WO2015117551A1 - 吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途 - Google Patents

吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途 Download PDF

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WO2015117551A1
WO2015117551A1 PCT/CN2015/072230 CN2015072230W WO2015117551A1 WO 2015117551 A1 WO2015117551 A1 WO 2015117551A1 CN 2015072230 W CN2015072230 W CN 2015072230W WO 2015117551 A1 WO2015117551 A1 WO 2015117551A1
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pyrrole
substituted
compound
group
pharmaceutically acceptable
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PCT/CN2015/072230
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English (en)
French (fr)
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胡立宏
赵韶华
刘鹏
李向军
安军永
周梦夏
张丽丽
姚子俭
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石家庄以岭药业股份有限公司
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Priority to MX2016010272A priority Critical patent/MX369473B/es
Priority to JP2016552314A priority patent/JP6211205B2/ja
Priority to CA2939012A priority patent/CA2939012C/en
Priority to ES15746066.8T priority patent/ES2687418T3/es
Priority to KR1020167024807A priority patent/KR101805693B1/ko
Priority to AU2015215335A priority patent/AU2015215335B2/en
Priority to US15/117,400 priority patent/US9556154B2/en
Priority to PL15746066T priority patent/PL3106459T3/pl
Application filed by 石家庄以岭药业股份有限公司 filed Critical 石家庄以岭药业股份有限公司
Priority to EP15746066.8A priority patent/EP3106459B1/en
Priority to BR112016018371-1A priority patent/BR112016018371B1/pt
Priority to SG11201606545SA priority patent/SG11201606545SA/en
Priority to RU2016136351A priority patent/RU2650682C2/ru
Publication of WO2015117551A1 publication Critical patent/WO2015117551A1/zh
Priority to SA516371644A priority patent/SA516371644B1/ar

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a pyrrole-substituted indolone derivative or a pharmaceutically acceptable salt thereof, a process for producing the same, a composition comprising the same, and use thereof, and more particularly, the present invention relates to a multi-target cheese
  • the tyrosine kinase inhibitor pyrrole replaces the fluorenone derivative, as well as its pharmaceutical compositions and medical uses.
  • Cancer is the disease that threatens people's health in today's society.
  • the anticancer drugs widely used in the market so far are still some cytotoxic drugs discovered in the last century. These cytotoxic drugs in the process of treating tumors kill a large number of normal cells to bring unbearable side effects to patients, and the drug resistance with the large-scale use of such drugs is becoming another insurmountable problem.
  • Tumor vascular inhibition is a new method developed at the end of the last century for the treatment of tumors. Its research is based on the belief that the survival, growth and metastasis of tumors depend on a large number of new blood vessels (Folkman. J. et. al. N. Engl. J. Med., 1971, 285, 1182-1186.). A large number of clinically discovered tumor tissues contain a large number of new blood vessels, and the growth and metastasis of tumor cells requires a large number of blood vessels to provide sufficient oxygen and nutrients.
  • tumor cell blood vessel growth can "starve" tumor cells, while there are few new blood vessels around normal cells, and the inhibition of neovascularization on normal cells is small, which makes angiogenesis antitumor drugs efficient, safe and low. Poison and other characteristics.
  • Vascular inhibition can be divided into direct inhibition and indirect inhibition.
  • Direct inhibition is the endothelial cells acting on blood vessels, inhibiting the formation and expansion of blood vessels and nutritional support for tumor cells.
  • the main method currently used is the rhythm of cytotoxic drugs. Treatment, rhythmic treatment can reduce the side effects of cytotoxic drugs, but it is still difficult to change the harm of drugs to the human body.
  • Indirect inhibition inhibits angiogenesis by inhibiting angiogenic factors required during angiogenesis (Cao, Y. et. al. Int. J. Biochem. Cell Biol., 2001, 33, 357-369.).
  • the process of angiogenesis includes: activation of vascular endothelial cells by activators; secretion of proteases by the endothelial cells to degrade the basement membrane; migration and proliferation of endothelial cells; formation of new capillary compartments; recruitment of pericytes to stabilize newly generated capillaries Peripheral structure.
  • angiogenesis inhibitors can be divided into two major groups according to the specificity of action. class. One type is an angiogenesis inhibitor that specifically acts on endothelial cells, including angiostatin and endostatin.
  • the other type is an angiogenesis inhibitor that acts non-specifically on endothelial cells, including cytokines, tissue metalloproteinase inhibitors, serine protease inhibitors, and tumor suppressor gene products.
  • Proangiogenic factors include epidermal growth factor (EGF), endothelial cell growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) (Hanks, SK, et. al. FASEB, 1995, 9,576-696). High expression of different pro-angiogenic factors can be seen in different types of tumors, high expression of EGF is common in epithelial cell tumors, and high expression of PDGF is common in gliomas.
  • EGF epidermal growth factor
  • VEGF endothelial cell growth factor
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor
  • the strategy for developing anticancer drugs for tumor neovascular pathway is mainly to increase angiogenesis inhibitory factor and reduce proangiogenic factors.
  • the inhibition of high expression of angiogenic factors, especially on VEGF/VEGFR signaling pathway, is the mainstream of current research.
  • VEGF is a glycoprotein in the human body that plays an important role in the process of blood vessel formation.
  • the human VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and PLGF.
  • VEGF can selectively act on VEGFR (VEGF receptor).
  • VEGFR is a type of tyrosine kinase transmembrane protein. When VEGF binds to VEGFR, it changes the conformation of VEGFR and leads to the dimerization of the receptor. Phosphorylation occurs within the tyrosine site and activates the downstream transduction pathway (Joukov, V., et. al. EMBO J., 1996, 15, 290-298.).
  • VEGF/VEGFR signal transduction pathway is the most important pro-angiogenic and metastatic pathway in the cell. By inhibiting this pathway, it can inhibit the growth and metastasis of endothelial cells, thereby inhibiting tumor growth.
  • drugs have been successfully marketed, and more than 30 are in clinical research. More important is the recombinant humanized VEGF monoclonal antibody, bevacizumab (trade name Avastin), the first successfully marketed anti-tumor angiogenesis drug that specifically binds to VEGF-A. Thereby blocking the VEGF/VEGFR pathway. The drug achieved great success at the beginning of the market, but as the use time prolonged, the problem of drug resistance gradually emerged.
  • VEGF-A causes cells to release a large number of other pro-angiogenic factors, such as PLGF and FGF, a phenomenon known as angiogenesis rescue response.
  • PLGF and FGF pro-angiogenic factors
  • angiogenesis rescue response a phenomenon known as angiogenesis rescue response.
  • Sunitinib is one of these multi-target anticancer drugs.
  • Sunitinib is an inhibitor of multi-target tyrosine kinase developed by Pfizer, which can effectively inhibit VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- ⁇ , c-Kit, FLT-3
  • the receptor tyrosine kinase inhibits the expression of various pro-angiogenic factors in cancerous cells by inhibiting these proteins, thereby inhibiting neovascularization and "starving" cancer cells (Abrams, TJet.al. Mol. Cancer Ther., 2003, 2, 1011-1021.).
  • c-Kit FLT-3 Mutant tumor cells also have specific direct inhibition.
  • Sunitinib was approved by the FDA in 2006 and is mainly used for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. It is the first anticancer drug approved for both types of indications. Although sunitinib has obvious anti-tumor effects, it still shows side effects such as fatigue, myelosuppression and fever in patients with clinical use, and its tissue accumulation is strong and cannot be taken continuously. The clinical use is stopped after 4 weeks of continuous use. Two-week program. The study found that tumor angiogenesis can be restored during withdrawal. Therefore, it is necessary to find a safer and more effective ideal drug through chemical structure changes to reduce toxic side effects and optimize drug formation.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising the above pyrrole-substituted indolone derivative.
  • a further object of the present invention is to provide the use of the above pyrrole-substituted indolone derivatives and pharmaceutical compositions comprising the same.
  • the present invention provides a pyrrole-substituted anthrone derivative having a structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
  • n 0, 1, 2;
  • n is selected from 1, 2, 3;
  • R is selected from hydrogen, C 1 -C 6 straight or branched alkyl, C 3 -C 7 cycloalkyl, formyl substituted with C 1 -C 6 straight or branched alkyl, C 3 -C 7 Cycloalkyl formyl, tert-butyloxycarbonyl, substituted carbamoyl, or 5-7 membered cyclic carbamoyl.
  • R is preferably selected from hydrogen, C 1 -C 3 straight or branched alkyl, C 4 -C 6 cycloalkyl, straight chain with C 1 -C 3 or Branched alkyl substituted formyl, C 3 -C 6 cycloalkyl formyl, tert-butyloxycarbonyl, N,N-dimethylformyl, N,N-diethylformyl, N,N- Dipropyl formyl, pyrrolidin-1-yl, or piperidine-1-formyl.
  • R is more preferably selected from the group consisting of hydrogen, methyl, t-butyloxycarbonyl, N,N-dimethylformyl or pyrrolidine-1-formyl.
  • the pyrrole-substituted anthrone derivative having the structure represented by the general formula (I) is preferably selected from the following compounds 1-15:
  • the pharmaceutically acceptable salt of the pyrrole-substituted anthrone derivative of the present invention is not particularly limited and may be a hydrochloride, a fumarate, a maleate, a citrate, a phosphate, a sulfate or a tartaric acid. Salt, methanesulfonate and besylate.
  • a hydrochloride When a hydrochloride is used, high crystallinity and high solubility can be obtained, and hygroscopicity is improved, and thus it is preferred to use a hydrochloride.
  • the 3,5-dimethyl-2-pyrrolidine represented by the structural formula I is dissolved in concentrated sulfuric acid, and the temperature is lowered to about 10 ° C, and potassium nitrate is added thereto to keep the reaction. After completion of the reaction, the mixture was vigorously stirred in cold water and filtered to obtain Compound II, which was recrystallized to give a pure product.
  • the compound of the formula IV is dissolved in tetrahydrofuran, a mixed solution of water and methanol, heated to 50 ° C, saturated ammonium chloride and zinc powder are added, and the reaction is kept warm. After completion of the reaction, the solvent was evaporated to dryness to ethyl acetate.
  • the compound represented by Structural Formula V is dissolved in tetrahydrofuran, and a base (DIPEA, DMAP, pyridine, etc.) and a condensing agent (EDCI, DCC, etc.) are added at room temperature to carry out a heat retention reaction. After completion of the reaction, the solvent is evaporated to give a crude compound of the formula VII, washed with water, and rinsed with a solvent (ethyl acetate, methanol, etc.) to give the pure compound VII.
  • a base DIPEA, DMAP, pyridine, etc.
  • EDCI condensing agent
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more pyrrole substituted porphyrin derivatives of the formula (I) or a pharmaceutically acceptable salt thereof, which composition can be further Pharmacological conventional excipients such as excipients, sweeteners and the like are included.
  • the pyrrole-substituted porphyrin derivative of the present invention or a pharmaceutically acceptable salt thereof has an activity of inhibiting tyrosine kinase and can be used for the preparation of a medicament for treating a tumor caused by abnormal expression of tyrosine kinase. That is, the pyrrole-substituted indolone derivative of the present invention or a pharmaceutically acceptable salt thereof can be used for the treatment of tyrosine kinase-mediated tumors and inhibition of related tumor cell growth, including administration of a therapeutically effective amount of pyrrole to a patient.
  • the substituted porphyrin derivative or a pharmaceutically acceptable salt thereof can also be used for the preparation of a medicament for treating tyrosine kinase-mediated tumors and inhibiting the growth of related tumor cells.
  • the pyrrole-substituted porphyrinone derivative prepared by the present invention or a pharmaceutically acceptable salt thereof has an inhibitory effect on various tyrosine kinases, and the whole animal test shows that the compound has an effect of inhibiting tumor growth.
  • the pyrrole-substituted porphyrinone derivative of the present invention or a pharmaceutically acceptable salt thereof has a low toxic side effect.
  • Such compounds are useful in the treatment of a variety of neoplastic diseases.
  • the compound of the invention is simple in synthesis, easy to prepare, and rich in synthetic raw materials.
  • the raw material 3,5-dimethyl-2-pyrrolidine I (5 g, 40 mmol) was dissolved in 60 mL of concentrated sulfuric acid, and then the temperature of the system was lowered to -10 ° C, and potassium nitrate (4.35 g) was slowly added in portions at this temperature. , 42mmol), added in about 2h. During this process, the temperature was maintained at -10 ° C. After the addition, the mixture was stirred at this temperature for about 2 h. After the TLC reaction was completed, the solution was added to 1 L of ice water and extracted twice with 1 L of ethyl acetate. The organic layer was washed with saturated aqueous sodium sulfate and dried over anhydrous sodium sulfate.
  • the compound 2 (383 mg, 1 mmol) was added to 20 mL of tetrahydrofuran, and DIPEA (260 mg, 2 mmol) and dimethylformyl chloride (214 mg, 2 mmol) were added at room temperature. After the addition, the reaction was continued for about 12 h, and the TLC detection reaction was almost complete. . After completion of the reaction, the solvent was evaporated to dryness, and then evaporated to ethyl ether.
  • the synthesis method of Compound 8 is the same as 3.
  • the synthesis method of Compound 8 is the same as 3.
  • the target compound 9 is obtained by substituting 4 for 2.
  • the synthesis method of Compound 8 is the same as 3.
  • the synthesis method of the compound 12 is the same as 2.
  • the synthesis method of Compound 13 is the same as 3.
  • the target compound 13 is obtained by substituting 12 for 2.
  • the synthesis method of Compound 14 is the same as that of 11.
  • the hydrochloride salt of all other compounds can be prepared by reacting the corresponding compound with a dilute hydrochloric acid ethanol solution by this method.
  • Comparative Compound 1 is the same as Compound 2 except that the rightmost piperidinyl group is bonded to the carbonyl group by an N atom.
  • Comparative compound 2 is the same as compound 6, except that the rightmost pyrrolidinyl group is bonded to the carbonyl group by a N atom.
  • Comparative Compound 3 was identical to Compound 2 except that the rightmost piperidinyl group was attached to the carbonyl group via a methylene group.
  • Test Example 1 Determination of in vitro biochemical activity of KDR tyrosine kinase
  • the in vitro inhibitory activity of the compound against KDR (VEGF receptor) tyrosine kinase was determined by the HTRF (homogeneous time-resolved fluorescence) method.
  • HTRF homogeneous time-resolved fluorescence
  • Staurosporine a positive control compound
  • Test Example 2 Cytotoxicity against HUVEC and VEGF-induced proliferation of HUVEC cells in vitro
  • VEGF-induced proliferation inhibition of human umbilical vein endothelial cell line Human umbilical vein endothelial cells (HUVEC) were cultured in F-12K containing 10% FBS, 18 u/mL heparin and 30 ⁇ g/mL ECGS. 4-8 generation HUVEC. The cells were trypsinized, resuspended in a culture medium (1 ⁇ 10 5 /mL), and 100 ⁇ L per well was added to a 96-well plate and allowed to adhere overnight. Replace the F-12K medium containing 5% FBS and incubate for 24 hours. The test compound or sunitinib or control 5% FBS-F-12K medium was added and incubated for 30 min.
  • a 0.1% FBS-F-12K culture solution having a final concentration of 30 ng/mL VEGF165 or vehicle (DMSO) was added, and culture was induced for 72 hours.
  • the culture solution was aspirated, 120 ⁇ L of MTS test solution was added to each well, and incubated at 37 ° C to read OD490.
  • the 5% FBS-F-12K culture solution was used as the negative control.
  • the OD value of the negative control group was subtracted from the OD value of the VEGF165-stimulated group to obtain the VEGF-stimulated growth value, and the inhibition rate was calculated.
  • the dose-response curve was prepared by GraphPad Prism software. calculate the median effect concentration (EC 50).
  • Cytotoxicity assay The above HUVEC cells were cultured in F-12K medium containing 10% fetal bovine serum (FBS), 100 U/ml penicillin, 100 ⁇ g/mL streptomycin, 30 ug/mL ECGS, and 18 u/mL heparin. Digest the HUVEC in logarithmic growth phase, adjust the cell density to the required concentration with 5% FBS F-12K complete medium, inoculate 150 ⁇ L of the cells in 96-well plates, 3000/well, and add 5% FBS after 24 hours. 50 ⁇ L of the test compound diluted 4 times in complete medium, using the same volume of DMSO dilution as a control.
  • FBS fetal bovine serum
  • Comparative Compounds 1 and 2 since the rightmost nitrogen-containing heterocyclic group is bonded to the carbonyl group by a hetero atom, the therapeutic index (TI) is roughly equivalent to that of sunitinib, and is significantly lower than the compound of the present invention.
  • Comparative Compound 3 since the rightmost nitrogen-containing heterocyclic group is attached to the carbonyl group via a methylene group, its therapeutic index (TI) is also roughly equivalent to that of sunitinib, which is significantly lower than the compound of the present invention.
  • Test Example 3 Determination of proliferation activity of human MV-4-11 tumor cell line
  • Human acute leukemia cell MV-4-11 is a Flt-3 mutant cell line.
  • the anti-proliferative activity of the compound against MV-4-11 was determined by MTS method: trypsinize the cells in the log phase of growth, count, and resuspend the appropriate amount of cells in the culture medium, 150 ⁇ L per well was added to the 96-well plate. After overnight incubation. 50 ⁇ L of a 4-fold gradient dilution of the test compound or control medium was added to each well and cultured for 72 hours. The culture broth was blotted, 120 ⁇ L of MTS assay solution (100 ⁇ L of fresh medium and 20 ⁇ L of MTS solution) was added to each well, and incubated at 37 ° C to read the OD490 value. The processed data was analyzed using Graphpad Prism 5 software to determine the IC 50 .
  • Example Compounds 1-15 showed significant antiproliferative activity against MV-4-11, and some of the compound activities were comparable or stronger than sunitinib (see the table below).
  • FLT-3 FMS-like tyrosine kinase 3
  • FLT-3 is a type III receptor tyrosine kinase widely found in the system, immune system and nervous system. Mutations and overexpression of the FLT-3 gene will result in tumorigenesis.
  • the antiproliferative activity of compounds 1-15 specific for MV-4-11 also suggested that the example compounds were similar to sunitinib and were FLT-3 inhibitors.
  • Test Example 4 Inhibition of MV-4-11 xenografts in nude mice in vivo
  • MV-4-11 cells were cultured in vitro, cells in logarithmic growth phase were harvested, resuspended in serum-free EMEM medium, and the cell suspension was injected into the male right axilla of the Balb/c nude mice with a syringe. Animals and transplanted tumors were observed regularly. When the tumor volume grew to about 100-300 mm 3 , animals with moderate tumor size were randomly divided into groups of 6 animals.
  • a blank vehicle (0.5% CMC) or a suspension of the above-mentioned compound 6 or sunitinib was administered by intragastric administration at a dose of 80 mg/kg once daily for 3 weeks; during the monitoring period, Tumor diameter, animal body weight, animal life status were observed; the test was terminated after 3 weeks of administration, CO 2 was sacrificed and the animals were dissected.
  • the compound 6 of the present invention has a good inhibitory effect on the MV-4-11 xenograft, and the 80 mg/kg dose can completely disappear the tumor, while the body weight The effect is small, and sunitinib makes the animal's body weight drop significantly, and the toxicity is obvious.
  • the results show that the series of compounds have anti-tumor effects comparable to sunitinib, but the toxicity is smaller, the therapeutic window is larger, and the development value is better.

Abstract

本发明涉及一种吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途，所述吡咯取代吲哚酮类衍生物具有通式(I)所示结构。本发明还涉及所述吡咯取代吲哚酮类衍生物在治疗受体酪氨酸激酶介导的疾病中的用途，以及含有此类结构化合物的用于治疗肿瘤等相关疾病的药物组合物。

Description

吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途 技术领域
本发明涉及一种吡咯取代吲哚酮类衍生物或其药学上可接受的盐、其制备方法、包含该衍生物的组合物、及其用途，更具体而言，本发明涉及多靶点酪氨酸激酶抑制剂吡咯取代吲哚酮类衍生物，以及其药物组合物和医药用途。
背景技术
癌症是当今社会对人们的健康威胁最大的疾病。目前为止市场上大量使用的抗癌药物仍然是上世纪发现的一些细胞毒药物。这些细胞毒药物在治疗肿瘤的过程中大量杀死正常细胞给病人带来难以忍受的副作用，并且随着这类药物的大量使用耐药性正成为另一个难以克服的问题。
肿瘤血管抑制是上世纪末发展的用于治疗肿瘤的新方法。它的研究基础是基于Folkman提出的肿瘤的存活、生长和转移依赖大量新生血管的观点(Folkman.J.et.al.N.Engl.J.Med.，1971，285，1182-1186.)。大量的临床发现肿瘤组织含有数量众多的新生血管，肿瘤细胞的生长和转移需要大量的血管提供足够的氧气和营养。抑制肿瘤细胞血管的生长即可“饿死”肿瘤细胞，同时正常细胞周围的新生血管很少，新生血管抑制对正常细胞的影响很小，这使得血管抑制类抗肿瘤药物具有高效、安全、低毒等特点。
血管抑制可分为直接抑制和间接抑制两类，直接抑制作用是作用于血管的内皮细胞，抑制血管的生成、扩展和对肿瘤细胞的营养支持，目前使用的主要方法为细胞毒药物的节律化治疗，节律化的治疗虽然可以减轻细胞毒药物的副作用但仍然难以改变药物对人体的伤害。间接抑制作用通过抑制血管生成过程中所需要的血管生成因子来抑制血管的新生(Cao，Y.et.al.Int.J.Biochem.Cell Biol.，2001，33，357-369.)。血管新生的过程包括：血管内皮细胞在激活因子的作用下激活；内皮细胞分泌蛋白酶降解基底膜；内皮细胞的迁移和增殖；新毛细血管官腔的形成；募集周细胞，以稳定新生成的毛细管的外围结构。生理条件下存在两类作用于血管生成的因子，分别是血管生成抑制因子和促血管生成因子。血管生成抑制因子按照作用的特异性不同可分为两大 类。一类是特异性作用于内皮细胞的血管生成抑制因子，包括血管生成抑制素和内皮细胞生成抑制素等。另一类是非特异性作用于内皮细胞的血管生成抑制因子，包括细胞因子，组织金属蛋白酶抑制剂，丝氨酸蛋白酶抑制剂与抑癌基因产物等。促血管生成因子包括表皮生长因子(EGF)、内皮细胞生长因子(VEGF)、血小板衍生生长因子(PDGF)和成纤维细胞生长因子(FGF)等(Hanks，S.K.，et.al.FASEB，1995，9，576-696)。在不同类型的肿瘤中可见不同促血管生成因子的高表达，如上皮细胞肿瘤中常见EGF的高表达，胶质瘤中常见PDGF的高表达。目前针对肿瘤新生血管路径开发抗癌药物的策略主要是增加血管生成抑制因子和减少促血管生成因子，其中抑制促血管新生因子的高表达特别是作用于VEGF/VEGFR信号通路是当前研究的主流。
VEGF是人体内的一种糖蛋白，在血管的生成过程中发挥重要的作用。人类的VEGF家族包括VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E和PLGF。VEGF能选择性的作用于VEGFR(VEGF受体)，VEGFR是一类酪氨酸激酶跨膜蛋白，VEGF与VEGFR结合后使VEGFR的构象发生改变，并导致受体的二聚化，同时使胞内的酪氨酸位点发生磷酸化并激活下游的转导通路(Joukov，V.，et.al.EMBO J.，1996，15，290-298.)。大量的研究表明，VEGF/VEGFR信号转导通路是细胞内最重要的促血管生成和转移通路，通过抑制此通路可以抑制内皮细胞的生长和转移，从而抑制肿瘤的生长。目前已有多个药物成功上市，同时还有超过三十个在临床研究阶段。比较重要的是重组人源化VEGF单克隆抗体-贝伐单抗(商品名Avastin)，贝伐单抗是第一个成功上市的抗肿瘤血管生成药物，其能够特异性的与VEGF-A结合从而阻断VEGF/VEGFR通路。此药物在上市初期取得了非常大的成功，但随着使用时间的延长，耐药性的问题渐渐显露出来。进一步的研究发现，特异性的抑制VEGF-A的作用会使细胞释放出大量其他的促血管生成因子，如PLGF和FGF等，这种现象被称为血管生成救援反应。为了解决耐药性的问题，发展多靶点的抑制剂是一条可行的策略。
舒尼替尼(sunitinib)就是这类多靶点的抗癌药物。舒尼替尼是辉瑞公司开发的作用于多靶点酪氨酸激酶的抑制剂，它可以有效的抑制VEGFR-1、VEGFR-2、VEGFR-3、PDGFR-β、c-Kit、FLT-3等受体酪氨酸激酶，通过抑制这些蛋白阻断癌变细胞中多种促血管生成因子的表达，达到抑制新生血管生成，“饿死”癌细胞的目的(Abrams，T.J.et.al.Mol.Cancer Ther.，2003，2，1011-1021.)。另外，对存在c-Kit、FLT-3 突变的肿瘤细胞也有特异性的直接抑制作用。舒尼替尼于2006年被FDA批准上市，主要用于胃肠道间质瘤和肾细胞癌的治疗，是首个被同时批准用于两类适应症的抗癌药物。舒尼替尼虽然抗肿瘤药效明显，但在临床使用的患者上仍然表现出乏力、骨髓抑制及发热等副作用，而且其组织蓄积性强，不能连续服用，临床采用连续服用4周后停用两周的方案。而研究发现，肿瘤新生血管形成作用可在停药期间恢复。因此，有必要通过化学结构的改变以降低毒副作用、优化成药性，寻找到更为安全有效的理想药物。
发明内容
本发明的目的是提供一种高效低毒副作用的多靶点受体酪氨酸激酶抑制剂。
本发明的又一目的是提供一类具有抑制肿瘤生长的吡咯取代吲哚酮类衍生物。
本发明的再一目的是提供包含上述吡咯取代吲哚酮类衍生物的药物组合物。
本发明的再一目的是提供上述吡咯取代吲哚酮类衍生物和包含该衍生物的药物组合物的用途。
本发明提供一种具有如下通式(I)所示结构的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐：
Figure PCTCN2015072230-appb-000001
其中：
m选自0、1、2；
n选自1、2、3；
R选自氢、C1-C6直链或支链烷基、C3-C7环烷基、用C1-C6直链或支链烷基取代的甲酰基、C3-C7环烷基甲酰基、叔丁基氧羰基、取代的氨基甲酰基、或者5-7元环状氨基甲酰基。
在上述吡咯取代的吲哚酮类衍生物中，R优选选自氢、C1-C3直链或支链烷基、C4-C6环烷基、用C1-C3直链或支链烷基取代的甲酰基、C3-C6环烷基甲酰基、叔丁基氧羰基、N，N-二甲基甲酰基、N，N-二乙基甲酰基、N，N-二丙基甲酰基、、吡咯烷-1-甲酰基、或者哌啶-1-甲酰基。
在上述吡咯取代的吲哚酮类衍生物中，R更优选选自氢、甲基、叔丁基氧羰基、N，N-二甲基甲酰基、或者吡咯烷-1-甲酰基。
本发明中，所述具有通式(I)所示结构的吡咯取代的吲哚酮类衍生物优选选自下列化合物1-15：
Figure PCTCN2015072230-appb-000002
Figure PCTCN2015072230-appb-000003
Figure PCTCN2015072230-appb-000004
本发明的吡咯取代的吲哚酮类衍生物的药学上可接受的盐不作特别限定，可以为盐酸盐、富马酸盐、马来酸盐、柠檬酸盐、磷酸盐、硫酸盐、酒石酸盐、甲磺酸盐和苯磺酸盐等。在使用盐酸盐时，可以获得高结晶度和高溶解度，并且改善了吸湿性，因此优选使用盐酸盐。
在本发明的第二方面，还提供了一种制备本发明的吡咯取代的吲哚酮类衍生物的方法，所述方法包括以下步骤：
(a)使结构式I所示的3，5-二甲基-2-吡咯甲醛与硝酸钾浓硫酸发生硝化反应生成结构式II所示的化合物：
Figure PCTCN2015072230-appb-000005
具体而言，取结构式I所示的3，5-二甲基-2-吡咯甲醛溶于浓硫酸，降温至零下10℃左右，再加入硝酸钾，保温反应。反应结束后，加入冷水中剧烈搅拌后过滤得到化合物II，重结晶得纯品。
(b)使结构式II所示的3，5-二甲基-4-硝基-2-吡咯甲醛与结构式III所示的5-氟吲哚啉酮在吡咯烷的催化作用下发生缩合反应生成结构式IV所示的化合物：
Figure PCTCN2015072230-appb-000006
具体而言，将结构式II所示的3，5-二甲基-4-硝基-2-吡咯甲醛加入乙醇中，升温到50℃，再加入结构式III所示的5-氟吲哚啉酮，保温反应。反应结束后，过滤得到化合物IV的纯品。
(c)使结构式IV所示的化合物与锌粉发生还原反应生成结构式V所示的化合物：
Figure PCTCN2015072230-appb-000007
具体而言，取结构式IV所示的化合物溶于四氢呋喃，水和甲醇的混合溶液中，升温至50℃，加入饱和氯化铵和锌粉，保温反应。反应结束后，蒸干溶剂用乙酸乙酯，萃取得到化合物V的纯品。
(d)使结构式V所示的化合物与相应的酸VI发生缩合反应生成结构式VII所 示的化合物：
Figure PCTCN2015072230-appb-000008
具体而言，取结构式V所示的化合物溶于四氢呋喃中，于室温下加入碱(DIPEA、DMAP、吡啶等)和缩合剂(EDCI、DCC等)进行保温反应。反应结束后，蒸干溶剂，得到结构式VII所示的化合物粗品，水洗，用溶剂(乙酸乙酯、甲醇等)淋洗，得到纯品化合物VII。
根据本发明，本发明提供包含治疗有效剂量的一种或多种通式(I)的吡咯取代吲哚啉酮类衍生物或其药学上可接受的盐的药物组合物，该组合物可以进一步包括药学上的常规辅料，例如赋形剂、甜味剂等。
本发明的吡咯取代吲哚啉酮类衍生物或其药学上可接受的盐，具有抑制酪氨酸激酶的活性，可用于制备用于治疗酪氨酸激酶表达异常引起的肿瘤的药物。即，本发明的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐可以用于治疗酪氨酸激酶介导的肿瘤及抑制相关肿瘤细胞生长，包括向病人给予治疗有效量的吡咯取代吲哚啉酮类衍生物或其药学上可接受的盐，同时可以用于制备用于治疗酪氨酸激酶介导的肿瘤及抑制相关肿瘤细胞生长的药物。
有益效果
本发明制备的吡咯取代吲哚啉酮衍生物或其药学上可接受的盐对多种酪氨酸激酶具有抑制作用，整体动物试验表明，该类化合物具有抑制肿瘤生长之功效。特别是本发明的吡咯取代吲哚啉酮衍生物或其药学上可接受的盐的毒副作用很低。该类化合物可用于治疗多种肿瘤类疾病。本发明化合物合成简单，易于制备，且合成原料丰富。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但本发明不局限于此。
下述制备例中，1H-NMR用Varian Mercury AMX300，400，500型仪器测定。MS用VG ZAB-HS或VG-7070型以及Esquire 3000plus-01005测定。所有溶剂在使用前均经过重新蒸馏，所使用的无水溶剂均是按标准方法干燥处理获得。除另有说明外，所有反应均是在氩气保护下进行并用TLC跟踪，后处理时均经饱和食盐水洗和无水硫酸镁干燥过程。产品的纯化除另有说明外均使用硅胶的柱色谱法，所使用的硅胶为200-300目，GF254为青岛海洋化工厂或烟台缘博硅胶公司生产。
制备例1：化合物1的制备
Figure PCTCN2015072230-appb-000009
将原料3，5-二甲基-2-吡咯甲醛I(5g，40mmol)溶于60mL浓硫酸中，然后将体系温度降到-10℃，在此温度下分批缓慢加入硝酸钾(4.35g，42mmol)，于2h左右加完。在此过程中温度保持在-10℃，加完后在此温度下继续搅拌2h左右，TLC检测反应完全后，将此溶液加入1L冰水中，并用1L乙酸乙酯分两次萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，过滤后减压蒸干有机溶剂得到7g粗品，将此粗品加入10-20mL乙酸乙酯中，剧烈搅拌后过滤得到目标化合物II纯品5g。
Figure PCTCN2015072230-appb-000010
取化合物II(1.68g，10mmol)和化合物III(1.8g，12mmol)加入50mL无水乙醇中，在室温下加入四氢吡咯(850mg，12mmol)。加完后，体系颜色变黄，升高温度到50℃，并在此温度下继续反应2h。反应结束后直接对体系进行过滤，滤饼用少量乙醇和乙酸乙酯洗涤，得到目标化合物IV纯品2.7g。1H NMR(400MHz，DMSO-d6)δ11.14(s，1H)，7.88(dd，J＝9.2，2.4Hz，1H)，7.82(s，1H)，7.05-6.97(m，1H)，6.88(dd，J＝8.5，4.5Hz，1H)，2.64(s，3H)，2.58(s，3H)。
Figure PCTCN2015072230-appb-000011
取化合物IV(900mg，3mmol)于500mL两口瓶中，然后分别向其中加入200mL四氢呋喃、100mL甲醇、60mL水、60mL饱和氯化铵溶液。加完后升温到50℃，接着在搅拌下加入锌粉(1.8g，30mmol)，加完锌粉后在此条件下继续反应2h，此过程中体系变澄清后又变浑浊。变浑浊后，LC-MS检测反应完全结束。反应完全后，将溶液蒸干，加入饱和碳酸钠溶液将体系调至碱性并用2L乙酸乙酯分两次萃取。乙酸乙酯层用饱和食盐水洗，无水硫酸钠干燥，过滤后减压蒸干有机溶剂得到目标化合物V(800mg)。
Figure PCTCN2015072230-appb-000012
取化合物V(270mg，1mmol)溶于四氢呋喃(20mL)中，于室温下加入Boc保护的4-哌啶甲酸(270mg，1.2mmol)，EDCI(220mg，1.1mmol)，DIPEA(260mg，2mmol)及催化量的DMAP。加完后，于室温继续反应8h左右，TLC检测反应结束。反应结束后，蒸干四氢呋喃溶液，加入大量乙酸乙酯和水分层并过滤得到目标化合物粗品。粗品用甲醇淋洗后得到纯品1。1H NMR(400MHz，DMSO-d6)δ13.59(s，1H)，10.83(s，1H)，9.12(s，1H)，7.71(dd，J＝9.5，2.6Hz，1H)，7.66(s，1H)，6.93-6.86(m，1H)，6.86-6.81(m，1H)，3.99-3.95(m，2H)，3.10-2.94(m，1H)，2.79-2.75(m，2H)，2.17(s，3H)，2.15(s，3H)，1.82-1.78(m，2H)，1.55-1.45(m，2H)，1.41(s，9H)。
制备例2：化合物2的制备
Figure PCTCN2015072230-appb-000013
取化合物1(480mg，1mmol)加入10mL四氢呋喃中，于室温下加入10mL三氟乙酸，接着将温度升到50℃继续反应2h左右，LC-MS检测反应完全。反应结束后，蒸干大部分溶液，余下用饱和碳酸钠溶液中和过滤得到产物粗品。粗品经乙酸乙酯和甲醇淋洗得到纯品2。1H NMR(400MHz，DMSO-d6)δ13.60(s，1H)，10.85(s，1H)，9.26(s，1H)，7.71(dd，J＝9.5，2.4Hz，1H)，7.67(s，1H)，6.94-6.86(m，1H)，6.87-6.83(m，1H)，3.34(d，J＝12.3Hz，2H)，3.06-2.89(m，2H)，2.74-2.59(m，1H)，2.18(s，3H)，2.16(s，3H)，2.05-1.94(m，2H)，1.89-1.74(m，2H)。
制备例3：化合物3的制备
Figure PCTCN2015072230-appb-000014
取化合物2(383mg，1mmol)加入到20mL四氢呋喃中，于室温下加入DIPEA(260mg，2mmol)和二甲胺基甲酰氯(214mg，2mmol)，加完后继续反应12h左右，TLC检测反应几乎完全。反应结束后，蒸干溶剂用20mL乙酸乙酯和10mL甲醇淋洗固体得到目标化合物纯品3。1H NMR(400MHz，DMSO-d6)δ13.58(s，1H)，10.82(s，1H)，9.10(s，1H)，7.70(dd，J＝9.5，2.5Hz，1H)，7.66(s，1H)，6.95-6.86(m，1H)，6.85-6.77(m，1H)，3.87-3.70(m，1H)，3.63-3.54(m，2H)，2.86-2.58(m，8H)，2.18(s，3H)，2.15(s，3H)，1.85-1.76(m，2H)，1.71-1.55(m，2H)。
制备例4：化合物4的制备
Figure PCTCN2015072230-appb-000015
实验操作如方法1的合成，用Boc保护的脯氨酸取代Boc保护的哌啶甲酸得到目标化合物4。1H NMR(400MHz，DMSO)δ13.59(s，0.6H)，13.58(s，0.4H)，10.84(s， 1H)，9.20(s，0.6H)，9.13(s，0.4H)，7.70(dd，J＝9.5，2.5Hz，1H)，7.66(d，J＝3.0Hz，1H)，6.89(dd，J＝12.5，5.5Hz，1H)，6.83(dd，J＝8.4，4.7Hz，1H)，4.38-4.15(m，1H)，3.52-3.41(m，1H)，3.35-3.28(m，1H)，2.35-2.22(m，1H)，2.21(s，2H)，2.18(s，3H)，2.16(s，1H)，1.98-1.79(m，3H)，1.43(s，3H)，1.39(s，6H)(Boc取代基不能自由旋转产生异构)。
制备例5：化合物5的制各
Figure PCTCN2015072230-appb-000016
取化合物2(383mg，1mmol)加入到20mL四氢呋喃和甲醇的混合溶剂中(1∶1)，于室温下加入甲醛水溶液(500mg，5mmol)和氰基硼氢化钠(120mg，2mmol)，加完后继续反应12h，TLC检测反应进程，反应结束后蒸干溶剂，柱层析得到目标化合物5。1H NMR(400MHz，DMSO-d6)δ13.58(s，1H)，10.83(s，1H)，9.05(s，1H)，7.70(dd，J＝9.5，2.4Hz，1H)，7.66(s，1H)，6.93-6.86(m，1H)，6.85-6.80(m，1H)，2.87-2.77(m，2H)，2.36-2.21(m，1H)，2.17(s，3H)，2.16(s，3H)，2.15(s，3H)，1.94-1.59(m，6H)。
制备例6：化合物6的制各
Figure PCTCN2015072230-appb-000017
化合物6的合成方法同2。用4取代1得到目标化合物6。1H NMR(400MHz，DMSO-d6)δ13.60(s，1H)，10.83(s，1H)，9.23(s，1H)，7.71(dd，J＝9.3，2.4Hz，1H)，7.67(s，1H)，6.93-6.87(m，1H)，6.83(dd，J＝8.4，4.6Hz，1H)，3.70(dd，J＝8.7，5.5Hz，1H)，2.91(t，J＝6.6Hz，1H)，2.18(s，2H)，2.16(s，2H)，2.10-1.98(m，1H)，1.85-1.74(m，1H)，1.72-1.63(m，2H)。
制备例7：化合物7的制各
Figure PCTCN2015072230-appb-000018
化合物7的合成方法同1。用Boc保护的2-哌啶甲酸取代Boc保护的4-哌啶甲酸得到目标化合物7。1H NMR(400MHz，DMSO-d6)δ13.60(s，1H)，10.84(s，1H)，9.16(s，1H)，7.71(dd，J＝9.5，2.5Hz，1H)，7.67(s，1H)，6.94-6.87(m，1H)，6.85-6.81(m，1H)，4.79-4.63(m，1H)，3.87-3.75(m，1H)，3.30-3.09(m，1H)，2.19(s，3H)，2.17(s，3H)，1.81-1.59(m，3H)，1.41(s，9H)，1.44-1.22(m，3H)。
制备例8：化合物8的制各
Figure PCTCN2015072230-appb-000019
化合物8的合成方法同3。用4取代2得到目标化合物8。1H NMR(400MHz，DMSO-d6)δ13.59(s，1H)，10.84(s，1H)，8.99(s，2H)，7.74-7.68(m，1H)，7.66(s，1H)，6.93-6.86(m，1H)，6.83(dd，J＝8.4，4.6Hz，1H)，4.39(t，J＝7.4Hz，1H)，3.60-3.44(m，1H)，3.43-3.37(m，1H)，2.80(s，6H)，2.28-2.20(m，1H)，2.16(s，3H)，2.14(s，3H)，1.97-1.88(m，1H)，1.87-1.70(m，2H)。
制备例9：化合物9的制各
Figure PCTCN2015072230-appb-000020
化合物8的合成方法同3。用4取代2得到目标化合物9。1H NMR(400MHz，DMSO-d6)δ13.59(s，1H)，10.83(s，1H)，8.97(s，1H)，7.70(dd，J＝9.6，2.5Hz，1H)，7.66(s，1H)，6.92-6.86(m，1H)，6.84-6.81(m，1H)，3.30-3.25(m，1H)，2.99(d，J＝13.2Hz，1H)，2.60(t，J＝11.3Hz，1H)，2.18(s，2H)，2.16(s，2H)，1.91-1.73(m，2H)，1.56-1.33(m，4H)。
制备例10：化合物10的制备
Figure PCTCN2015072230-appb-000021
化合物8的合成方法同3。用4取代2得到目标化合物10。1H NMR(400MHz，DMSO-d6)δ13.59(s，1H)，10.83(s，1H)，9.20(s，1H)，7.71(dd，J＝9.4，2.5Hz，1H)，7.67(s，1H)，6.89(dd，J＝13.8，6.7Hz，1H)，6.86-6.82(m，1H)，4.13-4.02(m，1H)，3.89(d，J＝13.1Hz，1H)，2.94-2.72(m，2H)，2.48-2.41(m，1H)，2.18(s，3H)，2.16(s，3H)，2.01-1.94(m，1H)，1.73-1.57(m，2H)，1.42(s，9H)，1.39-1.24(m，1H)。
制备例11：化合物11的制备
Figure PCTCN2015072230-appb-000022
取化合物2(383mg，1mmol)加入到20mL四氢呋喃中，于室温下加入DIPEA(260mg，2mmol)和对硝基氯甲酸苯酯(240mg，1.2mmol)，加完后继续反应12h左右，TLC检测反应几乎完全。反应结束后，加入四氢吡咯(142mg，2mmol)和过量的DIPEA(260mg，2mmol)，加完后继续反应12h以上，TLC检测反应。反应结束后蒸干溶剂用20mL乙酸乙酯和10mL甲醇淋洗固体得到目标化合物纯品11。1H NMR(400MHz，DMSO-d6)δ13.58(s，1H)，10.82(s，1H)，9.09(s，1H)，7.70(dd，J＝9.4，2.5Hz，1H)，7.66(s，1H)，6.93-6.86(m，1H)，6.83(dd，J＝8.5，4.6Hz，1H)，3.70(d，J＝13.5Hz，2H)，3.27(t，J＝6.4Hz，4H)，2.73(t，J＝11.6Hz，1H)，2.18(s，3H)，2.15(s，3H)，1.86-1.71(m，6H)，1.67-1.54(m，2H)。
制备例12：化合物12的制备
Figure PCTCN2015072230-appb-000023
化合物12的合成方法同2。用10取代1得到目标化合物12。1H NMR(400MHz，DMSO-d6)δ13.59(s，1H)，10.90(s，1H)，9.17(s，0H)，7.69(dd，J＝9.4，2.4Hz，1H)，7.65(s，1H)，6.94-6.82(m，2H)，3.67-3.52(m，2H)，3.15-2.56(m，3H)，2.45(d，J＝10.0Hz，2H)，2.17(s，3H)，2.15(s，3H)，1.89(d，J＝9.2Hz，1H)，1.61(d，J＝10.4Hz，2H)，1.42(s，1H)。
制备例13：化合物13的制备
Figure PCTCN2015072230-appb-000024
化合物13的合成方法同3。用12取代2得到目标化合物13。1H NMR(400MHz， DMSO-d6)δ13.59(s，1H)，10.83(s，1H)，9.18(s，1H)，7.71(dd，J＝9.4，2.4Hz，1H)，7.66(s，1H)，6.89(dd，J＝9.2，2.4Hz，1H)，6.86-6.80(m，1H)，3.72-3.59(m，1H)，3.51(d，J＝13.2Hz，1H)，2.90-2.81(m，1H)，2.78-2.68(m，7H)，2.64-2.55(m，1H)，2.18(s，3H)，2.15(s，3H)，1.97(d，J＝14.9Hz，1H)，1.73-1.57(m，2H)，1.53-1.38(m，1H)。
制备例14：化合物14的制备
Figure PCTCN2015072230-appb-000025
化合物14的合成方法同11。用12取代2得到目标化合物14。1H NMR(400MHz，DMSO-d6)δ13.59(s，1H)，10.83(s，1H)，9.18(s，1H)，7.71(dd，J＝9.4，2.5Hz，1H)，7.66(s，1H)，6.93-6.86(m，1H)，6.83(dd，J＝8.4，4.8Hz，1H)，3.75(d，J＝12.7Hz，1H)，3.61(d，J＝12.4Hz，1H)，3.28(s，4H)，2.90-2.81(m，1H)，2.73(t，J＝11.4Hz，1H)，2.60-2.50(m，1H)，2.06-1.91(m，1H)，1.76(s，4H)，1.74-1.59(m，2H)，1.55-1.39(m，1H)。
制备例15：化合物15的制备
Figure PCTCN2015072230-appb-000026
此步的合成方法同化合物6的合成，用D型的N-Bn脯氨酸替代L型的N-Bn脯氨酸得到目标化合物。1H NMR(400MHz，DMSO)δ13.60(s，1H)，10.83(s，1H)，9.23(s，1H)，7.71(dd，J＝9.3，2.4Hz，1H)，7.67(s，1H)，6.93-6.87(m，1H)，6.83(dd，J＝8.4，4.6Hz，1H)，3.70(dd，J＝8.7，5.5Hz，1H)，2.91(t，J＝6.6Hz，1H)，2.18(s，2H)，2.16(s，2H)，2.10-1.98(m，1H)，1.85-1.74(m，1H)，1.72-1.63(m，2H)。
制备例16：化合物6盐酸盐的制备
取饱和的乙醇氯化氢溶液0.5mL，将其用无水乙醇稀释十倍后，加入化合物6 (368mg，1mmol)，搅拌5～10分钟后，将反应液减压浓缩，用少量甲醇洗涤可得到化合物6盐酸盐。
所有其它化合物的盐酸盐，均可以用此方法将相应的化合物与稀盐酸乙醇液反应进行制备。
以上吡咯取代的吲哚酮类衍生物的制备例作参考，其它的此类衍生物也可以参照上述方法制得。
另外，申请人通过与上述类似方法或其他本领域的公知方法，合成了以下比较化合物1-3。
Figure PCTCN2015072230-appb-000027
比较化合物1与化合物2相同，区别在于最右侧的哌啶基以N原子与羰基相连
Figure PCTCN2015072230-appb-000028
比较化合物2与化合物6相同，区别在于最右侧的吡咯烷基以N原子与羰基相连。
Figure PCTCN2015072230-appb-000029
比较化合物3与化合物2相同，区别在于最右侧的哌啶基通过亚甲基与羰基相连。
实施例
下面结合具体实施例对本发明作进一步阐述，但这些实施例不应解释为限制本发明。
试验实施例1：KDR酪氨酸激酶体外生化活性测定
采用HTRF(homogeneous time-resolved fluorescence)方法测定化合物对KDR(VEGF受体)酪氨酸激酶体外抑制活性。将激酶缓冲液、受试化合物或舒尼替尼、底物和ATP溶液的混合物加至10μL终体积至384孔板，室温孵育适当时间；每孔加入10μL SA-XL665和TK抗体，室温孵育1h，采用Synergy2读数。
结果显示：在0.1μM、1μM浓度，上述实施例化合物对KDR均具有显著抑制活性。化合物3、6、8、9、11、13等活性与舒尼替尼相当。
表1实施例化合物对KDR的体外抑制活性
  IC50(nM)
2 290
3 78
5 141
6 83
8 66
9 89
11 74
12 142
13 77
14 143
15 65
舒尼替尼 62
Staurosporine 8.14
Staurosporine(星形孢菌素)：阳性对照化合物
试验实施例2：对HUVEC的细胞毒作用及VEGF诱导的HUVEC细胞体外增殖活性测定
VEGF诱导的人脐静脉内皮细胞系(HUVEC)增殖抑制活性检测：将人脐静脉内皮细胞(HUVEC)培养于含10％FBS，18u/mL肝素和30μg/mL ECGS的F-12K中，实验选取4-8代的HUVEC。用胰酶消化细胞，重悬于培液中(1×105/mL)，每孔100μL加于96孔板中，贴壁过夜。更换含5％FBS的F-12K培液，培养24h。加 入受试化合物或舒尼替尼或对照的5％FBS-F-12K培养液，孵育30min。加入终浓度为30ng/mLVEGF165或溶媒(DMSO)的0.1％FBS-F-12K培养液，诱导培养72h。吸去培养液，每孔加入120μL MTS检测液，37℃孵育，读取OD490。以5％FBS-F-12K培养液处理组为阴性对照，从VEGF165刺激组OD值中减去阴性对照组OD值，得到VEGF刺激生长值，计算抑制率，用GraphPad Prism软件制作量效曲线并计算半数效应浓度(EC50)。
细胞毒性检测：上述HUVEC细胞培养于含10％胎牛血清(FBS)、100U/ml青霉素、100μg/mL链霉素、30ug/mL ECGS、18u/mL肝素的F-12K培养基中，胰酶消化处于对数生长期的HUVEC，用含有5％的FBS F-12K完全培养基调整细胞密度至需要的浓度，接种细胞150μL于96孔板中，3000/孔，24小时后加入含有5％FBS完全培养基稀释的4倍浓度受试化合物50μL，以同样体积的DMSO稀释液的作为对照。细胞继续培养72h后每孔加入20μL MTS、1μl PMS。1-2小时后检测OD490，以OD650值作为参考。用GraphPad Prism软件制作量效曲线并计算半数细胞毒性浓度(CC50)。计算受试化合物对人脐静脉内皮细胞(HUVEC)的治疗指数(Therapeutic Index，TI)，TI＝CC50/EC50。
结果显示：上述实施例化合物均可显著抑制VEGF刺激的HUVEC细胞增殖，但活性弱于舒尼替尼。不过，部分化合物(化合物2，3，5，6，8，11，13，14，15)对HUVEC的细胞毒作用显著低于舒尼替尼。化合物2，3，5，6，8，11，14，15的治疗指数(TI)约为舒尼替尼的2-3倍，显示出更大的治疗窗。
在比较化合物1和2中，由于最右侧的含氮杂环基团以杂原子与羰基相连，其治疗指数(TI)与舒尼替尼大致相当，明显低于本发明的化合物。在比较化合物3中，由于最右侧的含氮杂环基团通过亚甲基与羰基相连，其治疗指数(TI)也与舒尼替尼大致相当，明显低于本发明的化合物
表2.部分化合物对HUVEC的细胞毒作用、VEGF诱导的体外增殖活性及治疗指数
化合物 EC50(nM) CC50(nM) TI＝CC50/EC50
2 16.15 ＞20000 ＞1238
3 13.74 ＞20000 ＞1456
5 18.43 ＞20000 ＞1085
6 13.35 17566.77 1316
8 11.35 ＞20000 ＞1762
11 13.93 ＞20000 ＞1436
14 13.04 ＞20000 ＞1534
15 14.21 17732.12 1247
舒尼替尼 7.73 4144.09 536
比较化合物1 13.23 5689.26 430
比较化合物2 12.31 6982.25 567
比较化合物3 14.64 8054.61 550
试验实施例3：抑制人源MV-4-11肿瘤细胞株增殖活性测定
人源急性白血病细胞MV-4-11是Flt-3突变细胞株。采用MTS方法测定化合物对MV-4-11的体外抗增殖活性：胰酶消化处于生长对数期的细胞，计数，取适量细胞重悬于培液中，每孔150μL加于96孔板中，过夜培养后。每孔加入50μL4倍梯度稀释的受试化合物或对照的培养液，培养72h。吸干培养液，每孔加入120μL MTS检测液(100μL新鲜培养基和20μL MTS溶液)，37℃孵育，读取OD490值。采用Graphpad Prism5软件分析处理数据，求得IC50。
结果显示：上述实施例化合物1-15对MV-4-11均显示显著抗增殖活性，部分化合物活性与舒尼替尼相当或更强(见下表)。FLT-3(FMS样酪氨酸激酶3)是一种III型受体酪氨酸激酶，广泛存在于系统、免疫系统和神经系统中。FLT-3基因突变以及过度表达将会导致肿瘤的发生。化合物1-15对MV-4-11特异性的抗增殖活性也提示实施例化合物与舒尼替尼相似，为FLT-3抑制剂。
表3.部分化合物对人源MV-4-11细胞株体外增殖的抑制作用
化合物 IC50(nM) 最大抑制率(％)
2 4.70 92.6
3 10.67 92.1
5 1.68 95.0
6 11.58 92.4
9 5.34 94.3
12 7.87 93.1
13 6.41 90.2
15 12.34 92.5
舒尼替尼 3.94 94.4
试验实施例4：体内对MV-4-11裸鼠移植瘤的抑制作用
MV-4-11细胞体外培养扩增，收取对数生长期的细胞，重悬于无血清EMEM培养液中，用注射器将细胞悬液注入雄性Balb/c裸小鼠前右肢腋窝皮下。定期观察动物及移植瘤生长情况；待瘤体积生长至约100-300mm3左右时，选取肿瘤大小适中的动物随机分组，每组6只。分别给予空白溶媒(0.5％CMC)或上述实施例化合物6或舒尼替尼的混悬液，灌胃给药，剂量为80mg/kg，每天一次，给药周期3周；给药期间，监测瘤径、动物体重，观察动物生活状态；给药3周后结束试验，CO2处死并解剖动物。
肿瘤体积(tumor volume，TV)的计算公式为：TV＝1/2×a×b2，其中，a表示肿瘤长径；b表示肿瘤短径。
结果显示：灌胃21天，溶剂对照组肿瘤增长至起始体积的近6倍，而化合物6治疗组移植肿瘤完全消失，而且化合物6对动物体重没有显著影响。舒尼替尼虽然也显示出明显抗肿瘤效果，大多数动物肿瘤消失，但动物体重显著下降，毒性明显。
表4.化合物6对MV-4-11裸鼠移植瘤的抑制作用
Figure PCTCN2015072230-appb-000030
**：P＜0.01，与溶剂对照比较
从MV-4-11裸鼠移植瘤实验结果中可以发现，本发明中的化合物6对MV-4-11移植瘤具有很好的抑制作用，80mg/kg剂量可使肿瘤完全消失，而对体重的影响较小，舒尼替尼则使动物体重明显下降，毒性明显。结果显示该系列化合物具有与舒尼替尼相当的抗肿瘤效果，但毒性更小，治疗窗更大，具有更好的开发价值。

Claims (10)

  1. 具有如下通式(I)所示结构的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐：
    Figure PCTCN2015072230-appb-100001
    其中：
    m选自0、1、2；
    n选自1、2、3；
    R选自氢、C1-C6直链或支链烷基、C3-C7环烷基、用C1-C6直链或支链烷基取代的甲酰基、C3-C7环烷基甲酰基、叔丁基氧羰基、取代的氨基甲酰基、或者5-7元环状氨基甲酰基。
  2. 如权利要求1所述的吡咯取代的吲哚酮类衍生物，其中R选自氢、C1-C3直链或支链烷基、C4-C6环烷基、用C1-C3直链或支链烷基取代的甲酰基、C3-C6环烷基甲酰基、叔丁基氧羰基、N，N-二甲基甲酰基、N，N-二乙基甲酰基、N，N-二丙基甲酰基、吡咯烷-1-甲酰基、或者哌啶-1-甲酰基。
  3. 如权利要求1所述的吡咯取代的吲哚酮类衍生物，其中R选自氢、甲基、叔丁基氧羰基、N，N-二甲基甲酰基、或者吡咯烷-1-甲酰基。
  4. 如权利要求1所述的吡咯取代的吲哚酮类衍生物，其中所述吡咯取代的吲哚酮类衍生物选自以下化合物1-15：
    Figure PCTCN2015072230-appb-100002
    Figure PCTCN2015072230-appb-100003
    Figure PCTCN2015072230-appb-100004
    Figure PCTCN2015072230-appb-100005
  5. 根据权利要求1～4中任一项所述的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐，其中，所述盐为盐酸盐。
  6. 一种药物组合物，其包含治疗有效剂量的一种或多种根据权利要求1～5中任一项所述的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐；和可选的辅料。
  7. 根据权利要求1～5中任一项所述的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐或根据权利要求6所述的药物组合物在制备酪氨酸激酶抑制剂中的用途。
  8. 根据权利要求1～5中任一项所述的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐或根据权利要求6所述的药物组合物在用于治疗和/或预防哺乳动物中与受体酪氨酸激酶相关疾病的药物中的用途。
  9. 根据权利要求1～5中任一项所述的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐或根据权利要求6所述的药物组合物在用于治疗或辅助治疗和/或预防哺乳动物由受体酪氨酸激酶介导的肿瘤或由受体酪氨酸激酶驱动的肿瘤细胞增殖和迁移的药物中的用途。
  10. 根据权利要求8或9所述的用途，其中，所述哺乳动物为人类。
PCT/CN2015/072230 2014-02-10 2015-02-04 吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途 WO2015117551A1 (zh)

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