WO2022205586A1 - Preparation method for pyrrole-2-sulfonamide compound and application thereof in preparing anti-tumor drug - Google Patents
Preparation method for pyrrole-2-sulfonamide compound and application thereof in preparing anti-tumor drug Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- -1 pyrrole-2-sulfonamide compound Chemical class 0.000 title claims abstract description 16
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 14
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 7
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 206010009944 Colon cancer Diseases 0.000 claims description 9
- 238000004587 chromatography analysis Methods 0.000 claims description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 6
- GBXHRWDXXLDJKB-UHFFFAOYSA-N 1h-pyrrole-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN1 GBXHRWDXXLDJKB-UHFFFAOYSA-N 0.000 claims description 5
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 claims description 5
- WRZOMWDJOLIVQP-UHFFFAOYSA-N 5-Chloro-ortho-toluidine Chemical compound CC1=CC=C(Cl)C=C1N WRZOMWDJOLIVQP-UHFFFAOYSA-N 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 5
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 230000035755 proliferation Effects 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- DBKWCXVKWCJGMA-UHFFFAOYSA-N CC(C=CC(Cl)=C1)=C1NS(C1=CC=C(C2=NN=C(C(C=C3)=CC=C3F)O2)N1)(=O)=O Chemical compound CC(C=CC(Cl)=C1)=C1NS(C1=CC=C(C2=NN=C(C(C=C3)=CC=C3F)O2)N1)(=O)=O DBKWCXVKWCJGMA-UHFFFAOYSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 16
- 239000000047 product Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- UOHPEWIBMAQKCN-UHFFFAOYSA-N 1,3,5,5,6-pentafluoro-1,3-diazinane-2,4-dione Chemical compound FC1C(C(N(C(N1F)=O)F)=O)(F)F UOHPEWIBMAQKCN-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- USZKOIUIZMUMSE-UHFFFAOYSA-N 1h-pyrrole-2-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CN1 USZKOIUIZMUMSE-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the invention belongs to the field of antitumor drugs, and in particular relates to a preparation method of a pyrrole-2-sulfonamide compound and its application in the preparation of antitumor drugs.
- small molecule compounds have a wide range of potential applications as medicinal drugs and diagnostics. Especially in clinical anti-cancer, anti-tumor, etc., a large number of small molecule compounds have been successfully developed, sold and widely used in the prevention and treatment of various diseases. It has been widely used in many fields such as chemistry, medicine, biology and materials science.
- Small chemical molecules can pass through the cell membrane and affect the expression and function of intracellular targets, and have a wide range of applications; in addition, small chemical molecules have good oral bioavailability after chemical modification. Better compliance; regardless of price or dosage form, the research on chemical small molecule drugs is more mature than biological drugs, and in contrast, it has good potential and market competitiveness. Therefore, it is of great significance to find new structural types of antitumor drugs.
- the purpose of the present invention is to provide a preparation method of pyrrole-2-sulfonamide compound and its application in the preparation of antitumor drugs. Very good inhibitory activity.
- the invention provides the application of a pyrrole-2-sulfonamide compound or a pharmaceutically acceptable salt thereof in the preparation of antitumor drugs,
- the pyrrole-2-sulfonamide compound has the structure shown in formula I:
- the pharmaceutically acceptable salts are hydrochloride, phosphate, sulfate, acetate, maleate, citrate, benzenesulfonate, toluenesulfonate, fumaric acid salt or tartrate.
- the tumor includes colon cancer, gastric cancer or lung cancer.
- the anti-tumor is inhibiting the proliferation of tumor cells.
- the tumor cells are colon cancer cells SW480, drug-resistant colon cancer cells SW620, gastric cancer cells SGC7901 or lung cancer cells A549.
- the present invention also provides a preparation method of pyrrole-2-sulfonamide compound, comprising the following steps:
- the molar ratio of trichloroacetyl chloride to 1H-pyrrole-2-sulfonyl chloride in the step A) is (1.0-1.5):1, preferably (1.2-1.3):1;
- the temperature of the reaction in the step A) is room temperature, and the reaction time is 1.5 to 3 hours, preferably 2 to 2.5 hours;
- the step A) is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to flash column chromatography;
- the solvent in the step A) is diethyl ether.
- the molar ratio of the pure product a to hydrazine is 1:(1.2-1.8), preferably 1:(1.5-1.6);
- the temperature of the reaction in the step B) is room temperature, and the reaction time is 2 to 5 hours, preferably 2.5 to 3 hours;
- the step B) is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to flash column chromatography;
- the solvent in the step B) is acetonitrile.
- the molar ratio of pure product b, POCl 3 and 4-fluorobenzoic acid is 1:(1.0 ⁇ 2.0):(1.0 ⁇ 1.5), preferably 1:(1.5 ⁇ 1.6):( 1.2 ⁇ 1.3);
- the temperature of the reflux reaction in the step C) is 60 ⁇ 75°C, preferably 65 ⁇ 70°C; the time of the reflux reaction is 5 ⁇ 8 hours, preferably 6 ⁇ 7 hours;
- the step C) is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to flash column chromatography;
- the solvent in the step C) is tetrahydrofuran.
- the molar ratio of pure product c to 5-chloro-2-methylaniline is 1:(0.9 ⁇ 1.2), preferably 1:(1 ⁇ 1.1);
- the temperature of the reaction in the step D) is room temperature, and the reaction time is 3 to 5 hours, preferably 4 hours;
- the step D) is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to flash column chromatography;
- the solvent in the step D) is ethanol.
- the present invention provides an application of a pyrrole-2-sulfonamide compound or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug, wherein the pyrrole-2-sulfonamide compound has the structure shown in formula I: the present invention finds out The compound represented by formula I N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-1H-
- the pyrrole-2-sulfonamide has anti-tumor activity, has a good inhibitory effect on multiple primary and transformed tumor cells, and can be used as an anti-tumor drug.
- Fig. 1 is the compound N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)-1,3,4-oxadiazole-2- base)-1H-pyrrole-2-sulfonamide hydrogen NMR spectrum;
- Figure 2 shows the inhibitory activity of test compounds on colon cancer cell SW480 in vitro
- Figure 3 shows the inhibitory activity of test compounds against drug-resistant colon cancer cells SW620 in vitro.
- the pure target compound N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)-1,3,4-oxadiene was prepared according to the scheme and preparation method shown in formula II oxazol-2-yl)-1H-pyrrole-2-sulfonamide.
- Step 1 Trichloroacetyl chloride (1.2 equiv) was slowly added to a solution of 1H-pyrrole-2-sulfonyl chloride (1 equiv) in ether (10 vol), stirred at room temperature for 2 hours, and the reaction progress was detected by TLC; The crude product a was extracted with ethyl acetate and dried over anhydrous magnesium sulfate; the pure product a was obtained by flash column chromatography.
- Step 2 Dissolve compound a (1 equiv) in acetonitrile (10 vol), slowly add a solution of hydrazine (1.5 equiv) in acetonitrile dropwise, stir at room temperature for 2.5 hours, check the reaction progress by TLC; use ethyl acetate after the reaction Crude product b was extracted and dried over anhydrous magnesium sulfate; pure product b was obtained by flash column chromatography.
- Step 3 To the tetrahydrofuran solution of compound b (1 equiv.) was slowly added dropwise POCl 3 (1.5 equiv.) at room temperature, and then the tetrahydrofuran solution of 4-fluorobenzoic acid (1.2 equiv.) was added dropwise, and the mixture was refluxed at 65° C. for 6 hours. The reaction progress was detected by TLC; after the reaction, the crude product c was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate; the pure product c was obtained by flash column chromatography.
- Step 4 Compound c (1 equiv.) and 5-chloro-2-methylaniline (1 equiv.) were mixed and dissolved in ethanol solution, stirred at room temperature for 4 hours, and the reaction progress was detected by TLC; after the reaction was completed, extracted with ethyl acetate The crude product was obtained and dried over anhydrous magnesium sulfate; the pure target compound was obtained by flash column chromatography.
- the selected tumor cells include colon cancer cells SW480, drug-resistant colon cancer cells SW620, gastric cancer cells SGC7901, and lung cancer cells A549.
- Cells in the logarithmic growth phase were taken, digested and counted, and the cell state was adjusted before plating.
- the cells were seeded at a density of 3000 cells/well in a 96-well plate and placed in an incubator overnight. (Note: the outer circle is filled with PBS.) After 18-24h, the drug administration operation was performed. Aspirate the cell culture medium and add a culture medium containing a certain concentration of the drug.
- the experiment set blank group (solvent control group) and experimental group.
- the drug concentrations in the experimental group were 1 ⁇ M, 5 ⁇ M, 20 ⁇ M, 50 ⁇ M, 100 ⁇ M, and 200 ⁇ M.
- Three sub-wells were set in each group of experiments, the positive control was pentafluorouracil, and the method was the same as that of the test compound.
- the survival rate of cells in each well was calculated based on the absorbance value to calculate the IC 50 value of the drug. The results are shown in Table 1.
- test compound N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl) -1H-pyrrole-2-sulfonamide has anti-tumor activity, has a good inhibitory effect on multiple primary and transformed tumor cells, and can be used as an anti-tumor drug.
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- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
A preparation method for a pyrrole-2-sulfonamide compound or a pharmaceutically acceptable salt thereof, and an application thereof in preparing an anti-tumor drug, the pyrrole-2-sulfonamide compound having a structure represented by formula I. The compound N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)-1, 3, 4-oxadiazole-2-yl)-1H-pyrrole-2-sulfonamide represented by formula I has anti-tumor activity, has a good inhibitory effect on a plurality of primary and transformed tumor cells, and can be used to prepare an anti-tumor drug.
Description
本申请要求于2021年04月02日提交中国专利局、申请号为202110360488.9、发明名称为“一种吡咯-2-磺酰胺化合物的制备方法及其在制备抗肿瘤药物中的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application is required to be submitted to the China Patent Office on April 2, 2021, the application number is 202110360488.9, and the invention name is "a preparation method of pyrrole-2-sulfonamide compound and its application in the preparation of antitumor drugs" Chinese patent priority to the application, the entire contents of which are incorporated herein by reference.
本发明属于抗肿瘤药物领域，尤其涉及一种吡咯-2-磺酰胺化合物的制备方法及其在制备抗肿瘤药物中的应用。The invention belongs to the field of antitumor drugs, and in particular relates to a preparation method of a pyrrole-2-sulfonamide compound and its application in the preparation of antitumor drugs.
恶性肿瘤是全球排名第二的致死性疾病，而肺癌、前列腺癌、结直肠癌和乳腺癌位列榜首，近十几年来癌症的发病率和死亡率均呈持续上升态势。其常规治疗手段有多种如手术、化疗、放疗等。但传统治疗手段大多无法达到治愈效果，特别是中晚期恶性肿瘤患者，死亡率高居不下。小分子靶向抗肿瘤药物因具有高疗效，低毒副作用及高度特异性优点，逐渐成为国内外创新药物研发的热点项目。与传统药物不同的是，小分子药物能与人体靶点特异性结合，能有效针对原发性肿瘤发挥抑制作用，其具有低毒性，高生物利用度，广泛的生物活性、良好生物相容性和疗效。许多突出成果表明，小分子类化合物具有广泛的潜在应用作为药用药物和诊断剂。尤其是临床抗癌，抗肿瘤等，大量小分子化合物已经被成功开发，销售和广泛应用于预防和治疗各种疾病。在化学、医学、生物学和材料科学等众多领域得到了广泛应用。Malignant tumors are the second leading cause of death in the world, while lung cancer, prostate cancer, colorectal cancer, and breast cancer rank first. Over the past decade, both the incidence and mortality of cancer have continued to rise. There are various conventional treatment methods such as surgery, chemotherapy, radiotherapy and so on. However, most of the traditional treatment methods cannot achieve curative effect, especially in patients with advanced malignant tumors, the mortality rate remains high. Small molecule targeted antitumor drugs have gradually become a hot project in the research and development of innovative drugs at home and abroad due to their high efficacy, low toxicity and high specificity. Different from traditional drugs, small molecule drugs can specifically bind to human targets and can effectively inhibit primary tumors. They have low toxicity, high bioavailability, wide biological activity, and good biocompatibility. and efficacy. Many outstanding achievements have shown that small molecule compounds have a wide range of potential applications as medicinal drugs and diagnostics. Especially in clinical anti-cancer, anti-tumor, etc., a large number of small molecule compounds have been successfully developed, sold and widely used in the prevention and treatment of various diseases. It has been widely used in many fields such as chemistry, medicine, biology and materials science.
化学小分子能够穿过细胞膜，影响细胞内靶点的表达和功能，其应用范围非常广泛；此外，化学小分子经过化学修饰后具有良好的口服生物利用度，服用化学小分子对患者来说，具有更好的依从性；不管是售价还是剂型的给药方式，化学小分子药物的研究都比生物药物更为成熟，相比之下，它具有良好的潜力和市场竞争力。因此寻找新结构类型的抗肿瘤药物具有重要的意义。Small chemical molecules can pass through the cell membrane and affect the expression and function of intracellular targets, and have a wide range of applications; in addition, small chemical molecules have good oral bioavailability after chemical modification. Better compliance; regardless of price or dosage form, the research on chemical small molecule drugs is more mature than biological drugs, and in contrast, it has good potential and market competitiveness. Therefore, it is of great significance to find new structural types of antitumor drugs.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一种吡咯-2-磺酰胺化合物的制备方法及其在制备抗肿瘤药物中的应用，本发明中的吡咯-2-磺酰胺化合物对多株原发及转型肿瘤细胞具有很好的抑制活性。The purpose of the present invention is to provide a preparation method of pyrrole-2-sulfonamide compound and its application in the preparation of antitumor drugs. Very good inhibitory activity.
本发明提供一种吡咯-2-磺酰胺化合物或其可药用的盐在制备抗肿瘤药物中的应用，The invention provides the application of a pyrrole-2-sulfonamide compound or a pharmaceutically acceptable salt thereof in the preparation of antitumor drugs,
所述吡咯-2-磺酰胺化合物具有式I所示结构：The pyrrole-2-sulfonamide compound has the structure shown in formula I:
优选的，所述可药用的盐为盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、枸橼酸盐、苯磺酸盐、甲基苯磺酸盐、富马酸盐或酒石酸盐。Preferably, the pharmaceutically acceptable salts are hydrochloride, phosphate, sulfate, acetate, maleate, citrate, benzenesulfonate, toluenesulfonate, fumaric acid salt or tartrate.
优选的，所述肿瘤包括结肠癌、胃癌或肺癌。Preferably, the tumor includes colon cancer, gastric cancer or lung cancer.
优选的，所述抗肿瘤为抑制肿瘤细胞的增殖。Preferably, the anti-tumor is inhibiting the proliferation of tumor cells.
优选的，所述肿瘤细胞为结肠癌细胞SW480、耐药结肠癌细胞SW620、胃癌细胞SGC7901或肺癌细胞A549。Preferably, the tumor cells are colon cancer cells SW480, drug-resistant colon cancer cells SW620, gastric cancer cells SGC7901 or lung cancer cells A549.
本发明还提供了一种吡咯-2-磺酰胺化合物的制备方法，包括以下步骤：The present invention also provides a preparation method of pyrrole-2-sulfonamide compound, comprising the following steps:
A)将三氯乙酰氯与1H-吡咯-2-磺酰氯在溶剂中混合，进行反应，反应结束后经萃取、干燥和层析，得到纯净产物a；A) trichloroacetyl chloride and 1H-pyrrole-2-sulfonyl chloride are mixed in a solvent to react, and after the reaction finishes, extraction, drying and chromatography are performed to obtain pure product a;
B)将所述纯净产物a与肼混合，进行反应，反应结束后经萃取、干燥和层析，得到纯净产物b；B) the pure product a is mixed with hydrazine to react, and after the reaction finishes, extraction, drying and chromatography are carried out to obtain pure product b;
C)将所述纯净产物b、POCl
3和4-氟苯甲酸在溶剂中混合，回流反应，反应结束之后经萃取、干燥和层析，得到纯净产物c；
C) by described pure product b, POCl 3 and 4-fluorobenzoic acid are mixed in solvent, backflow reaction, after reaction finishes, through extraction, drying and chromatography, obtain pure product c;
D)将所述纯净产物c与5-氯-2-甲基苯胺在溶剂中混合，进行反应，反应结束后经萃取、干燥和层析，得到式I所示结构化合物；D) described pure product c and 5-chloro-2-methylaniline are mixed in solvent, react, after reaction finishes, through extraction, drying and chromatography, obtain the structural compound shown in formula I;
优选的，所述步骤A)中的三氯乙酰氯与1H-吡咯-2-磺酰氯的摩尔比为(1.0～1.5)：1，优选为(1.2～1.3)：1；Preferably, the molar ratio of trichloroacetyl chloride to 1H-pyrrole-2-sulfonyl chloride in the step A) is (1.0-1.5):1, preferably (1.2-1.3):1;
优选的，所述步骤A)中反应的温度为室温，反应的时间为1.5～3小时，优选为2～2.5小时；Preferably, the temperature of the reaction in the step A) is room temperature, and the reaction time is 1.5 to 3 hours, preferably 2 to 2.5 hours;
优选的，所述步骤A)使用乙酸乙酯萃取，无水硫酸镁干燥，快速柱进行层析；Preferably, the step A) is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to flash column chromatography;
优选的，所述步骤A)中的溶剂为乙醚。Preferably, the solvent in the step A) is diethyl ether.
优选的，所述步骤B)中纯净产物a与肼的摩尔比为1：(1.2～1.8)，优选为1：(1.5～1.6)；Preferably, in the step B), the molar ratio of the pure product a to hydrazine is 1:(1.2-1.8), preferably 1:(1.5-1.6);
优选的，所述步骤B)中反应的温度为室温，反应的时间为2～5小时，优选为2.5～3小时；Preferably, the temperature of the reaction in the step B) is room temperature, and the reaction time is 2 to 5 hours, preferably 2.5 to 3 hours;
优选的，所述步骤B)使用乙酸乙酯萃取，无水硫酸镁干燥，快速柱进行层析；Preferably, the step B) is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to flash column chromatography;
优选的，所述步骤B)中的溶剂为乙腈。Preferably, the solvent in the step B) is acetonitrile.
优选的，所述步骤C)中纯净产物b、POCl
3和4-氟苯甲酸的摩尔比为1：(1.0～2.0)：(1.0～1.5)，优选为1：(1.5～1.6)：(1.2～1.3)；
Preferably, in the step C), the molar ratio of pure product b, POCl 3 and 4-fluorobenzoic acid is 1:(1.0～2.0):(1.0～1.5), preferably 1:(1.5～1.6):( 1.2～1.3);
所述步骤C)中回流反应的温度为60～75℃，优选为65～70℃；所述回流反应的时间为5～8小时，优选为6～7小时；The temperature of the reflux reaction in the step C) is 60～75°C, preferably 65～70°C; the time of the reflux reaction is 5～8 hours, preferably 6～7 hours;
优选的，所述步骤C)使用乙酸乙酯萃取，无水硫酸镁干燥，快速柱进行层析；Preferably, the step C) is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to flash column chromatography;
优选的，所述步骤C)中的溶剂为四氢呋喃。Preferably, the solvent in the step C) is tetrahydrofuran.
优选的，所述步骤D)中纯净产物c与5-氯-2-甲基苯胺的摩尔比为1： (0.9～1.2)，优选为1:(1～1.1)；Preferably, in the step D), the molar ratio of pure product c to 5-chloro-2-methylaniline is 1:(0.9～1.2), preferably 1:(1～1.1);
优选的，所述步骤D)中反应的温度为室温，反应的时间为3～5小时，优选为4小时；Preferably, the temperature of the reaction in the step D) is room temperature, and the reaction time is 3 to 5 hours, preferably 4 hours;
优选的，所述步骤D)使用乙酸乙酯萃取，无水硫酸镁干燥，快速柱进行层析；Preferably, the step D) is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to flash column chromatography;
优选的，所述步骤D)中的溶剂为乙醇。Preferably, the solvent in the step D) is ethanol.
本发明提供了一种吡咯-2-磺酰胺化合物或其可药用的盐在制备抗肿瘤药物中的应用，所述吡咯-2-磺酰胺化合物具有式I所示结构：本发明首次发现了式I所示化合物N-(5-氯-2-甲基苯基)-5-(5-(4-氟苯基)-1,3,4-恶二唑-2-基)-1H-吡咯-2-磺酰胺具备抗肿瘤活性，对对多株原发及转型肿瘤细胞具有很好的抑制作用，可以用作制备抗肿瘤的药物。The present invention provides an application of a pyrrole-2-sulfonamide compound or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug, wherein the pyrrole-2-sulfonamide compound has the structure shown in formula I: the present invention finds out The compound represented by formula I N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-1H- The pyrrole-2-sulfonamide has anti-tumor activity, has a good inhibitory effect on multiple primary and transformed tumor cells, and can be used as an anti-tumor drug.
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图获得其他的附图。In order to explain the embodiments of the present invention or the technical solutions in the prior art more clearly, the following briefly introduces the accompanying drawings that need to be used in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only It is an embodiment of the present invention. For those of ordinary skill in the art, other drawings can also be obtained according to the provided drawings without creative work.
图1为本发明中式I所示化合物N-(5-氯-2-甲基苯基)-5-(5-(4-氟苯基)-1,3,4-恶二唑-2-基)-1H-吡咯-2-磺酰胺的核磁氢谱图；Fig. 1 is the compound N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)-1,3,4-oxadiazole-2- base)-1H-pyrrole-2-sulfonamide hydrogen NMR spectrum;
图2为受试化合物体外对结肠癌细胞SW480抑制活性；Figure 2 shows the inhibitory activity of test compounds on colon cancer cell SW480 in vitro;
图3为受试化合物体外对耐药结肠癌细胞SW620抑制活性。Figure 3 shows the inhibitory activity of test compounds against drug-resistant colon cancer cells SW620 in vitro.
按照式II所示流程和制备方法制备得到纯净目标化合物N-(5-氯-2-甲基苯基)-5-(5-(4-氟苯基)-1,3,4-恶二唑-2-基)-1H-吡咯-2-磺酰胺。The pure target compound N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)-1,3,4-oxadiene was prepared according to the scheme and preparation method shown in formula II oxazol-2-yl)-1H-pyrrole-2-sulfonamide.
步骤1：将三氯乙酰氯(1.2当量)缓慢加到1H-吡咯-2-磺酰氯(1当量)的乙醚(10体积)溶液中，室温下搅拌2小时，TLC检测反应进程；反应结束后用乙酸乙酯萃取出粗产物a，无水硫酸镁干燥；快速柱层析得到纯净产物a。Step 1: Trichloroacetyl chloride (1.2 equiv) was slowly added to a solution of 1H-pyrrole-2-sulfonyl chloride (1 equiv) in ether (10 vol), stirred at room temperature for 2 hours, and the reaction progress was detected by TLC; The crude product a was extracted with ethyl acetate and dried over anhydrous magnesium sulfate; the pure product a was obtained by flash column chromatography.
步骤2：将化合物a(1当量)溶于乙腈(10体积)中，逐滴缓慢加入肼(1.5当量)的乙腈溶液，室温下搅拌2.5小时，TLC检测反应进程；反应结束后用乙酸乙酯萃取出粗产物b，无水硫酸镁干燥；快速柱层析得到纯净产物b。Step 2: Dissolve compound a (1 equiv) in acetonitrile (10 vol), slowly add a solution of hydrazine (1.5 equiv) in acetonitrile dropwise, stir at room temperature for 2.5 hours, check the reaction progress by TLC; use ethyl acetate after the reaction Crude product b was extracted and dried over anhydrous magnesium sulfate; pure product b was obtained by flash column chromatography.
步骤3：室温下向化合物b(1当量)的四氢呋喃溶液中缓慢滴加入POCl
3(1.5当量)，再滴加入4-氟苯甲酸(1.2当量)的四氢呋喃溶液，混合物65℃回流反应6小时，TLC检测反应进程；反应结束后用乙酸乙酯萃取出粗产物c，无水硫酸镁干燥；快速柱层析得到纯净产物c。
Step 3: To the tetrahydrofuran solution of compound b (1 equiv.) was slowly added dropwise POCl 3 (1.5 equiv.) at room temperature, and then the tetrahydrofuran solution of 4-fluorobenzoic acid (1.2 equiv.) was added dropwise, and the mixture was refluxed at 65° C. for 6 hours. The reaction progress was detected by TLC; after the reaction, the crude product c was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate; the pure product c was obtained by flash column chromatography.
步骤4：将化合物c(1当量)与5-氯-2-甲基苯胺(1当量)混合溶于乙醇溶液中，室温下搅拌4小时，TLC检测反应进程；反应结束后用乙酸乙酯萃取出粗产物，无水硫酸镁干燥；快速柱层析得到纯净目标化合物。Step 4: Compound c (1 equiv.) and 5-chloro-2-methylaniline (1 equiv.) were mixed and dissolved in ethanol solution, stirred at room temperature for 4 hours, and the reaction progress was detected by TLC; after the reaction was completed, extracted with ethyl acetate The crude product was obtained and dried over anhydrous magnesium sulfate; the pure target compound was obtained by flash column chromatography.
对目标化合物进行核磁共振氢谱检测，结果如下：
1H NMR(500MHz,DMSO-d
6)δ13.05(s,1H),9.46(s,1H),8.18(m,J＝7.4,1.2Hz,2H),7.44(m,J＝ 2.1Hz,3H),7.12(m,J＝7.4,1.9Hz,4H),2.26(d,J＝1.0Hz,3H)。如图1所示，由图1可知，本实施例制备得到了式I所示化合物N-(5-氯-2-甲基苯基)-5-(5-(4-氟苯基)-1,3,4-恶二唑-2-基)-1H-吡咯-2-磺酰胺。
1H NMR (500MHz, DMSO-d 6 )δ13.05(s, 1H), 9.46(s, 1H), 8.18(m, J=7.4, 1.2Hz) , 2H), 7.44 (m, J=2.1 Hz, 3H), 7.12 (m, J=7.4, 1.9 Hz, 4H), 2.26 (d, J=1.0 Hz, 3H). As shown in Figure 1, it can be seen from Figure 1 that the compound N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)- 1,3,4-oxadiazol-2-yl)-1H-pyrrole-2-sulfonamide.
1.化合物的抗肿瘤活性测定1. Determination of the antitumor activity of the compounds
选用的肿瘤细胞有结肠癌细胞SW480，耐药结肠癌细胞SW620，胃癌细胞SGC7901，肺癌细胞A549，取处于对数生长期细胞，消化计数，将细胞状态调整好后，进行铺板操作。按3000/孔细胞密度接种于96孔板，在培养箱中放置过夜。(注：外圈PBS填满。)18-24h后，进行给药操作。吸走细胞培养基，加入含有一定浓度的药物的培养液。实验设置空白组(溶剂对照组)、实验组。实验组的药物浓度依次为1μM、5μM、20μM、50μM、100μM、200μM。每组实验均设置3个副孔，阳性对照为五氟尿嘧啶，方法与受试化合物相同。The selected tumor cells include colon cancer cells SW480, drug-resistant colon cancer cells SW620, gastric cancer cells SGC7901, and lung cancer cells A549. Cells in the logarithmic growth phase were taken, digested and counted, and the cell state was adjusted before plating. The cells were seeded at a density of 3000 cells/well in a 96-well plate and placed in an incubator overnight. (Note: the outer circle is filled with PBS.) After 18-24h, the drug administration operation was performed. Aspirate the cell culture medium and add a culture medium containing a certain concentration of the drug. The experiment set blank group (solvent control group) and experimental group. The drug concentrations in the experimental group were 1 μM, 5 μM, 20 μM, 50 μM, 100 μM, and 200 μM. Three sub-wells were set in each group of experiments, the positive control was pentafluorouracil, and the method was the same as that of the test compound.
给药72h后，每孔加入10μL MTT溶液，置于细胞培养箱继续孵育2h。用酶标仪检测每孔在492nm波长处的光吸收值。After 72 hours of administration, 10 μL of MTT solution was added to each well and placed in a cell incubator for further incubation for 2 hours. The absorbance value of each well at 492nm wavelength was detected with a microplate reader.
根据吸光值计算每孔细胞的存活率，从而算出药物的IC
50值。结果如表1所示。
The survival rate of cells in each well was calculated based on the absorbance value to calculate the IC 50 value of the drug. The results are shown in Table 1.
表1 受试化合物的体外抗肿瘤活性筛选Table 1 In vitro antitumor activity screening of test compounds
由表1可知，受试化合物N-(5-氯-2-甲基苯基)-5-(5-(4-氟苯基)-1,3,4-恶二唑-2-基)-1H-吡咯-2-磺酰胺具备抗肿瘤活性，对多株原发及转型肿瘤细胞具有很好的抑制作用，可以用作制备抗肿瘤的药物。As can be seen from Table 1, the test compound N-(5-chloro-2-methylphenyl)-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl) -1H-pyrrole-2-sulfonamide has anti-tumor activity, has a good inhibitory effect on multiple primary and transformed tumor cells, and can be used as an anti-tumor drug.
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made. It should be regarded as the protection scope of the present invention.
Claims (9)
- 一种吡咯-2-磺酰胺化合物或其可药用的盐在制备抗肿瘤药物中的应用，An application of a pyrrole-2-sulfonamide compound or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug,所述吡咯-2-磺酰胺化合物具有式I所示结构：The pyrrole-2-sulfonamide compound has the structure shown in formula I:
- 根据权利要求1所述的应用，其特征在于，所述可药用的盐为盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、枸橼酸盐、苯磺酸盐、甲基苯磺酸盐、富马酸盐或酒石酸盐。The application according to claim 1, wherein the pharmaceutically acceptable salt is hydrochloride, phosphate, sulfate, acetate, maleate, citrate, benzenesulfonate, Tosylate, fumarate or tartrate.
- 根据权利要求1所述的应用，其特征在于，所述肿瘤包括结肠癌、胃癌或肺癌。The use according to claim 1, wherein the tumor comprises colon cancer, gastric cancer or lung cancer.
- 根据权利要求1所述的应用，其特征在于，所述抗肿瘤为抑制肿瘤细胞的增殖。The use according to claim 1, wherein the anti-tumor is inhibiting the proliferation of tumor cells.
- 一种吡咯-2-磺酰胺化合物的制备方法，包括以下步骤：A preparation method of pyrrole-2-sulfonamide compound, comprising the following steps:A)将三氯乙酰氯与1H-吡咯-2-磺酰氯在溶剂中混合，进行反应，反应结束后经萃取、干燥和层析，得到纯净产物a；A) trichloroacetyl chloride and 1H-pyrrole-2-sulfonyl chloride are mixed in a solvent to react, and after the reaction finishes, extraction, drying and chromatography are performed to obtain pure product a;B)将所述纯净产物a与肼混合，进行反应，反应结束后经萃取、干燥和层析，得到纯净产物b；B) the pure product a is mixed with hydrazine to react, and after the reaction finishes, extraction, drying and chromatography are carried out to obtain pure product b;C)将所述纯净产物b、POCl 3和4-氟苯甲酸在溶剂中混合，回流反应，反应结束之后经萃取、干燥和层析，得到纯净产物c； C) by described pure product b, POCl 3 and 4-fluorobenzoic acid are mixed in solvent, backflow reaction, after reaction finishes, through extraction, drying and chromatography, obtain pure product c;D)将所述纯净产物c与5-氯-2-甲基苯胺在溶剂中混合，进行反应，反应结束后经萃取、干燥和层析，得到式I所示结构化合物；D) described pure product c and 5-chloro-2-methylaniline are mixed in solvent, react, after reaction finishes, through extraction, drying and chromatography, obtain the structural compound shown in formula I;
- 根据权利要求5所述的制备方法，其特征在于，所述步骤A)中的三氯乙酰氯与1H-吡咯-2-磺酰氯的摩尔比为(1.0～1.5)：1；The preparation method according to claim 5, wherein the molar ratio of trichloroacetyl chloride and 1H-pyrrole-2-sulfonyl chloride in the step A) is (1.0～1.5):1;所述步骤A)中反应的温度为室温，反应的时间为1.5～3小时。In the step A), the reaction temperature is room temperature, and the reaction time is 1.5 to 3 hours.
- 根据权利要求5所述的制备方法，其特征在于，所述步骤B)中纯净产物a与肼的摩尔比为1：(1.2～1.8)；The preparation method according to claim 5, wherein the molar ratio of the pure product a and the hydrazine in the step B) is 1: (1.2～1.8);所述步骤B)中反应的温度为室温，反应的时间为2～4小时。The temperature of the reaction in the step B) is room temperature, and the reaction time is 2 to 4 hours.
- 根据权利要求5所述的制备方法，其特征在于，所述步骤C)中纯净产物b、POCl 3和4-氟苯甲酸的摩尔比为1：(1.0～2.0)：(1.0～1.5)； The preparation method according to claim 5, wherein the molar ratio of pure product b, POCl and 4 -fluorobenzoic acid in the step C) is 1:(1.0～2.0):(1.0～1.5);所述步骤C)中回流反应的温度为60～75℃；所述回流反应的时间为5～8小时。The temperature of the reflux reaction in the step C) is 60-75°C; the time of the reflux reaction is 5-8 hours.
- 根据权利要求5所述的制备方法，其特征在于，所述步骤D)中纯净产物c与5-氯-2-甲基苯胺的摩尔比为1：(0.9～1.2)；preparation method according to claim 5, is characterized in that, in described step D), the mol ratio of pure product c and 5-chloro-2-methylaniline is 1:(0.9～1.2);所述步骤D)中反应的温度为室温，反应的时间为3～5小时。The temperature of the reaction in the step D) is room temperature, and the reaction time is 3 to 5 hours.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87103542A (en) * | 1986-05-17 | 1988-02-03 | 先灵农业化学品公司 | Herbicide |
| WO2002088097A1 (en) * | 2001-04-27 | 2002-11-07 | Vertex Pharmaceuticals Incorporated | Triazole-derived kinase inhibitors and uses thereof |
| CN1549714A (en) * | 2001-08-06 | 2004-11-24 | Aminoisoxazole derivatives active as kinase inhibitors | |
| CN1735611A (en) * | 2003-01-02 | 2006-02-15 | 霍夫曼-拉罗奇有限公司 | CB 1 receptor inverse agonists |
| WO2006116355A1 (en) * | 2005-04-22 | 2006-11-02 | Kalypsys, Inc. | Ortho-terphenyl inhibitors of p38 kinase and methods of treating inflammatory disorders |
| CN101910165A (en) * | 2007-10-29 | 2010-12-08 | 先灵公司 | Thiazole derivatives as protein kinase inhibitors |
| WO2020170203A1 (en) * | 2019-02-22 | 2020-08-27 | Insilico Medicine Ip Limited | Methods of inhibiting kinases |
-
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- 2021-05-21 WO PCT/CN2021/095190 patent/WO2022205586A1/en active Application Filing
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87103542A (en) * | 1986-05-17 | 1988-02-03 | 先灵农业化学品公司 | Herbicide |
| WO2002088097A1 (en) * | 2001-04-27 | 2002-11-07 | Vertex Pharmaceuticals Incorporated | Triazole-derived kinase inhibitors and uses thereof |
| CN1549714A (en) * | 2001-08-06 | 2004-11-24 | Aminoisoxazole derivatives active as kinase inhibitors | |
| CN1735611A (en) * | 2003-01-02 | 2006-02-15 | 霍夫曼-拉罗奇有限公司 | CB 1 receptor inverse agonists |
| WO2006116355A1 (en) * | 2005-04-22 | 2006-11-02 | Kalypsys, Inc. | Ortho-terphenyl inhibitors of p38 kinase and methods of treating inflammatory disorders |
| CN101910165A (en) * | 2007-10-29 | 2010-12-08 | 先灵公司 | Thiazole derivatives as protein kinase inhibitors |
| WO2020170203A1 (en) * | 2019-02-22 | 2020-08-27 | Insilico Medicine Ip Limited | Methods of inhibiting kinases |
Non-Patent Citations (1)
| Title |
|---|
| K. JONES M. SWAPNAJA, SATYANARAYANA YENNAM, MURTHY CHAVALI, Y. POORNACHANDRA, C. GANESH KUMAR, KRUBAKARAN MUTHUSAMY, VENKATESH BAB: "Design, synthesis and biological evaluation of diaziridinyl quinone isoxazole hybrids", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 117, no. 126, 6 April 2016 (2016-04-06), AMSTERDAM, NL , pages 85 - 98, XP055489809, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2016.03.042 * |
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| CN113069451A (en) | 2021-07-06 |
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