WO2015180693A1 - Complexe de dithiocarbamate de bismuth (iii) et son procédé de préparation et utilisation - Google Patents

Complexe de dithiocarbamate de bismuth (iii) et son procédé de préparation et utilisation Download PDF

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WO2015180693A1
WO2015180693A1 PCT/CN2015/080495 CN2015080495W WO2015180693A1 WO 2015180693 A1 WO2015180693 A1 WO 2015180693A1 CN 2015080495 W CN2015080495 W CN 2015080495W WO 2015180693 A1 WO2015180693 A1 WO 2015180693A1
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group
alkyl
ring
mixture
membered
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PCT/CN2015/080495
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English (en)
Chinese (zh)
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张健
郭应臣
卓立宏
张强
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天津博美开泰生物医药科技有限公司
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Priority claimed from CN201410235209.6A external-priority patent/CN103980174B/zh
Priority claimed from CN201410238159.7A external-priority patent/CN104072443B/zh
Priority claimed from CN201410234616.5A external-priority patent/CN104030979A/zh
Priority claimed from CN201410239290.5A external-priority patent/CN103980183B/zh
Application filed by 天津博美开泰生物医药科技有限公司 filed Critical 天津博美开泰生物医药科技有限公司
Publication of WO2015180693A1 publication Critical patent/WO2015180693A1/fr

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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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/21—Radicals derived from sulfur analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/94—Bismuth compounds

Definitions

  • the present application relates to a ruthenium (III) amide complex, a process for its preparation and its use in the field of medicine.
  • Chemotherapy is one of the currently used therapies for the treatment of malignant tumors (cancers).
  • cancers malignant tumors
  • chemotherapeutic agents lack sufficient effectiveness and cause serious side effects in patients. Therefore, there is an urgent need to develop highly effective and low-toxic anti-tumor drugs.
  • ⁇ is a heavy metal element of Group V A in the sixth cycle of the Periodic Table of the Elements. It is located at the junction of metal and non-metal and has special physical and chemical properties. Because it is non-toxic and non-carcinogenic, it is called green metal.
  • ruthenium compounds have been widely used in medicine, chemical engineering, and biology. Among them, ruthenium complexes have been found to inhibit the growth of cancer cells without side effects.
  • This application relates to new ruthenium (III) complexes of ammonium sulphate.
  • the present application also encompasses the use of such ruthenium (III) complexes of ammonium anamate in the treatment of tumors and pharmaceutical compositions comprising such ruthenium (III) complexes.
  • the application relates to a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the present application is directed to a compound of Formula I, or a stereoisomer, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • a ring is selected from the group consisting of an optionally substituted pyrrolidinyl group, an optionally substituted piperazinyl group, and optionally substituted Piperidinyl and optionally substituted benzopiperidinyl.
  • the present application relates to a compound selected from the group consisting of: or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • R is -CH 3 , -CH 2 CH 3 , -CH 2 C 6 H 5 , or
  • R 2 is H, and R 1 is -H, -COOH or -CO 2 C 2 H 5 ;
  • R 1 is H and R 2 is -OCH 3 ;
  • R 4 and R 5 are H and R 3 is -CH 3 ; -COOH or -CO 2 C 2 H 5 ;
  • R 3 and R 5 are H, and R 4 is F;
  • R 3 and R 4 are H, and R 5 is F;
  • R 3 is H, and R 4 and R 5 are F;
  • R 6 is -CH 3 ;
  • R 8 is H
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof Or solvates and pharmaceutically acceptable vehicles, carriers, excipients and/or diluents:
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the invention provides a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the preparation of Use in drugs for treating tumors:
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the tumor is a malignant tumor selected from the group consisting of gastric adenocarcinoma, gastric cancer, lung cancer, liver cancer, colorectal cancer, cervical cancer, ovarian cancer, breast cancer, leukemia, and colon cancer.
  • the invention provides a method of treating a tumor in an individual comprising administering to a subject in need thereof a compound of formula I, or a stereoisomer, enantiomer, diastereomer thereof or a mixture, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof:
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the tumor is a malignant tumor selected from the group consisting of gastric adenocarcinoma, gastric cancer, lung cancer, liver cancer, colorectal cancer, cervical cancer, ovarian cancer, breast cancer, leukemia, and colon cancer.
  • the invention provides a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, for use in treating a tumor of an individual, or a pharmaceutically acceptable thereof Salt or solvate or pharmaceutical composition thereof:
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the tumor is a malignant tumor selected from the group consisting of gastric adenocarcinoma, gastric cancer, lung cancer, liver cancer, colorectal cancer, cervical cancer, ovarian cancer, breast cancer, leukemia, and colon cancer.
  • the invention provides a process for the preparation of a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof :
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused,
  • the ruthenium (III) complex of the present invention or its stereoisomers, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof has good resistance Tumor activity, for gastric adenocarcinoma, gastric cancer, lung cancer, liver cancer, colorectal cancer, cervical cancer, ovarian cancer, breast cancer, leukemia, colon cancer, especially for gastric adenocarcinoma, gastric cancer, liver cancer, colon cancer, cervical cancer, leukemia and colon cancer
  • Equivalent malignant tumors have significant inhibitory activity, and their preparation methods are simple and easy to implement, so they have broad application prospects as new anti-tumor agents.
  • Figures 1a-1c are the results of in vitro growth inhibition test of complex N058 for tumor cells.
  • 2a-2c are the results of in vitro growth inhibition test of the complex N059 against tumor cells.
  • Figures 3a-3c show the results of in vitro growth inhibition test of complex N063 for tumor cells.
  • Figures 4a-4d are the results of in vitro growth inhibition test of complex N048 on tumor cells.
  • Figures 5a-5c are the results of in vitro growth inhibition assay of complex N055 for tumor cells.
  • Figures 6a-6c are the results of in vitro growth inhibition test of complex N060 for tumor cells.
  • Figures 7a-7c are the results of in vitro growth inhibition test of complex N061 for tumor cells.
  • Figures 8a-8c are the results of in vitro growth inhibition test of complex N062 for tumor cells.
  • Figures 9a-9c are the results of in vitro growth inhibition test of complex N056 for tumor cells.
  • Figures 10a-10c are the results of in vitro growth inhibition test of complex N057 for tumor cells.
  • Figure 11 is a graph showing the growth inhibition test of the complex N059 against a solid tumor model.
  • Figure 12 is a graph showing the growth inhibition test of the complex N063 on a solid tumor model.
  • Figure 13 is a graph showing the growth inhibition test of the complex N048 on a solid tumor model.
  • Figure 14 is a graph showing the results of growth inhibition test of complex N060 on a solid tumor model.
  • Figure 15 is a graph showing the results of growth inhibition test of complex N056 on a solid tumor model.
  • references to “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are meant to be included in the at least one embodiment.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “base” includes a base, or two or more bases.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • C 1 -C 8 alkyl describes an alkyl group as defined below having a total of from 1 to 8 carbon atoms
  • a C 3 -C 7 cycloalkyl group describes a ring as defined below having a total of from 3 to 7 carbon atoms alkyl.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • Halogen means fluoro, chloro, bromo or iodo. In certain embodiments, the halogen is preferably fluorine and chlorine; in certain embodiments, the halogen is more preferably fluorine.
  • Alkyl means a straight or branched hydrocarbon chain radical consisting of only carbon and hydrogen atoms, free of unsaturated bonds, having from 1 to 8 carbon atoms and having a single bond attached to the remainder of the molecule. a group such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, 1,1-dimethylethyl (tert-butyl) ), n-pentyl, neopentyl, tepentyl, n-hexyl, n-heptyl, 2-ethylhexyl and the like.
  • the alkyl group is a C 1 -C 8 alkyl group. In certain embodiments, the alkyl group is a C 1 -C 6 alkyl group. In certain embodiments, the alkyl group is a C 1 -C 4 alkyl group. In certain embodiments, the alkyl group is a C 1 -C 2 alkyl group.
  • Alkylene means consisting only of carbon and hydrogen atoms, free of unsaturated bonds and having from 1 to 8 carbon atoms, excellent a linear or branched divalent hydrocarbon chain of from 1 to 6 carbon atoms, linking the remainder of the molecule to a group, such as methylene, ethylene, propylene, isopropylidene, butylene , isobutylene and so on.
  • the alkylene chain can be attached to the remainder of the molecule and to the group through one carbon in the chain or through any two of the carbons in the chain.
  • the alkylene group is a C 1 -C 8 alkylene group. In certain embodiments, the alkylene group is a C 1 -C 6 alkylene group. In certain embodiments, the alkylene group is a C 1 -C 4 alkylene group. In certain embodiments, the alkylene group is a C 1 -C 2 alkylene group.
  • Cycloalkyl means a stable, non-aromatic monocyclic alkyl group consisting solely of carbon and hydrogen atoms, having from 3 to 7 carbon atoms, and being saturated, and attached to the remainder of the molecule by a single bond. Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • Heterocyclyl means a 5- or 6-membered non-aromatic cyclic group consisting of a carbon atom and 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless otherwise specified in the specification, a heterocyclic group herein may be optionally fused or bridged with a benzene or naphthalene ring; and optionally a nitrogen, carbon or sulfur atom in the heterocyclic group; The ring group can be partially saturated or fully saturated.
  • heterocyclic groups include, but are not limited to, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, pyranyl, dioxolyl, dioxanyl, Dithiaalkyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, trioxoalkyl, trithiaalkyl, tetrahydropyranyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl and pyrazole alkyl.
  • Heteroaryl means a 5- to 12-membered aromatic ring group consisting of a carbon atom and 1 to 5 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroaryl group can be a monocyclic, bicyclic or tricyclic ring system which can comprise a fused or bridged ring system; and the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; The nitrogen atom can optionally be quaternized.
  • heteroaryl groups include, but are not limited to, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazole , isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridazinyl, fluorenyl, isodecyl, quinolinyl, isoquinolinyl , naphthyridinyl, acridinyl, quinoxalinyl and pyridazinyl and the like.
  • the heteroaryl is a 5- to 12-membered heteroaryl. In certain embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In certain embodiments, the heteroaryl is a 5- to 6-membered heteroaryl.
  • alkyl, alkylene, cycloalkyl, heterocyclyl and heteroaryl groups defined above may be optionally substituted, i.e. substituted or unsubstituted.
  • each substituent is independently selected from the group consisting of hydrogen, OH, -SH, -NH 2 , halogen, -COOH, -SO 3 H, -SO 2 H, C 1-8 alkyl, -OC 1-8 Alkyl, -C(O)-C 1-8 alkyl, -C(O)-OC 1-8 alkyl, C 3-7 cycloalkyl, 5- or 6-membered heterocyclic, 5- or 6-membered A heteroaryl group, a phenyl group and a naphthyl group.
  • the compounds described herein, or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be based on absolute stereochemistry. It is defined as (R)- or (S)-, or the amino acid is (D)- or (L)-. This application is intended to include all such possible isomers, as well as the racemic and optically pure forms thereof.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or The column is subjected to resolution by conventional techniques such as HPLC.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond, but having different three-dimensional structures that are not interchangeable.
  • the present application includes various stereoisomers and mixtures thereof, and includes “enantiomers”, which refer to two stereoisomers in which the molecules are non-superimposable mirror images of each other.
  • “Pharmaceutically acceptable salts” include the acid addition salts and base addition salts of the compounds of formula I.
  • the pharmaceutically acceptable salts of the compounds provided herein are synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Usually such salts are for example made in water or in an organic solvent or a mixture of the two These compounds in free acid or base form are prepared by reaction with a stoichiometric amount of a suitable base or acid. Generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are formed using inorganic or organic acids.
  • the inorganic acid is, for example but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, Aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexyl Alkyl sulfamic acid, dodecyl sulphate, ethane-1,2-d
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylaminoethanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine , histidine, caffeine, procaine, seabamin, choline, betaine, benzylamine, phenethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, Tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like.
  • solvate refers to an aggregate comprising one or more molecules of a compound of the present application bearing one or more solvent molecules.
  • the solvent may be water, in which case the solvate is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present application may exist in the form of hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as in the corresponding solvated forms.
  • the compounds of the present application may be true solvates, but in other instances, the compounds of the present application may retain only amorphous water or the compound is a mixture of water and some indefinite solvent.
  • the solvate of the present application is a hydrate.
  • composition refers to a formulation of a compound of the present application and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes all pharmaceutically acceptable carriers, excipients and/or diluents.
  • carrier is defined as a compound that facilitates the introduction of a compound into a cell or tissue.
  • DMSO dimethyl sulfoxide
  • carrier because it is easy to introduce certain organic compounds into cells or tissues of an organism.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, approved by the National Drug Administration for human or domestic use. Dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • “Mammal” includes humans and domestic animals such as cats, dogs, pigs, cows, sheep, goats, horses, rabbits, and the like.
  • “Therapeutically effective amount” means an amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect effective inhibition of the tumor in a mammal, preferably a human, as defined below.
  • the amount of the compound of the present invention which constitutes a “therapeutically effective amount” varies depending on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal to be treated, but can be conventionally determined by one of ordinary skill in the art. Knowledge and the content of this disclosure are determined.
  • treating encompasses treating a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
  • the application relates to a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the A ring is fused to a five or six membered heteroaryl or benzene ring, preferably to a six membered heteroaryl or benzene ring, more preferably to a benzene ring.
  • the A ring further contains at least one hetero atom selected from N, O and S, preferably further one or two heteroatoms selected from N, O and S, more preferably further A hetero atom selected from N, O and S, most preferably also contains an N atom.
  • the A ring is fused to a five- or six-membered heteroaryl or benzene ring, and further contains at least one hetero atom selected from N, O, and S; preferably, the A ring is a five- or six-membered heteroaryl or benzene ring fused, and further containing one or two heteroatoms selected from N, O and S; more preferably, the A ring is thickened with a six-membered heteroaryl ring or a benzene ring And also containing a hetero atom selected from N, O and S; most preferably, the A ring is condensed with a benzene ring and further contains a hetero atom selected from N, O and S.
  • the A ring is substituted by one or more substituents, preferably by up to four substituents, more preferably by up to three substituents, even more preferably up to two substituents. Replace.
  • each substituent independently selected from hydrogen, -OH, -SH, -NH 2, halo, -COOH, -SO 3 H, -SO 2 H, C 1-8 alkyl, -OC 1-8 alkyl, -C(O)-C 1-8 alkyl, -C(O)-OC 1-8 alkyl, -C 1-8 alkylene- C 6 H 5 , C 3-7 cycloalkyl, 5- or 6-membered heterocyclic, 5- or 6-membered heteroaryl, phenyl and naphthyl.
  • each substituent independently selected from hydrogen, halo, -COOH, C 1-8 alkyl, -OC 1-8 alkyl, -C (O) -C 1-8 alkyl, -C(O)-OC 1-8 alkyl, -C 1-8 alkylene-C 6 H 5 , 5- or 6-membered heterocyclic, 5- or 6-membered hetero Aryl and phenyl.
  • each substituent independently selected from hydrogen, halo, -COOH, C 1-6 alkyl, -OC 1-6 alkyl, -C (O) -C 1-6 alkyl, -C(O)-OC 1-6 alkyl, -C 1-6 alkylene-C 6 H 5 , a five-membered heterocyclic group, a six-membered heteroaryl group, and a phenyl group.
  • each substituent independently selected from hydrogen, halo, -COOH, C 1-6 alkyl, -OC 1-6 alkyl, -C (O) -C 1-6 alkyl, -C(O)-OC 1-6 alkyl, -C 1-6 alkylene-C 6 H 5 , pyrrolidinyl, pyridyl and phenyl.
  • each substituent is independently selected from the group consisting of hydrogen, -OH, -SH, -NH 2 , halogen, -COOH, -SO 3 H, -SO 2 H, C 1-8 alkyl, -OC 1-8 alkyl, -C(O)-C 1-8 alkyl, -C(O)- OC 1-8 alkyl, -C 1-8 alkylene-C 6 H 5 , ternary to seven-membered cycloalkyl, five- or six-membered heterocyclic group, five- or six-membered heteroaryl, phenyl And naphthyl; preferably, each substituent is independently selected from the group consisting of hydrogen, halogen, -COOH, C 1-6 alkyl, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl,
  • the A ring is fused to a five- or six-membered heteroaryl or benzene ring and/or further contains at least one heteroatom selected from N, O, and S, and when the A ring is When substituted, each substituent is independently selected from the group consisting of hydrogen, -OH, -SH, -NH 2 , halogen, -COOH, -SO 3 H, -SO 2 H, C 1-8 alkyl, -OC 1-8 alkane a group, -C(O)-C 1-8 alkyl, -C(O)-OC 1-8 alkyl, -C 1-8 alkylene-C 6 H 5 , C 3-7 cycloalkyl, Five or six-membered heterocyclic, five or six-membered heteroaryl, phenyl and naphthyl.
  • the A ring is fused to a five or six membered heteroaryl or benzene ring and/or further contains one or two heteroatoms selected from N, O and S, and when said A When the ring is substituted, each substituent is independently selected from the group consisting of hydrogen, halogen, -COOH, C1-8 alkyl, -OC 1-8 alkyl, -C(O)-C 1-8 alkyl, -C ( O) -OC 1-8 alkyl, -C 1-8 alkylene-C 6 H 5 , 5- or 6-membered heterocyclic, 5- or 6-membered heteroaryl and phenyl.
  • the A ring is fused to a six-membered heteroaryl or benzene ring and/or further contains one or two heteroatoms selected from N, O and S, and when the A ring is substituted
  • Each substituent is independently selected from the group consisting of hydrogen, halogen, -COOH, C 1-6 alkyl, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)- OC 1-6 alkyl, -C 1-6 alkylene-C 6 H 5 , five-membered heterocyclic group, six-membered heteroaryl group and phenyl group.
  • the A ring is fused to a benzene ring and/or further contains one or two heteroatoms selected from N, O and S, and when the A ring is substituted, each substituent is independently Selected from hydrogen, halogen, -COOH, C 1-6 alkyl, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)-OC 1-6 alkyl , -C 1-6 alkylene-C 6 H 5 , a five-membered heterocyclic group, a six-membered heteroaryl group, and a phenyl group.
  • the A ring is fused to a benzene ring and/or further contains a hetero atom selected from N, O and S, and when the A ring is substituted, each substituent is independently selected from Hydrogen, halogen, -COOH, C 1-6 alkyl, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)-OC 1-6 alkyl, -C 1-6 alkylene-C 6 H 5 , pyrrolidinyl, pyridyl and phenyl.
  • the present application is directed to a compound of Formula I, or a stereoisomer, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • a ring is selected from the group consisting of an optionally substituted pyrrolidinyl group, an optionally substituted piperazinyl group, an optionally substituted piperidinyl group, and an optionally substituted benzopiperidinyl group.
  • the optionally substituted benzopiperidinyl is an optionally substituted 1,2,3,4-tetrahydroquinolinyl.
  • the A ring is substituted by one or more substituents, preferably by up to four substituents, more preferably by up to three substituents, even more preferably up to two substituents. Replace.
  • each substituent independently selected from hydrogen, -OH, -SH, -NH 2, halo, -COOH, -SO 3 H, -SO 2 H, C 1-8 alkyl, -OC 1-8 alkyl, -C(O)-C 1-8 alkyl, -C(O)-OC 1-8 alkyl, -C 1-8 alkylene- a C 6 H 5 , a C 3-7 cycloalkyl group, a five- or six-membered heterocyclic group, a five- or six-membered heteroaryl group, a phenyl group and a naphthyl group, preferably each substituent is located at the 1-position of the piperazinyl group.
  • each substituent independently selected from hydrogen, halo, -COOH, C 1-8 alkyl, -OC 1-8 alkyl, -C (O) -C 1-8 alkyl, -C(O)-OC 1-8 alkyl, -C 1-8 alkylene-C 6 H 5 , 5- or 6-membered heterocyclic, 5- or 6-membered hetero Aryl and phenyl, preferably each substituent is at the 1-position of the piperazinyl group, at the 2-position and/or 3-position of the pyrrolidinyl group, at the 2-position, the 3-position and/or the 4-position of the piperidinyl group, and in the benzo group.
  • the 3, 6 and/or 7 positions of piperidine are independently selected from hydrogen, halo, -COOH, C 1-8 alkyl, -OC 1-8 alkyl, -C (O) -C 1-8 alkyl, -C(O)-OC 1-8 alkyl, -C 1-8 alkylene-
  • each substituent independently selected from hydrogen, halo, -COOH, C 1-6 alkyl, -OC 1-6 alkyl, -C (O) -C 1-6 alkyl, -C(O)-OC 1-6 alkyl, -C 1-6 alkylene-C 6 H 5 , five-membered heterocyclic group, six-membered heteroaryl group and phenyl group,
  • each substituent is located at the 1-position of the piperazinyl group, at the 2-position and/or 3-position of the pyrrolidinyl group, at the 2-position, the 3-position and/or the 4-position of the piperidinyl group, and at the 3-position of the benzopiperidine, 6 and/or 7 digits.
  • each substituent independently selected from hydrogen, halo, -COOH, C 1-6 alkyl, -OC 1-6 alkyl, -C (O) -C 1-6 alkyl, -C(O)-OC 1-6 alkyl, -C 1-6 alkylene-C 6 H 5 , pyrrolidinyl, pyridyl and phenyl, preferably each substituent Located at the 1-position of the piperazinyl group, at the 2-position and/or 3-position of the pyrrolidinyl group, at the 2-position, 3-position and/or 4-position of the piperidinyl group, and at the 3-position, 6-position and/or on the benzopiperidinyl group. 7 digits.
  • each substituent is independently selected from the group consisting of hydrogen, -OH, -SH, -NH 2 , halogen, -COOH, -SO 3 H, -SO 2 H, C 1-8 alkyl, -OC 1-8 alkyl, -C(O)-C 1-8 alkyl, -C(O)- OC 1-8 alkyl, -C 1-8 alkylene-C 6 H 5 , ternary to seven-membered cycloalkyl, five- or six-membered heterocyclic group, five- or six-membered heteroaryl, phenyl And naphthyl; preferably, each substituent is independently selected from the group consisting of hydrogen, halogen, -COOH, C 1-6 alkyl, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl,
  • the present application relates to a compound selected from the group consisting of: or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • R is -CH 3 , -CH 2 CH 3 , -CH 2 C 6 H 5 ,
  • R 2 is H, and R 1 is -H, -COOH or -CO 2 C 2 H 5 ;
  • R 1 is H and R 2 is -OCH 3 ;
  • R 4 and R 5 are H and R 3 is -CH 3 ; -COOH or -CO 2 C 2 H 5 ;
  • R 3 and R 5 are H, and R 4 is F;
  • R 3 and R 4 are H, and R 5 is F;
  • R 3 is H, and R 4 and R 5 are F;
  • R 6 is -CH 3 ;
  • R 8 is H
  • the invention provides a process for the preparation of a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof :
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused,
  • the method of preparation further comprises further purifying the resulting compound of formula I by silica gel column chromatography or recrystallization.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, triethylamine, or mixtures thereof.
  • the reaction is carried out in an alcohol solvent, preferably the alcohol is selected from the group consisting of anhydrous methanol, absolute ethanol, or mixtures thereof.
  • the onium salt is selected from the group consisting of antimony trichloride, antimony tribromide, antimony triiodide, or antimony nitrate.
  • the five- or six-membered nitrogen heterocycle is sequentially reacted with CS 2 and a phosphonium salt, and is carried out at a temperature of from -5 ° C to 10 ° C, preferably from 0 ° C to 5 ° C.
  • the reaction of a five- or six-membered nitrogen heterocycle with CS 2 is carried out, and the reaction with a phosphonium salt is continued at room temperature.
  • the solvent used for recrystallization is selected from the group consisting of chloroform, dichloromethane, methanol, ethanol, acetonitrile, or mixtures thereof.
  • the five- or six-membered nitrogen heterocycle is sequentially reacted with CS 2 and a phosphonium salt, and the reaction time of the five- or six-membered nitrogen heterocycle with CS 2 is from 3 h to 8 h, preferably 4 h. -6h; followed by a reaction time with a phosphonium salt of 2h-6h, preferably 3h-5h.
  • the application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvent thereof
  • pharmaceutically acceptable vehicles, carriers, excipients and/or diluents
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the present application is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer, enantiomer, diastereomer thereof, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or Solvates and pharmaceutically acceptable vehicles, carriers, excipients and/or diluents:
  • a ring is selected from the group consisting of an optionally substituted pyrrolidinyl group, an optionally substituted piperazinyl group, an optionally substituted piperidinyl group, and an optionally substituted benzopiperidinyl group.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from the group consisting of: or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable thereof Salts or solvates and pharmaceutically acceptable vehicles, carriers, excipients and/or diluents:
  • R is -CH 3 , -CH 2 CH 3 , -CH 2 C 6 H 5 ,
  • R 2 is H, and R 1 is -H, -COOH or -CO 2 C 2 H 5 ;
  • R 1 is H and R 2 is -OCH 3 ;
  • R 4 and R 5 are H and R 3 is -CH 3 ; -COOH or -CO 2 C 2 H 5 ;
  • R 3 and R 5 are H, and R 4 is F;
  • R 3 and R 4 are H, and R 5 is F;
  • R 3 is H, and R 4 and R 5 are F;
  • R 6 is -CH 3 ;
  • R 8 is H
  • the pharmaceutical compositions of the present application include pharmaceutically acceptable surfactants, carriers, diluents, excipients, smoothing agents, suspending agents, lubricants, film-forming materials, coating aids or Combinations thereof, as well as the compounds of the invention.
  • Preservatives, stabilizers, dyes, flavoring agents, coloring agents, antioxidants, sweeteners, fragrances, perfumes and the like can be provided in the pharmaceutical compositions.
  • Suitable routes of administration may, for example, include oral administration, rectal administration, transmembrane administration, topical administration or enteral administration; parenteral delivery includes injection administration, such as intramuscular injection, subcutaneous injection, intravenous injection or peritoneal administration. Injection inside.
  • parenteral delivery includes injection administration, such as intramuscular injection, subcutaneous injection, intravenous injection or peritoneal administration. Injection inside.
  • an oral administration form is preferred.
  • compositions of the present application can be produced by known methods, for example, by conventional methods of mixing, dissolving, granulating, making tablets, grinding, emulsifying, encapsulating, retaining or tableting.
  • the present application relates to a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament Use in cancer drugs:
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the present application is directed to a compound of Formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the preparation of Use in drugs for treating tumors:
  • a ring is selected from the group consisting of an optionally substituted pyrrolidinyl group, an optionally substituted piperazinyl group, an optionally substituted piperidinyl group, and an optionally substituted benzopiperidinyl group.
  • the present application relates to a compound selected from the group consisting of the following structural formula, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, in the preparation Use in drugs for the treatment of tumors:
  • R is -CH 3 , -CH 2 CH 3 , -CH 2 C 6 H 5 ,
  • R 2 is H, and R 1 is -H, -COOH or -CO 2 C 2 H 5 ;
  • R 1 is H and R 2 is -OCH 3 ;
  • R 4 and R 5 are H and R 3 is -CH 3 ; -COOH or -CO 2 C 2 H 5 ;
  • R 3 and R 5 are H, and R 4 is F;
  • R 3 and R 4 are H, and R 5 is F;
  • R 3 is H, and R 4 and R 5 are F;
  • R 6 is -CH 3 ;
  • R 8 is H
  • the application relates to a method of treating a tumor in an individual comprising administering to the individual in need thereof a compound of formula I, or a stereoisomer, enantiomer, diastereomer thereof or a mixture, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof:
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the present application relates to a method of treating a tumor in an individual comprising administering to the individual in need thereof a compound of formula I, or a stereoisomer, enantiomer, diastereomer thereof or a mixture, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof:
  • a ring is selected from the group consisting of an optionally substituted pyrrolidinyl group, an optionally substituted piperazinyl group, an optionally substituted piperidinyl group, and an optionally substituted benzopiperidinyl group.
  • the present application relates to a method of treating a tumor of an individual comprising administering to the individual in need thereof a compound selected from the group consisting of the following structural formula, or a stereoisomer, enantiomer thereof, diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof:
  • R is -CH 3 , -CH 2 CH 3 , -CH 2 C 6 H 5 ,
  • R 2 is H, and R 1 is -H, -COOH or -CO 2 C 2 H 5 ;
  • R 1 is H and R 2 is -OCH 3 ;
  • R 4 and R 5 are H and R 3 is -CH 3 ; -COOH or -CO 2 C 2 H 5 ;
  • R 3 and R 5 are H, and R 4 is F;
  • R 3 and R 4 are H, and R 5 is F;
  • R 3 is H, and R 4 and R 5 are F;
  • R 6 is -CH 3 ;
  • R 8 is H
  • the application relates to a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a tumor Or a pharmaceutical composition thereof:
  • ring A represents an optionally substituted five- or six-membered nitrogen-containing heterocyclic group, and said five- or six-membered nitrogen-containing heterocyclic group is optionally bonded to a five- or six-membered heteroaryl or benzene ring Fused.
  • the present application relates to a compound of formula I, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt or solvent thereof, for use in treating a tumor.
  • Compound or its pharmaceutical composition :
  • a ring is selected from the group consisting of an optionally substituted pyrrolidinyl group, an optionally substituted piperazinyl group, an optionally substituted piperidinyl group, and an optionally substituted benzopiperidinyl group.
  • the present application relates to a compound selected from the formulae, or a stereoisomer, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a tumor Or a solvate or a pharmaceutical composition thereof:
  • R is -CH 3 , -CH 2 CH 3 , -CH 2 C 6 H 5 ,
  • R 2 is H, and R 1 is -H, -COOH or -CO 2 C 2 H 5 ;
  • R 1 is H and R 2 is -OCH 3 ;
  • R 4 and R 5 are H and R 3 is -CH 3 ; -COOH or -CO 2 C 2 H 5 ;
  • R 3 and R 5 are H, and R 4 is F;
  • R 3 and R 4 are H, and R 5 is F;
  • R 3 is H, and R 4 and R 5 are F;
  • R 6 is -CH 3 ;
  • R 8 is H
  • the tumor is selected from the group consisting of gastric adenocarcinoma, gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, ovarian cancer.
  • a malignant tumor of breast cancer, leukemia or colon cancer preferably the tumor is selected from the group consisting of gastric adenocarcinoma, gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, ovarian cancer, leukemia and colon cancer; more preferably said tumor is selected from the group consisting of Gastric adenocarcinoma, gastric cancer, liver cancer, colorectal cancer, cervical cancer, leukemia and colon cancer.
  • the compound or pharmaceutical composition can be administered to a patient in any suitable manner.
  • methods of administration include (a) administration by the oral route, including administration in the form of capsules, tablets, granules, sprays, syrups, or the like; (b) by For administration by a non-oral route, such as the rectum, the administration includes administration in the form of an aqueous suspension, an oily preparation, or the like, or in the form of drops, sprays, suppositories, ointments, ointments, etc.; (c) subcutaneous injection, intraperitoneal injection Administration by injection, intravenous injection, intramuscular injection, intradermal injection, etc., including infusion pump delivery; and (e) topical administration; suitable delivery means are compounds of the invention as recognized by those skilled in the art Contact with living tissue; preferably administered orally.
  • compositions suitable for administration include those in which an effective amount of the active ingredient is included in such compositions.
  • the dose required for a therapeutically effective amount of a pharmaceutical composition disclosed herein will depend on the route of administration, the type of animal being treated, including the human, and the physical characteristics of the particular animal in question. The dosage can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent medical therapy, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of a compound that is effective to prevent, alleviate or ameliorate the symptoms of the disease, or to prolong the life of the individual being treated. The actual ability of a person skilled in the art can well determine a therapeutically effective amount, particularly in accordance with the detailed disclosure provided by the present invention.
  • the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight and type of mammal being treated, the particular compound employed, and the compound employed. Specific use. Those skilled in the art will be able to achieve the objective of determining the level of effective amount, i.e., the dosage level necessary to determine the desired effect, using conventional pharmacological methods. Typically, human clinical application of the compound begins at a lower dosage level as the dosage level increases until the desired effect is achieved. Alternatively, an established in vitro study can be used to establish an effective amount and route of administration of the compositions identified by the methods using established pharmacological methods.
  • Example 2 1-ethylpiperazine ammonium hydride (complex N063)
  • Example 14 4-(1-Pyrrolidinyl)piperidinium amide (complex N057)
  • Cancer cell leukemia cell line (HL-60), lung cancer cell line (A-549), liver cancer cell line (BEL-7402), colon cancer cell line (SW-1116), cervical cancer cell line (HELA), ovarian cancer Cancer cells such as cell line (3AO), breast cancer cell line (MCF-7), gastric cancer cell line (MKN-28) and gastric adenocarcinoma cell line (SGC-7901) were cultured in 10% inactivated fetal bovine serum, 100 U/mL Penicillin, 100 ⁇ g/mL streptomycin in RPMI1640 or DMEM medium was cultured in a 10% CO 2 incubator at 37 ° C under saturated humidity conditions.
  • adherent cells were trypsinized and digested with 1-fold trypsin-EDTA, and the cells were passaged every 3 to 4 days at a ratio of 1:5 to 1:20 (when the cells were cultured). When the area covered in the dish is 80-90%).
  • the cells were trypsinized in a 1-fold trypsin-EDTA solution for about 5 minutes (in a 37 ° C incubator), suspended in 10 mL of DMEM or RPMI medium, and then inoculated into a 96-well plate. .
  • the cells were seeded in standard DMEM or RPMI medium at a density of 1 to 2 x 10 4 /well in a volume of 50 ⁇ L.
  • each plate also included a positive control (0.5 [mu]M doxorubicin) and a negative control (DMSO).
  • Table 1 Test protocol for the final concentration of 96-well plates and test compounds in the test
  • cell growth inhibition rate [(negative control group OD) Value - experimental group OD value) / negative control group OD value] ⁇ 100%.
  • the IC50 value (the half-inhibition rate IC50, the cell growth inhibition rate of 50% of the drug concentration) was calculated by software from the cell growth inhibition rate and the corresponding concentration. This assay was repeated an additional two times for each compound and once the three assays were completed, the IC50 values were calculated using the raw data.
  • mice 8-12 weeks old healthy Balb/c mice, half male and half female (body weight 22-25 g), 5 mice per cage, placed in a clean animal breeding room, free to eat drinking water.
  • a heterologous solid tumor model was made subcutaneously on both sides of Balb/c mice using mouse colon cancer cell line C26.
  • test complexes (complex N059, complex N063, complex N048, complex N060 and complex N056) were formulated in 20% DMSO carrier solution at a concentration of 4 mg/mL.
  • the C26 solid tumor model was established by subcutaneous injection of 5 ⁇ 10 6 cultured cells in the anterior and posterior iliac crest of the mouse. When 80% of the tumor volume was greater than 80 mm 3 , all the mice were randomly divided into the example treatment group and the vehicle control group.
  • All of the complexes were administered by intraperitoneal injection at 30 mg/kg/day, and the control group received a drug-free carrier injection. 5 days a week for 3 weeks, rest for a week, or until the mice have to be killed due to a large tumor.
  • MTGI maximal tumor growth inhibition
  • the maximum tumor inhibition rate of complex N059 was 28%, p ⁇ 0.05; the maximum tumor inhibition rate of complex N063 was 18%, p ⁇ 0.05.
  • the tumor growth curves plotted by one-way ANOVA are shown in Figures 11 and 12.
  • the maximum tumor inhibition rate of complex N048 was 16%, p ⁇ 0.05; the maximum tumor inhibition rate of complex N060 was 10%, p ⁇ 0.05.
  • the tumor growth curves plotted by one-way ANOVA are shown in Figures 13 and 14.
  • Results according to statistical analysis, the maximum tumor inhibition rate of complex N056 was 38%, p ⁇ 0.05.
  • the tumor growth curve plotted by one-way ANOVA is shown in Figure 15.
  • the experimental data show that the samarium (III) complex of the present invention has significant anti-tumor effect on malignant tumors such as gastric adenocarcinoma, gastric cancer, lung cancer, liver cancer, colon cancer, cervical cancer, ovarian cancer, breast cancer, leukemia and colon cancer. Its activity and its development as a new anti-tumor agent have broad application prospects.

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Abstract

Cette invention concerne un composé de formule générale I, ou un stéréoisomère, un énantiomère, un diastéréoisomère de celui-ci ou leur mélange, ou des sels pharmaceutiquement acceptables et des solvates de ceux-ci : I, Cycle A dans la formule désignant un groupe hétérocyclique à cinq ou six chaînons contenant un atome d'azote et éventuellement substitué, ledit groupe hétérocyclique à cinq ou six chaînons étant éventuellement condensé avec un cycle hétéroaromatique à cinq ou six chaînons ou avec un cycle benzène.
PCT/CN2015/080495 2014-05-30 2015-06-01 Complexe de dithiocarbamate de bismuth (iii) et son procédé de préparation et utilisation WO2015180693A1 (fr)

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CN201410238159.7 2014-05-30
CN201410238159.7A CN104072443B (zh) 2014-05-30 2014-05-30 N-取代哌嗪氨荒酸铋(ⅲ)配合物及其制备方法和在制备抗肿瘤药物中的应用
CN201410235209.6 2014-05-30
CN201410234616.5A CN104030979A (zh) 2014-05-30 2014-05-30 氨荒酸铋(ⅲ)化合物及其制备方法
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Publication number Priority date Publication date Assignee Title
WO1999063013A1 (fr) * 1998-05-29 1999-12-09 Ppg Industries Ohio, Inc. Composition de revetement electrodeposable contenant des diorganodithiocarbamates de bismuth et procede d'electrodeposition
US20060142621A1 (en) * 2003-01-29 2006-06-29 Tiekink Edward R T Bismuth dithiocarbamate compounds and uses thereof

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HONGYU LI ET AL.: "Cytotoxicity, qualitative structure-activity relationship(QSAR), and anti-tumor activity of bismuth dithiocarbamate complexes", JOURNAL OF INORGANIC BIOCHEMIST, vol. 101, no. 5, 3 February 2007 (2007-02-03), pages 809 - 816, XP022024119 *
LI, FENG: "Study on syntheses, characterization and supramolecular structures of Bismuth (I complexes with ligands of N,N-dialkyldithiocarbamate and xanthate", THE FULL TEXT DATABAS OF CHINESE MASTER'S DEGREE THESIS, 23 January 2008 (2008-01-23), pages 12 *

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