CN116535343A - Hydroxamic acid compound and application thereof - Google Patents

Hydroxamic acid compound and application thereof Download PDF

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CN116535343A
CN116535343A CN202210219254.7A CN202210219254A CN116535343A CN 116535343 A CN116535343 A CN 116535343A CN 202210219254 A CN202210219254 A CN 202210219254A CN 116535343 A CN116535343 A CN 116535343A
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methyl
cancer
piperazin
carbonyl
hydroxamic acid
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王贤亲
温从丛
马建设
黄雪丽
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Wenzhou Medical University
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    • 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
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a hydroxamic acid compound and application thereof, wherein the hydroxamic acid compound is a compound with the following chemical structural general formula or a chemical isomer or a salt thereof:

Description

Hydroxamic acid compound and application thereof
Technical Field
The invention relates to the technical field of biological medicines, in particular to a hydroxamic acid compound and application thereof.
Background
Tumors are major diseases threatening human health, and the treatment of tumors has been closely focused worldwide. Traditional chemotherapy drugs nonspecifically block cell division to cause cell death, and kill tumor cells and destroy normal cells of the human body. And many cytotoxic drugs have limited therapeutic scope and are prone to cause treatment-related adverse effects.
In recent years, with the continuous improvement of molecular biology technology and the further understanding of tumor pathogenesis from cellular and molecular level, and the rapid development of technologies such as combinatorial chemistry, structure-based drug design, computer science and the like, tumor biological treatment has advanced to a great extent, and has entered the era of molecular targeted treatment. Targeted anticancer drugs can target specific pathways, prevent tumor growth and reduce toxicity to normal cells. They are characterized in that they have non-cytotoxicity and tumor cell targeting; has cell regulating and stabilizing effects; dose limiting toxicity and maximum tolerated doses are generally not achievable in clinical studies; can kill tumor cells insensitive to or resistant to chemotherapy, and has better effect when being combined with conventional treatment (radiotherapy and chemotherapy).
Many antitumor targets have been discovered, with histone deacetylases being an important target for the development of current new anticancer drugs. Factors responsible for aberrant tumor gene expression and gene expression product activity come from two major changes, genetic (Genetics) and epigenetic (Epigenetics). Wherein epigenetic refers to a regulation mode of gene expression which affects the transcriptional activity of genes without involving DNA sequence changes, and the molecular basis mainly involves two aspects: one is directed to methylation modification of DNA and the other is directed to acetylation modification of chromatin histones. Histone acetylation and deacetylation of chromatin are one of the key links to regulate gene expression, and two classes of enzymes determine the degree of acetylation of histones, namely histone acetyl transferase (Histone acetyltransferases, HAT) and histone deacetylase (Histone deacetylases, HDAC). Acetylation of histones may activate transcription of specific genes, whereas HDACs inhibit transcriptional expression of genes. Meanwhile, HDACs also have an important influence on the acetylation-deacetylation process of non-histone proteins, including transcription factors, signaling proteins, DNA repair enzymes, etc., and these target proteins play a decisive role in the regulation of gene expression. In summary, HDAC plays an extremely important role in epigenetic regulation by influencing histone and non-histone acetylation processes, and abnormality of this regulation mechanism is closely related to tumor occurrence and development, and development of small molecule drugs aiming at important molecular targets influencing epigenetic properties such as HDAC has become a hotspot in the field of international tumor targeted therapy at present.
Histone deacetylase inhibitors can be divided into four classes by structure: benzamide, hydroxamic acids, fatty acids and cyclic peptides. SAHA (also known as Vorinostat), which is a hydroxamic acid, is the first histone deacetylase inhibitor marketed for the treatment of cutaneous T cell lymphomas. The application of the HDAC inhibitor in solid tumor treatment is also in a clinical test stage, marks the end of a conceptual verification research stage of the HDAC as a novel drug target, and also predicts that the HDAC inhibitor has wide development prospect as an anti-tumor drug.
Hydroxamic acid HDAC inhibitors consist of three parts, an aromatic ring, a fatty chain and hydroxamic acid, respectively an enzyme surface recognition region, a linking region and a metal binding region (zinc ion binding region). In order to find compounds with better activity than SAHA enzyme inhibition, researchers have conducted a great deal of research on the compounds, wherein the hydroxamic acid groups of the metal binding region are kept unchanged, and the structure of the enzyme surface recognition region and the connecting region are optimized to find that derivatives with stronger activity, higher selectivity and higher safety are the main research directions of hydroxamic acid inhibitors. While improving antitumor activity, reducing the influence on normal tissues or cells is a very important issue.
The invention aims to obtain a series of compounds through drug design and synthesis means, and carry out in-vitro enzyme inhibition and tumor inhibition tests on the compounds so as to find that compared with the SAHA which is a drug on the market, the invention has more ideal anti-tumor drug development.
Disclosure of Invention
In order to make up the deficiency of the prior art, the invention discloses a hydroxamic acid compound and application thereof, which are applied as antitumor drugs to meet the requirements of clinical application.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a hydroxamic acid compound, which is a compound having the following chemical structural formula or a chemical isomer or a salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
r is hydrogen, methyl, methoxy, trifluoromethyl or halogen;
x is NH, O or S.
The hydroxamic acid compounds specifically comprise the following compounds:
4- ((4- (1H-indole-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide,
4- ((4- (5-fluoro-1H-indole-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide,
N-hydroxy-4- ((4- (5-methoxy-1H-indole-2-carbonyl) piperazin-1-yl) methyl) benzamide,
4- ((4- (benzofuran-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide,
N-hydroxy-4- ((4- (5- (trifluoromethyl) benzofuran-2-carbonyl) piperazin-1-yl) methyl) benzamide,
4- ((4- (benzo [ b ] thiophene-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide,
4- ((4- (5-chlorobenzo [ b ] thiophene-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide, or
N-hydroxy-4- ((4- (6-methoxybenzo [ b ] thiophene-2-carbonyl) piperazin-1-yl) methyl) benzamide.
The aforementioned hydroxamic acid compounds, wherein the salt comprises hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate.
The application of the hydroxamic acid compound in preparing medicaments for treating tumors.
The aforementioned uses, the tumor includes liver cancer, lung cancer, breast cancer, esophagus cancer, stomach cancer, nasopharyngeal cancer, ovarian cancer, bladder cancer, rectal cancer, skin cancer and lymphoma.
For the foregoing use, the tumor is selected from the group consisting of non-small cell lung cancer and colorectal cancer.
The compounds of the present invention may be administered in the form of compositions to mammals (including humans) in need of oncological treatment by oral, injectable, and the like routes.
The composition comprises a therapeutically effective amount of a hydroxamic acid compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The carrier refers to a carrier conventional in the pharmaceutical field, for example: diluents, excipients such as water, and the like; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, and the like; fillers such as starch and the like; disintegrating agents such as calcium carbonate, sodium bicarbonate; in addition, other adjuvants such as flavoring agents and sweeteners may be added to the composition.
The composition of the invention can be prepared into conventional solid preparations, such as tablets, capsules and the like, for oral administration; it can also be made into injection.
The various dosage forms of the composition of the present invention can be prepared by a method conventional in the pharmaceutical arts, wherein the content of the hydroxamic acid compound as an active ingredient is 0.1 to 99.5% by weight of the composition.
The hydroxamic acid compounds of the present invention can be administered to mammals, including humans, by oral or injectable means, with oral means being particularly preferred. The dosage of the medicine is 0.0001 mg/kg-200 mg/kg body weight per day. The optimal dose will depend on the individual, and will generally be smaller at the beginning and then gradually increase.
Compared with the prior art, the compound has the following beneficial effects:
1) The compound has good HDAC enzyme inhibition activity and good inhibition activity on various tumor cells of human bodies.
2) The compound provided by the invention has weak inhibition effect on normal cells while effectively inhibiting tumor cells, shows better selective inhibition activity, and has good anti-tumor clinical application prospect.
In conclusion, the compound disclosed by the invention has smaller toxic and side effects when being applied as an anti-tumor drug, and is easier to be used as the anti-tumor drug.
Detailed Description
The present invention will be described in further detail with reference to examples. The following examples are only illustrative of the present invention and are not intended to limit the scope of the invention.
Example 1: a hydroxamic acid compound, characterized by: is a compound having the following chemical structural general formula or a chemical isomer or a salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
r is hydrogen, methyl, methoxy, trifluoromethyl or halogen;
x is NH, O or S.
For the convenience of understanding the present invention, the following specific compounds and salts thereof are preferred among the compounds of the structure of formula V, but the present invention is not limited to the following compounds:
TABLE 1
The hydroxamic acid compound can be salified with inorganic acid and organic acid to obtain a salt form substance of the hydroxamic acid compound, wherein the salt is hydrochloride, hydrobromide, sulfate, bisulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate.
Preferably, the hydroxamic acid compound is in the form of a salt selected from the group consisting of hydrochloride, hydrobromide, bisulfate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate.
More preferably, the hydroxamic acid compound is in the form of a salt selected from the group consisting of hydrochloride, acetate, sulfate, tartrate, and malate.
According to the salt form of the hydroxamic acid compound, the hydroxamic acid compound is obtained by salifying the hydroxamic acid compound with a corresponding inorganic acid or organic acid selected from the group consisting of acid, hydrobromic acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, tannic acid, citric acid, trifluoroacetic acid, malic acid, maleic acid, succinic acid, p-toluenesulfonic acid and methanesulfonic acid.
The hydroxamic acid compounds are prepared as follows:
the preparation method can further comprise the reaction of the hydroxamic acid compound with inorganic acid (or inorganic base) and organic acid (or organic base), and cooling to separate out salt of the compound with the structure of formula V.
The compounds of the present invention may be administered in the form of compositions to mammals (including humans) in need of oncological treatment by oral, injectable, and the like routes.
The composition comprises a therapeutically effective amount of a hydroxamic acid compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The carrier refers to a carrier conventional in the pharmaceutical field, for example: diluents, excipients such as water, and the like; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, and the like; fillers such as starch and the like; disintegrating agents such as calcium carbonate, sodium bicarbonate; in addition, other adjuvants such as flavoring agents and sweeteners may be added to the composition.
The composition of the invention can be prepared into conventional solid preparations, such as tablets, capsules and the like, for oral administration; it can also be made into injection.
The various dosage forms of the composition of the present invention can be prepared by a method conventional in the pharmaceutical arts, wherein the content of the hydroxamic acid compound as an active ingredient is 0.1 to 99.5% by weight of the composition.
The hydroxamic acid compounds of the present invention can be administered to mammals, including humans, by oral or injectable means, with oral means being particularly preferred. The dosage of the medicine is 0.0001 mg/kg-200 mg/kg body weight per day. The optimal dose will depend on the individual, and will generally be smaller at the beginning and then gradually increase.
Example 2: synthesis of 4- ((4- (1H-indole-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide (T1):
the preparation is carried out according to a synthesis general method, and the synthesis route is as follows:
synthesis of methyl 4- (4- (1H-indole-2-carbonyl) piperazin-1-yl) methyl) benzoate:
0.50g (3.10 mmol) of indole-2-carboxylic acid was dissolved in 15mL of N, N-dimethylformamide, 0.63g (6.21 mmol) of triethylamine and 0.79g (3.10 mmol) of O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) were added, stirred at room temperature for 30min, 0.76g (3.26 mmol) of methyl 4- (piperazin-1-ylmethyl) benzoate were added, stirred at room temperature overnight, and the TLC detection reaction was complete. A15% sodium chloride solution was added dropwise to the reaction solution to precipitate a solid, which was stirred at room temperature for 2 hours, suction-filtered and dried under vacuum to give 0.934g of an off-white solid, the yield of which was 79.8%.
Synthesis of 4- ((4- (1H-indole-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide (T1):
2.00g (29 mmol) of hydroxylamine hydrochloride and 2.09g (32 mmol) of potassium hydroxide were dissolved in 50mL of methanol, stirred at room temperature for 2 hours, precipitated potassium chloride solid was filtered, 0.588g (1.56 mmol) of intermediate 6a was added to the above filtrate, reacted at 40℃for 3 hours, and the reaction was completed by TLC. The reaction mixture was adjusted to pH 7.0 with 2N hydrochloric acid, solids precipitated, filtered, the solvent was distilled off under reduced pressure from the mother liquor, diluted with 30mL of water, extracted with ethyl acetate (20 mL. Times.3), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.422g of an off-white solid (T1) in 71.5% yield. ESI-MS M/z [ M+H ]]+:379.10； 1 H NMR(400MHz,DMSO-d6)δ:11.60–11.53(m,1H),11.17(s,1H),9.04(s,1H),7.74(d,J＝8.0Hz,2H),7.60(d,J＝8.0Hz,1H),7.41(dd,J＝8.2,3.8Hz,3H),7.18(t,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),6.78(d,J＝1.8Hz,1H),3.92–3.64(m,4H),3.57(s,2H),2.45(t,J＝5.0Hz,4H)。
Example 3: synthesis of 4- ((4- (5-fluoro-1H-indole-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide (T2):
t2 was prepared according to the general procedure. ESI-MS M/z [ M+H ]]+:397.16； 1 H NMR(400MHz,DMSO-d6)δ:11.60–11.56(m,1H),11.15(s,1H),9.04(s,1H),7.71(d,J＝8.0Hz,2H),7.60(d,J＝8.0Hz,1H),7.41(dd,J＝8.2,3.8Hz,2H),7.18(t,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),6.75(d,J＝1.8Hz,1H),3.92–3.64(m,4H),3.52(s,2H),2.44(t,J＝5.0Hz,4H)。
Example 4: synthesis of N-hydroxy-4- ((4- (5-methoxy-1H-indole-2-carbonyl) piperazin-1-yl) methyl) benzamide (T3):
t3 was prepared according to the general procedure. ESI-MS M/z [ M+H ] +:409.19;1H NMR (400 MHz, DMSO-d 6) δ:11.71-11.65 (m, 1H), 11.15 (s, 1H), 9.03 (s, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.41 (dd, J=8.2, 3.8Hz, 2H), 7.04 (t, J=7.5 Hz, 1H), 6.75 (d, J=1.8 Hz, 1H), 3.92-3.64 (m, 4H), 3.79 (s, 3H), 3.52 (s, 2H), 2.44 (t, J=5.0 Hz, 4H).
Example 5: synthesis of 4- ((4- (benzofuran-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide (T4):
t4 was prepared according to the general procedure. ESI-MS M/z [ M+H ]]+:380.15； 1 H NMR(400MHz,DMSO-d6)δ:11.60–11.54(m,1H),9.04(s,1H),7.74(d,J＝8.0Hz,2H),7.60(d,J＝8.0Hz,1H),7.41(dd,J＝8.2,3.8Hz,3H),7.18(t,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),6.78(d,J＝1.8Hz,1H),3.92–3.64(m,4H),3.57(s,2H),2.45(t,J＝5.0Hz,4H)。
Example 6: synthesis of N-hydroxy-4- ((4- (5- (trifluoromethyl) benzofuran-2-carbonyl) piperazin-1-yl) methyl) benzamide (T5):
t5 was prepared according to the general procedure. ESI-MS M/z [ M+H ] +:448.14;1H NMR (400 MHz, DMSO-d 6) δ:11.78 (m, 1H), 9.04 (s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.41 (dd, J=8.2, 3.8Hz, 3H), 7.18 (t, J=7.6 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 3.92-3.64 (m, 4H), 3.53 (s, 2H), 2.41 (t, J=5.0 Hz, 4H).
Example 7: synthesis of 4- ((4- (benzo [ b ] thiophene-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide (T6):
according to the general methodT6 was prepared. ESI-MS M/z [ M+H ]]+:396.13； 1 H NMR(400MHz,DMSO-d6)δ:11.71–11.73(m,1H),9.10(s,1H),7.75(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,1H),7.41(dd,J＝8.2,3.8Hz,3H),7.17(t,J＝7.6Hz,1H),7.08(t,J＝7.5Hz,1H),6.75(d,J＝1.8Hz,1H),3.92–3.94(m,4H),3.53(s,2H),2.41(t,J＝5.0Hz,4H)。
Example 8: synthesis of 4- ((4- (5-chlorobenzo [ b ] thiophene-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide (T7):
t7 was prepared according to the general procedure. ESI-MS M/z [ M+H ] +:430.09;1H NMR (400 MHz, DMSO-d 6) δ:11.75 (m, 1H), 9.04 (s, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.41 (dd, J=8.2, 3.8Hz, 3H), 7.18 (t, J=7.6 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 6.74 (d, J=1.8 Hz, 1H), 3.92-3.99 (m, 4H), 3.51 (s, 2H), 2.43 (t, J=5.0 Hz, 4H).
Example 9: synthesis of N-hydroxy-4- ((4- (6-methoxybenzo [ b ] thiophene-2-carbonyl) piperazin-1-yl) methyl) benzamide (T8):
t8 was prepared according to the general procedure. ESI-MS M/z [ M+H ] +:410.14;1H NMR (400 MHz, DMSO-d 6) δ:11.71-11.85 (m, 1H), 9.03 (s, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.41 (dd, J=8.2, 3.8Hz, 2H), 7.04 (t, J=7.5 Hz, 1H), 6.75 (d, J=1.8 Hz, 1H), 3.92-3.64 (m, 4H), 3.77 (s, 3H), 3.52 (s, 2H), 2.42 (t, J=5.0 Hz, 4H).
Example 10: compound in vitro HDACs enzyme inhibitory Activity
The HDACs aprotinin IC50 was tested using the K340-100 kit test compound from Biovision, and experimental procedures were performed with reference to the kit instructions. The experimental results are shown in Table 2.
Compounds of formula (I) HDACsIC 50 (nM)
SAHA 95.12
T1 89.21
T2 56.30
T3 144.5
T4 34.62
T5 201.2
T6 79.03
T7 50.27
T8 168.7
TABLE 2
From the table above, the compounds of the present invention have strong inhibitory activity against HDAC, wherein the inhibitory activity of compounds T1, T2, T4, T6 and T7 is superior to that of the positive control SAHA.
Example 11: compounds antiproliferative activity assays
Selected tumor cells: HCT116 (human colon cancer cells), a549 (human lung adenocarcinoma cells), hut78 (T lymphocyte leukemia cells), H1993 (human lung cancer non-small cells); the anti-proliferation activity test is carried out by adopting the CCK-8 method by taking SAHA as a control drug. The specific results are shown in Table 3 (unit: IC 50 μM)：
TABLE 3 Table 3
From the above table, some of the compounds of the present invention tested had better anti-tumor cell proliferation activity, wherein the compounds had better anti-proliferation activity against HCT116 (human colon cancer cells), a549 (human lung adenocarcinoma cells) and H1993 (human lung cancer non-small cells) than the positive control SAHA.
Example 12: test for Effect of Compounds on Normal cells
Test of in vitro inhibition Activity of the inventive compounds against Normal cells MRC-5 (human embryonic lung cells), HL-7702 (human liver cells), HEK-293 (embryonic kidney cells). The specific results are as follows:
compounds of formula (I) MRC-5 HL-7702 HEK-293
SAHA 2.83 12.42 5.31
T1 15.31 20.33 11.62
T2 >30 19.02 >30
T4 18.11 27.39 >30
T6 >30 >30 19.60
T7 21.35 >30 22.34
TABLE 4 Table 4
As can be seen from Table 4, the compound of the present invention has weaker inhibitory activity on normal cells and lower toxic and side effects than the control drug SAHA, indicating lower toxic and side effects when used as an antitumor drug, and is easy to use as a antitumor drug.
Example 13: the application of hydroxamic acid compounds in preparing medicaments for treating tumors.
Preparation of tablets:
the preparation method comprises the following steps: mixing the compound of any one of examples 2-9 or pharmaceutically acceptable salt thereof with sucrose and corn starch, adding water for wetting, stirring uniformly, drying, pulverizing, sieving, adding calcium stearate, mixing uniformly, and tabletting. Each tablet weighs 200mg, and the content of the active ingredients is 10mg.
Example 14: the application of hydroxamic acid compounds in preparing medicaments for treating tumors.
The preparation of injection comprises the following steps:
80mg of water for injection
The preparation method comprises the following steps: dissolving the active ingredient and water for injection, mixing uniformly, filtering, sub-packaging the obtained solution in ampoule bottles under aseptic condition, wherein the content of the active ingredient is 2 mg/bottle per bottle of 10mg of the solution.
In summary, pharmacological tests show that the compound has a strong inhibition effect on HDAC enzyme (example 10), and has a strong inhibition effect on HDAC enzyme, wherein the inhibition activity of the compounds T1, T2, T4, T6 and T7 is superior to that of the positive control SAHA.
The anti-proliferation test is carried out by selecting part of the compounds of the invention, and the experimental result shows that the compounds of the invention have better anti-tumor cell proliferation activity, wherein, the anti-proliferation activity of the compounds on HCT116 (human colon cancer cells), A549 (human lung adenocarcinoma cells) and H1993 (human lung cancer non-small cells) is better than that of positive control SAHA. Meanwhile, the compound has weaker inhibition activity on normal cells and lower toxic and side effects, which indicates that the compound has lower toxic and side effects when being used as an anti-tumor drug and is easy to be used as the tumor drug.
Although the present invention has been described in terms of the preferred embodiments, it is not intended to be limited to the embodiments, and any person skilled in the art can make any possible variations and modifications to the technical solution of the present invention by using the methods and technical matters disclosed above without departing from the spirit and scope of the present invention, so any simple modifications, equivalent variations and modifications to the embodiments described above according to the technical matters of the present invention are within the scope of the technical matters of the present invention.

Claims (6)

1. A hydroxamic acid compound, characterized by: is a compound having the following chemical structural general formula or a chemical isomer or a salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
r is hydrogen, methyl, methoxy, trifluoromethyl or halogen;
x is NH, O or S.
2. The hydroxamic acid compound according to claim 1, characterized in that: specifically comprises the following compounds:
4- ((4- (1H-indole-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide,
4- ((4- (5-fluoro-1H-indole-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide,
N-hydroxy-4- ((4- (5-methoxy-1H-indole-2-carbonyl) piperazin-1-yl) methyl) benzamide,
4- ((4- (benzofuran-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide,
N-hydroxy-4- ((4- (5- (trifluoromethyl) benzofuran-2-carbonyl) piperazin-1-yl) methyl) benzamide,
4- ((4- (benzo [ b ] thiophene-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide,
4- ((4- (5-chlorobenzo [ b ] thiophene-2-carbonyl) piperazin-1-yl) methyl) -N-hydroxybenzoamide, or
N-hydroxy-4- ((4- (6-methoxybenzo [ b ] thiophene-2-carbonyl) piperazin-1-yl) methyl) benzamide.
3. The hydroxamic acid compound according to claim 1 or 2, characterized in that: the salt comprises hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate.
4. Use of a hydroxamic acid compound according to any of claims 1-3 in the preparation of a medicament for treating a tumor.
5. The use according to claim 4, characterized in that: the tumors include liver cancer, lung cancer, breast cancer, esophagus cancer, stomach cancer, nasopharyngeal cancer, ovarian cancer, bladder cancer, rectal cancer, skin cancer and lymphoma.
6. The use according to claim 5, characterized in that: the tumor is selected from the group consisting of non-small cell lung cancer and colorectal cancer.
CN202210219254.7A 2022-03-08 2022-03-08 Hydroxamic acid compound and application thereof Pending CN116535343A (en)

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