WO2016206138A1 - Inhibiteur de l'histone désacétylase, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de l'histone désacétylase, son procédé de préparation et son utilisation Download PDF

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WO2016206138A1
WO2016206138A1 PCT/CN2015/083753 CN2015083753W WO2016206138A1 WO 2016206138 A1 WO2016206138 A1 WO 2016206138A1 CN 2015083753 W CN2015083753 W CN 2015083753W WO 2016206138 A1 WO2016206138 A1 WO 2016206138A1
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histone deacetylase
deacetylase inhibitor
cancer
structural formula
inhibitor according
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PCT/CN2015/083753
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程义强
杨思遥
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清安医药科技武汉有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • 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

Definitions

  • the invention relates to the field of anticancer compound histone deacetylase inhibitors, in particular to histone deacetylase inhibitors and preparation methods and applications thereof.
  • Histone deacetylase is a series of zinc-dependent metalloproteinases involved in the modification and modification of chromosome structure, regulating gene transcription and some important factors such as tumor suppressor p53 heat shock protein 90 and ⁇ -tubulin.
  • the activity of proteins and cytokines plays a key role in tumorigenesis and is a new target for antitumor drug design in recent years.
  • Histone deacetylase inhibitor is a series of compounds that interfere with the function of histone deacetylase and can effectively inhibit the proliferation of cancer cells and induce apoptosis.
  • Histone deacetylase inhibitors inhibit the proliferation of tumor cells and induce cell differentiation and/or apoptosis by increasing the degree of acetylation of intracellular histones and increasing the expression levels of p21 and other genes.
  • Histone deacetylase inhibitors have become a new research hotspot in tumor-targeted therapy. Their inhibitory effects on tumor cell migration, invasion, metastasis and anti-tumor angiogenesis have also been confirmed. Some of them have better activity in vivo and in vitro. HDACI has entered clinical trials.
  • Oxaliplatin, irinotecan, 5-FU/leucovorin or capecitabine, which are used to treat colorectal cancer, are traditional cytotoxic drugs, and new targeted drugs are urgently needed to further improve the efficacy and reduce side effects.
  • Breast cancer is a common malignant tumor in women. According to statistics published by CA: A Cancer Journal for Clinicians (influence factor 94.262 in 2010), there were 232,670 women with breast cancer in the United States in 2014, accounting for 29% of women's new malignant tumors, ranking the incidence of female malignancies. first. Statistics in major cities such as Beijing, Shanghai, and Tianjin show that breast cancer is also the most common malignant tumor in women in China, and the incidence rate is increasing year by year. The age distribution of breast cancer is different in Eastern and Western countries. In high-incidence areas such as Northern Europe and North America, breast cancer begins to appear around the age of 20, and maintains a rapid upward trend before the menopause, 45-50 years old, about every age.
  • Cytotoxic chemicals currently used clinically to treat breast cancer such as docetaxel and methotrexate, have large side effects; while targeted new drugs, such as the monoclonal antibodies Herceptin and Avastin, are very expensive.
  • FK228 histone deacetylase inhibitor
  • romidepsin histone deacetylase inhibitor
  • Istodax histone deacetylase inhibitor
  • the R1 group is a methyl group, an ethyl group or an isopropyl group
  • the R2 group is a methyl group or an n-octyl group
  • the R3 group is a methyl group, an ethyl group or an isopropyl group.
  • the compound is mainly used for the preparation of a medicament for preventing or treating a mammalian disease associated with dysregulation of histone deacetylase, including cancer, neurodegenerative disease, malaria and diabetes; lymphoma, lung cancer, stomach cancer, pancreatic cancer Breast cancer, prostate cancer, leukemia and cervical cancer.
  • Chinese Patent No. 201110364545.7 discloses a histone deacetylase inhibitor, a synthesis method thereof and a pharmaceutical use, and the structural formula is:
  • R 5 group is hydrogen, C 1-12 alkyl, C 3-12 cycloalkyl, -O-(C 1-12 alkyl), -NH-(C 1-12 alkyl) or -S -(C 1-12 alkyl), R 1 - R 8 As defined in the specification, these compounds are mainly used in the preparation of a medicament for the prevention or treatment of a mammalian disease associated with histone deacetylase dysregulation.
  • the object of the present invention is to provide a novel structure of histone deacetylase inhibitor which has less toxicity and restores the normal expression of tumor suppressor genes and promotes cancer by acting on the epigenetic process of cancerous cells.
  • Apoptosis in order to achieve cancer-causing carcinogenesis, they act on specific molecular targets, high selectivity, low side effects, and clear mechanism of action.
  • Another object of the present invention is to provide a process for the preparation of the histone deacetylase inhibitor.
  • a third object of the present invention is to provide a use of the novel structure of a histone deacetylase inhibitor for the preparation of a pharmaceutical composition for treating colorectal cancer and breast cancer.
  • the histone deacetylase inhibitor has the following structural formula or a pharmaceutically acceptable salt thereof,
  • R3 is selected from the group consisting of hydrogen, triphenylmethylthio, p-methoxybenzylthio, 2-(trimethylsilyl)ethylthio, 9-fluorenylthio, n-pentylthio, n-hexylthio , n-heptylthio or n-octanoylthio;
  • R4 is selected from the group consisting of triphenylmethyl, p-methoxybenzyl, 2-(trimethylsilyl)ethyl, 9-fluorenylmethyl, n-pentanoyl, n-hexanoyl, n-heptanoyl or n-octanoyl.
  • the histone deacetylase inhibitor provided by the invention has less toxicity, high selectivity, low side effects, clear mechanism of action and less objection.
  • R1 is H
  • R2 is OH
  • R3 is n-octanoylthio or H.
  • R4 is n-octanoyl.
  • CA101 histone deacetylase inhibitor Qing An 101
  • CA102 histone deacetylase inhibitor Qing An 102
  • CA103 histone deacetylase inhibitor Qing An 103
  • the above three compounds CA101-CA103 belong to cyclic peptide high-efficiency histone deacetylase inhibitors, which act on specific molecular targets with high selectivity, low side effects, and clear mechanism of action.
  • the present invention also provides a synthesis method for preparing the above-mentioned histone deacetylase inhibitor, and the reaction process is as follows:
  • the peptide bond condensing agent is: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino) Phosphonium hexafluorophosphate, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-one, O-benzotriazole-N,N,N' , N'-tetramethylurea tetrafluoroboric acid, hexafluorophosphate Any one of acid benzotriazol-1-yl-oxytripyrrolidinyl or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride.
  • the base is a basic inorganic salt or an organic base.
  • the basic inorganic salt is any one of sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate or potassium phosphate;
  • the organic base is triethylamine, diisopropylethylamine or pyridine. Any of them.
  • the organic solvent is N,N-dimethylformamide, dichloromethane or acetonitrile.
  • the molar ratio of the n-octanoic acid to the reactant is 1-10:1;
  • n-octanoic acid peptide bond condensing agent: 1-hydroxybenzotriazole or 1-hydroxy-7-azobenzotriazole: base molar ratio: 1:1-2:1- 3:1-3:1-5.
  • the organic solvent is any one of dichloromethane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or acetone.
  • the oxidizing agent is any one of pyridinium chlorochromate, pyridine dichromate, 2-iodobenzoic acid, and Dess-Martin oxidant.
  • the molar ratio of the oxidizing agent to the reactants is from 1 to 20:1.
  • This series of synthesis methods is the first proposed new method, which uses known small molecular materials and known intermediates for synthesis, and chemical synthesis improves the yield of the compound and reduces the production cost.
  • the invention also provides the use of the histone deacetylase inhibitor in the preparation of a medicament for treating colorectal cancer and breast cancer.
  • the invention also provides the histone deacetylase inhibitor for treating cancer including but not limited to colorectal, breast; skin; lymph node; cervical; uterus; Pancreas, lung; ovary; prostate; mouth; brain; head and neck; throat; testis; kidney; pancreas; bone; spleen; liver; bladder; larynx; or nasal cancer and relapsed or refractory cancer.
  • cardiac hypertrophy chronic heart failure, inflammation, cardiovascular disease, hemoglobinopathy, thalassemia, sickle cell disease, CNS disease, autoimmune disease, diabetes, osteoporosis, MDS, benign prostatic hypertrophy, oral mucosa White spot, genetically related metabolic disorders, infection, Rubens-Taybi, Fragile X syndrome or alpha-1 antitrypsin deficiency, or used to accelerate wound healing, or to protect hair follicles or as an immunosuppressive agent.
  • the medicament may also be used to alleviate the effects of chronic lymphocytic leukemia, T-cell lymphoma or skin inflammation, particularly psoriasis, acne or eczema.
  • a pharmaceutical composition comprising a histone deacetylation inhibitor of the invention and a pharmaceutically acceptable carrier or diluent.
  • the drug is a pharmaceutically acceptable carrier or diluent
  • the carrier or diluent is a tablet, a capsule, a tablet, a lozenge, a water, an oil suspension, a dispersible powder, a granule, a sublingual tablet. Agent or injection.
  • the medicament is in a form suitable for oral, rectal, parenteral, intranasal or transdermal administration or administration by inhalation or by suppository or injection.
  • the compounds are capable of simultaneously or sequentially using other HDAC inhibitors, chemotherapy or anti-tumor agents, respectively, in the treatment or prevention of HDAC-mediated disorders.
  • Preclinical test data indicates that the inhibitors provided by the present invention can be used independently, especially low doses of CA101, CA102, CA103 and the current mainstream treatment of colon cancer drug 5-fluorouracil (5-FU) to the colorectal cancer HCT-116
  • 5-fluorouracil 5-fluorouracil
  • Figure 1 is a graph showing the anti-proliferative effect of the compounds CA101, CA102, CA103 and 5-FU on the tumor cell line HCT116;
  • FIG. 2 is a graph showing the anti-proliferative effect of the compounds CA101, CA102, CA103 and 5-FU on the tumor cell line SW480;
  • Figure 3 is a graph showing the anti-proliferative effect of the compounds CA101, CA102, CA103 and TAX on the human breast cancer cell line MCF-7.
  • the synthetic route of the histone deacetylase inhibitors CA101, CA102, CA103 in the examples of the present invention is as follows:
  • Example 1 A specific preparation method for synthesizing CA101 includes the following steps:
  • the CA101-2 structure is:
  • the raw material CA101-1 (2.88 g, 4.54 mmol) was weighed, and the structural formula of CA101-1 was The mixture was placed in a 50 mL flask, and 25 mL of dichloromethane was added, and the mixture was stirred to dissolve all the solid, and then 5.76 mL of trifluoroacetic acid was slowly added dropwise. After the completion of the dropwise addition, the reaction was stirred at room temperature for 2 hours, and the progress of the reaction was observed by TLC dot plate, and there was no remaining material. The reaction solution was spun dry, dissolved in toluene (5 mL ⁇ 2) and then dried. It was then drained with a low pressure oil pump for 1 hour to give a light brown, clear, semi-solid, which was used directly in the next step without further purification.
  • the CA101-4 structure is:
  • the product obtained from the upper reaction was dissolved in 25 mL of anhydrous N,N-dimethylformamide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride was added sequentially under ice bath. (1.73g, 9.08mmol), 1-hydroxybenzotriazole (1.23g, 9.08mmol), hydrogencarbonate (2.29g, 27.22mmol) and CA101-3 (2.89g, 5.45mmol), structural formula of CA101-3 for After stirring for 10 minutes, the ice bath was removed, and the reaction was stirred at room temperature for 16 hours. The reaction progress was observed by TLC dot plate.
  • reaction solution was poured into 100 mL of distilled water, stirred for 10 minutes, and extracted with ethyl acetate (40 mL ⁇ 4). The organic phase was combined, washed with saturated brine and dried over anhydrous sodium sulfate.
  • a white solid (CA101-4) of 3.54 g was obtained in a two-step total yield of 74.4%.
  • CA101-5 The structural formula of CA101-5 is:
  • the raw material CA101-4 (3.50 g, 3.33 mmol) was weighed and dissolved in tetrahydrofuran (25 mL), and a lithium hydroxide solution (0.5 mol/L, 33.3 mL, 16.7 mmol) was slowly added dropwise with stirring under ice bath, and added dropwise. After stirring, the mixture was stirred for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 2 hours. The reaction progress was checked by TLC dot plate. After confirming that there was no remaining material, the reaction solution was spun dry, toluene was added and then spun twice, and the oil pump was drained for 1 hour. , a light brown transparent semi-solid is obtained. It was used directly in the next reaction without further purification.
  • CA101-6 The structural formula of CA101-6 is:
  • CA101-7 The structural formula of CA101-7 is:
  • the raw material CA101-6 (406 mg, 0.398 mmol) was weighed and dissolved in dichloromethane (5 mL), and triethylsilane (334 mg, 1.99 mmol, 459 ⁇ L) and trifluoroacetic acid (453 mg) were added with stirring under ice bath. 3.98mmol, 296 ⁇ L), stirring for 10 minutes, removing the ice bath, stirring the reaction at room temperature for 2 hours, the reaction of the starting material was completed, the reaction solution was spun dry, and then added with an appropriate amount of toluene, and then the solution was dissolved twice.
  • the crude silica gel was slurried and separated by column chromatography.
  • the starting material CA101-7 (141 mg, 0.26 mmol) was dissolved in 5 mL of anhydrous N,N-dimethylformamide, and 1-ethyl-(3-dimethylaminopropyl) carbon was added in sequence under ice bath.
  • Diimine hydrochloride 200 mg, 1.04 mmol
  • 1-hydroxybenzotriazole 141 mg, 1.04 mmol
  • sodium hydrogencarbonate 175 mg, 2.08 mmol.
  • n-octanoic acid (93.6 mg, 103 ⁇ L, 0.65 mmol)
  • the mixture was stirred for 10 minutes in an ice bath, and then the reaction was stirred at room temperature for 16 hours.
  • Example 2 A specific preparation method for synthesizing CA102 includes the following steps:
  • the CA102-2 structure is:
  • CA102-3 The structural formula of CA102-3 is:
  • Step 3 Preparation of CA102-4: The preparation method of this step is the same as that of CA101-2, and the same reaction solvent is added to obtain CA102-4.
  • CA102-4 The structural formula of CA102-4 is:
  • Step 4 Preparation of CA102-5: The preparation method of this step was the same as that of CA101-4, and the same reaction solvent was added to obtain CA102-5.
  • CA102-5 The structural formula of CA102-5 is:
  • Step 5 Preparation of CA102-6: The preparation method of this step is the same as that of CA101-5, and the same reaction solvent is added to obtain CA102-6.
  • CA102-6 The structural formula of CA102-6 is:
  • Step 6 Preparation of CA102-7: The preparation method of this step was the same as that of CA101-6, and the same reaction solvent was added to obtain CA102-7.
  • CA102-7 The structural formula of CA102-7 is:
  • Step 7 Preparation of CA102-8: The preparation method of this step was the same as that of CA101-7, and the same reaction solvent was added to obtain CA102-8.
  • CA102-8 The structural formula of CA102-8 is:
  • CA102-8 (190 mg, 0.38 mmol) was dissolved in 5 mL of anhydrous N,N-dimethylformamide. At 0 ° C, 1-ethyl-(3-dimethylaminopropyl)carbodiene was added in sequence. Amine hydrochloride (146 mg, 0.72 mmol), 1-hydroxybenzotriazole (103 mg, 0.72 mmol), sodium hydrogencarbonate (191.5 mg, 2.28 mmol), then octanoic acid (67 ⁇ L, 0.42 mmol), stirred at 0 ° C for 10 min and stirred at room temperature for 12 h.
  • the specific preparation method of the synthetic CA103 includes the following steps:
  • CA101, CA102, CA103 and 5-FU were diluted with DMSO to a final concentration of 10 mM, of which 5-FU (5-fluorouracil) was the first clinical drug for colorectal cancer.
  • CA101, CA102, CA103 and 5-FU 4 candidate compounds were applied at a final concentration ranging from 100 ⁇ M to 0 ⁇ M, 4 fold dilutions, for a total of 10 or 12 concentration points.
  • Collect logarithmic growth phase cells count, resuspend the cells with complete medium, adjust the cell concentration to the appropriate concentration, inoculate 96-well plates, inoculate 100 ⁇ l of cell suspension per well, incubate at 37 ° C, 100% relative humidity, 5% CO 2 Incubate in the box for 24 hours.
  • the logarithmic growth phase cells were collected, counted, and the cells were resuspended in complete medium, and the cell concentration was adjusted to an appropriate concentration (determined according to the cell density optimization test results), and 96-well plates were seeded, and 100 ⁇ l of the cell suspension was added to each well. After incubating the cells for 24 hours at 37 ° C, 100% relative humidity, 5% CO 2 incubator, dilute the test compound with DMSO, 4 times gradient dilution 8 or 10 times; then dilute the diluted compound 20 times with medium. A total of 9 or 11 points were added to the cells at 25 ⁇ l/well. The final concentration of the compound was from 100 ⁇ M to 0 ⁇ M, 4 fold dilutions, for a total of 10 or 12 concentration points.
  • the cells were incubated for 72 hours at 37 ° C in 100% relative humidity in a 5% CO 2 incubator.
  • the medium was aspirated, and the complete medium containing 10% CCK-8 was added and incubated in a 37 ° C incubator for 2-6 hours.
  • the absorbance at a wavelength of 450 nm was measured on a Spectra Max M5 Microplate Reader with gentle shaking, and the absorbance at 650 nm was used as a reference to calculate the inhibition rate.
  • tumor cell growth inhibition rate % [(Ac-As) / (Ac-Ab)] ⁇ 100%;
  • IC50 curves were fitted using software Graphpad Prism 5 and IC50 values were calculated.
  • Tables 1 and 2 show the IC50 values of the respective compounds in different cell lines, respectively, and the graphs are shown in Figures 1 and 2, respectively.
  • CA101, CA102 and CA103 had strong inhibitory effects on the proliferation of these two tumor cell lines (HCT-116 and SW480) with IC50 values between 1 and 50 nM.
  • CA101, CA102, CA103 and TAX were diluted in DMSO to a final concentration of 10 mM.
  • TAX (Paclitaxel) is a first-line drug for treating breast cancer.
  • CA101, CA102, CA103 and TAX, 4 candidate compounds were applied at a final concentration ranging from 10 ⁇ M to 1 nM, 10-fold gradient dilution, for a total of 5 concentration points.
  • Collect logarithmic growth phase cells count, resuspend the cells with complete medium, adjust the cell concentration to the appropriate concentration, inoculate 96-well plates, inoculate 100 ⁇ l of cell suspension per well, incubate at 37 ° C, 100% relative humidity, 5% CO 2 Incubate in the box for 24 hours.
  • the logarithmic growth phase cells were collected, counted, and the cells were resuspended in complete medium, and the cell concentration was adjusted to an appropriate concentration (determined according to the cell density optimization test results), and 96-well plates were seeded, and 100 ⁇ l of the cell suspension was added to each well. After incubating the cells for 24 hours at 37 ° C, 100% relative humidity, 5% CO 2 incubator, dilute the test compound with DMSO, 4 times gradient dilution 8 or 10 times; then dilute the diluted compound 20 times with medium. A total of 5 points were added to the cells at 25 ⁇ l/well. The final concentration of the compound was from 10 ⁇ M to 1 nM, 10-fold dilution, for a total of 5 concentration points.
  • the cells were incubated for 72 hours at 37 ° C in 100% relative humidity in a 5% CO 2 incubator.
  • the medium was aspirated, and the complete medium containing 10% CCK-8 was added and incubated in a 37 ° C incubator for 2-6 hours.
  • the absorbance at a wavelength of 450 nm was measured on a SpectraMax M5 Microplate Reader with gentle shaking, and the absorbance at 650 nm was used as a reference to calculate the inhibition rate.
  • tumor cell growth inhibition rate % [(Ac-As) / (Ac-Ab)] ⁇ 100%.
  • IC50 curves were fitted using software Graphpad Prism 5 and IC50 values were calculated.
  • Table 3 shows the IC50 values of the above respective compounds in different cell lines, and the graph is shown in Fig. 3.

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Abstract

L'invention concerne un composé permettant d'inhiber une histone désacétylase (HDAC) et un procédé de préparation et d'utilisation de celui-ci. En particulier, la présente invention concerne un composé représenté par la formule générale suivante, un groupe de substitution étant tel que défini dans la description. Ledit composé a un effet inhibiteur sur le cancer colorectal et sur les cellules du cancer du sein.
PCT/CN2015/083753 2015-06-23 2015-07-10 Inhibiteur de l'histone désacétylase, son procédé de préparation et son utilisation WO2016206138A1 (fr)

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CN1524850A (zh) * 2003-09-12 2004-09-01 深圳市海粤门生物科技开发有限公司 组蛋白去乙酰化酶抑制剂及其药用制剂的制备和应用
WO2015131355A1 (fr) * 2014-03-05 2015-09-11 清安医药科技武汉有限公司 Préparation du produit naturel thaïlandepsine b inhibiteur de l'histone désacétylase

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CN1524850A (zh) * 2003-09-12 2004-09-01 深圳市海粤门生物科技开发有限公司 组蛋白去乙酰化酶抑制剂及其药用制剂的制备和应用
WO2015131355A1 (fr) * 2014-03-05 2015-09-11 清安医药科技武汉有限公司 Préparation du produit naturel thaïlandepsine b inhibiteur de l'histone désacétylase

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