 5a and 5f for HDAC2. Compounds 5a and 5f are shown as dark orange and bright orange bars, respectively. The most important parts for the enzyme to interact with these compounds are represented by stick models in which carbon, nitrogen and oxygen are expressed in gray, blue and red, respectively. Zn ^{2 +} ions are represented by light gray spheres.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Experimental material

Chemical reagents and equipment

All reagents and solvents were purchased from Sigma-Aldrich, Fluka Chemical Corp., Milwaukee, WI, USA or Merck. Solvents were used as purchased unless otherwise noted. Thin-film chromatography was performed using Whatman® 250 μm Silica Gel GF Uniplates and visualized under ultraviolet light at 254 and 365 nm to pre-evaluate the progress of the reaction and the homogeneity of the compounds. In all cases, the resulting compound had a purity of at least 97% as estimated by the HPLC method. Melting points were measured using a Gallenkamp Melting Point Apparatus (LabMerchant, London, United Kingdom) and not calibrated. Purification of the compound was carried out using crystallization method and / or open flash silica gel column chromatography using Merck silica gel 60 (240-400 mesh) as a stationary phase. Nuclear magnetic resonance spectra ( ¹ H NMR) were recorded on a Bruker 500 MHz spectrometer using DMSO-d ₆ as solvent, unless otherwise stated, and tetramethylsilane was used as the internal standard. The chemical shifts are reported in parts per million (ppm) based on tetramethylsilane. Mass spectra according to different ionization schemes, including EI, electron ionization (ESI) and electrospray ionization (ESI), were measured using PE Biosystems API 2000 (Perkin Elmer, Palo Alto, Were recorded using a Mariner® (Azco Biotech, Inc. Oceanside, CA, USA) mass spectrometer.

Experimental Method

Synthesis of Compound 4-6 of the present invention

K ₂ CO ₃ (165.5 mg, 1.2 mmol) was added to a solution of 1 mmol of isatin compound 1a-g in DMF (diethylformamide) (3 mL). The resulting mixture was stirred at 80 < 0 > C for 1 hour and then KI (8.3 mg, 0.05 mmol) was added. After stirring for an additional 15 minutes, 0.15 ml of an 80% strength propargyl bromide toluene solution was added slowly to the mixture. The reaction mixture was stirred at 60 < 0 > C for 3 hours. After the stirring was completed, the resulting mixture was cooled, poured into ice water, and then acidified to a pH of about 4. The orange solid formed was filtered off and dried to give propargylated isatin compound 2 which was used in the next step without further purification.

A solution of each of the above compounds 2 and 1 mmol of methyl azidoester in acetonitrile (2 mL) was stirred at room temperature for 10 minutes and then CuI (19.1 mg, 0.1 mmol) was added. The mixture was stirred at 50 < 0 > C until the reaction was complete (12-24 h). The resulting mixture was evaporated under reduced pressure to give a residue which was redissolved in 50 ml of dichloromethane. The mixture was filtered and the DCM layer was evaporated under reduced pressure to give the intermediate ester compound 3. [ Compound 3 was dissolved in a mixed solution of methanol / tetrahydrofuran (2/1, 5 ml). Then, hydroxylamine-HCl (685 mg, 10 mmol) was added, and then NaOH solution (400 mg in 1 mL of water) was added dropwise. The mixture was stirred at room temperature until the reaction was complete. The resulting mixture was poured into ice water, neutralized to a pH of about 7, and acidified by dropping 5% HCl solution to induce precipitation. The precipitate was filtered, dried and then recrystallized from methanol to obtain the compound 4-6 of the present invention.

The compound names of the compound 4-6 and the physical properties thereof are as follows.

N - Hydroxy -3- (4 - ((3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) 프로탄 나드  (4a)

Yellow solid; Yield: 64%. _{^{mp: 185.5-186.0 o C. R f =}} 0.40 (DCM: MeOH: AcOH = 90: 5: 1). ^{IR (KBr, cm -1):} 3423 (NH), 3287, 3197 (OH), 3064 (CH, aren), 2895 (CH, CH 2), 1723,1672 (C = O), 1609,1549 (C = C), 1462 (CN). ESI-MS ( m / z): 353 [M + Na] < ⁺ >. ¹ H-NMR ( 500 MHz, DMSO- d ₆ , ppm) :? 10.47 (1H, s, NH); 8.82 (1H, s, OH); 8.02 (1H, s, H-5 '); 7.99 (1H, d, J = 7.0 Hz, H-4 "); 7.39 (1H, t, J = 8.0 Hz, H-6 "); 7.11 (1H, t, J = 8.5 Hz, H-5 "); 7.07 (1H, d, J = 7.5 Hz, H-7 "); 4.96 (2H, s, H-6'a, H-6'b); 4.51 (2H, t, J = 7.0 Hz, H-3a, H-3b); 2.57 (2H, t, J = 7.0 Hz, H-2a, H-2b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 165.82, 162.75, 143.39, 142.54, 141.69, 131.88, 126.77, 123.51, 122.69, 115.27, 109.62, 45.58, 34.57, 32.49. Anal. Calcd. _{For C 14 H 14 N 6 O} 4 (330.30): C, 50.91; H, 4.27; N, 25.44. Found: C, 50.94; H, 4.31; N, 25.47.

3- (4 - ((5- Fluoro -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) - N -hydroxypropanamide (4b)

Yellow solid; Yield: 63%. _{^{mp: 187.5-188.5 o C. R f =}} 0.42 (DCM: MeOH: AcOH = 90: 5: 1). ^{IR (KBr, cm -1):} 3293 (OH), 3069 (CH, aren), 2921, 2856 (CH, CH 2), 1719 (C = O), 1616 (C = C), 1480,1439 (CN ). ESI- MS ( m / z): 347 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 10.38 (1H, s, NH); 8.05 (1H, s, H-5 '); 7.74 (1H, dd, J = 8.0 Hz, J = 2.0 Hz, H-4 "); 7.28 (1H, td, J = 8.5 Hz, J = 2.0 Hz, H-6"); 7.13 (1H, dd, J = 8.5 Hz, J = 4.0 Hz, H-7 "); 4.97 (2H, s, H-6 ' a, H-6 'b); 4.53-4.48 (2H, m, H-3a, H-3b); 2.86 (1H, t, J = 6.75 Hz, H-2a) 2.57 (2H, t, J = 6.75 Hz, H-2b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 165.85, 162.64, 157.06, 143.07, 141.55, 138.90, 123.62, 118.15, 115.77, 113.78, 110.77, 45.65, 34.72, 32.55. Anal. Calcd. _{For C 14 H 13 FN 6 O} 4 (348.29): C, 48.28; H, 3.76; N, 24.13. Found: C, 48.31; H, 3.75; N, 24.15.

3- (4 - ((5- Chloro -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) - N -hydroxypropanamide (4c)

Yellow solid; Yield: 63%. _{^{mp: 187.0-189.0 o C. R f =}} 0.41 (DCM: MeOH: AcOH = 90: 5: 1). ^{IR (KBr, cm -1):} 3420 (NH), 3255, 3151 (OH), 3035 (CH, aren), 2851 (CH, CH 2), 1713,1647 (C = O), 1609 (C = C ), 1464 (CN). ESI- MS ( m / z): 365 [M + H] < ⁺ >. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 14.70 (1H, s, NH); 10.48 (1H, s, NH); 8.83 (1H, s, OH); 8.03 (1H, s, H-5 '); 7.96 (1H, d, J = 1.75 Hz, H-4 "); 7.48 (1H, dd, J = 8.5 Hz, J = 1.75 Hz, H-6 "); 7.14 (1H, d, J = 8.5 Hz, H-7 "); 4.98 (2H, s, H-6'a, H-6'b); 4.52 (2H, t, J = 6.75 Hz, H-3a, H-3b); 2.57 (2H, t, J = 6.75 Hz, H-2a, H-2b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 165.83, 162.40, 142.66, 141.43, 141.31, 131.37, 126.55, 126.08, 123.59, 116.40, 111.27, 45.62, 34.72, 32.51. Anal. Calcd. _{For C 14 H 13 ClN 6 O} 4 (364.74): C, 46.10; H, 3.59; N, 23.04. Found: C, 46.13; H, 3.62; N, 23.07.

N - Hydroxy -4- (4 - ((3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) butanamide  (5a)

Yellow solid; Yield: 68%. _{^{mp: 181.0-182.5 o C. R f =}} 0.45 (DCM: MeOH: AcOH = 90: 5: 1). ^{IR (KBr, cm -1):} 3135 (OH), 3022 (CH, aren), 2918, 2856 (CH, CH 2), 1721,1640 (C = O), 1608 (C = C), 1463 (CN ). ESI- MS ( m / z): 343 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.58 (1H, s, NH); 10.52 (1H, s, OH); 10.40 (1H, s, NH); 8.12 (1H, s, H-5 '); 7.97 (1H, d, J = 7.5 Hz, H-4 "); 7.39 (1H, td, J = 8.0 Hz, J = 1.0 Hz, H-6 "); 7.11 (1H, d, J = 7.5 Hz, H-7 "); 7.07 (1H, t, J = 7.5 Hz, H-5 "); 4.97 (2H, s, H-6 ' a, H-6 'b); 4.29 (2H, t, J = 6.5 Hz, H-4a, H-4b); 1.99-1.95 (4H, m, H-3a, H-3b, H-2a, H-2b). ^{13 C} NMR (125 MHz, DMSO-d ₆ , ppm) :? 168.16, 162.83, 143.36, 142.60, 141.87, 131.94, 126.83, 123.39, 122.77, 115.32, 109.68, 48.93, 34.67, 29.01, 25.85. Anal. Calcd. _{For C 15 H 16 N 6 O} 4 (344.33): C, 52.32; H, 4.68; N, 24.41. Found: C, 52.37; H, 4.71; N, 24.38.

4- (4 - ((5- Fluoro -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) - N -hydroxybutanamide (5b)

Yellow solid; Yield: 72%. _{^{mp: 180.0-182.0 o C. R f =}} 0.43 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3441 (NH), 3208, 3137 (OH), 3029 (CH, aren), 2872 (CH, CH ₂ ), 1722, 1640 (C = O), 1477 (CN). ESI- MS ( m / z): 361 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ10.40 (1H, s, NH); 8.72 (1H, s, OH); 8.11 (1H, s, H-5 '); 7.75 (1H , dd, J = 7.5 Hz, J = 2.5 Hz, H-4 "); 7.28 (1H, td, J = 8.5 Hz, J = 2.5 Hz, H-6"); 7.13 (1H, dd, J = 8.5 Hz, J = 4.0 Hz, H-7 "); 4.98 (2H, s, H-6'a, H-6'b); 4.32-4.29 (2H, m, H-4a, H-4b); 1.99-1.92 (4H, m, H-3a, H-3b, H-2a, H-2b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 168.05, 162.64, 157.06, 143.13, 141.72, 138.92, 123.43, 118.14, 115.79, 113.80, 110.75, 48.91, 34.79, 28.96, 25.77. Anal. Calcd. _{For C 15 H 15 FN 6 O} 4 (362.32): C, 49.72; H, 4.17; N, 23.20. Found: C, 49.75; H, 4.21; N, 23.24.

4- (4 - ((5- Chloro -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) - N -hydroxybutanamide (5c)

Yellow solid; Yield: 64%. _{^{mp: 187.5-188.5 o C. R f =}} 0.42 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3417 (NH), 3219, 3138 (OH), 3044 (CH, aren), 2874 (CH, CH ₂ ), 1720,1643 ), 1463 (CN). ESI- MS ( m / z): 401 [M + Na] < ⁺ >. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.82 (1H, s, NH); 10.38 (1H, s, NH); 8.71 (1H, s, OH); 8.10 (1H, s, H-5 '); 7.96 (1H, d, J = 1.75 Hz, H-4 "); 7.47 (1H, dd, J = 7.5 Hz, J = 1.75 Hz, H-6 "); 7.14 (1H, d, J = 8.5 Hz, H-7 "); 4.98 (2H, s, H-6'a, H-6'b); 4.30 (2H, t, J = 6.5Hz, H-4a, H-4b); 2.00-1.92 (4H, m, H-3a, H-3b, H-2a, H-2b). ^{13 CNMR (125MHz, DMSO-d} 6, ppm): δ 168.05, 162.41, 142.71, 141.63, 141.38, 131.40, 126.56, 126.12, 123.33, 116.43, 111.28, 48.92, 34.82, 28.96, 25.76. Anal. Calcd. _{For C 15 H 15 ClN 6 O} 4 (378.77): C, 47.56; H, 3.99; N, 22.19. Found: C, 47.61; H, 3.95; N, 22.22.

4- (4 - ((5- Bromo -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) - N -hydroxybutanamide (5d)

Yellow solid; Yield: 68%. _{^{mp: 188.5-189.5 o C. R f =}} 0.47 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3407 (NH), 3138 (OH), 3023 (CH, aren), 2968, 2853 (CH, CH ₂ ), 1731,1704 ), 1463 (CN). ESI- MS ( m / z): 421 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 10.42 (1H, s, NH); 8.72 (1H, s, OH); 8.10 (1H, s, H-5 '); 8.08 (1H, d, J = 1.5 Hz, H-4 "); 7.60 (1H, dd, J = 8.25 Hz, J = 1.5 Hz, H-6 "); 7.10 (1H, d, J = 8.25 Hz, H-7 "); 4.98 (2H, s, H-6'a, H-6'b); 4.30 (2H, t, J = 6.5Hz, H-4a, H-4b); 2.00-1.94 (4H, m, H-3a, H-3b, H-2a, H-2b). ^{13 C} NMR ( 125MHz, DMSO- d ₆ , ppm) :? 168.07, 162.34, 142.52, 141.72, 141.60, 134.17, 128.76, 123.35, 116.88, 114.20, 111.78, 48.92, 34.79, 28.97, 25.78. Anal. Calcd. _{For C 15 H 15 BrN 6 O} 4 (422.23): C, 42.57; H, 3.57; N, 19.86. Found: C, 42.59; H, 3.61; N, 19.85.

N - Hydroxy -4- (4 - ((3- ( hydroxyimino ) -5-methyl-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -1-yl) butanamide < / RTI > (5e)

Yellow solid; Yield: 71%. _{^{mp: 179.5-181.0 o C. R f =}} 0.41 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3280 (NH), 3184 (OH), 3068 (CH, aren), 2908 (CH, CH ₂ ), 1713,1673 ), 1476 (CN). ESI- MS ( m / z): 381 [M + Na] < ⁺ >. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.44 (1H, s, NH); 10.38 (1H, s, NH); 8.71 (1H, s, OH); 8.08 (1H, s, H-5 '); 7.83 (1H, s, H-4 "); 7.20 (1H, d, J = 8.0 Hz, H-7 "); 6.99 (1H, d, J = 8.0 Hz, H-6 "); 4.95 (2H, s, H-6'a, H-6'b); 4.30 (2H, t, J = 6.5Hz, H-4a, H-4b); _{2.27 (3H, s, -CH 3} ); 1.98-1.93 (4H, m, H-3a, H-3b, H-2a, H-2b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 168.08, 162.77, 143.59, 141.93, 140.39, 132.14, 131.77, 127.38, 123.26, 115.35, 109.42, 48.89, 34.67, 28.97, 25.78, 20.51. Anal. Calcd. For C ₁₆ H ₁₈ N ₆ O ₄ (358.35): C, 53.63; H, 5.06; N, 23.45. Found: C, 53.67; H, 5.11; N, 23.42.

N - Hydroxy -4- (4 - ((3- ( hydroxyimino ) -5- 메틸oxy -2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -1-yl) butanamide (5f)

Yellow solid; Yield: 60%. _{^{mp: 180.0-182.0 o C. R f =}} 0.45 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3281 (NH), 3187 (OH), 3071 (CH, aren), 2916 (CH, CH ₂ ), 1711, 1673 ), 1552, 1480 (CN). ESI-MS ( m / z): 373 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.53 (1H, s, NH); 10.40 (1H, s, NH); 8.09 (1H, s, H-5 '); 7.58 (1H, d, J = 2.5 Hz, H-4 "); 7.04-6.98 (2H, m, H-6 ", H-7 "); 4.94 (2H, s, H-6'a, H-6'b); 4.30 (2H, t, J = 7.0Hz, H-4a, H-4b); _{3.72 (3H, s, -OCH 3} ); 2.00-1.92 (4H, m, H-3a, H-3b, H-2a, H-2b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 168.05, 162.62, 155.21, 143.68, 141.94, 136.24, 123.28, 116.86, 115.85, 113.09, 110.26, 55.65, 48.90, 34.70, 28.97, 25.78. Anal. Calcd. _{For C 16 H 18 N 6 O} 5 (374.35): C, 51.33; H, 4.85; N, 22.45. Found: C, 51.35; H, 4.89; N, 22.42.

4- (4 - ((7- Chloro -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) - N -hydroxybutanamide (5 g)

Yellow solid; Yield: 70%. _{^{mp: 187.5-188.5 o C. R f =}} 0.43 (DCM: MeOH: AcOH = 90: 5: 1). ^{IR (KBr, cm -1):} 3517, 3378 (NH), 3248 (OH), 3030 (CH, aren), 2897 (CH, CH 2), 1717,1664 (C = O), 1634,1608 (C = C), 1441 (CN). ESI-MS ( m / z): 377 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 10.41 (1H, s, NH); 8.72 (1H, s, OH); 8.07 (1H, dd, J = 7.75 Hz, J '= 1.0 Hz, H-4 "); 8.06 (1H, s, H-5 '); 7.39 (1H, dd, J = 7.75 Hz, J = 1.0 Hz, H-6 "); 7.11 (1H, t, J = 7.75 Hz, H-5 "); 5.31 (2H, s, H-6'a, H-6'b); 4.29 (2H, t, J = 6.5 Hz, H-4a, H-4b); 2.00-1.92 (4H, m, H-3a, H-3b, H-2a, H-2b). ^{13 C} NMR ( 125MHz, DMSO- d ₆ , ppm) :? 168.07, 163.64, 143.38, 142.19, 138.46, 133.78, 125.84, 124.23, 122.49, 118.30, 114.80, 48.88, 37.06, 28.96, 25.84. Anal. Calcd. _{For C 15 H 15 ClN 6 O} 4 (378.77): C, 47.56; H, 3.99; N, 22.19. Found: C, 47.55; H, 3.97; N, 22.17.

N- Hydroxy -5- (4 - ((3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) pentanamide (6a)

Yellow solid; Yield: 68%. _{^{mp: 189.0-191.5 o C. R f =}} 0.48 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3399, 3312 (NH), 3196 (OH), 3059 (CH ₂ ), 2876 (CH ₂ CH ₂ ), 1714, 1678 ), 1455 (CN). ESI- MS ( m / z): 357 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.45 (1H, s, NH); 10.35 (1H, s, NH); 8.67 (1H, s, OH); 8.09 (1H, s, H-5 '); 7.98 (1H, d, J = 7.5 Hz, H-4 "); 7.40 (1H, t, J = 7.5 Hz, H-6 "); 7.12-7.06 (2H, m, H-5 ", H-7 "); 4.98 (2H, s, H-6'a, H-6'b); 4.29 (2H, t, J = 7.0Hz, H-5a, H-5b); 1.95 (2H, t, J = 7.5 Hz, H-2a, H-2b); 1.79-1.71 (2H, m, H-4a, H-4b); 1.45-1.39 (2H, m, H-3a, H-3b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 168.68, 162.74, 143.44, 142.61, 141.80, 131.95, 126.85, 123.26, 122.73, 115.28, 109.64, 49.05, 34.67, 29.22, 22.04. Anal. Calcd. For C ₁₆ H ₁₈ N ₆ O ₄ (358.35): C, 53.63; H, 5.06; N, 23.45. Found: C, 53.67; H, 5.09; N, 23.41.

5- (4 - ((5- Fluoro -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) - N -hydroxypentanamide (6b)

Yellow solid; Yield: 69%. _{^{mp: 194.5-196.0 o C. R f =}} 0.48 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3396, 3320 (NH), 3172 (OH), 3058 (CH, aren), 2876 (CH, CH ₂ ), 1715, 1680 ), 1477 (CN). ESI -MS (m / z): 375 [MH] -. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.76 (1H, s, NH); 10.34 (1H, s, NH); 8.67 (1H, s, OH); 8.08 (1H, s, H-5 '); 7.75 (1H, dd, J = 8.0 Hz, J = 2.5 Hz, H-4 "); 7.28 (1H, td, J = 8.75 Hz, J = 2.5 Hz, H-6 "); 7.12 (1H, dd, J = 8.75 Hz, J = 4.0 Hz, H-7 "); 4.98 (2H, s, H-6'a, H-6'b); 4.29 (2H, t, J = 7.0Hz, H-5a, H-5b); 1.95 (2H, t, J = 7.5 Hz, H-2a, H-2b); 1.76-1.73 (2H, m, H-4a, H-4b); 1.45-1.40 (2H, m, H-3a, H-3b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 168.68, 162.61, 158.00, 143.16, 141.64, 138.93, 123.29, 118.15, 115.77, 113.83, 110.72, 49.06, 34.79, 31.51, 29.19, 22.03. Anal. Calcd. For C ₁₆ H ₁₇ FN ₆ O ₄ (376.34): C, 51.06; H, 4.55; N, 22.33. Found: C, 51.09; H, 4.59; N, 22.30.

5- (4 - ((5- Chloro -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -1-yl) - N -hydroxypentanamide (6c)

Yellow solid; Yield: 69%. _{^{mp: 194.5-196.0 o C. R f =}} 0.48 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3286 (NH), 3143 (OH), 3042 (CH, aren), 2851 (CH, CH ₂ ), 1708, 1647 1461 (CN). ESI- MS ( m / z): 391 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 10.36 (1H, s, NH); 8.68 (1H, s, OH); 8.08 (1H, s, H-5 '); 7.95 (1H, s, H-4 "); 7.48 (1H, d, J = 8.0 Hz, H-6 "); 7.14 (1H, d, J = 8.0 Hz, H-7 "); 4.98 (2H, s, H-6'a, H-6'b); 4.29 (2H, t, J = 7.0Hz, H-5a, H-5b); 1.95 (2H, t, J = 7.5 Hz, H-2a, H-2b); 1.77-1.72 (2H, m, H-4a, H-4b); 1.45-1.40 (2H, m, H-3a, H-3b). ^{13 C} NMR ( 125 MHz, DMSO- d ₆ , ppm) :? 168.73, 162.44, 142.71, 141.57, 141.38, 131.42, 126.59, 126.14, 123.31, 116.44, 111.29, 49.09, 34.84, 31.53, 29.22, Anal. Calcd. For C ₁₆ H ₁₇ ClN ₆ O ₄ (392.80): C, 48.92; H, 4.36; N, 21.40. Found: C, 48.95; H, 4.34; N, 21.44.

5- (4 - ((5- Bromo -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) - N -hydroxypentanamide (6d)

Yellow solid; Yield: 74%. _{^{mp: 201.5-203.0 o C. R f =}} 0.51 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3420,3289 (NH), 3147 (OH), 3031 (CH, aren), 2862 (CH, CH ₂ ), 1708, 1646 ), 1462 (CN). ESI- MS ( m / z): 437 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 10.34 (1H, s, NH); 8.67 (1H, s, OH); 8.08 (2H, s, H-5 ', H-4''); 7.60 (1H, d, J = 7.75 Hz, H-6 "); 7.09 (1H, d, J = 7.75 Hz, H-7 "); 4.98 (2H, s, H-6'a, H-6'b); 4.29 (2H, t, J = 6.0Hz, H-5a, H-5b); 1.95 (2H, t, J = 6.5 Hz, H-2a, H-2b); 1.75-1.73 (2H, m, H-4a, H-4b); 1.45-1.41 (2H, m, H-3a, H-3b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 168.68, 162.31, 142.57, 141.73, 141.54, 134.20, 128.79, 123.27, 116.86, 114.21, 111.76, 49.07, 34.80, 31.51, 29.20, 22.04. Anal. Calcd. For C ₁₆ H ₁₇ BrN ₆ O ₄ (437.25): C, 43.95; H, 3.92; N, 19.22. Found: C, 43.91; H, 3.94; N, 19.25.

N - Hydroxy -5- (4 - ((3- ( hydroxyimino ) -5-methyl-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -1-yl) pentanamide (6e)

Yellow solid; Yield: 75%. _{^{mp: 199.5-201.6 o C. R f =}} 0.46 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3317 (NH), 3188 (OH), 3061 (CH, aren), 2879 (CH, CH ₂ ), 1713, 1680 1460 (CN). ESI- MS ( m / z): 371 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.43 (1H, s, NH); 10.34 (1H, s, NH); 8.66 (1H, s, OH); 8.06 (1H, s, H-5 '); 7.83 (1H, s, H-4 "); 7.21 (1H, s, H-6 "); 6.99 (1H, d, J = 6.0 Hz, H-7 "); 4.94 (2H, s, H-6'a, H-6'b); 4.29 (2H, s, H-5a, H-5b); _{2.27 (3H, s, -CH 3} ); 1.95 (2H, s, H-2a, H-2b); 1.74 (2H, s, H-4a, H-4b); 1.42 (2H, s, H-3a , H-3b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 168.25, 163.25, 144.08, 142.45, 140.86, 132.61, 132.25, 127.86, 123.74, 115.83, 109.89, 49.54, 35.17, 32.00, 29.69, 22.52, 20.97. Anal. Calcd. _{For C 17 H 20 N 6 O} 4 (372.38): C, 54.83; H, 5.41; N, 22.57. Found: C, 54.86; H, 5.44; N, 22.55.

N - Hydroxy -5- (4 - ((3- ( hydroxyimino ) -5- 메틸oxy -2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -1-yl) pentanamide (6f)

Yellow solid; Yield: 64%. _{^{mp: 196.0-197.5 o C. R f =}} 0.48 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm ^-1 ): 3421 (NH), 3134 (OH), 3047 (CH, aren), 2929, 2838 (CH, CH ₂ ), 1718, 1628 ), 1480 (CN). ESI- MS ( m / z): 387 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 10.35 (1H, s, NH); 8.67 (1H, s, OH); 8.05 (1H, s, H-5 '); 7.57 (1H, d, J = 2.5 Hz, H-4 "); 7.03-6.98 (2H, m, H-6 ", H-7 "); 4.94 (2H, s, H-6'a, H-6'b); 4.29 (2H, t, J = 7.0Hz, H-5a, H-5b); _{3.72 (3H, s, -OCH 3} ); 1.95 (2H, t, J = 7.0 Hz, H-2a, H-2b); 1.75-1.72 (2H, m, H-4a, H-4b); 1.45-1.40 (2H, m, H-3a, H-3b). _{^{13 CNMR (125MHz, DMSO -d 6}} , ppm): δ 168.74, 162.66, 155.25, 143.71, 141.87, 136.25, 123.24, 116.90, 115.87, 113.14, 110.28, 55.68, 49.07, 34.73, 31.54, 29.22, 22.06. Anal. Calcd. _{For C 17 H 20 N 6 O} 5 (388.38): C, 52.57; H, 5.19; N, 21.64. Found: C, 52.61; H, 5.21; N, 21.67.

5- (4 - ((7- Chloro -3- ( hydroxyimino )-2- oxoindolin -One- yl ) methyl) -1 H -1,2,3- triazole -One- yl ) - N -hydroxypentanamide (6g)

Yellow solid; Yield: 73%. _{^{mp: 198.5-201.0 o C. R f =}} 0.47 (DCM: MeOH: AcOH = 90: 5: 1). ^{IR (KBr, cm -1):} 3422 (NH), 3165 (OH), 3057 (CH, aren), 2959, 2866 (CH, CH 2), 1724,1618 (C = O), 1608 (C = C ), 1469 (CN). ESI- MS ( m / z): 391 [MH] ^<">. ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.83 (1H, s, NH); 10.34 (1H, s, NH); 8.66 (1H, s, OH); 8.07 (1H, d, J = 7.0 Hz, H-4 "); 8.03 (1H, s, H-5 '); 7.39 (1H, d, J = 8.0 Hz, H-6 "); 7.11 (1H, t, J = 7.5 Hz, H-5 "); 5.31 (2H, s, H-6'a, H-6'b); 4.29 (2H, t, J = 7.0Hz, H-5a, H-5b); 1.95 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77-1.71 (2H, m, H-4a, H-4b); 145-139 (2H, m, H-3a, H-3b). ¹³ CNMR ( 125 MHz, DMSO- d ₆ , ppm) :? 168.67, 163.63, 143.26, 142.20, 138.45, 133.77, 125.84, 124.22, 122.44, 118.29, 114.80, 49.01, 37.06, 31.50, 29.24, Anal. Calcd. For C ₁₆ H ₁₇ ClN ₆ O ₄ (392.80): C, 48.92; H, 4.36; N, 21.40. Found: C, 48.93; H, 4.39; N, 21.42.

The structure of the final product was determined directly using spectroscopy including IR, MS, ¹ H NMR and ¹³ C NMR.

Cytotoxicity assay

Cytotoxicity of the inventive compounds 4-6 synthesized against three human cancer cell lines including SW620 (colon cancer), PC3 (prostate cancer) and AsPC-1 (pancreatic cancer) was evaluated. The cell line was purchased from the Cancer Cell Bank of Korea Research Institute of Bioscience and Biotechnology (KRIBB). The medium, serum and other reagents used for cell culture were obtained from GIBCO Co. Ltd. (Grand Island, New York, USA). The cells were cultured in DMEM (Dulbecco's Modified Eagle Medium) medium until confluency was achieved. The cells were then trypsinized and suspended in cell culture medium at a number of 3x10 ⁴ cells / mL. On day 0, 180 μL of cell suspension was dispensed into each well of a 96-well plate. The 96-well plate was then incubated in a 5% CO ₂ incubator at 37 ° C for 24 hours. The compounds (4a-c, 5a-g and 6a-g) were initially dissolved in dimethyl sulfoxide (DMSO) and diluted to the appropriate concentration using a culture medium (DMEM). Then, 20 μL of each compound sample prepared in each well of a 96-well plate cultured for 24 hours inoculated with the cell suspension was added at various concentrations. 96-well plates were further incubated for 48 hours. The cytotoxicity of the compounds was determined by the colorimetric method with a slight modification of the method used in the previous literature [21, 23-24]. IC ₅₀ values were calculated using the Probits method [27] and the mean value of three independent measurements (SD ≤ 10%).

HDAC2 enzyme assay (HDAC2 enzyme assay)

HDAC2 enzyme was purchased from BPS Bioscience (San Diego, CA, USA). HDAC enzyme assays were performed using the Fluorogenic HDAC Assay Kit (BPS Bioscience) according to the manufacturer's instructions. The HDAC2 enzyme was incubated with the vehicle or at various concentrations of the analyzed sample or SAHA for 30 min at 37 [deg.] C in the presence of a HDAC fluorimetric substrate. The HDAC assay developer (producing a fluorescent substance in the reaction mixture) was added and excited at 360 nm using VICTOR3 (PerkinElmer, Waltham, MA, USA) and fluorescence emitted at 460 nm was measured. The measured activity was subtracted from the vehicle-treated control enzyme activity and IC ₅₀ values were calculated using GraphPad Prism (GraphPad Software, San Diego, Calif., USA).

Docking studies

Docking tests were performed using the AutoDock Vina program [26] (Scripps Research Institute, CA, USA). The three-dimensional crystal structure of the HDAC2 protein complexed with SAHA was obtained from the Protein Data Bank (PDB ID: 4LXZ).

The coordinates of the compounds were generated using the GlycoBioChem PRODRG2 server (http://davapc1.bioch.dundee.ac.uk/prodrg/) [28]. In the docking test, the grid map was at the center of the SAHA binding sites and contained 26 X 26 X 22 points with 1.0 A spacing after removing the SAHA from the composite structure as described in the previous prior art [18-21]. The AutoDock Vina program was implemented using 8-way multithreading, with the other parameters defaulted.

Experiment result

HDAC2 inhibition and cytotoxicity of the compounds of the present invention

The synthesized compounds were evaluated for their histone deacetylase inhibitory effect using HDAC2 and at the same time were evaluated for their ability to inhibit histone deacetylase inhibition in a dose-dependent manner, including SW620 (colorectal cancer), PC3 (prostate cancer), AsPC-1 (pancreatic cancer) and NCI- Cytotoxicity to four human cancer cell lines was evaluated.

The results are shown in Table 1.

<Inhibition of HDAC2 activity of synthesized compounds and cytotoxicity against cancer cells>

¹ Calculated with ChemDraw 9.0 software; The concentration (mM) of the ² enzyme activity or 50% reduction in cell growth represents the average result of three experiments with deviations of less than 10%. ³ cell line: SW620, colon cancer; PC3, prostate cancer; AsPC-1, pancreatic cancer; ⁴ SAHA, suberoylanilide acid, positive control.

As shown in Table 1 above, only Compound 5f showed similar efficacy in terms of HDAC2 inhibition compared to SAHA. All other compounds showed less inhibitory effect than SAHA as a result of HDAC2 inhibition assay.

Compound 5a-g showed a relatively high correlation between HDAC2 inhibition and cytotoxicity of the compound to cancer cells.

Compounds 5d and 5e, which exhibited the strongest HDAC2 inhibitory effect among the compounds of the compound 5, were found to have the strongest cytotoxicity against all three types of cancer cells tested. In contrast, compounds 5b and 5g, which exhibited the weakest HDAC2 inhibitory potency, showed the weakest cytotoxicity. Of the series of compounds 5, compound 5e was the most likely candidate with up to 8 times stronger cytotoxicity than SAHA in all three cancer cell types tested.

In designing these compounds, the inventors of the present invention have found that initially the triazole moieties still act as part of the linker between the 2-oxo-doline and the hydroxamic acid moiety, and at the active binding site of the HDAC, And a stronger hydrogen bond. Also, since there is only 2C between the triazole and the hydroxamic acid (compound 4a-c), the linker between the 2-oxoindoline and the hydroxamic acid moiety is less than SAHA's 6C linker.

Therefore, the present inventors decided to design a 5a-g compound having n = 1 as a target compound. (N = 2) 6a-g compounds with one additional C were also synthesized for comparison with 5a-g compounds. The results were generally confirmed that compound 5a-g was stronger in terms of cytotoxicity compared to compound 6a-g.

From the viewpoint of HDAC2 inhibition, three or more compounds (5c, 5e and 5f) in compound 5a-g were more potent than compound 6a-g.

Docking test result

Since histone-H3 and histone-H4 deacetylation have been proven to be regulated mainly by HDAC2 and HDAC3 [29], in order to investigate the interaction between the hydroxamic acid compounds and the HDAC binding site of the present invention, HDAC2 Docking test was performed. The crystal structure of HDAC2 complexed with SAHA (PDB ID: 4LXZ) has been previously reported (Lauffer et al. [26]), and the crystal structure of HDAC2 complexed with SAHA was used as a docking template. Following the removal of SAHA from the complex structure, the SAHA was docked to the crystal structure of HDAC2 as a control, following the previously reported method [18-21].

The results are shown in Table 2 and Fig. 2 and Fig.

&Lt; Binding Affinity for HDAC2 of Compound 4-6 of the Present Invention >

* FIELD: suberoylanilide hydroxamic acid.

As shown in Table 2, all of the synthesized hydroxamic acids exhibited a stabilization energy in the range of -6.7 to -8.1 kcal / mol, which is comparatively or significantly lower than that of SAHA, and higher than that of SAHA Binding affinity and is located at the active site of the HDAC enzyme. For example, the stabilization energy of the predicted binding mode of SAHA and HDAC2 was 7.4 kcal / mol (rmsd distance from the original SAHA in the crystal structure: 0.609 / 2.056 A), but the calculated values for compounds 5e and 5f were -8.1 and 7.4 kcal / mol.

Compound 5e and 5f showed the IC ₅₀ value of 1.28 μM and 0.91 show the strongest compared to the 1.06 μM reported for SAHA (positive control) HDAC2 inhibitory potency in inhibiting HDAC2 efficacy.

From the above docking test it was found that zinc ions (gray spheres) were coordinated by three amino acid residues of HDAC2, including Asp181, His183 and Asp269. All hydroxamic acids synthesized in the present invention interacted with zinc ions in a manner similar to SAHA. The synthesized compounds of the present invention are characterized in that a 1-alkyl-4-methyl- 1H -1,2,3-triazole linker between the indoline and the hydroxy acid residue is tightly laminated between the Phe155 and Phe210 amino acid residues of the enzyme Stacking has been identified (Figures 2 and 3), and this stacking interaction may be a key contributor to the compounds of the present invention that contribute to good binding affinity with HDAC2.

However, in these docking studies, the indolin moiety was found to interact negatively with the enzyme. As a result, little change in the binding affinity between the compounds having different substituents was observed. In some instances, the predicted binding affinity of the compounds was not readily correlated with the experimental data obtained from the HDAC2 inhibition assay. For example, the stabilization energies of the expected binding modes for HDAC2 of compounds 5b and 5c were found to be quite similar to -7.7 and 7.8 kcal / mol, respectively. These results were difficult to explain the 5-fold difference in HDAC2 inhibitory effect between compounds 5b and 5c. However, Compound 5f with the same stabilization energy as SAHA (-7.4 kcal / mol) showed similar SAHA-like potency in HDAC2 inhibition (Compound 5f has an IC ₅₀ value of 0.91 μM and SAHA of 1.06 μM).

From the above results, the inventors "3-hydroxyimino-2-oxo-indole -" of the second species, including 1-alkyl-4-methyl -1 H -1,2,3- triazol-linker hydroxide based on the structure It has been shown that rock acid has strong cytotoxic effects against several human cancer cell lines including strong HDAC2 inhibitory effect and SW620 (human colon cancer), PC-3 (prostate cancer) and AsPC-1 (pancreatic cancer).

Further, the present inventors confirmed from the above results that 3-hydroxyimino-2-oxoindolin can function well as a cap group of a hydroxamic acid HDAC inhibitor. In addition, it has been found that the type of substituent on the benzene ring of the 3-hydroxyimino-2-oxoindoline moiety can substantially affect both HDAC inhibition and cytotoxicity of the resulting compound.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

A hydroxamic acid-based compound represented by the following formula (1): &lt; EMI ID =
[Chemical Formula 1]

Wherein R is a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a C _1-6 lower alkyl group and a C _1-6 lower alkoxy group, and n is an integer of 0-5.
The compound according to claim 1, wherein R is a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a methyl group and a methoxy group.
According to claim 1, wherein the compound is N-hydroxy-3- (4-1-yl) methyl turn of ((3- (hydroxyimino) -2-oxo) -1 H -1,2,3 -triazol-1-yl) propanoic amide (4a), 3- (4 - (( 5-fluoro-3- (hydroxyimino) -2-oxo-in turned-1-yl) methyl) -1 H- 1,2,3-triazol-1-yl) -N -hydroxypropanamide (4b), and 3- (4 - ((5-chloro-3- (hydroxyimino) -2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- triazol -1 -yl) - N-hydroxy-propanoic amide (4c). &Lt; / RTI &gt;
According to claim 1, wherein the compound is N-hydroxy-4- (4-1-yl) methyl turn of ((3- (hydroxyimino) -2-oxo) -1 H -1,2,3 (5-Fluoro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) - 1 H- (5-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) - N -hydroxybutanamide (5b) yl) methyl) -1 H -1,2,3- triazol-1-yl) - N - hydroxy-butane amide (5c), 4- (4 - ((5- bromo-3- (hydroxyimino ) -2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- triazol-1-yl) - N - hydroxy-butane amide (5d), N - hydroxy-4- ( 4 - ((3- (hydroxyimino) -5-methyl-2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- triazol-1-yl) butane amide (5e) , N-hydroxy-4- (4 - ((3- (hydroxyimino) -5-methoxy-2-oxo-in turned-1-yl) methyl) -1 H -1,2,3- triazole (4-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1 H -1,2,3-triazol-1-yl) -N -hydroxybutanamide (5 g).
The compound according to claim 1, wherein the compound isN-Hydroxy-5- (4 - ((3- (hydroxyimino) -2-oxoindolin-1-yl) methyl)H-1,2,3-triazol-1-yl) pentanamide (6a), 5- (4- ((5-fluoro-3- (hydroxyimino) -2-oxoindolin-HL, 2,3-triazol-l-yl) -N- hydroxypentanamide (6b), 5- (4- (5-chloro-3- (hydroxyimino) -2-oxoindolin-HL, 2,3-triazol-l-yl) -N- hydroxypentanamide (6c), 5- (4- (5-bromo-3- (hydroxyimino) -2-oxoindolin-HL, 2,3-triazol-l-yl) -N- hydroxypentanamide (6d),N- (4 - ((3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) pentanamide (6e),N(4 - ((3- (hydroxyimino) -5-methoxy-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) pentanamide (6f) and 5- (4 - ((7-chloro-3- (hydroxyimino) -2-oxoindolin-HL, 2,3-triazol-l-yl) -N- hydroxypentanamide (6g). &Lt; / RTI &gt;
A pharmaceutical composition for preventing or treating cancer comprising the compound of any one of claims 1 to 5, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
7. The composition of claim 6, wherein the cancer is selected from the group consisting of liver cancer, stomach cancer, brain cancer, bladder cancer, cervical cancer, ovarian cancer, colon cancer, prostate cancer, pancreatic cancer and lung cancer.
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