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WO2018192445A1 - Composé polycyclique ayant une activité d'inhibition de parp, et ses utilisations - Google Patents

Composé polycyclique ayant une activité d'inhibition de parp, et ses utilisations Download PDF

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Publication number
WO2018192445A1
WO2018192445A1 PCT/CN2018/083212 CN2018083212W WO2018192445A1 WO 2018192445 A1 WO2018192445 A1 WO 2018192445A1 CN 2018083212 W CN2018083212 W CN 2018083212W WO 2018192445 A1 WO2018192445 A1 WO 2018192445A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
solvate
polycyclic compound
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English (en)
Chinese (zh)
Inventor
林当
胡海
许勇
黄璐
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Guangzhou Wellhealth Bio-Pharmaceutical Co Ltd
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Guangzhou Wellhealth Bio-Pharmaceutical Co Ltd
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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
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Definitions

  • the present invention belongs to the field of biomedicine and relates to a series of polycyclic compounds as PARP inhibitory activity, and in particular to a polycyclic compound of the formula I as a PARP inhibitory activity or a pharmaceutically acceptable salt thereof and use thereof.
  • PARP poly(ADP-ribose) polymerase
  • Clovis Oncology also announced that the US FDA has accelerated the approval of its new drug Rubraca (rucaparib) as a monotherapy for the treatment of advanced ovarian cancer carrying harmful BRCA mutations (growth and/or somatic), which have been accepted by these women. More or more chemotherapy treatments.
  • Rubraca rucaparib
  • a series of compounds, whether as single-administration or as a combination therapy, are in clinical research, such as veliparib from Abbvie, niraparib from Tesaro, and talazoparib (BMN-673) from BioMarin.
  • the technical problem to be solved by the present invention is to provide a novel polycyclic compound, a pharmaceutical composition thereof, a preparation method and use thereof.
  • the polycyclic compounds of the present invention have PARP inhibitory activity and provide a new commercial option for PARP inhibitors for the treatment and/or prevention of tumors, stroke, myocardial ischemia, inflammation or diabetes.
  • the present invention provides a polycyclic compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, stereoisomer or prodrug thereof,
  • the R 3 and R 4 are independently
  • R 5 is independently H or C 1 -C 4 alkyl (such as methyl or isopropyl);
  • R 2 is H, halogen (for example fluorine, chlorine or bromine), CN, OH, NH 2 , C 1 -C 4 alkyl (for example methyl or isopropyl) or C 1 -C 4 alkoxy ( For example methoxy).
  • halogen for example fluorine, chlorine or bromine
  • CN OH
  • NH 2 for example methyl or isopropyl
  • C 1 -C 4 alkoxy For example methoxy
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • the R 1 is
  • the R 3 and R 4 are independently
  • the R 5 is independently H or C 1 -C 4 alkyl
  • the R 2 is H, halogen, CN, OH, NH 2 , C 1 -C 4 alkyl or C 1 -C 4 alkoxy; preferably, R 2 is H, F, Cl, Br, methyl, Methoxy or isopropyl.
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • the R 1 is
  • the R 3 and R 4 are independently
  • R 5 is independently H or C 1 -C 4 alkyl (such as methyl or isopropyl);
  • the R 2 is H, halogen (e.g., fluorine, chlorine or bromine) or CN.
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • the R 1 is
  • the R 3 and R 4 are independently
  • the R 5 is independently C 1 -C 4 alkyl (eg methyl or isopropyl);
  • the R 2 is a halogen (e.g., fluorine, chlorine or bromine) or CN.
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • the R 1 is
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • the R 3 and R 4 are independently
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • the R 5 is independently a C 1 -C 4 alkyl group (e.g., methyl or isopropyl).
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • the R 2 is H, halogen (e.g., fluorine, chlorine or bromine) or CN.
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • the R 2 is a halogen (e.g., fluorine, chlorine or bromine) or CN.
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • the R 2 is a halogen (e.g., fluorine, chlorine or bromine).
  • each group in the compound I can be as follows (unannotated definitions are as described above):
  • R 2 is H, F, Cl, Br, methyl, methoxy or isopropyl.
  • the solvate refers to a steadily present compound formed by combining a compound molecule with a solvent molecule, wherein the molar ratio of the compound molecule to the solvent molecule may be a common ratio of solvate, generally including 1:1, 1 : 2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10.
  • the solvent compound is preferably a hydrate such as a monohydrate, a dihydrate or the like.
  • R 1 , R 2 , R 3 , R 4 and substituents thereof in the compounds of Formula I can select groups of R 1 , R 2 , R 3 , R 4 and substituents thereof in the compounds of Formula I to provide the present invention.
  • polycyclic compound as shown in Formula I may be any of the following compounds:
  • the stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers.
  • polycyclic compounds of the formula I according to the invention can be prepared according to conventional chemical synthesis methods in the art, the steps and conditions of which can be referred to the steps and conditions of similar reactions in the art.
  • reaction solvent used in each reaction step of the present invention is not particularly limited, and any solvent which can dissolve the starting materials to some extent and does not inhibit the reaction is included in the present invention.
  • solvents, solvent combinations, and solvent combinations described herein are considered to be within the scope of the invention.
  • the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the polycyclic compound of formula I and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient can be an excipient.
  • the present invention also provides the polycyclic compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, stereoisomer or prodrug thereof, or the use of the pharmaceutical composition in the preparation of a PARP inhibitor .
  • the PARP inhibitor can be used in vivo; it can also be used in vitro, mainly for experimental purposes, for example, providing alignment as a standard or control, or preparing a kit according to a conventional method in the art, and inhibiting PARP Provide fast detection.
  • the PARP can be PARP1.
  • the present invention also provides the polycyclic compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, stereoisomer or prodrug thereof, or the pharmaceutical composition for the treatment and/or prevention of PARP Use in drugs that rely on or PARP-mediated diseases or symptoms.
  • the PARP can be PARP1.
  • the present invention also provides the polycyclic compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, stereoisomer or prodrug thereof, or the pharmaceutical composition for the preparation of a tumor, a stroke, a myocardial Use in drugs for ischemia, inflammation or diabetes.
  • the tumor may be cancer or one or more of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, leukemia, colon cancer, glioblastoma and lymphoma.
  • the invention employs conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, or pharmacological detection, and the various steps and conditions can be referenced to routine procedures and conditions routine in the art.
  • the invention employs standard nomenclature and standard laboratory procedures and techniques for analytical chemistry, organic synthetic chemistry, and medical chemistry. In some cases, standard techniques are used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and drug delivery, and treatment of patients.
  • pharmaceutically acceptable as used in the present invention is directed to those compounds, materials, compositions and/or dosage forms which are within the scope of sound medical judgment and are suitable for use with humans and animals. Tissue contact use without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • 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
  • Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.
  • 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.
  • the "pharmaceutically acceptable salt” as used in the present invention is a derivative of the compound of the present 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, hydroxynaphthalene, isethionate, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxy Naphthenic acid, pantothenic acid, phenylacetic acid, phosphoric
  • 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 provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention.
  • a compound containing a carboxyl group can form a physiologically hydrolyzable ester which is prepared by hydrolysis in vivo to give the compound of formula I itself.
  • the prodrug is preferably administered orally because hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester itself is active or hydrolysis occurs in the blood.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • 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.
  • the compounds described herein exist as stereoisomers in which asymmetric or chiral centers are present.
  • Stereoisomers are named according to the substituent configuration around the chiral carbon atom. Or (S). Terms used in this article And (S) is the configuration defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem, (1976), 45: 13-30, the contents of which are incorporated herein by reference.
  • Embodiments described herein specifically include various stereoisomers and mixtures thereof.
  • Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers.
  • each stereoisomer of a compound is prepared synthetically from a commercial starting material containing an asymmetric or chiral center, or by preparing a racemic mixture, followed by resolution.
  • the method of resolution is, for example: (1) combining a mixture of enantiomers with a chiral auxiliary, and releasing a mixture of diastereomers by recrystallization or chromatography to release an optically pure product from the auxiliary; or (2) Direct separation of the mixture of optical enantiomers on a chiral column.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • alkoxy refers to an alkyl group, as defined herein, appended to the remainder of the molecule through an oxygen atom.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.
  • alkyl refers to a straight or branched chain hydrocarbon radical containing from 1 to 4 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl.
  • C 1 -C 4 alkyl means a straight or branched hydrocarbon group having 1 to 4 carbon atoms.
  • bond or “single bond” refers to a chemical bond between two atoms or between two moieties.
  • the term "ring” refers to any covalently closed structure.
  • the ring includes, for example, a carbocyclic ring (for example, an aryl group and a cycloalkyl group), a heterocyclic ring (for example, a heteroaryl group and a heterocycloalkyl group), an aromatic group (for example, an aryl group and a heteroaryl group), and a non-aromatic group (for example, Cycloalkyl and heterocycloalkyl).
  • ring system refers to two or more rings in which two or more rings are fused.
  • fused refers to a structure in which two or more rings share one or more bonds.
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • a group which does not indicate a substitution means an unsubstituted, for example, "C 1 -C 4 alkoxy” means an unsubstituted C 1 -C 4 alkoxy group.
  • a therapeutic agent comprising a packaging material, a compound and a label provided herein within the packaging material, wherein the compound is effective for modulating the activity of PARP, or for treating, preventing or ameliorating PARP dependence Or one or more symptoms of a PARP-mediated disease or condition, and wherein the label indicates the compound or composition, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, pharmaceutically active metabolism
  • a pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate is used to treat, prevent or ameliorate one or more symptoms of a PARP-dependent or PARP-mediated disease or condition. Any combination of the various variables of the above is also within the scope of the description herein.
  • the PARP can be PARP1.
  • a pharmaceutical composition comprising a compound or stereoisomer of Formula I, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, a pharmaceutically acceptable prodrug.
  • the pharmaceutical composition further contains a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises a second pharmaceutically active ingredient.
  • the compound of the formula I of the present invention has good PARP inhibitory activity, and the compound of the present invention can be effectively used as a PARP inhibitor for treating one or more diseases related to PARP activity, and is prepared for having The PARP inhibitory activity drug has good clinical application and medical use.
  • the PARP can be PARP1.
  • the PARP inhibitors provided by the present invention can be used to treat a wide range of diseases including tumors, stroke, myocardial ischemia, inflammation and diabetes.
  • Tumors that can be treated by PARP inhibitors include, but are not limited to, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, and leukemia.
  • the PARP can be PARP1.
  • Some embodiments provide the use of a compound of Formula I, or a therapeutically acceptable salt thereof, in the manufacture of a medicament for PARP inhibitory activity in an individual considered to be in need of treatment.
  • the PARP can be PARP1.
  • Some embodiments provide the use of a compound of Formula I or a therapeutically acceptable salt thereof for the manufacture of a medicament for inhibiting tumor growth in an individual considered to be in need of treatment.
  • Some embodiments provide the use of a compound of Formula I, or a therapeutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in an individual considered to be in need of treatment.
  • Some embodiments provide the use of a compound of Formula I or a therapeutically acceptable salt thereof for the manufacture of a medicament for the treatment of leukemia, colon cancer, glioblastoma, lymphoma in an individual considered to be in need of treatment.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progressive effect of the present invention is that the polycyclic compound of the present invention has PARP inhibitory activity, and has good water solubility and good stability, and provides a new commercial option for PARP inhibitors, which can be used for treating and/or preventing tumors, Stroke, myocardial ischemia, inflammation or diabetes.
  • An embodiment of the invention provides a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer or prodrug thereof, for the preparation of a compound of formula iridium or a pharmaceutically acceptable compound thereof Methods and intermediates of salts, hydrates, solvates, stereoisomers or prodrugs, pharmaceutical compositions, and the use of the compounds and pharmaceutical compositions of the invention in the manufacture of a medicament.
  • a compound of the formula I-7 was synthesized using a compound of the formula 700 and a compound of the formula 710 as a starting compound.
  • the compound of the formula I-43 was synthesized using the compound of the formula 720 and the compound of the formula 730 as a starting compound.
  • a compound of the formula 720 (315 mg, 1.0 mmol), a mixture of the compound of formula 730 (840 mg, 10 mmol) in methanol (15 ml) was heated to 55 ° C and stirred for 1 hour, then Sodium cyanoborohydride (1257 mg, 20 mmol) was added, and the mixture was stirred at 55 ° C for 15 hours, and concentrated under reduced pressure to remove methanol. The residue was purified by column chromatography to yield compound ESI-MS (m) /z): 384(M+1) + .
  • 3M methylmagnesium bromide (53.1 mL, 159.3 mmol) was added dropwise to a mixture of CuI (15.1 g, 79.7 mmol) in dry THF (100 mL) at -60 °C - -70 °C. After stirring at 0 ° C for 1 h and cooling to -60 ° C to -70 ° C, a solution of the compound of formula I-35-2 (15.6 g, 53.1 mmol) in THF (50 mL) was added and the mixture was stirred at 20 ° C overnight. The reaction was quenched with aqueous saturated 4 Cl NH. Filtered and the aqueous layer was extracted with EtOAc EtOAc.
  • Triethylamine (3.4 g, 34 mmol) and the compound of formula I-46-3 (3.9 g, 17 mmol) were added to 50 mL of DCM.
  • a solution of MsCl (2.9 g, 25.5 mmol) in DCM (20 mL). The mixture was stirred for 2 hours at 0 °C, and treated with saturated aqueous NaHCO 3 (50mL). The organic layer was dried over Na 2 SO 4, filtered and evaporated.
  • the compound shown in Formula I-46-11 (922mg, 2.2mmol) and 1N NaOH (3.3mL, 3.3mmol) in DMSO (10mL) was added dropwise 30% H 2 O 2 (5mL ). After the completion of the dropwise addition, the reaction solution was stirred at 50 ° C for 3 hours. The mixture was diluted with EA (200 mL) and washed with brine (100 mL ⁇ 4). The organic layer was dried over Na 2 SO 4, filtered and evaporated to give a yellow solid as the compound of formula I-46-12 (831 mg, 86% yield).
  • TEA 0.8 mmol
  • compound of formula I-46-13 50 mg, 0.16 mmol
  • DCM a solution of 3-chloropropanoyl chloride (24 mg, 0.19 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 72 hours. The mixture was diluted with DCM (50 mL) and brine. The organic layer was dried over Na 2 SO 4, filtered and evaporated.
  • Formula I-1 to Formula I-6, Formula I-8 to Formula I-33, Formula I-36 to Formula I-42, and Formula I-44 to I-45 were synthesized in a similar manner to Example 1 or 2.
  • the compounds shown differ only in that the starting compounds are adapted to the type of substituents R 1 and R 2 of the product and will not be described again.
  • the ESI-MS (m/z) data of the obtained final product are summarized in Table 1 below.
  • the ESI-MS (m/z) data for the compounds of the formulae I-1 to I-47 are as follows:
  • HCC1937 cells were seeded in 96-well plates at 4 x 104 cells/well and cultured overnight in a 37 °C incubator. The cells were treated with the test compound for 30 minutes and then treated with 1 mM hydrogen peroxide for 10 minutes. Cells were washed twice with 200 UL pre-cooled PBS and fixed with 100 ul of pre-cooled methanol/acetone (7:3) for 30 minutes in an ice bath. After air drying, the cells were blocked with PBS-Tween-20 blocking solution (0.05%) in 5% skim milk powder for 30 minutes at room temperature.
  • the cells and the anti-PAR10H antibody were incubated at a ratio of 1:100 in blocking solution for 1 hour at room temperature, then washed three times with PBS-Tween-20, and then fluorescein-5(6)-isosulfide containing goat anti-mouse was added.
  • the cyanate ester (FITC)-conjugated secondary antibody and 1 ⁇ g/mL DAPI blocking solution were incubated for 1 hour at room temperature in the dark. After rinsing three times with PBS-Tween-20, the data was analyzed using a fluorescent microplate counter (Flexstation III, Molecular Device).
  • PARP enzyme assay (according to the HT Universal PARP1 Colorimetric Assay Kit).
  • Histones were packaged in 96-well plates and incubated overnight at 4 °C. After washing the plate 3 times with 200UL PBST solution, it was blocked with a blocking solution, incubated at room temperature for 30 minutes, and then washed 3 times with a PBST solution.
  • the test compound was treated to be added to the well plate, and then 20 ⁇ l of diluted PARP1 (1 nM) or 20 ⁇ l of PARP2 (3 nM) solution was added to the reaction system for 1 or 2 hours.
  • a mixture of 50 ⁇ l streptavidin-HRP (1:50) was added to the well plate and incubated for 30 minutes at room temperature, and washed three times with PBST buffer. 100 ⁇ l (HRP) (chemiluminescent substrate A and substrate B (1:1)) were added to the well plates. Immediately read on a microplate reader (Envision, PerkinElmer).
  • MDA-MB-436 and MDA-MB-231 cells were seeded in 96-well plates at a density of 500 and 2000 cells per well, respectively, and cultured overnight.
  • the medium was RPMI 1640 containing 10% (v/v) FBS and 1% (v/v) penicillin-streptomycin. After the test compound was added, it was treated for 8 days. Cell viability was measured by the CCK8 kit. Specific Methods 10UL CCK8 reagent was added to each well and incubated at 37 ° C in a 5% CO 2 incubator for 3 hours. After shaking for 10 minutes, the light absorption value (OD value) was measured with a Flexstation III (Molecular Device) 450 nm.
  • PARP-1 enzyme inhibition a compound of the present invention to provide IC 50 in Table 2 below.
  • test results show that the compounds of the formulae I-1 to I-45 of the present invention all have good PARP kinase inhibitory activity, whereby the compound of the present invention can be used as a PARP inhibitor for treating one or one
  • the above tumor diseases related to PARP activity are used for preparing tumor drug.
  • Multi-plate reader SpectraMax M4 Microplate Reader (Molecular Devices), PARP1 Colorimetric Assay Kit (BPS, Cat#80580), PBS (Life Technologies, Cat#003000), Tween-20 (Sigma, Cat) #P9416-100ml), H2SO4 (Chinese medicine, Cat#10021618), and the compounds of the formulas I-1 to I-47 of the present invention.
  • the Colorimetric Assay Kit contains:
  • 1x PBS Take a packet of PBS powder and add 1L of deionized water to dissolve completely;
  • 2M H2SO4 dilute H2SO4 to 2M with deionized water
  • 1x PARP assay buffer Dilute 10x PARP assay buffer in 1:10 with deionized water to obtain 1x PARP assay buffer.
  • the compound was dissolved in DMSO to a 10 mM stock solution and further diluted to 1 mM or 100 ⁇ M in DMSO for later use.
  • the 100 ⁇ M compound stock solution was diluted to 10 ⁇ M with 1 ⁇ PARP assay buffer, and then the compound was serially diluted 10-fold with 1 ⁇ PARP assay buffer containing 10% DMSO to obtain a series of concentrations of the compound for use. 5 ⁇ l of the diluted compound (total volume 50 ⁇ l) was added to each well, such that the final concentration of the compound was 1 ⁇ M starting at a series of 10-fold dilutions.
  • a reaction solution was prepared in a ratio of 2.5 ⁇ l of 10x PARP buffer + 2.5 ⁇ l of 10x PARP Assaymixture + 5 ⁇ l of Activated DNA + 15 ⁇ l of deionized water per well, and 25 ⁇ l of the reaction solution was added to each well (see Table 1).
  • the inhibition rate is calculated using the following formula:
  • Inhibition rate (ODsample-OD0%) / (OD100% - OD0%) ⁇ 100%
  • ODsample the OD value of the sample test well
  • OD100% OD value of the whole live control well.
  • the PARP1 Colorimetric Assay kit was used to detect the inhibitory activity of the compound represented by Formulas I-1 to I-47 on the PARP1 enzyme.
  • IC 50 data PARP1 enzyme inhibiting compounds of the invention are provided in Table 4 below.
  • IC 50 of the compound between 1 to 50nM are denoted +++;
  • Compound IC 50 of between 101 to 1000nm is denoted ++, IC 50 greater than 1000nm compound is designated as +.
  • the experimental results show that the compounds of the formulae I-1 to I-47 of the present invention have an IC 50 value of about 1 nM to 100 nM for the PARP1 enzyme, and both show strong inhibition. All of the present invention have good PARP kinase inhibitory activity, whereby the compounds of the present invention are useful as PARP inhibitors for the treatment of one or more tumor diseases associated with PARP activity for the preparation of tumors. drug.
  • the kinetic solubility of the compounds of the formulae I-1 to I-47 of the present invention was tested.
  • the test of kinetic solubility is commonly used in high-throughput screening of drugs during the drug discovery phase.
  • a good solubility should help produce reliable data in vitro and in vivo. Since the kinetic solubility is pH dependent, the pH of the aqueous phase is always specified, usually measured at a pH of 7.4 (physiological pH of body fluids).
  • Test method Weighed quantitative compound samples were dissolved in pure DMSO to a final concentration of 10 mM, and the test compound and the control compound (10 mM DMSO mother liquor, 10 ⁇ L per well) were added to a 96-well plate containing 490 ⁇ L of buffer per well. After 2 minutes of vortexing, the sample plates were incubated for 24 hours at room temperature (22 ⁇ 2 °C) on a shaker. 200 ⁇ L of the sample was then transferred to a MultiScreen filter plate (polycarbonate membrane), filtered through a millipore vacuum manifold and the filtrate was collected. The concentration of the compound in the filtrate was determined by HPLC-UV. Three different concentrations of the UV standard solution and the solubility test sample were injected successively. Each sample was inserted twice, and the standard curve was taken to calculate the concentration and averaged.
  • the in vitro metabolic stability of the compounds of the formulae I-1 to I-47 of the present invention was tested.
  • the in vitro metabolic stability test assesses the clearance rate of a compound in one-phase metabolism and predicts its intrinsic clearance rate in hepatocytes and in vivo.
  • the control sample is ABT888.
  • Buffer solution phosphate buffer (100 mM KH 2 PO 4 -K 2 HPO 4 ), made by Shanghai Medicil Biomedical Laboratory.
  • test article is a compound of the formula I-1 to I-47 described in the present invention, and a control sample ABT888 thereof.
  • Metabolic stability test The compound of the present invention was mixed with plasma and incubated at 37 ° C for 0, 5, 15, 30, 60 and 120 minutes, respectively. At the indicated incubation time point, 4 times the volume of the internal standard solution was added to stop the reaction. Finally, the sample was centrifuged and the supernatant was taken for detection by LC-MS/MS.
  • NADPH purchased from Roche, the number is 10621706001
  • Buffer solution phosphate buffer (100 mM KH 2 PO 4 -K 2 HPO 4 ), made by Shanghai Medicil Biomedical Laboratory.
  • test product is a compound represented by the formula I-1 to I-47 according to the present invention, and a control sample ABT888 thereof
  • the concentration of the compound in each sample was expressed by the peak area ratio (the ratio of the peak area of the compound to the internal standard peak area), and then the percentage of the compound remaining at each incubation time point was calculated with reference to the compound concentration of 0 minutes (%Remaining). ), the ln logarithm of the remaining percentage is linearly fitted to the incubation time, and the half-life and the intrinsic clearance are calculated according to the following formula.

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Abstract

La présente invention concerne un composé polycyclique servant en tant qu'inhibiteur de PARP et ses utilisations. Le composé polycyclique de la présente invention est représenté par la formule (I). Le composé polycyclique selon la présente invention a une activité d'inhibition de PARP, fournit un nouveau choix commercial pour les inhibiteurs de PARP, et peut être utilisé dans le traitement et/ou la prévention de tumeurs, d'accidents vasculaires cérébraux, de l'ischémie myocardique, de l'inflammation ou du diabète.
PCT/CN2018/083212 2017-04-17 2018-04-16 Composé polycyclique ayant une activité d'inhibition de parp, et ses utilisations Ceased WO2018192445A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11072596B2 (en) * 2017-06-14 2021-07-27 Selection Bioscience Llc Poly(ADP-ribose) polymerase inhibitor, preparation method and use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101506214A (zh) * 2006-06-20 2009-08-12 艾博特公司 作为parp抑制剂的吡唑并喹唑啉酮
CN104974161A (zh) * 2014-04-10 2015-10-14 南京明德新药研发股份有限公司 作为PARP抑制剂的4H-吡唑并[1,5-α]苯并咪唑化合物的类似物
WO2017054755A1 (fr) * 2015-09-30 2017-04-06 湖北生物医药产业技术研究院有限公司 Composé 4h-pyrazolo-[1,5-alpha]-benzimidazole de type sel et de type cristal, son procédé de préparation et son intermédiaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101506214A (zh) * 2006-06-20 2009-08-12 艾博特公司 作为parp抑制剂的吡唑并喹唑啉酮
CN104974161A (zh) * 2014-04-10 2015-10-14 南京明德新药研发股份有限公司 作为PARP抑制剂的4H-吡唑并[1,5-α]苯并咪唑化合物的类似物
WO2017054755A1 (fr) * 2015-09-30 2017-04-06 湖北生物医药产业技术研究院有限公司 Composé 4h-pyrazolo-[1,5-alpha]-benzimidazole de type sel et de type cristal, son procédé de préparation et son intermédiaire

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11072596B2 (en) * 2017-06-14 2021-07-27 Selection Bioscience Llc Poly(ADP-ribose) polymerase inhibitor, preparation method and use

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