WO2017045271A1 - Dérivés de benzofuranne, leur procédé de préparation et leur utilisation thérapeutique - Google Patents

Dérivés de benzofuranne, leur procédé de préparation et leur utilisation thérapeutique Download PDF

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WO2017045271A1
WO2017045271A1 PCT/CN2015/095735 CN2015095735W WO2017045271A1 WO 2017045271 A1 WO2017045271 A1 WO 2017045271A1 CN 2015095735 W CN2015095735 W CN 2015095735W WO 2017045271 A1 WO2017045271 A1 WO 2017045271A1
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mmol
methylbenzofuran
nmr
yield
alkyl
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PCT/CN2015/095735
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English (en)
Chinese (zh)
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尤启冬
孙昊鹏
杨英睿
魏金莲
张晓进
郭小可
徐晓莉
姜正羽
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中国药科大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • 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
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • 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

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a class of benzofuran derivatives having antitumor use and medical therapeutic effects as HIF1 ⁇ inhibitors.
  • benzofuran structure As a kind of important heterocyclic compound, benzofuran structure is widely used in various natural products and clinical medicines, and has a wide range of pharmacological activities, such as anti-tumor, antibacterial, anti-viral, anti-arrhythmia and the like.
  • hypoxic environment is an environmental condition that must be met during the development of solid tumors.
  • radiotherapy combined with nicotinamide and inhaled carbopol gas, biological reducing agent, hypoxia-inducible factor-1 ⁇ (HIF-1 ⁇ ) inhibitor, hypoxia-regulated gene therapy Etc.
  • HIF-l ⁇ inhibitors have become a hot spot in current anti-tumor drug research.
  • HIF-l ⁇ is a key regulatory protein of cells found by Semenza et al. (Semenza, GL Moll Cell Biol. 1992, 12(12): 5447-5454) under hypoxic conditions, which is a key factor for malignant tumors to adapt to hypoxic microenvironment. It can cause anaerobic glycolysis of tumor cells, trigger tumor angiogenesis, promote the proliferation, invasion and migration of tumor cells, so that tumor cells can adapt to hypoxic environment, and its expression level is positively correlated with poor prognosis.
  • HIF-l ⁇ inhibitors are classified into the following categories according to their different characteristics: l) compounds that act on the upstream signaling pathway of HIF-1 ⁇ , such as the mTOR inhibitor rapamycin and its esterified compounds; 2) inhibition of HIF- 1 ⁇ mRNA expression, such as HIF-1 ⁇ antisense oligonucleotide E Z N-2968; 3) inhibition of HIF-1 ⁇ protein synthesis, such as camptothecin Top l inhibitor topotecan; 4) promote HIF -l ⁇ protein degradation, including YC-1; 5) blocking HIF-1 ⁇ DNA binding to target genes, such as doxorubicin; 6) inhibiting H IF-l ⁇ protein by inhibiting HIF-1 ⁇ -p300 protein protein interaction Guided downstream gene transcriptional activation, such as Chetomin, benzopyran derivatives KCN1, etc.; 7) Others such as niacin / isonicotinic acid, ibuprofen and celecoxib.
  • the invention discloses a kind of benzofuran derivative (I), and the pharmacodynamic test proves that the compound of the invention has good anti-tumor proliferative activity, especially various solid solid tumors, including colorectal cancer, liver cancer and gastric cancer. , breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, cervical cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, perianal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, Vaginal cancer, vulvar cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureteral cancer, renal cell carcinoma, renal pelvic cancer and central nervous system tumors.
  • the benzofuran derivative of the invention can also effectively inhibit the HIF1 ⁇ signaling pathway, thereby inhibiting the transcriptional activation of the downstream gene of HIF1 ⁇ , and has an effect on angiogenesis, drug resistance, proliferation, energy metabolism, etc. of solid solid tumors, thereby inhibiting tumors.
  • HIF inhibitor KCN1 The mechanism was studied to find that the structure of this compound is similar to the HIF inhibitor KCN1. It inhibits the activity of the HIF1 ⁇ signaling pathway, and some of its effects are produced by inhibiting the interaction of HIF1a-p300.
  • HIF inhibitor KCN1 has a good HIF1 ⁇ inhibitory activity, its water solubility is poor, and its benzopyran structure has poor stability in vivo, and its inhibitory effect on tumor cells in vitro cytotoxicity is not strong.
  • the benzofuran structure of the present invention is more stable than the benzopyran structure, and the inhibition effect in the cytotoxicity test is stronger in vitro.
  • the antitumor activity of the derivatives and their effects on the HIF1 ⁇ signaling pathway were tested. Most of these compounds were found to have a good inhibitory activity on the HIF1 ⁇ signaling pathway, and some of them inhibited ⁇ IF1 ⁇ -p300. And they all have good anti-tumor proliferation activity.
  • R 1 represents hydrogen, C 1 -C 3 alkyl, carboxyl, C 1 -C 3 carbamoyl,
  • R 2 represents hydrogen, C 1 -C 3 alkyl, carboxyl or R 5 represents C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, morpholinyl, piperidinyl, piperazinyl, piperazinone group, N- methylpiperazinyl, NR 6 R 7 or -NH-(CH) 2m -NR 6 R 7 wherein m is 2 or 3; R 6 and R 7 each independently represent hydrogen, C 1 -C 4 alkyl, acetyl or phenyl, or R 6 and R 7 are bonded to a four to six membered heterocyclic ring;
  • R 3 represents a C 3 -C 7 cycloalkyl group or R 8 represents a mono- or di-substituted H, halogen, nitro, carboxyl, hydroxy, cyano, trifluoromethyl, C 1 -C 4 alkyl, methoxy, acetylamino, C 1 -C 3 alkyl group Amine;
  • X represents a bond, -CH 2 -,
  • R 4 represents hydrogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl substituted methylene or R 9 is mono or disubstituted H, halogen, carboxyl, hydroxy, cyano, C 1 -C 4 alkyl or methoxy;
  • R 1 preferably represents a C 1 -C 3 alkyl group, a carboxyl group,
  • R 2 preferably represents a carboxyl group or R 5 represents piperazinyl, morpholinyl, piperazinone, N-methylpiperazinyl,
  • R 3 preferably represents X preferably represents -CH 2 - or R 8 preferably represents a mono- or di-substituted halogen, a trifluoromethyl group, a C 1 -C 4 alkyl group, a methoxy group.
  • R 4 represents hydrogen or R 9 preferably represents a mono- or di-substituted halogen, cyano or methoxy group.
  • the preparation method of the compound of the present invention comprises:
  • R 1, R 2, R 3 , R 4, Y is defined as previously.
  • R 1 , R 2 , R 3 , R 4 and Y have the same meanings as defined above.
  • the invention also includes hydrates, stereoisomers, solvates and pharmaceutically acceptable salts of the compounds of formula I. They have the same pharmacological activity as the compounds of formula I.
  • the compound of the present invention may be added into a pharmaceutically acceptable carrier to prepare a common pharmaceutical preparation, such as a tablet, a capsule, a powder, a syrup, a liquid, a suspension, an injection, and may be added to a fragrance, a sweetener, a liquid or Common pharmaceutical excipients such as solid fillers or thinners.
  • a pharmaceutically acceptable carrier such as a tablet, a capsule, a powder, a syrup, a liquid, a suspension, an injection, and may be added to a fragrance, a sweetener, a liquid or Common pharmaceutical excipients such as solid fillers or thinners.
  • the compound of the present invention is used in a clinical dose of 0.01 mg to 1000 mg/day, and may be deviated from this range depending on the severity of the condition or the dosage form.
  • the MCF cells were evenly spotted in a 32-well plate, and pGL2-HRE-luciferase and SV40 luciferase were used.
  • Lipofectamine 2000 was transfected into MCF cells. After incubation for 24 hours, the medium was aspirated, and the medium containing 20 ⁇ M compound was added. After incubating for 24 h at 37 ° C 1% oxygen concentration, the cells were lysed, and the cell lysate was diluted 10 times into 96 wells. In the white plate, firefly luciferase was added and the luminescence value was immediately detected. Then add sea cucumber luciferase and immediately detect the luminescence value. No compound was added to the control wells.
  • a 384-well plate was spiked with a final concentration of 50 nM His-p300 at a final concentration of 100 ⁇ M. After incubation for 1 h, a final concentration of 10 nM FITC-labeled HIF fluorescent probe was added and the fluorescence polarization was measured using an instrument. The blank space is only HIF fluorescent probe, and the negative well is HIF fluorescent probe and p300 protein.
  • MCF7 cells were uniformly spotted in 96-well plates, and after 12 h, the medium was aspirated and the medium containing the compound was added. After 72 h, 20 ⁇ L of MTT was added to each well, and after incubating at 37 ° C for 4 h, the medium was aspirated and DMSO was added to measure the absorbance. The blank is only added to the medium, and the negative is the addition of the medium and the cells.
  • the positive drug KCN1 has a very strong inhibitory activity against the HIF1 ⁇ signaling pathway, but its antitumor activity in vitro is not strong.
  • the analog of the N-(benzofuran-5-yl)-benzenesulfonamide structure has a good HIF1 ⁇ inhibitory activity at a concentration of 20 ⁇ M. Further fluorescence polarization tests against HIF1 ⁇ -p300 inhibition revealed that such compounds exert HIF1 ⁇ inhibitory activity not primarily by inhibiting HIF1 ⁇ -p300 interaction.
  • N-trisubstituted benzenesulfonamide structure also has a good HIF1 ⁇ inhibitory activity, and a compound with better activity is also stronger in inhibiting HIF1 ⁇ -p300 interaction. And after introduction of a suitable hydrophilic group, the antitumor activity is greatly increased.
  • N-(4-Methoxyphenyl)acetamide (3.30 g, 0.02 mol) was dissolved in dichloromethane (100 ml), chloroacetyl chloride (2.7 ml, 0.06 mol), aluminum trichloride (7.98 g). , 0.06 mol), heated to reflux, reacted for 6 h, cooled, quenched with dilute hydrochloric acid, extracted with chloroform, and evaporated under reduced pressure to give a white solid, 2.82 g (yield: about 84.0%)
  • N-(3-carbonyl-2,3-dihydrobenzofuran-5-yl)acetamide (0.33 g, 1.73 mmol) was dissolved in ethanol (30 ml), 5% palladium carbon (183 mg), hydrogen atmosphere After stirring at room temperature overnight, palladium on carbon was filtered off. 3M dilute hydrochloric acid (30 ml) was added directly, and the mixture was heated to reflux for 6 h.
  • N-phenylbenzofuran-5-amine (0.31 g, 1.48 mmol) and then 4-(bromomethyl)-1,2-dimethoxybenzene (0.68 g. 2.96 mmol), potassium carbonate (0.41 g) , 2.96 mmol), according to the reaction of Step 5 in Example 1, N-(3,4-dimethoxybenzyl)-N-phenylbenzofuran-5-amine 0.38 g (yield 71.4%)
  • N-isopropylbenzofuran-5-amine (0.2 g, 1.14 mmol) was dissolved in acetone, potassium carbonate (0.32 g, 2.28 mmol), p-hydroxybenzyl chloride (0.33 g, 2.28 mmol). The mixture was refluxed, reacted for 2 h, and the insoluble material was filtered. Column chromatography separated 0.21 g (yield 65.4%)
  • N-(4-methoxyphenyl)acetamide (10.1 g, 0.065 mol) was reacted with acetyl chloride (20.5 g, 0.26 mol) of aluminum trichloride (34.9 g, 0.26 mol), and worked up in the same manner as in Example 1. step 1. 8.1 g of solid was formed (yield 64.1%)
  • N-(3-Acetyl-4-hydroxyphenyl)acetamide (4.4 g, 0.022 mol) was dissolved in 25 ml of N,N-dimethylformamide, and potassium carbonate (6.3 g, 0.046 mol) was added, bromoacetic acid Ethyl ester (7.6 g, 0.046 mol).
  • the tube is heated to 150 degrees. Reaction 4h. After cooling to room temperature, it was poured into water, suction-filtered, and the solid on the filter cake was washed with water several times to obtain a crude product, which was purified by column chromatography to yield white solid (2.1 g, yield: 35.3%)
  • step 3 in Example 5 ethyl 5-amino-3-methylbenzofuran-2-carboxylate (0.8 g, 3.65 mmol) was obtained according to the conditions of step 4 in Example 5 and 4-trifluoromethylsulfonyl chloride (1.07 g, 4.38 mmol), potassium carbonate (1.01 g, 7.30 mmol), The product ethyl 3-methyl-5-(4-(trifluoromethyl)benzenesulfonyl)benzofuran-2-carboxylate 0.78 g (yield 50.0%)
  • Step 2 Ethyl 5-(N-(4-bromobenzyl)-4-trifluoromethyl)benzenesulfonamide)-3-methylbenzofuran-2-carboxylate
  • Step 3 5-(N-(4-Bromophenyl)-4-(trifluoromethyl)benzenesulfonamido)-3-methylbenzofuran-2-carboxylic acid
  • Example 5 The intermediate ethyl 5-amino-3-methylbenzofuran-2-carboxylate (0.8 g, 3.65 mmol) of Example 5 was used as a starting material, and reacted with 4-bromobenzenesulfonyl chloride according to the conditions in Step 4 of Example 5. A solid of 1.2 g (yield 75.0%) was obtained.
  • Example 8 Ethyl 5-(4-bromobenzenesulfonamide)-3-methylbenzofuran-2-carboxylate (0.20 g, 0.46 mmol) was used as material and potassium carbonate (0.126 mg, 0.91 mmol). Bromomethylcyclopentane (0.149 g, 0.91 mmol), anhydrous tetrahydrofuran as a solvent, and reacted at 60 ° overnight. Column chromatography separated 0.101 g of solid (yield 42.1%)
  • Example 11 The product of Example 11 was used as the starting material ethyl 3-methyl-5-(4-methylbenzenesulfonamide)benzofuran-2-carboxylate (0.2 g, 0.62 mmol), and p-bromo bromide (0.31) g, 1.24 mmol) under sodium hydrogen (0.11 g, 4.94 mmol) as a solvent under THF (20 mL). Add water to extract. The organic layer was combined and dried over anhydrous sodium sulfate and then purified by column chromatography to yield 0.1 g (yield: 33.8%)
  • Step 2 (0.5 g, 1.22 mmol) was added to thionyl chloride (10 ml), and heated to reflux. After completion of the reaction, the obtained acid chloride was dissolved in dichloromethane and added to a 10% aqueous solution of piperazine (20 ml). . The reaction was overnight. Direct filtration to obtain the product 0.44 g (yield 77.5%)
  • step 13 of Example 13 5-(4-bromobenzenesulfonamide)-3-methylbenzofuran 2-carboxylic acid (0.5 g, 1.22 mmol) was dissolved in 10 ml of thionyl chloride solution and heated to reflux. The resulting acid chloride was then added to dichloromethane dissolved in N-methylpropanediamine (0.50 g, 4.88 mmol) and allowed to react overnight. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to yield 0.34 g (yield 56.4%)
  • Step 1 Using the product of the step 3 in Example 5, ethyl 5-amino-3-methylbenzofuran-2-carboxylate (0.8 g, 3.65 mmol) as a starting material, according to the conditions of step 4 of Example 5 and p-chloro The reaction of benzenesulfonyl chloride yielded 0.67 g (yield 45.3%)
  • Step 2 Ethyl 5-(4-chlorobenzenesulfonamide)-3-methylbenzofuran-2-carboxylate (0.6 g, 1.58 mmol) and p-chlorobenzyl chloride (0.51 g, 3.16 mmol), Potassium (0.44 g, 3.16 mmol), KI (0.26 g, 1.58 mmol) was refluxed in acetone for 2h, and insolubles were filtered. The mixture was evaporated to dryness under reduced pressure, and purified by column chromatography to yield 0.69 g of solid (yield 86.6%)
  • Step 3 Ethyl 5-((4-chloro-N-(4-chlorobenzyl)phenyl)sulfonamide)benzofuran-2-carboxylate (0.6 g, 1.19 mmol) in sodium hydroxide The solution was refluxed for 1 h. After the reaction, the pH is adjusted to be acidic. Ethanol was distilled off under reduced pressure, and a large amount of solid was precipitated, and filtered to give 0.44 g of solid (yield: 75.43%)
  • Step 4 5-((4-Chloro-N-(4-chlorobenzyl)phenyl)sulfonyl chloride)-3-methylbenzofuran-2-carboxylic acid (0.3 g, 0.61 mmol). With 1-(2-aminoethyl)-4-methylpiperazine (0.18 g, 1.22 mmol), 0.21 g of solid was obtained (yield 55.8%)
  • Step 2 Ethyl 5-((4-chloro-N-cyclohexylmethyl)-3-fluorophenyl)sulfonamide)-3-methylbenzofuran-2-carboxylate as ethyl 5-(( (4-Chloro-3-fluorophenyl)sulfonamide)-3-methylbenzofuran-2-carboxylate (0.5 g, 1.26 mmol) as a starting material, according to the method of Step 1 of Example 10 and bromomethyl Cyclohexylamine (0.45 g, 2.51 mmol) was reacted to give 0.32 g (yield 50.1%)
  • Step 1 Ethyl 5-(N-cyclobutyl-N-(4-methoxyphenyl)aminesulfonyl)-3-methylbenzofuran-2-carboxylate
  • Example 25 Product ethyl 5-(N-cyclobutylaminesulfonyl)-3-methylbenzofuran-2-carboxylate (0.5 g, 1.48 mmol) was dissolved in 20 mL dichloromethane. Methoxybenzyl bromide (0.59 g, 2.96 mmol), potassium carbonate (0.41 g, 2.96 mmol). Column chromatography separated 0.47 g (yield 69.2%)
  • Step 2 5-(N-Cyclobutyl-N-(4-methoxyphenyl)aminesulfonyl)-3-methylbenzofuran-2-carboxylic acid
  • Step 1 The final product of Example 29, methyl 2-methyl-5-(N-phenylaminesulfonyl)benzofuran-3-carboxylate (0.5 g, 1.45 mmol) was obtained according to step 2 of Example 26 The product obtained 0.42 g (yield 87.6%)
  • Step 2 2-methyl-5--(N-phenylaminesulfonyl)benzofuran-3-carboxylic acid (0.4 g, 1.21 mmol). 64.0%
  • Step 2 5-(N-(4-(tert-butyl)benzyl)-N-phenylsulfonamide)-N-isopropyl-2-methylbenzofuran-3-carboxamide

Abstract

La présente invention concerne le domaine de la chimie pharmaceutique, et spécifiquement une classe de dérivés de benzofuranne (I). Des tests pharmacodynamiques prouvent que ces composés peuvent être utilisés en tant qu'anti-tumoraux et présentent un effet thérapeutique médical en tant qu'inhibiteurs de HIF1α.
PCT/CN2015/095735 2015-09-14 2015-11-27 Dérivés de benzofuranne, leur procédé de préparation et leur utilisation thérapeutique WO2017045271A1 (fr)

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JP2024516592A (ja) * 2021-04-16 2024-04-16 ベイジン・ベスト・パスウェイ・マネージメント・コンサルティング・センター（リミテッド・パートナーシップ） Ｆｘｒモジュレーター、その製造方法、医薬組成物及び使用
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