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WO2017181974A1 - Composé hétérocyclique à cinq chaînons, procédé de préparation correspondant, composition pharmaceutique et utilisation - Google Patents

Composé hétérocyclique à cinq chaînons, procédé de préparation correspondant, composition pharmaceutique et utilisation Download PDF

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Publication number
WO2017181974A1
WO2017181974A1 PCT/CN2017/081294 CN2017081294W WO2017181974A1 WO 2017181974 A1 WO2017181974 A1 WO 2017181974A1 CN 2017081294 W CN2017081294 W CN 2017081294W WO 2017181974 A1 WO2017181974 A1 WO 2017181974A1
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group
compound
formula
substituted
cells
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Chinese (zh)
Inventor
罗成
姚志艺
乔刚
蒋华良
周宇
陈丽敏
刘静秋
丁宏
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Suzhou Suplead Life Sciences Co Ltd
Shanghai Institute of Materia Medica of CAS
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Suzhou Suplead Life Sciences Co Ltd
Shanghai Institute of Materia Medica of CAS
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Priority claimed from CN201610880829.4A external-priority patent/CN107304202A/zh
Application filed by Suzhou Suplead Life Sciences Co Ltd, Shanghai Institute of Materia Medica of CAS filed Critical Suzhou Suplead Life Sciences Co Ltd
Priority to CN201780024845.6A priority Critical patent/CN109476650B/zh
Publication of WO2017181974A1 publication Critical patent/WO2017181974A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of biomedicine, in particular to a multi-substituted five-membered heterocyclic compound, a preparation method thereof, a pharmaceutical composition and use thereof.
  • Microtubules are composed of tubulin, which are found in the cytoplasm of all eukaryotes. They play an important cytoskeleton role in cells, maintain cell morphology, assist intracellular transport, and assemble into spindles, granules, and other proteins. Central granules, flagella, ciliated neural tube and other structures. Microtubule-associated proteins bind to microtubules and regulate microtubule function, including MAP1, MAP12, MAP4, tau, and the like. Microtubules play a key role in cell mitosis and chromosome segregation and can affect tumor cell proliferation as a target for antitumor drugs. Tubulin inhibitors can effectively prevent mitosis of tumor cells and cause cells to enter apoptotic phase, thereby inhibiting tumor growth.
  • tubulin and microtubule-associated proteins have been shown to be closely associated with key proteins in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Therefore, there is an urgent need in the art to develop novel tubulin modulators.
  • a use of a compound of formula (I), an isomer, a racemate, a pharmaceutically acceptable salt, a crystalline hydrate, a solvate or a mixture thereof characterized in that In order to (a) prepare a drug for treating or preventing a mammalian disease associated with abnormality of tubulin; (b) inhibit microtubule polymerization activity; (c) inhibit tumor cell growth:
  • X 1 is selected from N or CR 1 (when R1 is H, denoted as C);
  • X 2 is selected from NR 1 , O or S;
  • R 1 is selected from the group consisting of hydrogen, hydrazine, halogen, amino, hydroxy, nitro, cyano, carboxy, C 2-6 ester, C 1-6 amide, unsubstituted or halogenated C 1-12 alkane Or cycloalkyl, -CH 2 -Y-(C 1-12 alkyl or cycloalkyl) (wherein Y is O or NH or S), C 1-12 aryl or heteroaryl, -CH 2 - (C 1-12 aryl or heteroaryl);
  • the Ar 1 group is a substituted or unsubstituted C 1-18 aryl or heteroaryl group, a substituted or unsubstituted -CH 2 -(C 1-12 aryl or heteroaryl), substituted or unsubstituted C 1 -18 heterocyclic group, substituted or unsubstituted -CH 2 -(C 1-12 heterocyclic group);
  • the Ar 2 group is hydrogen, substituted or unsubstituted C 1-12 alkyl or cycloalkyl, substituted or unsubstituted -CH 2 -Y-(C 1-12 alkyl or cycloalkyl) (where Y is O or NH or S), substituted or unsubstituted C 1-12 aryl or heteroaryl, substituted or unsubstituted -CH 2 -(C 1-12 aryl or heteroaryl), substituted or unsubstituted C 1-12 heterocyclic group;
  • n is selected from 0, 1, 2, 3, 4, 5, 6;
  • n is selected from 0, 1, 2, 3, 4, 5, 6;
  • the R 1 is selected from the group consisting of hydrogen, hydrazine, halogen, amino, hydroxy, nitro, cyano, carboxy, ester, amide, unsubstituted C 1-6 alkyl or cycloalkyl, (1 3) fluoro C 1-6 alkyl or cycloalkyl, (1-3) C 1-6 amine substituted C 1-6 alkyl or cycloalkyl, (1-3) C 1-6 alkoxy Substituted C 1-6 alkyl or cycloalkyl, -CH 2 -Y-(C 1-6 alkyl), C 1-12 aryl or heteroaryl, -CH 2 -(C 1-12 aryl or Heteroaryl).
  • the C 5-12 aryl or heteroaryl group is selected from the group consisting of:
  • n 0, 1, 2, 3, 4, 5;
  • n 0, 1, 2, 3, 4, 5.
  • X 1 , X 2 , X 3 , R 1 , Ar 1 , Ar 2 , m and n are each independently a corresponding group corresponding to the compound 1-630.
  • the Ar 1 is selected from the group consisting of C 1-8 heteroaryl and C 2-10 heteroaryl, C 4-8 heteroaryl and C 2-10 heterocyclic.
  • the C 1-8 heteroaryl contains 1-3 nitrogen atoms.
  • the C 1-8 heteroaryl group is a six-membered ring.
  • the C 2-10 heteroaryl or C 2-10 heterocyclic group contains 1-3 nitrogen atoms.
  • the C 2-10 heteroaryl or C 2-10 heterocyclic group is a six-membered ring.
  • the heterocyclic group is a saturated or partially unsaturated heterocyclic group, and the heterocyclic group is a non-aromatic group.
  • the compound is Compound 1 to Compound 630.
  • the mammalian disease associated with dysregulation of microtubule-associated proteins is a disease selected from the group consisting of cancer, neurodegenerative diseases, malaria, AIDS, gout, diabetes.
  • the cancer is selected from the group consisting of colon cancer, cervical cancer, breast cancer, liver cancer, stomach cancer, kidney cancer, Lung cancer, fibrosarcoma, epidermal squamous cell carcinoma, prostate cancer, leukemia, pancreatic cancer, oral cancer, glioblastoma, neuroblastoma.
  • the tumor cell is a tumor cell selected from the group consisting of colon cancer cells, cervical cancer cells, breast cancer cells, liver cancer cells, gastric cancer cells, kidney cancer cells, lung cancer cells, and fibrosarcoma cells.
  • the tumor cells are selected from the group consisting of HCT116, Hela, MCF-7, LM3, NCI-N87, Caki-1, A549, HT1080, A431, PC3, HL60, Panc-1, KB. , U87-MG, K562, Kasumi-1, THP-1, Jurkat, REH, Raji, RNK-16, KMS-1, P39, U118-MG, H4, SK-N-SH, SH-SY5Y, A549/Taxol , KB/VCR, K562/Adr.
  • the mammalian disease associated with dysregulation of microtubule-associated proteins is a disease selected from the group consisting of lymphoma, lung cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia, brain tumor, and Cervical cancer.
  • X 1 , X 2 , X 3 , R 1 , Ar 1 , Ar 2 , m and n are as defined in the first aspect of the invention
  • the method comprises the steps of:
  • X is a halogen
  • U is selected from the group consisting of halogen, OMs, OTs, boric acid, and pinacol borate
  • Q is O, S or NR 1
  • P is selected from the group consisting of p-methoxybenzyl, benzyl. , tert-butoxycarbonyl;
  • R 1 is halogen (fluorine, chlorine, bromine or iodine)
  • X 1 , X 2 , X 3 , R 1 , Ar 1 , Ar 2 , m and n are as defined in the first aspect of the invention
  • the method comprises the steps of:
  • the ring closure reaction is carried out by inorganic salt catalysis
  • V is halogen, OMs, or OTs; the remaining groups are as defined in the first aspect of the invention, but R 1 is a non-halogen group.
  • a compound which is a compound of any one of compound 1 to compound 630.
  • Figure 1 is a schematic representation of the concentration of neutrophil in compound 492 in a concentration-dependently inhibited urate sodium salt-induced peritonitis in mice.
  • a compound having the structure of the formula (I) has an effect of inhibiting the activity of tubulin, and can be used for preparing or treating breast milk associated with abnormality of tubulin regulation.
  • a drug for animal diseases A drug for animal diseases.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, amino, hydroxy, nitro, cyano, trifluoromethyl.
  • C 1-12 alkyl refers to a straight or branched alkyl group having from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. , tert-butyl, or the like.
  • C 1-12 cycloalkyl refers to a cycloalkyl group having from 1 to 12, preferably from 3 to 12 (ie C 3-12 ) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, Cycloheptyl, or a similar group.
  • C 1-12 alkoxy refers to a straight or branched alkoxy group having from 1 to 12 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 1-12 alkylamino refers to a C 1-12 alkyl group substituted by an amine group, for example having "C 1-12 alkyl-NH-” or “(alkyl) 2 -N- (total number of carbon atoms) Is 1-12)", “-C 1-12 alkylene-NH 2 ", “alkyl-N-alkylene- (total number of carbon atoms 1-12)", or "(alkyl) 2 - a group of an N-alkylene-(having a total of 1-12 carbon atoms) structure, such as CH 3 NH-, C 2 H 5 NH-, C 3 H 7 NH-, (CH 3 ) 2 N-, - 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 definition of C 1-12 alkyl is as defined above.
  • C 2 -C 6 ester group refers to a substitution of a structure such as "linear or branched alkyl/cycloalkyl/aryl/heteroaryl-carbonyl-oxy-- having 1 to 5 carbon atoms".
  • a group such as an ethyl ester group, a propyl ester group, a butyl ester group, or the like.
  • C 1 -C 6 amido refers to a substitution of a structure such as "linear or branched alkyl/cycloalkyl/aryl/heteroaryl-carbonyl-amino-" having 0 to 5 carbon atoms.
  • a group such as an acetamide group, a propionamide group, a butanamide group, or the like.
  • C 1 -C 12 aryl refers to an aryl group having 1 to 12 (preferably 6 to 10, ie C 6-10 ) carbon atoms, such as phenyl, naphthyl, etc., said aryl group being Is replaced or unsubstituted.
  • C 1 -C 12 heteroaryl refers to a heteroaryl group having 1 to 12 carbon atoms and one or more (preferably 1 to 3) heteroatoms selected from O, S and/or N, preferably 5 -8-membered heteroaryl.
  • the heteroaryl group can be substituted or unsubstituted.
  • C 1 -C 12 heterocyclyl refers to a non-aromatic cyclic group having from 1 to 12 carbon atoms and one or more (preferably one to three) heteroatoms selected from O, S and/or N.
  • the group is preferably a 5- to 8-membered heterocyclic group.
  • the heterocyclic group may be substituted or unsubstituted.
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • compound of the invention refers to a compound of formula I.
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the present invention provides a compound of the formula:
  • X 1 , X 2 , X 3 , R 1 , Ar 1 , Ar 2 , m and n are as defined above.
  • a preferred compound is any one of compounds 1-630.
  • the compound can be prepared by the following preparation method:
  • the method comprises the steps of:
  • X is a halogen
  • U is selected from the group consisting of halogen, OMs, OTs, boric acid, and pinacol borate
  • Q is O, S or NR 1
  • P is selected from the group consisting of p-methoxybenzyl, benzyl. , tert-butoxycarbonyl;
  • R 1 is halogen (fluorine, chlorine, bromine or iodine).
  • the compounds can also be prepared by the following steps:
  • the ring closure reaction is carried out by inorganic salt catalysis
  • V is halogen, OMs, or OTs; the remaining groups are as defined above, but R 1 is a non-halogen group.
  • the respective inert solvents are not particularly limited and may be selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), and Methyl sulfoxide (DMSO), ethylene glycol dimethyl ether, 1,2-dichloroethane, dimethyl phthalate (DMP), N-methylpyrrolidone (NMP), methanol, ethanol, n-butyl A solvent for alcohol, isopropanol, petroleum ether, ethyl acetate, n-hexane or diethyl ether.
  • the necessary base may be selected from, for example, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, calcium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium t-butoxide, tert-butanol.
  • the acid may be selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid or p-toluenesulfonic acid and the like.
  • the necessary inorganic salts may be selected from sodium fluoride (NaF), potassium fluoride (KF), cesium chloride, aluminum chloride and the like.
  • a catalyst may optionally be employed in each step of the above preparation process, and the catalyst may be selected from the group consisting of tetrakistriphenylphosphorus palladium (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAC) 2 ), dichloro Palladium (PdCl 2 ) palladium carbon, ditriphenylphosphine palladium dichloride (PdCl 2 (PPh) 2 ), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (PdCl 2 (dppf) 2 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), iodine (or bromine or chlorine) cuprous, iodine (or bromine or chlorine) copper, copper powder, etc.
  • Pd(PPh 3 ) 4 tetrakistriphenylphosphorus palladium
  • the necessary catalytic ligand may be selected from the group consisting of triphenylphosphine, 2-biscyclohexylphosphine-2', 4',6'-triisopropylbiphenyl (Xphos) and 2-dicyclohexyl. Phosphine-2',6'-dimethoxybiphenyl (Sphos) and the like.
  • the organometallic reagent may be n-butyllithium, sodium borohydride, lithium borohydride or sodium triacetylborohydride or the like.
  • the halogenating agent may be phosphorus tribromide, phosphorus oxychloride, bromine, iodine, nitrogen chloride (or bromine or iodine) succinimide (NCS, NBS or NIS) or phenyl trimethyl three. Ammonium bromide.
  • the oxidizing agent may be a Dess-Martin oxidizing agent, a Swern oxidizing agent, m-chloroperoxybenzoic acid, chlorodichromic acid pyridine (PDC) or chlorochromic acid pyridine (PCC).
  • PDC chlorodichromic acid pyridine
  • PCC chlorochromic acid pyridine
  • the compound of the present invention has excellent inhibitory activity against tubulin, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are mainly
  • the pharmaceutical composition of the active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with tubulin activity or expression levels, particularly for diseases in which tubulin activity or expression levels are all related.
  • the compounds of the invention are useful in the treatment of diseases such as cancer, neurodegenerative diseases, malaria, AIDS, gout, diabetes and the like.
  • 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) Absorbing accelerators, 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 also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening Agents, flavors and fragrances.
  • 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 a tubulin inhibitory activity is provided.
  • the nuclear magnetic resonance spectrum was recorded using a Bruker AMX-400 type, a Gemini-300 type or an AMX-600 type nuclear magnetic resonance apparatus, and the unit of the chemical shift ⁇ was ppm. All solvents are analytically pure reagents. Color development was carried out by iodine or ultraviolet fluorescence. The organic solvent was distilled off under reduced pressure in a rotary evaporator. The starting reactants used in the present invention are commercially available unless otherwise specified.
  • the conventional post-treatment method is: after the reaction is completed, an appropriate amount of an organic solvent and water are added to the reaction liquid, the organic phase and the aqueous phase are separated, the organic phase is combined, and dried using NaSO 4 . After filtration, it was evaporated to dryness under reduced pressure to give a crude material, which was purified by column chromatography to give the final product.
  • Example 2-55 The compound of Example 2-55 was prepared in the same manner as in Example 1 except that the compound b or d was different.
  • the cesium fluoride (679 mg, 2 eq) was dissolved in 15 mL of tetrahydrofuran, and protected with nitrogen.
  • Pd2(dba)3 (205 mg, 0.1 eq) and tri-tert-butylphosphonate (90 mg, 0.2 eq) were added, and the reaction was refluxed for 10 hours, and the reaction was completed. Directly evaporating the solvent column to give 5-(4-methoxyanilino)-3-(2-methylimidazolium [1,2-a]pyrimidin-3-)furan (107 mg);
  • Example 56-59 and 61-238 are the same as those of Example 60 except that the compounds b or d are different.
  • Example 239-500, 502-618 and Examples 624-630 were the same as those of Example 501 except that the compounds a or b were different, as shown in the following table.
  • Example 620-621 The preparation of Examples 620-621 was the same as Example 619 except that Compound a was different, see the table below.
  • the compound (200 mg, 1 eq) was dissolved in acetonitrile / water (4 mL / 1 mL), and then trifluoroiodomethane (157.6 mg, 1.5 eq), sodium sulphate (93.4 mg, 1 eq) and sodium bicarbonate (45 mg) ), reacted at room temperature for 12 hours, and the reaction was completed. After adding 20 mL of water and ethyl acetate (10 mL ⁇ 3), the organic layer was dried over sodium sulfate and evaporated to dryness.
  • Microtubules are multimers of tubulin. Tubulin ⁇ and ⁇ are joined end to end to form a heterodimer, which is then multi-polymerized into microtubule fibrils. The microtubules are composed of 13 fibrils, and each micrometer long microtubule is composed of 1,650 heterodimers.
  • tubulin can be polymerized. The effect of the compound on tubulin polymerization was examined using a Tubulin polymerization assay kit (BK011P, Cytoskeleton, Inc.). The kit contains specific reporter fluorescence, which is inserted into the microtube during microtubule polymerization, and the polymerization of the microtube can be monitored according to the intensity of the fluorescence.
  • microtubule polymerization inhibitory activity indicates a method: + represents 1-10 ⁇ M; ++ represents 0.1-1 ⁇ M; and +++ represents ⁇ 0.1 ⁇ M.
  • the IC 50 in the above table refers to the inhibitor concentration (50% inhibitory concentration) when the microtubule polymerization is inhibited by half.
  • the above compounds also significantly inhibited the polymerization of tubulin as compared with the positive control vincristine (VCR).
  • Colon cancer cells HCT116 were cultured in modified 5A medium containing 10% fetal bovine serum and trypsinized for passage. After about 70% of cell fusion, trypsinization was performed to prepare a cell suspension, and the cells were counted under a microscope, and then seeded in a 96-well plate at 5 ⁇ 10 3 cells per well. After the overnight culture, the above compound was administered. Changes in cell proliferation after 72 hours of administration were observed by MTT method.
  • IC 50 The specific inhibition rates are shown in Tables 2 and 3, wherein the inhibition of cell proliferation activity (IC 50 ) indicates the method: + means 1-10 ⁇ M; ++ means 0.1-1 ⁇ M; +++ means 0.01-0.1 ⁇ M; ++++ means 0.01-0.001 ⁇ M; +++++ means ⁇ 0.001 ⁇ M; "-" means no activity.
  • IC 50 represents the concentration of 50% growth inhibition required for cell growth inhibition.
  • cancer cell lines used are Hela (human cervical cancer cells), MCF-7 (human breast cancer cells), LM3 (human liver cancer cells), NCI-N87 (human gastric cancer cells), and Caki-1 (human kidney cancer cells). ), A549 (human lung cancer cells), HT1080 (human fibrosarcoma cells), A431 (human epidermal squamous cell carcinoma cells), PC3 (human prostate cancer cells), HL60 (human leukemia cells), Panc-1 (human pancreatic cancer) Cells), KB (human oral cancer cells), U87-MG (human glioma cells), K562 (human chronic granulocyte leukemia cells), Kasumi-1 (human leukemia cells), THP-1 (human leukemia cells) ), Jurkat (human T lymphocytic leukemia cells), REH (human B lymphocyte leukemia cells), Raji (human Burkitt cell leukemia cells), RNK-16 (human NK cell leukemia cells), KMS-1 (human multiple bone marrow) Tumor cells), P
  • the compounds of the present invention have inhibitory activities against the growth of different types of tumor cells, suggesting that the compounds of the present invention have a broad spectrum of antitumor activity.
  • the compounds of the present invention are useful for various types of blood cancer cells (acute myeloid leukemia cells, acute or chronic lymphocytic leukemia cells, multiple myeloma cells, myelodysplastic syndrome cells).
  • the growth of both has an inhibitory activity, suggesting that the compounds of the present invention have a broad spectrum of activity for inhibiting the growth of blood cancer cells.
  • the compound of the present invention has an inhibitory activity on the growth of brain tumor cells (glioma cells and neuroblastoma cells), suggesting that the compound of the present invention is suitable for inhibiting the growth of brain tumor cells. active.
  • the above compounds have significant inhibition of the listed cancer cells compared with the positive controls of vincristine (VCR), paclitaxel (Taxol) and adriamycin (Adrmycin, Adr).
  • VCR vincristine
  • Taxol paclitaxel
  • Adrmycin Adrmycin
  • Compound 492 inhibits neutrophils to relieve gout symptoms
  • Tubulin inhibitors are widely used, in addition to their use as anti-neoplastic agents, in the treatment of gout, as well as antifungal agents and broad-spectrum anthelmintics.
  • mice 1 mg of sodium urate was dissolved in 0.5 ml of endotoxin-free phosphate buffer solution to prepare a solution.
  • C57BL/6 mice were intraperitoneally injected with sodium urate solution to establish a model of peritonitis.
  • mice On days 1-4 after injection of sodium urate solution, mice were treated with different concentrations of compound 492 (0, 0.25, 0.5, and 1 mg/kg) daily, and compound 492 was found to significantly inhibit the gout model in mice.
  • the neutrophil flow ( Figure 1) inhibits inflammation and relieves gout in mice.
  • the compound 492 inhibited the neutrophil flow in the peritonitis mice induced by sodium urate salt crystal in a concentration-dependent manner, suggesting that the compound exhibited an effect of relieving the ventilation condition in the mouse in vivo experiment.

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Abstract

L'invention concerne un composé hétérocyclique à cinq chaînons, un procédé pour sa préparation, une composition pharmaceutique et une utilisation. Plus particulièrement, l'invention concerne un composé présentant la formule (I), les définitions des divers groupes étant indiquées dans la description. Le composé de formule (I) présente un effet d'inhibition de l'activité de la tubuline et peut être utilisé pour préparer un médicament traitant ou prévenant des maladies de mammifères liées à des anomalies de régulation de la tubuline.
PCT/CN2017/081294 2016-04-20 2017-04-20 Composé hétérocyclique à cinq chaînons, procédé de préparation correspondant, composition pharmaceutique et utilisation Ceased WO2017181974A1 (fr)

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WO2023135330A1 (fr) * 2022-01-17 2023-07-20 Centre National De La Recherche Scientifique Inhibiteurs de désoxycytidine kinase

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