WO2016110237A1 - Composé d'a-carboline, procédé de préparation correspondant et ses utilisations - Google Patents

Composé d'a-carboline, procédé de préparation correspondant et ses utilisations Download PDF

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WO2016110237A1
WO2016110237A1 PCT/CN2016/070110 CN2016070110W WO2016110237A1 WO 2016110237 A1 WO2016110237 A1 WO 2016110237A1 CN 2016070110 W CN2016070110 W CN 2016070110W WO 2016110237 A1 WO2016110237 A1 WO 2016110237A1
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compound
group
substituted
formula
unsubstituted
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PCT/CN2016/070110
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杨春皓
缪泽鸿
张小飞
衣君玫
贺茜
宦霞娟
宋姗姗
王迎庆
陈奕
丁健
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中国科学院上海药物研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the fields of medicinal chemistry and medical treatment. Specifically, it relates to a kind of mother core compound containing ⁇ -carboline (9H-pyrido[2,3-b]indole), a pharmaceutically acceptable salt thereof and a hydrate thereof, and a preparation method thereof and their treatment and topological difference
  • ⁇ -carboline 9H-pyrido[2,3-b]indole
  • a pharmaceutically acceptable salt thereof and a hydrate thereof and a preparation method thereof and their treatment and topological difference
  • the use of enzyme II and drugs for tubulin-related diseases such as tumors.
  • DNA plays a very important role in the entire life process.
  • DNA topoisomerase regulates and maintains the complex topology of DNA. Since J.C. Wang discovered the first ⁇ protein that can change the DNA topology in 1971, researchers have studied the DNA topoisomerase in detail.
  • DNA topoisomerases are classified into topoisomerase I and topoisomerase II, depending on the mechanism of action and biological structure.
  • the eukaryotic topoisomerase II is a homodimer comprising two subtypes: TopoII ⁇ and TopoII ⁇ .
  • TopoII ⁇ tends to act on positive supercoiled DNA, while TopoII ⁇ does not show specific selectivity to supercoiled DNA conformation; TopoII ⁇ plays an important role in cell proliferation, in cell fast The high proliferative phase can be used as a marker to judge the degree of cell proliferation; TopoII ⁇ is relatively stable in cells and has no correlation with cell proliferation status and cell cycle. TopoI produces a single-strand break on the DNA duplex, allowing another single strand to pass through the gap, altering the situation of DNA supercoil or helix.
  • TopoII differs from TopoI in its mechanism of cleavage, which produces a double-strand break on the DNA backbone, allowing another double-stranded DNA to pass through the gap. In addition to performing all TopoI functions, TopoII also separates sister chromatids that crosslink each other after DNA replication is complete. DNA topoisomerase II inhibitors disrupt enzyme activity by affecting various stages of the TopoII enzyme action process. It can act directly on DNA, or on topoisomerase II, and can also act on DNA topoisomerase II-DNA cleavage complex to complete the inhibition of topoisomerase II activity and ultimately lead to cell death. Die.
  • topoisomerase II inhibitors Based on the understanding of the key role of TopoII in cells, the study of topoisomerase II inhibitors has been one of the hot spots in the development of anti-tumor drugs.
  • topoisomerase II inhibitors are etoposide, teniposide, doxorubicin, idarubicin, epirubicin and mitoxantrone.
  • Microtubules are the main components of the cytoskeleton. They are composed of ⁇ -tubulin and ⁇ -tubulin heterodimer and have the characteristics of hollow tubular structure. In addition, there is a gamma tubulin, which is not a component of microtubules but participates in the assembly of microtubules. Microtubules have the kinetic properties of polymerization and depolymerization and play an important role in maintaining cell morphology, cell division, signal transduction and material transport. Microtubules polymerize into spindles in the early stage of cell division, and the spindle in the mitosis pulls the chromosomes into the two poles and moves into the two daughter cells to complete cell proliferation.
  • tubulin inhibitors acting on microtubule systems have also become an effective class of antitumor drugs.
  • Tubulin inhibitors are classified into two types depending on the mechanism of action: a tubulin depolymerization inhibitor that inhibits tubulin polymerization and a tubulin polymerization agent that promotes tubulin polymerization.
  • tubulin inhibitors acting on the colchicine site and tubulin inhibitors acting on the vinblastine site.
  • tubulin inhibitors acting on the vinblastine site and acting on yew Tubulin inhibitor at the alcohol site.
  • a large number of structurally diverse tubulin inhibitors have been synthesized, and some compounds have shown strong anti-tumor effects.
  • DNA topoisomerase II inhibitors and tubulin inhibitors are often used in combination to treat tumors.
  • Common doxorubicin, etoposide combined with vincristine and paclitaxel are used to treat leukemia, lung cancer, breast cancer and stomach cancer. .
  • Combination therapy has many advantages. For example, the combination of paclitaxel and doxorubicin not only synergizes the treatment of cancer, but also reduces side effects caused by drug toxicity. In addition, combination therapy can also slow tumor resistance to a certain extent.
  • dual inhibitors of DNA topoisomerase II and tubulin will be easier and easier to control than combination therapy. However, there are no reports of DNA topoisomerase II and tubulin dual inhibitors at this stage.
  • the ⁇ -carboline (9H-pyrido[2,3-b]indole) is one of the porphyrin compounds.
  • the porphyrin is a pyridoindole structure. According to the difference of the pyridine nitrogen atom, the Greek letters are different in the porphyrin prefix.
  • the ⁇ -carboline compound is the most common in the natural product, and the ⁇ -porphyrin compound. There are relatively few studies.
  • ⁇ -carboline compounds have excellent biological activity, and exhibit excellent antiviral and anticancer activities due to their binding activity to DNA or inhibitory activity against Topo-II.
  • the ⁇ -carboline compounds also have antidepressant and antipsychotic effects.
  • Alpha-carboline derivatives are also useful as kinase inhibitors, such as cell cycle dependent kinase inhibitors, tyrosine kinase inhibitors and the like.
  • ⁇ -carboline compounds have antimalarial activity.
  • R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of hydrogen, halogen, nitro, amino, hydroxy, substituted or unsubstituted C1-C4 straight or branched alkyl, substituted or unsubstituted Substituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 linear or branched alkoxy group, substituted or unsubstituted C1-C4 linear or branched alkylene-amino group, substituted Or an unsubstituted C1-C4 linear or branched amine group, and a substituted or unsubstituted saturated five- or six-membered heterocyclic group containing oxygen or nitrogen;
  • R 5 is selected from the group consisting of hydrogen, a substituted or unsubstituted C1-C4 linear or branched alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 linear chain. Or a branched alkoxy group, a substituted or unsubstituted C1-C4 linear or branched alkylene-hydroxy group, a substituted or unsubstituted C1-C4 linear or branched amine group, and a substituted or unsubstituted a saturated five- or six-membered heterocyclic group containing oxygen or nitrogen;
  • R 6 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, methylamino, dimethylamino, substituted or unsubstituted C1-C4 straight or branched alkoxy, substituted or unsubstituted C1-C4 straight a branched or branched amino group, a substituted or unsubstituted C1-C4 linear or branched amino-oxy group;
  • R 7 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, methyl, methoxy, methylamino, dimethylamino, -OAc, methoxycarbonyl, acetylamino, substituted or unsubstituted C1-C4 straight chain Or a branched alkyl group, a substituted or unsubstituted C1-C4 linear or branched alkoxy group, a substituted or unsubstituted C1-C4 linear or branched amine group;
  • R 8 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, methyl, methoxy, methylamino, dimethylamino, methoxycarbonyl, acetylamino, methylsulfonyl, substituted or unsubstituted C1-C4 straight a branched or branched alkyl group, a substituted or unsubstituted C1-C4 linear or branched alkoxy group, a substituted or unsubstituted C1-C4 linear or branched amine group;
  • X is a linking group selected from the group consisting of methylene, oxygen, sulfur, carbonyl, sulfoxide, sulfone,
  • said one or more hydrogen atoms on the substituent group are substituted with a substituent selected from the group consisting of halogen, C1-C8 alkyl-amino group, hydroxyl group, methylamino group, amino group, C1-C8 Alkyl-oxyl.
  • the substituted alkyl group is substituted with a substituent selected from the group consisting of an oxygen-containing group, a nitrogen-containing group, or a fluorine atom.
  • R 5 is selected from the group consisting of hydrogen, hydroxyethyl, N,N-dimethylaminoethyl;
  • R 6 is selected from the group consisting of hydrogen, hydroxy, -NH-CH 3 , -NH 2 , -N(CH 3 ) 2 , -O(CH 2 ) 2 OH, -O(CH 2 ) 2 N(CH 3 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, fluorine, hydroxyl, methyl, methoxy, acetylamino, -OAc;
  • R 8 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, acetylamino, dimethylamino, methylsulfonate;
  • X is selected from the group consisting of oxygen, sulfur, Carbonyl, sulfoxide, sulfone,
  • R 1 is hydrogen or halogen
  • R 2 is hydrogen, halogen, methoxy, dimethylamino, morpholinyl
  • R 3 is hydrogen, halogen, methoxy
  • R 4 is hydrogen, halogen or methoxy
  • R 5 is hydrogen, hydroxyethyl, N,N-dimethylaminoethyl
  • R 6 is H, -OH, -O(CH 2 ) 2 OH, -O(CH 2 ) 2 N(CH 3 ) 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH 2 ;
  • R 7 is H, halogen, -OCH 3 , -OH, -OAc;
  • R 8 is H, halogen, methyl, -OCH 3 , -SO 2 -CH 3 , -N(CH 3 ) 2 , -NHAc.
  • R 1 is hydrogen or fluorine
  • R 2 is hydrogen, fluorine, chlorine, methoxy, dimethylamino, morpholinyl
  • R 3 is hydrogen, fluorine, chlorine or methoxy
  • R 4 is hydrogen, fluorine or methoxy
  • R 5 is hydrogen, hydroxyethyl, N,N-dimethylaminoethyl
  • R 6 is hydrogen, hydroxy, amino, methylamino, dimethylamino, -O(CH 2 ) 2 OH, -O(CH 2 ) 2 N(CH 3 ) 2 ;
  • R 7 is hydrogen, fluorine, hydroxyl, methoxy, -OAc
  • R 8 is hydrogen, fluorine, chlorine, bromine, methoxy, acetylamino, dimethylamino, methylsulfonate;
  • X is a linked sulfur, methylamino, carbonyl, sulfoxide, sulfone group,
  • any one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and X is a specific compound described in the examples. The corresponding group in the middle.
  • the compound of formula I has a structure selected from the group consisting of:
  • the compound is a compound selected from the group consisting of I-4, I-11, I-16, I-23, I-28, I-32, I-33, I-37. , I-36, I-34, I-41.
  • a process for the preparation of a compound according to the first aspect of the invention comprising the step (b) and optionally (c), (c1) and/or (c2):
  • the method further comprises the steps of:
  • Y is selected from the group consisting of chlorine, iodine, bromine, mesylate, p-toluenesulfonate, triflate; the remainder of each group is as defined in the first aspect of the invention Said.
  • step (a) is carried out in the presence of acetic anhydride and/or sodium acetate.
  • the molar ratio of the compound of formula 1 to sodium acetate is from 1:0.8 to 1.2.
  • the molar ratio of the compound of formula 1 to the compound of formula 2 is from 1:0.8 to 1.2.
  • the step (a) is carried out in the presence of titanium tetrachloride and pyridine (preferably, the molar ratio of the compound of the formula 1 to titanium tetrachloride is 1:1 to 3).
  • the organic solvent is selected from the group consisting of acetic anhydride, pyridine, tetrahydrofuran, dioxane, DMF, N-methylpyrrolidone, dichloromethane, Chloroform, or a combination thereof.
  • the reaction temperature is 70-100 °C.
  • the reducing agent is selected from the group consisting of hydrogen, iron powder, zinc powder, sulfide; more preferably iron powder or zinc powder.
  • step (b) is carried out under reflux of acetic acid.
  • the organic solvent is selected from the group consisting of acetic acid, tetrahydrofuran, dioxane, N,N-dimethylformamide, and N-methylpyrrolidone. , or a combination thereof.
  • the reaction temperature is from 90 to 130 °C.
  • the base is selected from the group consisting of sodium hydride, potassium t-butoxide, sodium t-butoxide, or a combination thereof; preferably sodium hydride.
  • the reaction temperature is 10 to 40 ° C (preferably room temperature).
  • the organic solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, or Its combination.
  • a process for the preparation of a compound according to the first aspect of the invention which comprises the step (d):
  • the method comprises the step (e) and the optional step (f):
  • the base is selected from the group consisting of sodium t-butoxide, and/or potassium t-butoxide.
  • the reaction in the step (d), is carried out in the presence of a transition metal, preferably Pd or Cu.
  • the reaction in the step (d), is carried out in the presence of a catalyst; preferably, the catalyst is selected from the group consisting of zero-valent palladium, a phosphine ligand, or a combination thereof. .
  • the reaction temperature is from 100 to 120 °C.
  • the inert solvent is t-butanol.
  • the base is selected from the group consisting of methyl lithium, n-butyl lithium, t-butyl lithium, or a combination thereof; preferably methyl lithium, uncle Butyl lithium, or a combination thereof.
  • the reaction temperature is -80 ° C to room temperature (10 to 40 ° C).
  • the inert solvent is anhydrous tetrahydrofuran.
  • the oxidizing agent is selected from the group consisting of chromium trioxide/pyridine, chromium trioxide/sulfuric acid, Dess-Martin oxidizing agent or manganese dioxide, or a combination thereof; Preferred is the Dess-Martin oxidant.
  • the inert solvent is dichloromethane.
  • the reaction temperature is 10 to 40 ° C (preferably room temperature).
  • the method further comprises an optional step (d1) of preparing a compound of formula Ic' with a compound of formula Ic;
  • X' is selected from the group consisting of methylene, oxygen, sulfur, carbonyl, sulfoxide, sulfone, And X' is different from X.
  • a fourth aspect of the invention provides a use of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, for (a) non-therapeutic inhibition of tumors in vitro Cell growth; (b) preparation of a pharmaceutical composition for treating tumor; (c) non-therapeutic inhibition of topoisomerase II activity in vitro; (d) non-therapeutic inhibition of tubulin activity in vitro; (e) in vitro Non-therapeutic depolymerization of cell microtubules; (f) non-therapeutic inhibition of proliferation of tumor cells in vitro; (g) preparation of a pharmaceutical composition having topoisomerase II and tubulin dual inhibitory activity.
  • the tumor cells are selected from the group consisting of oral cancer cells, lung cancer cells, liver cancer cells, leukemia cells, gastric cancer cells, cervical cancer cells, ovarian cancer cells, breast cancer cells, colon cancer cells, prostate cells. Cancer cells, or a combination thereof.
  • the inhibitory activity when the compound of formula I is used to inhibit tumor cell proliferation growth, has an IC 50 value of from 1 to 2000 nmol, preferably from 2 to 1000 nmol, more preferably from 10 to 500 nmol.
  • a topoisomerase II activity inhibitor comprising an inhibitory effective amount of a compound according to the first aspect of the invention, or a pharmaceutical thereof An acceptable salt or hydrate.
  • a cell microtubule depolymerizing agent comprising a depolymerization effective amount of a compound according to the first aspect of the invention, or a pharmaceutically acceptable thereof, is provided Salt or hydrate.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof.
  • the pharmaceutical composition is a pharmaceutical composition for treating a tumor.
  • the pharmaceutical composition is for inhibiting the activity of topoisomerase II.
  • the pharmaceutical composition is for inhibiting the activity of tubulin.
  • the pharmaceutical composition of the pharmaceutical composition comprises an oral preparation, an injection, and an external preparation.
  • a topoisomerase II and a tubulin dual inhibitor comprising a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof or Hydrate.
  • the dual inhibitor is used to treat a tumor.
  • the dual inhibitor inhibits expression of a protein selected from the group consisting of MCL-1 (myeloid cell leukemia-1), cIAP1 (cellular inhibitor of apoptosis protein-1) or XIAP (X- Linked inhibitor of apoptosis protein).
  • MCL-1 myeloid cell leukemia-1
  • cIAP1 cellular inhibitor of apoptosis protein-1
  • XIAP X- Linked inhibitor of apoptosis protein
  • a ninth aspect of the invention provides a method of treating a tumor, the method comprising the steps of: administering to a subject in need thereof a safe and effective amount of a compound as described in the first aspect of the invention or as in the seventh aspect of the invention Said pharmaceutical composition.
  • Figure 1 is an antitumor spectrum of Compound I-4;
  • Figure 2 is the effect of Compound I-4 on cell microtubules (the scale length in the figure indicates 10 ⁇ M);
  • Figure 3 is a graph showing the inhibitory effect of Compound I-4 on Top2 enzyme activity
  • Figure 4 shows the difference between Compound I-4 and the combination in HeLa cells.
  • the inventors have conducted long-term and intensive studies to provide a class of compounds having the structure shown in Formula I, which inhibits the kDNA helicase activity of topoisomerase II and promotes the depolymerization of cellular tubulin. In turn, the growth of tumor cells is inhibited. Based on the above findings, the inventors completed the present invention.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 naphthenic a group, a C 1 -C 10 alkoxy group, a halogen, a hydroxyl group, a carboxyl group (-COOH), a C 1 -C 10 aldehyde group, a C 2 -C 10 acyl group, a C 2 -C 10 ester group, an amino group, a phenyl group;
  • the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, cyano, OH, nitro, C 3 ⁇ C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • C 1 -C 4 alkyl refers to a straight or branched alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Base, tert-butyl, or the like.
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like.
  • C 1 -C 4 alkoxy refers to a straight or branched alkoxy group having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy , isobutoxy, sec-butoxy, tert-butoxy, or the like.
  • halogen refers to F, Cl, Br and I.
  • C 1 -C 4 amine group means a group having a structure of "C 1 -C 4 alkyl-NH-" or "(alkyl) 2 -N- (total number of carbon atoms 1-4)", for example CH 3 NH-, C 2 H 5 NH-, C 3 H 7 NH-, (CH 3 ) 2 N-, or the like. Wherein, the definition of C 1 -C 4 alkyl is as defined above.
  • C 1 -C 4 alkylene-amino refers to having "C 1 -C 4 alkylene-NH 2 ", “alkyl-N-alkylene- (total number of carbon atoms 1-4)" Or a group of "(alkyl) 2 -N-alkylene-(the total number of carbon atoms is 1-4)" structure, such as -CH 2 NH 2 , -C 2 H 5 NH 2 , -C 3 H 7 NH 2 , -C 2 H 4 N(CH 3 ) 2 , or the like.
  • the C 1 -C 4 alkylene group is a group in which a C 1 -C 4 alkyl group loses one hydrogen atom, and the C 1 -C 4 alkyl group has the same meaning as defined above.
  • R 1 , R 2 , R 3 , R 4 are hydrogen or halogen, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, C1-C4 containing oxygen, nitrogen or fluorine. a linear or branched alkyl group, an alcohol or an amine, and a saturated five- or six-membered heterocyclic group containing oxygen or nitrogen;
  • R 5 is hydrogen, a C1-C4 linear or branched alkyl group, a C3-C6 cycloalkyl group, an oxygen or nitrogen-containing C1-C4 linear or branched alkyl group, an alcohol or an amine, and an oxygen or a saturated five- or six-membered heterocyclic group of nitrogen;
  • R 6 is hydrogen, halogen, hydroxy, amino, methylamino, dimethylamino, a C1-C4 linear or branched alkyl group, an alcohol or an amine containing oxygen or nitrogen;
  • R 7 is hydrogen, halogen, hydroxy, amino, methoxy, methylamino, dimethylamino, methoxycarbonyl, acetylamino, a C1-C4 linear or branched alkyl group, an alcohol or an amine containing oxygen or nitrogen;
  • R 8 is hydrogen, halogen, hydroxy, amino, methoxy, methylamino, dimethylamino, methoxycarbonyl, acetylamino, methylsulfonyl, a C1-C4 linear or branched alkyl group containing oxygen or nitrogen, Alcohol or amine;
  • X is a linking group and may be a methylene group, an oxygen group, a sulfur group, a carbonyl group, a sulfoxide group, a sulfone group,
  • R 1 , R 2 , R 3 , R 4 are hydrogen, halogen, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, C1 containing oxygen, nitrogen or fluorine. a linear or branched alkyl group, an alcohol or an amine of -C4, and a saturated five- or six-membered heterocyclic group containing oxygen or nitrogen;
  • R 5 is hydrogen, hydroxyethyl, N,N-dimethylaminoethyl
  • R 6 is hydrogen, hydroxy, amino, methylamino, dimethylamino, -O(CH 2 ) 2 OH, -O(CH 2 ) 2 N(CH 3 ) 2 ;
  • R 7 is hydrogen, fluorine, hydroxyl, methoxy, methoxycarbonyl, acetylamino
  • R 8 is hydrogen, fluorine, chlorine, bromine, methoxy, acetylamino, dimethylamino, methylsulfonate;
  • X is the link of oxygen, sulfur, Carbonyl, sulfoxide, sulfone,
  • R 1 is hydrogen, fluorine
  • R 2 is hydrogen, fluorine, chlorine, methoxy, dimethylamino, morpholinyl
  • R 3 is hydrogen, fluorine, chlorine or methoxy
  • R 4 is hydrogen, fluorine, methoxy
  • R 5 is hydrogen, hydroxyethyl, N,N-dimethylaminoethyl
  • R 6 is hydrogen, hydroxy, amine, methylamino, dimethylamino, -O(CH 2 ) 2 OH, -O(CH 2 ) 2 N(CH 3 ) 2 ;
  • R 7 is hydrogen, fluorine, hydroxyl, methoxy or methoxycarbonyl
  • R 8 is hydrogen, fluorine, chlorine, bromine, methoxy, acetylamino, dimethylamino, methylsulfonate;
  • X is a linked sulfur, methylamino, carbonyl, sulfoxide, sulfone group,
  • the invention provides a compound as shown below:
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula I, the synthesis route being as shown in Scheme 1 or 2:
  • the step a) is that the compound 1 and the compound 2 are dissolved in acetic anhydride, and the reaction is stirred overnight at 70-100 ° C under the action of sodium acetate, and the reaction is complete by thin layer chromatography.
  • step b) The condition of the step b) is that the compound 3 is refluxed under the reduction of iron powder or zinc powder, and the reaction is completed by thin layer chromatography.
  • step c) The condition of the step c) is that the compound 4 is substituted with room temperature to form the compound I under the action of sodium hydride.
  • Part of Compound 8 is further oxidized to the final production I under the action of an oxidizing agent (chromium trioxide/pyridine, chromium trioxide/sulfuric acid, Dess-Martin oxidizing agent or manganese dioxide).
  • an oxidizing agent chromium trioxide/pyridine, chromium trioxide/sulfuric acid, Dess-Martin oxidizing agent or manganese dioxide.
  • the conditions of the step d) are: compound 7 and compound 8 are treated with t-butanol as a solvent, sodium tert-butoxide as a base, 0-valent palladium and a phosphine ligand as a catalyst, and reacted at 100-120 ° C to a thin layer chromatography. The reaction is complete.
  • the conditions of the step e) are: anhydrous tetrahydrofuran as a solvent, methyl lithium, t-butyllithium as a base, and reacted at -80 ° C to room temperature.
  • the condition of the step f) is: dichloromethane as a solvent, the oxidant is a Dess-martin oxidant, and reacted to a thin room at room temperature. The reaction was confirmed by layer chromatography.
  • the inventors designed to synthesize a class of topoisomerase II and tubulin dual inhibitors containing an alpha-carboline parent core as shown in Formula I.
  • the compounds of formula I have a well-defined structure-activity relationship, and some of the compounds show strong cell proliferation inhibition, such as compounds I-4, I-32, I-33 and the like.
  • Such new structures of ⁇ -carboline compounds are expected to become novel antitumor drugs, including oral cancer, lung cancer, liver cancer, leukemia, gastric cancer, cervical cancer, ovarian cancer, breast cancer, colon cancer and prostate cancer.
  • the compound of formula I exhibits a mechanism of action different from that of a topoisomerase II inhibitor (such as etoposide) and a tubulin inhibitor (such as vincristine) in an apoptosis-inducing assay.
  • the dual inhibitor inhibits the expression of a protein selected from the group consisting of MCL-1 (myeloid cell leukemia-1), cIAP1 (cellular inhibitor of apoptosis protein-1) or XIAP (X-linked inhibitor). Of apoptosis protein, and the above-mentioned protein was not observed to be inhibited in the combination.
  • the compound of the present invention Since the compound of the present invention has excellent dual inhibitory activity against topoisomerase II and tubulin, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, And a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with topoisomerase II and/or tubulin activity or expression, particularly suitable for topoisomerase II A disease associated with both tubulin activity or expression. According to the prior art, the compounds of the present invention are useful for the treatment of diseases such as oral cancer, lung cancer, liver cancer, leukemia, gastric cancer, cervical cancer, ovarian cancer, breast cancer, colon cancer and prostate cancer.
  • diseases such as oral cancer, lung cancer, liver cancer, leukemia, gastric cancer, cervical cancer, ovarian cancer, breast cancer, colon cancer and prostate cancer.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorption Speeding agents, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • a novel structure of a compound having both inhibitory activity of topoisomerase II and tubulin inhibitory activity is provided.
  • starting compound 1, compound 2, compound 5 compound 6 and compound 7 were purchased from Shanghai Shuiya Pharmaceutical Technology Co., Ltd., Haoyuan Technology (Shanghai) Co., Ltd., Beijing Bailingwei Technology Co., Ltd., Shanghai Jingchun Biochemical Technology Co., Ltd. Co., Ltd., Shanghai Titan Technology Co., Ltd.
  • the palladium catalyst and phosphine ligand were purchased from Beijing Belling Technology Co., Ltd.
  • other starting reagents, solvents, and materials are all sourced from Sinopharm Reagent Group.
  • 1 H NMR was recorded by a Brucher AM-400 or GEMINI-300 nuclear magnetic resonance apparatus, and chemical shifts were expressed in ⁇ (ppm).
  • inhibition rate (%) (OD control well- OD administration well ) / OD control well ⁇ 100%, and according to the logit method, the 50% inhibition rate was calculated.
  • Compound concentration, ie IC 50 value The experiment was repeated 3 times and the mean and standard deviation were calculated.
  • Top2-mediated supercoiled pBR322 relaxation (Reference: Meng LH, Zhang JS, Ding J. Salvicine, a novel DNA topoisomerase II inhibitor, exerting its effects by trapping enzyme-DNA cleavage Complexes. Biochemical Pharmacology 2001; 62(6): 733-41).
  • the principle is that the kDNA structure is network-like, the molecular weight is too large to enter the 1% agarose gel, and Top2 can catalyze its de-coupling reaction, producing 2.5KB of monomeric circular DNA, which can quickly enter 1% agar. In the glycogel, the effect of the compound on the ring-shaped DNA of the monomer is examined to reflect its effect on Top2 activity.
  • Buffer 4 ⁇ l 10 ⁇ DNA Top2 buffer (mixed by buffer A and B in the Top2 assay kit,
  • Compound I-4 induces tumor cell apoptosis and the difference between etoposide (Top2 inhibitor) and vincristine (tubulin inhibitor)
  • the HeLa cells in the logarithmic growth phase were seeded in a 6-well culture plate at a suitable density, and the cells were adhered to the corresponding concentration of the compound overnight, and the corresponding time was applied at 37 °C.
  • the transfer condition and the position of the protein band on the nitrocellulose membrane were determined by Ponceau S staining, and the blocking solution containing 5% skim milk powder was used after labeling [5% skim milk powder, 20 mM Tris-HCl pH 7.2-7.4, 150 mM NaCl, 0.1% Tween-20] was blocked at room temperature for 30 min at room temperature. Then, the membrane was placed in a primary antibody diluted in blocking solution (5% skimmed milk powder) at 4 ° C overnight.
  • the experimental results show that in the induction of apoptosis experiments, in combination with concentration and time, the mechanism of apoptosis induced by compound I-4 is similar to that of vincristine, but different from etoposide, which is different from the combination of the two.
  • the combination of the two drugs could not inhibit the expression of MCL-1 (myeloid cell leukemia-1), cIAP1 (cellular inhibitor of apoptosis protein-1) and XIAP (X-linked inhibitor of apoptosis protein) in HeLa cells.
  • the experiment showed that the compound I-4 differed from the combination in the mechanism of inducing tumor cell apoptosis (Fig. 4).
  • the resistant cell lines were vincristine-resistant KB cells (KB/VCR), doxorubicin-resistant MES-SA cells (MES-SA/DX5) and rice Detoxified resistant HL60 cells (HL60/MX2).
  • the growth inhibition effect of compound I-4 on drug-resistant tumor cells and parental tumor cells is shown in Table 2.
  • the compounds have obvious anti-tumor effects, and also have strong effects on drug-resistant tumor cells, especially the strong killing effect of such compounds on drug-resistant tumor cell lines is worthy of attention.
  • the initial mechanism of action shows that the results of this class of compounds are not exactly the same as the combination, such as the combination of etoposide VP-16 (Top2 inhibitor) and vincristine (tubulin inhibitor). These dual inhibitors make future medications easier and less susceptible to drug resistance.

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Abstract

La présente invention concerne un composé d'α-carboline, un procédé de préparation correspondant et ses utilisations. En particulier, la présente invention concerne un composé d'α-carboline représenté par la formule générale suivante (I), dans laquelle chaque groupe est tel que défini dans la description. Ledit composé de formule I possède des effets doubles sur l'inhibition de la topoisomérase II et de la microtubuline, et peut inhiber la prolifération de cellules cancéreuses.
PCT/CN2016/070110 2015-01-05 2016-01-05 Composé d'a-carboline, procédé de préparation correspondant et ses utilisations WO2016110237A1 (fr)

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CN108129479B (zh) * 2018-01-19 2020-02-21 四川理工学院 一种5,6-二氢苯并[f]吲哚并[2,3-b]喹啉类化合物及其合成方法

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
WO2017038650A1 (fr) * 2015-08-28 2017-03-09 積水メディカル株式会社 Composé benzyle
JP6201076B1 (ja) * 2015-08-28 2017-09-20 積水メディカル株式会社 ベンジル化合物
JP2018002700A (ja) * 2015-08-28 2018-01-11 積水メディカル株式会社 ベンジル化合物
CN108026116A (zh) * 2015-08-28 2018-05-11 积水医疗株式会社 苄基化合物
US10822357B2 (en) 2015-08-28 2020-11-03 Sekisui Medical Co., Ltd. Benzyl compound
US11591351B2 (en) 2015-08-28 2023-02-28 Sekisui Medical Co., Ltd. Benzyl compound

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