WO2016119646A1 - 一种舒尼替尼前药及药物组合物 - Google Patents

一种舒尼替尼前药及药物组合物 Download PDF

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WO2016119646A1
WO2016119646A1 PCT/CN2016/071951 CN2016071951W WO2016119646A1 WO 2016119646 A1 WO2016119646 A1 WO 2016119646A1 CN 2016071951 W CN2016071951 W CN 2016071951W WO 2016119646 A1 WO2016119646 A1 WO 2016119646A1
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compound
ethyl
pyrrole
oxo
fluoro
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PCT/CN2016/071951
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English (en)
French (fr)
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王�忠
李庆
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广州葳澜生物科技有限公司
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Priority to CN201680007128.8A priority Critical patent/CN107849020A/zh
Priority to US15/546,599 priority patent/US20180022734A1/en
Priority to EP16742708.7A priority patent/EP3252048A4/en
Priority to JP2017540761A priority patent/JP2018508495A/ja
Priority to AU2016212555A priority patent/AU2016212555A1/en
Priority to KR1020177024118A priority patent/KR20170106478A/ko
Priority to CA2975315A priority patent/CA2975315A1/en
Publication of WO2016119646A1 publication Critical patent/WO2016119646A1/zh

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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
    • C07D403/02—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 two hetero rings
    • C07D403/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a prodrug compound of sunitinib, a pharmaceutical composition comprising any of the prodrug compounds, and to the use of these compounds.
  • Sunitinib is a multi-target kinase inhibitor that has been approved by the FDA for the treatment of metastatic renal cell carcinoma (MRCC) and gastrointestinal stromal tumors (GIST).
  • MRCC metastatic renal cell carcinoma
  • GIST gastrointestinal stromal tumors
  • the product already on the market is sunitinib malate, which has the following structure:
  • Sunitinib is a multi-kinase inhibitor that blocks vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, stem cell factor receptors (c-Kit), and FMS-like tyrosine kinases. 3 and glial cell line derived neurotrophin receptor (RET).
  • VEGFRs vascular endothelial growth factor receptors
  • c-Kit stem cell factor receptors
  • FMS-like tyrosine kinases 3 and glial cell line derived neurotrophin receptor (RET).
  • Multi-targeted kinase inhibitors can inhibit multiple single or cross-signal pathways simultaneously against cancer cells and tumor microenvironments, thus inhibiting complex multi-molecular lesions that drive tumor growth and survival; It is more likely to have a significant impact on cancers with complex mechanisms, especially solid tumors.
  • sunitinib has failed to work on many other cancers, including liver cancer, in clinical trials.
  • the main cause of failure is treatment-related toxicity.
  • sunitinib is significantly toxic to 50% of patients with kidney cancer.
  • the invention provides a sunitinib prodrug having the structure of Formula I:
  • R 12 and R 13 are selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocyclic group and 5-15 membered heteroaryl;
  • R 14 is selected from R′, OR′, SR′ or N(R′) 2 ;
  • R' is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 A heterocyclic group, a 5-15 membered heteroaryl group, a hydroxyl group, a C 1 -C 6 alkyl group, a carboxy C 1 -C 6 alkyl group, a C 1 -C 6 alkylamido group, and a phosphate group.
  • R 12 , R 13 are H
  • R 14 is selected from the group consisting of N,N-dimethylaminomethyl, tert-butyl, phenyl, p-fluorophenyl, biphenyl, dimethylamine Base, cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclobutyl, pentyl, isopentyl, neopentyl, cyclopentyl, 1-methyl ring Butyl, N-methylamino, N-ethylamino, N,N-methylethylamino, n-hexyl, cyclohexyl, methyl, ethyl, propyl, isopropyl fluorenyl, cyclopropyl fluorenyl , butyl fluorenyl, isobutyl fluorenyl, cyclobutyl de
  • the compound can be formulated in the form of a pharmaceutically acceptable salt or in the form of a pharmaceutically acceptable salt.
  • Desirable pharmaceutically acceptable salt forms include, but are not limited to, mono-, di-, tri-, tetra-, etc. salts.
  • the pharmaceutically acceptable salts are non-toxic in the amounts and concentrations to which they are administered. Without preventing them from exerting physiological effects The preparation of such salts can be facilitated by pharmacological applications by altering the physical properties of the compounds. Physically useful changes include lowering the melting point for transmucosal administration, and increasing solubility for administration of higher concentrations of the drug.
  • the invention provides a pharmaceutically acceptable salt of a compound of Formula I, an acid capable of forming a salt with a compound of Formula I, including but not limited to: a mineral acid such as hydrochloric acid, sulfuric acid; an organic acid such as acetic acid, Trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid; and amino acids such as alanine, aspartic acid, lysine; Sulfonic acid, such as methanesulfonic acid, p-toluenesulfonic acid.
  • a mineral acid such as hydrochloric acid, sulfuric acid
  • an organic acid such as acetic acid, Trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic
  • the invention provides a pharmaceutical composition comprising a compound of Formula I or a salt thereof, the pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
  • the invention provides the use of a compound of Formula I or a salt thereof for the manufacture of a medicament for the treatment of cancer.
  • the cancer is metastatic renal cell carcinoma, gastrointestinal stromal tumor or liver cancer.
  • the compound is N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1-(N,N-dimethylamino)) Methylcarboxymethyl-2,3-dihydroindol-3-ylmethylene)]-2,4-dimethyl-1H-pyrrole-3-carboxamide (Compound A); N-[2- (diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1-(tert-butylcarboxymethyl)-2,3-dihydroindol-3-ylmethylene) ]-2,4-dimethyl-1H-pyrrole-3-carboxamide (Compound 1); or N-[
  • the invention provides a method of treating cancer, the method comprising administering an effective amount of any of the compounds of the invention, or a salt or pharmaceutical composition thereof, to a patient in need thereof.
  • the cancer is metastatic renal cell carcinoma, gastrointestinal stromal tumor, or liver cancer.
  • the invention provides a method of inhibiting tumor cell growth, the method comprising contacting an effective amount of any one of the compounds of the invention, or a salt or pharmaceutical composition thereof, with the tumor cell.
  • the tumor cell is a metastatic renal cell carcinoma cell, a gastrointestinal stromal tumor cell, or a liver cancer cell.
  • the invention provides the use of a compound of the invention or a salt thereof for the manufacture of a medicament for the treatment of cancer.
  • the cancer is metastatic renal cell carcinoma, gastrointestinal stromal tumor, or liver cancer.
  • the invention provides a method of reducing the toxicity of sunitinib, the method comprising administering an effective amount of any of the compounds of the invention, or a salt or pharmaceutical composition thereof, to a patient in need thereof.
  • the cancer is metastatic renal cell carcinoma, gastrointestinal stromal tumor, or liver cancer.
  • the terms “therapeutically effective” and “effective amount” mean that the amount of the substance and substance is one or more symptoms that prevent, alleviate or ameliorate the disease or condition, and/or prolong the subject being treated. Survival is effective.
  • an effective amount of each compound is determined by standard procedures can be administered, for example, the considerations compound IC 50, the biological half life of the compound, the age, size and weight of the object-related disorders. The importance of these and other factors is well known to those of ordinary skill in the art. In general, the dosage will be between about 0.01 mg/kg to 50 mg/kg, preferably between 0.1 mg/kg and 20 mg/kg, of the subject being treated. Multiple doses can be used.
  • the compounds of the invention may also be used in combination with other therapeutic agents that treat the same disease. Such combined use includes administering the compound and one or more additional therapeutic agents at different times, or simultaneously using the compound and one or more additional therapeutic agents.
  • the dosage of one or more compounds of the invention or other therapeutic agents used in combination may be modified, for example, by methods known to those skilled in the art to reduce the relative to the compound or therapeutic agent used alone. dose.
  • the combined use includes use with other therapies, drugs, medical procedures, and the like, wherein the other therapies or procedures can be at a different time than the compounds of the present invention (eg, in a short period of time (eg, several hours, such as 1 , 2, 3, 4-24 hours) or for a longer period of time (eg 1-2 days, 2-4 days, 4-7 days, 1-4 weeks) or at the same time as the compound of the invention
  • Combination use also includes administration with a treatment or medical procedure (such as surgery) that is administered once or infrequently, with administration of a compound of the invention for a short or longer period of time before or after the other therapy or procedure.
  • the invention is used to deliver a compound of the invention and one or more other pharmaceutical therapeutics that are delivered by the same or different routes of administration.
  • Combination administration of any route of administration includes the administration of the same route of administration
  • the compound of the invention and one or more other pharmaceutical therapeutic agents are delivered together in any formulation, including formulations in which the two compounds are chemically linked and which maintain their respective therapeutic activity upon administration.
  • the compound Other drug therapies may be co-administered with one or more compounds of the invention.
  • Combinations involving co-administration include administration of a co-formulation or a chemically linked compound, or in a short period of time (eg, within one hour, within 2 hours) Compounds in the form of two or more separate formulations, administered within 3 hours, up to 24 hours, are administered in the same or different routes.
  • Co-administration of separate formulations includes co-administration via delivery via a device, such as the same inhalation Devices, identical syringes, etc., or administered by different devices in a short period of time relative to each other.
  • Co-formulation of a compound of the invention and one or more additional drug therapies delivered by the same route of administration includes preparing the materials together such that they pass one
  • the device is administered, including combinations of different compounds in one formulation, or the compounds are modified such that they are chemically linked together but still retain their respective biological activities.
  • Such chemically linked compounds may include two active ingredients. Separate linker that is substantially maintained in the body or may degrade in vivo .
  • the compounds of the invention are selected from the group consisting of
  • the invention further provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprising a compound of formula I in a weight ratio of from 0.1 to 99.9%, in a composition, a pharmaceutically acceptable carrier in the composition The weight ratio is from 0.1 to 99.9%.
  • the pharmaceutical compositions are in the form of a pharmaceutically acceptable preparation. Medicinal preparations are tablets, capsules, granules, pills, powders, ointments, suspensions, injections, powders, suppositories, creams, drops, or patches.
  • the tablet is a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet or a sustained-release tablet;
  • the capsule is a hard capsule, a soft capsule, a sustained release capsule;
  • the powder injection is Freeze-dried powder injection.
  • each dose means each preparation unit, such as each tablet of a tablet, each capsule It can also mean taking each dose, such as taking 100mg each time.
  • the pharmaceutical composition of the present invention can be used in the preparation of solid or semisolid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories and ointments.
  • the solid carrier which can be used is preferably one or more selected from the group consisting of a diluent, a flavoring agent, a solubilizing agent, a lubricant, a suspending agent, a binder, a swelling agent and the like, or may be an encapsulating substance.
  • 5 to 70% of the micronized active ingredient is contained in the carrier.
  • Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low boiling waxes, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets, and capsules represent the most advantageous oral solid preparations.
  • Liquid preparations of the invention include solutions, suspensions and emulsions.
  • an injection preparation for parenteral administration may be in the form of water or a water-propylene glycol solution, adjusting its isotonicity, pH, etc. to suit physiological conditions of a living body.
  • Liquid preparations can also be prepared in the form of solutions in polyethylene glycol, aqueous solutions.
  • An oral aqueous solution can be prepared by dissolving the active ingredient in water, followed by the addition of a suitable amount of coloring, flavoring, stabilizing and thickening agents.
  • the micronized active ingredient can be dispersed in viscous materials such as natural and synthetic gums, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents to prepare aqueous suspensions suitable for oral administration.
  • Dosage unit form of the formulation refers to physically discrete units suitable as a single dose, each unit containing a calculated predetermined amount of active ingredient that produces the desired therapeutic effect.
  • Such dosage unit forms can be in the form of a package such as a tablet, a capsule or a powder in a vial or vial, or an ointment or gel contained in a tube or vial. Or cream.
  • the amount of active ingredient contained in the dosage unit form may vary, it will generally be in the range of from 1 to 800 mg, depending on the potency of the active ingredient selected.
  • the dosage administered may vary depending on the needs of the patient, the severity of the condition to be treated, the selected compound, and the like.
  • the preferred dosage for a particular situation can be determined in a conventional manner. Generally, the amount of treatment initiated is lower than the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved. For therapeutic purposes, the total daily dose can be administered in a single dose or in divided doses.
  • Figure 1 is a pharmacokinetic study of intravenous administration of sunitinib and compound A in mice.
  • Figure 2 is a graph showing the time of intravenous administration of sunitinib and Compounds 1, 2 in mice, wherein (a) heart; (b) liver; (c) spleen; (d) lung; (e) kidney; (f) Plasma.
  • Figure 3 is a graph showing the time of administration of sunitinib and compounds 1, 2 by intragastric administration of mice, wherein (a) the heart; (b) plasma.
  • Figure 4 is a comparison of the effects of sunitinib and compound 1, 2 on pSTAT3 dephosphorylation.
  • Figure 5 is an experiment of sunitinib and compound 1, 2 against cytotoxicity of different cell lines, wherein (a) A549; (b) NCI-H460; (c) 786-O; (d) Caki-1; ) HT-29; (f) MCF-7.
  • Figure 6 is a graph showing acute toxicity test of oral administration of Compound 2 and sunitinib in mice, wherein (a) 28 mg/kg; (b) 70 mg/kg; (c) 175 mg/kg; (d) 50 mg/kg (e) 100 mg/kg; (f) 200 mg/kg.
  • Figure 7 is a control panel showing the average tumor size after subcutaneous injection of Compound 1, 2 and sunitinib in mouse xenograft cancer cells, wherein (a) 1.5 mg/kg; (b) 7.5 mg/kg; (c) 30 mg/kg.
  • Figure 8 is a control plot of mean tumor size after oral administration of Compound 1, 2 and sunitinib in mouse xenografted cancer cells, wherein (a) 5 mg/kg; (b) 15 mg/kg; (c) 45 mg /kg.
  • Figure 9 shows the effect of compound 1 or 2 on cell morphology and survival, wherein (a) sunitinib, compound Effects of Compound 1 and Compound 2 on cell morphology; (b) Effects of sunitinib, Compound 1 and Compound 2 on cell viability after co-culture with 786-O cells or A549 cells at different concentrations for 8 hours; The effect of compound A sunitinib, compound 1 and compound 2 on cell viability after co-culture with A549 cells for 8 hours at different concentrations; (d) sunitinib, compound 1 and compound 2 at different concentrations The effect of HUVEC cells on cell viability after 8 hours of co-culture.
  • Figure 10 shows the effects of sunitinib and compound 2 on key biochemical indicators, in which (a) sunitinib significantly increased aspartate aminotransferase (AST), alanine aminotransferase (ALT) and cholinesterase (CHE) (b) Sunitinib raises blood uric acid and blood urea nitrogen levels, but lowers blood glucose; (c) sunitinib and compound 2 against lactate dehydrogenase (LDH), creatine kinase (CK), creatine The effect of the kinase-MB (CKMB) indicator.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • CHE cholinesterase
  • Figure 11 shows the effect of the compound of the present invention on the survival rate of the A549 human non-small cell lung cancer cell line in the short term (8 h), wherein (a) to (h) represent the compound 6 to the compound 13, respectively.
  • Figure 12 is a graph showing the effect of the compound of the present invention on the survival rate of the A549 human non-small cell lung cancer cell line after short-term (8h) treatment, and the recovery of the compound after 24 hours of recovery, wherein (a) to (h) respectively represent the compound 6 To compound 13.
  • Figure 13 shows the effect of the compound of the present invention on the survival rate of the A549 human non-small cell lung cancer cell line after long-term 72 h treatment, wherein (a) to (h) represent Compound 6 to Compound 13, respectively.
  • Prodrug refers to a compound that is inactive or has low activity in the body after chemical structural modification. It releases pharmacological action by enzymatic or non-enzymatic action in the body.
  • prodrugs use "lipophilic”, “hydrophilic”, “active transport” and “dual drug” strategies to modify the drug.
  • the purpose of preparing the prodrug is to improve the bioavailability of the drug and increase the stability of the drug. Reduce toxic side effects, promote long-acting drugs, mask discomfort and so on.
  • the most successful prodrugs, such as Fusha are the "hydrophilic" drugs of the phosphate ester precursor of amprenavir. It is now widely used in the treatment of AIDS.
  • sunitinib On the basis of sunitinib, in order to make sunitinib have better characteristics, the structure of sunitinib is modified, and various prostitute design principles are used to design a variety of former sunitinib.
  • the drug has unexpectedly found that the concentration of the compound of the present invention in the liver is much higher than that of sunitinib, which is more damaging to liver cancer, and the compound of the present invention can reduce systemic toxicity, particularly cardiotoxicity, and reduce adverse reactions.
  • sunitinib as the parent compound for the preparation of prodrugs, but the use of which substituents, the effect of how to become a problem, it is known that thousands of substituents for prodrugs, from which to select suitable and suitable substitution Base and its difficulties.
  • the present invention provides a sunitinib prodrug having the structural formula shown in Formula I:
  • R 12 and R 13 are selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocyclic group and 5-15 membered heteroaryl;
  • R 14 is selected from R′, OR′, SR′ or N(R′) 2 ;
  • R' is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 A heterocyclic group, a 5-15 membered heteroaryl group, a hydroxy C 1 -C 6 alkyl group, a carboxy C 1 -C 6 alkyl group, a C 1 -C 6 alkylamido group, and a phosphate group.
  • R 12 , R 13 are H
  • R 14 is selected from the group consisting of N,N-dimethylaminomethyl, tert-butyl, phenyl, p-fluorophenyl, biphenyl, dimethylamine Base, cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclobutyl, pentyl, isopentyl, neopentyl, cyclopentyl, 1-methyl ring Butyl, N-methylamino, N-ethylamino, N,N-methylethylamino, n-hexyl, cyclohexyl, methyl, ethyl, propyl, isopropyl decyl, cyclopropyl Base, butyl fluorenyl, isobutyl fluorenyl, cyclobutyl decyl, meth
  • R 12 and R 13 are both H and R 14 is t-butyl, phenyl or t-butoxy.
  • Compound A Six mice in each group were sacrificed at 0.083h, 0.25h, 0.5h, 1h, 3h, 8h after drug injection in the tail vein, and the mice were sacrificed by cervical dislocation and the whole tissue was perfused with physiological saline. The liver and kidney tissues were washed with physiological saline and dried with a filter paper; the plasma was centrifuged to obtain a supernatant; the sample was stored frozen at -20 ° C for storage.
  • Relative uptake rate (RE)RE (AUCi sample/(AUCi) control
  • AUCi the area under the drug-time curve of the i-th organ or tissue obtained from the concentration-time curve; an RE greater than 1 indicates that the drug preparation is targeted in the organ or tissue, and the greater the RE, the better the targeting effect; Less than 1 means no targeting;
  • the AUC organization represents the area under the curve of a tissue for a moment.
  • the comprehensive targeting efficiency refers to the ratio of the ratio of the tissue dose of the experimental group to the total amount of the drug in the experimental group compared with the ratio of the control group.
  • the RTE value indicates the experimental group drug pair.
  • the tissue has a targeting enhancement effect. The larger the positive, the larger the targeting enhancement factor, the stronger the targeting enhancement effect, and the negative RTE is vice versa. If it is 0, it means no effect on the tissue.
  • the pharmacokinetic parameters of the experiment were calculated by Winnonlin, since the pharmacokinetics of mice were composed of multiple animals. Cheng, therefore, is to calculate the mean value of the drug time curve and then enter the software calculation parameters.
  • the clearance rate of Compound A (sample A) in the heart, liver, spleen, lung and kidney is sunitinib, respectively, from the clearance rate of the two drug groups.
  • S, Sunitinib) 7, 3, 5, 5, 4, 4 times of the drug-administered group that is, the clearance rate of each organ is significantly increased, and the fold increase in the liver is the smallest, so it is possible that compound A ( Sample A)
  • the special product of metabolism induces CPY metabolic enzymes, or affects other clearance pathways, resulting in greater clearance of sunitinib, which affects the exposure value of sunitinib in the drug A (sample A)-administered group. The reduction.
  • Compound A is a prodrug that metabolizes to sunitinib during the process of reaching the blood. It may be that the specific structure of drug A itself guides its targeted distribution, so even if metabolism is faster, Its proportion in the liver is still increasing.
  • the RTE of the kidney is close to 0, the RTE of plasma and other organs are less than 1, and only the RTE of the liver (0.48) is significantly greater than 0, indicating that the compound A (sample A) is administered with sunitinib.
  • the distribution of distribution in other organs decreased, while the proportion of distribution in the liver increased, that is, Compound A (sample A) promoted the liver distribution of sunitinib.
  • Compound A does not increase the absolute exposure of sunitinib in various organs and tissues, but it can increase the distribution of sunitinib in the liver, improve the targeting, and reduce the distribution of other organs. Assuming that Compound A (sample A) is not toxic and that other metabolites are not toxic, Compound A (sample A) can reduce the toxic effects of the drug in other non-targeted organs than Sunitinib.
  • Example 14 Comparative Example 1 of Compound 1, Compound 2 and Sunitinib
  • Plasma sample processing method 50 ⁇ l plasma sample ⁇ l and each 50 ⁇ L The internal standard (clozapine) working solution was vortexed with 300 ⁇ L of methanol, centrifuged, 150 ⁇ L of the upper organic phase was taken, and 150 ⁇ L of water was vortexed and mixed, and 10 ⁇ L of the supernatant was centrifuged for analysis.
  • Tissue sample processing method The tissue sample was weighed, 10 times by weight of pure water was added, and uniformly mixed.
  • the half-life of the sunitinib control is the longest (1.24h), while the half-lives of the compounds 1 and 2 are relatively close, within 1h, that is, compound 1 and 2 Scunitinib was cleared faster; from Cmax, compounds 1 and 2 were larger than sunitinib, which was about five times that of the control group, while AUC was similar, indicating the time of compounds 1 and 2.
  • the curve is steep and the sunitinib is relatively flat; the apparent volume of distribution is in the range of 350-500 mL, indicating a significant distribution in the tissue.
  • Compound 1 increased the proportion of distribution in liver and spleen; Compound 2 increased the proportion of distribution in spleen and lung; the distribution of heart and kidney decreased.
  • the proportion of distribution in plasma is greatly increased.
  • sunitinib itself was administered orally in patients, we conducted a pharmacokinetic study of sunitinib with Compounds 1 and 2 for oral administration.
  • Sunitinib, Compound 1 and Compound 2 were dissolved in a malic acid solution to adjust the pH to around 7.
  • Sunitinib malic acid is dissolved in pure water.
  • Kg compound 2 Kg compound 2.
  • mice in each group were divided into 8 groups, respectively, 0.25h, 0.5h, 1h, 1.5h, 2h, 4h, 6h, 10h after intragastric administration, blood was taken from the eyeball and the cervical spine was sacrificed. Rats were perfused with normal saline, and liver and kidney tissues were taken. The surface was washed with physiological saline and dried with filter paper. The plasma was centrifuged to obtain the supernatant; the sample was stored at -20 °C. save.
  • Table 3 The experimental results are shown in Figure 3 and the following table:
  • the results of the intragastric administration showed a large difference between the animals, and the difference between the animals administered intravenously was small, which may be due to the difference in the process of gastrointestinal absorption.
  • the AUC of Compound 1 and Compound 2 was about 3.5 times higher than that of the sunitinib control group, and the C max was much higher than that of the control group, indicating that the degree of absorption of Compound 1 and Compound 2 after the transformation was better than that of sunitinib.
  • compound 1 and compound 2 are in the vicinity of 50%, respectively, and have higher bioavailability, while the sunitinib group is only 15%; from the apparent distribution In terms of volume, the sunitinib control group had a higher apparent volume of distribution, indicating that the control group had more tissue accumulation after intragastric administration and the accumulation ratio of Compound 1 and Compound 2 in the heart was decreased.
  • the human hepatoma cell line of PLC/PRF-5 and the hepatocarcinoma cell line of Hepa 1-6 were obtained from the Shanghai Institute of Bioscience and Biochemistry (SIBCB).
  • Cell lines A549, Caki-1, HT-29, MDA-MB-231, MCF-7, PLC/PRF-5 and Hepa1-6 were cultured in DMEM medium (Gibco, Life Technologies, China), while cell line NCI -H460,786-O in RPMI-1640 medium (Gibco, Life Technologies, China). 10% HI fetal bovine serum (Gibco, Life Technologies, USA) and 1% penicillin/streptomycin (Hyclone the company).
  • CCK8 reagent Dojindo
  • Sunitinib is an RTK inhibitor that inhibits multiple signaling pathways, such as RAS/RAF/MAPK, so we analyzed some of the major downstream proteins, including MEK, ERK and STAT3. For pSTAT3, sunitinib and prodrug compound 2, at a concentration of 10 ⁇ M, showed a strong inhibitory effect on the A549 cell line (Fig. 4). These results indicate that the prodrug compound and sunitinib have the same anti-tumor mechanism.
  • human umbilical vein endothelial cells were used to test the cytotoxicity of compounds 1 and 2. With 786-O and A549 Similar to the cells observed, less than 50% of HUVEC survived after 8 hours of treatment with Compound 1 or 2 (Fig. 9d).
  • Acute Toxicity Test Maximum Tolerated Dose (MTD) Determination
  • mice 4 to 5 weeks old were used for this experiment.
  • the average weight of the mice was greater than 17 g, and the animals were orally administered with 3 doses (28 mg/kg, 70 mg/kg, 175 mg/kg) once daily.
  • the duration of this test is 14 days. The weight and condition of all mice were recorded.
  • mice performed extremely weakly throughout the test, while in the same dose group of Compound 2, the performance of the mice was similar to that of the negative control group. Therefore, acute toxicity tests indicate that Compound 2 is better tolerated in mice.
  • AST Aspartate aminotransferase
  • ALT alanine aminotransferase
  • CHE cholinesterase
  • A549 human non-small cell lung cancer cell lines were cultured in DMEM medium (Gibco, Life Technologies, China), 0% HI fetal bovine serum (Gibco, Life Technologies, USA) and 1% penicillin/ Streptomycin (Hyclone).
  • the compound recovers for 24 hours and kills cells.
  • A549 human non-small cell lung cancer cell line in DMEM medium (Gibco, Life Technologies, China), 10% HI fetal bovine serum (Gibco, Life Technologies, USA) and 1% penicillin/ Streptomycin (Hyclone).
  • A549 human non-small cell lung cancer cell line in DMEM medium (Gibco, Life Technologies, China), 10% HI fetal bovine serum (Gibco, Life Technologies, USA) and 1% penicillin/ Streptomycin (Hyclone).
  • the sunitinib prodrug provided by the present invention has better pharmacokinetics and pharmacodynamics: pharmacokinetic studies after intravenous injection of mice indicate that the compound The Cmax of both 1 and 2 was much larger than that of sunitinib, but the AUC was not much different from each other; the pharmacokinetic study after intragastric administration of mice showed that the Cmax and AUC of compounds 1 and 2 were much larger than that of sulphonate.
  • the sunitinib prodrugs provided by the present invention have better safety: the ratio of relative drug distribution in the liver, Compound 2 shows a relatively higher distribution than sunitinib.
  • Compound 2 showed a relatively low distribution compared to sunitinib.
  • the three prodrug compounds have relatively low drug concentrations in the heart, demonstrating that the sunitinib prodrugs provided by the present invention are effective in reducing systemic toxicity, particularly cardiotoxicity. It has better safety and sustained drug concentration; (3)
  • the sunitinib prodrug provided by the present invention has better curative effect: research using mouse xenograft model shows that sunitinib prodrug and sunitone Compared with Ni, there is a better effect.
  • the sunitinib prodrug provided by the present invention has a relatively high distribution in the liver compared with sunitinib, and has a relatively low distribution in the heart; and the sunitinib prodrug has a better than sunitinib Better treatment of tumors. Therefore, the sunitinib prodrug provided by the present invention has better pharmacological effects in the treatment of cancer, but at the same time has lower toxic side effects, and the compound of the present invention can be used for the failure of sunitinib in clinical trials.
  • the liver cancer disease can be used as a lead compound for the development of anti-tumor drugs with both effectiveness and low toxicity, and has good application development prospects.

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Abstract

本发明提供一种舒尼替尼前药，其具有式I所示的结构式，其中，R12、R13选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环基和5-15元杂芳基；R14选自R'、OR'、SR'或N(R')2；并且R'选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环基、5-15元杂芳基、羟基C1-C6烷基、羧基C1-C6烷基、C1-C6烷基酰胺基和磷酸基。本发明提供的舒尼替尼前药具有更好的药代动力学和药效学、更好的安全性和更低的毒性。

Description

一种舒尼替尼前药及药物组合物
相关申请的交叉引用
本申请要求2015年1月28日提交的中国专利申请201510045099.1号、名称为“一种舒尼替尼前药”、申请人为“广州艾衡昊医药科技有限公司”的专利申请的优先权，其全部内容通过引用合并至本文中。
技术领域
本发明涉及一种舒尼替尼的前药化合物、包含任何一种前药化合物的药物组合物，并且涉及这些化合物的用途。
背景技术
舒尼替尼(Sunitinib)是一种治疗转移性肾细胞癌(MRCC)和胃肠道间质瘤(GIST)，已被FDA批准了的多靶点激酶抑制剂。已经上市的产品为苹果酸舒尼替尼，结构如下：
Figure PCTCN2016071951-appb-000001
舒尼替尼是一种多激酶抑制剂，阻止血管内皮生长因子受体(VEGFRs)，血小板衍生的生长因子受体，干细胞因子受体(的c-Kit)，FMS-样酪氨酸激酶-3和神经胶质细胞系衍生神经营养因子受体(RET)。多靶点激酶抑制剂可以同时针对癌细胞及肿瘤微环境，抑制多个单独或交叉信号通路，因此，可针对驱动肿瘤生长和存活的复杂的多分子病变起抑制作用；与单个靶向剂相比，更可能对有复杂机制的癌症起显著影响，特别是实体肿瘤。
然而，舒尼替尼临床试验中未能对许多其它癌症(包括肝癌)起到作用。失败的主要原因是治疗相关的毒性。例如，舒尼替尼对肾癌患者的50％有显著毒性。
发明内容
在一些实施方式中，本发明提供一种舒尼替尼前药，其具有式I所示的结构：
式(I)
其中，
R12、R13选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环基和5-15元杂芳基；
R14选自R’、OR’、SR’或N(R’)2；并且
R’选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环基、5-15元杂芳基、羟基,C1-C6烷基、羧基C1-C6烷基、C1-C6烷基酰胺基和磷酸基。
在一些实施方式中，R12、R13为H，R14选自N,N-二甲基氨基甲基、叔丁基、苯基、对氟苯基、联二苯基、二甲基胺基、环丙基、甲基、乙基、丙基、异丙基、丁基、异丁基、环丁基、戊基、异戊基、新戊基、环戊基、1-甲基环丁基、N-甲基氨基、N-乙基氨基、N,N-甲基乙基胺基、正己基、环己基、甲巯基、乙巯基、丙巯基、异丙基巯基、环丙基巯基、丁基巯基、异丁基巯基、环丁基巯基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、环丁氧基、戊胺基、戊巯基、戊氧基、异戊胺基、新戊胺基、叔丁基胺基、环戊胺基、环戊巯基、环戊氧基、环己基胺基、环己基巯基、环己基氧基、对甲氧基苯基、对氯苯基和邻氟苯基。
化合物可以被配制为药学上可接受盐的形式或者为药学上可接受盐的形式。预期的药学上可接受的盐形式包括，但不限于，单、双、三、四等盐。药学上可接受盐在它们被施用的量和浓度下是无毒的。在不阻止其发挥生理效应的情况 下，通过改变化合物的物理特性，这样的盐的制备可以便于药理学应用。在物理性质上有用的改变包括降低熔点以便经粘膜给药，以及增加溶解度以便施用更高浓度的药物。
在一些实施方式中，本发明提供式I的化合物的药学上可接受的盐，能够与式I的化合物形成盐的酸包括但不限于：无机酸，如盐酸、硫酸；有机酸，如乙酸、三氟乙酸、柠檬酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸；以及氨基酸，如丙氨酸、天冬氨酸、赖氨酸；磺酸，如甲磺酸、对甲苯磺酸。
在一些实施方式中，本发明提供包含式I的化合物或其盐的药物组合物，所述药物组合物还包含药学上可接受的载体。
在一些实施方式中，本发明提供式I的化合物或其盐在制备治疗癌症的药物中的用途。在一个实施方式中，所述癌症为转移性肾细胞癌、胃肠道间质瘤或肝癌。在一个实施方式中，所述化合物为N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N,N-二甲基氨基)甲基羧甲基-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物A)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(叔丁基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物1)；或N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(苯基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物2)N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(1-甲基环丁基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物3)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N-甲基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物4)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N-乙基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物5)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N,N-二甲基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物6)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(叔丁氧基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物7)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(乙氧基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物8)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(环己基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3- 甲酰胺(化合物9)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(甲基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物10)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(环丙基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物11)；N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(异丙基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物12)；或N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(对甲氧基苯基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物13)。
在一些实施方式中，本发明提供一种治疗癌症的方法，所述方法包括将有效量的本发明的任一化合物或其盐或药物组合物施用至有此需要的患者。在一些实施方式中，所述癌症为转移性肾细胞癌、胃肠道间质瘤或肝癌。
在一些实施方式中，本发明提供一种抑制肿瘤细胞生长的方法，所述方法包括将有效量的本发明的任一化合物或其盐或药物组合物与所述肿瘤细胞接触。在一些实施方式中，所述肿瘤细胞为转移性肾细胞癌细胞、胃肠道间质瘤细胞或肝癌细胞。
在一些实施方式中，本发明提供一种任何一种本发明的化合物或其盐在制备治疗癌症药物中的应用。在一些实施方式中，所述癌症为转移性肾细胞癌、胃肠道间质瘤或肝癌。
在一些实施方式中，本发明提供一种降低舒尼替尼的毒性的方法，所述方法包括将有效量的本发明的任一化合物或其盐或药物组合物施用至有此需要的患者。在一些实施方式中，所述癌症为转移性肾细胞癌、胃肠道间质瘤或肝癌。
在本文中，术语“治疗上有效的”和“有效量”表示所述物质和物质的量对于预防、减轻或改善疾病或病症的一种或多种症状，和/或延长接受治疗的对象的存活是有效的。
通过标准程序可以确定待施用的各种化合物的有效量，考虑的因素例如所述化合物IC50、所述化合物的生物半衰期、对象的年龄、大小和体重以及与对象有关的病症。这些因素和其它因素的重要性对本领域普通技术人员而言是熟知的。一般而言，剂量将在被治疗的对象的大约0.01mg/kg至50mg/kg之间，优选在0.lmg/kg至20mg/kg之间。可以使用多次剂量。
本发明的化合物还可以与治疗相同疾病的其他治疗剂结合使用。这种结合使用包括在不同时间施用这些化合物以及一种或多种其他治疗剂，或同时使用这种化合物和一种或多种其他治疗剂。在一些实施方式中，可对本发明的一种或多种化合物或结合使用的其他治疗剂的剂量进行修改，例如，通过本领域技术人员已知的方法降低相对于单独使用的化合物或治疗剂的剂量。
要理解的是，结合使用包括与其他疗法、药物、医学程序等一起使用，其中该其他疗法或程序可在不同于本发明的化合物的时间(例如，在短期内(如几个小时，如1、2、3、4-24小时)或在较长时间内(如1-2天、2-4天、4-7天、1-4周)或在与本发明的化合物相同的时间被施用。结合使用还包括与一次或不频繁施用的疗法或医学程序(如手术)一起使用，并伴随本发明的化合物在该其他疗法或程序之前或之后的短期或较长时间段内的施用。在一些实施方式中，本发明用于递送本发明的化合物和一种或多种其他药物治疗剂，它们通过相同或不同给药途径递送。任何给药途径的结合施用包括通过相同给药途径将本发明的化合物和一种或多种其他药物治疗剂以任何制剂形式一起递送，包括两种化合物化学地相连且它们在施用时保持各自治疗活性的制剂。在一个方面，该其他药物疗法可与本发明的一种或多种化合物共同施用。通过共同施用的结合使用包括施用共制剂或化学上连接的化合物的制剂，或在短期内(例如，一个小时内、2小时内、3小时内、直至24小时内)施用两种或多种独立制剂形式的化合物，它们以相同或不同的途径给药。独立制剂的共同施用包括经由一个装置的递送的共同施用，例如相同吸入装置、相同注射器等，或相对彼此短期内由不同装置施用。通过相同给药途径递送的本发明的化合物和一种或多种额外的药物疗法的共制剂包括将材料一起制备从而它们可通过一个装置被施用，包括不同化合物组合在一种制剂中，或化合物被修饰从而使得它们在化学上连接在一起但仍保持各自的生物学活性。这种化学上连接的化合物可包括将两个活性成分分开的连接体，该连接体在体内基本维持，或在体内可能降解。
在一些实施方式中，本发明的化合物选自：
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N,N-二甲基氨基)甲基羧甲基-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物A)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(叔丁基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物1)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(苯基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物2)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(1-甲基环丁基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物3)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N-甲基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物4)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N-乙基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物5)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N,N-二甲基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物6)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(叔丁氧基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物7)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(乙氧基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物8)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(环己基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物9)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(甲基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物10)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(环丙基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物11)；
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(异丙基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物12)；和
N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(对甲氧基苯基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物13)。
药物组合物
本发明还提供含有式I化合物或其药用盐的药物组合物，所述药物组合物含有的式I化合物在组合物中的重量比为0.1～99.9％，药物可接受的载体在组合物中的重量比为0.1～99.9％。药物组合物以适合药用的制剂形式存在。药用的制剂为片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、粉针剂、栓剂、霜剂、滴剂或贴剂。其中，所述片剂为糖衣片剂、薄膜衣片剂、肠溶衣片剂或缓释片剂；所述胶囊剂为硬胶囊剂、软胶囊剂、缓释胶囊剂；所述粉针剂为冻干粉针剂。
本发明的药物组合物，作为制剂形式，每剂中含有的发明化合物的有效量为0.1～1000mg，所述每剂指的是，每一制剂单位，如片剂的每片，胶囊的每粒，也可指每次服用剂量，如每次服用100mg。
本发明的药物组合物在制备成粉剂、片剂、可分散粉剂、胶囊、扁囊剂、栓剂和软膏形式的固体或半固体药物制剂时，可使用固体载体。可使用的固体载体优选为选自稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、膨胀剂等中的一种或多种物质，或可为包封物质。在粉状制剂中，在载体中含有5～70％的微粒化活性成分。适宜的固体载体包括碳酸镁、硬脂酸镁、滑石粉、蔗糖、乳糖、果胶、糊精、淀粉、明胶、甲基纤维素、羧甲基纤维素钠、低沸点蜡、可可脂等。由于它们易于给药，片剂，粉剂、扁囊剂和胶囊等代表最有利的口服固体制剂。
本发明的液体制剂包括溶液、悬液和乳液。例如，非胃肠道给药的注射制剂可为水或水-丙二醇溶液形式，调节其等渗度，pH等使适于活体的生理条件。液体制剂还可制成在聚乙二醇、水溶液中的溶液形式。可通过将活性成分溶解在水中，再加入适量的着色剂、调味剂、稳定剂和增稠剂，来制备口服水溶液。可将微粒化的活性成分分散在粘性物质如天然和合成胶、甲基纤维素、羧甲基纤维素钠和其它已知悬浮剂中制备适于口服的水悬液。
为了易于给药及剂量均一，将上述药物制剂配制成剂量单位形式是特别有利的。制剂的剂量单位形式指适于作为单一剂量的物理分离单位，每个单位含有产生所期望的治疗效果的计算好的预定量的活性成分。这种剂量单位形式可为包装形式，如片剂、胶囊或装在小管或小瓶中的粉剂，或装在管或瓶中的软膏、凝胶 或霜剂。
虽然剂量单位形式中所含活性成分的量可以变化，但一般根据所选择活性成分的效力，调节在1～800mg范围内。
当本发明的式(I)活性化合物用作治疗抗肿瘤药物时，给药剂量可随着病人的需要、欲治疗的病情的严重性、所选化合物等而变化。
本领域技术人员可按常规方法确定适于某种情况的优选剂量。一般，开始治疗的量低于活性成分的最佳剂量，然后逐渐增加给药剂量，直到达到最佳治疗效果。为治疗需要，总的日剂量可一次给药或分数次给药。
附图说明
图1为小鼠静脉注射给药舒尼替尼和化合物A的药动学研究图。
图2为小鼠静脉注射给药舒尼替尼和化合物1、2的药时曲线图，其中(a)心脏；(b)肝脏；(c)脾脏；(d)肺；(e)肾脏；(f)血浆。
图3为小鼠灌胃给药舒尼替尼和化合物1、2的药时曲线图，其中(a)心脏；(b)血浆。
图4为舒尼替尼和化合物1、2对pSTAT3去磷酸化的作用的对比图。
图5为舒尼替尼和化合物1、2对不同细胞系细胞毒的实验，其中(a)A549；(b)NCI-H460；(c)786-O；(d)Caki-1；(e)HT-29；(f)MCF-7。
图6为对小鼠口服给药化合物2与舒尼替尼的急性毒性试验图，其中(a)28mg/kg；(b)70mg/kg；(c)175mg/kg；(d)50mg/kg；(e)100mg/kg；(f)200mg/kg。
图7为对小鼠异种移植癌细胞后皮下注射化合物1、2和舒尼替尼后平均肿瘤大小的对照图，其中(a)1.5mg/kg；(b)7.5mg/kg；(c)30mg/kg。
图8为对小鼠异种移植癌细胞后口服给药化合物1、2和舒尼替尼后平均肿瘤大小的对照图，其中(a)5mg/kg；(b)15mg/kg；(c)45mg/kg。
图9显示化合物1或2对细胞的形态及生存率的影响，其中(a)舒尼替尼、化合 物1和化合物2对细胞形态的影响；(b)舒尼替尼、化合物1和化合物2在不同浓度下与786-O细胞或A549细胞共培养8小时后对细胞存活率的影响；(c)化合物A舒尼替尼、化合物1和化合物2在不同浓度下与A549细胞共培养8小时后对细胞存活率的影响；(d)舒尼替尼、化合物1和化合物2在不同浓度下与HUVEC细胞共培养8小时后对细胞存活率的影响。
图10显示舒尼替尼和化合物2对关键生化指标的影响，其中(a)舒尼替尼显著升高天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)和胆碱酯酶(CHE)；(b)舒尼替尼升高血尿酸和血尿素氮水平，但降低血糖；(c)舒尼替尼和化合物2对乳酸脱氢酶(LDH)、肌酸激酶(CK)、肌酸激酶-MB(CKMB)指标的影响。
图11显示本发明的化合物对A549人非小细胞肺癌细胞系的短期处(8h)理后对其生存率的影响，其中(a)至(h)分别代表化合物6至化合物13。
图12显示本发明的化合物对A549人非小细胞肺癌细胞系的短期(8h)处理后，除去化合物，恢复24小时后对其生存率的影响，其中(a)至(h)分别代表化合物6至化合物13。
图13显示本发明的化合物对A549人非小细胞肺癌细胞系的长期72h)处理后对其生存率的影响，其中(a)至(h)分别代表化合物6至化合物13。
具体实施方式
前体药物是指药物经过化学结构改造后在体内无活性或活性很低的化合物，在体内经酶促或非酶促作用又释放出原药发挥药理作用。
一般情况下，前药是用“亲脂性”、”亲水性”、“主动运输”和“双药”策略来修改药物，制备前药的目的是提高药物生物利用度，增加药物稳定性，减小毒副作用，促进药物长效化，掩饰不适臭味等。最成功的前药，如福沙，是安普那韦的磷酸盐酯前体“亲水性”药物。它现在广泛用于艾滋病治疗。
本发明在舒尼替尼的基础上，为使舒尼替尼具有更优良的特性，对舒尼替尼的结构进行改造，使用相关前药设计原理，设计了多种舒尼替尼的前药，意外地发现本发明的化合物在肝脏中的浓度远高于舒尼替尼，其对肝癌具有更大的杀伤性，同时本发明化合物可以降低全身毒性，特别是心脏毒性，减少不良反应。
以舒尼替尼为母体化合物，进行前药的制备，但使用何种取代基，其效果如何成了难题，众所周知，用于前药的取代基成千上万，从中筛选出合适并适用的取代基及其困难。
本发明提供一种舒尼替尼前药，其具有式I所示的结构式：
Figure PCTCN2016071951-appb-000003
式(I)
其中，
R12、R13选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环基和5-15元杂芳基；
R14选自R’、OR’、SR’或N(R’)2；并且
R’选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环基、5-15元杂芳基、羟基C1-C6烷基、羧基C1-C6烷基、C1-C6烷基酰胺基和磷酸基。
在一些实施方式中，R12、R13为H，R14选自N,N-二甲基氨基甲基、叔丁基、苯基、对氟苯基、联二苯基、二甲基胺基、环丙基、甲基、乙基、丙基、异丙基、丁基、异丁基、环丁基、戊基、异戊基、新戊基、环戊基、1-甲基环丁基、N-甲基胺基、N-乙基胺基、N,N-甲基乙基胺基、正己基、环己基、甲巯基、乙巯基、丙巯基、异丙基巯基、环丙基巯基、丁基巯基、异丁基巯基、环丁基巯基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、环丁氧基、戊胺基、戊巯基、戊氧基、异戊胺基、新戊胺基、叔丁基胺基、环戊胺基、环戊巯基、环戊氧基、环己基胺基、环己基巯基、环己基氧基、对甲氧基苯基、对氯苯基和邻氟苯基。
在一些实施方式中，R12、R13都为H，R14为叔丁基、苯基或叔丁氧基。
实施例1N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-羟甲基-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物X)及其制备方法
Figure PCTCN2016071951-appb-000004
在0℃，向舒尼替尼(1.25mmol,0.5g)的二甲基甲酰胺(14ml)溶液中添加甲醛(30％,405mg,5mmol)和三乙胺(506mg,5mmol)。混合物搅拌过夜。反应混合物再次冷却到0℃，加入水，同时搅拌混合物，形成黄色固体沉淀。过滤、洗涤并在空气中干燥数日，得到400mg的产物(化合物X)(产率75％)。1H NMR(400MHz,DMSO-d6):13.56(s,1H),7.84(d,1H,J＝9.2Hz),7.77(s,1H),7.49(t,1H,J＝5.2Hz),7.15～7.00(m,2H),6.35(s,1H),5.24(s,2H),3.31～3.26(m,2H),2.56～2.52(m,6H),2.49～2.44(m,6H),0.98(t,6H,J＝7.2Hz).
实施例2N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N,N-二甲基氨基)甲基羧甲基-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物A)及其制备方法
Figure PCTCN2016071951-appb-000005
将实施例1中制备的化合物X(437mg,1.02mmol)溶解于5mL无水DMF和2mL吡啶(Py)中。向混合物中加入N,N-二甲基氨基吡啶(12mg,0.1mmol)、N,N-二甲基甘氨酸(206mg,mmol)和EDC(384mg,2mmol)。混合物在室温搅 拌2小时。减压除去溶剂，产物用DCM萃取，盐水洗涤，在无水硫酸钠上干燥，并经硅胶柱色谱纯化，用DCM/MeoH(DCM中加入0.1％Et3N)。收集馏分并在真空下干燥，得到50mg橘黄色固体化合物A(产率10％)。1H NMR(400MHz,DMSO-d6):13.25(s,1H),7.86(dd,1H,J＝7.2,2Hz),7.81(s,1H),7.50(t,1H,J＝4.4Hz),7.19(dd,1H,J＝7.2,3.2Hz),7.05(td,1H,J＝7.2,2Hz),5.93(s,2H),3.31～3.27(m,4H),3.19(s,2H)；2.56～2.44(m,10H),2.21(s,6H),0.98(t,6H,J＝7.2Hz)。
实施例3N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(叔丁基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物1)及其制备方法
向实施例1中制备的化合物X(1.65g，3.86mmol，1eq.)在吡啶(50mL)中的溶液中加入新戊酸酐(2.87g，15.42mmol，4eq.)和DMAP(50mg)。将混合物在室温下搅拌过夜。后浓缩至干，将饱和NaHCO3溶液(20mL)加入到残余物中，并用EtOAc(2x 20mL)萃取。合并的有机相经干燥(无水硫酸钠)，过滤，浓缩，并通过硅胶色谱法，用DCM洗脱：甲醇＝10：1，得到化合物1，为黄色固体(1g，产率51％，由1H NMR，HPLC确认，批次编号：MC09179-056-15S)。1H NMR(400MHz,DMSO-d6)δ13.26(br s,1H),8.87(dd,J1＝9.6Hz,J2＝2.4Hz,1H),7.81(s,1H),7.54-7.52(m,1H),7.17-7.05(m,2H),5.90(s,2H),3.32-3.27(m,4H),2.58-2.45(m,10H),1.11(s,9H),0.98(t,J＝7.2Hz,6H)；HPLC纯度:96.27％(254nm)。
实施例4N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(苯基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物2)及其制备方法
向实施例1中制备的化合物X(1.65g,3.86mmol,1eq.)在吡啶(50mL)中的溶液中加入(PhCO)2O的溶液(1.7g,7.7mmol,2eq.)和DMAP(50mg)。将混合物在室温下搅拌过夜。后浓缩至干，饱和NaHCO3溶液(20mL)加入到残余物中，并用EtOAc(2x 20mL)萃取。合并的有机相经干燥(无水硫酸钠)，过滤，浓缩，并通过硅胶色谱法，用DCM洗脱：甲醇＝10：1，得到化合物2，为黄色固体(1.2g,产率58％，由1H NMR，HPLC确认，批次编号：MC09179-055-11S)。1H NMR(400MHz,DMSO-d6)δ13.28(br s,1H),7.95-7.84(m,4H),7.67(t,J＝7.2Hz,1H),7.54-7.50(m,3H),7.34-7.31(m,1H), 7.10-7.05(m,1H),6.18(s,2H),3.32-3.27(m,4H),2.57-2.45(m,10H),0.98(t,J＝7.2Hz,6H)；HPLC纯度:96.86％(254nm)。
实施例5N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N,N-二甲基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物6)及其制备方法
Figure PCTCN2016071951-appb-000006
向实施例1中制备的化合物X(150mg,0.35mmol)在无水DMF(2mL)的溶液中加入CDI(62.4mg,0.385mmol,1.1eq)。混合物在室温下搅拌30min。向混合物中加入三乙胺(56.7mg,0.56mmol)和盐酸二甲胺(45.67mg,0.56mmol)。反应物在室温下搅拌1小时，随后向混合物中加入5ml水，并用CH2Cl2(3X 2mL)。合并的有机相经干燥(无水硫酸钠)，过滤，浓缩，并通过TLC法纯化，用DCM:MeOH＝10:1洗脱，得到黄色固体形式的化合物6(20mg,产率45％,Lot#:MC10188-20-6,1H NMR和MS确认,HPLC:98％，254nm)。1H NMR(400MHz,CDCl3):13.37(1H,s),11.58(1H,br s),7.92(s,1H),7.36(s,1H),7.14～7.18(m,2H),6.88-6.93(m,1H),5.91(s,2H),3.97-3.91(m,2H),3.25～3.31(m,2H),3.15-3.20(m,2H),2.99-2.30(m,6H),2.64(s,3H),2.57(s,3H),1.57-1.59(br s,4H),1.42-1.45(m,6H)。
实施例6N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(叔丁氧基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物7)及其制备方法
Figure PCTCN2016071951-appb-000007
向实施例1中制备的化合物X(100mg,0.26mmol)在无水Py(3m)的溶液中加入DMAP(3.16mg,0.026mmol,0.1eq.)和SM 3(173mg,1.04mmol)。混合物在室温下搅拌16h。浓缩干燥后，向残渣中加入饱和的NaHCO3溶液，并用EA萃取。合并的有机相经干燥、过滤、浓缩，并通过硅胶色谱纯化，用DCM:MeOH＝10:1洗脱，得到黄色固体形式的化合物7(80mg,产率58.4％,Lot#:MC10188-004--6,1H NMR和MS确认,HPLC:95.6％，254nm)。1H NMR(400MHz,CDCl3-d6):δppm 13.31(bs,1H),7.38(s,1H),7.21-7.19(m,1H),7.09-7.06(m,1H),6.94-6.88(m,1H),6.47(bs,1H),5.88(s,2H),3.49-3.48(m,2H),2.67(m,2H),2.60-2.57(m,7H),2.51-2.39(m,3H),1.11(s,9H),1.04(t,J＝7Hz,6H)。
实施例7N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(乙氧基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物8)及其制备方法
Figure PCTCN2016071951-appb-000008
向实施例1中制备的化合物X(100mg,0.26mmol)在无水Py(3mL)的溶液中加入DMAP(3.16mg,0.026mmol,0.1eq.)和SM 2(169mg,1.04mmol)。混合物在室温下搅拌16h。浓缩干燥后，向残渣中加入饱和的NaHCO3溶液，并用EA萃取。合并的有机相经干燥、过滤、浓缩，并通过硅胶色谱纯化，用DCM: MeOH＝10:1洗脱，得到黄色固体形式的化合物8(70mg,产率53.8％,Lot#:MC10188-002--6,1H NMR和MS确认,HPLC:98.7％,254nm)。1H NMR(400MHz,CDCl3-d6):δppm 13.29(bs,1H),7.38(s,1H),7.22-7.19(m,1H),7.09-7.06(m,1H),6.94-6.91(m,1H),6.47(bs,1H),5.94(s,2H),4.26-4.21(m,2H),3.51-3.47(m,2H),2.67-2.63(m,2H),2.60-2.57(m,7H),2.55-2.51(m,3H),1.30(t,J＝7Hz,3H),1.4(t,J＝7Hz,6H)。
实施例8N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(环己基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物9)及其制备方法
Figure PCTCN2016071951-appb-000009
向实施例1中制备的化合物X(100mg,0.26mmol)在无水Py(3mL)的溶液中加入DMAP(3.16mg,0.026mmol,0.1eq.)和SM 4(248mg,1.04mmol)。混合物在室温下搅拌16h。浓缩干燥后，向残渣中加入饱和的NaHCO3溶液，并用EA萃取。合并的有机相经干燥、过滤、浓缩，并通过硅胶色谱纯化，用DCM:MeOH＝10:1洗脱，得到黄色固体形式的化合物9(60mg,产率43％,Lot#:MC10188-006-6,1H NMR和MS确认,HPLC:99％,254nm)。1H NMR(400MHz,CDCl3-d6):δppm 13.41(bs,1H),7.39(s,1H),7.22-7.18(m,1H),7.04-7.01(m,1H),6.93-6.89(m,1H),6.47(bs,1H),5.92(s,2H),3.49-3.48(m,2H),2.67-2.61(m,2H),2.57-2.52(m,7H),2.47-2.45(m,3H),2.36-2.35(m,1H),1.89-1.85(m,2H),1.67-1.62(m,2H),1.43-1.40(m,3H),1.26-1.20(m,3H),1.04(m,6H)。
实施例9N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(甲基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物10)及其制备方法
Figure PCTCN2016071951-appb-000010
向实施例1中制备的化合物X(100mg,0.26mmol)在无水Py(3mL)的溶液中加入DMAP(3.16mg,0.026mmol,0.1eq.)和SM 1(106mg,1.04mmol)。混合物在室温下搅拌16h。浓缩干燥后，向残渣中加入饱和的NaHCO3溶液，并用EA萃取。合并的有机相经干燥、过滤、浓缩，并通过硅胶色谱纯化，用DCM:MeOH＝10:1洗脱，得到黄色固体形式的化合物10(60mg,产率49％,Lot#:MC10188-005-6,1H NMR和MS确认,HPLC:96.5％,254nm)。1H NMR(400MHz,CDCl3-d6):δppm 13.32(bs,1H),7.39(s,1H),7.21-7.19(m,1H),7.07-7.05(m,1H),6.94-6.89(m,1H),6.60(bs,1H),5.91(s,2H),3.53-3.52(m,2H),2.71-2.67(m,2H),2.63-2.52(m,7H),2.45-2.44(m,3H),2.09(s,3H),1.07(s,6H)。
实施例10N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(环丙基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物11)及其制备方法
Figure PCTCN2016071951-appb-000011
向实施例1中制备的化合物X(200mg,0.467mmol)在吡啶(5mL)的溶液中加入DMAP(5mg)。随后在冰浴中加入化合物RI/吡啶(288mg,1.87mmol,4.0eq.)。混合物在室温下搅拌过夜。浓缩并通过硅胶色谱纯化，用DCM:MeOH＝50:1洗脱，得到黄色固体形式的化合物11(138mg,产率60％,Lot#: MC09163-034-P1,1H NMR和MS确认,HPLC:99％,254nm)。1H NMR(400MHz,DMSO-d6):13.26(s,1H),7.88(dd,1H,J＝11.6Hz),7.82(s,1H),7.52(t,1H,J＝10.8Hz),7.22～7.16(m,1H),7.10～7.02(m,1H),5.91(s,2H),3.35～3.28(m,2H),2.57～2.53(m,4H),2.52～2.51(m,8H),1.69～1.62(m,1H),0.99(t,6H,J＝14Hz),0.95～0.85(m,4H)。
实施例11N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(异丙基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物12)及其制备方法
Figure PCTCN2016071951-appb-000012
向实施例1中制备的化合物X(200mg,0.47mmol)在吡啶(5mL)的溶液中加入DMAP(5mg)。随后在冰浴中加入化合物RJ/吡啶(295mg,1.87mmol,4.0eq.)。混合物在室温下搅拌过夜。浓缩并通过硅胶色谱纯化，用DCM:MeOH＝50:1洗脱，得到黄色固体形式的化合物12(135mg,产率58％,Lot#:MC09163-040-P,1H NMR和MS确认,HPLC:99％,254nm)。1H NMR(400MHz,DMSO-d6):13.26(s,1H),7.88(dd,1H,J＝8.4Hz),7.81(s,1H),7.54～7.52(m,1H),7.19～7.15(m,1H),7.05(t,1H,J＝17.6Hz),5.89(s,2H),2.58～2.56(m,8H),2.48～2.44(m,6H),1.06(d,7H,J＝6.8Hz),1.0～0.97(m,6H)。
实施例12N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(对甲氧基苯基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物13)及其制备方法
Figure PCTCN2016071951-appb-000013
向实施例1中制备的化合物X(200mg,0.47mmol)在吡啶(5mL)的溶液中加入DMAP(5mg)。随后在冰浴中加入化合物RL/吡啶(534mg,1.87mmol,4.0eq.)。混合物在室温下搅拌过夜。浓缩并通过硅胶色谱纯化，用DCM:MeOH＝50:1洗脱，得到黄色固体形式的化合物13(120mg,产率45％,Lot#:MC09163-041-P1,1H NMR和MS确认,HPLC:98.9％,254nm)。1H NMR(400MHz,DMSO-d6):13.29(s,1H),7.89(d,3H,J＝8.8Hz),7.83(s,1H),7.55(s,1H),7.33～7.29(m,1H),7.09～7.02(m,3H),6.13(s,2H),3.83(s,3H),3.0～2.5(m,7H),2.49～2.45(m,7H),0.84(s,6H)。
实施例13化合物A的药代动力学实验和稳定性研究
药代动力学
将舒尼替尼和化合物A溶于苹果酸溶液，调节pH＝7左右，向对照组小鼠尾静脉注射5.14mg/kg舒尼替尼苹果酸，样品A组小鼠尾静脉注射13mg/kg化合物A。将每组6只小鼠分别在尾静脉注射药物后的0.083h、0.25h、0.5h、1h、3h、8h后摘眼取血并颈椎脱臼处死小鼠，使用生理盐水灌流全体组织，并取肝肾组织，再用生理盐水将表面洗干净，并用滤纸擦干；将血浆进行离心取上层清液；将样品冻存于-20℃的温度下保存。将50μL血浆样品μl和各50μL内标(氯氮平)工作液与300μL甲醇涡旋混合，离心，取150μL上层有机相，再加入150μL水涡旋混合，离心后取10μL上层清液进样分析。将组织样品称重，加入10倍重量的纯水，均匀混合。(因为组织样品被稀释了10倍，因此组织的浓度结果应为组织样品匀浆液测定的结果的10倍。心浓度较低则稀释倍数为5倍。)取100μL均匀混合后的浆液，各50μL内标(氯氮平)工作液，再加入甲醇300μL涡旋混合，离心，取150μL上层有机相，加入150μL水涡旋混合，离心后取 10μL上层清液进样分析。
结果处理与分析方法
相对摄取率(RE)RE＝(AUCi样品/(AUCi)对照
AUCi-由浓度-时间曲线求得的第i个器官或组织的药时曲线下面积；RE大于1表示药物制剂在该器官或组织有靶向性，RE愈大靶向效果愈好；等于或小于1表示无靶向性；
相对综合靶向效率(RTE)
AUC组织表示某组织药一时曲线下面积，综合靶向效率指合用实验组的组织药量占体内药物总量的比值与对照组该比值相比较增加的倍数，RTE值为正则表示实验组药物对该组织有靶向性增强作用，正越大则靶向增强倍数越大，靶向性增强作用越强，RTE为负则反之，为0则表示对该组织无影响。
实验结果见图1及下表：
表1药物在各个器官的分布分析
Figure PCTCN2016071951-appb-000014
表2靶向参数的计算
Figure PCTCN2016071951-appb-000015
实验的药动学参数由Winnonlin算出，由于小鼠的药动学是由多只动物构 成，因此是算出药时曲线的均值再输入软件算参数。
从药动学参数看，从两个给药组的清除率看，我们可以看出化合物A(sample A)给药组的清除率在心，肝，脾，肺，肾分别是舒尼替尼(S,Sunitinib)给药组的7、3、5、5、4、4倍，也就是各个脏器的清除率都明显增大了，而肝中增大倍数是最小的，因此可能化合物A(sample A)代谢的特殊产物会诱导CPY代谢酶，或者是影响了其他清除途径使得舒尼替尼的清除率变大，导致影响了化合物A(sample A)给药组的舒尼替尼暴露值的降低。
而化合物A(sample A)药物是一个前药，在入血后到达器官这个过程会代谢为舒尼替尼，可能是A药物本身特殊的结构会引导其靶向分布，因此即使代谢变快，其在肝分布的比例依旧是提高的。
而从RTE来看，肾的RTE接近0，血浆及其他脏器的RTE均小于1，只有肝的RTE(0.48)明显大于0，这说明化合物A(sample A)给药组的舒尼替尼分布在其他脏器的分布比例降低了，而在肝脏的分布比例提高了，即化合物A(sample A)能促进舒尼替尼的肝脏分布。
综上所述，化合物A并不能提高各脏器及组织的舒尼替尼的绝对暴露量，但却能提高舒尼替尼在肝脏的分布比例，提高靶向性，降低其他器官的分布，假设化合物A(sample A)没有毒性，以及其他代谢物也没有毒性，那么化合物A(sample A)比舒尼替尼能降低药物在其他非靶向器官的毒性作用。
实施例14化合物1、化合物2和舒尼替尼进行对比实验
药代动力学
将舒尼替尼、化合物1和化合物2溶于苹果酸溶液，调节pH＝7左右，向对照组小鼠尾静脉注射5.14mg/kg舒尼替尼苹果酸，样品1组小鼠尾静脉注射5.13mg/kg化合物1，样品2组小鼠尾静脉注射5.32mg/kg化合物2。将每组36只小鼠分为6小组，分别在尾静脉注射药物后的0.083h,0.25h,0.5h,1h,3h,8h后摘眼取血并颈椎脱臼处死小鼠，使用生理盐水灌流全体组织，并取肝肾组织，再用生理盐水将表面洗干净，并用滤纸擦干；将血浆进行离心取上层清液；将样品冻存于-20℃的温度下保存。血浆样品处理方法：将50μl血浆样品μl和各50μL 内标(氯氮平)工作液与300μL甲醇涡旋混合，离心，取150μL上层有机相，再加入150μL水涡旋混合，离心后取10μL上层清液进样分析。组织样品处理方法：将组织样品称重，加入10倍重量的纯水，均匀混合。(因为组织样品被稀释了10倍，因此组织的浓度结果应为组织样品匀浆液测定的结果的10倍。心浓度较低则稀释倍数为5倍。)取100μL均匀混合后的浆液，各50μL内标(氯氮平)工作液，再加入甲醇300μL涡旋混合，离心，取150μL上层有机相，加入150μL水涡旋混合，离心后取10μL上层清液进样分析。实验结果见图2及下表：
表3药物动力学研究
Figure PCTCN2016071951-appb-000016
表4药物在各个器官的分布分析
Figure PCTCN2016071951-appb-000017
从血浆的药时曲线算出的药动学参数可以发现，舒尼替尼对照物的半衰期是最长的(1.24h)，而化合物1与2的半衰期比较接近，在1h内，即化合物1和2中舒尼替尼的清除是比较快的；从Cmax看，化合物1和2均大于舒尼替尼，大概为对照组的五倍，而AUC却相差不多，说明化合物1和2的药时曲线比较陡而舒尼替尼相对平缓；表观分布容积范围在350-500mL，说明明显在组织分布广。
表5靶向参数的计算
Figure PCTCN2016071951-appb-000018
从相对摄取率(RE)分析，图中只有血浆的RE值大于1，即在当前的给药浓度下，血浆的相对摄取率提高了，而在其他脏器都降低了。
从相对综合靶向效率(RTE)分析，图中化合物1在肝，脾脏器中都提高了分布的比例；化合物2在脾和肺则提高了分布的比例；心，肾均分布比例降低。血浆中分布的比例大大提高。
化合物处理中发现除了脾外其他化合物都没有检测到原型药，前期的实验证明，化合物1和2在甲醇贮存液较稳定(稳定性测定时间：7天)，而在有生物基质共存的情况下很容易降解，这可能是在处理过程中或在体内原型药已代谢为舒尼替尼或其他结构。
药物动力学研究
因为舒尼替尼本身在病人用药是口服，我们进行了舒尼替尼与化合物1、2口服用药的药物动力学研究。将舒尼替尼、化合物1和化合物2溶于苹果酸溶液，调节pH到7附近。舒尼替尼苹果酸用纯水溶解。给药剂量：向对照组小鼠灌胃给药20mg/kg舒尼替尼苹果酸,样品1组小鼠灌胃给药19.248mg/kg化合物1，样品2组小鼠灌胃给药20mg/kg化合物2。动物实验：将每组24只小鼠分为8小组，分别在灌胃给药后的0.25h,0.5h,1h,1.5h，2h,4h，6h，10h摘眼球取血并颈椎脱臼处死小鼠，使用生理盐水灌流全体组织，并取肝肾组织，再用生理盐水将表面洗干净，并用滤纸擦干；再将血浆进行离心取上层清液；将样品冻存于-20℃的温度下保存。实验结果见图3及下表：
表6药物动力学研究数据
Figure PCTCN2016071951-appb-000019
表7药物动力学参数比较
Figure PCTCN2016071951-appb-000020
灌胃给药的实验结果动物间的差异比较大，而静脉注射给药的动物间差异较小，这可能是因为胃肠吸收的过程造成的差异比较大。化合物1和化合物2的AUC大概比舒尼替尼对照组高了3.5倍，Cmax也远远高于对照组，这说明，改造后的化合物1和化合物2比舒尼替尼吸收的程度变大了，从算出的绝对生物利用度也可以看出，化合物1和化合物2分别在50％附近，有较高的生物利用度，而舒尼替尼给药组只有15％；从表观分布容积看，舒尼替尼对照组有更高的表观分布容积，这表明灌胃给药后对照组有更多组织蓄积性而化合物1和化合物2在心脏的蓄积比例是降低的。
实施例15化合物1、化合物2和舒尼替尼的药效学和毒理学比较实验
细胞系和培养方法
A549人非小细胞肺癌细胞系，NCI-H460人非小细胞肺癌细胞株，786-O人肾细胞癌细胞系，Caki-1人类肾细胞癌细胞系，HT-29人结肠癌细胞系，MDA-MB-231人乳腺癌细胞系，MCF-7人乳腺癌细胞系，从中国科学院上海分院购买所得。PLC/PRF-5的人肝癌细胞株，和Hepa1-6鼠肝癌细胞株来自生物化学与细胞生物学研究所上海生命科学研究院(SIBCB)。细胞系A549，Caki-1，HT-29，MDA-MB-231，MCF-7，PLC/PRF-5和Hepa1-6培养在DMEM培养基(Gibco，Life Technologies公司，中国)，而细胞系NCI-H460，786-O在RPMI-1640培养基(Gibco，Life Technologies公司，中国)。10％HI胎牛血清(Gibco公司，Life Technologies公司，美国)和1％青霉素/链霉素(Hyclone 公司)。
将约2000个细胞，50μl的完全培养基在96孔板/孔，37℃下(5％CO2)温育过夜。将范围从0.02至10μM不同浓度的药物，溶解在0.1％DMSO后加入到各孔中。72小时温育后，取10μL CCK8试剂(Dojindo公司)加入到每一个孔，再37℃下培养4小时，然后使用TECAN酶标仪在450nm测定OD值。
化合物的处理
对于在体外测定中，化合物直接溶解于的10mM浓度的DMSO中，并于-20℃下贮存药物；而对于体内测定法，将化合物溶解于DMSO中，并吐温80(DMSO：吐温80＝1:1)中，然后用PBS(pH 7.4)中和，DMSO的终浓度和吐温80(Tween-80)稀释为5％。
对MEK、ERK和STAT3磷酸化的影响
舒尼替尼是RTK抑制剂，能抑制多种信号通路，如RAS/RAF/MAPK，因此，我们分析了一些主要的下游蛋白，包括MEK，ERK和STAT3。对pSTAT3，舒尼替尼和前药化合物2，在10μM的浓度，显示出对A549细胞系(图4)较强的抑制作用。这些结果表明，前药化合物和舒尼替尼，有相同的抗肿瘤作用机制。
根据研究结果，无论是舒尼替尼，或3种前体药物，在体外都显示出较强的肿瘤细胞杀伤作用。舒尼替尼IC50和化合物1或2的IC50对多种细胞系接近(图5a-f)。这些结果证明，无论是舒尼替尼还是化合物1或2具有强烈的细胞毒性作用。
但是，与舒尼替尼不同，我们观察到化合物1或2处理的细胞在培养过程中细胞形态变化更快。癌细胞在与化合物1或2培养4小时后变成圆形且受应力影响，而舒尼替尼处理的细胞仍然附着、细长且形态与正常细胞无异(图9a)。与化合物1或2共培养8小时后，细胞大量死亡，而舒尼替尼处理8小时不影响细胞存活率(图9b)，表明化合物1和2比舒尼替尼能更快速地杀死癌细胞，并且不可逆。化合物A也表现出与化合物1和2类似的快速杀死癌细胞的活性(图9c)。因为舒尼替尼在体内的主要靶标是肿瘤血管内皮细胞，因而使用人脐静脉内皮细胞(HUVEC)来测试化合物1和2的细胞毒性。与786-O和A549 细胞观察到的类似，在用化合物1或2处理8小时后少于50％的HUVEC存活(图9d)。
急性毒性试验：最大耐受剂量(MTD)测定
4～5周龄的雌性BALB/c小鼠用于本试验。小鼠的平均重量是大于17g，动物口服用药，每日一次使用3个剂量(28mg/kg、70mg/kg、175mg/kg)。这个测试的持续时间为14天。对所有小鼠的体重和条件进行了记录。
根据结果显示(图6a-c)：在28mg/kg和70mg/kg的浓度下，无论是舒尼替尼还是3种化合物对动物的体重的影响小，并且所有小鼠被确定为正常。然而，当剂量增加至为175mg/kg时，舒尼替尼显示出严重的毒性，小鼠的平均重量减少率为17.6％，而化合物2组的小鼠重量平均增加了6.0％。此外，舒尼替尼175mg/kg组，小鼠在整个测试过程中表现极其微弱，而化合物2的相同剂量组，小鼠的表现状况与阴性对照组类似。因此，急性毒性试验表明，小鼠对化合物2有更好的耐受性。
重复急性毒性试验：动物口服，舒尼替尼和3种化合物，每日一次使用3个剂量(50mg/kg，100mg/kg，200mg/kg)。根据结果显而易见的是(图6d-f)：在50mg/kg浓度，无论是舒尼替尼和3种化合物对动物的体重的影响小，并且所有小鼠被确定为正常；在100mg/kg浓度，化合物2对动物的体重的影响小，并且所有小鼠被确定为正常；在100mg/kg浓度，舒尼替尼对动物的体重已经开始有影响，小鼠体重没有下降，可是也没有增加；然而，当剂量增加至为200mg/kg时，舒尼替尼显示出严重的毒性，平均重量减少率近20％，而化合物2组的重量平均增加了6.0％。此外，舒尼替尼200mg/kg组，小鼠在整个测试过程中表现极其微弱，而化合物2的相同剂量组，小鼠的表现状况与阴性对照组类似。因此，急性毒性试验表明，在小鼠中，化合物2有更好的耐受性。
为了进一步研究其毒性，在用药物处理14天后，采集血样并分析关键生化指标。在以200mg/kg舒尼替尼处理的小鼠中，天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)和胆碱酯酶(CHE)显著升高(图10a)，表明可能存在的肝脏、心脏、肾脏或其他组织的毒性；尿酸和血尿素氮水平更高，但血糖降低(图10b)，表明可能存在肾脏毒性；乳酸脱氢酶(LDH)、肌酸激酶(CK)、肌酸激 酶-MB(CKMB)也显著升高(图10c)，表明可能存在心脏或其他器官毒性。相反，在以200mg/kg化合物2处理的小鼠中，除AST和ALT之外，这些指标均在正常范围以内(图10c)。这些数据进一步支持了化合物2的毒性小于舒尼替尼的论断，特别是在心脏、肝脏或肾脏毒性方面。
对小鼠异种移植模型的药效试验
首先，将5×106癌细胞注射到小鼠右胁皮下。当平均肿瘤大小达到一定大小(75～150立方毫米)，开始向腹腔注射用药(1.5mg/kg,7.5mg/kg,30mg/kg)，每日一次，并持续2周。每隔一天，测定肿瘤的大小。结果表明，化合物2比舒尼替尼有更好的疗效。化合物1效果较弱。结果见图7。
然后，我们进行口服用药的实验，5×106癌细胞注射到每只小鼠右胁皮下。当平均肿瘤大小达到一定大小(75-150立方毫米)，开始口服用药(5mg/kg,15mg/kg,45mg/kg)，每日一次，并持续2周。每隔一天，测定肿瘤的大小。结果同样表明，化合物2比舒尼替尼有更好的疗效。结果见图8。
实施例16其他化合物的肿瘤细胞杀伤作用
化合物8小时(短期)细胞杀伤作用
细胞系和培养方法：将A549人非小细胞肺癌细胞系在DMEM培养基(Gibco，Life Technologies公司，中国)，0％HI胎牛血清(Gibco公司，Life Technologies公司，美国)和1％青霉素/链霉素(Hyclone公司)。
约2000个细胞，50μl的完全培养基在96孔板/孔，37℃(5％CO2)温育过夜。加入有不同浓度的药物，范围2.5μM，5μM，和10μM,溶解在0.1％DMSO加入到各孔中。8小时温育后，取10μL CCK8试剂(Dojindo公司)加入到每一个孔，培养37℃4小时，然后使用TECAN酶标仪在450nm测定OD值。
化合物的处理：对于在体外测定中，化合物直接溶解于DMSO的10mM的浓度，药物储存贮存于-20℃。
结果见图11a-h，显示这些化合物的短期处理未显示出对细胞的生存率的显 著影响。
化合物8小时作用后，恢复24小时，对细胞杀伤作用
细胞系和培养方法：将A549人非小细胞肺癌细胞系在DMEM培养基(Gibco，Life Technologies公司，中国)，10％HI胎牛血清(Gibco公司，Life Technologies公司，美国)和1％青霉素/链霉素(Hyclone公司)。
约2000个细胞，50μl的完全培养基在96孔板/孔，37℃(5％CO2)温育过夜。加入有不同浓度的药物，范围2.5μM、5μM和10μM,溶解在0.1％DMSO加入到各孔中。8小时温育后，替换成无化合物的100μl完全培养基，然后温育24小时后，取10μL CCK8试剂(Dojindo公司)加入到每一个孔，培养37℃4小时，然后使用TECAN酶标仪在450nm测定OD值。
化合物的处理：对于在体外测定中，化合物直接溶解于DMSO的10mM的浓度，药物储存贮存于-20℃。
结果见图12a-h，显示这些化合物经同样时间(8h)的处理，在24小时后，开始显现出对细胞生存率的影响，且呈浓度依赖性。可能的原因在于，化合物进入细胞的速度较慢，因而表现出滞后的活性。
化合物72小时(长期)细胞杀伤作用
细胞系和培养方法：将A549人非小细胞肺癌细胞系在DMEM培养基(Gibco，Life Technologies公司，中国)，10％HI胎牛血清(Gibco公司，Life Technologies公司，美国)和1％青霉素/链霉素(Hyclone公司)。
约2000个细胞，50μL的完全培养基在96孔板/孔，37℃(5％CO2)温育过夜。加入有不同浓度的药物，范围从0.02至10μM，溶解在0.1％DMSO加入到各孔中。72小时温育后，取10μL CCK8试剂(Dojindo公司)加入到每一个孔，培养37℃4小时，然后使用TECAN酶标仪在450nm测定OD值。
化合物的制备：对于在体外测定中，化合物直接溶解于DMSO的10mM的浓度，药物储存贮存于-20℃。
结果见下表8和图12a-h，显示这些化合物均具有良好的抑瘤活性，且呈浓度依赖性。
表8–示例性化合物IC50值
Figure PCTCN2016071951-appb-000021
综合以上实验结果，可以看出：(1)本发明提供的舒尼替尼前药具有更好的药代动力学和药效学：对小鼠进行静脉注射后的药物动力学研究表明，化合物1和2的Cmax均远大于舒尼替尼，而AUC彼此差异不大；对小鼠进行灌胃给药后的药物动力学研究表明，化合物1和2的Cmax和AUC均远大于舒尼替尼；(2)本发明提供的舒尼替尼前药具有更好的安全性：在肝脏的相对药物的分配比率，与舒尼替尼相比，化合物2显示了相对较高的分布。而在其它器官，尤其是心脏，与舒尼替尼相比，化合物2显示了相对较低的分布。三种前药化合物，在心脏都有相对较低的药物浓度，证明本发明提供的舒尼替尼前药可以有效地降低全身毒性，尤其是心脏毒性。它具有更好的安全性，持续的药物浓度；(3)本发明提供的舒尼替尼前药具有疗效更好：利用小鼠异种移植模型研究表明，舒尼替尼前药与舒尼替尼相比，有更好的疗效。本发明提供的舒尼替尼前药与舒尼替尼相比在肝脏有相对较高的分布，而在心脏有相对较低的分布；并且舒尼替尼前药能比舒尼替尼有更好的治疗肿瘤的效果。因此，本发明提供的舒尼替尼前药在癌症的治疗方面有更好的药效，但同时又有更低的毒副作用，本发明化合物可用于舒尼替尼未能在临床试验中使用的肝癌疾病，可作为兼具有效性和低毒性的抗肿瘤药物开发的先导化合物，具有良好的应用开发前景。
所有说明书中引用的专利和其他参考文献都表示本领域技术人员的水平，并且通过引用将它们以整体形式合并至本文中，包括任何表格和图，如同每个文献被单独以整体方式合并至本文中一样。
此外，本发明的特征或方面以马库什群组或其他替代性群组的形式描述时，本领域技术人员将意识到，本发明也以该马库什群组或其他群组的任何单个成员或子群组成员的形式被描述。

Claims (7)

  1. 式I的化合物或其药学上可接受的盐：
    Figure PCTCN2016071951-appb-100001
    其中：
    R12、R13选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环基和5-15元杂芳基；
    R14选自R’、OR’、SR’或N(R’)2；并且
    R’选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环基、5-15元杂芳基、羟基C1-C6烷基、羧基C1-C6烷基、C1-C6烷基酰胺基和磷酸基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R12、R13都为H，R14选自N,N-二甲基氨基甲基、叔丁基、苯基、对氟苯基、联二苯基、二甲基胺基、环丙基、甲基、乙基、丙基、异丙基、丁基、异丁基、环丁基、戊基、异戊基、新戊基、环戊基、1-甲基环丁基、N-甲基胺基、N-乙基胺基、N,N-甲基胺乙基、正己基、环己基、甲巯基、乙巯基、丙巯基、异丙基巯基、环丙基巯基、丁基巯基、异丁基巯基、环丁基巯基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、环丁氧基、戊胺基、戊巯基、戊氧基、异戊胺基、新戊胺基、叔丁基胺基、环戊胺基、环戊巯基、环戊氧基、环己基胺基、环己基巯基、环己基氧基、对甲氧基苯基、对氯苯基、邻氟苯基。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R12、R13都为H，R14为叔丁基、苯基或叔丁氧基。
  4. 以下任一种化合物或其药学上可接受的盐：
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N,N-二甲基氨基)甲基羧甲基-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物A)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(叔丁基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物1)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(苯基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物2)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(1-甲基环丁基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物3)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N-甲基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物4)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N-乙基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物5)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(N,N-二甲基氨基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物6)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(叔丁氧基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物7)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(乙氧基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物8)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(环己基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物9)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(甲基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物10)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(环丙基羧甲基)-2,3-二氢吲哚-3-基 亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物11)；
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(异丙基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物12)；和
    N-[2-(二乙胺基)乙基]-5-[(5-氟-2-氧代-1-(对甲氧基苯基羧甲基)-2,3-二氢吲哚-3-基亚甲基)]-2,4-二甲基-1H-吡咯-3-甲酰胺(化合物13)。
  5. 一种药物组合物，包含有效量的权利要求1-4任何一项所述的化合物或其药学上可接受的盐，以及药学上可接受的载体。
  6. 权利要求1-4的任一项所述的化合物或其药学上可接受的盐在制备治疗癌症药物中的应用。
  7. 根据权利要求6所述的应用，其中所述癌症为转移性肾细胞癌、胃肠道间质瘤或肝癌。
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US20180022734A1 (en) 2018-01-25
CN104610231B (zh) 2016-08-17
CA2975315A1 (en) 2016-08-04
JP2018508495A (ja) 2018-03-29
KR20170106478A (ko) 2017-09-20
CN104610231A (zh) 2015-05-13

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