WO2015016441A1 - Novel isatin-based hydroxamic acid and anti-cancer composition containing same as active ingredient - Google Patents

Novel isatin-based hydroxamic acid and anti-cancer composition containing same as active ingredient Download PDF

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Publication number
WO2015016441A1
WO2015016441A1 PCT/KR2013/012035 KR2013012035W WO2015016441A1 WO 2015016441 A1 WO2015016441 A1 WO 2015016441A1 KR 2013012035 W KR2013012035 W KR 2013012035W WO 2015016441 A1 WO2015016441 A1 WO 2015016441A1
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WIPO (PCT)
Prior art keywords
cancer
formula
oxoindolin
compound
hydroxyheptanamide
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PCT/KR2013/012035
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French (fr)
Korean (ko)
Inventor
한상배
김영수
홍진태
남응우옌하이
마이덩두티
푸옹덩판티
킴오안다오티
Original Assignee
한국보건산업진흥원
충북대학교 산학협력단
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Publication of WO2015016441A1 publication Critical patent/WO2015016441A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring

Definitions

  • Novel isatin-based hydroxytoxane and an active ingredient comprising the same as an active ingredient
  • the present invention relates to a novel isatin-based hydroxamic acid and an anticancer composition comprising the same as an active ingredient. [Background technology]
  • Histone acetylases HATs
  • histone deacetylases HDACs
  • HDACs histone deacetylases
  • Class II HDACs known as sirtuin, include Sirtl-7, a NAD + -dependent enzyme.
  • Class IV contains only one enzyme HDAC11, which characterizes both class I and class II HDACs [2].
  • HDACs In some cancer cell lines and in vivo preclinical models, it is known that inhibition of HDACs induces cell differentiation, aptosis and cell cycle arrest. Therefore, HMC inhibitors are currently attracting attention as anticancer agents [3-6].
  • HDAC inhibitors such as trichostatin A, SAHA (Vorinostat), MS-27-275 (Entinostat), LBH-589 (Panobinostat), PXD-101, And oxamf latin et al. [7-12] (see FIG. 1).
  • SAHA was licensed in 2006 as a treatment for several types of lymphomas. 5
  • HDAC histone deacetylase
  • an object of the present invention is to provide a novel isatin-based hydroxamic acid compound.
  • Another object of the present invention to provide an anticancer pharmaceutical composition comprising the novel isatin-based hydroxamic acid compound as an active ingredient.
  • Still another object of the present invention is to provide a method for treating cancer, comprising administering the novel isatin-based hydroxamic acid compound to a patient in need thereof.
  • Still another object of the present invention is to provide a use of the isatin-based hydroxytoxane compound for the manufacture of a medicament for the treatment of cancer.
  • Still another object of the present invention is to provide a method for preparing the novel isatin-based hydroxamic acid compound.
  • the present invention provides a isatin-based hydroxamic acid compound represented by the following Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof.
  • R is hydrogen, halogen, C ⁇ C 5 alkyl, or nitro.
  • R is hydrogen, halogen, d-Cs alkyl, or nitro. According to a preferred embodiment of the present invention, the formula 1 or formula
  • the substituent R in 2 is at the 5 or 7 carbon position of the isatin ring.
  • halogen as said R substituent is fluorine (F), chlorine (C1), or bromine (Br).
  • pharmaceutically acceptable salt in the present invention is meant to include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. If the compounds of the present invention have basic properties, the base forms can be converted to pharmaceutically acceptable acid addition salts by treating with a suitable acid.
  • Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; Or acetic acid, trifluoroacetic acid, propanoic acid, hydroxyacetic acid, lactic acid, fibric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methane sulfonic acid, ethanesulfonic acid, banzen Organic acids such as sulfonic acid, P-toluenesulfonic acid, cyclic acid, salicylic acid, P-aminosalicylic acid and pamoic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; Or acetic acid, trifluoroacetic acid, propanoic acid, hydroxyacetic acid, lactic acid, fibric acid, oxalic acid, mal
  • the acid forms can be converted to their pharmaceutically acceptable base addition salts by treatment with a suitable organic or inorganic base.
  • suitable base salt forms are, for example, ammonium salts, alkali and alkaline earth metal salts (eg lithium, sodium, potassium, magnesium, calcium salts, etc.), salts with organic bases (eg benzatin, N- Methyl-glucamine, hydravamin salts and salts with amino acids (eg arginine, lysine and the like).
  • the isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy-7- (3- (hydroxythoxyimino) ⁇ 2-oxoindolin -1 ⁇ Yl) heptanamide; the (5-fluoro-3- (hydroxyimino) ⁇ 2-oxoindolin-1-yl;) -N-hydroxyheptanamide; the (5-chloro-3- (hydroxyi) Mino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide; 7- (5-bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) -N- Hydroxyheptanamide; N-hydroxy-g (3- (hydroxyimino) -5-nitro—2-oxoindolin-1-yl) heptanamide; N-hydroxy-7- (3 ′ Mino) -5-methyl-2-oxoindolin-1-
  • the present invention provides a pharmaceutical composition for anticancer comprising the compound of Formula 1 or Formula 2 described above as an active ingredient.
  • the compound of the present invention has the effect of promoting the acetylation of histones through the inhibitory activity of histone deacetylase. That is, the isatin-based hydroxamic acid compound of the present invention induces intracellular histones into a high acetylation state by inhibiting the activity of histone deacetylase.
  • the compounds of the present invention exhibit anti-cancer efficacy by exhibiting cytotoxic effects on various cancer cell lines, as demonstrated in the specific examples below.
  • Cancer the disease to be treated by the pharmaceutical composition of the present invention, is characterized by aggressive characteristics in which cells divide and grow, ignoring normal growth limits, invasive characteristics infiltrating surrounding tissues, and It is a generic term for diseases caused by cells having metastatic properties that spread to other parts of the body.
  • the cancer to be treated is breast cancer, lung cancer, stomach cancer, liver cancer, hematologic cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye sarcoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer , Colorectal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer. More preferably colon cancer, breast cancer, prostate cancer, pancreatic cancer, or lung cancer.
  • the pharmaceutical composition for anticancer of the present invention comprises (i) a pharmaceutically effective amount of the hydroxamic acid compound of Formula 1 or Formula 2 described above; And ( ⁇ ) pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in the formulation, lactose, dextrose sucrose, sorbbi, mantle, starch, acacia rubber, calcium phosphate, alginate, gelatin, 'siliceous kalseum microcrystalline selrol Ross, polyvinyl an pyrrolidone, selreul Ross, water syrup, methyl selreul Ross, methylhydroxy benzoate, propylhydroxy-ethoxy-benzoate, talc, magnesium stearate, and mineral oils such as Including but not limited to.
  • the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • a lubricant e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • Appropriate dosages of the pharmaceutical compositions of the present invention may be prescribed in a variety of ways depending on factors such as formulation method, mode of administration, age, body weight, morbidity, food, time of administration, route of administration, rate of excretion, and reaction response. Can be. On the other hand, the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg / kg (body weight) per day.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.
  • the concentration of the active ingredient included in the composition of the present invention is determined in consideration of the purpose of treatment, the duration of the patient's condition, the severity of the disease and the like, and is not limited to a specific range of concentration.
  • the pharmaceutical composition of the present invention can be easily carried out by those skilled in the art to which the present invention pertains.
  • the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of axes, powders, granules, tablets or capsules, and may further include a dispersant or stabilizer.
  • the present invention provides a method for administering a pharmaceutically effective amount of a isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof to a patient in need of treatment of cancer. It provides a method of treating cancer comprising.
  • R is hydrogen, halogen, d-Cs alkyl, or nitro.
  • R is hydrogen, halogen, d-Cs alkyl, or nitro.
  • halogen in Formula 1 or Formula 2 is fluorine (F), chlorine (C1) or bromine (Br).
  • the isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy- (3 ′ (hydroxyimino) -2 -Oxoindolin-1-yl) heptanamide; 7- (5-fluoro-3— (hydroxyimino) -2-oxoindolin-1 ⁇ yl) -N-hydroxyheptanamide; (5-chloro ⁇ 3 ′ (hydroxyimino) -2-oxo Indolin-1-yl)- N-hydroxyheptanamide; 7- (5-Bromo-3 ′ (hydroxythoxymino) -2-oxoindolin-1-yl;)-N-hydroxyheptanamide; N-hydroxy-7- (3- (hydroxyoxyimino) -5-nitro-2-oxoindolin-1 ylyl) heptanamide, N-hydroxy-7- (3- (hydroxyimino) -5-methyl-2-oxoindolin
  • the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, hematologic cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, Colorectal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.
  • the compound has an activity of promoting acetylation of histones through the inhibition of histone deacetylase.
  • the present invention provides the use of an isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer. -[Formula 1]
  • R is hydrogen, halogen, dC 5 alkyl, or nitro o
  • R is hydrogen, halogen, dC 5 alkyl, or nitro. According to a preferred embodiment of the present invention, the formula 1 above . Or halogen in Formula 2 is fluorine (F), chlorine (C1) or bromine (Br).
  • the isatin-based hydroxytoxane compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy- (3- (hydroxyimino) —2- Oxoindolin-1-yl) heptanamide; 7- (5-fluoro-3- (hydroxyimino) -2-oxoindolin-1 boilyl) -N-hydroxyheptanamide; 7- (5-chloro-3- (hydroxyimino) ⁇ 2-oxoindolin-1-yl) -N-hydroxyheptanamide; 7- (5-bromo-3- (hydroxyimino) -2 -oxo the turned-yl;) -N- hydroxy-heptanoic acid amide; N- hydroxy-7- (3- (hydroxyimino) -5-nitro-2-oxo -1 is turned euil) heptane amide; N-hydroxy-he (3- (hydroxyimino) -5-methyl-2-oxoind
  • the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, hematological cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye sarcoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer , Fallopian tube cancer, endometrial cancer, Cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.
  • the compound has an activity of promoting acetylation of histones through the inhibition of histone deacetylase.
  • the present invention provides a method for preparing the isatin-based hydroxamic acid compound of Formula 1, comprising the following steps:
  • the invention comprises the following steps It provides a method for preparing the isatin-based hydroxamic acid compound of Formula 2:
  • the present invention relates to a novel isatin-based hydroxamic acid and an anticancer composition comprising the same as an active ingredient.
  • the hydroxamic acid compound of the present invention has an inhibitory activity of histone deacetylase (HDAC) and exhibits cytotoxicity in various cancer cells, thereby exhibiting anticancer efficacy, and thus can be developed as an active ingredient of a powerful anticancer agent.
  • HDAC histone deacetylase
  • FIG 1 shows the chemical structures of histone deacetylase (HDAC) inhibitors known to date.
  • HDAC histone deacetylase
  • Figure 2 shows the results confirming the effect of the synthetic compounds of the present invention on histone acetylation in SW620 cells.
  • the cells were treated for 24 hours at a concentration of compound ⁇ ⁇ .
  • the levels of acetylated histones - ⁇ 3 and - ⁇ 4 in total cell lysates were determined by Western blot analysis.
  • SAHA is represented by a stick model by marking carbon, nitrogen and oxygen atoms in yellow, blue and red, respectively.
  • Compounds 3a and 6a represent carbon atoms in cyan and magenta, and nitrogen and oxygen atoms in blue and red, respectively, in a stick model.
  • Important parts of the enzyme interactions are represented by stick models representing carbon, nitrogen and oxygen in green, blue and red, respectively.
  • Zn 2+ ions are shown as dark gray spheres.
  • N- (4-aminophenyl-3-yl) benzamide is a carbon, nitrogen and oxygen atom yellow, Indicated by the stick model by marking in blue and red, respectively.
  • Compounds 3a and 6a represent carbon atoms in grey-blue and white, and nitrogen and oxygen atoms in blue and red, respectively, in a stick model.
  • Important parts of the enzyme interactions are represented by stick models representing carbon, nitrogen and oxygen in green, blue and red, respectively.
  • Zn 2+ ions are represented by gray spheres.
  • Electron ionization (EI), electrospray ionizat ion (ESI) and high resolution mass spectra were measured using PE Biosystems API 2000 and Mar iner ⁇ E mass spectrometers, respectively.
  • Reagents and solvents are available from Aldrich or Fluka Chemical Corp. (Mi lwaukee, WI, USA) or purchased from Merk. The solvent was used by distillation and drying.
  • N-hydroxy'7- (5 / 7-substituted-3-hydroxyimino-2-oxoindolein '1 ⁇ yl) heptanamide (3a-g) was synthesized according to the following formula (1).
  • Banungsik 1 shows the synthesis process of isatin-3-oxime hydroxamic acid of the present invention.
  • the reagents and conditions of the reaction in the synthesis are as follows: a) ethyl gbromoheptanoate, K 2 CO 3 , KI, DMF; b) hydroxylamine hydrochloride, NaOH, MeOH, THF.
  • Banungsik 2 is a synthetic process of the 3 ' -methoxime isatin hydroxamic acid Shows.
  • the reagents and conditions in the synthesis are as follows: (a) methoxylamine hydrochloride, pyridine, ethanol, 8 (rc, 3 hours; (b) ethyl 7-bromoheptanoate, C0 3 , I, DMF, rt, 24 h; (c) hydroxylamine hydrochloride, NaOH, MeOH, THF, 0 ° C. 30 min.Compounds of compound 6a-6g start each 5- / substituted isatin-3-metaspecific.
  • Ester compounds were dissolved in a mixture of methanol-tetrahydrofuran (1/1). Hydroxylamine hydrochloride (10 mol equiv.) was added and the resulting suspension was cooled to -5 ° C. NaOH (10 mol equiv) solution was slowly dropped into the reaction mixture which was kept constant at _5 ° C. After 30 minutes, the reaction contents were poured into cooling water and the crude product was precipitated by adjusting the pH to 7 using HC1 15% solution. The crude product was recrystallized from ethane to give 3a-3g of compound in medium to high yield (5% to 90%).
  • Compound 6a-6g was synthesized through the procedure of Banung Formula 2. Isatin-3'-meroxime hydroxamic acid (Compound 6a-6g) was synthesized by converting isatin to 3-meroxime derivative 4 using mexylamine hydrochloride under reflux under conditions (Ref. 2) Reference). The structures of the obtained compounds and intermediates were clearly identified directly through spectral studies including IR, MS, 1H NMR, 13C NMR, and elemental analysis.
  • HDAC Histone Deacetylase
  • the inhibitory activity of histone- ⁇ 3 and histone- ⁇ 4 deacetylation at ⁇ concentration was evaluated by Western blot analysis for the synthesized hydroxamic acid compound (Compound 3a 3g and Compound 6a-6g).
  • Western blot was performed by the following method. First, the cells were lysed in RIPA complete solution (50 mM Tris HC1 [pH 8.0], 5 mM EDTA, 150 mM NaCl, 1% NP-40, 0.1% SDS, and 1 mM phenylraethylsul fonyl f luoride). Protein extract was obtained.
  • Protein concentration in lysates was measured using the Bio-Rad Protein Assay Kit (Bio-Rad Laboratories Inc., Hercules, CA, USA) according to the manufacturer's instructions. Samples were separated on SDS-PAGE and the nitrocells were transferred to the rose membrane. Membranes were incubated with blocking complete fluid (TBS with 0.2% Tween-20 and 3% skim milk) and then searched using primary antibodies against acetyl histone ⁇ H3, -H4, and GAPDH. After washing, the membranes were searched using a red pepper peroxidase conjugated secondary antibody. Detection was done using an enhanced chemi luminescent protein (ECL) detection system (Amersham Biosciences, Litt le Chal font, UK). (2) Activity measurement result of compound
  • compounds 3a-3d and 3f —3g markedly increased the acetylation of histone- ⁇ 3 and histone- ⁇ 4 through inhibition of HDAC enzymes at ⁇ ⁇ concentration.
  • SAHA a well-known HDAC inhibitor, increased histone acetylation in a similar manner.
  • SRB Sulprohodamine B cell proliferation assays were used to assess the antiproliferative activity of the synthesized compounds.
  • these compounds were screened to inhibit the growth of these cancer cells against SW620 (human colorectal cancer) cell line at a concentration of 30 ⁇ .
  • SW620 human colorectal cancer
  • both Compounds 3a-3f and 6a-6f completely inhibit the growth of SW620 cells at a concentration of 30 ⁇ . Therefore, all of these compounds were converted into SW620 and four additional human cancer cell lines, MCF-7 (breast cancer), PC-3 (prostate cancer) at five different concentrations (30, 10, 3, 1, 0.3 ⁇ ).
  • cytotoxic activity against cancer cells was generally correlated with HDAC inhibitory activity. As shown in FIG. 2, Compounds 6d-6f that did not inhibit HDAC enzyme activity showed the lowest cytotoxic activity against cancer cells. On the other hand, compounds 6a-6c, and 6g, which showed a strong inhibitory activity of HDAC enzymes, as confirmed by the significant increase in acetylation levels of histones—H3 and -H4, all of the five cancer cell lines tested. It also showed strong cytotoxicity against.
  • Compound 6e alone showed an indeterminate biological activity profile, which compound Although it did not inhibit HDAC activity at the analyzed concentration (1 ⁇ M), it showed strong cytotoxicity against four cancer cell lines (SW620, MCF-7, PC-3, AsPC-l) that measured activity. It showed weak anticancer activity only against NCI-H460 cell line. Except for compound 3e and compound 6d-6f, all other compounds showed stronger activity than positive control compound SAHA in terms of cytotoxic activity against cancer cell lines. In particular, compound 3d showed 45-fold stronger cytotoxicity than SAHA against the ' AsPC-l cell line (pancreatic cancer cell line). Compound 3b also showed about 30-fold stronger cytotoxicity against SW620 cell line (colon cancer cell line).
  • 1 represents the concentration of a compound that reduces cell growth by 50% and the number represents the average result of three replicates with a deviation of less than 10%.
  • 2 is cell line: SW620, colon cancer; MCF-7, breast cancer; PC3, prostate cancer; AsPC-l, pancreatic cancer; NCI-H460, lung cancer; 3 SAHA (suberoyl ni 1 ide hydroxamic acid), positive control.
  • HDAC2 complex with N- (2—aminophenyl) benzamide was selected (27, PDB ID: 3MAX). Because histone-H3 and histone-H4 deacetylation are regulated by HDAC1 and HDAC2, docking experiments of Compound 3a and Compound 6a against HDAC2 were performed. As a result of the docking experiment, it was confirmed that both compounds 3a and 6a are well located at the active site of HDAC2, and that the hydroxamic acid part is well located at the zinc-binding site (FIG. 4).

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Abstract

The present invention relates to a novel isatin-based hydroxamic acid and an anti-cancer composition containing same as an active ingredient. The hydroxamic acid compound according to the present invention exhibits anti-cancer effects by having histone deacetylase (HDAC) inhibition activity and cytotoxicity in various cancer cells, and thus can be developed into a powerful active ingredient for an anti-cancer agent.

Description

【명세서】  【Specification】
【발명의 명칭】  [Name of invention]
신규 이사틴 기반 히드톡삼산 및 이를 유효성분으로 포함하는.항암용 조성물  Novel isatin-based hydroxytoxane and an active ingredient comprising the same as an active ingredient
【기술 분야】 [Technical field]
본 발명은 신규의 이사틴 기반 히드록삼산 및 이를 유효성분으로 포함하는 항암용 조성물에 관한 것이다. 【배경 기술】  The present invention relates to a novel isatin-based hydroxamic acid and an anticancer composition comprising the same as an active ingredient. [Background technology]
히스톤 아세틸화효소 (histone acetylases, HATs) 및 히스톤 탈아세틸화효소 (histone deacetylases , HDACs)는 각각 히스톤 꼬리부분에 존재하는 특정한 라이신 잔기의 아세틸화 및 탈아세틸화를 촉매하는 2 가지 효소이다. 이들 효소는 아세틸화가 염색체 구조를 열고 유전자를 전사 가능한 상태로 만드는 것과 관련되어 있기 때문에 유전자 전사에 있어서 매우 중요한 역할을 한다 [1]· 최근의 연구결과에 따르면, 이들 2 가지 효소는 염색체 구조 및 유전자 발현의 조절 뿐만 아니라 세포주기의 진행 및 발암과정도 조절한다 [2]. 인간에서는 18 개의 HDAC 효소들이 확인되었고， 이들은 효모 HDAC 와의 상동성에 기초하여 4 가지의 클래스로 나뉘어진다. 클래스 I은 HDAC 1， 2， 3ᅳ 및 8을 포함하고， 클래스 Π는 HDAC 4, 5, 6， 7, 9 및 10을 포함한다. Sirtuin으로 알려진 클래스 ΠΙ HDACs은 NAD+-의존성 효소인 Sirtl-7 을 포함한다. 클래스 IV는 오직 하나의 효소 HDAC11 을 포함하는데, 이 효소는 클래스 I 및 클래스 Π HDACs 모두의 특성을 나타낸다 [2]. 몇몇의 암세포주 및 인 비보 전임상 모델에서 HDACs 를 억제하면 세포 분화， 아픕토시스 및 세포주기정지가 유도된다는 것이 알려져 있다. 따라서 HMC 억제제가 현재 항암제로서 주목받고 있다 [3-6]. 세포증식성 질환의 치료에 대해 치료적 가능성에 기반하여 다양한 종류의 신규 HDAC 억제제들 예컨대， trichostatin A, SAHA (Vorinostat) , MS-27- 275 (Entinostat), LBH-589 (Panobinostat), PXD- 101, 및 oxamf latin 등이 개발되었다 [7-12] (도 1 참조). 이들 중에서 SAHA 는 몇가지 타입의 림프종 치료제로서 2006년에 허가되었다. 5 Histone acetylases (HATs) and histone deacetylases (HDACs) are two enzymes that catalyze the acetylation and deacetylation of specific lysine residues in the histone tail, respectively. These enzymes play a very important role in gene transcription because acetylation is associated with opening chromosomal structures and making genes transcribable [1]. In addition to regulating expression, it also regulates cell cycle progression and carcinogenesis [2]. Eighteen HDAC enzymes have been identified in humans, which are divided into four classes based on homology with yeast HDACs. Class I includes HDAC 1, 2, 3 kHz and 8, and class Π includes HDAC 4, 5, 6, 7, 9 and 10. Class II HDACs, known as sirtuin, include Sirtl-7, a NAD + -dependent enzyme. Class IV contains only one enzyme HDAC11, which characterizes both class I and class II HDACs [2]. In some cancer cell lines and in vivo preclinical models, it is known that inhibition of HDACs induces cell differentiation, aptosis and cell cycle arrest. Therefore, HMC inhibitors are currently attracting attention as anticancer agents [3-6]. Based on the therapeutic potential for the treatment of cell proliferative diseases, various types of new HDAC inhibitors such as trichostatin A, SAHA (Vorinostat), MS-27-275 (Entinostat), LBH-589 (Panobinostat), PXD-101, And oxamf latin et al. [7-12] (see FIG. 1). Of these, SAHA was licensed in 2006 as a treatment for several types of lymphomas. 5
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용아보다 명확하게 설명된다. Throughout this specification, many papers and patent documents are referenced and their citations are indicated. The disclosures of cited papers and patent documents are hereby incorporated by reference in their entirety, more clearly than the level of the technical field to which the present invention belongs and the contents of the present invention.
【선행기술문헌】 Prior Art Documents
【특허문헌】  [Patent literature]
대한민국 공개특허 제 2009-0094383호  Republic of Korea Patent Publication No. 2009-0094383
대한민국 등록특허 제 10-1261305호 .  Republic of Korea Patent No. 10-1261305.
대한민국 공개특허 제 200그0043978호  Republic of Korea Patent Publication No. 200
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【발명의 내용】 [Content of invention]
【해결하려는 과제】 본 발명자들은 히스톤 탈아세틸화 효소 (hi stone deacetylase , HDAC)에 대한 강력한 억제효과를 갖는 신규의 히드록삼산을 개발하기 위해 연구 노력하였다. 그 결과, 이사틴 기반의 새로운 히드록삼산을 합성하는데 성공하였고， 합성한 히드록삼산 화합물들이 히스톤 탈아세틸화 효소의 활성을 억제할 뿐만 아니라 다양한 종류의 암세포주에 대해 항암 활성을 가진다는 사실을 확인함으로써 본 발명을 완성하였다. [Problem to solve] The present inventors have tried to develop a novel hydroxamic acid having a strong inhibitory effect on histone deacetylase (HDAC). As a result, we succeeded in synthesizing new isatin-based hydroxamic acid, and the synthesized hydroxamic acid compounds not only inhibit the activity of histone deacetylase, but also have anticancer activity against various types of cancer cell lines. The present invention was completed by confirming.
따라서， 본 발명의 목적은 신규의 이사틴 기반 히드록삼산 화합물을 제공하는데 있다.  Accordingly, an object of the present invention is to provide a novel isatin-based hydroxamic acid compound.
본 발명의 다른 목적은 상기 신규 이사틴 기반 히드록삼산 화합물을 유효성분으로 포함하는 항암용 약제학적 조성물을 제공하는데 있다.  Another object of the present invention to provide an anticancer pharmaceutical composition comprising the novel isatin-based hydroxamic acid compound as an active ingredient.
본 발명의 또 다른 목적은 상기 신규 이사틴 기반 히드록삼산 화합물을 암의 치료가 필요한 환자에게 투여하는 단계를 포함하는 암의 치료 방법을 제공하는데 있다.  Still another object of the present invention is to provide a method for treating cancer, comprising administering the novel isatin-based hydroxamic acid compound to a patient in need thereof.
본 발명의 또 다른 목적은 암 치료용 약제를 제조하기 위한 상기 이사틴 기반 히드톡삼산 화합물의 용도를 제공하는데 있다.  Still another object of the present invention is to provide a use of the isatin-based hydroxytoxane compound for the manufacture of a medicament for the treatment of cancer.
본 발명의 또 다른 목적은 상기 신규 이사틴 기반 히드록삼산 화합물의 제조방법을 제공하는데 있다. 본 발명의 목적 및 장점은 하기의 발명의 상세한 설명， 청구의 범위 및 도면에 의해 보다 명확하게 된다.  Still another object of the present invention is to provide a method for preparing the novel isatin-based hydroxamic acid compound. The objects and advantages of the invention will become apparent from the following detailed description, claims and drawings.
【과제의 해결 수단】 ' [Measures for solving the problem]
본 발명의 일 양태에 따르면， 본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 이사틴 기반 히드록삼산 화합물 또는 이의 약제학적으로 허용 가능한 염올 제공한다.  According to one aspect of the present invention, the present invention provides a isatin-based hydroxamic acid compound represented by the following Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof.
[화학식 1]  [Formula 1]
Figure imgf000006_0001
상기 화학식 1에서 R은 수소, 할로겐, C厂 C5알킬， 또는 니트로이다. [화학식 2]
Figure imgf000006_0001
In Formula 1, R is hydrogen, halogen, C 厂 C 5 alkyl, or nitro. [Formula 2]
Figure imgf000007_0001
상기 화학식 2에서 R은 수소， 할로겐， d-Cs알킬， 또는 니트로이다. 본 발명의 바람직한 구현예에 따르면， 상기 화학식 1 또는 화학식
Figure imgf000007_0001
In Formula 2, R is hydrogen, halogen, d-Cs alkyl, or nitro. According to a preferred embodiment of the present invention, the formula 1 or formula
2에서 상기 치환기 R은 이사틴 고리의 5번 또는 7번 탄소위치에 존재한다. 본 발명의 다른 바람직한 구현예에 따르면, 상기 R 치환기로서 할로겐은 플루오르 (F) , 염소 (C1 ) , 또는 브롬 (Br )이다. The substituent R in 2 is at the 5 or 7 carbon position of the isatin ring. According to another preferred embodiment of the invention, halogen as said R substituent is fluorine (F), chlorine (C1), or bromine (Br).
본 발명에서 용어 "약제학적으로 허용 가능한 염"은 약제학적으로 허용 가능한 산부가염 및 약제학적으로 허용 가능한 염기 부가염을 포함하는 의미이다. 본 발명의 화합물이 염기 특성을 갖는다면 상기 염기 형태를 적당한 산으로 처리함으로써 약제학적으로 허용가능한 산부가염으로 전환시킬 수 있다. 적합한 산은 염산， 브롬화수소산， 황산， 질산， 인산 등의 무기산; 또는 예를 들면， 아세트산, 트리플루오로아세트산, 프로판산， 히드록시아세트산, 락트산, 피브루산， 옥살산， 말론산， 숙신산， 말레산， 푸마르산, 말산， 타르타르산， 시트르산, 메탄 술폰산， 에탄술폰산， 밴젠술폰산， P-틀루엔술폰산， 시클람산, 살리실산, P-아미노살리실산， 파모산 등의 유기산을 포함한다. 본 발명의 화합물이 산 특성을 갖는다면， 상기 산 형태를 적당한 유기 또는 무기 염기로 처리함으로써 이의 약제학적으로 허용 가능한 염기 부가염으로 전환시킬 수 있다. 적당한 염기 염 형태는 예를 들면， 암모늄 염， 알칼리 및 알칼리 토금속 염 (예를 들면, 리튬， 나트륨， 칼륨， 마그네슘， 칼슘 염 등) , 유기 염기를 갖는 염 (예를 들면， 벤자틴， N-메틸 -으글루카민， 하이드라바민 염 및 아미노산을 갖는 염 (예를 들면， 아르기닌， 리신 등)을 포함한다.  The term "pharmaceutically acceptable salt" in the present invention is meant to include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. If the compounds of the present invention have basic properties, the base forms can be converted to pharmaceutically acceptable acid addition salts by treating with a suitable acid. Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; Or acetic acid, trifluoroacetic acid, propanoic acid, hydroxyacetic acid, lactic acid, fibric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methane sulfonic acid, ethanesulfonic acid, banzen Organic acids such as sulfonic acid, P-toluenesulfonic acid, cyclic acid, salicylic acid, P-aminosalicylic acid and pamoic acid. If the compounds of the present invention have acid properties, the acid forms can be converted to their pharmaceutically acceptable base addition salts by treatment with a suitable organic or inorganic base. Suitable base salt forms are, for example, ammonium salts, alkali and alkaline earth metal salts (eg lithium, sodium, potassium, magnesium, calcium salts, etc.), salts with organic bases (eg benzatin, N- Methyl-glucamine, hydravamin salts and salts with amino acids (eg arginine, lysine and the like).
본 발명의 다른 바람직한 구현예에 따르면ᅳ 상기 화학식 1 또는 화학식 2으로 표시되는 이사틴 기반 히드록삼산 화합물은 다음의 화합물 중 어느 하나이다: N-히드록시 -7-(3- (히드톡시이미노)ᅳ 2-옥소인돌린 -1一 일 )헵탄아미드； 그 (5-플루오로 -3- (히드록시이미노 )ᅳ2-옥소인돌린 -1-일；) -N- 히드록시헵탄아미드； 그 (5-클로로 -3- (히드록시이미노) -2-옥소인돌린 -1-일 ) - N-히드록시헵탄아미드； 7-(5-브로모 -3- (히드록시이미노) -2-옥소인돌린 -1- 일 )-N-히드록시헵탄아미드； N-히드록시 -그 (3- (히드록시이미노) -5-니트로— 2- 옥소인돌린 -1-일 )헵탄아미드； N-히드록시 -7-(3ᅳ (히드록시이미노) -5-메틸 -2- 옥소인돌린 -1-일 )헵탄아미드； 그ᅳ (7-클로로 -3- (히드록시이口노 )-2- 옥소인돌린 -1-일 )— N-히드록시헵탄아미드； N-히드록시 -7-(3- (메특시ᄋ미노)ᅳ 2-옥소인돌린 -1-일)헵탄아미드； 7-(5-플루오로 -3- (메특시이 ϋ노 )-2ᅳ 옥소인돌린 -1-일 )-Ν-히드록시헵탄아미드 7-(5ᅳ클로로 -3- (메록시이口노) -2- 옥소인돌린 -1-일) -Ν-히드록시헵탄아미드 7- ( 5ᅳ브로모 -3- (메톡시이口노) -2ᅳ 옥소인돌린 -1-일 )-Ν-히드록시헵탄아미드 Ν-히드톡시 -7-(3- (메톡시。미노) - 5-니트로 -2-옥소인돌린 -1—일)헵탄아미드 Ν-히드록시 -7-(3- (메특시 0미노)ᅳ 5-메틸 -2-옥소인돌린— 1-일)헵탄아미드; 및 7— (7-클로로 -3- (메특시。미노) - 2-옥소인돌린 -1—일 )-Ν-히드록시헵탄아미드 . 본 발명의 다른 일 양태에 따르면, 본 발명은 상기 설명된 화학식 1 또는 화학식 2의 화합물을 유효성분으로 포함하는 항암용 약제학적 조성물을 제공한다. According to another preferred embodiment of the present invention ᅳ the isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy-7- (3- (hydroxythoxyimino) ᅳ 2-oxoindolin -1 一 Yl) heptanamide; the (5-fluoro-3- (hydroxyimino) ᅳ 2-oxoindolin-1-yl;) -N-hydroxyheptanamide; the (5-chloro-3- (hydroxyi) Mino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide; 7- (5-bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) -N- Hydroxyheptanamide; N-hydroxy-g (3- (hydroxyimino) -5-nitro—2-oxoindolin-1-yl) heptanamide; N-hydroxy-7- (3 ′ Mino) -5-methyl-2-oxoindolin-1-yl) heptanamide; G- (7-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) — N-hydride Roxyheptanamide; N-Hydroxy-7- (3- (Methoxymino) ᅳ 2-oxoindolin-1-yl) heptanamide; 7- (5-Fluoro-3- (Mexioxy Jyno) -2'oxoindolin-1-yl) -Ν-hydroxyheptanamide 7- (5'chloro-3- (methoxylamino) -2-oxoindolin-1-yl) -Ν-hydroxyheptane Amide 7- (5vinbromo-3- (Methoxyimino) -2'oxoindoline-1-yl) -Ν-hydroxyheptanamide Ν-hydroxythoxy-7- (3- (methoxy.mino) -5-nitro-2-oxoindolin -1-yl) heptanamide Ν-hydroxy-7- (3- (mesoteric 0 mino) ᅳ 5-methyl-2-oxoindolin- 1-yl) heptanamide; And 7— (7-chloro-3- (method. Mino)-2-oxoindolin-1-yl) -N-hydroxyheptanamide. According to another aspect of the present invention, the present invention provides a pharmaceutical composition for anticancer comprising the compound of Formula 1 or Formula 2 described above as an active ingredient.
본 발명의 바람직한 구현예에 따르면, 본 발명의 화합물은 히스톤 탈아세틸화효소 (hi stone deacetylase)의 억제 활성을 통해 히스톤의 아세틸화를 촉진하는 효능을 갖는다. 즉, 본 발명의 이사틴 기반 히드록삼산 화합물은 히스톤 탈아세틸화 효소의 활성을 억제함으로써 세포내 히스톤을 고아세틸화 상태로 유도한다.  According to a preferred embodiment of the present invention, the compound of the present invention has the effect of promoting the acetylation of histones through the inhibitory activity of histone deacetylase. That is, the isatin-based hydroxamic acid compound of the present invention induces intracellular histones into a high acetylation state by inhibiting the activity of histone deacetylase.
본 발명의 화합물은 하기 구체적인 일 실시예에서 입증되는 바와 같이， 다양한 암세포주에 대해 세포독성 효과를 나타내어 항암 효능을 발휘한다.  The compounds of the present invention exhibit anti-cancer efficacy by exhibiting cytotoxic effects on various cancer cell lines, as demonstrated in the specific examples below.
본 발명의 약제학적 조성물에 의한 치료 대상 질병인 "암 (cancer) " 은 세포가 정상적인 성장 한계를 무시하고 분열 및 성장하는 공격적 (aggressive) 특성， 주위 조직에 침투하는 침윤적 ( invasive) 특성， 및 체내의 다른 부위로 퍼지는 전이적 (metastat i c) 특성을 갖는 세포에 의한 질병을 총칭하는 의미이다. 본 발명의 바람직한 구현예에 의하면， 상기 치료 대상암은 유방암, 폐암， 위암， 간암, 혈액암， 뼈암, 췌장암, 피부암, 두경부암， 피부 또는 안구 혹색종， 자궁육종， 난소암， 직장암， 항문암， 대장암， 난관암, 자궁내막암， 자궁경부암， 소장암， 내분비암， 갑상선암， 부갑상선암， 신장암 연조직종양, 요도암， 전립선암， 기관지암， 또는 골수암이다. 보다 바람직하게는 대장암， 유방암, 전립선암， 췌장암， 또는 폐암이다. "Cancer", the disease to be treated by the pharmaceutical composition of the present invention, is characterized by aggressive characteristics in which cells divide and grow, ignoring normal growth limits, invasive characteristics infiltrating surrounding tissues, and It is a generic term for diseases caused by cells having metastatic properties that spread to other parts of the body. According to a preferred embodiment of the present invention, the cancer to be treated is breast cancer, lung cancer, stomach cancer, liver cancer, hematologic cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye sarcoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer , Colorectal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer. More preferably colon cancer, breast cancer, prostate cancer, pancreatic cancer, or lung cancer.
본 발명의 항암용 약제학적 조성물은 ( i ) 상기 설명된 화학식 1 또는 화학식 2의 히드록삼산 화합물의 약제학적 유효량; 및 ( Π ) 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물의 형태로 제공될 수 있다.  The pharmaceutical composition for anticancer of the present invention comprises (i) a pharmaceutically effective amount of the hydroxamic acid compound of Formula 1 or Formula 2 described above; And (Π) pharmaceutically acceptable carriers.
본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서， 락토스， 덱스트로스ᅳ 수크로스， 솔비를， 만니틀, 전분， 아카시아 고무， 인산 칼슘, 알기네이트， 젤라틴，'규산 칼슴， 미세결정성 셀롤로스, 폴리비닐피를리돈， 셀를로스， 물 시럽， 메틸 셀를로스， 메틸히드록시벤조에이트， 프로필히드톡시벤조에이트， 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제， 감미제 향미제， 유화제， 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington 's Pharmaceutical Sciences ( 19th ed . , 1995)에 상세히 기재되어 있다. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in the formulation, lactose, dextrose sucrose, sorbbi, mantle, starch, acacia rubber, calcium phosphate, alginate, gelatin, 'siliceous kalseum microcrystalline selrol Ross, polyvinyl an pyrrolidone, selreul Ross, water syrup, methyl selreul Ross, methylhydroxy benzoate, propylhydroxy-ethoxy-benzoate, talc, magnesium stearate, and mineral oils such as Including but not limited to. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법， 투여 방식 환자의 연령， 체중 성, 병적 상태， 음식， 투여 시간, 투여 경로， 배설 속도 및 반웅 감웅성과 같은 요인들에 따라 다양한 방법으로 처방될 수 있다. 한편， 본 발명의 약제학적 조성물의 투여량은 바람직하게는 1일 당 0.001-1000 mg/kg (체중)이다.  Appropriate dosages of the pharmaceutical compositions of the present invention may be prescribed in a variety of ways depending on factors such as formulation method, mode of administration, age, body weight, morbidity, food, time of administration, route of administration, rate of excretion, and reaction response. Can be. On the other hand, the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg / kg (body weight) per day.
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있고， 비경구로 투여되는 경우, 정맥내 주입, 피하 주입， 근육 주입， 복강 주입， 경피 투여 등으로 투여할 수 있다.  The pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.
본 발명의 조성물에 포함되는 유효성분의 농도는 치료 목적， 환자의 상태 필요 기간, 질환의 위중도 등을 고려하여 결정하며 특정 범위의 농도로 한정되지 않는다. 본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라， 약제학적으로 허용되는 담체 및 /또는 부형제를 이용하여 제제화 함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액， 현탁액 또는 유화액 형태이거나 액스제， 분말제， 과립제， 정제 또는 캅셀제 형태일 수도 있으며， 분산제 또는 안정화제를 추가적으로 포함할 수 있다. 본 발명의 다른 양태에 따르면， 본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 이사틴 기반 히드록삼산 화합물 또는 이의 약제학적으로 허용 가능한 염의 약제학적 유효량을 암의 치료가 필요한 환자에게 투여하는 단계를 포함하는 암을 치료하는 방법을 제공한다. The concentration of the active ingredient included in the composition of the present invention is determined in consideration of the purpose of treatment, the duration of the patient's condition, the severity of the disease and the like, and is not limited to a specific range of concentration. The pharmaceutical composition of the present invention can be easily carried out by those skilled in the art to which the present invention pertains. Thus, by formulating with pharmaceutically acceptable carriers and / or excipients, it may be prepared in unit dose form or may be prepared by incorporation into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of axes, powders, granules, tablets or capsules, and may further include a dispersant or stabilizer. According to another aspect of the present invention, the present invention provides a method for administering a pharmaceutically effective amount of a isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof to a patient in need of treatment of cancer. It provides a method of treating cancer comprising.
[화학식 1]  [Formula 1]
Figure imgf000010_0001
Figure imgf000010_0001
상기 화학식 1에서 R은 수소， 할로겐， d-Cs알킬， 또는 니트로이다. [화학식 2]  In Formula 1, R is hydrogen, halogen, d-Cs alkyl, or nitro. [Formula 2]
Figure imgf000010_0002
상기 화학식 2에서 R은 수소， 할로겐， d-Cs알킬， 또는 니트로이다. 본 발명의 바람직한 구현예에 따르면， 상기 화학식 1 또는 화학식 2에서 할로겐은 플루오르 (F) , 염소 (C1 ) 또는 브름 (Br)이다.
Figure imgf000010_0002
In Formula 2, R is hydrogen, halogen, d-Cs alkyl, or nitro. According to a preferred embodiment of the present invention, halogen in Formula 1 or Formula 2 is fluorine (F), chlorine (C1) or bromine (Br).
본 발명의 다른 바람직한 구현예에 따르면， 상기 화학식 1 또는 화학식 2으로 표시되는 이사틴 기반 히드록삼산 화합물은 다음의 화합물 중 어느 하나이다: N-히드록시-그 (3ᅳ (히드록시이미노) -2-옥소인돌린 -1- 일)헵탄아미드; 7-(5-플루오로 -3— (히드록시이미노) -2-옥소인돌린 -1ᅳ일) -N- 히드록시헵탄아미드； 그 (5-클로로ᅳ 3ᅳ (히드록시이미노) -2-옥소인돌린 -1-일 )- N-히드록시헵탄아미드; 7-(5-브로모 -3ᅳ (히드톡시이미노) -2-옥소인돌린 -1- 일；) -N-히드록시헵탄아미드； N-히드록시 -7- (3- (히드톡시이미노) -5-니트로 -2- 옥소인돌린 -1ᅳ일 )헵탄아미드； N-히드록시 -7-(3- (히드록시이미노) -5-메틸 -2- 옥소인돌린 -1ᅳ일)헵탄아미드; 7-(7-클로로 -3- (히드록시이 P노) -2- 옥소인돌린 -1-일 )-N-히드록시헵탄아미드； N-히드록시-그 (3- (메톡시 o미노) - 2-옥소인돌린 -1-일)헵탄아미드; 그 (5-플루오로ᅳ 3- (메록시이口노) -2- 옥소인돌린— 1ᅳ일 )-Ν-히드록시헵탄아미드； 그 ( 5-클로로 -3-(메록시이 노) -2- 옥소인돌린 -1-일 히드록시헵탄아미드； 7-(5-브로모 -3- (메톡시이 n노 )-2- 옥소인돌린 -1-일) -Ν-히드록시헵탄아 Ν-히드록시 -7-(3- (메톡시 ο미노) - 5-니트로 -2-옥소인돌린 -1-일)헵탄아 Ρ Ν—히드록시 -7-(3- (메톡시 0미노) -According to another preferred embodiment of the present invention, the isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy- (3 ′ (hydroxyimino) -2 -Oxoindolin-1-yl) heptanamide; 7- (5-fluoro-3— (hydroxyimino) -2-oxoindolin-1 돌 yl) -N-hydroxyheptanamide; (5-chloro ᅳ 3 ′ (hydroxyimino) -2-oxo Indolin-1-yl)- N-hydroxyheptanamide; 7- (5-Bromo-3 ′ (hydroxythoxymino) -2-oxoindolin-1-yl;)-N-hydroxyheptanamide; N-hydroxy-7- (3- (hydroxyoxyimino) -5-nitro-2-oxoindolin-1 ylyl) heptanamide, N-hydroxy-7- (3- (hydroxyimino) -5-methyl-2-oxoindolin-1 ylyl) heptanamide; 7- (7-Chloro-3- (hydroxyy-Pano) -2-oxoindolin-1-yl) -N-hydroxyheptanamide; N-hydroxy-he (3- (methoxy omino)- 2-oxoindolin-1-yl) heptanamide; The (5-fluoro- 3- (Methoxyimino) -2-oxoindoline—1xyl) -N-hydroxyheptanamide; (5-chloro-3- (methoxyino) -2-oxo Indolin-1-yl hydroxyheptanamide; 7- (5-bromo-3- (methoxyino n-2-)-2-oxoindolin-1-yl) -Ν-hydroxyheptana Ν-hydroxy- 7- (3- (methoxy omino) -5-nitro-2-oxoindolin-1-yl) heptana Ρ Ν—hydroxy-7- (3- (methoxy 0mino)-
5-메틸 -2-옥소인돌린 -1-일)헵탄아미드; 및 7-(7-클로로 -3- (메톡시 ο미노) -5-methyl-2-oxoindolin-1-yl) heptanamide; And 7- (7-chloro-3- (methoxy οmino)-
2-옥소인돌린 -1-일) -Ν-히드록시헵탄아미드. 2-oxoindolin-1-yl) -Ν-hydroxyheptanamide.
본 발명의 다른 바람직한 구현예에 따르면， 상기 암은 유방암， 폐암, 위암， 간암， 혈액암， 뼈암, 췌장암， 피부암, 두경부암， 피부 또는 안구 흑색종, 자궁육종, 난소암, 직장암, 항문암， 대장암， 난관암, 자궁내막암, 자궁경부암， 소장암, 내분비암， 갑상선암， 부갑상선암, 신장암， 연조직종양, 요도암， 전립선암， 기관지암， 또는 골수암이다.  According to another preferred embodiment of the present invention, the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, hematologic cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, Colorectal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.
본 발명의 다른 바람직한 구현예에 따르면, 상기 화합물은 히스론 탈아세틸화효소 (hi stone deacetylase)의 억제를 통해 히스톤의 아세틸화를 촉진하는 활성을 갖는다. 본 발명의 다른 양태에 따르면， 본 발명은 암 치료용 약제를 제조하기 위한 하기 화학식 1 또는 화학식 2로 표시되는 이사틴 기반 히드록삼산 화합물 또는 이의 약학적으로 허용 가능한 염의 용도를 제공한다. - [화학식 1]  According to another preferred embodiment of the present invention, the compound has an activity of promoting acetylation of histones through the inhibition of histone deacetylase. According to another aspect of the present invention, the present invention provides the use of an isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer. -[Formula 1]
Figure imgf000011_0001
상기 화학식 1에서 R은 수소， 할로겐, d-C5알킬， 또는 니트로 o [화학식 2]
Figure imgf000011_0001
In Formula 1, R is hydrogen, halogen, dC 5 alkyl, or nitro o [Formula 2]
Figure imgf000012_0001
상기 화학식 2에서 R은 수소， 할로겐， d-C5알킬， 또는 니트로이다. 본 발명의 바람직한 구현예에 따르면, 상기 화학식 1 .또는 화학식 2에서 할로겐은 플루오르 (F) , 염소 (C1 ) 또는 브름 (Br )이다.
Figure imgf000012_0001
In Formula 2, R is hydrogen, halogen, dC 5 alkyl, or nitro. According to a preferred embodiment of the present invention, the formula 1 above . Or halogen in Formula 2 is fluorine (F), chlorine (C1) or bromine (Br).
본 발명이 바람직한 구현예에 따르면, 상기 화학식 1 또는 화학식 2으로 표시되는 이사틴 기반 히드톡삼산 화합물은 다음의 화합물 중 어느 하나이다: N-히드록시-그 (3- (히드록시이미노)—2-옥소인돌린 -1- 일 )헵탄아미드; 7-(5-플루오로 -3- (히드록시이미노) -2-옥소인돌린 -1ᅳ일 )-N- 히드록시헵탄아미드; 7-(5-클로로 -3- (히드록시이미노 )ᅳ2-옥소인돌린 -1-일) - N-히드록시헵탄아미드； 7-(5-브로모 -3- (히드록시이미노) -2-옥소인돌린 -1- 일；) -N-히드록시헵탄아미드； N-히드록시 -7-(3- (히드록시이미노) -5-니트로 -2- 옥소인돌린 -1ᅳ일 )헵탄아미드； N-히드록시-그 (3- (히드록시이미노) -5-메틸 -2- 옥소인돌린 -1-일)헵탄아미드； 7-(7-클로로 -3- (히드록시이 노 )-2- 옥소인돌린 -1-일) -N-히드록시헵탄아미드; N-히드록시 -7-(3ᅳ (메톡시 o미노) - 2-옥소인돌린 -1-일)헵탄아미드; 7-(5-플루오로 -3- (메록시이口노)ᅳ 2- 옥소인돌린 -1-일) -N-히드록시헵탄아미드 7- (5-클로로 -3- (메톡시이口노) -2- 옥소인돌린 -1-일) -N-히드록시헵탄아미드 7-(5-브로모 -3- (메록시이口노) -2- 옥소인돌린 -1ᅳ일 )-N—히드록시헵탄아미드 Nᅳ히드톡시 -7— (3- (메특시 o미노) - 5-니트로 -2-옥소인돌린 -1ᅳ일 )헵탄아미드 Nᅳ히드톡시—그 (3- (메특시 o미노) -According to a preferred embodiment of the present invention, the isatin-based hydroxytoxane compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy- (3- (hydroxyimino) —2- Oxoindolin-1-yl) heptanamide; 7- (5-fluoro-3- (hydroxyimino) -2-oxoindolin-1 boilyl) -N-hydroxyheptanamide; 7- (5-chloro-3- (hydroxyimino) 노 2-oxoindolin-1-yl) -N-hydroxyheptanamide; 7- (5-bromo-3- (hydroxyimino) -2 -oxo the turned-yl;) -N- hydroxy-heptanoic acid amide; N- hydroxy-7- (3- (hydroxyimino) -5-nitro-2-oxo -1 is turned euil) heptane amide; N-hydroxy-he (3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) heptanamide; 7- (7-chloro-3- (hydroxyino) -2-oxo Indolin-1-yl) -N-hydroxyheptanamide; N-hydroxy-7- (3 ′ (methoxy omino) -2-2-oxoindolin-1-yl) heptanamide; 7- (5-Fluoro-3- (methoxyisocyno) ᅳ 2-oxoindolin-1-yl) -N-hydroxyheptanamide 7- (5-chloro-3- (methoxyisocyno)- 2-oxoindolin-1-yl) -N-hydroxyheptanamide 7- (5-bromo-3- (methyoxy-guno) -2-oxoindolin-1syl) -N—hydroxyheptanamide N-Hydroxy-7- (3- (Methocy o-mino)-5-nitro-2-oxoindolin-1xyl) heptanamide N-Hydroxy-he (3- (Methocy o-mino)-
5-메틸 -2-옥소인돌린 -1-일)헵탄아미드; 및 7-(7-클로로 -3- (메톡시 o미노) - 2-옥소인돌린 -1-일 )-N-히드록시헵탄아미드 . 5-methyl-2-oxoindolin-1-yl) heptanamide; And 7- (7-chloro-3- (methoxy omino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide.
본 발명의 바람직한 구현예에 따르면, 상기 암은 유방암, 폐암, 위암 간암， 혈액암， 뼈암， 췌장암， 피부암， 두경부암， 피부 또는 안구 혹색종， 자궁육종， 난소암， 직장암， 항문암， 대장암, 난관암， 자궁내막암, 자궁경부암， 소장암， 내분비암, 갑상선암， 부갑상선암， 신장암， 연조직종양， 요도암, 전립선암， 기관지암， 또는 골수암이다. According to a preferred embodiment of the present invention, the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, hematological cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye sarcoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer , Fallopian tube cancer, endometrial cancer, Cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.
본 발명의 바람직한 구현예에 따르면, 상기 화합물은 히스톤 탈아세틸화효소 (hi stone deacetyl ase)의 억제를 통해 히스톤의 아세틸화를 촉진하는 활성을 갖는다. 본 발명의 다른 양태에 따르면， 본 발명은 다음의 단계를 포함하는 상기 화학식 1의 이사틴 기반 히드록삼산 화합물을 제조하는 방법을 제공한다:  According to a preferred embodiment of the present invention, the compound has an activity of promoting acetylation of histones through the inhibition of histone deacetylase. According to another aspect of the present invention, the present invention provides a method for preparing the isatin-based hydroxamic acid compound of Formula 1, comprising the following steps:
a) 하기 일반식 1의 화합물을 에틸 7-브로모헵타노에이트와 반응시켜 하기 일반식 2의 화합물을 제조하는 단계로세 일반식 1에서 R은 수소， 할로겐， d— C5 알킬， 또는 니트로인 단계; 및 a) reacting a compound of formula 1 with ethyl 7-bromoheptanoate to prepare a compound of formula 2 wherein R is hydrogen, halogen, d—C 5 alkyl, or nitroin step; And
Figure imgf000013_0001
Figure imgf000013_0001
b) 하기 일반식 2의 화합물을 히드록실아민 하이드로클로라이드와 반웅시켜 하기 일반식 3의 화합물을 제조하는 단계.  b) reacting the compound of Formula 2 with hydroxylamine hydrochloride to prepare a compound of Formula 3.
Figure imgf000013_0002
본 발명의 다른 양태에 따르면， 본 발명은 다음의 단계를 포함하는 상기 화학식 2의 이사틴 기반 히드록삼산 화합물을 제조하는 방법을 제공한다:
Figure imgf000013_0002
According to another aspect of the invention, the invention comprises the following steps It provides a method for preparing the isatin-based hydroxamic acid compound of Formula 2:
a) 하기 일반식 1의 이사틴 화합물을 메톡실아민 히드로클로라이드와 반웅시켜 하기 일반식 4의 3-메톡심 유도체로 전환시키는 단계로서, 하기 일반식 1에서 R은 수소， 할로겐 C厂 C5알킬, 또는 트로인 단계; a) reacting the isatin compound of formula 1 with methoxylamine hydrochloride to convert it to a 3-methoxime derivative of formula 4 wherein R is hydrogen, halogen C 厂 C 5 alkyl Or troin step;
Figure imgf000014_0001
b) 하기 일반식 4의 화합물을 에틸 7-브로모헵타노이트와 반웅시켜 하기 일반식 5의 화합물을 제조하는 단계; 및
Figure imgf000014_0001
b) reacting the compound of formula 4 with ethyl 7-bromoheptanoite to prepare a compound of formula 5; And
Figure imgf000014_0002
c) 하기 일반식 5의 화합물을 히드록실아민 하이드로클로라이드와 반웅시켜 일반식 6의 화합물을 제조하는 단계.
Figure imgf000014_0002
c) reacting the compound of Formula 5 with hydroxylamine hydrochloride to prepare a compound of Formula 6.
Figure imgf000014_0003
Figure imgf000014_0003
Figure imgf000015_0001
Figure imgf000015_0001
【발명의 효과】 【Effects of the Invention】
본 발명은 신규의 이사틴 기반 히드록삼산 및 이를 유효성분으로 포함하는 항암용 조성물에 관한 것이다. 본 발명의 히드록삼산 화합물은 히스톤 탈아세틸화 효소 (hi stone deacetyl ase , HDAC)의 억제 활성을 가지며 다양한 암세포에서 세포독성을 나타내어 항암 효능을 발휘하므로， 강력한 항암제의 활성성분으로 개발될 수 있다. 【도면의 간단한 설명】  The present invention relates to a novel isatin-based hydroxamic acid and an anticancer composition comprising the same as an active ingredient. The hydroxamic acid compound of the present invention has an inhibitory activity of histone deacetylase (HDAC) and exhibits cytotoxicity in various cancer cells, thereby exhibiting anticancer efficacy, and thus can be developed as an active ingredient of a powerful anticancer agent. [Brief Description of Drawings]
도 1은 지금까지 알려진 히스톤 탈아세틸화 효소 (HDAC) 억제자들의 화학구조를 보여준다.  Figure 1 shows the chemical structures of histone deacetylase (HDAC) inhibitors known to date.
도 2는 SW620 세포에서 히스톤 아세틸화에 대한 본 발명의 합성 화합물들의 영향을 확인한 결과이다. 세포에 대해 화합물 Ι μ Μ의 농도로 24시간 동안 처리하였다. 총 세포 용해물에서 아세틸화된 히스톤 -Η3 및 - Η4의 수준을 웨스턴 블롯 분석을 통해 측정하였다.  Figure 2 shows the results confirming the effect of the synthetic compounds of the present invention on histone acetylation in SW620 cells. The cells were treated for 24 hours at a concentration of compound Ι μΜ. The levels of acetylated histones -Η3 and -Η4 in total cell lysates were determined by Western blot analysis.
도 3는 HDAC8에 대해 SAHA의 실제 결합 모습 및 화합물 3a 및 화합물 6a의 시물레이션 도킹 모습을 보여준다. SAHA는 탄소， 질소 및 산소 원자를 노란색， 파란색 및 빨간색으로 각각 표시하여 스틱 모델로 표시하였다. 화합물 3a 및 6a는 탄소 원자를 청록색 및 자홍색으로 표시하고， 질소 및 산소 원자는 각각 파랑 및 빨강색으로 표시하여 스틱 모델로 나타내었다. 효소의 상호작용시의 중요한 부분들은 탄소, 질소 및 산소를 각각 녹색， 파란색 및 빨간색으로 각각 나타내는 스틱 모델로 나타내었다. Zn2+ 이온은 짙은 회색구로 표시하였다. 3 shows the actual binding of SAHA to HDAC8 and the simulated docking of compounds 3a and 6a. SAHA is represented by a stick model by marking carbon, nitrogen and oxygen atoms in yellow, blue and red, respectively. Compounds 3a and 6a represent carbon atoms in cyan and magenta, and nitrogen and oxygen atoms in blue and red, respectively, in a stick model. Important parts of the enzyme interactions are represented by stick models representing carbon, nitrogen and oxygen in green, blue and red, respectively. Zn 2+ ions are shown as dark gray spheres.
도 4는 HDAC2에 대해 N-(4-아미노페닐 -3-일)벤즈아미드의 실제 결합 모습 및 화합물 3a 및 화합물 6a의 시물레이션 도킹 모습을 보여준다. N- (4-아미노페닐 -3ᅳ일)벤즈아미드는 탄소， 질소 및 산소 원자를 노란색， 파란색 및 빨간색으로 각각 표시하여 스틱 모델로 표시하였다. 화합물 3a 및 6a는 탄소 원자를 회색-파란색 및 백색으로 표시하고， 질소 및 산소 원자는 각각 파랑 및 빨강색으로 표시하여 스틱 모델로 나타내었다. 효소의 상호작용시의 중요한 부분들은 탄소， 질소 및 산소를 각각 녹색， 파란색 및 빨간색으로 각각 나타내는 스틱 모델로 나타내었다. Zn2+ 이온은 질은 회색구로 표시하였다. 4 shows the actual binding of N- (4-aminophenyl-3-yl) benzamide to HDAC2 and the simulated docking of compounds 3a and 6a. N- (4-aminophenyl-3xyl) benzamide is a carbon, nitrogen and oxygen atom yellow, Indicated by the stick model by marking in blue and red, respectively. Compounds 3a and 6a represent carbon atoms in grey-blue and white, and nitrogen and oxygen atoms in blue and red, respectively, in a stick model. Important parts of the enzyme interactions are represented by stick models representing carbon, nitrogen and oxygen in green, blue and red, respectively. Zn 2+ ions are represented by gray spheres.
【발명을 실시하기 위한 구체적인 내용】 [Specific contents to carry out invention]
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로， 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다. 시예  Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention more specifically, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. . Example
I . 화합물의 합성 I. Synthesis of Compound
1. 재료 및 방법  1. Materials and Methods
모든 화합물들은 균일하게 얻었으며， Whatman® 250 Jm Si l ica Gel GF Uniplates상에서 박막 크로마토그래피를 행하고 λ 254 nm 및 365 nm 파장의 UV광 하에서 시각화하여 확인하였다. 끓는점은 Electrothermal Melt ing Point apparatus를 사용하여 측정하였다. 크로마토그래피를 사용한 정제는 Merck si l ica gel 60 (240 to 400 mesh)를 사용하여 오픈 플래쉬 실리카젤 컬럼 크로마토그래피를 통해 행하였다. 핵자기공명스펙트럼 (1H NMR)은 다르게 지정하지 않으면 테트라메틸실란을 내부표준물질로 사용하고 DMS0-d6를 용매로 사용하여 Bruker DPX 500 丽 z FT NMR spectrometer상에서 측정하였다. 화학적 이동 (chemical shi ft )은 내부표준물질인 테트라메틸실란으로부터의 다운필드로 ppm (parts per mi 11 ion)으로 기록하였다. 전자이온화 (electron ioni zat ion, EI ) , 전기분무이온화 (electrospray ionizat ion, ESI ) 및 고해상도 질량스펙트럼은 각각 PE Biosystems API 2000 및 Mar iner^E mass spectrometers를 사용하여 측정하였다. 시약 및 용매는 Aldrich사 또는 Fluka Chemical Corp . (Mi lwaukee , WI , USA) 또는 Merk사로부터 구입하여 사용하였다. 용매는 증류 및 건조하여 사용하였다. All compounds were obtained uniformly and confirmed by thin layer chromatography on Whatman® 250 Jm Si Gel Gel GF Uniplates and visualized under UV light of λ 254 nm and 365 nm wavelength. Boiling point was measured using an electrothermal melting point apparatus. Purification using chromatography was performed via open flash silica gel column chromatography using Merck si gel gel 60 (240 to 400 mesh). Nuclear magnetic resonance spectra (1H NMR) were measured on a Bruker DPX 500 liza z FT NMR spectrometer using tetramethylsilane as internal standard and DMS0-d 6 as solvent unless otherwise specified. Chemical shifts were reported in parts per mi 11 ion (ppm) downfield from tetramethylsilane, an internal standard. Electron ionization (EI), electrospray ionizat ion (ESI) and high resolution mass spectra were measured using PE Biosystems API 2000 and Mar iner ^ E mass spectrometers, respectively. Reagents and solvents are available from Aldrich or Fluka Chemical Corp. (Mi lwaukee, WI, USA) or purchased from Merk. The solvent was used by distillation and drying.
2. 합성예 2. Synthesis Example
합성예 1: N-히드록시-그 (5/7-치환 -3-히드록시이미노 -2-옥소인돌인- 卜일)헵탄아미드 (화합물 3a-3g)의 합성  Synthesis Example 1 Synthesis of N-Hydroxy- (5 / 7-Substituted-3-hydroxyimino-2-oxoindolin-hoxyl) heptanamide (Compound 3a-3g)
N-히드록시ᅳ7-(5/7-치환 -3-히드록시이미노 -2-옥소인돌인ᅳ 1ᅳ 일)헵탄아미드 (3a-g)는 하기 반웅식 1에 따라 합성하였다.  N-hydroxy'7- (5 / 7-substituted-3-hydroxyimino-2-oxoindolein '1 ᅳ yl) heptanamide (3a-g) was synthesized according to the following formula (1).
[반응식 1]  Scheme 1
Figure imgf000017_0001
Figure imgf000017_0001
상기 반웅식 1은 본 발명의 이사틴 -3-옥심계 히드록삼산의 합성과정을 보여준다. 합성과정에서의 반응의 시약 및 조건은 다음과 같다: a) 에틸 그브로모헵타노에이트， K2C03, KI , DMF; b) 히드록실아민 하이드로클로라이드， NaOH, MeOH, THF. Banungsik 1 shows the synthesis process of isatin-3-oxime hydroxamic acid of the present invention. The reagents and conditions of the reaction in the synthesis are as follows: a) ethyl gbromoheptanoate, K 2 CO 3 , KI, DMF; b) hydroxylamine hydrochloride, NaOH, MeOH, THF.
(1) 화합물 3a: N-히드록시 -7-(3-히드록시이미노 -2-옥소인돌린 -1- 일)헵탄아미드의 합성 (1) Compound 3a: Synthesis of N-hydroxy-7- (3-hydroxyimino-2-oxoindolin-1-yl) heptanamide
DMF 내의 화합물 la 용액 (147 mg, 1 隱 ol )을 -5°C로 넁각시키고 2C03(165.5 mg , 1.2 麵 ol )을 첨가하였다. 흔합물을 5°C에서 1시간 동안 교반한 후 상온에서 45분간 교반하고， C¾0H (0.5 ml ) 및 KI (8.3 mg, 0.05 隱 ol )를 첨가하였다. 15분간 교반한 후에, DMF내의 에틸 7- 브로모헵타노에이트 용액 ((1 ml )을 첨가하고， 생성된 반웅 흔합물을 60°C에서 24 시간 동안 교반하였다. 반응이 종료된 후에 반웅흔합물을 냉각시키고， 10% HC1로 산성화시킨 후， DCM(50 ml x2)로 추 하였다. 추출물을 회수하여 DCM을 감압하에서 증발시켰다. 화합물 2a는 갈색- 노란색 오일형태로 최종 수득하였다. 수율: 80%; Rf = 0.8 (DCM/MeOH, 30/1). Compound la solution (147 mg, 1 μl) in DMF was angled to −5 ° C. and 2CO 3 (165.5 mg, 1.2 μl) was added. The mixture was stirred at 5 ° C. for 1 hour and then at room temperature for 45 minutes, and C¾0H (0.5 ml) and KI (8.3 mg, 0.05 隱 ol) were added. After stirring for 15 minutes, ethyl 7-bromoheptanoate solution ((1 ml) in DMF was added and the resulting reaction mixture was stirred at 60 ° C. for 24 hours. After cooling, acidified with 10% HC1, added with DCM (50 ml x2). The extract was recovered and DCM was evaporated under reduced pressure. Compound 2a was finally obtained in the form of a brown-yellow oil. Yield: 80%; Rf = 0.8 (DCM / MeOH, 30/1).
메탄을 /테트라하이드로푸란 흔합물 (1/1， 3 mL)내의 화합물 2a의 용액 (289 mg, 1 醒 oL)올 -5°C까지 냉각시킨 후에 히드록실암모늄 클로라이드 (195 mg, 10 腦 ol)를 첨가하였다. NaOH(0.4 g, 10 隱 ol)를 2 ml의 물에 용해시키고， -5°C로 넁각시켜 흔합물에 첨가하였다. 흔합물은 화합물 2a가 완전히 반응할 때까지 -5°C에서 교반하였다. 반웅 흔합물에 HC1 15% 용액을 가하여 pH 7까지 산성화시킴으로써 침전을 유도하였다. 침전물을 여과하고 물로 세정하여 6( C에서 건조시키고， 에탄을로부터 재결정화하여 노란색 고체의 화합물을 얻었다. Hydrogenammonium chloride (195 mg, 10 μl) after cooling the methane to a solution of compound 2a (289 mg, 1 μL) ol at −5 ° C. in a / tetrahydrofuran mixture (1/1, 3 mL) Was added. NaOH (0.4 g, 10 μl ol) was dissolved in 2 ml of water and added to the mixture by stirring at −5 ° C. The mixture was stirred at -5 ° C until compound 2a fully reacted. Precipitation was induced by adding HC1 15% solution to the reaction mixture and acidifying to pH 7. The precipitate was filtered, washed with water, dried at 6 (C and recrystallized from ethane to give a yellow solid compound.
수율: 65%. mp: 192- 194 °C. Rf = 0.65 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3420， 325K0H), 3050 (NH) , 2927, 2865 (CH, CH2), 1650， 1629 (00)， 1558 (C=C). ESI -MS (m/z): 305.4 [M-H]-. 1H-NMR (500 丽 z, DMS0- d6, ppm): δ 13.45 (1H, s, OH, oxime), 10.35 (1H, s, NH), 8.68 (1H, brs, OH), 7.97 (1H, d, J = 7.5 Hz), 7.42 (1H, t, J = 7.5 Hz), 7.06-7.10 (2H, m), 3.67 (2H, t, J = 7.0 Hz, CH2), 1.91 (2H, t, J = 8.5 Hz, CH2), 1.55-1.57 (2H, m, CH2), 1.44-1.47 (2H, m, CH2), 1.25-1.26 (4H, m, CH2). 13C 匪 R (125 MHz, DMS0— d6, ppm)： δ 169.20, 163.00, 143.00, 143.00, 132.12, 126.12， 126.98， 122.56, 115.24, 109.18， 32.21, 30.70, 28.21， 26.90， 25.96, 25.01. Anal. Calcd. For C15H20N304 (306.34) ： C, 58.81； H, 6.58； N, 13.72. Found: 58.64； H, 6.61； N, 13.55. 다른 화합물 3b-3g는 상기 화합물 3a의 합성에서 사용하였던 방법과 유사한 방법을 통해 각각의 5-/그치환된 이사틴을 출발물질로 하여 합성하였다. Yield 65%. mp: 192- 194 ° C. Rf = 0.65 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3420, 325K0H), 3050 (NH), 2927, 2865 (CH, CH2), 1650, 1629 (00), 1558 (C = C). ESI-MS (m / z): 305.4 [M−H] −. 1 H-NMR (500 lj, DMS0-d6, ppm): δ 13.45 (1H, s, OH, oxime), 10.35 (1H, s, NH), 8.68 (1H, brs, OH), 7.97 (1H, d , J = 7.5 Hz), 7.42 (1H, t, J = 7.5 Hz), 7.06-7.10 (2H, m), 3.67 (2H, t, J = 7.0 Hz, CH2), 1.91 (2H, t, J = 8.5 Hz, CH 2), 1.55-1.57 (2H, m, CH 2), 1.44-1.47 (2H, m, CH 2), 1.25-1.26 (4H, m, CH 2). 13C 匪 R (125 MHz, DMS0—d6, ppm): δ 169.20, 163.00, 143.00, 143.00, 132.12, 126.12, 126.98, 122.56, 115.24, 109.18, 32.21, 30.70, 28.21, 26.90, 25.96, 25.01. Anal. Calcd. For C 15 H 20 N 304 (306.34): C, 58.81; H, 6.58; N, 13.72. Found: 58.64; H, 6.61; N, 13.55. Other compounds 3b-3g were synthesized using each 5- / substituted isatin as a starting material in a similar manner to that used for the synthesis of compound 3a.
(2) 화합물 3b: 7-(5-플루오로 -3ᅳ (히드록시이미노) -2—옥소인돌린 -1- 일) - ^히드록시헵탄아미드의 합성 (2) Compound 3b: Synthesis of 7- (5-fluoro-3 ′ (hydroxyimino) -2—oxoindolin-1-yl)-^ hydroxyheptanamide
수율: 67.5%. mp: 188- 190 °C. Rf = 0.67 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3417, 3220 (OH), 3057 (NH) , 2936， 2859 (CH, CH2), 1714, 1662 (C=0) , 1618， 1598 (OC) · ESI -MS (m/z): 323.1 [M-H]-, 346.0 [M+Na] +. IH-NMR (500 MHz, DMS0-d6, ppm): δ 12.65 (1H, s, OH, oxime), 10.32 (1H, s, NH), 8.64 (1H, brs, OH), 7.75 (1H, dd, J = 8.0， 2.5 Hz), 7.30 (1H, td, J = 9.0, 2.5 Hz, H6), 7.14 (1H, dd, J = 8.5， 4.0 Hz, H7), 3.68 (2H, t, J = 7.0 Hz, CH2), 1.92 (2H, t, J = 7.5 Hz, CH2), 1.54-1.57 (2H, m, CH2), 1.44-1.47 (2H, m, CH2), 1.26-1.27 (4H, m, CH2). 13C NMR (125丽 z, DMS0-d6, ppm): δ 169.58, 163.32, 159.31, 143.71, 139.89, 118.74, 118.55, 116.24, 116.17, 114.51， 114.30， 110.67, 110.61, 32.65, 28.67, 27.27, 26.39, 25.45. Anal. Calcd. For C15H18FN304 (323.32)： C, 55.72； H, 5.61； N, 13.00. Found: C, 55.75； H, 5.57； N, 13.21. Yield 67.5%. mp: 188-190 ° C. Rf = 0.67 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3417, 3220 (OH), 3057 (NH), 2936, 2859 (CH, CH2), 1714, 1662 (C = 0), 1618, 1598 (OC) ESI-MS (m / z) : 323.1 [M−H] −, 346.0 [M + Na] +. IH-NMR (500 MHz, DMS0-d6, ppm): δ 12.65 (1H, s, OH, oxime), 10.32 (1H, s, NH), 8.64 (1H, brs, OH), 7.75 (1H, dd, J = 8.0, 2.5 Hz), 7.30 (1H, td, J = 9.0, 2.5 Hz, H6), 7.14 (1H, dd, J = 8.5, 4.0 Hz, H7), 3.68 (2H, t, J = 7.0 Hz , CH2), 1.92 (2H, t, J = 7.5 Hz, CH2), 1.54-1.57 (2H, m, CH2), 1.44-1.47 (2H, m, CH2), 1.26-1.27 (4H, m, CH2) . 13 C NMR (125 δ z, DMS0-d6, ppm): δ 169.58, 163.32, 159.31, 143.71, 139.89, 118.74, 118.55, 116.24, 116.17, 114.51, 114.30, 110.67, 110.61, 32.65, 28.67, 27.27, 26.39, 25.39 . Anal. Calcd. For C 15 H 18 FN 304 (323.32): C, 55.72; H, 5.61; N, 13.00. Found: C, 55.75; H, 5.57; N, 13.21.
(3) 화합물 3c: 7-(5-클로로 -3- (히드록시이미노) -2-옥소인돌린 -1- 일) - 히드록시헵탄아미드의 합성 (3) Compound 3c: Synthesis of 7- (5-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) -hydroxyheptanamide
수율: 60.0%. mp: 197.0-199°C. Rf = 0.60 (DCM/MeOH = 9/1). IRYield 60.0%. mp: 197.0-199 ° C. Rf = 0.60 (DCM / MeOH = 9/1). IR
(KBr, cm-1): 3424, 3216 (OH), 3050 (NH), 2933， 2859 (CH, CH2), 1714, 1659 (C=0), 1608 (C=C) . ESI -MS (m/z): 338.5 [M-H]-. IH-NMR (500 丽 z, DMS0-d6, ppm): δ 10.32 (1H, s, NH), 8.65 (1H, brs, OH), 7.95 (1H, d, J = 2.5 Hz, H4), 7.49 (1H, dd, J = 8.5， 2.5 Hz, H6), 7.16 (1H, d, J = 8.5 Hz, H7), 3.68 (2H, t, J = 7.0 Hz, CH2), 1.91 (2H, t, J = 7.5 Hz, CH2), 1.54-1.56 (2H, m, CH2), 1.44-1.47 (2H, m, CH2), 1.25-1.26 (4H, m, CH2). 13C NMR (125 腿 z, DMS0— d6, ppm): δ 169.00, 162.61, 142.73, 141.79， 131.38, 126.23, 126.13, 116.32, 110.71， 32.12, 28.14， 26.75, 25.84， 24.91. Anal. Calcd. For C15H18C1N304 (339.77)： C, 53.02； H, 5.34； N, 12.37. Found: C, 53.13； H, 5.29； N, 12.42. (KBr, cm-1): 3424, 3216 (OH), 3050 (NH), 2933, 2859 (CH, CH2), 1714, 1659 (C = 0), 1608 (C = C). ESI-MS (m / z): 338.5 [M-H] < '>. IH-NMR (500 lj, DMS0-d6, ppm): δ 10.32 (1H, s, NH), 8.65 (1H, brs, OH), 7.95 (1H, d, J = 2.5 Hz, H4), 7.49 ( 1H, dd, J = 8.5, 2.5 Hz, H6), 7.16 (1H, d, J = 8.5 Hz, H7), 3.68 (2H, t, J = 7.0 Hz, CH2), 1.91 (2H, t, J = 7.5 Hz, CH 2), 1.54-1.56 (2H, m, CH 2), 1.44-1.47 (2H, m, CH 2), 1.25-1.26 (4H, m, CH 2). 13 C NMR (125 腿 z, DMS0—d6, ppm): δ 169.00, 162.61, 142.73, 141.79, 131.38, 126.23, 126.13, 116.32, 110.71, 32.12, 28.14, 26.75, 25.84, 24.91. Anal. Calcd. For C 15 H 18 C 1 N 304 (339.77): C, 53.02; H, 5.34; N, 12.37. Found: C, 53.13; H, 5.29; N, 12.42.
(4) 화합물 3d: 7-(5-브로모 -3- (히드록시이미노) -2—옥소인돌린 -1- 일) 히드톡시헵탄아미드의 합성 (4) Compound 3d: Synthesis of 7- (5-bromo-3- (hydroxyimino) -2—oxoindolin-1-yl) hydroxyheptanamide
수율: 62.0%. mp: 192-195 °C . Rf = 0.61 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3455 (OH), 2926, 2856 (CH, CH2), 1665 (00)， 1602 (C=C) . ESI -MS (m/z): 384.9 [M-H, 81Br]-. , 382.9 [M-H, 79Br]-. IH-NMR (500 MHz, DMS0-d6 + CD0D3, ppm)： δ 8.31 (1H, d, J = 2.0 Hz, H4) , 7.22 (1H, dd, J = 8.0, 2.0 Hz, H6), 6.88 (1H, d, J = 8.0 Hz, H7), 3.68 (2H, t, J = 7.0 Hz, CH2), 1.92 (2H, t, J = 7.5 Hz, CH2), 1.55 (2H, m, CH2), 1.44-1.47 (2H, m, CH2), 1.26 (4H, m, CH2) . 13C NMR (125 MHz, DMS으 d6 + CD0D3, ppm): δ 169.07, 165.95, 143.86, 136.80, 127.46, 122.44, 117.93, 112.88 108.88, 38.45, 32.15, 28.23, 27.41， 25.99, 25.00. Anal. Calcd. For C15H18BrN304 (384.23)： C, 46.89； H, 4.72； N, 10.94. Found: C, 46.90； H 4.74； N, 10.97. (5) 화합물 3e: 히드록시 -7-(3— (히드록시이미노) -5—니트로 -2- 옥소인돌린 -1-일)헵탄아미드의 합성 Yield: 62.0%. mp: 192-195 ° C. Rf = 0.61 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3455 (OH), 2926, 2856 (CH, CH 2), 1665 (00), 1602 (C = C). ESI-MS (m / z): 384.9 [M−H, 81 Br] −. , 382.9 [M−H, 79 Br] −. IH-NMR (500 MHz, DMS0-d6 + CD0D3, ppm): δ 8.31 (1H, d, J = 2.0 Hz, H4), 7.22 (1H, dd, J = 8.0, 2.0 Hz, H6), 6.88 (1H, d, J = 8.0 Hz , H7), 3.68 (2H, t, J = 7.0 Hz, CH2), 1.92 (2H, t, J = 7.5 Hz, CH2), 1.55 (2H, m, CH2), 1.44-1.47 (2H, m, CH2 ), 1.26 (4H, m, CH 2). 13 C NMR (125 MHz, d6 + CD0D3, ppm in DMS): δ 169.07, 165.95, 143.86, 136.80, 127.46, 122.44, 117.93, 112.88 108.88, 38.45, 32.15, 28.23, 27.41, 25.99, 25.00. Anal. Calcd. For C 15 H 18 BrN 304 (384.23): C, 46.89; H, 4.72; N, 10.94. Found: C, 46.90; H 4.74; N, 10.97. (5) Compound 3e: Synthesis of hydroxy-7- (3— (hydroxyimino) -5—nitro-2-oxoindolin-1-yl) heptanamide
수율: 61.0%. mp: 201-203 °C . Rf = 0.67 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3307 (OH), 2936, 2858 (CH, CH2), 1747, 1729 (C=0) , 1630, 1611 (C=C). ESI -MS (m/z): 348.5 [M-H]-. 1H—匪 R (500 MHz, DMS으 d6, ppm): δ 14.13 (1H, s, OH, oxime), 10.34 (1H, s, NH), 8.67 (2H, s, H4-0H overlap), 8.34 (1H, d, J = 8.0 Hz, H6), 7.35 (1H, d, J = 9.0 Hz, H7) , 3.75 (2H, t, CH2), 1.92 (2H, t, J = 7.0 Hz, CH2), 1.58 (2H, m, CH2), 1.46-1.47 (2H, m, CH2), 1.27 (4H, m, CH2). 13C NMR (125 MHz, DMS0-d6, ppm): δ 169.01, 163.26, 148.27, 142.32, 142.10， 128.30, 121.47， 115.02 109.42, 32.12, 28.15， 26.84, 25.83, 24.91. Anal. Calcd. For C15H18N406 (350.33)： C, 51.43； H, 5.18； N, 15.99. Found: C, 51.45； H, 5.21； N, 15.85. Yield 61.0%. mp: 201-203 ° C. Rf = 0.67 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3307 (OH), 2936, 2858 (CH, CH 2), 1747, 1729 (C = 0), 1630, 1611 (C = C). ESI-MS (m / z): 348.5 [M−H] −. 1H— 匪 R (500 MHz, d6 at DMS, ppm): δ 14.13 (1H, s, OH, oxime), 10.34 (1H, s, NH), 8.67 (2H, s, H4-0H overlap), 8.34 ( 1H, d, J = 8.0 Hz, H6), 7.35 (1H, d, J = 9.0 Hz, H7), 3.75 (2H, t, CH2), 1.92 (2H, t, J = 7.0 Hz, CH2), 1.58 (2H, m, CH 2), 1.46-1.47 (2H, m, CH 2), 1.27 (4H, m, CH 2). 13 C NMR (125 MHz, DMS0-d6, ppm): δ 169.01, 163.26, 148.27, 142.32, 142.10, 128.30, 121.47, 115.02 109.42, 32.12, 28.15, 26.84, 25.83, 24.91. Anal. Calcd. For C 15 H 18 N 406 (350.33): C, 51.43; H, 5.18; N, 15.99. Found: C, 51.45; H, 5.21; N, 15.85.
(6) 화합물 3f: —히드록시 -7-(3— (히드톡시이미노 )_5-메틸 -2- 옥소인돌린 -1-일)헵탄아미드의 합성 (6) Compound 3f: Synthesis of —Hydroxy-7- (3— (Hythoxyimino) _5-methyl-2-oxoindolin-1-yl) heptanamide
수율: 70.0%. mp: 181-183°C. Rf = 0.67 (DCM/MeOH = 9/1). IR (KBr, cm-1)： 3304 (OH), 3039 (NH) , 2929， 2862 (CH, CH2), 1699 (C=0) , 1650, 1618 (C=C) . ESI -MS (m/z): 318.1 [M-H]-, 288.2 [M-N0H]-, 342.0 [M+Na]-. 1H-NMR (500 腿 z, DMS0-d6, ppm): δ 13.36 (1H, sᅳ OH, oxime), 8.65 (1H, brs, OH), 10.32 (1H, s, NH), 7,82 (1H, s, H4) , 7.23 (1H, d, J - 7.5 Hz H6), 6.98 (1H, d, J = 7.5 Hz, H7), 3.64 (2H, tᅳ CH2), 2.28 (3H, s, CH3), 1.91 (2H, t, J = 7.0 Hz, CH2)ᅳ 1.55 (2H, m, CH2), 1.45 (2H, m, CH2), 1.25 (4H, ra, CH2),. 13C 匪 R (125 MHz, DMS0-d6, ppm): δ 169.01, 162.95, 143.65, 140.84, 132.21, 131.45, 127.47, 115.25, 108.86, 32.15, 28.16, 26.85, 25.90, 24.95, 20.48. Yield: 70.0%. mp: 181-183 ° C. Rf = 0.67 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3304 (OH), 3039 (NH), 2929, 2862 (CH, CH2), 1699 (C = 0), 1650, 1618 (C = C). ESI-MS (m / z): 318.1 [M−H] −, 288.2 [M−N 0 H] −, 342.0 [M + Na] −. 1 H-NMR (500 腿 z, DMS0-d6, ppm): δ 13.36 (1H, s ᅳ OH, oxime), 8.65 (1H, brs, OH), 10.32 (1H, s, NH), 7,82 (1H , s, H4), 7.23 (1H, d, J-7.5 Hz H6), 6.98 (1H, d, J = 7.5 Hz, H7), 3.64 (2H, t ᅳ CH2), 2.28 (3H, s, CH3), 1.91 (2H, t, J = 7.0 Hz, CH2) ᅳ 1.55 (2H, m, CH2), 1.45 (2H, m, CH2), 1.25 (4H, ra, CH2),. 13C 匪 R (125 MHz, DMS0-d6, ppm): δ 169.01, 162.95, 143.65, 140.84, 132.21, 131.45, 127.47, 115.25, 108.86, 32.15, 28.16, 26.85, 25.90, 24.95, 20.48.
(7) 화합물 3g: 7-(7-클로로 -3- (히드록시이미노) -2-옥소인돌린 -1- 일) 히드톡시헵탄아미드의 합성 (7) Compound 3g: Synthesis of 7- (7-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) hydroxymethoxyheptanamide
수율: 65.0%. mp: 190- 192 °C . Rf = 0.62 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3353, 3297 (OH), 3109 (NH), 3021 (OH, aren) , 2930， 2862 (CH, CH2), 1702， 1649 (00)， 1602 (C=C) . ESI -MS (m/z): 338.1 [M-H]-. IH-NMR (500 MHz, DMS0-d6 + CD0D3, ppm): δ 8.65 (IH, brs, OH), 10.34 (IH, s, NH), 8.03 (IH, dd, J = 7.5, 1.0 Hz, H6), 7.42 (IH, dd, J = 8.5 , 1.0 Hz, H4), 7.08 (IH, t, J = 8.0 Hz, H5), 3.97 (2H, t, J = 7.5 Hz, CH2), 1.93 (2H, t, J = 7.5 Hz, CH2), 1.59-1.61 (2H, m, CH2), 1.46-1.49 (2H, m, CH2), 1.27-1.28 (4H, m, CH2). 13C NMR (125 MHz, DMS0-d6 + CD0D3, ppm): δ 169.01, 163.41, 142.15， 138.59, 133.85, 125.87, 123.99, 118.18 114.29, 40.73, 32.12, 29.15, 28.15, 25.73, 24.96. 합성예 2: N-히드록실 -7-(5/7-치환 -3-메톡시이미노 -2-옥소인돌린- 일)헵탄아미드 (화합물 6a-6g)의 합성 Yield 65.0%. mp: 190-192 ° C.. Rf = 0.62 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3353, 3297 (OH), 3109 (NH), 3021 (OH, aren), 2930, 2862 (CH, CH2), 1702, 1649 (00), 1602 (C = C) . ESI-MS (m / z): 338.1 [M−H] −. IH-NMR (500 MHz, DMS0-d6 + CD0D3, ppm): δ 8.65 (IH, brs, OH), 10.34 (IH, s, NH), 8.03 (IH, dd, J = 7.5, 1.0 Hz, H6) , 7.42 (IH, dd, J = 8.5, 1.0 Hz, H4), 7.08 (IH, t, J = 8.0 Hz, H5), 3.97 (2H, t, J = 7.5 Hz, CH2), 1.93 (2H, t , J = 7.5 Hz, CH 2), 1.59-1.61 (2H, m, CH 2), 1.46-1.49 (2H, m, CH 2), 1.27-1.28 (4H, m, CH 2). 13 C NMR (125 MHz, DMS0-d6 + CD0D3, ppm): δ 169.01, 163.41, 142.15, 138.59, 133.85, 125.87, 123.99, 118.18 114.29, 40.73, 32.12, 29.15, 28.15, 25.73, 24.96. Synthesis Example 2 Synthesis of N-hydroxyl-7- (5 / 7-substituted-3-methoxyimino-2-oxoindolin-yl) heptanamide (Compound 6a-6g)
[반웅식 2]  [Bungungsik 2]
Figure imgf000021_0001
Figure imgf000021_0001
상기 반웅식 2는 3' -메톡심이사틴계 히드록삼산의 합성과정을 보여준다. 합성과정에서의 시약 및 조건은 다음과 같다: (a) 메톡실아민 하이드로클로라이드， 피리딘, 에탄올， 8(rc, 3 시간; (b) 에틸 7- 브로모헵타노에이트， C03, I, DMF, rt, 24 시간; (c) 히드록실아민 하이드로클로라이드， NaOH, MeOH, THF, 0°C. 30분. 화합물 6a-6g의 화합물들은 각각의 5-/그치환된 이사틴 -3-메특심을 출발물질로 사용하여 화합물 3a에서 사용하였던 방법과 유사한 방법을 통해 합성하였다. 5-/7- 치환된이사틴 -3-메록심은 5-/7-치환된 이사틴으로부터 좋은 수율 (75- 96%)으로 합성되었다. (1) 화합물 6a: -히드록시 -7-(3— (메록시이미노) -2-옥소인돌린 -1- 일)헵탄아미드의 합성 Banungsik 2 is a synthetic process of the 3 ' -methoxime isatin hydroxamic acid Shows. The reagents and conditions in the synthesis are as follows: (a) methoxylamine hydrochloride, pyridine, ethanol, 8 (rc, 3 hours; (b) ethyl 7-bromoheptanoate, C0 3 , I, DMF, rt, 24 h; (c) hydroxylamine hydrochloride, NaOH, MeOH, THF, 0 ° C. 30 min.Compounds of compound 6a-6g start each 5- / substituted isatin-3-metaspecific. Synthesis was carried out in a similar manner to that used for compound 3a using the substance 5- / 7-substituted isatin-3-meroxime in good yield (75-96%) from 5- / 7-substituted isatin. (1) Compound 6a: Synthesis of -hydroxy-7- (3— (methoxyimino) -2-oxoindolin-1-yl) heptanamide
수율: 75.0%. mp: 191-193°C. Rf = 0.71 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3399 (OH), 3249 (NH) , 3038 (OH, aren), 2933， 2862 (CH, CH2), 1704, 1647 (00)， 1621, 1607 (OC). ESI -MS (m/z): 318.2 [M-H]-, 287.0 [M-NHOH]-. 1H-NMR (500 MHz, DMS0— d6, ppm): δ 10.33 (1H, s, NH), 8.66 (1H, brs, OH), 7.87 (1H, d, J = 7.5 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.12 (1H, d, J = 8.0 Hz), 7.07 (1H, t, J = 7.5 Hz), 4.20 (3H, s, 0CH3), 3.66 (2H, t, J = 7.0 Hz, CH2), 1.92 (2H, t, J = 7.0 Hz, CH2), 1.56 (2H, m, CH2), 1.45-1.47 (2H, m, CH2), 1.26 (4H, m, CH2). 13C NMR (125 MHz, DMS0-d6, ppm): δ 169.06, 162.15, 143.68, 143.28, 132.96, 127.34, 122.61, 114.87， 109.40, 64.40, 32.14, 28.14, 26.77, 25.87, 24.95. Anal. Calcd. For C16H21N304 (319.36)： C, 60.17； H, 6.63； N, 13.16. Found: C, 60.21； H, 6.59； N, 13.22. (2) 화합물 6b: 7-(5-플루오로 -3- (메특시이미노) -2-옥소인돌린 -1- 일) - 히드록시헵탄아미드의 합성 Yield: 75.0%. mp: 191-193 ° C. Rf = 0.71 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3399 (OH), 3249 (NH), 3038 (OH, aren), 2933, 2862 (CH, CH2), 1704, 1647 (00), 1621, 1607 (OC). ESI-MS (m / z): 318.2 [M−H] −, 287.0 [M—NHOH] −. 1 H-NMR (500 MHz, DMS0—d6, ppm): δ 10.33 (1H, s, NH), 8.66 (1H, brs, OH), 7.87 (1H, d, J = 7.5 Hz), 7.46 (1H, t , J = 7.5 Hz), 7.12 (1H, d, J = 8.0 Hz), 7.07 (1H, t, J = 7.5 Hz), 4.20 (3H, s, 0CH3), 3.66 (2H, t, J = 7.0 Hz , CH2), 1.92 (2H, t, J = 7.0 Hz, CH2), 1.56 (2H, m, CH2), 1.45-1.47 (2H, m, CH2), 1.26 (4H, m, CH2). 13 C NMR (125 MHz, DMS0-d6, ppm): δ 169.06, 162.15, 143.68, 143.28, 132.96, 127.34, 122.61, 114.87, 109.40, 64.40, 32.14, 28.14, 26.77, 25.87, 24.95. Anal. Calcd. For C 16 H 21 N 304 (319.36): C, 60.17; H, 6.63; N, 13.16. Found: C, 60.21; H, 6.59; N, 13.22. (2) Compound 6b: Synthesis of 7- (5-fluoro-3- (methoxyimino) -2-oxoindolin-1-yl) -hydroxyheptanamide
수율: 72.0%. mp: 200-202 °C . Rf = 0.70 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3331 (OH), 3234 (NH)， 3045 (OH, aren), 2931, 2861 (CH, CH2), 1702， 1655 (C=0) , 1622， 1602 (OC) . ESI -MS (m/z): 334.7 [M-2H]-, 697.4 [2M+Na]-. 1H-NMR (500 MHz, DMS0-d6, ppm): δ 10.33 (1H, s, NH), 8.66 (1H, brs, OH), 7.65 (1H, dd, J = 8.0, 2.5 Hz, H4), 7.33 (1H, td, J = 9.25, 2.5 Hz, H6), 7.14 (1H, dd, J = 8.5, 4.0 Hz, H7), 4.21 (3H, s, 0CH3), 3.66 (2H, t, J = 7.0 Hz, CH2), 1.91 (2H, t, J = 7.0 Hz, CH2), 1.53-1.56 (2H( m, CH2), 1.44-1.46 (2H, m, CH2), 1.25-1.26 (4H, m, CH2) 13C NMR (125 丽 z, DMS0-d6, ppm): δ 169.10, 162.03, 158.83， 156.93, 142.96, 140.02, 119.23， 119.04, 115.41, 115.33， 114.50, 114.29, 110.52 110.46， 64.67, 32.15, 28.16, 26.71, 25.86, 24.95. Yield: 72.0%. mp: 200-202 ° C. Rf = 0.70 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3331 (OH), 3234 (NH), 3045 (OH, aren), 2931, 2861 (CH, CH2), 1702, 1655 (C = 0), 1622, 1602 (OC) . ESI-MS (m / z): 334.7 [M-2H]-, 697.4 [2M + Na]-. 1 H-NMR (500 MHz, DMS0-d6, ppm): δ 10.33 (1H, s, NH), 8.66 (1H, brs, OH), 7.65 (1H, doublet of doublets, J = 8.0, 2.5 Hz, H4), 7.33 (1H, td, J = 9.25, 2.5 Hz, H6), 7.14 (1H, dd, J = 8.5, 4.0 Hz, H7), 4.21 (3H, s, 0CH3), 3.66 (2H, t, J = 7.0 Hz, CH2), 1.91 (2H , t, J = 7.0 Hz, CH2), 1.53-1.56 (2H ( m, CH2), 1.44-1.46 (2H, m, CH2), 1.25-1.26 (4H, m, CH2) 13 C NMR (125 liza z, DMS0-d6, ppm): δ 169.10, 162.03, 158.83, 156.93, 142.96, 140.02, 119.23, 119.04, 115.41, 115.33, 114.50, 114.29, 110.52 110.46, 64.67, 32.15, 28.16, 26.71, 25.86, 24.95.
(3) 화합물 6c: 7-(5-클로로 -3- (메록시이미노)— 2-옥소인돌린ᅳ 1-일) - 히드록시헵탄아미드의 합성 (3) Compound 6c: 7- (5-chloro-3- (methoxyimino) — 2-oxoindolinyl 1-yl)-synthesis of hydroxyheptanamide
수율: 78.0%. mp: 198- 199 °C. Rf = 0.70 (DCM/MeOH = 9/1). IR (KBr, cm-1)： 3431 (OH), 3259 ( H), 2935, 2859 (CH, CH2), 1714, 1645 (C=0) , 1609 (C=C). ESI -MS (m/z): 352.2 [M— H]-, IH-NMR (500 MHz, DMS0-d6, ppm): δ 10.45 (1H, s, NH) , 7.81 (1H, s, H4)， 8.70 (1H, brs, OH), 7.50 (1H, d, J = 8.0 Hz, H6), 7.16 (1H, d, J = 8.0 Hz, H7), 4.22 (3H, s, 0CH3), 3.65 (2H, t, J = 6.5 Hz, CH2), 1.93 (2H, t, J = 7.0 Hz, CH2), 1.53 (2H, m, CH2), 1.44 (2H, m, CH2),1.25 (4H, m, CH2). 13C NMR (125 MHz, DMS0-d6 , ppm): δ 169.04, 161.77， 142.44, 142.41, 132.30, 126.54, 126.38, 115.97, 111.00, 64.71， 33.92, 33.57, 32.09, 28.11, 26.67, 25.80, 24.91. ' Yield: 78.0%. mp: 198-199 ° C. Rf = 0.70 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3431 (OH), 3259 (H), 2935, 2859 (CH, CH 2), 1714, 1645 (C = 0), 1609 (C = C). ESI-MS (m / z): 352.2 [M— H]-, IH-NMR (500 MHz, DMS0-d6, ppm): δ 10.45 (1H, s, NH), 7.81 (1H, s, H4), 8.70 (1H, brs, OH), 7.50 (1H, d, J = 8.0 Hz, H6), 7.16 (1H, d, J = 8.0 Hz, H7), 4.22 (3H, s, 0CH3), 3.65 (2H, t, J = 6.5 Hz, CH2), 1.93 (2H, t, J = 7.0 Hz, CH2), 1.53 (2H, m, CH2), 1.44 (2H, m, CH2), 1.25 (4H, m, CH2) . 13 C NMR (125 MHz, DMS0-d6, ppm): δ 169.04, 161.77, 142.44, 142.41, 132.30, 126.54, 126.38, 115.97, 111.00, 64.71, 33.92, 33.57, 32.09, 28.11, 26.67, 25.80, 24.91. '
(4) 화합물 6d: 7-(5-브로모 -3- (메록시이미노)— 2-옥소인돌린 -1-일) - 히드록시¾탄아미드의 합성 (4) Compound 6d: Synthesis of 7- (5-bromo-3- (methoxyimino) — 2-oxoindolin-1-yl) -hydroxy¾tanamide
수율: 70.0%. mp: 205-207 °C . Rf = 0.76 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3400 (OH), 3222 (NH) , 2935, 2856 (CH, CH2) , 1722， 1647 (C=0) , 1604 (OC). ESI -MS (m/z): 398.0 [M -]， 382.9 [M-CH3]-. IH-NMR (500 丽 z, DMS0-d6 + CD0D3, ppm): δ 7.94 (1H, s, H4), 7.62 (1H, d, J = 7.5 Hz, H6), 7.11 (1H, d, J = 8.0 Hz, H7) , 4.22 (3H, s, 0CH3) , 1.53 (2H, m, CH2), 3.65 (2H, t, J = 6.5 Hz, CH2), 1.91 (2H, t, J = 7.0 Hz, CH2), 1.44 (2H, m, CH2), 1.25 (4H, m, CH2), . 13C NMR (125 MHz, DMS0~d6 + CD0D3 , ppm)： δ 168.69, 161.66, 142.80, 142.32, 135.13, 129.22, 116.41, 114.00, 111.47, 64.72， 32.21, 28.15， 26.68, 26.18, 25.84, 25.03. (5) 화합물 6e: ^히드록시 -7-(3- (메톡시이미노) -5-니트로—2- 옥소인돌린 -1-일)헵탄아미드의 합성 Yield: 70.0%. mp: 205-207 ° C. Rf = 0.76 (DCM / MeOH = 9/1). IR (KBr, cm < -1 >): 3400 (OH), 3222 (NH), 2935, 2856 (CH, CH2), 1722, 1647 (C = 0), 1604 (OC). ESI-MS (m / z): 398.0 [M −], 382.9 [M-CH 3] −. IH-NMR (500 lj, DMS0-d6 + CD0D3, ppm): δ 7.94 (1H, s, H4), 7.62 (1H, d, J = 7.5 Hz, H6), 7.11 (1H, d, J = 8.0 Hz, H7), 4.22 (3H, s, 0CH3), 1.53 (2H, m, CH2), 3.65 (2H, t, J = 6.5 Hz, CH2), 1.91 (2H, t, J = 7.0 Hz, CH2) , 1.44 (2H, m, CH 2), 1.25 (4H, m, CH 2),. 13C NMR (125 MHz, DMS0 to d6 + CD0D3, ppm): δ 168.69, 161.66, 142.80, 142.32, 135.13, 129.22, 116.41, 114.00, 111.47, 64.72, 32.21, 28.15, 26.68, 26.18, 25.84, 25.03. (5) Compound 6e: Synthesis of ^ hydroxy-7- (3- (methoxyimino) -5-nitro—2-oxoindolin-1-yl) heptanamide
수율: 70.0%. mp: 203-205 °C. Rf = 0.67 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3210 (OH), 2934, 2856 (CH, CH2), 1729 (C=0) , 1611 (C=C) . ESI -MS (m/z): 363.0 [M-H]-, 348.0 [M-CH3]-. 1H—匪 R (500 MHz, DMS으 d6, ppm): δ 10.33 (1H, s, NH), 8.66 (1H, s, OH), 8.35 (ΙΗ,' dd, J = 9.0， 2.5 Hz, H6), 8.49 (1Hᅳ d, J = 2.0 Hz, H4), 7.35 (1H, d, J = 9.0 Hz, H7), 4.29 (3H, s, 0CH3), 3.73 (2H, t, J = 7.0 Hz, CH2), 1.92 (2H, t, J = 7.0 Hz, CH2), 1.54 -1.58 (2H, m, CH2), 1.43-1.49 (2H, m, CH2), 1.26 -1.27 (4H, m, CH2). 13C NMR (125 MHz, DMS0-d6, ppm)： δ 169.05, 162.43, 148.87, 142.34, 141.79, 129.06, 121.84, 114.74， 109.72, 65.20, 32.11, 28.13, 26.76, 25.80, 24.91. (6) 화합물 6f: 히드록시-그 (3- (메톡시이미노) -5-메틸 -2- 옥소인들린— 1-일)헵탄아미드의 합성 Yield: 70.0%. mp: 203-205 ° C. Rf = 0.67 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3210 (OH), 2934, 2856 (CH, CH 2), 1729 (C = 0), 1611 (C = C). ESI-MS (m / z): 363.0 [M−H] −, 348.0 [M—CH 3] −. 1H— 匪 R (500 MHz, d6 at DMS, ppm): δ 10.33 (1H, s, NH), 8.66 (1H, s, OH), 8.35 (ΙΗ, dd, J = 9.0, 2.5 Hz, H6) , 8.49 (1H ᅳ d, J = 2.0 Hz, H4), 7.35 (1H, d, J = 9.0 Hz, H7), 4.29 (3H, s, 0CH3), 3.73 (2H, t, J = 7.0 Hz, CH2 ), 1.92 (2H, t, J = 7.0 Hz, CH2), 1.54--1.58 (2H, m, CH2), 1.43-1.49 (2H, m, CH2), 1.26-1.27 (4H, m, CH2). 13 C NMR (125 MHz, DMS0-d6, ppm): δ 169.05, 162.43, 148.87, 142.34, 141.79, 129.06, 121.84, 114.74, 109.72, 65.20, 32.11, 28.13, 26.76, 25.80, 24.91. (6) Compound 6f: Synthesis of hydroxy-g- (3- (methoxyimino) -5-methyl-2-oxoindlyn— 1-yl) heptanamide
수율: 78.0%. mp: 193-195 °C . Rf = 0.75 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3400 (OH), 3217 (NH), 3047 (C— H, arren), 2926， 2856 (CH, CH2), 1706, 1638 (C=0), 1616, 1594 (C=C) - ESI -MS (m/z): 332.0 [M-H]-. IH-NMR (500 MHz, DMS0-d6, ppm): δ 10.34 (1H, s, NH) , 7.70 (1H, s, H4) , 7.26 (1H, d, J = 8.0 Hz, H6), 7.00 (1H, d, J = 8.0 Hz, H7), 4.19 (3H, s, 0CH3), 3.64 (2H, t, J = 7.0 Hz, CH2), 2.27 (3H, s, CH3), 1.91 (2H, t, J = 7.5 Hz, CH2), 1.53-1.55 (2H, m, CH2), 1.43 -1.46 (2H, m, CH2), 1.24-1.25 (4H, m, CH2). 13C NMR (125 MHz, DMS0_d6, ppm): δ 169.02, 162.11， 143.38, 141.44, 133.13, 131.65, 127.81, 114.90, 109.15, 64.34, 32.12, 28.13, 26.76， 25.85, 24.93, 20.40. Yield: 78.0%. mp: 193-195 ° C. Rf = 0.75 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3400 (OH), 3217 (NH), 3047 (C— H, arren), 2926, 2856 (CH, CH2), 1706, 1638 (C = 0), 1616, 1594 ( C = C)-ESI-MS (m / z): 332.0 [M−H] −. IH-NMR (500 MHz, DMS0-d6, ppm): δ 10.34 (1H, s, NH), 7.70 (1H, s, H4), 7.26 (1H, d, J = 8.0 Hz, H6), 7.00 (1H , d, J = 8.0 Hz, H7), 4.19 (3H, s, 0CH3), 3.64 (2H, t, J = 7.0 Hz, CH2), 2.27 (3H, s, CH3), 1.91 (2H, t, J = 7.5 Hz, CH2), 1.53-1.55 (2H, m, CH2), 1.43 -1.46 (2H, m, CH2), 1.24-1.25 (4H, m, CH2). 13 C NMR (125 MHz, DMS0_d6, ppm): δ 169.02, 162.11, 143.38, 141.44, 133.13, 131.65, 127.81, 114.90, 109.15, 64.34, 32.12, 28.13, 26.76, 25.85, 24.93, 20.40.
(7) 화합물 6g: 7-(7-클로로 -3- (메특시이미노) -2-옥소인돌린 -1—일) - 히드록시헵탄아미드의 합성 (7) Compound 6g: Synthesis of 7- (7-chloro-3- (methoxyimino) -2-oxoindolin-1-yl) -hydroxyheptanamide
수율: 75.0%. mp: 189-191 °C . Rf = 0.72 (DCM/MeOH = 9/1). IR (KBr, cm-1): 3232 (NH), 3059 (C— H, aren) 2937, 2858 (CH, CH2), 1728 (C=0)， 1605 (OC). ESI -MS (m/z): 352.0 [M-H]-, 338.1 [M—CH3]— . 1H-NMR (500 MHz, DMS0-d6, ppm): δ 10.36 (1H, s, NH) , 8.66 (1H, brs, OH), 7.90 (1H, d, J = 7.5 Hz, H6), 7.47 (1H, d, J = 8.0 Hz, H4), 7.09 (1H, t, J = 8.0 Hz, H5), 4.22 (3H, s, 0CH3), 3.95 (2H, t, J = 7.0 Hz, CH2), 1.93 (2H, t, J = 7.5 Hz, CH2), 1.56-1.60 (2H, m, CH2), 1.44-1.50 (2H, m, CH2) , 1.27 (4H, m, CH2). 13C NMR (125 MHz, DMS0-d6, ppm): δ 169.00, 162.57, 141.92, 139.21, 134.76, 126.36, 124.10, 117.84， 114.49， 64.79, 40.87, 32.10, 29.06, 28.13, 25.69, 24.95. 3. 화합물의 합성 결과의 요약 Yield: 75.0%. mp: 189-191 ° C. Rf = 0.72 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3232 (NH), 3059 (C— H, aren) 2937, 2858 (CH, CH2), 1728 (C = 0), 1605 (OC). ESI-MS (m / z): 352.0 [M−H] −, 338.1 [M—CH 3] —. 1 H-NMR (500 MHz, DMS0-d6, ppm): δ 10.36 (1H, s, NH), 8.66 (1H, brs, OH), 7.90 (1H, d, J = 7.5 Hz, H6), 7.47 (1H , d, J = 8.0 Hz, H4), 7.09 (1H, t, J = 8.0 Hz, H5), 4.22 (3H, s, 0CH3), 3.95 (2H, t, J = 7.0 Hz, CH2), 1.93 ( 2H, t, J = 7.5 Hz, CH 2), 1.56-1.60 (2H, m, CH 2), 1.44-1.50 (2H, m, CH 2), 1.27 (4H, m, CH 2). 13 C NMR (125 MHz, DMS0-d6, ppm): δ 169.00, 162.57, 141.92, 139.21, 134.76, 126.36, 124.10, 117.84, 114.49, 64.79, 40.87, 32.10, 29.06, 28.13, 25.69, 24.95. 3. Summary of Synthesis Results of Compounds
히드특삼산 화합물 3a-3g의 합성과정은 상기 반응식 1에 도시하였다. 첫 번째 단계로서， 이사틴 및 이의 5- 또는 7-치환 유도체들 및 1몰 당량의 K2C03를 DMF (다이메틸포름아마이드)에 용해시키고， 이어서， 1몰 당량의 에틸 그브로모헵타노에이트를 상온에서 적하 하여 가하였다. 반웅 흔합물을 24시간 동안 교반 하면서 60°C까지 가열하고 상온까지 다시 넁각시켰다. 각각의 대웅하는 반응 흔합물을 냉각된 HC1 10% 용액에 부어 에스테르 화합물 2a-2g를 침전시켰다. n-핵산 /아세톤으로부터 재결정화를 통해 중간체 화합물 23-¾를 좋은 수율 (65-90%)로 얻었다. 에스테르 화합물들을 메탄올-테트라하이드로푸란 (1/1)의 흔합물내에 용해시켰다. 히드록실아민 하이드로클로라이드 (10 mol equiv.)를 가하고 생성된 현탁액을 -5°C까지 냉각시켰다. NaOH(10 mol equiv) 용액을 _5°C에서 일정하게 유지시킨 반응 흔합물에 천천히 떨어뜨렸다. 30분 후에， 반응 내용물을 냉각수에 붓고 HC1 15% 용액을 사용하여 pH를 7으로 조절하여 조생성물을 침전시켰다. 조생성물을 에탄을로부터 재결정시켜 화합물 3a—3g를 중간 내지 높은 수율 (5으 90%)로 생성하였다. Synthesis process of the hydric triacid compound 3a-3g is shown in Scheme 1. As a first step, isatin and its 5- or 7-substituted derivatives and 1 molar equivalent of K 2 CO 3 are dissolved in DMF (dimethylformamide), followed by 1 molar equivalent of ethyl gbromoheptanoate. Was added dropwise at room temperature. The reaction mixture was heated to 60 ° C. with stirring for 24 hours and re-extracted to room temperature. Each diaphragm reaction mixture was poured into cooled HC1 10% solution to precipitate the ester compounds 2a-2g. Recrystallization from n-nucleic acid / acetone gave intermediate compound 2 3 -¾ in good yield (65-90%). Ester compounds were dissolved in a mixture of methanol-tetrahydrofuran (1/1). Hydroxylamine hydrochloride (10 mol equiv.) Was added and the resulting suspension was cooled to -5 ° C. NaOH (10 mol equiv) solution was slowly dropped into the reaction mixture which was kept constant at _5 ° C. After 30 minutes, the reaction contents were poured into cooling water and the crude product was precipitated by adjusting the pH to 7 using HC1 15% solution. The crude product was recrystallized from ethane to give 3a-3g of compound in medium to high yield (5% to 90%).
화합물 6a-6g는 상기 반웅식 2의 과정을 통해 합성하였다. 이사틴- 3'-메록심 히드록삼산 (화합물 6a-6g)는 이사틴을 에탄을 조건내의 환류하에서 메록실아민 히드로클로라이드를 사용하여 3-메록심 유도체 4로 전환시켜서 합성하였다 (반웅식 2 참조). 얻어진 화합물들 및 중간체들의 구조는 IR, MS, 1H NMR, 13C NMR 및 원소분석 등을 포함하는 스펙트럼 연구를 통해 직접적으로 명확하게 확인하였다. 3—옥심 화합물 3a 내지 화합물 3g와 대조적으로， 이사틴 -3-메록심 히드록삼산 (화합물 6a 내지 화합물 6g)에서, ᅳ 0H 양성자는 메틸기로 치환되었기 때문에， 인접한 2' - 위치에서 카르보닐기와의 수소결합은 존재하지 않는다. 이사틴 -3- 메특심 (화합물 6a 내지 화합물 6g)는 분광학 데이터 및 상관분석 (correlat ion)에 확인된 바와 같이 순수한 E-이소머로서 얻어졌다. 선택된 화합물 3b에 대해 행한 N0E 분석 결과 H-4 ' 및 3 '메록심기의 메틸 양성자 사이에 깨끗한 상관관계 (correlat ion)가 확인되었다. 추가적으로， 화합물 6a 내지 화합물 6g의 ¾ NMR 스펙트럼에서， H-4'에 해당하는 피크는 화합물 3a 내지 화합물 3g의 것과 비교하여 일관되게 0.2-0.3 ppm 만큼 위쪽으로 더 이동하였다. 이는 E—메특심기의 보호효과에 의한 것이었다. 이사틴 -3 '—알킬옥심에 대해 E-이소머가 선호적으로 형성되는 것은 문헌들에서 언급되고 검토되어 있다 [23-25] . Compound 6a-6g was synthesized through the procedure of Banung Formula 2. Isatin-3'-meroxime hydroxamic acid (Compound 6a-6g) was synthesized by converting isatin to 3-meroxime derivative 4 using mexylamine hydrochloride under reflux under conditions (Ref. 2) Reference). The structures of the obtained compounds and intermediates were clearly identified directly through spectral studies including IR, MS, 1H NMR, 13C NMR, and elemental analysis. 3—oxime compound 3a to A compound 3g contrast, moving tin-3-methoxy roksim hydroxamic acid from (compound 6a-6g compound), because eu 0H proton been substituted with a methyl group, the adjacent 2 ' - hydrogen bonding to the carbonyl group in position do not exist . Isatin-3-methyst (compounds 6a to 6g) was obtained as pure E-isomer, as confirmed by spectroscopy data and correlation. NOE analysis of the selected compound 3b confirmed a clear correlation between the methyl protons of the H-4 ′ and 3 ′ meroxime groups. Additionally, in the ¾ NMR spectrum of Compounds 6a to 6g, the peaks corresponding to H-4 'shifted further upwards by 0.2-0.3 ppm consistently with that of Compounds 3a to 3g. This was due to the protective effect of E-Specialty. Isatin-3'—preferably forming E-isomers for alkyloximes is mentioned and reviewed in the literature [23-25].
Π . 화합물들의 생물학적 활성의 평가 Π. Assessment of Biological Activity of Compounds
1. 히스톤 탈아세틸화 효소 (HDAC)의 억제 활성 측정  1. Measurement of Inhibitory Activity of Histone Deacetylase (HDAC)
(1) 웨스턴 블롯  (1) Western blot
합성한 히드록삼산 화합물 (화합물 3a ᅳ 3g 및 화합물 6a - 6g)에 대해 웨스턴 블롯 분석을 통해 , Ι μ Μ 농도에서의 히스톤 -Η3 및 히스톤 -Η4 탈아세틸화의 억제 활성을 평가하였다. 웨스턴 블롯은 다음의 방법을 통해 수행하였다. 먼저， RIPA 완층액 (50 mM Tri sᅳ HC1 [pH 8.0] , 5 mM EDTA, 150 mM NaCl , 1% NP-40 , 0.1% SDS, 및 1 mM phenylraethylsul fonyl f luoride)내에서 세포를 용해시켜 총 단백질 추출물을 얻었다. 용해물내의 단백질 농도는 제조사의 지시서에 따라 Bio-Rad 단백질 분석 키트 (Bio-Rad Laboratories Inc . , Hercules , CA, USA)를 사용하여 측정하였다. 시료를 SDS-PAGE에서 분리하고， 니트로셀를로오스 멤브레인으로 이동시켰다. 멤브레인을 블로킹 완층액 (0.2% Tween-20 및 3% 탈지유를 포함하는 TBS)과 함께 인큐베이션한 후， 아세틸 히스톤ᅳ H3 , -H4, 및 GAPDH에 대한 1차 항체를 사용하여 탐색하였다. 세정후에 멤브레인을 서양고추넁이 퍼옥시다아제ᅳ컨쥬게이트된 2차 항체를 사용하여 탐색하였다. 검출은 ECL( enhanced chemi luminescent protein) 검출 시스템 (Amersham Biosciences , Li tt le Chal font , UK)을 사용하여 행하였다. (2) 화합물의 활성측정결과 The inhibitory activity of histone- Η3 and histone- Η4 deacetylation at ΙμΜ concentration was evaluated by Western blot analysis for the synthesized hydroxamic acid compound (Compound 3a 3g and Compound 6a-6g). Western blot was performed by the following method. First, the cells were lysed in RIPA complete solution (50 mM Tris HC1 [pH 8.0], 5 mM EDTA, 150 mM NaCl, 1% NP-40, 0.1% SDS, and 1 mM phenylraethylsul fonyl f luoride). Protein extract was obtained. Protein concentration in lysates was measured using the Bio-Rad Protein Assay Kit (Bio-Rad Laboratories Inc., Hercules, CA, USA) according to the manufacturer's instructions. Samples were separated on SDS-PAGE and the nitrocells were transferred to the rose membrane. Membranes were incubated with blocking complete fluid (TBS with 0.2% Tween-20 and 3% skim milk) and then searched using primary antibodies against acetyl histone ᅳ H3, -H4, and GAPDH. After washing, the membranes were searched using a red pepper peroxidase conjugated secondary antibody. Detection was done using an enhanced chemi luminescent protein (ECL) detection system (Amersham Biosciences, Litt le Chal font, UK). (2) Activity measurement result of compound
도 2의 결과에서 보여지는 바와 같이, 화합물 3a - 3d 및 3f — 3g는 Ι μ Μ 농도에서 HDAC 효소의 억제를 통해 히스톤 -Η3 및 히스톤 -Η4의 아세틸화를 현저하게 증가시켰다. 잘 알려진 HDAC 억제제인 SAHA도 유사한 방식으로 히스톤 아세틸화를 증가시켰다/ 이사틴 부분상에 5-니트로기를- 갖는 화합물인 3e만이 HDAC 효소를 억제하지 않아 히스톤 -H3 및 히스톤- H4이 완전히 탈아세틸화되었다.  As shown in the results of FIG. 2, compounds 3a-3d and 3f —3g markedly increased the acetylation of histone- Η3 and histone- Η4 through inhibition of HDAC enzymes at Ι μΜ concentration. SAHA, a well-known HDAC inhibitor, increased histone acetylation in a similar manner. Only 3e, a compound having 5-nitro group- on the isatin moiety, did not inhibit the HDAC enzyme, resulting in complete deacetylation of histone-H3 and histone-H4. It became.
화합물 6a - 6g에 대해서는， 화합물 6a - 6c 및 6g의 4가지 화합물이 SAHA, 화합물 3a - 3d 및 3f - 3g와 유사하게 히스톤— H3 및 히스톤 -H4의 아세틸화를 현저하게 증가시켰다. 그러나, 화합물 6d (5-Br 치환체)， 화합물 6e (5-니트로 치환체) 및 화합물 6f (5-C¾기를 포함하는 화합물)은 분석한 농도에서 HDAC 효소의 현저한 억제활성을 보이지 않았다. 상기 얻어진 결과로부터 U ) 이사틴 부분의 5번 위치에 니트로기가 존재하면 HDAC 억제에 유리하지 않다; ( ii ) 3' -옥심기의 메틸화와 함께 이사틴환상의 5번 위치에 -Br 또는 -CH3와 같이 부피가 큰 치환체가 동시에 존재하게 되면 (화합물 6d 및 6f ) 효소 억제 활성에 좋지 않다는 점을 알 수 있었다. 1 2. 암세포에 대한 세포독성 측정을 통한 항암활성 평가 For compounds 6a-6g, four compounds of compounds 6a-6c and 6g markedly increased the acetylation of histone-H3 and histone-H4 similarly to SAHA, compounds 3a-3d and 3f-3g. However, Compound 6d (5-Br substituent), Compound 6e (5-nitro substituent) and Compound 6f (compound containing 5-C¾ group) did not show significant inhibitory activity of HDAC enzyme at the analyzed concentration. From the results obtained, the presence of a nitro group at position 5 of the isatin moiety is not advantageous for HDAC inhibition; (Ii) 3 '- oxide when a methylation and a bulky substituent, such as with -Br or -CH 3 in the 5-position of the moving tin cyclic planting be present at the same time (compound 6d, and 6f) that is not good for the enzyme-inhibitory activity And it was found. 12 2. Evaluation of anticancer activity by measuring cytotoxicity against cancer cells
(1) 평가방법  (1) Evaluation method
인간 암세포주， NCI-H460 (폐암)， PC3 (전립선암)ᅳ SW620 (대장암) , MCF-7 (유방암)， 및 AsPC-1 (췌장암) 세포주는 American Type Cul ture Col lect ion (ATCC, Manassas , VA, USA)으로부터 구입하였다. 세포들을 96웰 플레이트에서 9 X 103 세포 /웰의 농도로 플레이팅하고， 하룻밤 인큐베이션하여 48 시간 동안 시료로 처리하였다. 화합불은 디메틸설폭사이드 (dimethyl sul foxide , DMS0)에 용해시켜 사용하였다. 세포독성은 문헌 [Skehan P, Storeng R, Scudiero D, Monk A, MacMahon J , Vist ica D, Warren JT, Bokesch H, Kenney S, Boyd MR. New color imetric cytotoxicity assay for ant icancer drug screening. J . Nat 1 Cancer Inst 1990； 82： 1107-1112] 에 기술된 방법을 약간 변형한 방법 [12]을 통해 측정하였다. IC50 값은 Probi ts 방법에 따라 산출하였다. 각 화합물에 대해 측정한 값은 3회의 독립적 측정결과의 평균값이다. Human cancer cell lines, NCI-H460 (lung cancer), PC3 (prostate cancer) ᅳ SW620 (colon cancer), MCF-7 (breast cancer), and AsPC-1 (pancreatic cancer) cell lines American Type Culture Collect ion (ATCC, Manassas) , VA, USA). Cells were plated at a concentration of 9 × 10 3 cells / well in 96 well plates, incubated overnight and treated with samples for 48 hours. Compound fire was used by dissolving in dimethyl sulfoxide (DMS0). Cytotoxicity is described by Skehan P, Storeng R, Scudiero D, Monk A, MacMahon J, Vist ica D, Warren JT, Bokesch H, Kenney S, Boyd MR. New color imetric cytotoxicity assay for ant icancer drug screening. J. Nat 1 Cancer Inst 1990; 82: 1107-1112] through a slightly modified method [12] Measured. IC 50 values were calculated according to the Probi ts method. The measured value for each compound is the average of three independent measurements.
(2) 암세포주에 대한 항증식 활성 평가 결과 (2) Antiproliferative Activity Evaluation Results for Cancer Cell Lines
SRB (sul forhodamine B) 세포 증식 분석을 사용하여 합성한 화합물의 항증식 활성을 평가하였다. 먼저， 이들 화합물들은 30 μ Μ의 농도에서 SW620 (인간 대장암) 세포주에 대해 이 암세포의 성장을 억제하는지 스크리닝하였다. 스크리닝 결과， 화합물 3a - 3f 및 화합물 6a - 6f 모두가 30 μ Μ의 농도에서 SW620 세포의 성장을 완전히 억제함을 확인하였다. 따라서， 이들 화합물 모두를 5 종류의 상이한 농도 (30， 10, 3， 1， 0.3 μ Μ)에서 SW620 및 추가 4 가지 종류의 인간 암세포주， MCF-7 (유방암)， PC-3 (전립선암)， AsPC-1 (췌장암)， 및 NCI-H460 (폐암) 세포주에 대해 암세포 증식 억제 활성을 측정하였다. 각 화합물의 IC50 (50%의 세포 증식 억제를 달성하는 농도) 값을 측정하고 하기 표 1에 정리하였다. SAHA는 양성 대조군으로 사용하였다. 하기 표 1에 나타난 실험데이터에 따르면 화합물 3a - 3f의 암세포주에 대한 세포독성은 HDAC 억제 활성과 잘 일치함을 보여주었다. 즉， Ι μ Μ의 농도에서 HDAC 효소 활성을 완전하게 억제하였던 화합물 3a - 3d 및 3f - 3g는 테스트한 5개 종류의 모든 암세포주에 대해서 마이크로몰 이하 또는 매우 낮은 마이크로몰 농도 범위의 IC50 값을 가지면서 암세포주에 대한 매우 뛰어난 세포독성 효과를 나타내었다. 반면에, Ι μ Μ의 농도에서 HDAC 효소 억제 활성을 나타내지 않았던 화합물 3e은 IC50 값이 19.69 y M으로 높은 값을 가지면서 암세포에 대한 세포독성 활성이 가장 낮았다 (도 2) . Sulprohodamine B (SRB) cell proliferation assays were used to assess the antiproliferative activity of the synthesized compounds. First, these compounds were screened to inhibit the growth of these cancer cells against SW620 (human colorectal cancer) cell line at a concentration of 30 μΜ. As a result of screening, it was confirmed that both Compounds 3a-3f and 6a-6f completely inhibit the growth of SW620 cells at a concentration of 30 μΜ. Therefore, all of these compounds were converted into SW620 and four additional human cancer cell lines, MCF-7 (breast cancer), PC-3 (prostate cancer) at five different concentrations (30, 10, 3, 1, 0.3 μΜ). Cancer cell proliferation inhibitory activity was measured on AsPC-1 (pancreatic cancer), and NCI-H460 (lung cancer) cell lines. IC 50 (concentrations that achieve 50% cell proliferation inhibition) values of each compound were measured and summarized in Table 1 below. SAHA was used as a positive control. According to the experimental data shown in Table 1, the cytotoxicity of the compound 3a-3f against cancer cell lines was shown to be in good agreement with the HDAC inhibitory activity. In other words, compounds 3a-3d and 3f-3g, which completely inhibited HDAC enzymatic activity at the concentration of Ι μΜ, exhibited IC 50 values in submicromolar or very low micromolar concentration ranges for all five cancer cell lines tested. It showed a very excellent cytotoxic effect on cancer cell lines. On the other hand, Compound 3e, which did not exhibit HDAC enzyme inhibitory activity at the concentration of ΙμΜ, had the lowest cytotoxic activity against cancer cells with an IC 50 value of 19.69 y M (Fig. 2).
화합물 6a - 6f에 대해서도， 일반적으로 암세포에 대한 세포독성활성은 HDAC 억제 활성과 상관성을 보였다. 도 2에 나타난 바와 같이 HDAC 효소 활성을 억제하지 않은 화합물 6d - 6f는 암세포에 대한 세포독성활성이 가장 낮게 나타났다. 반면에서， 히스톤— H3 및 -H4의 아세틸화 수준이 크게 증가되는 것에 의해 확인된 바와 같이， HDAC 효소를 강하게 억제하는 활성을 보인 화합물 6a - 6c， 및 6g는 테스트한 5 가지 종류의 모든 암세포주에 대해서도 강력한 세포독성을 나타내었다. 화합물 6e 만이 분명하지 않은 생물학적 활성 프로파일을 보였는데， 이 화합물은 분석한 농도 (1 μ Μ)에서 HDAC의 활성을 억제하지 않았으나， 활성을 측정한 4가지 암세포주 (SW620 , MCF-7 , PC-3 , AsPC-l)에 대해서는 강력한 세포독성을 보여 항암활성을 나타내었으며, NCI-H460 세포주에 대해서만 약한 항암활성을 보였다. 화합물 3e 및 화합물 6d - 6f를 제외하고， 다른 모든 화합물들은 암세포주에 대한 세포독성활성의 면에서 양성대조군 화합물 SAHA 보다 더 강한 활성을 보였다. 특히 , 화합물 3d는' AsPC-l 세포주 (췌장암 세포주)에 대해서 SAHA 보다 45배 강한 세포독성을 보였다. 화합물 3b도 SW620 세포주 (대장암 세포주)에 대해서 약 30배 강한 세포독성을 보였다. 3-옥심 시리즈 화합물 (3a-3g)에서 상이한 크기 및 전자 영향을 갖는 치환체들은 세포독성에 대해 큰 영향을 주지 않는 것 같다. 반면에， 이사틴 고리상의 5번 위치에서 큰 치환체들은 3'메톡심 화합물 (6d 및 6f )의 세포독성에 대해서는 부정적인 영향을 미쳤다. 이사틴 la-lg, 이들의 대응하는 3-옥심 및 3ᅳ메록심 유도체가 테스트한 5가지 종류의 암세포주에 대해서 세포독성을 특별히 나타내지 않았다 (데이터는 보이지 않음) . 따라서， 화합물 3a-3g 및 6a-6g에 의해 유도된 히스톤 -H3 및 히스톤 -H4 아세틸화 수준이 강하게 상승된다는 것으로부터 증명되는 바와 같이, 히드록삼산 부분의 도입이 화합물 3a-3g 및 6a-6g의 암세포에 대한 세포독성효과 및 HDAC에 대한 억제에 대해서 매우 중요한 역할을 한다는 것이 이들 화합물들의 항암 세포독성에 대한 중요한 메카니즘일 것으로 추정된다. As for compounds 6a-6f, cytotoxic activity against cancer cells was generally correlated with HDAC inhibitory activity. As shown in FIG. 2, Compounds 6d-6f that did not inhibit HDAC enzyme activity showed the lowest cytotoxic activity against cancer cells. On the other hand, compounds 6a-6c, and 6g, which showed a strong inhibitory activity of HDAC enzymes, as confirmed by the significant increase in acetylation levels of histones—H3 and -H4, all of the five cancer cell lines tested. It also showed strong cytotoxicity against. Compound 6e alone showed an indeterminate biological activity profile, which compound Although it did not inhibit HDAC activity at the analyzed concentration (1 μM), it showed strong cytotoxicity against four cancer cell lines (SW620, MCF-7, PC-3, AsPC-l) that measured activity. It showed weak anticancer activity only against NCI-H460 cell line. Except for compound 3e and compound 6d-6f, all other compounds showed stronger activity than positive control compound SAHA in terms of cytotoxic activity against cancer cell lines. In particular, compound 3d showed 45-fold stronger cytotoxicity than SAHA against the ' AsPC-l cell line (pancreatic cancer cell line). Compound 3b also showed about 30-fold stronger cytotoxicity against SW620 cell line (colon cancer cell line). Substituents with different sizes and electronic influences in the 3-oxime series compounds (3a-3g) do not seem to have a significant effect on cytotoxicity. In contrast, the large substituents at position 5 on the isatin ring had a negative effect on the cytotoxicity of the 3'methoxime compounds (6d and 6f). Cytotoxicity was not specifically shown for the five types of cancer cell lines tested by isatin la-lg and their corresponding 3-oxime and 3′meroxime derivatives (data not shown). Thus, as evidenced by the strong elevation of histone-H3 and histone-H4 acetylation levels induced by compounds 3a-3g and 6a-6g, the introduction of the hydroxamic acid moiety resulted in compounds 3a-3g and 6a-6g. It is assumed that these compounds play an important role in the cytotoxic effect on cancer cells and the inhibition of HDAC by the anticancer cytotoxicity of these compounds.
【표 1】  Table 1
Figure imgf000029_0001
화합물 6a -H 319.36 0.73 1.71 1.67 1.22 0.75 화합물 6b 5-F 337.35 1.11 2.42 1.15 0.97 0.97 화합물 6c 5-C1 353.80 0.49 1.56 2.33 0.49 0.76 화합물 6d 5-Br 398.25 2.32 7.79 8.91 1.68 2.90 화합물 6e 5-N02 364.35 1.35 0.94 1.69 0.84 14.27 화합물 6f 5-CH3 333.38 1.07 16.67 0.35 5.48 1. 19 화합물 6g 7-C1 353.80 0.26 0.34 0.29 0.63 0.35
Figure imgf000029_0001
Compound 6a -H 319.36 0.73 1.71 1.67 1.22 0.75 Compound 6b 5-F 337.35 1.11 2.42 1.15 0.97 0.97 Compound 6c 5-C1 353.80 0.49 1.56 2.33 0.49 0.76 Compound 6d 5-Br 398.25 2.32 7.79 8.91 1.68 2.90 Compound 6e 5-N0 2 364.35 1.35 0.94 1.69 0.84 14.27 Compound 6f 5-CH 3 333.38 1.07 16.67 0.35 5.48 1.19 Compound 6g 7-C1 353.80 0.26 0.34 0.29 0.63 0.35
SAHA 264.32 3.70 6.42 4.31 3.66 2.77 상기 표 1에서 1은 세포 성장올 50% 감소시키는 화합물의 농도이고 숫자는 10% 보다 작은 편차로서 3회 반복 실험의 평균 결과값을 나타낸다. 2은 세포주: SW620 , 대장암; MCF-7, 유방암; PC3, 전립선암; AsPC-l , 췌장암; NCI-H460 , 폐암; 3 SAHA (suberoyl ni 1 ide hydroxamic acid) , 양성대조군. SAHA 264.32 3.70 6.42 4.31 3.66 2.77 In Table 1, 1 represents the concentration of a compound that reduces cell growth by 50% and the number represents the average result of three replicates with a deviation of less than 10%. 2 is cell line: SW620, colon cancer; MCF-7, breast cancer; PC3, prostate cancer; AsPC-l, pancreatic cancer; NCI-H460, lung cancer; 3 SAHA (suberoyl ni 1 ide hydroxamic acid), positive control.
3. HDAC 효소와의 결합 구조 시뮬레이션 3. Simulation of binding structure with HDAC enzyme
HDAC 효소와 이 효소의 억제화합물들 사이의 상호작용에 대해 알아보기 위해， HDAC의 활성자리를 사용하여 도킹 시뮬레이션 (docking simulat ion)을 수행하였다. AutoDock Vina program [14]을 사용하여 도킹 연구 (docking study)를 수행하였다. HDAC8 효소의 초기 구조 (SAHA와의 복합체, 25) 및 HDAC2 효소의 초기 구조 [N-(2-아미노페닐)벤즈아미드와의 복합체， 2기는 Protein Data Bank (PDB) (각각 PDB ID: 1T69 and PDB ID: 3MAX)으로부터 얻었고 화합물들에 대한 좌표는 GlycoBioChem PR0DRG2 Server (ht tp : //davapcl . bi och . dundee . ac . uk/prodrg/ )를 사용하여 생성시켰다 [30] · 도킹 연구에 대한 그리드 맵 (grid map)은 SAHA 결합자리상의 중앙에 위치하게 하였고， 복합체 구조로부터 SAHA(HDAC8의 경우) 또는 N-(2-아미노페닐)벤즈아미드 (HDAC2의 경우)를 제거한 후에 1.0 A 공간으로 26 X 26 X 22 포인트를 포함하였다 [13-15] . AutoDock Vina program을 four -way mult i threading으로ᅵ 수행시키고， AutoDock Vina program 에서의 다른 파라미터들은 디폴트 세팅에 두었다. To investigate the interaction between the HDAC enzyme and its inhibitors, docking simulat ions were performed using the active sites of HDAC. Docking studies were performed using the AutoDock Vina program [14]. Initial structure of the HDAC8 enzyme (complex with SAHA, 25) and initial structure of the HDAC2 enzyme [complex with N- (2-aminophenyl) benzamide, 2 groups of Protein Data Bank (PDB) (PDB ID: 1T69 and PDB ID, respectively) : 3MAX) and the coordinates for the compounds were generated using the GlycoBioChem PR0DRG2 Server (ht tp: //davapcl.bioch.dundee.ac.uk/prodrg/) [30] · Grid maps for docking studies The grid map is centered on the SAHA binding site, and after removal of SAHA (in case of HDAC8) or N- (2-aminophenyl) benzamide (in case of HDAC2) from the complex structure, 26 X 26 X 22 points were included [13-15]. We ran the AutoDock Vina program four-way mult i threading and left the other parameters in the AutoDock Vina program at the default settings.
SAHA를 복합체 구조로부터 제거한 후에 AutoDock Vina program [28]을 사용하여 HDAC8의 결정구조에 대해 SAHA와 함께 대조군 도킹 실험을 수행하였다 [ 14， 15] . AutoDock Vina program after removing SAHA from complex structure A control docking experiment with SAHA was performed on the crystal structure of HDAC8 using [28] [14, 15].
화합물들과 HDAC 사이의 상호결합에 대한 정보를 얻기 위해， HDAC의 활성자리를 사용하여 도킹 시뮬레이션을 행하였다. 도킹 주형으로서, SAHA와 복합체를 형성한 HDAC8의 구조를 선택하였는데， 선택한 이유는 이 결정 구조를 입수하기 쉽기 때문이다 (25， Protein Dat a Bank ID : 1T69) . 복합체 구조로부터 SAHA를 제거한 후에 AutoDock Vina program [26]를 사용하여 HDAC8의 결정구조에 대해 SAHA를 대조군으로 하여 도킹 실험을 수행하였다. 도킹 실험결과, 활성자리에 위치한 화합물 3a 및 6a가 SAHA 보다 더 안정한 에너지를 가짐을 확인하였다 (도 3) . 화합물 3a 및 6a에 대한 예상 결합 모드의 안정화 에너지는 -5.3 및 -5.6 kcal /mol 인데 반해, SAHA는 ᅳ4.4 kcal /mol이었다. 따라서， 도킹 실험 결과에 의하면, 화합물 3a 및 6a는 HDAC8에 대해서 SAHA 보다 더 큰 친화도를 갖는 것으로 확인하였다.  Docking simulations were performed using active sites of HDAC to obtain information about the interaction between compounds and HDAC. As the docking template, the structure of HDAC8 complexed with SAHA was selected because this crystal structure is readily available (25, Protein Dat a Bank ID: 1T69). After removing SAHA from the complex structure, docking experiments were performed using SAHA as a control for the crystal structure of HDAC8 using the AutoDock Vina program [26]. As a result of the docking experiment, it was confirmed that the compounds 3a and 6a located in the active site have more stable energy than SAHA (FIG. 3). The stabilization energies of the expected binding modes for compounds 3a and 6a were -5.3 and -5.6 kcal / mol, whereas SAHA was ᅳ 4.4 kcal / mol. Thus, the results of the docking experiments confirmed that compounds 3a and 6a had greater affinity than SAHA for HDAC8.
HDAC8에 대한 도킹 연구에 추가하여, N-(2— 아미노페닐)벤즈아미드와의 HDAC2 복합체를 선정하였다 (27， PDB ID : 3MAX) . 히스톤 -H3 및 히스톤 -H4 탈아세틸화는 HDAC1 및 HDAC2에 의해 조절되기 때문에， HDAC2에 대한 화합물 3a 및 화합물 6a의 도킹 실험을 추가적으로 시행하였다. 도킹 실험결과， 화합물 3a 및 6a 모두 HDAC2의 활성자리에 잘 위치하고 있음올 확인하였고， 히드록삼산 부분이 아연 -결합 자리에도 잘 위치하고 있음을 확인하였다 (도 4) . 예상되는 결합 모드의 안정화 에너지는 화합물 3a 및 6a 모두에 대해 각각 -6.7 kcal /n l이었던 반면, N-(2- 아미노페닐)벤즈아미드의 경우는 -7.5 kcal /mo l이었다. 따라서， 양쪽 모두의 화합물은 HDAC2에 대해 강한 결합 친화도를 나타내었다. 이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바， 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서， 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.  In addition to the docking studies for HDAC8, an HDAC2 complex with N- (2—aminophenyl) benzamide was selected (27, PDB ID: 3MAX). Because histone-H3 and histone-H4 deacetylation are regulated by HDAC1 and HDAC2, docking experiments of Compound 3a and Compound 6a against HDAC2 were performed. As a result of the docking experiment, it was confirmed that both compounds 3a and 6a are well located at the active site of HDAC2, and that the hydroxamic acid part is well located at the zinc-binding site (FIG. 4). The expected stabilization energy of the binding mode was -6.7 kcal / n l for both compounds 3a and 6a, while -7.5 kcal / mo l for N- (2-aminophenyl) benzamide. Thus, both compounds showed strong binding affinity for HDAC2. Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the invention will be defined by the appended claims and equivalents thereof.

Claims

【청구의 범위】 【청구항 1】 하기 화학식 1 또는 화학식 2로 표시되는 이사틴 기반 히드록삼산 화합물 또는 이의 약제학적으로 허용 가능한 염 . Claims [Claim 1] An isatin-based hydroxamic acid compound represented by the following formula (1) or (2), or a pharmaceutically acceptable salt thereof.
[화학식 1]  [Formula 1]
Figure imgf000032_0001
Figure imgf000032_0001
상기 화학식 1에서 R은 수소， 할로겐， d-C5알킬， 또는 니트로이다. [화학식 2] In Formula 1, R is hydrogen, halogen, dC 5 alkyl, or nitro. [Formula 2]
Figure imgf000032_0002
상기 화학식 2에서 R은 수소， 할로겐， d-Cs알킬 , 또는 니트로이다.
Figure imgf000032_0002
In Formula 2, R is hydrogen, halogen, d-Csalkyl, or nitro.
【청구항 2】 [Claim 2]
제 1 항에 있어서， 상기 화학식 1 또는 화학식 2에서의 할로겐은 플루오르 (F) , 염소 (C1 ) 또는 브름 (Br )인 것을 특징으로 하는 화합물.  The compound of claim 1, wherein the halogen in Formula 1 or Formula 2 is fluorine (F), chlorine (C1) or bromine (Br).
【청구항 3】 [Claim 3]
제 1 항에 있어서, 상기 화학식 1 또는 화학식 2으로 표시되는 이사틴 기반 히드톡삼산 화합물은 다음의 화합물 중 어느 하나인 것을 특징으로 하는 화합물: N-히드록시ᅳ 7-(3— (히드록시이미노) 2-옥소인돌린 -1- 일)헵탄아미드; 7-(5-플루오로 -3- (히드록시이미노 )ᅳ2-옥소인돌린 -1-일) -N- 히드록시헵탄아미드; 7-(5-클로로 -3— (히드록시이미노) -2-옥소인돌린— 1-일) - N-히드록시헵탄아미드； 7-(5_브로모 3- (히드록시이미노) -2-옥소인돌린 -1- 일)— N-히드록시헵탄아미드; N-히드록시ᅳ7-(3- (히드록시이미노 )ᅳ5-니트로 -2- 옥소인돌린 -1ᅳ일)헵탄아미드; N-히드록시 -7-(3- (히드록시이미노) -5-메틸 -2- 옥소인돌린 -1-일)헵탄아미드; 그 (7-클로로 -3- (히드록시이口노) -2- 옥소민돌린 -1-일 )-N-히드록시헵탄아미드 N-히드록시ᅳ 7-(3- (메톡시ᄋ미노) -The compound according to claim 1, wherein the isatin-based hydroxytoxane compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy- 7- (3— (hydroxyimino ) 2-oxoindolin-1-1-yl) heptanamide; 7- (5-fluoro-3- (hydroxyimino) ᅳ 2-oxoindolin-1-yl) -N-hydroxyheptanamide; 7- (5-chloro-3— (hydroxyimino) -2-oxoindolin— 1-yl) -N-hydroxyheptanamide; 7- (5_bromo 3- (hydroxyimino) -2- Oxoindolin-1-yl) —N-hydroxyheptanamide; N-hydroxy ᅳ 7- (3- (hydroxyimino) ᅳ 5-nitro-2- Oxoindolin-1-1-yl) heptanamide; N-hydroxy-7- (3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) heptanamide; The (7-chloro-3- (hydroxyimino) -2-oxomindololin-1-yl) -N-hydroxyheptanamide N-hydroxy ᅳ 7- (3- (methoxymino)-
2-옥소인돌린ᅳ 1-일 )헵탄아미드； 7-(5-플루오로 -3- (메록시이 노) -2- 옥소인돌린 -1-일) -N-히드록시헵탄아미드 7-(5_클로로 -3- (메톡시이 노 )-2- 옥소인돌린 -1ᅳ일) -N-히드록시헵탄아미드 7-(5-브로모 -3- (메록시이 D노 )-2- 옥소인돌린 -1ᅳ일 )-N-히드록시헵탄아미드 Ν-히드록시 -7— (3— (메톡시 ο미노) -2-oxoindolinin-l-yl) heptanamide; 7- (5-fluoro-3- (methoxyino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide 7- (5 Chloro-3- (methoxyino) -2-oxoindolin-1-1-yl) -N-hydroxyheptanamide 7- (5-bromo-3- (methoxyyi Dno) -2-oxoindolin- 1-yl) -N-hydroxyheptanamide Ν-hydroxy-7- (3— (methoxy οmino)-
5-니트로 -2-옥소인돌린 -1-일)헵탄아미드 Ν-히드록시 -7— ( 3- (메톡시 0미노) -5-nitro-2-oxoindolin-1-yl) heptanamide Ν-hydroxy-7- (3- (methoxy 0mino)-
5-메틸 -2-옥소인돌린 -1-일)헵탄아미드； 및 7-(7-클로로 -3- (메톡시。미노) -5-methyl-2-oxoindolin-1-yl) heptanamide; and 7- (7-chloro-3- (methoxy.mino)-
2-옥소인돌린 -1-일) -N-히드록시헵탄아미 2-oxoindolin-1-yl) -N-hydroxyheptanami
【청구항 4】 [Claim 4]
상기 제 1 항의 화합물 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 포함하는 항암용 약제학적 조성물.  An anticancer pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
【청구항 5] [Claim 5]
제 4 항에 있어서, 상기 암은 유방암, 폐암， 위암， 간암， 혈액암， 뼈암, 췌장암， 피부암， 두경부암， 피부 또는 안구 흑색종， 자궁육종， 난소암, 직장암， 항문암, 대장암， 난관암， 자궁내막암， 자궁경부암， 소장암， 내분비암， 갑상선암， 부갑상선암 신장암, 연조직종양, 요도암, 전립선암， 기관지암, 또는 골수암인 것을 특징으로 하는 항암용 약제학적 조성물.  The method of claim 4, wherein the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, hematologic cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tubes Cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer kidney cancer, soft tissue tumors, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.
【청구항 6】 [Claim 6]
제 4 항에 있어서, 상기 화합물은 히스톤 탈아세틸화효소 (hi stone deacetyl ase)의 억제를 통해 히스톤의 아세틸화를 촉진하는 활성을 갖는 것을 특징으로 하는 항암용 약제학적 조성물.  The pharmaceutical composition for anticancer according to claim 4, wherein the compound has an activity of promoting acetylation of histones through inhibition of histone deacetylase.
【청구항 7】 [Claim 7]
하기 화학식 1 또는 화학식 2로 표시되는 이사틴 기반 히드록삼산 화합물 또는 이의 약제학적으로 허용 가능한 염의 약제학적 유효량을 암의 치료가 필요한 환자에게 투여하는 단계를 포함하는 암을 치료하는 방법. [화학식 1] A method of treating cancer comprising administering to a patient in need thereof a pharmaceutically effective amount of an isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof. [Formula 1]
Figure imgf000034_0001
Figure imgf000034_0001
상기 화학식 1에서 R은 수소， 할로겐， c厂 c5알킬， 또는 니트로이다. [화학식 2] In Formula 1, R is hydrogen, halogen, c 厂 c 5 alkyl, or nitro. [Formula 2]
Figure imgf000034_0002
상기 화학식 2에서 R은 수소， 할로겐， d-C5알킬 또는 니트로이다.
Figure imgf000034_0002
In Formula 2, R is hydrogen, halogen, dC 5 alkyl or nitro.
【청구항 8] [Claim 8]
제 7 항에 있어서， 상기 화학식 1 또는 화학식 2에서 할로겐은 폴루오르 (F) , 염소 (C1 ) 또는 브롬 (Br )인 것을 특징으로 하는 방법.  8. The method of claim 7, wherein the halogen in Formula 1 or Formula 2 is polour (F), chlorine (C1) or bromine (Br).
【청구항 9】 [Claim 9]
제 7 항에 있어서, 상기 화학식 1 또는 화학식 2으로 표시되는 이사틴 기반 히드록삼산 화합물은 다음의 화합물 중 어느 하나인 것을 특징으로 하는 방법: N-히드록시 -7-(3ᅳ (히드록시이미노) -2-옥소인돌린ᅳ 1- 일 )헵탄아미드 7— (5-플루오로— 3- (히드록시이미노) -2-옥소인돌린 -1ᅳ일 )-N- 히드록시헵탄아미드； 7— (5-클로로 -3— (히드록시이미노) -2ᅳ옥소인돌린 -1-일 ) - N-히드록시헵탄아미드; 7-(5-브로모 -3ᅳ (히드톡시이미노) -2-옥소인돌린ᅳ 1- 일 )-N-히드록시헵탄아미드； N-히드록시ᅳ그 (3ᅳ (히드록시이미노) -5-니트로ᅳ 2- 옥소인돌린 -1-일)헵탄아미드; N-히드록시 -7-(3- (히드록시이미노) -5-메틸ᅳ 2- 옥소인돌린 -1ᅳ일 )헵탄아미드； 7-(7-클로로 -3- (히드록시이미노)ᅳ 2- 옥소인돌린 -1ᅳ일) -N-히드록시헵탄아미드； N-히드록시ᅳ그 (3- (메록시이미노) - 2ᅳ옥소인돌린 -1-일 )헵탄아미드； 그 (5-플루오로 -3- (메특시이미노) -2- 옥소인돌린 -1-일) -N-히드록시헵탄아미드 7-(5-클로로 -3- (메특시이미노) -2- 옥소인돌린 -1-일 )-N-히드록시헵탄아미드 7- (5-브로모 -3- (메특시이미노) -2- 옥소인돌린 -1-일) -N-히드록시헵탄아미드 N-히드록시 -7-(3- (메톡시이미노)ᅳ 5-니트로 -2-옥소인돌린 -1-일 )헵탄아미드 N-히드록시-그 (3- (메톡시이미노) - 5-메틸 -2-옥소인돌린 -1-일)헵탄아미드; 7- (그클로로 -3- (메특시이미노) - 2-옥소인돌린 -1-일) 히드록시헵탄아미 . 8. The method according to claim 7, wherein the isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy-7- (3 ′ (hydroxyimino ) -2-oxoindolinyl 1-yl) heptanamide 7— (5-fluoro— 3- (hydroxyimino) -2-oxoindolin-1 ylyl) -N-hydroxyheptanamide; 7— ( 5-chloro-3— (hydroxyimino) -2) oxoindolin-1-yl) -N-hydroxyheptanamide; 7- (5-Bromo-3 ′ (hydroxythoxymino) -2-oxoindolin® 1-yl) -N-hydroxyheptanamide; N-hydroxyslag (3 ′ (hydroxyimino) -5 Nitroche 2-oxoindolin-1-yl) heptanamide; N-hydroxy-7- (3- (hydroxyimino) -5-methyl ᅳ 2-oxoindolin-1xyl) heptanamide; 7- (7-chloro-3- (hydroxyimino) ᅳ 2-oxo Indolin-1syl) -N-hydroxyheptanamide; N-hydroxyslag (3- (methoxyimino) -2 xooxoindolin-1-yl) heptanamide; (5-fluoro-3) -(Meikoshiimino) -2- Oxoindolin-1-yl) -N-hydroxyheptanamide 7- (5-chloro-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide 7- ( 5-Bromo-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide N-hydroxy-7- (3- (methoxyimino) ᅳ 5-nitro- 2-oxoindolin-1-yl) heptanamide N-hydroxy-g- (3- (methoxyimino)-5-methyl-2-oxoindolin-1-yl) heptanamide; 7- (Glochloro-3- (methoxyimino) -2-oxoindolin-1-yl) hydroxyheptanami.
【청구항 10】 [Claim 10]
제 7 항에 있어서, 상기 암은 유방암， 폐암 위암， 간암， 혈액암, 뼈암, 췌장암, 피부암， 두경부암， 피부 또는 안구 흑색종, 자궁육종， 난소암， 직장암, 항문암， 대장암, 난관암， 자궁내막암， 자궁경부암， 소장암 내분비암， 갑상선암， 부갑상선암, 신장암, 연조직종양， 요도암 전립선암， 기관지암, 또는 골수암인 것을 특징으로 하는 방법 .  The method of claim 7, wherein the cancer is breast cancer, lung cancer stomach cancer, liver cancer, hematologic cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tube cancer , Endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.
【청구항 11】 [Claim 11]
제 7 항에 있어서, 상기 화합물은 히스톤 탈아세틸화효소 (hi stone deacetyl ase)의 억제를 통해 히스톤의 아세틸화를 촉진하는 활성을 갖는 것을 특징으로 하는 방법.  8. The method of claim 7, wherein the compound has an activity of promoting acetylation of histones through inhibition of histone deacetylase.
【청구항 12】 [Claim 12]
암 치료용 약제를 제조하기 위한 하기 화학식 1 또는 화학식 2로 표시되는 이사틴 기반 히드록삼산 화합물 또는 이의 약학적으로 허용 가능한 염의 용도.  Use of the isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating cancer.
[화학식 1]  [Formula 1]
Figure imgf000035_0001
Figure imgf000035_0001
상기 화학식 1에서 R은 수소， 할로겐， C厂 C5알킬， 또는 니트로이다.In Formula 1, R is hydrogen, halogen, C 厂 C 5 alkyl, or nitro.
「 . [화학식 2] ``. [Formula 2]
Figure imgf000036_0001
상기 화학식 2에서 R은 수소, 할로겐， d-C5알킬， 또는 니트로이다.
Figure imgf000036_0001
In Formula 2, R is hydrogen, halogen, dC 5 alkyl, or nitro.
【청구항 13】 [Claim 13]
제 12 항에 있어서， 상기 화학식 1 또는 '화학식 2에서 할로겐은 플루오르 (F) , 염소 (C1 ) 또는 브름 (Br)인 것을 특징으로 하는 용도.  13. The use according to claim 12, wherein the halogen in Chemical Formula 1 or Chemical Formula 2 is fluorine (F), chlorine (C1) or bromine (Br).
【청구항 14】 [Claim 14]
제 12 항에 있어서， 상기 화학식 1 또는 화학식 2으로 표시되는 이사틴 기반 히드록삼산 화합물은 다음의 화합물 중 어느 하나인 것을 특징으로 하는 용도: N-히드록시 -7-(3ᅳ (히드록시이미노) -2-옥소인돌린 -1- 일)헵탄아미드; 7— (5—플루오로 -3- (히드록시이미노) -2-옥소인돌린ᅳ 1-일) 히드록시헵탄아미드; 7-(5-클로로 -3ᅳ (히드록시이미노)—2—옥소인돌린— 1-일) - N-히드록시헵탄아미드； 그 (5-브로모—3- (히드록시이미노) -2-옥소인돌린 -1- 일 )-N—히드록시헵탄아미드； N-히드톡시 -그 (3- (히드록시이미노) -5-니트로 -2- 옥소인돌린 -1-일 )헵탄아미드； N-히드록시 -그 (3— (히드톡시이미노) -5-메틸 -2- 옥소인돌린 -1-일)헵탄아미드； 7- (그클로로 -3-(히드록시이미노) -2- 옥소-인돌린 -1-일) -N-히드록시헵탄아미드; N-히드록시ᅳ7-(3ᅳ (메특시이미노) - 2-옥소인돌린 -1-일)헵탄아미드； 그 (5-플루오로— 3- (메록시이미노) -2- 옥소인돌린 -1-일) -N-히드톡시헵탄아미드 7-(5-클로로 -3- (메록시이미노 )-2- 옥소인돌린 -1-일 )-N-히드톡시헵탄아미드 7-(5-브로모 -3- (메톡시이미노 )-2- 옥소인돌린 -1-일 )-N-히드특시헵탄아미드 N-히드록시ᅳ 7-(3ᅳ (메특시이미노) - 5-니트로 -2-옥소인돌린 -1-일)헵탄아미드 N-히드록시ᅳ 7-(3ᅳ (메록시이미노) - 5-메틸 -2-옥소인돌린 -1-일)헵탄아미드; 및 7-( 7-클로로 -3- (메록시이미노) - 2-옥소인돌린 -1-일 )-N-히드록시헵탄아미 13. The use according to claim 12, wherein the isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy-7- (3 ′ (hydroxyimino ) -2-oxoindolin-1-yl) heptanamide; 7— (5—fluoro-3- (hydroxyimino) -2-oxoindolinyl 1-yl) hydroxyheptanamide; 7- (5-Chloro-3 '(hydroxyimino) —2—oxoindolin— 1-yl) -N-hydroxyheptanamide; (5-bromo—3- (hydroxyimino) -2- Oxoindolin-1-yl) -N—hydroxyheptanamide; N-hydroxytoxy-he (3- (hydroxyimino) -5-nitro-2-oxoindolin-1-yl) heptanamide; N- Hydroxy-g (3— (hydroxyethinomino) -5-methyl-2-oxoindolin-1-yl) heptanamide; 7- (gchloro-3- (hydroxyimino) -2-oxo-indolin -1-yl) -N-hydroxyheptanamide; N-hydroxy'7- (3 '(mephosimino) -2-oxoindolin-1-yl) heptanamide; (5-fluoro- 3- (methoxyimino) -2-oxoindolin- 1-yl) -N- hydroxyheptanamide 7- (5-chloro-3- (methoxyimino) -2-oxoindolin-1-yl) -N- hydroxyheptanamide 7- (5-bromo 3- (Methoxyimino) -2-oxoindolin-1-yl) -N- hydroxyspecificheptanamide N-hydroxy VII 7- (3 '(methoxyimino) -5-nitro-2-oxo Indolin-1-yl) heptanamide N-hydroxy ᅳ 7- (3 '(methoxyimino)-5-methyl-2-oxoindolin-1-yl) heptanamide; And 7- (7-chloro-3- (methoxyimino)-2-oxoindolin-1-yl) -N-hydroxyheptanamimi
【청구항 15】 [Claim 15]
제 12 항에 있어서， 상기 암은 유방암， 폐암, 위암, 간암， 혈액암, 뻐암， 췌장암, 피부암, 두경부암， 피부 또는 안구 혹색종， 자궁육종， 난소암， 직장암， 항문암， 대장암， 난관암， 자궁내막암, 자궁경부암， 소장암 내분비암， 갑상선암， 부갑상선암， 신장암， 연조직종양, 요도암， 전립선암， 기관지암, 또는 골수암인 것을 특징으로 하는 용도.  The method of claim 12, wherein the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye sarcoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tube Cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.
【청구항 16】 [Claim 16]
제 12 항에 있어서， 상기 화합물은 히스톤 탈아세틸화효소 (hi stone deacetylase)의 억제를 통해 히스톤의 아세틸화를 촉진하는 활성을 갖는 것을 특징으로 하는 용도.  13. The use according to claim 12, wherein the compound has an activity of promoting acetylation of histones through inhibition of histone deacetylases.
【청구항 17】 [Claim 17]
다음의 단계를 포함하는 상기 제 1 항의 화학식 1의 화합물을 제조하는 방법：  A process for preparing the compound of formula 1 according to claim 1 comprising the following steps:
a) 하기 일반식 1의 화합물을 에틸 7-브로모헵타노에이트와 반웅시켜 하기 일반식 2의 화합물을 제조하는 단계로서， 하기 일반식 1에서 R은 수소, 할로겐， d-C5 알킬， 또는 니트로인 단계; a) reacting a compound of formula 1 with ethyl 7-bromoheptanoate to prepare a compound of formula 2, wherein in formula 1, R is hydrogen, halogen, dC 5 alkyl, or nitro ;
Figure imgf000037_0001
Figure imgf000037_0001
b) 하기 일반식 2의 화합물을 히드록실아민 하이드로클로라이드와 반웅시켜 하기 일반식 3의 화합물을 제조하는 단계. b) reacting the compound of Formula 2 with hydroxylamine hydrochloride to prepare a compound of Formula 3.
Figure imgf000038_0001
Figure imgf000038_0001
【청구항 18】 [Claim 18]
다음의 단계를 포함하는 상기 제 1 항의 화학식 2의 화합물을 제조하는 방법 :  A process for preparing the compound of formula 2 of claim 1 comprising the following steps:
a) 하기 일반식 1의 이사틴 화합물을 메록실아민 히드로클로라이드와 반웅시켜 하기 알반식 4의 3—메톡심 유도체로 전환시키는 단계로서， 하기 일반식 1에서 R은 수소， 할로겐, d-Cs알킬, 또는 트로인 단계;  a) reacting the isatin compound of formula 1 with mexylamine hydrochloride and converting it to a 3—methoxime derivative of the following alban formula 4, wherein in formula 1, R is hydrogen, halogen, d-Csalkyl Or troin step;
Figure imgf000038_0002
Figure imgf000038_0002
b) 하기 일반식 4의 화합물을 에틸 7-브로모헵타노이트와 반응시켜 하기 일반식 5의 화합물을 제조하는 단계; 및  b) reacting the compound of formula 4 with ethyl 7-bromoheptanoite to prepare a compound of formula 5; And
Figure imgf000038_0003
c) 하기 일반식 5의 화합물을 히드록실아민 하이드로클로라이드와 반웅시켸일반식 6의 화합물을 제조하는 단계 . // O sszsSOSMldAV
Figure imgf000038_0003
c) preparing a compound of formula (5) with hydroxylamine hydrochloride and a compound of formula (6). // O sszsS O SM ld AV
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