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WO2019015672A1 - Composé de pyridoimidazole et son utilisation - Google Patents

Composé de pyridoimidazole et son utilisation Download PDF

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WO2019015672A1
WO2019015672A1 PCT/CN2018/096447 CN2018096447W WO2019015672A1 WO 2019015672 A1 WO2019015672 A1 WO 2019015672A1 CN 2018096447 W CN2018096447 W CN 2018096447W WO 2019015672 A1 WO2019015672 A1 WO 2019015672A1
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Chinese (zh)
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王大海
钱文远
刘世岚
陈曙辉
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Medshine Discovery Inc
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of pyridoimidazole compounds and their use as inhibitors of IDH mutants, and in particular to compounds of the formula ( ⁇ ), tautomers thereof or pharmaceutically acceptable salts thereof.
  • Isocitrate dehydrogenase is an important enzyme in the citric acid cycle, catalyzing the oxidative decarboxylation of isocitrate to 2-oxoglutaric acid (ie 2- ⁇ -ketoglutarate, ⁇ -KG).
  • the protein encoded by IDH 1 is a NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes, which contains a PTS-1 peroxidase targeting signal sequence. The presence of this enzyme in the oxidase body suggests an effect in the regeneration of the internal NADPH.
  • Non-mutation such as wild-type IDH, catalyzes the oxidative decarboxylation of isocitrate while reducing NAD + (NADP + ) to NADP (NADPH):
  • IDH 1/2 mutation has been found in a variety of tumors, including glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma, melanoma, prostate cancer, and angioimmunoblastic T-cell lymphoma.
  • Protein (IDH 1/2m) (Balss J. Acta Neuropathol. 2008 Dec; 1 16(6): 597-602, Mardis ER, N Engl J Med. 2009 Sep 10; 361(11): 1058-66, Amary MF, J Pathol.2011 Jul; 224(3): 334-43, Borger DR, Oncologist. 2012; 17(1): 72-9, Shibata T, Am J Pathol.
  • the IDH mutein has a novel protein function, namely catalytic reduction of ⁇ -KG to produce the oncogenic metabolite 2-hydroxyglutaric acid (2-HG).
  • the production of 2-HG is believed to contribute to the formation and development of cancer (Dang L, Nature, 2009 Dec 10; 462 (7274): 739-44).
  • the level of 2-HG produced in normal cells is very low, but cells with IDH mutations can produce high levels of 2-HG. High levels of 2-HG can also be found in tumors with IDH mutations.
  • the inhibition of mutant IDH and its novel activity is a potential method for cancer treatment, and there is a new effect of requiring an inhibitor of IDH mutant to inhibit its production of 2-HG.
  • the present invention provides a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from N or C(R 1 );
  • T 2 is selected from N or C (R 2 );
  • T 3 is selected from N or C(R 3 );
  • T 1 , T 2 , and T 3 is selected from N;
  • R 1 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 ;
  • R 2 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 ;
  • R 3 is selected from H, F, Cl, Br, I, OH, NH 2 or selected from C 1 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 ;
  • the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • the above T 1 is selected from N or CH.
  • the T 2 is selected from N or CH.
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 or selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R, C 1-3 alkoxy, R is as defined in the invention.
  • R 3 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , Me, Et, CF 3 ,
  • the T 3 is selected from the group consisting of: N, CH, C(F), C(Me), C(CF 3 ), C(Et), C(OCH 3 ).
  • T 1 is selected from N or CH, and other variables are as defined in the present invention.
  • the T 2 is selected from N or CH, and other variables are as defined herein.
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 or selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R, C 1-3 alkoxy, other variables are as defined in the present invention.
  • R 3 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , Me, Et, CF 3 , Other variables are as defined by the present invention.
  • the T 3 is selected from the group consisting of: N, CH, C (F), C (Me), C (CF 3 ), C (Et), C (OCH 3 ), and other variables such as the present invention. definition.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 and R 3 are as defined above.
  • the present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 1 , R 2 and R 3 are as defined above.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a drug related to an IDH mutant inhibitor.
  • the compounds of the present invention have good selectivity and brain permeability, and have significant inhibitory effects on IDH1 mutants in vitro.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the (R)- and (S)-enantiomers, and mixtures thereof, such as (R)- and (S)-enantiomerically enriched mixtures, all of which are Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group)
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted at most by two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • heteroalkyl by itself or in conjunction with another term denotes a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy", “alkylamino” and “alkylthio” (or thioalkoxy).
  • alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 .
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkoxy represents attached through an oxygen bridge, unless otherwise specified, C 1-3 alkoxy groups include C 1, C 2 and C 3 alkoxy is. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Example 2 inhibits the level of 2-HG in brain tumors of Balb/c mice, a) 2-HG content in mouse brain tumors after 0.25 hours, 2 hours and 8 hours of administration.
  • HNO 3 (814.83 mg, 12.93 mmol) was added dropwise to a solution of compound 11A (1.3 g, 6.47 mmol) in H 2 SO 4 (2 mL). After stirring for one hour, the reaction system was warmed to 15 ° C. After stirring for 1 hour, the reaction was poured into 20 ml of ice water, and the pH was adjusted to 7 by adding NaOH aqueous solution. The precipitated solid was washed with 10 ml of water, and the solid was further purified by column chromatography to give compound 11B.
  • Compound 17J was subjected to SFC chiral resolution (SFC resolution conditions: column: ChiralPak IC-3 150 x 4.6 mm ID, 3 um; mobile phase: A: CO 2 B: isopropanol (0.05% diethylamine); gradient: Isopropanol in CO 2 was obtained from 5% to 40% (5.5 minutes), maintained at 40% for 3 minutes, then at 5% for 1.5 minutes; flow rate of 2.5 mL/min. column temperature 40 ° C) to obtain Example 17, retained The time was 7.452 minutes; in Example 18, the retention time was 8.191 minutes.
  • SFC resolution conditions column: ChiralPak IC-3 150 x 4.6 mm ID, 3 um; mobile phase: A: CO 2 B: isopropanol (0.05% diethylamine); gradient: Isopropanol in CO 2 was obtained from 5% to 40% (5.5 minutes), maintained at 40% for 3 minutes, then at 5% for 1.5 minutes; flow rate of 2.5 mL/min. column temperature 40 ° C) to obtain
  • Ethyl (E)-3-(4,4,5,5) was added to a mixed solvent of compound 19B (8.2 g, 26.97 mmol) in dioxane (80 ml) and water (20 ml) at 20 °C. -tetramethyl-1,3,2-dioxoboran-2-yl)prop-2-enoate (7.93 g, 35.05 mmol), Pd(dppf)Cl 2 (3.95 g, 5.39 mmol) , 0.2 eq) and cesium carbonate (13.18 g, 40.45 mmol). After the reaction mixture was stirred at 100 ° C in a nitrogen atmosphere, the reaction was completed.
  • Example 19 To a mixed solvent of the compound 19I (0.31 g, 597.80 micromoles, 1 eq) in methanol (5 ml) and water (5 ml) was added LiOH ⁇ H 2 O (50.17 mg, 1.20 mmol, 2 eq). After completion of the reaction, the reaction solution was concentrated and then separated to give Example 19.
  • the IDH1 mutant catalyzes the reduction of NADPH-dependent ⁇ -KG to 2-HG, and the consumed NADPH can be read by fluorescence.
  • Base Reaction Buffer 50 mM KH 2 PO 4 , pH 7.5, 10 mM MgCl 2 , 10% glycerol (glycerol), 150 mM NaCl, 0.05% BSA (bovine serum albumin), 2 mM b-ME (2-mercaptoethanol), 0.003 %Brij35 (oxyethylene lauryl ether)
  • IDH1 wt wild type: 65 ⁇ M isocitric acid + 50 ⁇ M NADP
  • IDH1 (R132H): 1500 ⁇ M ⁇ -KG+15 ⁇ M NADPH
  • IDH1 (R132C): 500 ⁇ M ⁇ -KG+15 ⁇ M NADPH
  • 1.33X enzyme (not added in the control well), buffer and NADP or NADPH (control well) were added to the wells of the reaction plate, and the test compound was dissolved in 100% DMSO and added to the enzyme mixture (Echo550, Nanoscale). After simple centrifugation, the cells were incubated for 60 minutes, and a mixture of 4X substrate and cofactor was added to start the reaction. After simple centrifugation, the mixture was shaken and incubated at room temperature for 45 minutes.
  • Example IDH1 R132H(nM) Example 2 12.19
  • Example 3 93.01 Example 4 3.46
  • Example 5 1649
  • Example 6 166.9
  • Example 7 675.3
  • Example 8 53.01
  • Example 9 2137
  • Example 10 396.4
  • Example 11 639.8 Example 12 58.91
  • Example 15 3710
  • Example 17 ⁇ 0.5
  • Example 18 13.2 Example 19 1.91
  • IDH1 catalyzes the reduction of isocitrate to alpha-ketoglutarate ( ⁇ -KG) in vivo, while the IDH1 mutant further catalyzes the reduction of ⁇ -KG to 2-hydroxyglutarate (2HG).
  • the U87MG-IDH1-R132H cell line is a stable cell line stably expressing the IDH1-R132H mutant by transfecting U87MG cells with IDH1-R132H, and the HT1080 cell line contains an endogenous IDH1-R132C mutant.
  • the compound was diluted with DMSO in a 3-fold gradient and added to the cell culture plate for a total of 10 concentrations, each with double duplicate wells.
  • the negative control wells contained only DMSO and the positive control wells contained AGI-5198 at a final concentration of 5 [mu]M.
  • the final concentration of DMSO in all wells was 0.5%.
  • the IDH1 mutant cell strain was seeded at a density of 40,000 cells/well into a cell culture plate containing the compound. The cells were incubated with the compounds for 3 days at 37 ° C in a 5% CO 2 incubator.
  • Inhibition rate% (CPD-ZPE)/(HPE-ZPE) ⁇ 100%*
  • the cell viability data was used to calculate the percent cytotoxicity (% cytotoxicity) of the compound against the IDH1 mutant cell line, and the formula was:
  • Cytotoxicity% (1-CPD/ZPE) ⁇ 100%*
  • ZPE mean value of negative control well signal, replacing compound with 0.5% DMSO
  • HPE Mean value of positive control well signal, containing 5 ⁇ M AGI-5198
  • Example U87MG IDH1-R132H(nM) Example 1 137.82
  • Example 2 33.09
  • Example 3 189.2
  • Example 4 Example 4 42.58
  • Example 6 243.5
  • Example 7 419
  • Example 8 104.3
  • Example 9 1776 Example 10 396.4
  • Example 13 3003
  • Example 14 622.5 Example 17 49.99
  • Example HT1080 IDH1 R132C(nM) Example 2 13.32
  • Example 4 19.39
  • a U87 stable cell line expressing exogenous expression of IDH1R132H was established, and a brain orthotopic tumor model of the cell line was constructed to detect the reduction effect of IDH1 inhibitor on the level of carcinogenic metabolite 2-HG. And compared with BAY1436032 (BAY032).
  • mice bearing U87-IDH1R132H brain orthotopic tumors were divided into three groups and treated with 100 mg/kg BAY032 or 200 mg/kg for Example 2, twice daily for 3 times, and the other group.
  • the mice were not treated as a negative control.
  • the brain tumor, paracancerous brain tissue, and plasma of 3 mice were separately measured for 2-HG content, and the corresponding tissues of the negative control mice were used as controls.
  • Example 2 The experimental results are shown in Figure 1.
  • Administration of 0.25 hours of Example 2 can greatly reduce the content of the oncogenic metabolite 2-HG in the tumor, and the effect is faster than BAY032, and the effect can last at least 8 hours.
  • the total exposure (AUC) of Example 2 in plasma, normal paraventricular tissue, and brain tumors was 416,856 nM ⁇ hr, 97,429 nmol/kg.h, and 1967,33 nmol/kg.h, respectively, in BAY032 in plasma, normal paracranial tissues, and brain tumors.
  • the total exposure (AUC) was 387498 nM ⁇ hr, 125962 nmol/kg.h and 230405 nmol/kg.h, respectively, indicating that Example 2 has a blood-brain barrier permeability close to that of BAY032.
  • the compounds of the present invention have good selectivity and brain permeability, and have significant inhibitory effects on IDH1 mutants in vivo, and 2-HG inhibition in mouse brain tumors is superior to BAY032.

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Abstract

L'invention concerne un composé de pyridoimidazole et son utilisation en tant qu'inhibiteur d'IDH mutant. L'invention concerne particulièrement un composé représenté par la formule (I), un tautomère ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2018/096447 2017-07-21 2018-07-20 Composé de pyridoimidazole et son utilisation Ceased WO2019015672A1 (fr)

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WO2017016992A1 (fr) * 2015-07-27 2017-02-02 Bayer Pharma Aktiengesellschaft Inhibiteur d'isocitrate déshydrogénase mutée idh1 r132h
WO2017019429A1 (fr) * 2015-07-27 2017-02-02 Eli Lilly And Company Coposés de 7-phényléthylamino -4 h-pyrimido [4,5-d] [1,3] oxazin-2-one et leur utilisation en tant qu'inhibiteurs de idh1 mutante
CN106905256A (zh) * 2017-03-06 2017-06-30 中国药科大学 苯并五元杂环类ido1抑制剂、其制备方法及应用

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