WO2019015635A1 - Dérivé benzimidazole, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé benzimidazole, son procédé de préparation et son utilisation médicale Download PDF

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WO2019015635A1
WO2019015635A1 PCT/CN2018/096243 CN2018096243W WO2019015635A1 WO 2019015635 A1 WO2019015635 A1 WO 2019015635A1 CN 2018096243 W CN2018096243 W CN 2018096243W WO 2019015635 A1 WO2019015635 A1 WO 2019015635A1
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compound
formula
cancer
alkyl
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吕贺军
赵雯雯
王成喜
陈磊
白骅
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浙江海正药业股份有限公司
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a novel benzimidazole derivative, a preparation method thereof and a pharmaceutical composition containing the same, and their use as therapeutic agents, in particular as bromodomain protein inhibitors.
  • the bromodomain is a protein domain that recognizes N-acetylated lysine residues.
  • the BET family of bromodomain-containing proteins includes four members (BRD2, BRD3, BRD4, and BRDt). Each member of the BET family uses two bromodomains to recognize, primarily (but not exclusively) the discovery of N-acetylated lysine residues at the amino-terminal tail of histone proteins.
  • Gene expression is regulated by recruiting transcription factors to specific genomic locations within the chromatin. For example, histone-linked BRD4 recruits the transcription factor P-TEFb to a promoter, resulting in the expression of a subset of genes involved in cell cycle progression (Yang et al., Mol. Cell. Biol.
  • BRD2 and BRD3 also function as transcriptional regulators of growth-promoting genes. Recent studies have demonstrated the targeting of BET bromodomains to treat a variety of cancers (Zuber et al., Nature 478: 524-528 (2011); Mertz et al., Proc. Natl. Acad. Sci. 108: 16669-16674 (2011); Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478: 529-533 (2011)), atherosclerosis, inflammation (Huang et al. , Mol. Cell. Biol. 29: 1375-1387 (2009)) and HIV infection.
  • BRD4 protein-mediated epigenetic abnormalities are closely related to overexpression of oncogenes and are closely related to the growth and proliferation of cancer cells.
  • BRD4 is a member of the Bromo and extra C-terminal domain (BET) family of proteins, which has caused great potential for major pharmaceutical companies and research institutions due to its potential value in anti-tumor. attention. It has also recently been found that BRD4 also plays an important role in the transcriptional regulation of viral genes and is associated with the pathogenesis of viral tumors.
  • BRD4 protein is a very promising new epigenetic target, and small molecule inhibitors acting on the bromodomain of BRD4 protein have broad application prospects in tumor research, and it is possible to develop a new type of anti-tumor. drug.
  • bromodomain protein inhibitor patents include WO2011054846, WO2008092231, WO2012075383, and WO2016139292, among which WO2016139292 discloses the compound of Example 1.
  • the drug currently in clinical stage III is Apabetalone, and the drugs in clinical phase II include GSK-525762A, INCB-54329 and BMS-986158, and there are several drugs in clinical phase I.
  • these studies on anti-tumor are far from enough.
  • the compounds disclosed in the prior art and the test drugs are still unsatisfactory in terms of effectiveness, safety or applicability. It is still necessary to study and develop new bromo structures. Domain protein inhibitors to meet the growing medical and health needs of people.
  • the present inventors have unexpectedly discovered through experimental research that the compound of the following formula (I) can be effectively used as a bromodomain protein inhibitor for the treatment or prevention of a disease associated with a bromodomain protein.
  • the present invention provides a benzimidazole derivative of the formula (I):
  • R 1 is selected from an alkyl group; preferably a methyl group
  • R 2 is selected from a hydrogen atom or an alkyl group; preferably a methyl group;
  • R 3 is selected from alkyl, wherein said alkyl group is further substituted with one or more alkoxy groups;
  • R 4 is selected from halogen
  • R 7 is selected from a hydrogen atom or an alkyl group; preferably a hydrogen atom;
  • R 8 and R 9 together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group, wherein the 4 to 8 membered heterocyclic ring contains one or more N, O, S(O) p atoms, and 4
  • one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, 0
  • R 11 , R 12 and R 13 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylic acid Substituted by a substituent of an ester group;
  • p 0, 1, or 2.
  • the compound of formula (I) has the structure shown in formula (II),
  • R a and R b are each independently selected from a hydrogen atom or an alkoxy group, and R a and R b are not simultaneously a hydrogen atom; the alkoxy group is preferably a methoxy group;
  • n 1, 2, 3 or 4; preferably 1 or 2;
  • n 1, 2, 3 or 4; preferably 1 or 2;
  • R 1 , R 2 , and R 4 to R 7 are as defined in the formula (I).
  • the compound of the formula (II) has a structure represented by the formula (III).
  • R a is selected as a hydrogen atom
  • R b is selected from alkoxy groups, preferably methoxy groups
  • n 1, 2, 3 or 4; preferably 1 or 2;
  • n 1, 2, 3 or 4; preferably 1 or 2;
  • R 1 , R 2 , and R 4 to R 7 are as defined in the formula (I).
  • the compound of the formula (II) has a structure represented by the formula (IV).
  • R a is a hydrogen atom
  • R b is selected from alkoxy groups, preferably methoxy groups
  • n 1, 2, 3 or 4; preferably 1 or 2;
  • n 1, 2, 3 or 4; preferably 1 or 2;
  • R 1 , R 2 , and R 4 to R 7 are as defined in the formula (I).
  • R 4 is selected from fluoro, chloro or bromo; preferably fluoro.
  • R 6 is selected from heterocyclyl, preferably morpholinyl.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention provides a process for the preparation of a compound of formula (I), which process comprises:
  • X is selected from halogen, preferably chlorine or bromine
  • R 6 is selected from heterocyclic groups
  • R 1 to R 5 , R 7 , X 1 and X 2 are as defined in the formula (I).
  • the present invention also provides a compound represented by the formula (IA), including stereoisomers, tautomers thereof or pharmaceutically acceptable salts thereof,
  • X is selected from halogen, preferably chlorine or bromine
  • R 1 to R 5 , R 7 , X 1 and X 2 are as defined in the formula (I).
  • Typical compounds of formula (IA) include, but are not limited to:
  • stereoisomers include stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
  • the present invention provides a process for the preparation of a compound of formula (IA), which process comprises:
  • X is selected from halogen, preferably chlorine or bromine
  • R 1 to R 5 , R 7 , X 1 and X 2 are as defined in the formula (I).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III) or (IV) (including stereoisomers) And tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.
  • the present invention also provides a method of inhibiting a bromodomain protein comprising contacting the protein with a compound of formula (I), (II), (III) or (IV) or a pharmaceutical composition thereof,
  • the bromodomain proteins described therein are preferably BRD2, BRD3 and BRD4, more preferably BRD4.
  • the invention further provides a compound of formula (I), (II), (III) or (IV), including stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical combination thereof
  • a substance for the preparation of a medicament for use as a bromodomain protein inhibitor wherein said bromodomain protein is preferably BRD2, BRD3 and BRD4, more preferably BRD4.
  • the invention further provides a compound of formula (I), (II), (III) or (IV), including stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical combination thereof
  • a disease associated with a bromodomain protein wherein the disease is preferably cancer or inflammation, wherein the inflammation is preferably rheumatoid arthritis, cloning enemies, Eczema, giant cell arteritis, hepatitis, inflammatory bowel disease, osteoarthritis, pancreatitis, pneumonia, psoriasis, psoriatic arthritis, systemic lupus erythematosus, glomerulonephritis, lupus nephritis, Membranous glomerulonephritis or myocarditis; the inflammation is more preferably rheumatoid arthritis; wherein the cancer is preferably small cell lung cancer, non-small cell lung cancer, breast cancer, colorectal cancer, prostate
  • the present invention also provides a compound of the formula (I), (II), (III) or (IV), including stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical combination thereof
  • Preparation for the treatment or prevention of diabetic nephropathy, hypertensive nephropathy, HIV-related nephropathy, polycystic kidney disease, obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, fatty liver Use in drugs for type 2 diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy.
  • alkyl as a group or part of a group is meant to include a straight-chain or branched with C 1 -C 20 aliphatic hydrocarbon group. It is preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group, and particularly preferably a C 1 -C 4 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1, 1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait.
  • the alkyl group can be substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially saturated monocyclic, fused, bridged or spiro carbon ring. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • “Spirocycloalkyl” means a 5- to 18-membered polycyclic group having two or more cyclic structures and sharing a carbon atom (called a spiro atom) with each other, and the ring may contain 1 One or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5 to 18 membered all carbon polycyclic group having two or more cyclic structures that share a pair of carbon atoms with each other, wherein one or more of the rings may contain one or more A double bond, but none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecafluorophenanyl.
  • “Bridge cycloalkyl” refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two non-directly bonded carbon atoms, wherein one or more rings may contain One or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • a bicyclic ring a tricyclic ring, a pyridone or a polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Ring [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group can be optionally substituted or unsubstituted.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged, and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered double- or tricyclic ring which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetane, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine , 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclic group may be substituted or unsubstituted.
  • spiroheterocyclyl means a 5- to 18-membered polycyclic group having the meaning of two or more cyclic structures and sharing one atom with each other, having one or more double bonds in the ring. , but none of the rings have a fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) p (where p is selected from 0, 1 or 2) heteroatoms, the remainder The ring atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • spiroheterocyclyl include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, wherein one or more of the rings may contain one or more double bonds, but none of the rings have A fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) p (where p is selected from 0, 1 or 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic fused heterocyclic group, preferably a bicyclic ring or a tricyclic ring, and more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1. 0] hexyl, octahydrobenzo[b][1,4]dioxine.
  • “Bridge heterocyclyl” refers to a polycyclic group of 5 to 18 members, preferably 5 to 14 members, containing two or more cyclic structures and sharing two atoms which are not directly bonded to each other, one or more of which A ring may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) p (where p is selected from 0, 1 or 2) of a hetero atom, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring.
  • fused heterocyclic groups include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group.
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl means a carbocyclic aromatic system containing one or two rings wherein the rings may be joined together in a fused manner.
  • aryl includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • the aryl group can be substituted or unsubstituted.
  • the "aryl” may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to:
  • Heteroaryl means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo Dioxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindenyl, quinolyl, ox
  • Heteroaryl groups can be substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:
  • Alkoxy means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein.
  • the C 1 -C 6 alkoxy group is preferred, and a C 1 -C 4 alkoxy group is particularly preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo and iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • DMSO dimethyl sulfoxide
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are replaced by a corresponding number of substituents independently of one another. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an ethylenic bond.
  • substituted or “substituted”, unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds which retain their original biological activity and are suitable for pharmaceutical use.
  • the pharmaceutically acceptable salt of the compound of the formula (I) may be a metal salt, an amine salt formed with a suitable acid, a metal salt preferably an alkali metal or an alkaline earth metal salt, and suitable acids include inorganic acids and organic acids.
  • “Pharmaceutical composition” means a compound comprising one or more of the compounds described herein, including physiologically pharmaceutically acceptable salts or stereoisomers, tautomers or prodrugs thereof, and optionally other drugs Mixtures of the active ingredients may contain other optional ingredients such as pharmaceutically acceptable carriers and/or excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the term “plurality” includes two or more, such as two, three, four, and the like.
  • the preparation method of the compound of the formula (I) of the present invention comprises the following steps:
  • X is selected from halogen, preferably chlorine or bromine
  • R 6 is selected from heterocyclic groups
  • R 1 to R 5 , R 7 , X 1 and X 2 are as defined in the formula (I).
  • Example 1 is a graph showing changes in mean tumor volume of MV4-11 tumor-bearing BALB/c nude mice xenografts of the compound of Example 1 of WO2016139292 in Test Example 2, and the compounds of Example 1 and Example 4 of the present invention.
  • Figure 2 is a graph showing the mean relative tumor volume changes of the MV4-11 tumor-bearing BALB/c nude mice xenografts of the compound of Example 1 of WO2016139292 in Test Example 2, the compounds of Example 1 and Example 4 of the present invention.
  • Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD Deuterated methanol.
  • the argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.
  • the solution in the reaction means an aqueous solution unless otherwise specified.
  • the compound is purified by silica gel column chromatography and thin layer chromatography, wherein the eluent system is selected from the group consisting of: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: acetic acid Ethyl ester; wherein the volume ratio of the solvent varies depending on the polarity of the compound, and may also be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.
  • A petroleum ether and ethyl acetate system
  • B dichloromethane and methanol system
  • C dichloromethane: acetic acid Ethyl ester
  • the volume ratio of the solvent varies depending on the polarity of the compound, and may also be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.
  • N,N-dibenzyl-1,3-dimethoxypropan-2-amine 1c (5 g, 16.7 mmol) was dissolved in 50 mL of methanol under a hydrogen atmosphere, and a 10% palladium carbon catalyst (500 mg, 10%) was added. The hydrogen was replaced 3 times and reacted at room temperature for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded crude 1,3-dimethoxypropan-2-amine 1d (1.99 g, colorless oil).
  • Exemplary compounds of the invention are tested for their biological activity against the BRD4 protein by the following method.
  • This test method uses Cisbio Assays EPIGENEOUS TM BROMODOMAIN ASSAY company under in vitro conditions, test compounds on recombinant human interaction effect on the FRET (fluorescence resonance energy transfer) to express protein and BRD4 between acetylated histone peptide substrate The biological activity of the compound against BRD4.
  • the GST-tagged recombinant human BRD4(1/2) protein was derived from BPS Bioscience, and the acetylated histone polypeptide substrate [Lys(5,8,12,16)Ac]H4(1-21)-biotin peptide was purchased from AnaSpec.
  • the compounds of the invention were first dissolved in DMSO and subsequently diluted to the desired concentration for testing (final concentration range 10 ⁇ M - 0.1 nM) in the buffer provided in the kit. 2 ⁇ L of the compound was added to a 384-well microtiter plate, followed by the addition of 4 uL of GST-labeled recombinant human BRD4 (1/2) protein and 4 ⁇ L of acetylated histone polypeptide substrate diluted in buffer, and finally added to the well.
  • the inhibition rate of the compound at each concentration point was calculated by comparing with the fluorescence intensity values of the control group, and then the nonlinear regression analysis of the compound concentration log-inhibition rate in GraphPad Prism 5 software was performed to obtain the compound inhibiting BRD4 protein and acetylation.
  • Test Example 2 Inhibition of proliferation of prostate cancer cells (LNCaP) by the compound of the present invention
  • the cell-level activity of the exemplified compounds of the present invention is measured by an absorbance method by CCK-8 (Dojindo, Toray Chemical Technology) to inhibit the proliferation of the compound.
  • CCK-8 Diojindo, Toray Chemical Technology
  • the prostate cancer cell LNCaP purchased from the Shanghai Institute of Biological Sciences, Chinese Academy of Sciences
  • different concentrations of test compounds were added. (The final concentration range is from 30 ⁇ M to 0.1 nM).
  • the cells were cultured for 72 hours at 37 ° C, 5% CO 2 .
  • CCK-8 reagent purchased from Dongren Chemical Technology (Shanghai) Co., Ltd., item number CK04
  • CK04 Dongren Chemical Technology
  • the absorbance values at 450 nM for each well were taken.
  • the inhibition rate of the compound at each concentration point was calculated by comparison with the absorbance values of the control group, and then the nonlinear regression analysis of the compound concentration log-inhibition rate in GraphPad Prism 5 software was performed to obtain the IC 50 value of the compound inhibiting cell proliferation. .
  • the exemplified compounds of the present invention have a good inhibitory effect on the proliferation of prostate cancer cells LNCaP.
  • Test Example 3 Test of the growth inhibitory effect of the compound of the present invention on human acute myeloid leukemia cell line MV4-11 nude mice xenografts
  • test solution containing 90% PEG300 and 10% ethanol (10% TPGS, w/v) was prepared as a blank group.
  • Example 1 of WO2016139292 An appropriate amount of the compound of Example 1 of WO2016139292 was weighed, and an appropriate amount of a solvent containing 90% PEG300 and 10% ethanol (10% TPGS, w/v) was added thereto, and the mixture was vortexed uniformly to prepare a preparation having a concentration of 0.5 mg/mL. .
  • Example 1 An appropriate amount of the compound of Example 1 was weighed, and an appropriate amount of a solvent containing 90% PEG300 and 10% ethanol (10% TPGS, w/v) was added thereto, and the mixture was vortexed uniformly to prepare a preparation having a concentration of 0.5 mg/mL.
  • Example 4 An appropriate amount of the compound of Example 4 was weighed, and an appropriate amount of a solvent containing 90% PEG300 and 10% ethanol (10% TPGS, w/v) was added thereto, and the mixture was vortexed uniformly to prepare a preparation having a concentration of 0.5 mg/mL.
  • MV4-11 cells purchased from the American Type Culture Collection (ATCC) were subjected to conventional cell culture in IMDM medium containing 10% fetal calf serum under 5% CO 2 , 37 ° C culture conditions. Passage was digested with 0.25% trypsin and passaged according to cell growth conditions, with a passage ratio of 1:3 or 1:4.
  • MV4-11 cells in logarithmic growth phase were harvested, and the cells were counted and resuspended in 50% PBS (phosphate buffered saline) (pH 7.4, 0.01 M) and 50% matrigel (Matrigel). Adjust the cell concentration to 7.0 ⁇ 10 7 cells/mL; place the cells in an ice box, aspirate the cell suspension with a 1-mL syringe, and inject into the right axilla of the nude mouse, inoculate 200 ⁇ L (14 ⁇ 106) per animal. Cells/only), established a MV4-11 xenograft model.
  • PBS phosphate buffered saline
  • matrigel matrigel
  • Group 8 was divided into 4 groups.
  • Each group of animals was given a test substance once a day according to the body weight of the animal once a day (QD), orally (po), on the day of grouping (12 days after inoculation), the first administration was started for 22 consecutive days. And record the animal weight per day.
  • the first group was intragastrically administered with a blank solvent at a dose of 10 mL/kg, QD, PO; the second group was intragastrically administered with the compound of Example 1 of WO2016139292 at a dose of 5 mg/kg, QD, PO; Compound of Example 1, administered dose: 5 mg/kg on day 12-19, QD, PO; 2 mg/kg on day 20-33, QD, PO; Group 4 was administered compound of Example 4, dose: 5 to 19 days, 5 mg/kg, QD, PO; 20 to 33 days, 2 mg/kg, QD, PO.
  • the formation of tumors at the inoculation site of each group of animals was observed.
  • the tumor diameter was measured twice a week after the start of the experiment, the tumor volume was calculated, and the body weight of the animals was weighed and recorded.
  • the tumor volume (TV) is calculated as follows:
  • Evaluation index of antitumor activity tumor growth inhibition rate TGI (%), relative tumor growth rate T/C (%).
  • the relative tumor volume (RTV) is calculated as:
  • TV initial is the tumor volume measured before administration at the time of grouping
  • TV t is the tumor volume at each measurement during administration.
  • the relative tumor growth rate T/C (%) is calculated as:
  • RTV T represents the treatment group RTV
  • RTV C represents the solvent control group RTV.
  • the formula for calculating the tumor growth inhibition rate TGI (%) is:
  • TGI 100% ⁇ [1-(TV t(T) -TV initial(T) )/(TV t(C) -TV initial(C) )]
  • TV t(T) represents the tumor volume measured each time in the treatment group
  • TV initial (T) represents the tumor volume of the treatment group before administration in the group
  • TV t (C) represents the tumor volume measured each time in the solvent control group
  • TV initial (C) indicates the tumor volume of the solvent control group before administration at the time of grouping.
  • the formula for calculating the tumor weight inhibition rate IR (%) is:
  • W C represents the tumor weight of the control group
  • W T represents the tumor weight of the treatment group
  • Fig. 1 The average tumor volume change of the compound of Example 1 of WO2016139292, the compound of Example 1 and the compound of Example 4 for the transplanted tumor of MV4-11 tumor-bearing BALB/c nude mice is shown in Fig. 1;

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Abstract

La présente invention concerne un dérivé benzimidazole, son procédé de préparation et son utilisation médicale. En particulier, la présente invention concerne un dérivé benzimidazole tel que représenté par la formule générale (I), un procédé de préparation de celui-ci et un sel pharmaceutiquement acceptable correspondant et son utilisation en tant qu'agent thérapeutique, spécialement en tant qu'inhibiteur de la protéine de bromodomaine, la définition de chaque substituant dans la formule générale (I) étant la même que la définition dans la description.
PCT/CN2018/096243 2017-07-21 2018-07-19 Dérivé benzimidazole, son procédé de préparation et son utilisation médicale WO2019015635A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2439197A1 (fr) * 2010-10-07 2012-04-11 Santhera Pharmaceuticals (Schweiz) AG Dérivés de benzimidazole substitués en tant qu'antagonistes de récepteur 4 de mélanocortine
WO2015022332A1 (fr) * 2013-08-14 2015-02-19 Boehringer Ingelheim International Gmbh Pyridinones
WO2016139292A1 (fr) * 2015-03-05 2016-09-09 Glaxosmithkline Intellectual Property (No.2) Limited Composé de pyridinone, composition pharmaceutique le contenant et utilisation
WO2016146738A1 (fr) * 2015-03-19 2016-09-22 Glaxosmithkline Intellectual Property Development Limited Dérivés de benzimidazole comme inhibiteurs des bromodomaines

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2439197A1 (fr) * 2010-10-07 2012-04-11 Santhera Pharmaceuticals (Schweiz) AG Dérivés de benzimidazole substitués en tant qu'antagonistes de récepteur 4 de mélanocortine
WO2015022332A1 (fr) * 2013-08-14 2015-02-19 Boehringer Ingelheim International Gmbh Pyridinones
WO2016139292A1 (fr) * 2015-03-05 2016-09-09 Glaxosmithkline Intellectual Property (No.2) Limited Composé de pyridinone, composition pharmaceutique le contenant et utilisation
WO2016146738A1 (fr) * 2015-03-19 2016-09-22 Glaxosmithkline Intellectual Property Development Limited Dérivés de benzimidazole comme inhibiteurs des bromodomaines

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