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WO2021184958A1 - Inhibiteur de l'angiogenèse, son procédé de préparation et son utilisation - Google Patents

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

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Publication number
WO2021184958A1
WO2021184958A1 PCT/CN2021/073616 CN2021073616W WO2021184958A1 WO 2021184958 A1 WO2021184958 A1 WO 2021184958A1 CN 2021073616 W CN2021073616 W CN 2021073616W WO 2021184958 A1 WO2021184958 A1 WO 2021184958A1
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methyl
indol
fluoro
oxy
yloxy
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Chinese (zh)
Inventor
孙效华
杨阳
陈庆广
尹大伟
刘洋
王静
王静然
李玉花
杨红振
胡怀忠
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Beijing Konruns Pharmaceutical Co Ltd
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Beijing Konruns Pharmaceutical Co Ltd
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Priority to CN202180000162.3A priority Critical patent/CN112912373B/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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a compound used as an angiogenesis inhibitor and a preparation method and application thereof.
  • Receptor tyrosine kinase is a transmembrane protein with three parts: extracellular domain, transmembrane domain and intracellular domain.
  • the function of the intracellular domain is to act as a kinase to phosphorylate specific amino acid residues in proteins and affect cell proliferation. Variation of tyrosine kinase or abnormal activity changes will lead to the occurrence of the disease.
  • Tyrosine kinases can be classified into growth factor receptors (such as EGFR, VEGFR, PDGFR, FGFR, and erbB2) or non-receptor kinases (such as c-src, bcr-abl). These kinases may be abnormally expressed in human cancers, such as breast cancer, colorectal cancer, gastric cancer, blood cancer, and ovarian cancer.
  • Angiogenesis is an important part of general physiological processes, such as embryo formation and wound healing. However, variant angiogenesis can lead to related diseases, such as psoriasis, rheumatoid arthritis, atheroma, and tumors.
  • Tumor angiogenesis is mainly regulated by vascular endothelial cell growth factor (VEGF) in the tumor, which acts through at least two different receptors (VEGFR1, VEGFR2).
  • VEGF receptor is highly specific to vascular endothelial cells.
  • VEGF combines with its receptor VEGFR to produce a series of physiological and biochemical reactions, and ultimately promote the formation of new blood vessels.
  • angiogenesis factors and angiogenesis inhibitors maintain a relatively balanced level. In the process of tumor growth, the high expression of VEGF and VEGFR disrupts this balance and promotes the formation of tumor new blood vessels.
  • cediranib is a relatively powerful drug.
  • the chemical structure of cediranib is shown below.
  • Cediranib has been used in clinical research for ovarian cancer, gallbladder cancer, renal cell carcinoma, prostate cancer, cervical cancer, etc. However, due to the obvious adverse reactions of cediranib (mainly hypertension, fatigue, diarrhea, hand-foot syndrome, etc.), it was finally not approved for marketing in the EU.
  • the present invention provides a cyclobutyl-containing compound used as a tyrosine kinase inhibitor, the compound having a structure represented by formula (I).
  • the compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, isotopic derivatives and solvates, and pharmaceutical compositions containing the compounds, can be used for the treatment of tyrosine kinases, especially those related to VEGFR Treatment of tumor diseases.
  • the compound of the present invention has the structure shown in formula I:
  • X is selected from -C(H)-, N, -C(F)-, -C(CF 3 )-, -C(CN)-;
  • R is selected from a hydroxyl group, a carboxyl group, an ester group, -N(R 1 R 2 ), or R is selected from an oxygen atom and the oxygen atom forms a ketone carbonyl group with the cyclobutyl group directly connected to it;
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, Ar ;
  • R 1 and R 2 form a 4-10 membered heterocyclic group with the nitrogen atom to which they are connected, and the ring of the heterocyclic group further includes at least one atom of N, O, and S; and the heterocyclic ring
  • the hydrogen atom on the group is optionally substituted with 1-3 R 3 which are the same or different;
  • R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, ester group;
  • Ar is selected from C 6 -C 10 aryl groups, 5-10 membered heteroaryl groups, wherein the heteroaryl group contains 1-3 heteroatoms selected from N, O and S; Ar can be the same or 1-3 Different R 4 substitutions; R 4 is selected from hydrogen, hydroxyl, halogen, trifluoromethyl, nitro, amino, nitrile, sulfonic acid, sulfonamide, C 1 -C 6 alkyl, C 1 -C 6 Alkyl acyl, C 3 -C 6 cycloalkyl.
  • the inventors of the present invention analyzed the structure-activity relationship and in vivo pharmacokinetic characteristics of cediranib and found that there are functional groups in the structure that affect metabolism, which makes the half-life longer, exceeding 30 hours, leading to adverse reactions.
  • the present invention performs structure-activity relationship analysis on the basis of the structure of cediranib, and optimizes its structure. On the one hand, it maintains its activity (even higher than that of cediranib), and on the other hand, it improves its pharmacokinetics. Nature, shorten the half-life of the drug, and improve its druggability.
  • the presence of a cyclobutyl group on the molecular branch can increase the rigidity of the branch where the cyclobutyl is located.
  • the presence of a four-membered ring Make the 1,3-position substituents have cis and trans configurations, increase the directionality of the molecule, and make the compound easier to bind to the target, thereby increasing the activity of the drug, reducing the dose of the drug, and reducing the side effects of the drug.
  • the molecular branch of the compound of the present invention contains cyclobutyl, and the cyclobutyl makes the compound of the present invention have obvious advantages.
  • cyclopropyl can also increase the rigidity of molecular branches, but compounds containing cyclopropyl branches have obvious metabolic problems and have a particularly long half-life.
  • cyclopentyl and cyclohexyl have relatively more conformations (for example, cyclohexyl has a chair conformation and a boat conformation), resulting in insufficient rigidity of molecular branches.
  • X is selected from -C(F)-, -C(CF 3 )-, -C(CN)-.
  • Fluorine atoms, trifluoromethyl groups and cyano groups are all strong electron-withdrawing groups. These strong electron-withdrawing groups can form hydrogen bonds with the target protein to enhance the binding force with the target, thereby further enhancing the activity of the drug, reducing the dosage and reducing toxic side effect.
  • the group R and the methylene group (-CH 2 -) connected to R and the methylene group at the meta position of the methylene group can also form a cis group shown in formula II.
  • the formula structure or the trans structure shown in formula III is as follows.
  • the compound of the present invention exhibits a cis or trans structure.
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, Ar; Ar is selected from benzene Group, naphthyl, quinolinyl, pyridyl, furyl, thienyl, pyrrolyl.
  • the molecular structure contains the NR 1 R 2 group attached to the cyclobutyl group.
  • These terminal substituents connected to the cyclobutyl group have a certain degree of freedom, which leads to an increase in the probability of the substituent group contacting the target mutation site, thereby increasing the group selectivity.
  • R 1 and R 2 can form a chain and an aromatic ring separately, and an aromatic ring or an aromatic heterocyclic ring can increase the fat solubility of the entire molecule, so that the molecule can reach the patient's site.
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, Ar;
  • Ar is selected from benzene Group, naphthyl, quinolinyl, pyridyl, furyl, thienyl, pyrrolyl;
  • heterocyclic group is selected from 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, 4-methyl-1 -Piperidinyl, 1-cyclobutylamino.
  • the molecular structure contains a -N(R 1 R 2 ) group linked to a cyclobutyl group. These groups can extend the rigidity of the side chain of the cyclobutyl, further increase the rigidity of the branched molecule, so as to increase the directionality of the molecule, and it is easy to better combine with the target.
  • the compound of the present invention is selected from any one of the following compounds:
  • the present invention also provides a method for preparing the compound of formula I according to claim 1, said method comprising the following reaction route:
  • the method includes the following steps:
  • the solvent 1 is selected from at least one of DMSO, DMF, acetonitrile, methanol, ethanol, and tert-butanol;
  • the alkaline reagent is selected from cesium carbonate, potassium carbonate, and sodium carbonate , At least one of sodium methoxide, sodium ethoxide, and sodium tert-butoxide;
  • the solvent 2 is selected from at least one of methanol, ethanol, isopropanol, and tert-butanol.
  • the benzyl group in compound C01 can be removed using methods commonly used in the art. In the method of the present invention, the benzyl group is removed by a hydrogenation reaction, wherein the hydrogenation reduction reaction includes hydrogenation of the compound C01 with hydrogen under the catalysis of a Pd/C catalyst to remove the benzyl group.
  • the Pd/C catalyst can be 5wt% Pd/C or 10wt% Pd/C commonly used in industry (5wt% or 10wt% represents the mass ratio of metal palladium in the Pd/C catalyst mixture). Based on the mass of compound C01, the addition ratio of 5wt% Pd/C or 10wt% Pd/C ranges from 5% to 20%;
  • the solvent 3 is selected from at least one of THF (tetrahydrofuran), DMF (N,N-dimethylformamide), and DCM (dichloromethane).
  • the present invention also provides a pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt of the compound or a solvate of the compound, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be made into a variety of dosage forms.
  • the preparation form of the pharmaceutical composition of the present invention may be an oral preparation or an injection.
  • the compound of the present invention is an inhibitor of tyrosine kinase activity.
  • it can be used in the treatment of diseases caused by the abnormal activity of protein kinases VEGFR2, EGFR, FGFR, and RET.
  • diseases can be It is a malignant tumor or cancer.
  • the diseases are tumor angiogenesis.
  • the present invention provides a method for treating cancer or tumor angiogenesis, which method comprises administering an effective dose of the compound of the present invention to a patient in need of treatment.
  • Halogen means F, Cl, Br, I, At.
  • C 1 -C 10 alkyl refers to an alkyl chain having 1-10 carbon atoms, which may be straight or branched. For example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and so on.
  • the hydrogen atom on the C1-10 alkyl carbon may be further substituted with a predetermined substituent.
  • C 3 -C 7 cycloalkyl refers to a cycloalkyl chain having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • the hydrogen atom on the carbon atom in the cycloalkyl group may be substituted with a predetermined substituent.
  • C 2 -C 10 alkenyl refers to an alkene chain with 2-10 carbon atoms containing a carbon-carbon double bond.
  • the carbon-carbon double bond can be on the main chain or on a branch, such as ethylene Group, propenyl, butenyl, isobutenyl, etc.
  • the hydrogen atom on the carbon atom on C2-10 may be further substituted with a predetermined substituent.
  • C 2 -C 10 alkynyl refers to an alkene chain with 2-10 carbon atoms containing a carbon-carbon triple bond.
  • the carbon-carbon triple bond can be on the main chain or on a branch, such as acetylene Group, propynyl, butynyl, isobutynyl, etc.
  • the hydrogen on the carbon atom on C2-10 may be further substituted with a predetermined substituent.
  • Ar can refer to an aromatic monocyclic or bicyclic group having 6-10 carbon atoms, or a 5-10 membered monocyclic/bicyclic heteroaryl group.
  • the carbon atoms on the ring can be substituted by N, O, S atoms, such as phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, furyl, thienyl, pyrrolyl, etc.; ring carbon
  • the hydrogen of the atom may be further substituted with a predetermined substituent.
  • Prodrug refers to a derivative of the compound of the present invention that is converted into a derivative of the compound of the present invention by oxidation, reduction, hydrolysis and other reactions catalyzed by enzymes in the living body under physiological conditions.
  • Metal refers to all molecules derived from the compounds of the present invention produced in cells or organisms (preferably humans).
  • Isotopic derivative refers to the structure constituting the compound of the present invention that contains one or more isotope atoms existing in unnatural proportions. For example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N).
  • Solidvate means that the compound of the present invention and the solvent molecule form a solvent complex in the form of physical bonding. This physical bond includes hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, tetrahydrofuran, ethyl acetate, acetonitrile and the like.
  • Compounds of formula (I) can be prepared in crystalline form and can be in solvate form (including hydrate form).
  • the pharmaceutically acceptable salt of the compound of formula (I) contains one or more basic or acidic groups, especially the pharmaceutically usable salt thereof.
  • alkali metal salt, alkaline earth metal salt, ammonium salt More precisely, it may be sodium salt, potassium salt, calcium salt, magnesium salt or organic amine such as ethylamine, ethanolamine, triethylamine or amino acid salt.
  • the compounds of the present invention can form protonated compounds of formula (I) with inorganic or organic acids. Examples of acids include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, tartaric acid, etc. Other acids known to those skilled in the art.
  • “Pharmaceutical composition” when used as a medicine refers to the composition of the compound of formula (I) of the present invention and its salts, isotope derivatives, metabolites, prodrugs, solvates and other substances with or without biological activity, It can be used to treat or prevent proliferative diseases (including angiogenesis) related to protease tyrosine kinase receptors, such as solid tumors and hematomas.
  • proliferative diseases including angiogenesis
  • Figure 1 is the general structure of the compound of formula I according to the present invention.
  • Figure 2 shows the average tumor volume of the compound of Example 22 applied in an ovarian cancer SK-OV-3 model
  • Figure 3 shows the body weight changes of experimental animals in which the compound of Example 22 is applied in an ovarian cancer SK-OV-3 model
  • Figure 4 shows the average tumor volume of experimental animals in which the compound of Example 26 is applied in an ovarian cancer SK-OV-3 model
  • Figure 5 shows the weight change of experimental animals when the compound of Example 26 is applied in an ovarian cancer SK-OV-3 model
  • Figure 6 shows the average tumor volume of experimental animals in which the compound of Example 26 is applied in the Caki-1 model of renal cancer
  • Figure 7 shows the weight changes of experimental animals in each experimental group in the application of the compound of Example 26 in the Caki-1 model of renal cancer.
  • Example 22 cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclohexanone reductive amination reaction to synthesize cis-N-3-(((4-((4-fluoro-2-methyl-1H-indyl) Dol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclohexylamine.
  • Example 32 trans-3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yl (Oxy)methyl)cyclobutylamine hydrochloride reacts with 1,4-dibromobutane to synthesize trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)- 6-Methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy)quinazoline.
  • Example 23 trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclohexanone reductive amination reaction to synthesize trans-N-3-(((4-((4-fluoro-2-methyl-1H-indyl) Dol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclohexylamine.
  • trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride undergoes reductive amination reaction with cyclobutanone, and is separated and purified by preparative liquid chromatography under formic acid conditions to obtain trans-N,N-dicyclobutyl-3 -(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutylamine .
  • Example 23 trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclopentanone undergo reductive amination reaction to synthesize trans-N-3-(((4-((4-fluoro-2-methyl-1H- Indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclopentylamine.
  • Example 26 cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinoline-7- (Yl)oxy)methyl)cyclobutylamine hydrochloride and 1,4-dibromobutane to synthesize cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy) )-6-Methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy)quinoline formate.
  • Example 48 1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine salt
  • the acid salt is used as the raw material to undergo reductive amination reaction with paraformaldehyde, which is purified by preparative liquid chromatography under formic acid conditions to synthesize 1-(((4-((1H-indol-5-yl)oxy)-6-methoxy Quinolin-7-yl)oxy)methyl)-N,N-dimethylcyclopropylamine.
  • In vitro activity evaluation uses the HTRF KinEASE-TK detection kit produced by Cisbio.
  • HTRF KinEASE-TK detection kit is a universal kit for activity detection of tyrosine kinase.
  • VEGFR2 is a kind of tyrosine kinase.
  • the biotin-labeled substrate will undergo an enzymatic reaction under the catalysis of the kinase VEGFR2 to bring the substrate with a phosphate group.
  • the detection reagent Streptavidin-XL665 can be combined with biotin on the substrate through Streptavidin.
  • Another detection reagent, TK-antibody-Eu3+-Cryptate can bind to phosphorylated substrates. Energy is transferred from the donor Eu to the acceptor XL665, which makes the XL665 emit light.
  • the resulting signal is directly proportional to the level of phosphorylation of the substrate.
  • a small molecule inhibitor of VEGFR2 hinders the phosphorylation reaction of VEGFR2
  • the distance between Eu and XL665 will affect the occurrence of fluorescence energy transfer and the signal will be weakened.
  • the signal intensity change is used to judge the blocking of VEGFR2 kinase activity by small molecule inhibitors.
  • Cisbio's HTRF KinEASE-TK kit manual 62TK0PEB, 62TK0PEC and 62TK0PEJ for specific experimental operation methods. A brief description is as follows. Take a new 384-well ELISA plate, add 4 ⁇ L of enzyme reaction buffer to the positive reaction wells, add 6 ⁇ L of enzyme reaction buffer to the negative reaction wells, and add 4 ⁇ L of enzyme reaction buffer to the test wells. Dilute small molecule compounds of different concentrations to be tested. Then add 2 ⁇ L ATP, 2 ⁇ L substrate, 2 ⁇ L VEGFR2 enzyme to each well, and incubate at room temperature for 40min to 1h.
  • A means the activity range is 0.1-1 nM; B means the activity range is 1-10 nM; C means the activity range is greater than 10 nM.
  • the compounds in Examples 1-19 of the present invention have lower IC50 for the tyrosine kinases VEGFR, EGFR, FGFR, and RET, indicating that the tyrosine kinases VEGFR, EGFR, FGFR, and RET have a lower IC50 for the tyrosine kinases of the present invention.
  • the compound has good sensitivity and can be effectively used in the treatment of diseases related to abnormal tyrosine kinase activity.
  • Examples 48 to 52 are examples of cyclopropyl substitution.
  • the present invention uses cyclobutyl to replace the side chain, which greatly enhances the directionality and selectivity of the molecule, and makes it an order of magnitude improvement in enzymatic activity.
  • the structure of the compound in Example 33 (IC50 of 2.21 nM) is similar to that of the positive control cediranib (IC50 of 3.62 nM), but compared with cediranib, the drug activity has also been improved to a certain extent.
  • Example 22 has a four-membered cyclobutyl substituted side chain.
  • the bioavailability (F%) increased by 2-3 times, while the in vivo exposure (AUC inf ) increased by 4-6 times, the maximum blood concentration (C max ) was also significantly increased, indicating that the four-membered cyclobutyl substitution example has more Superior medicinal properties.
  • Example 22 To evaluate the anti-tumor effects of Example 22 and Example 26 on the CDX model of ovarian cancer SK-OV-3 cell subcutaneous tumor in mice.
  • Subcutaneous tumor transplantation method Inoculate 1 ⁇ 10 7 SK-OV-3 cells subcutaneously on the right back of the tested mouse BALB/c-nude mice (18-22g), and resuspend the cells in PBS suspension, each Inoculate 0.1mL. Regularly observe the tumor growth. When the average tumor volume reaches 100-200mm 3 , the drugs are randomly divided into groups according to the tumor size and the weight of the mice. The grouping day is set to Day 0, and the administration starts on Day 0.
  • the experiment is divided into vehicle control group, low-dose group (1.5mg/kg), medium-dose group (2.5mg/kg) and high-dose group (5mg/kg), vehicle control group 3 mice, Example 22 and Examples 26 low-, medium-, and high-dose groups of 6 mice in each group were administered orally once a day for three weeks.
  • T/C relative tumor proliferation rate
  • TGI% relative tumor inhibition rate
  • the experimental animals are kept in an independent ventilated IVC box with constant temperature and humidity, and adapt to the environment for at least 7 days in advance.
  • the breeding room temperature is 20-26°C
  • humidity is 40-70%
  • ventilation is 10-20 times per hour
  • Light give animals cobalt 60 radiation sterilized complete pellet feed for rats, and unlimited free intake of drinking tap water sterilized by high-pressure steam.
  • Example 22 and Example 26 exhibited significant dose-dependent tumor suppression on the CDX model of ovarian cancer SK-OV-3, and Example 22 at 1.5 mg/kg
  • the TGI% of, 2.5mg/kg and 5mg/kg were 77.53%, 97.67% and 113.82%, respectively.
  • the TGI% of Example 26 at 1.5 mg/kg, 2.5 mg/kg, and 5 mg/kg were 69.59%, 103.05% and 109.13%, respectively.
  • Example 26 showed a dose-dependent tumor suppression on the CDX model of renal cancer Caki-1. It has obvious tumor suppression effects at the doses of 2.5 mg/kg and 5 mg/kg, and the tumor growth inhibition rate (TGI%) is 63.43% and respectively. 77.45%, the tumor weight analysis result was consistent with the relative tumor volume analysis result, and compared with the control group, there was a statistically significant difference (p ⁇ 0.01). In all the treatment groups of Example 26, there were no animal deaths and compound-related toxicity reactions, and the animal weights increased at the end of the administration. The experimental results are shown in Figure 6, Figure 7, Table 6 and Table 7.
  • the present invention provides a compound containing cyclobutyl. Experimental results show that the compound of the present invention can be used in the treatment of tumor diseases caused by abnormal activity of tyrosine kinases such as VEGFR, and has good application prospects.

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Abstract

La présente invention relève du domaine de la technologie médicale, et concerne un composé tel que représenté par la formule I ou un sel pharmaceutiquement acceptable, un cis-isomère ou un trans-isomère, un promédicament, un métabolite, un dérivé isotopique et un solvate de celui-ci. Le composé selon la présente invention est un composé contenant du cyclobutyle utilisé en tant qu'inhibiteur de tyrosine kinase, et peut être utilisé pour le traitement de maladies tumorales associées à la tyrosine kinase, en particulier VEGFR. Du fait de la présence du groupe cyclobutyle, les substituants en position 1 et 3 ont des configurations cis et trans. La rigidité d'une molécule à chaîne ramifiée et la directivité de la molécule peuvent être améliorées, et le composé peut être facilement lié à une cible, de telle sorte que le dosage d'un médicament peut être diminué, et les effets secondaires du médicament sont réduits. La présente invention concerne également un procédé de préparation, l'activité kinase, des données pharmacocinétiques, et des données pharmacodynamiques du composé, et les résultats montrent que le composé selon la présente invention a une large gamme d'applications dans le traitement de maladies tumorales provoquées par une activité anormale des tyrosine kinases telles que VEGFR.
PCT/CN2021/073616 2020-03-18 2021-01-25 Inhibiteur de l'angiogenèse, son procédé de préparation et son utilisation Ceased WO2021184958A1 (fr)

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