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WO2018001084A1 - Inhibiteur de protéine de choc thermique, son procédé de fabrication et son application - Google Patents

Inhibiteur de protéine de choc thermique, son procédé de fabrication et son application Download PDF

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Publication number
WO2018001084A1
WO2018001084A1 PCT/CN2017/088019 CN2017088019W WO2018001084A1 WO 2018001084 A1 WO2018001084 A1 WO 2018001084A1 CN 2017088019 W CN2017088019 W CN 2017088019W WO 2018001084 A1 WO2018001084 A1 WO 2018001084A1
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group
compound
alkyl
heat shock
shock protein
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Chinese (zh)
Inventor
张健存
林财
李德耀
邹晴安
张袁超
顾自强
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Guangzhou Henovcom Bioscience Co Ltd
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Guangzhou Henovcom Bioscience 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/42—Oxazoles
    • 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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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 to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a heat shock protein inhibitor and a preparation method and application thereof.
  • Heat shock protein is a highly conserved protein that is ubiquitous in organisms. According to the molecular weight, heat shock proteins are divided into: HSP100 (100-110kD), HSP90 (83-90kD), HSP70 (66-78kD), HSP60 and small molecule HSP (15-30kD). Among them, heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone, involved in the activation of client protein and promotes its maturation, maintains the conformation and function of various proteins, and promotes cell proliferation, apoptosis, and cancer. Tumor development is closely related.
  • HSP90 In normal cells, the expressed HSP90 accounts for 1-2% of the total protein in the cell, and 3% of this is found in the nucleus, which has a function of affecting nuclear regulation. Under stress, as in cancer cells, the level of expressed HSP90 is increased to 4-6% of the entire proteomics. HSP90 interacts with more than 200 different client proteins involved in signal transduction, protein trafficking, receptor maturation, and adaptive immunity. A large number of key oncogenic proteins belong to the client protein, such as: Her2, AKT, CDK4, VEGF, MET, ALK, mutant p53 and so on.
  • HSP90 has four subtypes: HSP90 ⁇ and HSP90 ⁇ (located in the cytoplasm), Grp94 subtype (located in the endoplasmic reticulum), and TRAP1 subtype (located in the mitochondrial matrix).
  • the main molecular chaperones of HSP90 include Aha1, Hip, Hop, HSP70, CDC37/P50 and the like.
  • HSP90 is in an activated state, which forms a complex with the client protein and the co-molecular chaperones HSP70, p23, etc., to protect the client protein from degradation by the proteasome.
  • the occurrence and development of cancer is affected by multiple pathways and multiple links of HSP90 receptor protein, making it a new target for anticancer drugs.
  • HSP90 inhibitors can be classified into N-terminal inhibitors, intermediate-end inhibitors, and C-terminal inhibitors depending on their binding sites.
  • HSP90 client protein structure and function requires the participation of HSP, while the client protein plays an important role in promoting cell growth, proliferation and survival, and it is overexpressed or continuously expressed in malignant tumors, and has the development of tumors. close relationship.
  • NSCLC non-small cell lung cancer cells
  • fusion protein BCR-ABL in chronic myelogenous leukemia cells
  • maintenance and regulation of tumor-specific proteins such as Her2 in breast cancer cells require HSP90. participate.
  • HSP90 inhibitor 17-DMAG has anti-proliferative effect on 20 EGFR non-small cell lung cancer cell lines, and can significantly down-regulate the levels of p-EGFR, p-Akt, CyclinD1, Cdk4 in EGFR mutant cell lines. 17-AAG can down-regulate the level of WT-EGFR, but requires a higher concentration and duration of action.
  • the main cause of resistance to gefitinib and erlotinib in non-small cell lung cancer is the K-Ras mutation. Although there are no specific inhibitors for its treatment, Jamie et al. found that Ganetespib can degrade the substrate C-Raf of K-Ras and inactivate some downstream signaling molecules. These indicate that HSP90 inhibitors have a significant inhibitory effect on non-small lung cancer cells, thereby antagonizing the resistance of non-small lung cancer cells to gefitinib and erlotinib.
  • Herceptin monoclonal antibodies are used in some breast cancer patients overexpressing Her2/neu, but most patients develop resistance. Since Her2 is most dependent on HSP90 and most sensitive to HSP90 inhibitors, Scaltriti et al. used primary or secondary resistance models induced by PI3K mutation activation or decreased PTEN expression.
  • the HSP90 inhibitor IPI504 was treated with BT47R (Her2+) and BT477H1047R. (Her2+) role of breast cancer cell lines. The results showed that IPI504 could down-regulate the expression of Her2 in the above two cells and inhibit the AKT and MAPK signaling pathways, and inhibit cell proliferation in a dose-dependent manner.
  • PU-H71 can inhibit the activity of AKT and Bcl-xl proteins and down-regulate their levels, thereby inducing apoptosis in triple-negative breast cancer cells. It is a triple negative breast cancer cell line HCC-1806, The cell death rates of MAD-MB-231 and MAD-MB-468 were 80%, 65%, and 80%, respectively. As can be seen above, HSP90 inhibitors are of great significance as drug-resistant treatments for clinical breast cancer.
  • HSP90 inhibitors should be able to act on it.
  • HSP90 inhibitor tripterine can cause apoptosis of imatinib-resistant KMB5-T315I cells induced by T315I mutation, and immunohistochemical analysis showed that it inhibited the expression of BCL-ABL.
  • the synthetic small molecule HSP90 inhibitor 17-AAG can degrade mutant and wild-type BCL-ABL, thereby inhibiting cell proliferation. Therefore, imatinib-resistant chronic myeloid leukemia can be antagonized with HSP90 inhibitors.
  • HSP90 inhibitors can inhibit the activity of HSP90 and degrade a variety of similar kinases, which can produce better inhibitory effects on some drug-resistant tumors.
  • HSP90 inhibitors have anti-tumor effects either singly or in combination. Therefore, HSP90 is a research and development target for cancer therapy.
  • the present invention provides a novel heat shock protein inhibitor which is capable of inhibiting the activity of heat shock protein 90 and which can be used for the preparation of an antitumor drug.
  • a heat shock protein inhibitor having the structural features of Formula I, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 7 and R 8 are each independently selected from: H, C 1 -C 6 alkyl, C 2 -C 6 unsaturated alkyl, halogen, hydroxy, C 1 -C 6 alkoxy, NHCOOR, SO 2 NHR, NHSO 2 R, CN, NHCOR, CONHR;
  • R is selected from the group consisting of: H, C 1 -C 6 alkyl, C 3 -C 6 unsaturated alkyl, C 3 -C 8 cycloalkyl;
  • R 2 and R 3 are each independently selected from the group consisting of: H, D, C 1 -C 6 alkyl, C 3 -C 6 unsaturated alkyl, C 3 -C 8 cycloalkyl, phenyl, substituted phenyl, hetero Aryl group, acyl group;
  • R 4 is selected from the group consisting of: an amino group, a C 1 -C 6 saturated alkylamine, a C 2 -C 6 saturated heterocyclic amine, a C 1 -C 6 alkylamido group, an arylamide group, a substituted arylamide group, a hetero Arylamide group, substituted heteroarylamide group;
  • R 5 and R 6 are the same oxygen atom or are each independently selected from: H, D, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, carbonyl, cyano, C 1 -C 6 alkoxy ,COOR',NHCOR',CONHR';
  • R' is selected from the group consisting of: H, C 1 -C 6 alkyl, C 3 -C 6 unsaturated alkyl;
  • X, Y, Z, and W are each independently selected from: C, NH, CH, N, O, S.
  • the present inventors have found in the study that the morphine-linked benzyl site in the structure of AUY922 (which is a reported HSP90 inhibitor) may be easily metabolized and may cause toxic side effects. Based on the above research, the inventors discovered through experiments and research, based on their long-term experience, that the introduction of other groups at the benzyl site not only enhances the activity but also inhibits the metabolism of the site. Thereby eliminating potential toxic side effects.
  • the five-membered aromatic heterocycle comprising X, Y, Z, W is selected from the following structures:
  • the heat shock protein inhibitor is selected from the group consisting of the compounds of Formula II:
  • R 7 and R 8 are selected from the group consisting of: H, C 1 -C 6 alkyl, C 2 -C 6 unsaturated alkyl, halogen, hydroxy, C 1 -C 6 alkoxy, CN;
  • R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 unsaturated alkyl, C 1 -C 6 alkoxy.
  • the R 2 and R 3 are each independently selected from the group consisting of: H, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, C 3 -C 6 unsaturated alkyl.
  • R 4 is selected from the group consisting of: amino, C 1 -C 6 saturated alkylamine, C 2 -C 6 saturated heterocyclic amine, C 1 -C 6 alkylamido, arylamide, substituted Arylamide group, heteroarylamide group, substituted heteroarylamide group;
  • R 5 is selected from the group consisting of: H or the same oxygen atom as R 6 ;
  • R 6 is selected from the group consisting of CN, COOR', CONHR', or the same oxygen atom as R 5 ;
  • R' is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 unsaturated alkyl, C 3 -C 8 cycloalkyl.
  • R 4 is selected from the group consisting of:
  • the heat shock protein inhibitor is selected from the group consisting of compounds of the general formula III:
  • R 1 is selected from the group consisting of: C 1 -C 6 alkyl
  • R 7 and R 8 are selected from the group consisting of: a hydroxyl group
  • R 2 is selected from: H;
  • R 3 is selected from the group consisting of: C 1 -C 6 alkyl
  • R 4 is selected from the group consisting of:
  • R 5 is selected from the group consisting of: H or the same oxygen atom as R 6 ;
  • R 6 is selected from: CN, COOR', CONHR', or the same oxygen atom as R5
  • R' is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 unsaturated alkyl, C 3 -C 8 cycloalkyl.
  • the invention also discloses a preparation method of the above heat shock protein inhibitor or a pharmaceutically acceptable salt thereof, which is synthesized by the following route:
  • R 10 is a hydroxy protecting group.
  • R 10 is selected from the group consisting of: benzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, di-tert-butylmethylsilyl, methyl, acetyl, para Oxybenzyl, methoxymethyl.
  • the present invention also discloses the use of the above heat shock protein inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing and treating a disease having an pathological characteristic of increased expression of heat shock protein 90.
  • the disease having increased pathological characteristics of heat shock protein 90 expression is: cancer, metabolic disease, myelodysplastic syndrome, systemic mastocytosis, Hippel-Lindau syndrome, Multi-centered Castleman's disease, and at least one of psoriasis.
  • the present invention has the following beneficial effects:
  • the heat shock protein inhibitor of the present invention or a pharmaceutically acceptable salt thereof is a novel heat shock protein inhibitor, which retains the amino acid residue in the original molecule and the HSP90 receptor active pocket compared with the conventional inhibitor of the same type.
  • the atoms and functional groups that interact with each other further modify the position at which the backbone may have a force, thereby optimizing the inhibitory potency of the control compound, giving it the following advantages:
  • the drug patients acting on the two targets are more convenient to use and can avoid the interaction between the drug and the drug.
  • the compounds of the present invention and salts thereof can also be prepared by methods known for the preparation of chemically related compounds, and the starting materials involved in the examples can be obtained by similar methods in the prior art.
  • the straight line from the benzene ring to the benzene ring in the general formula I of the present invention indicates a substitution in which the position is not fixed.
  • the five-membered ring with a dotted line in the general formula I of the present invention is a five-membered aromatic heterocyclic ring containing X, Y, Z, W.
  • Alkyl means a saturated hydrocarbon group, including a straight or branched alkyl group, for example, a C 1 -C 6 alkyl group means a saturated straight or branched alkyl group having 1 to 6 carbon atoms, wherein the saturated Examples of the alkyl group include, but are not limited to, an ethyl group, a n-propyl group and the like, and examples of the saturated branched alkyl group include, but are not limited to, an isopropyl group, a t-butyl group and the like; and an "unsaturated alkyl group” means an alkenyl group or an alkyne.
  • the hydrocarbon group of the group includes a linear or branched unsaturated alkyl group, and examples of the unsaturated linear alkyl group include, but are not limited to, a vinyl group, a propenyl group and the like, and examples of the unsaturated branched alkyl group include, but are not limited to, 2- a methacryl group or the like;
  • cycloalkyl means an alkyl group having a cyclic structure, such as a C 3 -C 8 cyclic alkyl group means a saturated or unsaturated ring structure having 3 to 8 carbon atoms
  • Substituted refers to the replacement of a hydrogen group in a particular structure with a group of a given substituent. When more than one position in any particular structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at each position.
  • the term “substituted” is intended to include all permissible substituents of an organic compound.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound.
  • a heteroatom such as nitrogen can have a hydrogen substituent and/or any permissible substituent of an organic compound described herein that satisfies the valency of the hetero atom.
  • Heteroaryl means a 4n+2 aromatic ring system containing 5-6 membered monocyclic 6 and the aromatic ring system has a ring carbon atom and 1-4 ring heteroatoms, wherein each ring heteroatom is independently selected from Nitrogen, oxygen and sulfur.
  • a heteroaryl group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, if the chemical price permits.
  • Heteroaryl polycyclic systems can include one or more heteroatoms.
  • Heteroaryl also includes heteroaryl ring systems as defined above, fused with one or more carbocyclic or heterocyclic groups wherein the point of attachment is on the heteroaryl ring, and in this case The number of ring members includes only the number of members on the heteroaryl ring system.
  • Heteroaryl also includes heteroaryl ring systems as defined above, fused with one or more aryl groups, wherein the point of attachment may be on an aryl or heteroaryl ring, and in this case The number of ring members includes only the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • a polycyclic heteroaryl group one of which does not contain a hetero atom (for example, an anthracenyl group, a quinolyl group, a carbazolyl group, and the like), and the point of attachment thereof may be on any ring, that is, It is on a ring containing a hetero atom (for example, 2-fluorenyl) or on a ring containing no hetero atom (for example, 5-fluorenyl).
  • the 5-membered heteroaryl group includes, but is not limited to, imidazole, pyrazole, oxazole, isoxazolyl, thiazolyl, and isothiazole.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyridyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Heterocyclyl refers to a cyclic alkyl group, as defined herein, wherein the backbone further includes one or more heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus).
  • amino group means an organic compound in which a hydrogen atom of ammonia is replaced by an alkyl group, such as a heterocyclic amine, an aralkylamino group or the like.
  • “Amido” means a derivative in which the hydrogen of ammonia (or an amine) is substituted with an acyl group, such as a cycloalkylamide group, an alkylamide group, an arylamide group, a benzoarylamide group, a heteroarylamide group, A benzoheteroarylamide group, a heterocyclic amide group, a sulfonamide group, an alkyl urea or the like.
  • an acyl group such as a cycloalkylamide group, an alkylamide group, an arylamide group, a benzoarylamide group, a heteroarylamide group, A benzoheteroarylamide group, a heterocyclic amide group, a sulfonamide group, an alkyl urea or the like.
  • Compound 1 4-(4-(cyano(morpholino)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-methylisoxazole-3- Preparation of formamide).
  • 2,4-dihydroxyacetophenone I-1 (9.12 g, 60.00 mmol), potassium carbonate (21.00 g, 151.00 mmol), and 200 mL of acetonitrile in an oil bath were placed in a 500 mL two-necked flask equipped with a reflux condenser. Heat at reflux at 80 ° C for 1 h, then benzyl bromide (14.70 mL, 144.00 mmol) was injected with a syringe and refluxed overnight. After the reaction was detected by TLC (TLC), the reaction mixture was cooled to room temperature, filtered, filtered, filtered, washed with dichloromethane, and the filtrate was evaporated.
  • TLC TLC
  • the obtained yellow viscous product was beaten, petroleum ether was added thereto, and the mixture was allowed to stand at a low temperature to precipitate a white solid.
  • the yellow liquid was taken up, and the obtained solid oil pump was drained to obtain 25 mg of a white solid in a yield of 41.0%.
  • Compound 2 4-(4-(cyano(2S,6R)-2,6-dimethylmorpholine)methyl)-5-(2,4-dihydroxy-5-isopropylphenyl)- Preparation of N-ethylisoxazole-3-carboxamide.
  • Compound 5 4-(4-(cyano(2-oxa-6-azaspiro[3.3]hept-6-yl)methyl)phenyl)-5-(2,4-dihydroxy-5-
  • isopropylphenyl)-methylisoxazole-3-carboxamide refer to the method of Example 1.
  • Compound 8 4-(4-(2-thia-5-azabicyclo[2.2.1]hept-5-yl(cyano)methyl)phenyl)-5-(2,4-dihydroxy-
  • the preparation of 5-isopropylphenyl)-methylisoxazole-3-carboxamide was carried out in the same manner as in Example 1.
  • Compound 10 4-(4-(cyano(2-methoxyethyl)amino)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-methyl
  • isoxazole-3-carboxamide 4-(4-(cyano(2-methoxyethyl)amino)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-methyl
  • ESI-MS m/z: 479.1 (M+H) + , 477.2 (MH) - .
  • Compound 11 4-(4-(2-Amino-1-morpholino-2-oxoethyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-methyl Preparation of isoxazole-3-carboxamide.
  • the obtained yellow viscous product was beaten, petroleum ether was added, and the mixture was allowed to stand at a low temperature to precipitate a white solid, and the yellow liquid was taken up, and the obtained solid oil pump was drained to obtain 80 mg of a white solid.
  • the structure of the compound 18 is:
  • Extract retain the aqueous phase, add n-hexane and wash once, add EA to wash away the incomplete phenylboric acid, retain the aqueous phase, add saturated sodium bicarbonate solution, adjust the aqueous phase to alkaline, then add EA*2 extraction Dry with anhydrous sodium sulfate, spin dry and use directly in the next step.
  • the product was obtained as a colorless viscous product, 160 mg, 82%.
  • the structural formula of the compound 20 is:
  • a screening method for enzymatic activity of a target compound (1) A screening method for enzymatic activity of a target compound.
  • FITC-labeled geldanamycin binds to HSP90 and produces fluorescence polarization. If the compound can compete with geldanamycin for inhibition of HSP90 enzyme, no fluorescence polarization is detected.
  • Reagents and instruments fluorescently labeled geldanamycin (Sigma), Hsp90 ⁇ or Hsp90 ⁇ enzyme solution (Stressgen Bioreagents Corp, cat.no.SPP-776), DTT (Promega), bovine serum albumin (BSA) (Hyclone), DMSO (Sigma). Envision 2104 Fluorometer (Perkin Elmer, USA), sampler (Eppendorf), microplate (corning).
  • Each compound was set up in a plurality of different dose groups.
  • the high dose group was configured as a mother liquor, and the remaining dose group was diluted three times to the lowest dose group. All samples were dissolved in DMSO and stored at -20 ° C for use.
  • the experimental buffer contained 20 mmol/l HEPES (K), 50 mmol/l KCl, 5 mmol/l MgCl 2 , 20 mmol/l Na 2 MoO 4 and 0.01% NP40, and the pH was 7.3. 5 ⁇ l of a reaction buffer containing 40 mM DTT and 2 mg/ml BSA was added before each experiment, and then 2.5 ⁇ l of fluorescently-labeled geldanamycin (reaction concentration: 5 nM) was added.
  • reaction concentration 35 ng/ ⁇ l
  • reaction concentration 35 ng/ ⁇ l
  • the reaction was gently shaken at room temperature for 2 hours, and finally the reading was measured with a microplate reader, the excitation light was 485 nm, the emission light was 530 nm, and the data was processed by Graphpad Prism 5 software.
  • CCK kit works: Cell Counting Kit is called CCK kit, which is based on WST-8 (chemical name: 2-(2-methoxy) Base 4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazole monosodium salt) for cell proliferation and cytotoxicity Fast and highly sensitive detection kit.
  • WST-8 is an upgraded product of MTT. Its working principle is: in the presence of electron coupling reagent, it can be reduced by dehydrogenase in mitochondria to produce highly water-soluble orange-yellow formazan product (formazan) and precipitated in cells. Medium, while dead cells do not have this function. The depth of color is directly proportional to the proliferation of cells and inversely proportional to cytotoxicity. The absorbance was measured at a wavelength of 540/720 nm using an enzyme-linked detector to indirectly reflect the number of viable cells.
  • Reagents and instruments various cancer cell lines (ATCC, USA), penicillin, streptomycin, DMSO (Sigma), CCK8 (CK04, Japan Tongren Chemical), RPMI1640 (GIBCO), BSA (Hyclone), trypsin (Gino Corporation), 384-well cell culture plate (Corning).
  • Each cancer cell was suspended in the corresponding culture medium to prepare a suitable concentration, and the volume was 50 ⁇ l/well implanted in a 384-well plate, and cultured at 37 ° C in a 5% CO 2 incubator for 24 hours.
  • the compound was dissolved in DMSO into 10 mM mother liquor, and diluted with DMSO 1:3 to 10 concentration gradients of 1000 ⁇ compound series concentration stock solution, and the 1000 ⁇ series concentration compound storage solution was transferred to the cell 384 well using the compound transfer instrument Liquid Handler Echo520.
  • An appropriate volume of vehicle DMSO was added to the corresponding wells of the plate at 50 nL per well and blank control wells. Gently mix and continue to culture at 37 °C.
  • HSP90 ⁇ and HSP90 ⁇ of HSP90 protein were determined by the above methods.
  • the inhibitory activity of the leukemia cell line K562, the prostate cancer cell line DU145, and the test proliferation epidermal cancer cell line Hela are shown in Table 1.
  • the above compounds have inhibitory effects on both HSP90 isoforms, and most of the compounds have stronger binding ability to HSP90 ⁇ than HSP90 ⁇ .
  • the positive control compound NVP/AUY-922 CAS: 747412-49-3
  • most of the compounds showed stronger inhibitory activity, further demonstrating that the target backbone is more suitable for the active pocket of the target.
  • the above compounds have strong inhibitory activity against five types of cancer cell lines, and most of the compounds can reach several or several nanomolar levels, especially for the epidermal cancer cell line Hela. effect.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine de la chimie pharmaceutique. L'invention porte sur un inhibiteur de protéine de choc thermique, sur son procédé de fabrication et sur son application. L'inhibiteur de protéine de choc thermique a une structure caractéristique représentée par la formule I. Le composé peut inhiber une activité de la protéine de choc thermique 90 et peut être utilisé pour préparer un produit pharmaceutique antitumoral.
PCT/CN2017/088019 2016-06-29 2017-06-13 Inhibiteur de protéine de choc thermique, son procédé de fabrication et son application Ceased WO2018001084A1 (fr)

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CN116284202A (zh) * 2023-03-28 2023-06-23 华侨大学 白桦脂酸的PROTACs化合物及其制备方法和应用

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CN113087658B (zh) * 2021-04-06 2022-05-17 北京大学深圳研究生院 具有热休克热蛋白70抑制活性的化合物及其应用

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CN116284202A (zh) * 2023-03-28 2023-06-23 华侨大学 白桦脂酸的PROTACs化合物及其制备方法和应用

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