+

WO2018223909A1 - Molécule chimère, préparation et utilisation associées - Google Patents

Molécule chimère, préparation et utilisation associées Download PDF

Info

Publication number
WO2018223909A1
WO2018223909A1 PCT/CN2018/089652 CN2018089652W WO2018223909A1 WO 2018223909 A1 WO2018223909 A1 WO 2018223909A1 CN 2018089652 W CN2018089652 W CN 2018089652W WO 2018223909 A1 WO2018223909 A1 WO 2018223909A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
compound according
alkyl
aryl
Prior art date
Application number
PCT/CN2018/089652
Other languages
English (en)
Chinese (zh)
Inventor
樊磊
王飞
吴孝全
胥珂馨
陈锞
李兴海
陈元伟
Original Assignee
成都海创药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 成都海创药业有限公司 filed Critical 成都海创药业有限公司
Publication of WO2018223909A1 publication Critical patent/WO2018223909A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention belongs to the field of compound medicines, and in particular to a chimeric molecule.
  • the chimeric molecule (PROTAC) referred to in this patent is based on protein levels, regulates the expression of a target protein, and is used to treat diseases.
  • the BRD4 chimeric molecule of the present patent has a heterologous bifunctional molecule composed of a target protein (BRD4), an E3 ubiquitin ligase recognition group, and a linking group; the purpose of the coupling target is to interact with the ligand BRD4 in the molecule. Binding; the purpose of the E3 ubiquitin ligase recognition group is to bind to the target protein, resulting in ubiquitination of the target protein, and finally the target protein is degraded by the proteasome.
  • chimeric molecules From the knockout of functional genes at the gene level to the interference of small RNA at the mRNA level, more biochemical techniques have been used to study protein expression regulation; chimeric molecules do not affect the expression of DNA and mRNA. Direct regulation of protein expression at the protein level is therefore more ethically acceptable.
  • chimeric molecules as a new protein regulation method, have advantages that other methods do not have, and may become an alternative to gene therapy. Chimeric molecules target the degradation of functional proteins, and it is possible to develop drugs into new therapeutic methods.
  • the present invention first provides a compound represented by the formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof:
  • L is a linking unit, and one atom on M and N is substituted by one end of the linking group L, respectively;
  • Unit M is as shown in equation (a) or (c):
  • R 1 and R 2 is selected from the group consisting of halogen, -NH-SO 2 -R 7 , hydrogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl a heterocyclic aryl group, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heterocyclic aryl group is independently independently optionally further selected from one or more selected from the group consisting of ruthenium atoms Substituted by a halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl substituent ;
  • R 7 is selected from the group consisting of hydrogen, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl;
  • R 1 and R 2 is selected from the group consisting of -A-, wherein A is selected from -O-, -COX- or -XCO-, -NH-, -HNCONH-, -NH-SO 2 -R 7 , - SO 2 - or -CH 2 -, X is selected from -CH 2 -, -NH-, -SO 2 -, -O-, acylamino, ester or carbonyl, and A is bonded to linking unit L;
  • R 3 , R 4 and R 6 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, wherein Said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heterocyclic aryl group, respectively, optionally further optionally one or more selected from the group consisting of a halogen atom, a halogen, a cyano group, a nitrate Substituted with a substituent of an oxo group, an oxo group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a
  • R 5 is selected from the group consisting of alkyl, alkoxy, amino, amido, ester, carbonyl, and any combination of the above.
  • R 1 and R 2 is selected from the group consisting of halogen, -NH-SO 2 -R 7 , hydrogen, and another of R 1 and R 2 is selected from -A-, wherein A is selected from -O-, -COX- or -XCO-, X is selected from -CH 2 -, -NH-, -SO 2 -, -O-, acylamino, ester or carbonyl, and R 7 is selected from hydrogen, cyano, nitro, alkane Base, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl.
  • the X is selected from -CH 2 -, -NH-, -O-, an ester group or a carbonyl group.
  • M structure is represented by the formula (a1) or the formula (a2):
  • a 1 is selected from -COX- or -XCO-, and X is selected from -CH 2 -, -NH-, -O-, ester or carbonyl;
  • R 3 and R 6 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heterocyclic aryl groups are each independently optionally further selected from one or more selected from the group consisting of a halogen atom, a halogen, a cyano group, a nitro group, and an oxygen group.
  • R 7 is selected from the group consisting of hydrogen, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl.
  • the R 6 is selected from a C 1 -C 4 alkyl group; preferably, the R 6 is selected from a methyl group.
  • the R 7 is selected from a C 1 -C 4 alkyl group; preferably, the R 7 is an ethyl group.
  • M structure is represented by the formula (a3) or the formula (a4):
  • a 1 is selected from -COX- or -XCO-, and X is selected from -CH 2 -, -NH-, -O-, ester or carbonyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, wherein said alkyl, alkenyl, The alkynyl, cycloalkyl, heterocycloalkyl, aryl or heterocyclic aryl group, respectively, is optionally further optionally further selected from one or more selected from the group consisting of a halogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkyl group, Substituted by a substituent of a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heterocyclic aryl group.
  • R 3 is selected from the group consisting of hydrogen, halogen, and alkyl.
  • a 1 is selected from -COX- or -XCO-; and X is selected from -CH 2 -, -NH-, -O-, ester or carbonyl.
  • the X is selected from -NH- or -O-.
  • the L is selected from the group consisting of -(CH 2 CH 2 OCH 2 )n-CO-, -(CH 2 CH 2 O)n-CH 2 CO-, -(CH 2 OCH 2 CH 2 CH 2 O)n -CH 2 CO-, -(CH 2 OCH 2 )n-CO-, -(CH 2 OCH 2 CH 2 )n-CH 2 CO- or -(CH 2 CH 2 OCH 2 )n-CH 2 CO-, Where n is an integer from 0 to 20.
  • n is an integer of 1 to 3.
  • R 4 is selected from H or CH 3 (S or R).
  • R 5 is selected from an alkyl group or an amino group.
  • R 4 is selected from H or CH 3 (S or R).
  • N structure is represented by (b1), (b2) or (b3);
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • L is as defined in claim 12 or 13.
  • the compound is one of the following compounds:
  • the present invention also provides the use of the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a BRD4 inhibitor or a protein degradation agent.
  • the medicament is a medicament for treating cancer or coronary artery disease.
  • the cancer is prostate cancer, non-small cell lung cancer, breast cancer, melanoma, leukemia or rectal cancer.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, together with a pharmaceutically acceptable adjuvant Prepared preparation.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a - C b ) alkyl group indicates any alkyl group having "a" to "b” carbon atoms.
  • (C 1 -C 6 )alkyl means an alkyl group containing from 1 to 6 carbon atoms.
  • the C 1 -C 4 alkyl group means an alkyl group of C 1 , C 2 , C 3 , C 4 , that is, a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group or an ethyl group. , propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl and the like.
  • the cycloalkyl group means a cyclic alkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like.
  • the halogen means a fluorine atom, a bromine atom, a chlorine atom, or an iodine atom.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salt” refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts (within Salts) also include quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium.
  • Figure 1 is an electropherogram of the BRD4 protein of the compound of the present invention.
  • Example 1 Compound 1 (2S, 4R)-1-((S)-13-tert-butyl-1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7) -oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-1,11-dioxo-5,9-dioxo-2,12 Synthesis of -diazatetradecyl-14-carbonyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)phenyl)tetrahydropyrrole-2-amide (1)
  • reaction mixture was poured into 6 L of water to precipitate a solid, which was filtered, and the solid was dissolved in ethyl acetate (200 mL), and 600 mL of n-hexane was added to precipitate a solid, which was filtered to give intermediate compound 3 (188 g). .
  • the intermediate compound 12 (2.5 g, 13 mmol), 25 mL of tetrahydrofuran was added to a 250 ml reaction flask, and a solution of borane in tetrahydrofuran (20 mL, 1 mol/L) was added thereto, and the mixture was heated to 25 °C, stirred for 2 hours, and saturated. 7 mL of an aqueous solution of sodium acetate and 6 mL of 30% hydrogen peroxide were stirred for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate.
  • intermediate compound 16 o-phenylsuccinimide (0.4 g), potassium carbonate (0.5 g), and 10 mL of N,N-dimethylformamide, warmed to 95 degrees and stirred for 3 hours. . After completion of the reaction, 10 mL of water was added, and ethyl acetate was evaporated and dried over anhydrous sodium sulfate.
  • N,N',N'-tetramethyluronium hexafluorophosphate HATU (76 mg, 0.2 mmol), N,N-diisopropylethylamine DIPEA (52 mg, 0.4 mmol), 10 mL DMF, 10mL of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated and column chromatography, to obtain 98mg of compound 2 as a pale yellow solid, in 56% yield, MS: mass spectrum 982 (M + H +).
  • an intermediate compound 22 was added to a 50 mL reaction flask (according to the synthesis method of the intermediate compound 20, wherein the step (12) was synthesized by substituting ethylene glycol for the intermediate compound 13) (100 mg, 0.18 mmol), Intermediate compound 21 (synthesized according to US20170327469) (84 mg, 0.18 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU ( 76 mg, 0.2 mmol), N,N-diisopropylethylamine DIPEA (52 mg, 0.4 mmol), 10 mL DMF, EtOAc.
  • an intermediate compound 23 was added to a 50 mL reaction flask (according to the synthesis method of the intermediate compound 20, wherein the step (12) was synthesized from diethylene glycol instead of the intermediate compound 13) (100 mg, 0.18) Ment), intermediate compound 21 (synthesized according to US20170327469) (84 mg, 0.18 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate The ester HATU (76 mg, 0.2 mmol), N,N-diisopropylethylamine DIPEA (52 mg, 0.4 mmol), 10 mL DMF, EtOAc.
  • the intermediate compound 29 (1.1 g, 4 mmol), 4N potassium hydroxide, 10 mL of water and 10 mL of tetrahydrofuran was added to a 100 mL reaction flask, and stirred at room temperature for 30 minutes. After completion of the reaction, the pH was adjusted to 4 with 2N HCl and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated
  • Intermediate compound 33 was added to a 50 mL reaction flask (according to the synthesis method of intermediate compound 32, ethylene glycol was used instead of propylene glycol as a raw material (100 mg, 0.18 mmol), and intermediate compound 21 (synthesized according to US20170327469) (84 mg, 0.18 mmol) , 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate HATU (76 mg, 0.2 mmol), N,N-diisopropyl Ethylamine DIPEA (52 mg, 0.4 mmol), 10 mL DMF, EtOAc EtOAc. 54%, mass 955 (M+H+).
  • Intermediate compound 34 was added to a 50 mL reaction flask (according to the synthesis method of intermediate compound 32, diethylene glycol was used instead of propylene glycol as raw material (100 mg, 0.18 mmol), and intermediate compound 21 (synthesized according to US20170327469) (84 mg, 0.18) Ment), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate HATU (76 mg, 0.2 mmol), N,N-diisopropyl Ethylethylamine DIPEA (52 mg, 0.4 mmol), 10 mL DMF, EtOAc EtOAc EtOAc.
  • Example 8 Compound 37 (2S,4R)-1-S)-13-(tert-butyl)-1-4-(2,4-difluorophenoxy)-3-(6-methyl-7 -oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1,11 dioxo-5,9-dioxa-2 ,12-diazatetradecane-14 yl)-4-hydroxy N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- Preparation of formamide
  • intermediate compound 43 150 mg, 0.244 mmol
  • intermediate compound 16 70 mg, 0.244 mmol
  • cesium carbonate 163 mg, 0.5 mmo
  • 10 mg potassium iodide 10 mg potassium iodide and 20 mL DMSO, 10 mL water, and warm to 100 deg. Stir overnight. After completion of the reaction, 20 mL of water was added, and ethyl acetate was evaporated.
  • Example 10 Compound 39 (2S,4R)-1-((S)-13-(tert-butyl)-1-(4-fluoro-3-(6-methyl-7-oxo-6,7) -dihydro-1H-pyrrolo[2,1,3-c]pyridin-4-yl)phenyl)-1,11 dioxo-5,9-dioxa-2,12-diazatetradecane Synthesis of alkyl-14 acyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Intermediate compound 46 was added to a 50 mL reaction flask (synthesized from 3-bromo-4-fluorobenzoic acid methyl ester in place of intermediate compound 8 according to the synthesis method of intermediate compound 20) (78 mg, 0.18 mmol), intermediate Compound 21 (synthesized according to US20170327469) (84 mg, 0.18 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU (76 mg, 0.2 mmol), N,N-diisopropylethylamine DIPEA (52 mg, 0.4 mmol), 10 mL DMF, EtOAc EtOAc.
  • Test Example 1 Biological determination of the inhibitory effect of the compound of the present invention on proliferation of CWR22RV1 cells
  • Penicillin-streptomycin solution (Hyclone, Cat. No. SV30010)
  • 1CWR22RV1 cells were subcultured with cell culture medium, and cells grown in good condition were inoculated into 96-well plates at 80 ⁇ L per well, and the number of cells per well was 1500, and cultured overnight at 37 ° C in a 5% CO 2 cell incubator.
  • the drug was formulated with dimethyl sulfoxide (DMSO) as a 30 mM stock solution. Dilute 3 times with DMSO before use, then dilute by 3 times to obtain 9 concentration gradients, and then dilute the compound at each concentration 200 times with the culture solution (to ensure the DMSO concentration in the culture system is 0.1%). The concentration is made to repeat 2 holes. 20 ⁇ L of the diluted compound was added to the cell culture well (final concentration of 10 ⁇ M, 3.3 ⁇ M, 1.1 ⁇ MCertainly, and gently mixed by shaking. In addition, three cell-only negative control wells and three blank control wells (only 20 ⁇ L of culture medium diluted with 200 ⁇ L of DMSO) were placed.
  • DMSO dimethyl sulfoxide
  • the absorbance (OD value) was measured at 450 nm using a multi-function microplate reader.
  • the IC50 (nM) of the inhibition of the activity of the compound of the present invention on CWR22RV1 is shown in Table 1.
  • Test Example 2 Biological determination of protein expression of BRD4 (Bromodomain containing protein 4) of the present invention
  • Penicillin-streptomycin solution (Hyclone, Cat. No. SV30010)
  • 6-well cell culture cluster (Corning, Cat. No. 3516)
  • Protein Buffer Buffer (Beyotime, Cat.No.P0015L)
  • Anti- ⁇ -tubulin mouse monoclonal antibody Zaen Bioscience, Cat. No.200608
  • Anti-BRD4 rabbit monoclonal antibody (CST, Cat. No.13440)
  • HRP Peroxidase Affinipure
  • HRP Peroxidase Affinipure
  • 1CWR22RV1 cells were subcultured with cell culture medium, and cells grown in good condition were inoculated into 6-well plates, 2 ml per well, and the number of cells per well was 1 million, and cultured overnight at 37 ° C in a 5% CO 2 cell incubator.
  • the drug was formulated with dimethyl sulfoxide (DMSO) as a 30 mM stock solution. Dilute 3 times with DMSO before use, and add 2 ⁇ l of the diluted compound to the cell culture well (to ensure that the DMSO concentration in the culture system is 0.1%). Repeat 2 wells for each concentration and mix gently by shaking. A negative control well (plus equal amount of DMSO) and a positive control well were also set.
  • DMSO dimethyl sulfoxide
  • Protein was transferred from polyacrylamide gel to PVDF membrane, blocked with 5% skim milk for 1 hour at room temperature, primary antibody (Anti-BRD4 (E2A7X) rabbit mAb and Anti- ⁇ -Tubulin Mouse mAb) incubated overnight at 4 °C, TBST The solution was washed three times for 10 minutes each time, and the secondary antibody (horseradish peroxidase-labeled goat anti-mouse IgG) was incubated for 2 hours at room temperature, and the membrane was washed three times with TBST solution for 10 minutes each time.
  • primary antibody Anti-BRD4 (E2A7X) rabbit mAb and Anti- ⁇ -Tubulin Mouse mAb
  • the compound provided by the present invention has a good inhibitory effect on the proliferation of 22Rv1 cells, and the inhibitory effect is particularly good, indicating that the compound of the present invention can be prepared as an antitumor drug, particularly a drug for treating prostate cancer.
  • the present invention provides a chimeric molecule consisting of a small molecule compound unit of a target protein, an E3 ubiquitin ligase binding unit, and a linking unit, which is capable of binding to a BRD protein, thereby facilitating degradation of the BRD protein by proteases.
  • a chimeric molecule consisting of a small molecule compound unit of a target protein, an E3 ubiquitin ligase binding unit, and a linking unit, which is capable of binding to a BRD protein, thereby facilitating degradation of the BRD protein by proteases.
  • it can be used as a drug for the degradation of BRD protein for the treatment of cancer or coronary artery disease.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une molécule chimère constituée d'une petite unité de composé moléculaire d'une protéine cible, d'une unité de liaison de l'ubiquitine ligase E3 et d'une unité de liaison. La molécule chimère peut se lier à une protéine BRD, permet à la protéine BRD d'être dégradée plus facilement par les protéases, et joue ainsi un rôle dans l'inhibition de la prolifération cellulaire. La molécule chimère peut être utilisée en tant que médicament pour la dégradation de la protéine BRD afin de traiter des cancers ou des maladies des artères coronaires.
PCT/CN2018/089652 2017-06-05 2018-06-01 Molécule chimère, préparation et utilisation associées WO2018223909A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710415310.3 2017-06-05
CN201710415310 2017-06-05

Publications (1)

Publication Number Publication Date
WO2018223909A1 true WO2018223909A1 (fr) 2018-12-13

Family

ID=64540499

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/089652 WO2018223909A1 (fr) 2017-06-05 2018-06-01 Molécule chimère, préparation et utilisation associées

Country Status (2)

Country Link
CN (1) CN108976278B (fr)
WO (1) WO2018223909A1 (fr)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors
WO2020263830A1 (fr) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Protéines de fusion flt3l-fc et procédés d'utilisation
WO2021163064A2 (fr) 2020-02-14 2021-08-19 Jounce Therapeutics, Inc. Anticorps et protéines de fusion se liant à ccr8, et leurs utilisations
WO2022245671A1 (fr) 2021-05-18 2022-11-24 Gilead Sciences, Inc. Méthodes d'utilisation de protéines de fusion flt3l-fc
WO2023077030A1 (fr) 2021-10-29 2023-05-04 Gilead Sciences, Inc. Composés cd73
WO2023076983A1 (fr) 2021-10-28 2023-05-04 Gilead Sciences, Inc. Dérivés de pyridine-3(2h)-one
WO2023122581A2 (fr) 2021-12-22 2023-06-29 Gilead Sciences, Inc. Agents de dégradation de doigt de zinc de la famille ikaros et utilisations associées
WO2023122615A1 (fr) 2021-12-22 2023-06-29 Gilead Sciences, Inc. Agents de dégradation des doigts de zinc de la famille ikaros et leurs utilisations
WO2023147418A1 (fr) 2022-01-28 2023-08-03 Gilead Sciences, Inc. Inhibiteurs de parp7
EP4245756A1 (fr) 2022-03-17 2023-09-20 Gilead Sciences, Inc. Agents de dégradation de la famille des doigts de zinc de l'ikaros et leurs utilisations
WO2023205701A1 (fr) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Hétérocycles macrocycliques et leurs utilisations
WO2023205719A1 (fr) 2022-04-21 2023-10-26 Gilead Sciences, Inc. Composés modulateurs de kras g12d
WO2024006929A1 (fr) 2022-07-01 2024-01-04 Gilead Sciences, Inc. Composés cd73
US11969472B2 (en) 2018-08-22 2024-04-30 Cullgen (Shanghai), Inc. Tropomyosin receptor kinase (TRK) degradation compounds and methods of use
WO2024137852A1 (fr) 2022-12-22 2024-06-27 Gilead Sciences, Inc. Inhibiteurs de prmt5 et leurs utilisations
US12065442B2 (en) 2018-08-22 2024-08-20 Cullgen (Shanghai), Inc. Tropomyosin receptor kinase (TRK) degradation compounds and methods of use
WO2024215754A1 (fr) 2023-04-11 2024-10-17 Gilead Sciences, Inc. Composés modulateurs de kras
WO2024220917A1 (fr) 2023-04-21 2024-10-24 Gilead Sciences, Inc. Inhibiteurs de prmt5 et leurs utilisations
WO2024243441A1 (fr) 2023-05-24 2024-11-28 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2025007000A1 (fr) 2023-06-30 2025-01-02 Kumquat Biosciences Inc. Composés aminés tricycliques condensés substitués et leurs utilisations en tant qu'inhibiteurs de ras
WO2025006720A1 (fr) 2023-06-30 2025-01-02 Gilead Sciences, Inc. Composés modulateurs de kras
WO2025024811A1 (fr) 2023-07-26 2025-01-30 Gilead Sciences, Inc. Inhibiteurs de parp7
WO2025024663A1 (fr) 2023-07-26 2025-01-30 Gilead Sciences, Inc. Inhibiteurs de parp7
EP4313979A4 (fr) * 2021-03-25 2025-02-19 Technion Res & Dev Foundation Composés ciblant rnf4 et leurs utilisations
WO2025054530A1 (fr) 2023-09-08 2025-03-13 Gilead Sciences, Inc. Dérivés polycycliques contenant une pyrimidine utilisés comme composés de modulation de kras g12d
WO2025054347A1 (fr) 2023-09-08 2025-03-13 Gilead Sciences, Inc. Composés de modulation de kras g12d

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020233512A1 (fr) * 2019-05-17 2020-11-26 成都海创药业有限公司 Composé chimère de dégradation de protéine ciblant une amine aromatique ar et bet et son utilisation
CN110143961B (zh) * 2019-06-27 2022-03-29 江苏省中医药研究院 一种基于vhl配体诱导bet降解的吡咯并吡啶酮类双功能分子化合物
CN115109047B (zh) * 2021-09-08 2024-02-20 中国科学院化学研究所 一种基于protac设计的铁死亡诱导剂

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104136435A (zh) * 2011-12-30 2014-11-05 艾伯维公司 溴结构域抑制剂
CN104736569A (zh) * 2012-01-12 2015-06-24 耶鲁大学 通过e3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法
WO2016077380A1 (fr) * 2014-11-10 2016-05-19 Genentech, Inc. Pyrrolopyridines substituées utilisées en tant qu'inhibiteurs de bromodomaines
WO2016118666A1 (fr) * 2015-01-20 2016-07-28 Arvinas, Inc. Composés et procédés pour la dégradation ciblée du récepteur des androgènes
WO2017030814A1 (fr) * 2015-08-19 2017-02-23 Arvinas, Inc. Composés et procédés pour la dégradation ciblée de protéines contenant un bromodomaine
CN106749513A (zh) * 2017-01-23 2017-05-31 中国药科大学 基于vhl配体诱导bet降解的双功能分子及其制备和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085620B (zh) * 2015-06-25 2018-05-08 中山大学附属第一医院 一种靶向泛素化降解Smad3的化合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104136435A (zh) * 2011-12-30 2014-11-05 艾伯维公司 溴结构域抑制剂
CN104736569A (zh) * 2012-01-12 2015-06-24 耶鲁大学 通过e3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法
WO2016077380A1 (fr) * 2014-11-10 2016-05-19 Genentech, Inc. Pyrrolopyridines substituées utilisées en tant qu'inhibiteurs de bromodomaines
WO2016118666A1 (fr) * 2015-01-20 2016-07-28 Arvinas, Inc. Composés et procédés pour la dégradation ciblée du récepteur des androgènes
WO2017030814A1 (fr) * 2015-08-19 2017-02-23 Arvinas, Inc. Composés et procédés pour la dégradation ciblée de protéines contenant un bromodomaine
CN106749513A (zh) * 2017-01-23 2017-05-31 中国药科大学 基于vhl配体诱导bet降解的双功能分子及其制备和应用

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors
US12065442B2 (en) 2018-08-22 2024-08-20 Cullgen (Shanghai), Inc. Tropomyosin receptor kinase (TRK) degradation compounds and methods of use
US11969472B2 (en) 2018-08-22 2024-04-30 Cullgen (Shanghai), Inc. Tropomyosin receptor kinase (TRK) degradation compounds and methods of use
WO2020263830A1 (fr) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Protéines de fusion flt3l-fc et procédés d'utilisation
WO2021163064A2 (fr) 2020-02-14 2021-08-19 Jounce Therapeutics, Inc. Anticorps et protéines de fusion se liant à ccr8, et leurs utilisations
US11692038B2 (en) 2020-02-14 2023-07-04 Gilead Sciences, Inc. Antibodies that bind chemokine (C-C motif) receptor 8 (CCR8)
EP4313979A4 (fr) * 2021-03-25 2025-02-19 Technion Res & Dev Foundation Composés ciblant rnf4 et leurs utilisations
WO2022245671A1 (fr) 2021-05-18 2022-11-24 Gilead Sciences, Inc. Méthodes d'utilisation de protéines de fusion flt3l-fc
WO2023076983A1 (fr) 2021-10-28 2023-05-04 Gilead Sciences, Inc. Dérivés de pyridine-3(2h)-one
WO2023077030A1 (fr) 2021-10-29 2023-05-04 Gilead Sciences, Inc. Composés cd73
WO2023122615A1 (fr) 2021-12-22 2023-06-29 Gilead Sciences, Inc. Agents de dégradation des doigts de zinc de la famille ikaros et leurs utilisations
WO2023122581A2 (fr) 2021-12-22 2023-06-29 Gilead Sciences, Inc. Agents de dégradation de doigt de zinc de la famille ikaros et utilisations associées
WO2023147418A1 (fr) 2022-01-28 2023-08-03 Gilead Sciences, Inc. Inhibiteurs de parp7
EP4245756A1 (fr) 2022-03-17 2023-09-20 Gilead Sciences, Inc. Agents de dégradation de la famille des doigts de zinc de l'ikaros et leurs utilisations
WO2023178181A1 (fr) 2022-03-17 2023-09-21 Gilead Sciences, Inc. Agents de dégradation des doigts de zinc de la famille ikaros et leurs utilisations
EP4464703A2 (fr) 2022-03-17 2024-11-20 Gilead Sciences, Inc. Agents de dégradation de la famille des doigts de zinc de l'ikaros et leurs utilisations
WO2023205701A1 (fr) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Hétérocycles macrocycliques et leurs utilisations
WO2023205719A1 (fr) 2022-04-21 2023-10-26 Gilead Sciences, Inc. Composés modulateurs de kras g12d
WO2024006929A1 (fr) 2022-07-01 2024-01-04 Gilead Sciences, Inc. Composés cd73
WO2024137852A1 (fr) 2022-12-22 2024-06-27 Gilead Sciences, Inc. Inhibiteurs de prmt5 et leurs utilisations
WO2024215754A1 (fr) 2023-04-11 2024-10-17 Gilead Sciences, Inc. Composés modulateurs de kras
WO2024220917A1 (fr) 2023-04-21 2024-10-24 Gilead Sciences, Inc. Inhibiteurs de prmt5 et leurs utilisations
WO2024243441A1 (fr) 2023-05-24 2024-11-28 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2025007000A1 (fr) 2023-06-30 2025-01-02 Kumquat Biosciences Inc. Composés aminés tricycliques condensés substitués et leurs utilisations en tant qu'inhibiteurs de ras
WO2025006720A1 (fr) 2023-06-30 2025-01-02 Gilead Sciences, Inc. Composés modulateurs de kras
WO2025024811A1 (fr) 2023-07-26 2025-01-30 Gilead Sciences, Inc. Inhibiteurs de parp7
WO2025024663A1 (fr) 2023-07-26 2025-01-30 Gilead Sciences, Inc. Inhibiteurs de parp7
WO2025054530A1 (fr) 2023-09-08 2025-03-13 Gilead Sciences, Inc. Dérivés polycycliques contenant une pyrimidine utilisés comme composés de modulation de kras g12d
WO2025054347A1 (fr) 2023-09-08 2025-03-13 Gilead Sciences, Inc. Composés de modulation de kras g12d

Also Published As

Publication number Publication date
CN108976278B (zh) 2021-04-06
CN108976278A (zh) 2018-12-11

Similar Documents

Publication Publication Date Title
WO2018223909A1 (fr) Molécule chimère, préparation et utilisation associées
JP6959248B2 (ja) 癌治療用の４，６−ジヒドロピロロ［３，４−ｃ］ピラゾール−５（１Ｈ）−カルボニトリル誘導体
CN107148417B (zh) 苯并氮杂*磺酰胺化合物
US7449477B2 (en) 7-phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (protein kinase B)
ES2589801T3 (es) Derivados de dihidroquinolina como inhibidores de bromodominio
WO2019196812A1 (fr) Composé ciblant une dégradation protéique, utilisation antitumorale, intermédiaire de celui-ci et utilisation de l'intermédiaire
WO2020011246A1 (fr) Composé contenant un cycle benzénique, son procédé de préparation et son utilisation
CN111909108B (zh) 联苯类化合物及其制备方法和医药用途
KR20200115448A (ko) Nlrp3 인플라마좀의 선택적 억제제
JP2018508535A (ja) ベンザゼピンジカルボキサミド化合物
CN112739690A (zh) 用作smarca2拮抗剂的吡啶-2-酮化合物
BR112016017261B1 (pt) Composto, composição farmacêutica, uso de um composto e processo para a fabricação de um composto
WO2018137644A1 (fr) Inhibiteur de lsd1, son procédé de préparation et son application
WO2019170150A1 (fr) Composé bcr-abl ciblant la dégradation protéique et utilisation antitumorale associée
EP1663234A1 (fr) Derives de piperazine pour le traitement des infections vih
WO2022258040A1 (fr) Composé hétérocyclique pour inhibiteur de tead
WO2022166974A1 (fr) Dérivé de pyridopyrimidinone, son procédé de préparation et son utilisation
WO2020020288A1 (fr) Composé sulfoximine en tant qu'inhibiteur de protéine à bromodomaine et composition pharmaceutique et son utilisation médicale
CN102803223A (zh) 具有取代苯基的环状化合物
CN111471056B (zh) 一种大环类免疫调节剂
WO2019063015A1 (fr) COMPOSÉ BICYCLIQUE À SUBSTITUTION SULFONYLE AGISSANT EN TANT QU'INHIBITEUR DE RORγ
CN114409653A (zh) 一种桥环并嘧啶并环类化合物及其用途
CN118401512A (zh) 一种具有酰亚胺骨架的多蛋白降解剂
CN108863850A (zh) 联芳基类化合物及其制备方法和用途
KR20240022609A (ko) Cdk2 저해제로서의 치환된 피리미딜-피라졸

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18814296

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18814296

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载