WO2021136429A1 - 苯并吡唑类化合物 - Google Patents
苯并吡唑类化合物 Download PDFInfo
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- WO2021136429A1 WO2021136429A1 PCT/CN2020/141632 CN2020141632W WO2021136429A1 WO 2021136429 A1 WO2021136429 A1 WO 2021136429A1 CN 2020141632 W CN2020141632 W CN 2020141632W WO 2021136429 A1 WO2021136429 A1 WO 2021136429A1
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- -1 Benzopyrazole compound Chemical class 0.000 title abstract description 40
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- 125000001424 substituent group Chemical group 0.000 claims description 11
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- 229910052731 fluorine Inorganic materials 0.000 claims description 9
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- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- XMBWDFGMSWQBCA-YPZZEJLDSA-N iodane Chemical compound [125IH] XMBWDFGMSWQBCA-YPZZEJLDSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940118019 malondialdehyde Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000020763 muscle atrophy Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001718 repressive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention relates to a series of benzopyrazole compounds, in particular to compounds represented by formula (I) and pharmaceutically acceptable salts thereof.
- Rheumatoid Arthritis is a chronic inflammatory, "systemic" autoimmune disease.
- the joint manifestations of early rheumatoid arthritis are often difficult to distinguish from other types of inflammatory arthritis.
- Rheumatoid arthritis has more characteristic signs such as joint erosions, rheumatoid nodules and other extra-articular manifestations.
- Rheumatoid arthritis affects women more than men (3:1), and the age of onset is between 30-55 years old.
- the pathogenesis of rheumatoid arthritis is very complicated. The main reason is that autoantigens are presented to activated CD4+ T cells by MHC-II positive antigen-presenting cells (APC) to initiate specific immunity. Response: At the same time activated T cells, macrophages, etc. migrate to the synovium, increasing the secretion of various inflammatory cytokines such as TNF ⁇ , IL-1 and IL-6, infiltrating the lubricating membrane joints, leading to corresponding arthritis symptoms.
- MHC-II positive antigen-presenting cells APC
- T cells, macrophages, etc. migrate to the synovium, increasing the secretion of various inflammatory cytokines such as TNF ⁇ , IL-1 and IL-6, infiltrating the lubricating membrane joints, leading to corresponding arthritis symptoms.
- Glucocorticoids are widely used to treat inflammation and immune diseases for decades, including: rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, rheumatic fever, allergic rhinitis, systemic Lupus erythematosus, Crohn’s disease, inflammatory bowel disease, and ulcerative colitis.
- Glucocorticoid binds to the glucocorticoid receptor (GR), enters the nucleus, affects gene transcription (activation and inhibition), and reduces the production of inflammatory factors.
- Glucocorticoid receptor is a member of the conserved nuclear receptor superfamily and belongs to nuclear transcription factors. It is widely present in various tissues and cells of the body. Almost all cells are its target cells. Metabolism and immune function play an important regulatory role. GC usually has serious and irreversible side effects, such as: osteoporosis, hyperglycemia, diabetes, hypertension, muscle atrophy, Cushing syndrome, etc., which severely restrict the use of GC in chronic diseases.
- GR ligands which can selectively induce transcriptional inhibition without significant transcriptional activation, reduce the risk of systemic side effects, and maintain anti-inflammatory activity.
- selective glucocorticoid receptor modulators SGRM
- Selective glucocorticoid receptor modulators are different from GC. When combined with GR, they can trigger complete transcriptional inhibition and only trigger partial transcriptional activation, which can control related side effects while maintaining anti-inflammatory activity.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- X is selected from NH and O;
- Ring A is selected from phenyl, 5-membered heteroaryl, The 5-membered heteroaryl group, Optionally substituted with 1, 2 or 3 R a;
- T 1 is selected from CH 2 and O;
- T 2 , T 3 and T 4 are independently selected from CH and N;
- T 5 is selected from NH and O;
- T 6 is selected from CH and N;
- Ring B is selected from phenyl
- R 1 is selected from H and C 1-3 alkoxy, the C 1-3 alkoxy is optionally substituted with 1, 2 or 3 R b ;
- Each R 2 is independently selected from H, F, Cl, Br and CH 3 ;
- R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R c ;
- n 0, 1 and 2;
- n is selected from 1 and 2;
- R a is each independently selected from H and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R;
- R b is independently selected from H, F, Cl, Br and I;
- R c are each independently selected from H, F, Cl, Br, I and OH;
- R are each independently selected from F and OCH 3 .
- the compound or a pharmaceutically acceptable salt thereof has a structure selected from
- ring A, ring B, R 1 , R 2 , R 3 and m are as defined in the present invention.
- the R a is independently selected from H, CH 3, CF 3, CH 2 CH 3 and CH 2 CH 2 OCH 3, the other variables are as defined in the present invention.
- the R a is independently selected from H, CH 3, CF 3, CH 2 CH 3, C (CH 3) 2 and CH 2 CH 2 OCH 3, according to the present invention as other variables definition.
- the ring A is selected from phenyl, furyl, pyrazolyl, triazole, thiazolyl, isothiazolyl,
- R a substituents
- the ring A is selected from Said Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
- the ring A is selected from Other variables are as defined in the present invention.
- the structural unit Selected from Other variables are as defined in the present invention.
- the structural unit Selected from Other variables are as defined in the present invention.
- the R 1 is selected from H and OCH 3 , and the OCH 3 is optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
- the R 1 is selected from H and OCH 3 , and other variables are as defined in the present invention.
- the R 3 is selected from C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
- the R 3 is selected from CH 3 , CH 2 CH 3 and C(CH 3 ) 2 , and other variables are as defined in the present invention.
- the present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- X is selected from NR 4 or O;
- Ring A is selected from phenyl, Said Optionally substituted with 1, 2 or 3 R a;
- T 1 is selected from CH 2 and O;
- T 2 , T 3 and T 4 are independently selected from CH and N;
- T 5 is selected from NH and O;
- T 6 is selected from CH and N;
- Ring B is selected from phenyl
- R 1 is selected from H and C 1-3 alkoxy, the C 1-3 alkoxy is optionally substituted with 1, 2 or 3 R b ;
- Each R 2 is independently selected from H and F;
- R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R c ;
- R 4 is selected from H
- n 0, 1 and 2;
- n is selected from 1 and 2;
- R a is independently selected from H and CH 3 ;
- R b is independently selected from H, F, Cl, Br and I;
- R c are each independently selected from H, F, Cl, Br, I, and OH.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof has a structure selected from
- ring A, ring B, R 1 , R 2 , R 3 and m are as defined in the present invention.
- the above-mentioned ring A is selected from Said Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
- the above-mentioned ring A is selected from Said Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
- the above-mentioned ring A is selected from Other variables are as defined in the present invention.
- the above-mentioned ring B is selected from Other variables are as defined in the present invention.
- R 1 is selected from H and OCH 3 , and the OCH 3 is optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
- R 1 is selected from H and OCH 3 , and other variables are as defined in the present invention.
- R 3 is selected from C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
- R 3 is selected from CH 3 and C(CH 3 ) 2 , and other variables are as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from
- ring A, R 1 , R 2 , R 3 and m are as defined in the present invention.
- the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
- the present invention also provides the application of the compound or its pharmaceutically acceptable salt in the preparation of drugs for glucocorticoid receptor-related diseases.
- the disease related to glucocorticoid receptor refers to rheumatoid arthritis.
- the compound designed in the present invention has good hMMP1 transcription inhibitory activity, comparable MMTV transcription activation activity, and strong cellular level anti-inflammatory activity, and has good pharmacokinetic properties.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , 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 the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
- a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
- the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, 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 methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
- the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
- tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
- proton tautomer proton tautomer
- proton transfer tautomer includes interconversion through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence isomers include some recombination of bonding electrons to carry out mutual conversion.
- keto-enol tautomerization examples are the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- amine-enamine isomerization examples are as
- the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
- deuterium can be substituted for hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages.
- substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
- oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
- any variable such as R
- its definition in each case is independent.
- the group can optionally be substituted with up to two Rs, and R has independent options in each case.
- combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- any one or more sites of the group can be connected to other groups through chemical bonds.
- the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
- the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
- the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
- the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
- the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
- C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
- the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
- C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
- C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- 5-membered heteroaromatic ring and “5-membered heteroaryl” can be used interchangeably in the present invention.
- the term “5-membered heteroaryl” refers to a conjugated ⁇ -electron system composed of 5 ring atoms.
- the 1, 2, 3, or 4 ring atoms of the monocyclic group are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
- the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
- the 5-membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
- Examples of the 5-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) Etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazole) Base, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl
- C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1- 12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is from n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered
- leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, a nucleophilic substitution reaction).
- representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldi
- hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
- Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
- alkyl groups such as methyl, ethyl, and tert-butyl
- acyl groups such as alkanoyl groups (such as acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
- the single crystal X-ray diffraction method uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
- the light source is CuK ⁇ radiation
- the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
- THF tetrahydrofuran
- DCM dichloromethane
- DMF N,N-dimethylformamide
- n-BuLi n-butyl lithium
- NaH sodium hydrogen
- TFA trifluoroacetic acid
- CDI N,N-carbonyldiimidazole
- HOBt 1-hydroxybenzotriazole
- EDCI 1-ethyl-(3-dimethylaminopropyl) carbodiimide
- TBTU stands for O-benzo Triazole-N,N,N',N'-tetramethylurea tetrafluoroborate
- HATU stands for 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate
- HBTU stands for O-benzotriazole-tetramethyl
- reaction solution was washed with saturated citric acid aqueous solution (100 mL), saturated sodium bicarbonate aqueous solution (100 mL) and saturated brine (100 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound AA-1-2 .
- the aqueous phase was extracted with ethyl acetate (5L ⁇ 2), the organic phases were combined, washed with saturated brine (10L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
- the crude product was transferred to a 50L jacketed kettle, added petroleum ether (8L), and slurried at 25°C for 16 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with petroleum ether (5L) in batches, and the filter cake was collected to obtain the compound AA-1-5.
- Tetrahydrofuran 50mL was added to a dry three-necked flask, and after replacing it with nitrogen 3 times, the temperature of the system was reduced to -15°C, compound AC-1-3 (19.51g, 107.63mmol) was added dropwise, and compound AA-1 was added dropwise.
- -2 (10g, 43.05mmol) was added to tetrahydrofuran (150mL), and the above system was slowly added (the temperature was maintained at about -5°C). After the addition was completed, the reaction was stirred at 25°C for 12 hours.
- reaction solution was slowly poured into saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (300 mL ⁇ 3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Compound AC-1-4.
- Compound AC-1-4 (9g) was added to toluene (50mL), and then isopropanol (28.2g), aluminum isopropoxide (3.69g) were added in sequence, and the mixture was stirred at 25°C for 1 hour under nitrogen protection, and the temperature was raised to 65°C. The reaction was stirred for 12 hours.
- Example 2 Referring to the synthesis method of Example 2, replace WX002-1 with fragment 1 and replace AA-1 with fragment 2, and synthesize the examples in the following table.
- Example 26 replace WX026-1 with fragment 1 and replace AD-1 with fragment 2, and synthesize the examples in the following table.
- reaction solution was cooled to 50° C., filtered, the filter cake was washed with ethyl acetate (50 mL ⁇ 2), and the filtrate was concentrated under reduced pressure to obtain a crude product.
- the crude product was separated by preparative HPLC (column type: Phenomenex Luna C18 100 ⁇ 30mm ⁇ 5 ⁇ m; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; B(ACN)%: 35%-55%, 10min) Purified to obtain compound WX034.
- Example 35 Refer to the synthesis method of Example 35, and replace WX035-1 with fragment 1 to synthesize the examples in the following table.
- Example 37 Refer to the synthesis method of Example 37, and replace WX018-1 with fragment 1 to synthesize the examples in the following table.
- Example 39 Refer to the synthesis method of Example 39, replace WX039-1 with fragment 1, and replace AA-1 with fragment 2, to synthesize the examples in the following table.
- reaction solution was cooled to room temperature, added to water (20 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
- Example 49 Referring to the synthesis method of Example 49, replace WX049-1 with fragment 1, and replace AA-1 with fragment 2, to synthesize the examples in the following table.
- WX058-2 (196.08mg) and WX058-1 (0.5g) to a pre-dried round bottom flask, dissolve them in tetrahydrofuran (15mL), and add N,N,N',N'-tetramethylazobis Formamide (665.55 mg) and tributylphosphine (782.01 mg). After nitrogen substitution three times, the reaction was carried out at 20°C for 12 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL ⁇ 2).
- reaction solution was filtered, water (500 mL) was added to the filtrate, the layers were separated, and the aqueous phase was extracted with ethyl acetate (200 mL ⁇ 2).
- AI-1-6 (1.57g, hydrochloride) and 2,2-difluoropropionic acid (881.11mg) were added to ethyl acetate (20mL), and N-methylmorpholine (3.68g) was added at 0°C, A 50% ethyl acetate solution (6.95 g, 6.49 mL) of n-propyl phosphoric anhydride was added dropwise, and the reaction was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), separated into layers, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (20 mL), and the organic phases were combined.
- Example 60 Refer to the synthesis method of Example 60, replace AI-1-3 with fragment 1, and synthesize each of the examples in the following table.
- Experimental example 1 In vitro detection compounds inhibit hMMP1 transcription activity under the luciferase reporter gene screening system
- the human MMP-1 promoter region (contains two AP-1 binding sites and two PEA3 sites, a total of 249 bp, gene bank catalog #AF023338) was cloned upstream of the luciferase reporter gene.
- the hMMP-1 promoter reporter gene was constructed and transfected into Hela cells, so that the production of luciferase could be easily detected.
- the stable recombinant hMMP-1/luciferase cell line was used for the development and verification of this experiment.
- pGL6.0-TA-hMMP-1HeLa cells are usually passaged twice a week, diluted 1:3 or 1:6.
- the cell concentration is 5 ⁇ 10 3 cells/well.
- the cell plate is placed in a 37°C 5% CO 2 incubator for 18-24 hours.
- test compound was diluted to 30 mM with DMSO, and stored in aliquots in a refrigerator at -80°C for later use.
- the final DMSO concentration is 0.1%. PMA needs to be protected from light during use.
- Negative control 10nM PMA (0.1% DMSO)
- Test compound the highest concentration is 1000 nM, diluted 4 times, 10 wells in total, repeat.
- Dexamethasone the highest concentration is 1000nM, diluted 4 times, a total of 10 wells, repeat.
- the promoter of mouse mammary tumor virus contains a specific binding site that activates GR (GREs).
- GREs GR
- a reporter gene luciferase was inserted after the MMTV promoter, and the structure was expressed in a stable manner in the genome of the HeLa cell line.
- the test compound is used to activate the MMTV promoter, induce the expression of luciferase, and detect its activity by luminescence measurement.
- the cell plate is placed in a 37°C 5% CO 2 incubator for 18-24 hours.
- test compound was diluted to 30 mM with DMSO, and stored in aliquots in a refrigerator at -80°C for later use.
- the final experimental concentration of DMSO is 0.1%.
- Inoculation of cells Fresh cells were inoculated into a 384 white transparent bottom experimental plate at 4 ⁇ 10 3 cells/30 ⁇ L/well, and cultured in a 37°C 5% CO 2 incubator for 24 hours.
- Test compound the highest concentration is 1000 nM, diluted 4 times, 10 wells in total, repeat.
- Dexamethasone the highest concentration is 1000nM, diluted 4 times, a total of 10 wells, repeat.
- N/A means not detected; IC 50 means absolute IC 50 , EC 50 means absolute EC 50 ; Effect means maximum effect value.
- the compound of the present invention exhibits very good transcriptional repressive activity and comparable transcriptional activation activity.
- mice peripheral blood mononuclear cells
- PRMI 1640 medium (Invitrogen-11875093, lot 2003787)
- Fetal Bovine Serum (FBS) (Gibco-10091148, lot 1989478)
- PBMC cells AllCells, Cat.PB006F-C, lot LP190225B: RPMI 1640 + 10% FBS (Gibico) + 1% PS
- the cell plate After the compound is added, the cell plate is placed in a 37°C, 5% CO 2 incubator and incubated for 1 hour.
- the first step is to dilute LPS with ultrapure water to a storage concentration of 1 mg/ml.
- the storage concentration of LPS is diluted to 1ug/mL with serum-free medium.
- the third step is 1666.666 times dilution with medium without serum. Then transfer 16.8 ⁇ L of LPS that has been diluted with culture medium to 116.8 ⁇ L of cell plate. At this time, the final concentration of DMSO is 0.1%. After adding LPS, place the cell plate in a 37°C, 5% CO 2 incubator and incubate 18 Hours.
- Inhibition rate (1-(original value-HPE average)/(ZPE average-HPE average)) ⁇ 100%
- ZPE is: 0% inhibition (75pg/ml LPS, 0.1% DMSO), and HPE: 100% inhibition (without LPS, 0.1% DMSO).
- Z factor 1-(3 ⁇ (ZPE standard deviation + HPE standard deviation)/(ZPE average value-HPE average value))
- Model 205 in ⁇ Lfit statistical software was used for data analysis. Taking the concentration as the abscissa and the inhibition rate as the ordinate, the IC 50 calculation formula is: using a 4-parameter logistic dose-response equation to plot the concentration of the tested compound and the inhibition rate (%), and determine the 50% inhibition required Compound concentration (IC 50 ).
- the compound of the present invention exhibits good anti-inflammatory activity at the cellular level.
- the purpose of the research project is to use a 5-in-1 probe substrate of CYP isoenzymes to evaluate the inhibitory effect of the test product on human liver microsomal cytochrome P450 isoenzymes (CYP3A4).
- HLM human liver microsomes
- Test compound AZD9567 WX019 WX053 CYP3A4 (IC50, ⁇ M) 2.95 9.12 15.7
- AZD9567 has a moderate inhibitory effect on CYP3A4.
- Compounds WX019 and WX053 significantly improved the inhibition of CYP3A4.
- the purpose of this study is to determine the pharmacokinetic parameters of the compound in male SD rats.
- This project uses two male SD rats for intravenous injection.
- the dose is 2mg/kg and the concentration is 0.4mg/mL.
- the collected analysis data is used Phoenix WinNonlin 6.3 software to calculate the relevant pharmacokinetic parameters.
- the compound of the present invention has a good apparent volume of distribution and half-life.
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Abstract
苯并吡唑类化合物,具体公开了式(I)所示化合物及其药学上可接受的盐
Description
本发明主张如下优先权:
申请号:CN201911412430.3,申请日2019年12月31日;
申请号:CN202011389082.5,申请日2020年12月01日。
本发明涉及一系列苯并吡唑类化合物,具体涉及式(I)所示化合物及其药学上可接受的盐。
类风湿关节炎(Rheumatoid Arthritis,RA)是一种慢性炎症性、“系统性”自身免疫性疾病,早期类风湿关节炎的关节表现往往很难与其他类型的炎性关节炎区分。类风湿关节炎更具特征性的体征,如关节侵蚀,类风湿结节和其他关节外表现。类风湿性关节炎对女性的影响大于男性(3:1),发病年龄在30-55岁之间。
类风湿关节炎的发病机制十分复杂,主要是自身抗原被主要组织相容性复合体Ⅱ(MHC-Ⅱ)型阳性的抗原呈递细胞(APC)呈递给活化的CD4+T细胞,启动特异性免疫应答;同时活化的T细胞、巨噬细胞等向滑膜迁移,使多种炎性细胞因子如TNFα、IL-1和IL-6等分泌增多,浸润滑膜关节,导致相应关节炎症状。
糖皮质激素(GC)广泛用于治疗炎症和免疫疾病长达几十年,包括:类风湿性关节炎、哮喘、慢性阻塞性肺病(COPD)、骨关节炎、风湿热、过敏性鼻炎、系统性红斑狼疮、克罗恩病、炎性肠病以及溃疡性结肠炎。
糖皮质激素(GC)结合糖皮质激素受体(GR),进入细胞核影响基因转录(激活和抑制),减少炎症因子的产生。糖皮质激素受体是保守的核受体超家族中的一员,属于核转录因子,广泛存在于机体各种组织细胞中,几乎所有细胞都是它的靶细胞,对机体的发育、生长、代谢以及免疫功能等起着重要调节作用。GC通常具有严重且不可逆的副作用,如:骨质疏松、高血糖、糖尿病、高血压、肌肉萎缩、库欣综合征等,严重限制了GC在慢性疾病中使用。
目前已经找到GR配体的实例,可以选择性地诱导转录抑制而没有显著的转录激活,能降低全身性副作用的风险,同时维持抗炎活性,我们称之为选择性糖皮质激素受体调节剂(SGRM)。选择性糖皮质激素受体调节剂(SGRM)与GC不同,在结合GR时,它们能引发完全的转录抑制,只引发部分的转录激活,进而可以在保持抗炎活性的同时控制相关副作用。
Lena Ropa,et al,J.Med.Chem.2018,61,1785-1799报道了化合物AZD9567,具有抗炎作用的药效,以及溶解度差等理化性质,适宜口服给药。但是数据同时也显示其基因转录的抑制活性不够令人满意,抗炎效果不够理想,同时存在血浆骨钙素水平降低等糖皮质激素类药物的副作用,因此需要开发同时具备良好的基因转录的抑制活性和一般的基因转录激活活性的化合物,在提高抗炎活性的同时降低副作用。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐,
其中,
X选自NH和O;
T
1选自CH
2和O;
T
2、T
3和T
4分别独立地选自CH和N;
T
5选自NH和O;
T
6选自CH和N;
环B选自苯基;
R
1选自H和C
1-3烷氧基,所述C
1-3烷氧基任选被1、2或3个R
b取代;
各R
2分别独立地选自H、F、Cl、Br和CH
3;
R
3选自C
1-6烷基,所述C
1-6烷基任选被1、2或3个R
c取代;
m选自0、1和2;
n选自1和2;
R
a分别独立地选自H和C
1-3烷基,所述C
1-3烷基任选被1、2或3个R取代;
R
b分别独立地选自H、F、Cl、Br和I;
R
c分别独立地选自H、F、Cl、Br、I和OH;
R分别独立地选自F和OCH
3。
在本发明的一些方案中,所述化合物或其药学上可接受的盐,其结构选自
其中,环A、环B、R
1、R
2、R
3和m如本发明所定义。
在本发明的一些方案中,所述R
a分别独立地选自H、CH
3、CF
3、CH
2CH
3和CH
2CH
2OCH
3,其他变量如本发明所定义。
在本发明的一些方案中,所述R
a分别独立地选自H、CH
3、CF
3、CH
2CH
3、C(CH
3)
2和CH
2CH
2OCH
3,其他变量如本发明所定义。
在本发明的一些方案中,所述R
1选自H和OCH
3,所述OCH
3任选被1、2或3个R
b取代,其他变量如本发明所定义。
在本发明的一些方案中,所述R
1选自H和OCH
3,其他变量如本发明所定义。
在本发明的一些方案中,所述R
3选自C
1-3烷基,所述C
1-3烷基任选被1、2或3个R
c取代,其他变量如本发明所定义。
在本发明的一些方案中,所述R
3选自CH
3、CH
2CH
3和C(CH
3)
2,其他变量如本发明所定义。
本发明提还供了式(I)所示化合物或其药学上可接受的盐,
其中,
X选自NR
4或O;
T
1选自CH
2和O;
T
2、T
3和T
4分别独立地选自CH和N;
T
5选自NH和O;
T
6选自CH和N;
环B选自苯基;
R
1选自H和C
1-3烷氧基,所述C
1-3烷氧基任选被1、2或3个R
b取代;
各R
2分别独立地选自H和F;
R
3选自C
1-6烷基,所述C
1-6烷基任选被1、2或3个R
c取代;
R
4选自H;
m选自0、1和2;
n选自1和2;
R
a分别独立地选自H和CH
3;
R
b分别独立地选自H、F、Cl、Br和I;
R
c分别独立地选自H、F、Cl、Br、I和OH。
在本发明的一些方案中,上述化合物或其药学上可接受的盐,其结构选自
其中,环A、环B、R
1、R
2、R
3和m如本发明所定义。
在本发明的一些方案中,上述R
1选自H和OCH
3,所述OCH
3任选被1、2或3个R
b取代,其他变量如本发明所定义。
在本发明的一些方案中,上述R
1选自H和OCH
3,其他变量如本发明所定义。
在本发明的一些方案中,上述R
3选自C
1-3烷基,所述C
1-3烷基任选被1、2或3个R
c取代,其他变量如本发明所定义。
在本发明的一些方案中,上述R
3选自CH
3和C(CH
3)
2,其他变量如本发明所定义。
在本发明的一些方案中,所述化合物或其药学上可接受的盐,其化合物选自
其中,环A、R
1、R
2、R
3和m如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明还提供了下式所示化合物或其药学上可接受的盐,
本发明还提供了所述化合物或其药学上可接受的盐在制备与糖皮质激素受体相关疾病的药物中的应用。
在本发明的一些方案中,所述与糖皮质激素受体相关疾病是指类风湿关节炎。
技术效果
本发明所设计的化合物具有很好的hMMP1转录抑制活性、相当的MMTV转录激活活性,以及很强的细胞水平的抗炎活性,具有较好的药代动力学性质。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等) 的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
本发明的化合物可以存在特定的。除非另有说明,术语“互变异构体”或“互变异构体形式”是指在室温下,不同官能团异构体处于动态平衡,并能很快的相互转化。若互变异构体是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例如戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变,亚胺-烯胺异构化的具体实例如
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(
3H),碘-125(
125I)或C-14(
14C)。又例如,可用重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘化药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即=O)时,意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时,比如-(CRR)
0-,表示该连接基团为单键。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
除非另有规定,当某一基团具有一个或多个可连接位点时,该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的,且可连接位点存在H原子时,则连接化学键时,该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
直形虚线键
或波浪线
表示。例如-OCH
3中的直形实线键表示通过该基团中的氧原子与其他基团相连;
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连;
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连;
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连,至少包括
这4种连接方式,即使-N-上画出了H原子,但是
仍包括
这种连接方式的基团,只是在连接1个化学键时,该位点的的H会对应减少1个变成相应的一价哌啶基;
表示该吲哚基上的任意可连接位点可以通过1个化学键与其他基团相连,至少包括
这7种连接方式。
除非另有规定,术语“C
1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C
1-6烷基包括C
1-5、C
1-4、C
1-3、C
1-2、C
2-6、C
2-4、C
6和C
5烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基,异丁基,s-丁基和t-丁基)、戊基(包括n-戊基,异戊基和新戊基)、己基等。
除非另有规定,术语“C
1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。 所述C
1-3烷基包括C
1-2和C
2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定,术语“C
1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C
1-3烷氧基包括C
1-2、C
2-3、C
3和C
2烷氧基等。C
1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定,本发明术语“5元杂芳环”和“5元杂芳基”可以互换使用,术语“5元杂芳基”表示由5个环原子组成的具有共轭π电子体系的单环基团,其1、2、3或4个环原子为独立选自O、S和N的杂原子,其余为碳原子。其中氮原子任选地被季铵化,氮和硫杂原子可任选被氧化(即NO和S(O)
p,p是1或2)。5元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)。
除非另有规定,C
n-n+m或C
n-C
n+m包括n至n+m个碳的任何一种具体情况,例如C
1-12包括C
1、C
2、C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
11、和C
12,也包括n至n+m中的任何一个范围,例如C
1-
12包括C
1-3、C
1-6、C
1-9、C
3-6、C
3-9、C
3-12、C
6-9、C
6-12、和C
9-12等;同理,n元至n+m元表示环上原子数为n至n+m个,例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环,也包括n至n+m中的任何一个范围,例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如,代表性的离去基团包括三氟甲磺酸酯;氯、溴、碘;磺酸酯基,如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等;酰氧基,如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基;酰基,例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基);烷氧基羰基,如叔丁氧基羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc);芳基甲基,如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基;甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于:烷基,如甲基、乙基和叔丁基;酰基,例如链烷酰基(如乙酰基);芳基甲基,如苄基(Bn),对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基,DPM);甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方 式,优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:
扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词:THF代表四氢呋喃;DCM代表二氯甲烷;DMF代表N,N-二甲基甲酰胺;n-BuLi代表正丁基锂;NaH代表钠氢;TFA代表三氟乙酸;CDI代表N,N-羰基二咪唑;HOBt代表1-羟基苯并三唑;EDCI代表1-乙基-(3-二甲基氨基丙基)碳酰二亚胺;TBTU代表O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸;HATU代表2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯;HBTU代表O-苯并三氮唑-四甲基脲六氟磷酸酯;L-Glutamine代表左旋谷酰胺;TR代表转录抑制;TA代表转录激活;PMA代表佛波醇12-十四酸酯13-乙酸酯;DPBS代表和杜氏磷酸缓冲溶液;Trypsin代表胰蛋白酶;DMEM代表改良伊格尔培养基;FBS代表胎牛血清;NEAA代表非必需氨基酸;Sodium Pyruvate代表丙酮酸钠;G418
代表选择性抗生素(G418硫酸盐);MMTV代表小鼠乳腺肿瘤病毒;Hygromycin代表潮霉素。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1:化合物AA-1-6的合成
步骤1:化合物AA-1-2的合成
在干燥的三口瓶中加入化合物AA-1-1(10g),用二氯甲烷(100mL)溶解后,分批加入N,N-羰基二咪唑(10.72g),加料完毕,氮气置换三次,氮气氛围下25℃搅拌1小时。然后加入N-甲基N-甲氧基胺盐酸盐(6.44g),再加入三乙胺(5.35g),加料完毕,氮气置换3次后,氮气环境下25℃搅拌11小时。反应完毕,反应液依次用饱和柠檬酸水溶液(100mL),饱和碳酸氢钠水溶液(100mL)和饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得化合物AA-1-2。
MS–ESI m/z:133.1[M-100+H]
+。
步骤2:化合物AA-1-4的合成
在干燥的三口瓶中加入化合物AA-1-3(270.0g),将温度降至-15℃,缓慢滴加异丙基氯化镁的四氢呋喃溶液(2mol/L,700mL),加料完毕,维持-15℃搅拌2小时。然后将化合物AA-1-2(130g)溶于四氢呋喃(1.3L)溶液中,加入到反应体系(温度不超过5℃)。加料完毕,将反应液升温至60℃搅拌1小时。反应完毕,将反应液冷却至室温,倒入饱和氯化铵溶液(1.5L)中,搅拌,分液。向水相加入乙酸乙酯(1L×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得到化合物AA-1-4。
步骤3:化合物AA-1-5的合成
在50L夹套釜中加入异丙醇(3.16kg)和甲苯(12L),分批加入AA-1-4(1.15kg)。待溶解后加入异丙醇铝(412.73g),在25℃下搅拌1小时,然后升温至55℃继续搅拌15小时。反应完毕,将反应液减压浓缩得到粗品。粗品加入乙酸乙酯(5L),用1mol/L稀盐酸将pH调至5-6,分液,收集有机相。水相用乙酸乙酯(5L×2)萃取,合并有机相,用饱和食盐水(10L)洗涤,无水硫酸钠干燥,减压浓缩得到粗品。粗品转移到50L夹套釜中,加入石油醚(8L),在25℃下打浆16小时,反应完毕,将反应液过滤,滤饼用石油醚(5L)分次淋洗,收集滤饼得化合物AA-1-5。
1HNMR(400MHz,CD
3OD)δ=6.98(d,J=7.0Hz,2H),6.79(t,J=9.2Hz,1H),6.55(d,J=8.6Hz,1H),4.56(d,J=5.4Hz,1H),3.75-3.63(m,1H),1.37(s,9H),1.06(d,J=6.8Hz,3H)。
步骤4:化合物AA-1-6的合成
在干燥的单口瓶中加入化合物AA-1-5(145g),加入盐酸/乙酸乙酯(4mol/L,2L),在25℃下搅拌12小时。反应完毕,将反应液减压浓缩,粗品加入乙酸乙酯(1L)溶解,加入4mol/L氢氧化钠水溶液将pH调至7-8,分液,水相用乙酸乙酯(500mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得到化合物AA-1-6的盐酸盐。
1H NMR(400MHz,CD
3OD)δ=7.04-6.97(m,2H),6.84(tt,J=2.4,9.0Hz,1H),4.70(d,J=4.4Hz,1H),3.28-3.16(m,1H),1.02(d,J=6.6Hz,3H)。
参照参考例1的合成方法,合成下表中参考例。
参考例4:化合物AC-1-6的合成
步骤1:化合物AA-1-2的合成
将化合物AA-1-1(100g)溶于二氯甲烷(1.0L),于25℃缓慢加入N,N’-羰基二咪唑(107.1g,660.6mmol),搅拌3小时后,加入三乙胺(107.1g)和N-甲基-N-甲氧基胺盐酸盐(64.4g),在25℃下搅拌反应12小时。反应完毕,向反应体系加入水(300mL)和盐酸(1mol/L,100mL),分液,收集有机相,水相用二氯甲烷萃取(500mL×3),合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩。粗品 经柱层析(洗脱剂:石油醚/乙酸乙酯=2/1–1/1,体积比)分离纯化,得到化合物AA-1-2。
1H NMR(400MHz,DMSO-d
6)δ=7.05(J,1H)4.35-4.47(m,1H)3.73(s,3H)3.11(s,3H)1.38(s,9H)1.16(J,3H)。
步骤2:化合物AC-1-4的合成
在干燥的三口瓶中加入四氢呋喃(50mL),用氮气置换3次后,将体系温度降至-15℃,逐滴加入化合物AC-1-3(19.51g,107.63mmol),将化合物AA-1-2(10g,43.05mmol)加入四氢呋喃(150mL)中,缓慢加入上述体系(温度维持在-5℃左右),加料完毕,于25℃搅拌反应12小时。.反应完成,将反应液缓慢倒入饱和氯化铵溶液(50mL)中,用乙酸乙酯(300mL×3)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物AC-1-4。
步骤3:化合物AC-1-5的合成
将化合物AC-1-4(9g)加入甲苯(50mL)中,随后依次加入异丙醇(28.2g),异丙醇铝(3.69g),氮气保护下25℃搅拌1小时,升温至65℃搅拌反应12小时。反应完毕,减压浓缩,用乙酸乙酯(100mL)溶解,缓慢倒入搅拌的稀盐酸(1mol/L,100mL)中,分液,收集有机相,水相用乙酸乙酯萃取(150mL×3),合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物AC-1-5。
步骤4:化合物AC-1-6的合成
将化合物AC-1-5(8g,31.83mmol)溶于乙酸乙酯(90mL),加入盐酸/乙酸乙酯(4mol/L,30mL),在25℃下搅拌12小时。反应完毕,减压浓缩。粗品加甲基叔丁基醚(100mL),搅拌1小时,过滤,固体减压浓缩除去残留溶剂,得到化合物AC-1-6的盐酸盐。
1H NMR(400MHz,DMSO-d
6)δ=8.13(3H,br s)7.23-7.36(4H,m)7.19-7.40(1H,m)5.98(1H,d,J=4.6Hz)4.93(1H,t,J=3.6Hz)0.89(3H,d,J=7.2Hz)。
参考例5:化合物AD-1-6的合成
步骤1:化合物AD-1-2的合成
将化合物AD-1-1(100g)溶于二氯甲烷(1.0L),于25℃缓慢加入N,N’-羰基二咪唑(93.29g),加毕,在25℃搅拌12小时。然后加入N-甲基-N-甲氧基胺盐酸盐(56.12g),最后加入三乙胺(58.22g),氮气氛围下于25℃搅拌6小时。反应完毕,反应液用稀盐酸(1mol/L,1L×2)洗涤,分液。水相用二氯甲烷(1L×2)萃取,合并有机相。有机相分别用饱和碳酸氢钠水溶液(1L)洗涤,饱和食盐水(1L)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经柱层析(洗脱剂:石油醚/乙酸乙酯=10/1-2/1,体积比)纯化,得到化合物AD-1-2。
1H NMR(400MHz,DMSO-d
6)δ=6.78(d,J=8.8Hz,1H),4.30(m,1H),3.73(s,3H),3.11(s,3H),1.90(m,1H),1.37(s,9H),0.86(d,J=6.6Hz,3H),0.83(d,J=6.8Hz,3H)。
步骤2:化合物AD-1-4的合成
将化合物AC-1-3(3mol/L,96.03mL)加入干燥的三口瓶中,降温至0℃。然后将化合物AD-1-2(30g)溶于四氢呋喃(500mL)中,温度控制在5℃左右,缓慢加入到上述体系中,搅拌1小时。反应液升温至60℃继续搅拌1小时。反应完毕,将反应液缓慢倒入饱和氯化铵水溶液(500mL)中淬灭,分液,水相用乙酸乙酯(500mL×2)萃取。有机相合并,用饱和食盐水(500mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经柱层析(洗脱剂:石油醚/乙酸乙酯=10/1-3/1,体积比)分离纯化,得到化合物AD-1-4。
1H NMR(400MHz,DMSO-d
6)δ=8.01-7.92(m,2H),7.67-7.61(m,1H),7.56-7.49(m,2H),4.87(m,1H),2.08(m,1H),1.36(s,9H),0.85-0.86(m,3H),0.80-0.83(m,3H)。
步骤3:化合物AD-1-5的合成
将化合物AD-1-4(33g)加入异丙醇(118.42mL)和甲苯(300mL)中,然后加入异丙醇铝(24.30g)。氮气置换三次,在25℃下搅拌1小时,然后升温至60℃搅拌11小时。反应完毕,反应液减压浓缩。向残余物中加入乙酸乙酯(50mL),用盐酸(1mol/L)调节pH至5-6,分液后收集有机相。水相用乙酸乙酯(50mL×2)萃取。有机相合并,用饱和食盐水(100mL)洗涤,无水硫酸钠干 燥,过滤,滤液减压浓缩。粗品通过柱层析(洗脱剂:石油醚/乙酸乙酯=10/1-1/1,体积比)分离纯化,得到化合物AD-1-5。
1H NMR(400MHz,DMSO-d
6)δ=7.35-7.32(m,2H),7.24(t,J=7.6Hz,2H),7.17(br d,J=7.4Hz,1H),6.29(d,J=10.4Hz,1H),5.25(d,J=5.2Hz,1H),4.33(dd,J=5.2,9.4Hz,1H),3.52(dt,J=3.2,9.8Hz,1H),2.19(dt,J=3.2,7.0Hz,1H),1.16(s,9H),0.84(d,J=6.8Hz,3H),0.80(d,J=7.0Hz,3H)。
步骤4:化合物AD-1-6的合成
将化合物AD-1-5(31g)加入盐酸/乙酸乙酯(4mol/L,200mL)中,在25℃搅拌12小时。反应完毕,滤液减压浓缩至析出固体,过滤。滤饼用乙酸乙酯(20mL)分次淋洗,收集所得固体,得到化合物AD-1-6的盐酸盐。
1H NMR(400MHz,DMSO-d
6)δ=7.86(s,2H),7.29-7.41(m,5H),6.09(d,J=4.0Hz,1H),4.96(t,J=4.0Hz,1H),3.11(s,1H),1.74-1.61(m,1H),0.91(d,J=7.0Hz,6H)。
参考例6:化合物AA-1的合成
步骤1:化合物AA-1-8的合成
在干燥的反应瓶中加入中化合物AA-1-6(50g,盐酸盐),AA-1-7(87.65g)和正丁腈(1L)。然后依次加入N,N-二甲基甘氨酸(41.32g),碳酸铯(261.09g),最后加入碘化亚铜(25.44g),氮气置换三次后,在130℃条件下搅拌12小时。反应完毕后,体系加入水(1L)和氨水(100mL)搅拌淬灭。分液,水相用乙酸乙酯(1L×2)萃取,合并有机相。用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得到粗品。粗品经层析柱分离(流动相:二氯甲烷/甲醇=50/1-10/1,体积比)纯化得到化合物AA-1-8。
步骤2:化合物AA-1-10的合成
向干燥的单口瓶中加入化合物AA-1-8(43.5g)和N,N-二甲基甲酰胺(450mL),充分溶解后依次加入HOBt(30.34g),N,N-二异丙基乙胺(29.02g)和EDCI(64.57g)。加毕,最后加入AA-1-9(12.36g),在25℃下反应12小时。反应完毕,体系加入水(400mL)和乙酸乙酯(400mL),搅拌后分液。水相用乙酸乙酯(400mL×2)萃取,合并有机相。有机相用饱和食盐水(500mL×5)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经柱层析(流动相:石油醚/乙酸乙酯=5/1-1/1,体积比)分离纯化,得到化合物AA-1-10。
步骤3:化合物AA-1的合成
在干燥的瓶中加入化合物AA-1-10(43g)和二氯甲烷(450mL),搅拌至充分溶解后加入三氟乙酸(306.78g)。加料完毕,在25℃下搅拌12小时。反应完毕后,体系减压浓缩得到粗品。粗品加入二氯甲烷(200mL)溶解,用饱和碳酸氢钠水溶液调pH至8-9,分液,水相用二氯甲烷(100mL×2)萃取。合并有机相,用饱和食盐水(400mL)洗涤,无水硫酸钠干燥,减压浓缩得化合物AA-1。
参照参考例6的合成方法,用片段1替换AA-1-6,合成下表各参考例。
参考例9:化合物AD-1的合成
步骤1:化合物AD-1-8的合成
将化合物AD-1-6盐酸盐(10g)溶于正丁腈(20mL)中,加入碳酸铯(37.76g)搅拌1小时。然后依次加入化合物AA-1-7(12.68g),N,N-二甲基甘氨酸(5.98g),氮气置换后,加入碘化亚铜(3.68g),氮气置换三次,置于130℃油浴中搅拌15小时。反应完毕,加入水(30mL)和氨水(3mL),搅拌后分液,收集有机相,水相用乙酸乙酯(30mL×3)萃取。有机相合并,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经柱层析(洗脱剂:二氯甲烷/甲醇=20/1-5/1,体积比)分离纯化,得到化合物AD-1-8。
步骤2:化合物AD-1-10的合成
将化合物AA-1-9(1.28g),HOBt(2.85g)和N,N-二异丙基乙胺(4.09g)加入N,N-二甲基甲酰胺(40mL)中。然后加入EDCI(4.04g),最后加入化合物AD-1-8(4g)。反应液于25℃搅拌16小时。反应完毕,加入水(80mL),用乙酸乙酯(50mL×3)萃取,合并有机相。有机相用半饱和食盐水(100mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品通过快速柱层析(洗脱剂:石油醚/乙酸乙酯=20/1-5/1,体积比)分离纯化,得到化合物AD-1-10。
1H NMR(400MHz,DMSO-d
6)δ=8.24(d,J=10.2Hz,1H),7.91(s,1H),7.58(d,J=9.0Hz,1H),7.46(d,J=7.4Hz,2H),7.31-7.25(m,2H),7.23-7.17(m,1H),7.10-7.05(m,1H),7.00(s,1H),5.73(br d,J=7.4Hz,1H),5.25(d,J=9.4Hz,1H),4.20(dt,J=4.0,9.6Hz,1H),3.87-3.78(m,1H),3.74-3.64(m,1H),2.45-2.36(m,1H),2.35-2.27(m,1H),2.00(m,1H),1.94-1.86(m,1H),1.75-1.66(m,1H),1.55(d,J=3.4Hz,2H),1.38(t,J=19.4Hz,3H),0.94-0.88(m,6H)。
步骤3:化合物AD-1的合成
将化合物AD-1-10(600mg)溶于二氯甲烷(6mL)中。然后将三氟乙酸(5.08g,3.30mL)缓慢滴入体系中,25℃搅拌12小时。反应完毕后,反应液减压浓缩。粗产品溶于二氯甲烷(5mL),用饱和碳酸氢钠水溶液调节pH至8-9,分液。水相用二氯甲烷(5mL×3)萃取,合并有机相。有机相用饱和 食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经柱层析(洗脱剂:二氯甲烷:甲醇=20/1-5/1,体积比)分离纯化,得到化合物AD-1。
1H NMR(400MHz,DMSO-d
6)δ=12.86(s,1H),8.22(d,J=10.2Hz,1H),7.86(s,1H),7.47(d,J=7.0Hz,1H),7.18-7.42(m,5H),7.05-6.96(m,2H),5.24(d,J=9.6Hz,1H),4.19(dt,J=3.8,9.6Hz,1H),2.40(m,1H),1.43-1.33(m,3H),0.91(t,J=6.2Hz,6H)。
参考例13:化合物WX026-1的合成
步骤1:化合物WX026-1的合成
向预先干燥的单口瓶中加入化合物26-1A(500mg),氢溴酸(7.48g,40%水溶液),醋酸(3mL)和水(3mL),冷却至0-5℃下加入亚硝酸钠(280.83mg)。加料完毕,在0-5℃下反应0.5小时后,加入溴化亚铜(265.40mg),升温至80℃继续反应12小时。反应完成后,将反应液降至室温,减压浓缩得到粗品。向粗品中加入水(20mL),乙酸乙酯(20mL×3)萃取。合并有机相,饱和食盐水(50mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品用薄层层析(展开剂:石油醚/乙酸乙酯=5/1,体积比)分离纯化,得到化合物WX026-1。
1H NMR(400MHz,DMSO-d
6)δ=9.40(d,J=1.6Hz,1H),9.11(dd,J=1.4,4.5Hz,1H),8.34(d,J=4.6Hz,1H)。
MS–ESI m/z:198.9/200.9[M+H]
+。
参考例14:化合物WX027-1的合成
步骤1:化合物WX027-1的合成
向预先干燥好的拇指瓶中加入化合物27-1A(100mg),N-碘琥珀酰亚胺(207.75mg),溶于二氯甲烷(1mL),在0℃下加入醋酸(252.06mg)。加料完毕后在20℃下搅拌16小时。反应完毕,向反应液加水(5mL)稀释,二氯甲烷(5mL×3)萃取,合并有机相。有机相用饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到粗产物。粗品经薄层层析硅胶板(展开剂:二氯甲烷/甲醇=10/1,体积比)分离纯化,得到化合物WX027-1。
MS–ESI m/z:245.9[M+1]
+。
参考例15:化合物WX028-1的合成
步骤1:化合物WX028-1的合成
在预先干燥的圆底烧瓶中加入化合物28-1A(0.9g),丙二醛缩四甲醇(1.83g)和乙醇(10mL),然后加入醋酸(3.34g),反应液在100℃搅拌16小时。反应完毕,将反应液减压浓缩得到粗品。粗品加入水(30mL),用乙酸乙酯(30mL×3)萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品通过快速柱层析分离(洗脱剂:石油醚/乙酸乙酯=1/0-3/1,体积比),纯化得到化合物WX028-1。
1H NMR(400MHz,CDCl
3)δ=8.54(dd,J=0.76,7.04Hz,1H),8.43(dd,J=1.64,4.02Hz,1H),7.17-7.23(m,1H),6.68(s,1H)。
MS–ESI m/z:199.7[M+1]
+。
实施例1:化合物WX001的合成
步骤1:化合物WX001-4的合成
向预先干燥的三口瓶中加入化合物AA-1-6(30g),和AA-1-9(17.64g)溶于N,N-二甲基甲酰胺(80mL),依次缓慢加入HOBt(43.31g),EDCI(61.45g),N,N-二异丙基乙胺(62.14g),在30℃反应12小时。反应完成后,向反应液中加入饱和食盐水(100mL)和乙酸乙酯(150mL),搅拌后分液,收集有机相。有机相用无水硫酸钠干燥,过滤,减压浓缩,得到化合物WX001-4。
MS–ESI m/z:280.1[M+H]
+。
步骤2:化合物WX001-3的合成
向预先干燥的拇指瓶中加入化合物WX001-1(111.62mg),化合物WX001-2(50.0mg),醋酸铜(110.77mg),吡啶(48.24mg)和二氯甲烷(3mL)。反应瓶敞口在25-28℃反应15小时。反应结束后,向反应液中加入水(10mL),用乙酸乙酯(10mL×3)萃取,合并有机相。有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品用制备薄层层析(展开剂:石油醚/乙酸乙酯=5/1,体积比)分离纯化,得到化合物WX001-3。
1H NMR(400MHz,CDCl
3)δ=8.17-8.10(m,1H),8.06(s,1H),7.61(dd,J=1.6,8.8Hz,1H),7.44(s,1H),7.39(d,J=8.8Hz,1H),7.34(dd,J=2.4,8.5Hz,1H),6.90(d,J=8.4Hz,1H),4.67(t,J=8.6Hz,2H),3.30(t,J=8.7Hz,2H)。
MS–ESI m/z:363.0[M+H]
+。
步骤3:化合物WX001的合成
向预先干燥的拇指瓶中加入化合物WX001-3(50mg),化合物WX001-4(60mg),碘化亚铜(15.78mg),碳酸铯(161.94mg),N,N-二甲基甘氨酸(39.01mg)和正丁腈(5mL)。氮气氛围下升温至130℃搅拌12小时。反应完毕,将反应液降至室温,加入水(10mL)用乙酸乙酯(10mL×3)萃取。合并有机相,用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品经过制备HPLC(柱型:Phenomenex Luna C18 150mm×25mm 5μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:45%-65%,12 min)分离纯化,得到化合物WX001。
1H NMR(400MHz,CDCl
3)δ=7.96(s,1H),7.52(d,J=9.0Hz,1H),7.44(s,1H),7.33(dd,J=2.0,8.4Hz,1H),7.11(dd,J=2.2,9.0Hz,1H),7.00-6.93(m,2H),6.91(d,J=2.2Hz,1H),6.89(d,J=8.4Hz,1H),6.75(tt,J=2.2,8.8Hz,1H),6.69(d,J=8.6Hz,1H),5.35(d,J=2.8Hz,1H),4.66(t,J=8.6Hz,2H),4.43-4.33(m,1H),3.29(t,J=8.8Hz,2H),1.77(t,J=19.4Hz,3H),1.24(d,J=6.8Hz,3H)。
MS–ESI m/z:514.0[M+H]
+。
实施例2:化合物WX002的合成
向预先干燥的拇指瓶中加入化合物AA-1(70mg),化合物WX002-1(50.20mg),醋酸铜(64.32mg),吡啶(28.01mg)和N,N-二甲基甲酰胺(2mL),冷凝管敞口下在60℃反应12小时。反应完成后,将反应液降至室温后加入冰水(10mL),用乙酸乙酯(10mL×3)萃取。合并有机相,用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品经过制备HPLC(柱型:Phenomenex Luna C18 150mm×25mm 5μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:50%-70%,12min)分离纯化,得到化合物WX002。
1H NMR(400MHz,CDCl
3)δ=7.98(s,1H),7.54(d,J=9.0Hz,1H),7.37-7.28(m,2H),7.12(d,J=8.8Hz,1H),6.96(d,J=5.7Hz,2H),6.91(d,J=6.4Hz,2H),6.75(t,J=8.8Hz,1H),6.69(d,J=8.2Hz,1H),5.36(s,1H),4.45-4.33(m,1H),4.26-4.22(m,2H),2.86(t,J=6.2Hz,2H),2.09-2.02(m,2H),1.77(t,J=19.4Hz,3H),1.24(d,J=6.8Hz,3H)。
MS–ESI m/z:528.3[M+H]
+。
参照实施例2的合成方法,用片段1替换WX002-1,用片段2替换AA-1,合成下表各实施例。
实施例15:化合物WX015的合成
步骤1:化合物WX015-3合成
向预先干燥好的单口瓶中加入化合物WX015-1(12.18g),二氯甲烷(100mL),搅拌溶解后,加入化合物WX015-2(5.01g)和N,N’-羰基二咪唑(7.51g),20℃继续搅拌10分钟。反应完毕,向反应液中加水(100mL),有固体析出。过滤,真空干燥,得到化合物WX015-3。
MS–ESI m/z:354.1[M+H]
+。
步骤2:化合物WX015-4的合成
向预先干燥好的三口瓶中加入化合物WX015-3(1g)溶于乙醇(5mL)和稀盐酸(1mol/L,5mL) 的混合溶液中,由20℃缓慢升温至76℃反应10分钟,随后加入用水(1.5mL)溶解的亚硝酸钠(0.586g)溶液,76℃加热搅拌1小时。反应完毕,向反应液中加水(25mL)稀释,有固体析出,过滤,滤饼减压浓缩,得到粗品。粗品经打浆(石油醚/乙酸乙酯=10/1,体积比)纯化,得到化合物WX015-4。
MS–ESI m/z:337.0[M+H]
+。
步骤3:化合物WX015-5的合成
向预先干燥好的拇指瓶中加入化合物WX015-4(400mg)溶于二甲基亚砜(1mL),随后加入碳酸钾(493.42mg)和碘甲烷(506.74mg)。在30℃下搅拌2小时。反应完毕,向反应液加水(3mL)稀释,乙酸乙酯(3mL×3)萃取,合并有机相,用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到粗品。粗品经柱层析(洗脱剂:石油醚/乙酸乙酯=15/1至1/1,体积比)分离纯化,得到化合物WX015-5。
MS–ESI m/z:351.0[M+H]
+。
步骤4:化合物WX015的合成
向预先干燥好的拇指瓶中加入化合物WX001-4(80mg)溶于甲苯(1mL),随后加入碳酸铯(223.32mg),3,4,7,8-四甲基-1,10-菲罗啉(64.79mg),碘化亚铜(21.76mg)和化合物WX015-5(70.18mg),在85℃下搅拌6小时,然后升温110℃继续搅拌10小时。反应完毕,向反应液中加入水(5mL)稀释,乙酸乙酯(5mL×2)洗涤,合并有机相。有机相用饱和食盐水(15mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到粗品。粗品经过制备HPLC(柱型:Phenomenex Luna C18 150mm×25mm 5μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:60%-75%,12min)分离纯化,得到化合物WX015。
1H NMR(400MHz,CDCl
3)δ=7.64(d,J=7.8Hz,2H)7.58(d,J=9.0Hz,1H)7.48(t,J=7.8Hz,2H)7.22-7.26(m,1H)7.13(dd,J=9.0,2.2Hz,1H)6.97(d,J=6.0Hz,2H)6.89(d,J=1.8Hz,1H)6.76(t,J=8.82Hz,1H)6.64(d,J=7.6Hz,1H)5.36(d,J=2.8Hz,1H)4.35-4.43(m,1H)4.11(s,3H)1.78(t,J=19.2Hz,3H)1.24(d,J=6.8Hz,3H)。
MS–ESI m/z:502.2[M+H]
+。
实施例17:化合物WX017的合成
步骤1:化合物WX017-2的合成
在预先干燥的圆底烧瓶中加入化合物WX017-1(5g)和乙醇(50mL),然后加入水合肼(5.73g,98%含量),在80℃下搅拌2小时,后升温至100℃继续搅拌6小时。反应完毕,将反应液冷却至10℃左右,有大量固体析出,过滤,滤饼用乙醇淋洗。滤饼真空干燥得到化合物WX017-2。
MS–ESI m/z:236.0[M+H]
+。
步骤2:化合物WX017-3的合成
在干燥的单口瓶中加入化合物WX017-2(5g),溶于二氯甲烷(50mL),然后加入原甲酸三甲酯(9.03g)和三氟乙酸(2.43g),反应于20℃下搅拌2小时。反应完毕,向反应液中加入水(20mL),用碳酸钾固体调节pH=9-10,有大量固体析出。将反应液过滤,滤饼用二氯甲烷淋洗,真空干燥,得到化合物WX017-3。
MS–ESI m/z:245.9[M+H]
+。
步骤3:化合物WX017的合成
在预先干燥的拇指瓶中加入化合物AB-1(300mg),WX017-3(260.41mg),磷酸钾(300.80mg),氧化亚铜(56.36mg)和N,N-二甲基乙酰胺(3mL),反应于140℃反应16小时。反应完毕,向反应液加入水(50mL),乙酸乙酯(50mL)萃取,分液后收集有机相。水相用乙酸乙酯(20mL×2)萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,减压浓缩得到粗品。粗品通过薄层层析(展开剂:乙酸乙酯)分离纯化,再经过制备HPLC(柱型:Phenomenex Luna C18 150mm×25mm5μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:40%-45%,12min)纯化,得到化合物WX017。
1H NMR(400MHz,CD
3OD)δ=9.53(s,1H),9.33(s,1H),8.61(d,J=9.80Hz,1H),8.25(s,1H),8.21(d,J=9.92Hz,1H),7.94(d,J=9.16Hz,1H),7.34(dd,J=2.2,9.2Hz,1H),7.27(d,J=2.2Hz,1H),7.12(d,J=6.0Hz,2H),6.82-6.88(m,1H),5.35(d,J=9.2Hz,1H),4.36(dt,J=4.4,9.6Hz,1H),2.38-2.53(m,1H),1.56(t,J=19.0Hz,3H),1.03(t,J=7.4Hz,6H)。
MS–ESI m/z:541.2[M+H]
+。
实施例18:化合物WX018的合成
步骤1:化合物WX018-2的合成
向预先干燥好的单口瓶中加入化合物AD-1(4g)溶于N,N-二甲基甲酰胺(40mL)中,然后加入醋酸铜(3.75g),化合物WX018-1(2.91g)和吡啶(2.45g)。在氧气保护下(15psi),60℃搅拌16小时。反应完毕,将反应液倒入水(50mL)和氨水(50mL),乙酸乙酯(50mL×3)萃取,合并有机相。有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品柱层析(洗脱剂:石油醚/乙酸乙酯=1/0-9/1,体积比),纯化得到化合物WX018-2。
1H NMR(400MHz,CDCl
3)δ=8.48(d,J=1.4Hz,1H)7.99-8.05(m,1H)7.93(s,1H)7.84-7.90(m,1H)7.45(d,J=9.2Hz,1H)7.18-7.36(m,5H)6.99-7.00(m,2H)6.24(d,J=10.0Hz,1H)5.20(d,J=5.8Hz,1H)4.34(dt,J=10.4,5.2Hz,1H)1.98-2.08(m,1H)1.59(t,J=19.4Hz,3H)0.95(dd,J=6.6,4.4Hz,6H)。
步骤2:化合物WX018-3的合成
向预先干燥好的拇指瓶中加入化合物WX018-2(300mg),溶于乙醇(3mL),随后加入水合肼(158.81mg,98%含量),在80℃下搅拌20小时。反应完毕,将反应液减压浓缩,得到化合物WX018-3。
步骤3:化合物WX018的合成
向预先干燥好的拇指瓶中加入化合物WX018-3(300mg),溶于二氯甲烷(3mL),随后加入原甲酸三甲酯(257.50mg)和三氟乙酸(69.17mg)。在20℃搅拌8小时。反应完毕,向反应液加水(5mL),二氯甲烷(5mL×3)萃取,合并有机相。有机相用饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到粗产物。粗品经制备HPLC(柱型:Luna C18 100mm×30mm 5μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:38%-52%,10min)分离纯化,得到化合物WX018。
1H NMR(400MHz,CD
3OD)δ=9.36(s,1H)9.09(s,1H)8.21-8.26(m,1H)8.11-8.16(m,1H)8.02(d,J=9.8Hz,1H)7.80(d,J=9.2Hz,1H)7.48(d,J=7.4Hz,2H)7.27-7.33(m,2H)7.23-7.26(m,2H)7.20(d,J=1.8Hz,1H)5.31(d,J=9.0Hz,1H)4.35-4.44(m,1H)2.40-2.50(m,1H)1.40(t,J=19.0Hz,3H)1.02(dd,J=6.8,4.6Hz,6H)。
MS–ESI m/z:505.1[M+1]
+。
参照实施例18的合成方法,用片段1替换WX018-1,用片段2替换AD-1,合成下表各实施例。
实施例24:化合物WX024的合成
步骤1:化合物WX024的合成
向预先干燥好的拇指瓶中加入化合物WX018-2(300mg)溶于二甲基亚砜(3mL),随后加入叠氮钠(121.26mg)。加料完毕,在120℃下搅拌20小时。反应完毕,冷却至室温后,将反应液倒入氨水(5mL)和水(15mL),乙酸乙酯(20mL×3)萃取,合并有机相。有机相用饱和食盐水(30mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到粗产品。粗品经制备HPLC分离纯化,分离条件:柱型: Luna C18 100mm×30mm 5μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:45%-70%,10min,得到化合物WX024。
1H NMR(400MHz,CDCl
3)δ=9.17(s,1H)8.22-8.26(m,1H)8.15-8.19(m,1H)8.09(s,1H)7.67(d,J=9.0Hz,1H)7.37-7.45(m,4H)7.31-7.36(m,1H)7.25(d,J=2.2Hz,1H)7.05(d,J=2.0Hz,1H)6.32(d,J=10.8Hz,1H)5.31(d,J=5.8Hz,1H)4.43(dt,J=10.30,5.2Hz,1H)2.07-2.16(m,1H)1.69(t,J=19.4Hz,3H)1.04(d,J=6.8Hz,6H)。
MS–ESI m/z:506.1[M+1]
+。
实施例25:化合物WX025的合成
步骤1:化合物WX025-2的合成
在预先干燥的拇指瓶中加入化合物AD-1(500mg)和N,N-二甲基甲酰胺(5mL),在0℃下加入氢化钠(103.24mg,60%纯度)和化合物WX025-1(384.54mg),反应升温至20℃搅拌1小时。反应完毕,向反应液加入水(20mL),用乙酸乙酯(20mL×3)萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品经快速柱层析分离纯化(洗脱剂:石油醚/乙酸乙酯=1/0-5/1,体积比),得到化合物WX025-2。
1H NMR(400MHz,CDCl
3)δ=9.04(d,J=1.26Hz,1H),8.41(d,J=9.2Hz,1H),8.26-8.36(m,1H),7.96(s,1H),7.24-7.37(m,5H),7.13(dd,J=2.4,9.2Hz,1H),6.90(d,J=2.2Hz,1H),6.25(d,J=10.4Hz,1H),5.15-5.30(m,1H),4.34(td,J=5.2,10.4Hz,1H),1.96-2.09(m,1H),1.59(t,J=19.4Hz,3H),0.90-0.99(m,6H)。
MS–ESI m/z:500.0[M+1]
+。
步骤2:化合物WX025-3的合成
在预先干燥的圆底烧瓶中加入化合物WX025-2(370mg)和乙醇(5mL),反应降到0℃,缓慢加入水合肼(189.03mg,183.52μL,98%含量),加料完毕,将反应液升温至80℃搅拌16小时。反应完毕,将反应液减压浓缩得到粗品化合物WX025-3。
1H NMR(400MHz,CDCl
3)=9.12(d,J=1.4Hz,1H),8.49(d,J=9.00Hz,1H),8.35-8.42(m,1H),8.03-8.14(m,1H),7.28-7.45(m,3H),7.27-7.45(m,1H),7.07-7.24(m,1H),6.98(d,J=2.4Hz,1H),6.82(br s,2H),6.34(br s,1H),5.25-5.30(m,1H),4.42(td,J=4.84,10.4Hz,1H),2.07-2.17(m,1H),1.67(dt,J=1.8,19.4Hz,3H),0.98-1.06(m,5H)。
步骤3:化合物WX025的合成
在预先干燥的拇指瓶中加入化合物WX025-3(250mg)和二氯甲烷(3mL),将反应体系降到0℃,加入原甲酸三甲酯(214.16mg)和三氟乙酸(57.53mg)。然后升温至20℃搅拌4小时。反应完毕,向反应液加入水(10mL),二氯甲烷(10mL×3)萃取。有机相合并,用饱和食盐水(20mL)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品。粗品经制备HPLC纯化(柱型:Luna C18 100mm×30mm 5μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:40%-55%,10min),得到化合物WX025。
1H NMR(400MHz,CD
3OD)=9.41(d,J=10.8Hz,2H),8.97(s,1H),8.41(d,J=9.2Hz,1H),8.07(s,1H),7.49(br d,J=7.2Hz,2H),7.27-7.36(m,2H),7.18-7.27(m,2H),7.13(d,J=2.2Hz,1H),5.28(d,J=9.2Hz,1H),4.34-4.44(m,1H),2.47(qd,J=6.8,11.2Hz,1H),1.40(t,J=19.0Hz,3H),1.02(dd,J=4.6,6.8Hz,6H)。
MS–ESI m/z:506.2[M+1]
+。
实施例26:化合物WX026的合成
步骤1:化合物WX026的合成
在预先干燥的单口瓶中加入化合物AD-1(155.74mg),化合物WX026-1(80mg),磷酸钾(170.66mg),N,N-二甲基-1,2-环己基二胺(57.18mg)和N,N-二甲基甲酰胺(1mL)。置换氮气三次后,加入碘化亚铜(38.28mg)。反应液升温至65℃反应12小时。反应完成后,将反应液降至室温。向反应液 中加入水(10mL),乙酸乙酯(10mL×3)萃取,合并有机相。有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品经制备HPLC(柱型:Phenomenex Luna C18 100mm×30mm 5μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:35%-65%,10min)分离纯化,得到化合物WX026。
1H NMR(400MHz,CDCl
3)δ=9.32(s,1H),8.65(s,1H),8.49(d,J=9.2Hz,1H),8.28(s,2H),7.47-7.41(m,2H),7.38(t,J=7.4Hz,2H),7.32(t,J=7.0Hz,2H),7.02(s,1H),6.32(d,J=9.6Hz,1H),5.30(d,J=5.8Hz,1H),4.43(td,J=5.2,10.12Hz,1H),2.18-2.08(m,1H),1.67(t,J=19.4Hz,3H),1.04(t,J=6.4Hz,6H)。
MS–ESI m/z:506.2[M+H]
+。
参照实施例26的合成方法,用片段1替换WX026-1,用片段2替换AD-1,合成下表各实施例。
实施例31:化合物WX031的合成
步骤1:化合物WX031-2的合成
在预先干燥的圆底烧瓶中加入化合物AD-1(5g),化合物WX031-1(2.88g)和N,N-二甲基甲酰胺(20mL),然后加入吡啶(5.10g)和无水乙酸铜(4.69g),氧气置换三次,在氧气(15psi)保护下于60℃搅拌12小时。反应完毕,向反应液加入二氯甲烷(30mL),水(30mL)和氨水(5mL)混合溶液洗涤,分液后收集有机相。水相用二氯甲烷(20mL×2)萃取,合并有机相。有机相用饱和食盐水(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品经自动过柱机COMBI-FLASH分离纯化(80g
Silica Flash Column,洗脱剂:0~20%EA/PE,流速:60mL/min),得到化合物WX031-2。
1H NMR(400MHz,DMSO-d
6)δ=8.62(d,J=1.6Hz,1H),8.29-8.39(m,1H),8.18-8.29(m,2H),7.74(d,J=9.0Hz,1H),7.50(d,J=7.2Hz,2H),7.36-7.42(m,1H),7.25-7.33(m,2H),7.12-7.25(m,3H),5.33(d,J=9.4Hz,1H),4.23(dt,J=4.0,9.8Hz,1H),2.35-2.45(m,1H),1.39(t,J=19.4Hz,3H),0.93(t,J=6.2Hz,6H)。
步骤2:化合物WX031-3的合成
在预先干燥的反应瓶中加入化合物WX031-2(600mg)和乙醇(6mL),加入水合肼(635.22mg,616.72μL,98%含量),在80℃搅拌12小时。反应完毕,将反应液减压浓缩得到粗品化合物WX031-3。
1H NMR(400MHz,DMSO-d
6)δ=8.20-8.31(m,2H),8.10(s,1H),7.75(s,1H),7.71(dd,J=2.20,8.8Hz,1H),7.43-7.53(m,3H),7.29(br t,J=7.4Hz,2H),7.22(br d,J=7.2Hz,1H),7.04-7.14(m,2H),6.86(d,J=9.0Hz,1H),5.30(br d,J=9.4Hz,1H),4.21(br dd,J=5.8,9.4Hz,1H),2.41(br dd,J=6.8,11.2Hz,1H),1.39(br t,J=19.4Hz,3H),0.92(br t,J=6.4Hz,6H)。
步骤3:化合物WX031的合成
在预先干燥的反应瓶中加入化合物WX031-3(200mg)和二氯甲烷(2mL),然后加入三乙胺(122.77mg),氮气置换三次,在0℃加入双(三氯甲基)碳酸酯(60.01mg),加料完毕在30℃下搅拌1小时。反应完毕,向反应液加入水(10mL),用乙酸乙酯(10mL×5)萃取。有机相合并,用饱和食盐 水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品经制备HPLC(柱型:Luna C18 100mm×30mm 5μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:43%-58%,10min)纯化,得到化合物WX031。
1H NMR(400MHz,DMSO-d
6)δ=12.67(s,1H),8.26(d,J=9.80Hz,1H),8.22(s,1H),8.04(s,1H),7.67(d,J=9.16Hz,1H),7.55(d,J=10.92Hz,1H),7.49(d,J=7.28Hz,2H),7.41(d,J=10.04Hz,1H),7.26-7.33(m,2H),7.21(dd,J=8.06,15.06Hz,2H),7.13(s,1H),5.31(d,J=9.40Hz,1H),4.17-4.27(m,1H),2.41(d,J=4.64Hz,1H),1.39(t,J=19.38Hz,3H),0.92(t,J=6.22Hz,6H)。
MS–ESI m/z:521.2[M+1]
+。
实施例32:化合物WX032的合成
步骤1:化合物WX032的合成
在预先干燥的反应瓶中加入化合物WX031(100mg),碘化钠(115.19mg)和乙腈(1mL),然后滴加碘甲烷(81.80mg),反应于80℃搅拌48小时。反应完毕,向反应液加入饱和氯化铵溶液(10mL),乙酸乙酯(10mL×3)萃取,合并有机相。有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品。粗品通过薄层层析硅胶板(展开剂:乙酸乙酯)纯化,得到化合物WX032。
1H NMR(400MHz,CDCl
3)δ=8.09(s,1H),8.02(s,1H),7.61(dd,J=9.54,15.94Hz,2H),7.38-7.49(m,4H),7.33-7.37(m,1H),7.30(d,J=4.02Hz,1H),7.21(d,J=9.16Hz,1H),7.02(s,1H),6.36(d,J=9.54Hz,1H),5.31(d,J=5.78Hz,1H),4.45(td,J=4.96,10.16Hz,1H),3.76(s,3H),2.16(dd,J=6.54,11.80Hz,1H),1.71(t,J=19.26Hz,3H),1.07(t,J=6.20Hz,6H)。
MS–ESI m/z:535.2[M+1]
+。
实施例33:化合物WX033的合成
步骤1:化合物WX033-2的合成
在预先干燥的反应瓶中加入化合物WX031-2(400mg)和二甲基亚砜(4mL),然后加入盐酸羟胺(288.05mg)和碳酸氢钠(348.22mg),反应于90℃搅拌12小时。反应完毕,向反应液加水(20mL),二氯甲烷(20mL×3)萃取,合并有机相。有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品。粗品通过自动过柱机COMBI-FLASH分离(20g
Silica Flash,流动相0~70%EA/PE@35mL/min)纯化,得到化合物WX033-2。
1H NMR(400MHz,DMSO-d
6)δ=9.00(s,1H),8.77(d,J=1.52Hz,1H),8.35(d,J=2.38Hz,1H),8.26(d,J=9.92Hz,1H),8.15(s,1H),7.89(dd,J=2.64,8.92Hz,1H),7.55(d,J=8.92Hz,1H),7.48(d,J=7.16Hz,2H),7.27-7.34(m,2H),7.22(d,J=7.28Hz,1H),7.08-7.15(m,2H),6.98(d,J=8.92Hz,1H),5.29(d,J=9.54Hz,1H),4.21(dt,J=4.08,9.76Hz,1H),2.37-2.43(m,1H),1.38(t,J=19.46Hz,3H),0.91(t,J=6.54Hz,6H)。
MS–ESI m/z:496.2[M+1]
+。
步骤2:化合物WX033的合成
在预先干燥的反应瓶中加入化合物WX033-2(120mg)和二氯甲烷(2mL),然后加入三乙胺(73.52mg),氮气置换三次,之后在0℃加入三光气(35.93mg),在氮气氛围下于30℃搅拌0.5小时。反应完毕,向反应液加入水(10mL),乙酸乙酯(10mL×5)萃取,合并有机相。有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品。粗品通过薄层层析硅胶板(展开剂:乙酸乙酯)纯化,得到WX033。
1H NMR(400MHz,DMSO-d
6)δ=8.28-8.37(m,2H),8.14(s,1H),7.81(d,J=9.30Hz,1H),7.75(d,J=9.16Hz,1H),7.55(d,J=7.40Hz,2H),7.49(d,J=10.04Hz,1H),7.32-7.40(m,2H),7.28(t,J=6.96Hz,2H),7.19(s,1H),5.38(d,J=9.40Hz,1H),4.22-4.35(m,1H),2.42-2.50(m,1H),1.45(t,J=19.38Hz,3H),0.98(t,J=5.84Hz,6H)。
MS–ESI m/z:522.2[M+1]
+。
实施例34:化合物WX034的合成
步骤1:化合物WX034的合成
将化合物AA-1(500mg)溶于甲苯(10mL),依次加入化合物WX034-1(375.6mg),2-二叔丁基膦-2’,4’,6’-三异丙基联苯(107.4mg),叔丁醇钠(364.6mg)和三(二亚苄基丙酮)二钯(115.8mg),反应在120℃氮气氛围下搅拌12小时。反应完毕后,将反应液降温至50℃,过滤,滤饼用乙酸乙酯(50mL×2)洗涤,滤液减压浓缩得到粗品。粗品通过制备HPLC(柱型:Phenomenex Luna C18 100×30mm×5μm;流动相:[H
2O(10mM NH
4HCO
3)-ACN];B(ACN)%:35%-55%,10min)分离纯化,得到化合物WX034。
1H NMR(400MHz,DMSO-d
6)δ=9.46(s,1H)8.78(d,1H)8.63(s,1H)8.32(s,1H)8.02-8.10(m,2H)7.84(d,1H)7.21-7.29(m,2H)7.12-7.16(m,2H)5.30(d,1H)4.19-4.30(m,1H)1.58(t,3H)1.35(d,3H)。
MS–ESI m/z:512.5.[M+H]
+。
实施例35:化合物WX035的合成
步骤1:化合物WX035-2的合成
将化合物AA-1(500mg)溶于甲苯(25mL),依次加入WX035-1(244.8mg),三(二亚苄基丙酮)二钯(231.6mg),叔丁醇钠(243.1mg)和2-二叔丁基膦-2’,4’,6’-三异丙基联苯(107.4mg),反应在110℃氮气氛围下搅拌12小时。反应完毕后,将反应液过滤,滤饼用乙酸乙酯(50mL×2)洗涤,滤液减压浓缩得到粗品。粗品经制备HPLC(柱型:Phenomenex Luna C18 100mm×30mm×5μm;流动相:[H
2O(0.04%HCl)-ACN];B(ACN)%:40%-70%,10min)分离纯化,得到化合物WX035-2。
MS–ESI m/z:491.2[M+H]
+。
步骤2:化合物WX035的合成
将化合物WX035-2(200mg)溶于二甲基亚砜(3mL),然后加入叠氮钠(79.5mg),在氮气氛围下130℃反应12小时。反应完毕,将反应液冷却至室温后,倒入稀释的次氯酸钠水溶液(20mL)中,加入乙酸乙酯(20mL×3)萃取,分液,合并有机相。有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品经制备HPLC(柱型:Phenomenex Luna C18 100mm×30mm×5μm;流动相:[H
2O(0.04%HCl)-ACN];B(ACN)%:35%-65%,10min)分离纯化,得到化合物WX035。
MS–ESI m/z:514.1[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ=9.80(s,1H)8.36(d,J=10.0Hz,1H)8.34(s,1H)8.29(d,J=10.0Hz,1H)7.95(d,J=8.0Hz,1H)7.26(d,J=9.20Hz,1H)7.21(s,1H)7.09(d,J=8.0Hz,3H)5.26(d,J=7.4Hz,1H)4.12-4.27(m,1H)1.53(t,J=19.6Hz,3H)1.31(d,J=8.0Hz,3H)。
参照实施例35的合成方法,用片段1替换WX035-1,合成下表各实施例。
实施例37:化合物WX037的合成
步骤1:化合物WX037-1的合成
将化合物AA-1(2g)和化合物WX018-1(0.72g)溶于N,N-二甲基甲酰胺(20mL),加入吡啶(2.00g),无水醋酸铜(1.84g),氧气置换三次,氧气保护下(15psi)升温至60℃搅拌反应12小时。反应完毕,反应液倒入水中(50mL),加乙酸乙酯(20mL)萃取。有机相用半饱和食盐水(50mL)洗涤,饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液45℃减压浓缩。残余物通过柱层析分离纯化(洗脱剂:石油醚/乙酸乙酯=9/1–7/3,体积比),得到化合物WX037-1。
MS–ESI m/z:491.1[M+H]
+。
步骤2:化合物WX037-2的合成
将化合物WX037-1(300mg)加入乙醇(3mL)中,向其中缓慢加入水合肼(312.48mg,98%含量),80℃搅拌反应2小时。反应完毕,反应液50℃减压浓缩,得到化合物WX037-2。
MS–ESI m/z:503.1[M+H]
+。
步骤3:化合物WX037的合成
将化合物WX037-2(307.36mg)溶于二氯甲烷(5mL),氮气置换后,0℃下加入原乙酸三乙酯(396.95mg)和三氟乙酸(69.75mg),在20℃下搅拌12小时。反应完毕,向反应液中加水(10mL), 用二氯甲烷(5mL×3)萃取,合并有机相。有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品。粗品经制备HPLC(柱型:Luna Omega 5μm Polar C18 100A;流动相:[H
2O(0.04%HCl)-ACN];B(ACN)%:32%-48%,7min)分离纯化,得到化合物WX037。
1H NMR(400MHz,DMSO-d
6)δ=8.91(s,1H),8.73(d,J=8.8Hz,1H),8.32(s,1H),7.88-8.04(m,3H),7.22-7.29(m,2H),7.09-7.18(m,3H),5.30(d,J=7.6Hz,1H),4.19-4.29(m,1H),2.79(s,3H),1.56(t,J=19.6Hz,3H),1.34(d,J=6.4Hz,3H)。
MS–ESI m/z:527.1[M+H]
+。
参照实施例37的合成方法,用片段1替换WX018-1,合成下表各实施例。
实施例39:化合物WX039的合成
将化合物AA-1(200mg)和化合物WX039-1(147.24mg)溶于N,N-二甲基甲酰胺(2mL)中,向其中加入醋酸铜(183.77mg),吡啶(160.06mg),氧气置换三次,氧气氛围下(15psi)于100℃搅拌反应12小时。反应完毕,将反应液倒入水(10mL)中,加入氨水(1mL),加乙酸乙酯(10mL×3)萃取。有机相合并,依次用半饱和食盐水(20mL×2)洗,饱和食盐水(30mL)洗,无水硫酸钠干燥,过滤,滤液45℃减压浓缩。粗品经制备HPLC(柱型:Welch Xtimate C18 150×25mm×5μm;流动相:[H
2O(0.04%HCl)-ACN];B(ACN)%:35%-55%,8min)分离纯化,得到目标化合物WX039。
1H NMR(400MHz,DMSO-d
6)δ:8.74(d,J=8.4Hz,1H),8.33(s,1H),8.16(s,1H),7.82(s,1H),7.75 (d,J=9.2Hz,1H),7.23(dd,J=9.2,2.0Hz,1H),7.08-7.20(m,4H),7.03(d,J=0.8Hz,1H),5.26(d,J=7.2Hz,1H),4.17-4.29(m,1H),1.56(t,J=19.6Hz,3H),1.34(d,J=6.8Hz,3H)。
MS–ESI m/z:462.1[M+H]
+。
参照实施例39的合成方法,用片段1替换WX039-1,用片段2替换AA-1,合成下表各实施例。
实施例48:化合物WX048的合成
步骤1:化合物WX048的合成
在预先干燥好的单口瓶中加入化合物AG-1(0.3g),5-溴[1,2,4]三唑并[1,5-A]吡啶(174.14mg),加入甲苯(3mL)溶解,然后加入叔丁醇钠(211.28mg),2-二叔丁基膦-2’,4’,6’-三异丙基联苯(62.24mg),氮气置换三次,加入三(二亚苄基丙酮)二钯(134.21mg),氮气置换三次后,升温至90℃反应16小时。反应结束后,反应液降至室温,加入到水(20mL)中,用乙酸乙酯(10mL×3)萃取。合并有机相,依次用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩至干。粗品经柱层析(洗脱剂:石油醚/乙酸乙酯=5/1至0/1,体积比)纯化后,经制备HPLC(柱型:Welch Xtimate C18 150×25mm×5μm;流动相:[H
2O(0.04%HCl)-ACN];B(ACN)%:30%-50%,8min)分离纯化,得到WX048。
1H NMR(400MHz,CD
3OD)δ=8.56(s,1H),8.29(s,1H),7.97-7.94(m,2H),7.49(dd,J=3.0,5.6Hz,1H),7.32-7.26(m,1H),7.25-7.19(m,2H),7.07(br d,J=6.2Hz,2H),6.90-6.82(m,1H),5.27(d,J=7.0Hz,1H),4.18(ddd,J=3.0,7.2,10.4Hz,1H),2.04-1.95(m,1H),1.74(ddd,J=7.2,11.0,14.0Hz,1H), 1.60(t,J=19.2Hz,3H),0.97(t,J=7.4Hz,3H)。
MS-ESI m/z:527.3[M+H]
+。
实施例49:化合物WX049的合成
步骤1:化合物WX049的合成
在干燥的单口瓶中加入AA-1(0.2g)和N,N-二甲基甲酰胺(8mL),然后依次加入WX049-1(99.57mg),磷酸钾(214.77mg)和碘化亚铜(48.17mg)和(1R,2R)-(-)-N,N-二甲基环己烷-1,2-二胺(71.96mg),氮气置换三次,90℃下反应12小时。反应完毕,向反应液中加入氨水(3mL)和水(10mL),搅拌30min,过滤。滤液加入乙酸乙酯(15mL)萃取,有机相用饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品。粗品经制备HPLC(柱型:Phenomenex luna C18 80*40mm*3μm;流动相:[H
2O(0.04%HCl)-ACN];B(ACN)%:57%-77%,7min)分离纯化,得到化合物WX049。
1H NMR(400MHz,CD
3OD)δ=1.35(d,J=6.64Hz,3H)1.57(t,J=19.52Hz,3H)4.24(br dd,J=15.32,6.90Hz,1H)5.28(d,J=7.28Hz,1H)7.12(br d,J=7.78Hz,3H)7.16-7.23(m,2H)7.32(br s,1H)7.73(s,1H)8.27(br d,J=8.66Hz,1H)8.77(br d,J=8.54Hz,1H)9.28(s,1H)。
MS–ESI m/z:479.1[M+H]
+。
参照实施例49的合成方法,用片段1替换WX049-1,用片段2替换AA-1,合成下表各实施例。
实施例58:化合物WX058的合成
步骤1:化合物WX058-3的合成
在预先干燥的圆底烧瓶中加入WX058-2(196.08mg)和WX058-1(0.5g),溶于四氢呋喃(15mL),依次加入N,N,N',N'-四甲基偶氮二甲酰胺(665.55mg)和三丁基膦(782.01mg)。氮气置换三次后,20℃下反应12小时。反应完毕,向反应液中加入水(30mL),用乙酸乙酯(20mL×2)萃取。有机相合并后用饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗产品通过柱层析分离(洗脱剂:石油醚/乙酸乙酯=3/1至1/1,体积比),得到WX058-3。
步骤2:化合物WX058的合成
在预先干燥的拇指瓶中加入化合物AA-1(0.5g)和化合物WX058-3(317.67mg),溶于N,N-二甲基甲酰胺(10mL),依次加入和醋酸铜(457.71mg)和吡啶(498.33mg),氧气置换三次,80℃反应12小时。反应完毕,向反应液中加入氨水(3mL)和水(10mL),搅拌30min,过滤。滤液加入乙酸乙酯(20mL)萃取,有机相合并后用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗产品经制备HPLC(柱型:Phenomenex luna C18 250×50mm×10μm;流动相:[H
2O(0.1%TFA)-ACN];B(ACN)%:40%-60%,10min)分离纯化,向溶液中加入0.2mL浓盐酸,冻干得到WX058。
1H NMR(400MHz,CD
3OD)δ=8.12(s,1H),8.00(s,1H),7.88(s,1H),7.53(d,J=9.12Hz,1H),7.24(dd,J=9.12,2.24Hz,1H),7.01-7.12(m,3H),6.79-6.92(m,1H),5.27(d,J=6.38Hz,1H),4.38(t,J=5.08Hz,2H),4.29-4.35(m,1H),3.79(t,J=5.00Hz,2H),3.35(s,3H),1.60(t,J=19.08Hz,3H),1.38(d,J=6.76Hz,3H)。
MS–ESI m/z:520.2[M+H]
+。
实施例59:化合物WX059的合成
参照参考例4中AC-1-6盐酸盐的合成方法,合成AH-1-6的盐酸盐。
步骤1:化合物AH-1的合成
将AH-1-6(1g,盐酸盐)和2,2-二氟丙酸(654.81mg)加入乙酸乙酯(15mL)中,在0-5℃加入N-甲基吗啡啉(2.51g),滴加三正丙基环磷酸酐50%乙酸乙酯溶液(4.73g,4.42mL),20℃搅拌反应2小时。反应完毕,反应液倒入水(15mL)中,加乙酸乙酯(10mL×3)萃取。有机相合并后,加饱和食盐水(30mL)洗,无水硫酸钠干燥,过滤,滤液45℃减压浓缩。粗品加(石油醚/乙酸乙酯=3/1,体积比,20mL)的混合溶剂打浆,过滤,收集固体,得到AH-1。
1H NMR(400MHz,DMSO-d
6)δ:8.22(d,J=9.2Hz,1H),7.25-7.34(m,4H),7.17-7.23(m,1H),5.46(s,1H),4.48(d,J=7.6Hz,1H),3.69-3.82(m,1H),1.73-1.83(m,1H),1.49-1.55(m,1H),1.39-1.49(m,3H),0.77(t,J=7.4Hz,3H)。
步骤2:化合物AH-2的合成
在干燥的单口瓶中将5-碘-1H吲唑(5g)和4-溴-1-甲基-1H-1,2,3-三氮唑(4.31g)加入到1,4-二氧六环(100mL)中,再加入碳酸钾(8.50g)和(1R,2R)-N,N-二甲基-1,2-环己二胺(1.46g),氮气保 护下加入碘化亚铜(2.73g),加料完毕,置换氮气三次,110℃反应6小时。将反应液过滤,向滤液中加入水(500mL),分液,水相用乙酸乙酯(200mL×2)萃取。合并有机相,用饱和食盐水(300mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干。柱层析纯化(硅胶目数:100-200目,洗脱剂:石油醚/乙酸乙酯=10/1-1/1,体积比)得到AH-2。
1H NMR(400MHz,DMSO-d
6)δ=8.49(s,1H),8.33(d,J=14.00Hz,2H),8.06(d,J=8.76Hz,1H),7.81(dd,J=8.82,1.32Hz,1H),4.15(s,3H)。
步骤3:化合物WX059的合成
将化合物AH-1(400mg)和AH-2(505.46mg)加入N,N-二甲基乙酰胺(8mL)中,加入碳酸铯(1.52g),N,N-二甲基甘氨酸(160.33mg),氮气置换后,加入碘化亚铜(296.10mg),氮气置换三次,氮气保护下升温至125℃搅拌反应16小时。反应完毕,将反应液倒入水(20mL)中,加乙酸乙酯(10mL×3)萃取。有机相合并,加半饱和食盐水(30mL×2)洗,饱和食盐水(30mL)洗,无水硫酸钠干燥。过滤,滤液45℃减压浓缩。粗品经制备HPLC(柱型:Welch Xtimate C18 100×25mm×3μm;流动相:[H
2O(0.05%HCl)-ACN];B(ACN)%:30%-60%,8min)分离,得到目标化合物WX059。
1H NMR(400MHz,CD
3OD)δ=8.15(s,1H),8.03(d,J=9.2Hz,1H),8.01(s,1H),7.44-7.42(m,2H),7.34-7.30(m,2H),7.22-7.29(m,2H),7.06(d,J=2.4Hz,1H),5.23(d,J=6.8Hz,1H),4.18-4.25(m,1H),4.17(s,3H),1.93-2.05(m,1H),1.78-1.70(m,1H),1.49(t,J=19.0Hz,3H),0.95(t,J=7.6Hz,3H)。
MS–ESI m/z:455.2[M+H]
+。
实施例60:化合物WX060的合成
参照参考例4中AA-1-6的合成方法,合成AI-1-6的盐酸盐。
步骤1:化合物AI-1的合成
将AI-1-6(1.57g,盐酸盐)和2,2-二氟丙酸(881.11mg)加入乙酸乙酯(20mL)中,0℃加入N-甲基吗啡啉(3.68g),滴加正丙基磷酸酐的50%乙酸乙酯溶液(6.95g,6.49mL),20℃搅拌反应2小时。反应完毕,将反应液倒入水(50mL)中,分层,收集有机相。水相用乙酸乙酯(20mL)萃取,合并有机相。有机相用饱和食盐水(50mL)洗,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品加(石油醚/乙酸乙酯=3/1,体积比,30mL)的混合溶剂搅拌30分钟。过滤,收集固体,真空干燥,得到AI-1。
步骤2:化合物WX060的合成
将AI-1(300mg)和AH-2(359.50mg)加入N,N-二甲基乙酰胺(6mL)中,加入碳酸铯(1.08g),N,N-二甲基甘氨酸(114.03mg)。氮气置换后,加入碘化亚铜(210.60mg),氮气保护下升温至125℃搅拌反应16小时。反应完毕,将反应液倒入水(20mL)中,加乙酸乙酯(10mL×3)萃取。有机相加半饱和食盐水(30mL×2)洗,饱和食盐水(30mL)洗,无水硫酸钠干燥。过滤,滤液45℃减压浓缩。粗品先经制备HPLC(柱型:Phenomenex luna C18 80mm×40mm×3μm;流动相:[H
2O(0.04%HCl)-ACN];B(ACN)%:50%-68%,7min)分离,后经薄层层析(展开剂:石油醚/乙酸乙酯=1/1,体积比)分离纯化,得到化合物WX060。
1H NMR(400MHz,DMSO-d
6)δ:8.69(d,J=8.4Hz,1H),8.40(s,1H),8.20(s,1H),8.10(d,J=9.2Hz,1H),7.28(dd,J=9.0,2.2Hz,1H),7.08(d,J=2.0Hz,1H),7.01(s,2H),6.88(s,1H),5.21(d,J=6.4Hz,1H),4.13-4.19(m,1H),4.12(s,3H),2.23(s,6H),1.53(t,J=19.6Hz,3H),1.28(d,J=6.8Hz,3H)。
MS–ESI m/z:469.3[M+H]
+。
参照实施例60的合成方法,用片段1替换AI-1-3,合成下表各实施例。
各参考例的NMR和MS数据
各实施例的NMR和MS数据
实验例1:体外检测化合物在荧光素酶报告基因筛选体系下抑制hMMP1转录活性
实验目的:
人类MMP-1启动子区(含两个AP-1结合位点和两个PEA3位点,共249bp,基因库目录#AF023338)克隆到荧光素酶报告基因的上游。构建hMMP-1启动子报告基因并转染到Hela细胞中,从而可以容易地检测荧光素酶的产生。稳定重组细胞hMMP-1/荧光素酶的细胞株被用于本实验的开发和验证。
培养基及试剂:
1.常规细胞培养基
DMEM 90%,FBS 10%,1mM NEAA,1mM Sodium Pyruvate,4mM L-Glutamine,300μg/mL G418,4℃储存。
2.冷冻液
DMEM 75%,FBS 20%,DMSO 5%。使用前配制。
3.实验细胞培养基
DMEM 97%,活性炭处理的血清(Charcoal stripped serum)3%。
4.Bright-Glo试剂盒
将一瓶Bright Glo Buffer全部转移到棕色的荧光底物瓶中,倒置混合直至底物完全溶解,适量分装,-80℃储存。
方法
冷冻细胞制备细胞悬浮液
1.细胞解冻
1)冻存细胞快速解冻,置于37℃水浴中不断搅拌直至完全溶解。
2)将细胞加入到15mL离心管中(内含有5mL预热的细胞培养基),然后1000转,离心5分钟。
3)弃上清液,加入5mL预热细胞培养基重悬细胞
4)将细胞悬浮液转移至60mM细胞培养皿中,置于37℃5%CO
2培养箱中培养。.
2.传代培养
1)当细胞生长达到80-90%时,进行细胞传代培养。pGL6.0-TA-hMMP-1HeLa细胞通常每周传代两次,1:3或1:6稀释传代。
2)小心吸出所有培养基,用适量DPBS轻轻冲洗细胞层,然后吸出。
3)加适量的0.05%Typsine EDTA置于CO
2培养箱孵育在3-5分钟消化细胞。
4)用适量的预热的细胞培养基重悬细胞,并稀释传代培养。
3.每隔一天换一次培养基
1)轻轻吸掉所有培养基。
2)加入新鲜细胞培养基(37℃预热)(100mm皿加10mL或150mm皿加入20mL)。
4.冻存细胞
1)重复传代培养步骤1-4。
2)细胞1000转离心5分钟。
3)吸去上清液,用冻存液重新悬浮,计数并稀释到2-3×10
6个/mL。每个细胞冷冻管中加入1mL悬浮细胞。
4)把冻存管放入冻存盒中,然后将冻存盒转移到-80℃冰箱中并过夜。
5)将冻存管转移到到液氮中(-196℃)。
5.接种细胞
1)小心吸出所有培养基,用适量DPBS轻轻冲洗细胞层,然后吸出。
2)加适量的0.05%Typsine EDTA置于CO
2培养箱孵育在3-5分钟消化细胞。
3)用适量的细胞培养基重新悬浮细胞。
4)计算所需的细胞量。细胞浓度为5×10
3个/孔。
5)用适当的细胞培养液稀释细胞悬浮液。
6)细胞悬浮液分装到一次性无菌加样槽中。
7)30μL每孔接种到384孔板中。
8)细胞板放置在37℃5%CO
2培养箱培养18-24小时。
化合物配制
1.PMA:
PMA用DMSO稀释溶解到10mM,避光分装保存在-80℃冰箱中备用。
2.地塞米松(Dexamethasone):
用DMSO稀释溶解到30mM,避光分装保存在-80℃冰箱中备用。
3. 10倍浓度化合物配制:
试验化合物用DMSO稀释到30mM,分装保存在-80℃冰箱中备用。
用DMSO稀释化合物到1mM,0.25mM,0.0625mM,0.015625mM,0.0039mM,0.0009765mM,0.000244mM,0.000061mM,0.00001526mM和0.0000038125mM,然后用含有100nM的PMA无血清培养基稀释100倍,最后得到10×浓度化合物实验板。
最终DMSO浓度为0.1%。PMA使用中需要避光。
hMMP1 GR转录抑制活性试验
1)接种细胞:新鲜细胞以5×10
3个/30μL/孔接种到384白色实验板中,在37℃5%CO
2培养箱中培养24小时。
2)化合物配制:在实验开始前配置好化合物板,准备好10×浓度的参照化合物(地塞米松)和受试化合物,最后得到10×浓度化合物实验板。
3)加入化合物:用Bravo转移3.3μL 10×化合物并加入到细胞板中。在37℃5%CO
2培养箱中培养18小时。
4)30μL Bright-Glo荧光检测试剂转入到细胞板中。
5)离心孵育2分钟
6)用Envision读板机测定荧光数值。
数据处理及分析
阳性对照:10nM PMA+1000nM地塞米松(0.1%DMSO)
阴性对照:10nM PMA(0.1%DMSO)
试验化合物:最高浓度1000nM,4倍稀释,共10个孔,重复。
地塞米松:最高浓度1000nM,4倍稀释,共10个孔,重复。
利用作图软件GraphPad Prism5制作受试化合物浓度曲线,计算IC
50值。
实验结果见表1。
实验例2:体外检测化合物在荧光素酶报告基因筛选体系下激活MMTV转录活性
实验目的:
小鼠乳腺肿瘤病毒(MMTV)的启动子包含激活GR(GREs)的特异性结合位点。为了确定化合物的活性,在MMTV启动子后面插入了一个报告基因(荧光素酶),并且该结构在HeLa细胞系的基因组中以稳定的方式表达。采用待测化合物激活MMTV启动子,诱导荧光素酶的表达,通过发光测量来检测其活性。
培养基及试剂:
1.常规细胞培养基
DMEM 90%,FBS 10%,潮霉素(Hygromycin)100μg/mL
2.冷冻液
DMEM 75%,FBS 20%,DMSO 5%。
3.实验细胞培养基
DMEM 97%,活性炭处理血清(Charcoal stripped serum)3%。
4.Bright-Glo试剂盒
将一瓶Bright Glo Buffer全部转移到棕色的荧光底物瓶中,倒置混合直至底物完全溶解,适量分装,-80℃储存。
方法
冷冻细胞制备细胞悬浮液
1.细胞解冻
1)将冻存细胞置于37℃水浴中不断搅拌直至完全解冻。
2)将上述细胞加入到15mL离心管中(内含有5mL预热的细胞培养基),然后1000转,离心5分钟。
3)弃上清液,加入5mL预热细胞培养基重悬细胞。
4)将细胞悬浮液转移至60mm细胞培养皿中,置于37℃5%CO
2培养箱中培养。.
2.传代培养
1)当细胞生长达到80-90%时,进行细胞传代培养。通常每周传代两次,1:3或1:6稀释传代。
2)小心吸出所有培养基,用适量DPBS轻轻冲洗细胞层,然后吸出。
3)加适量的0.05%Typsine EDTA置于CO
2培养箱孵育在3-5分钟消化细胞。
4)用适量的预热的细胞培养基重悬细胞,并稀释传代培养。
3.每隔一天换一次培养基
1)轻轻吸掉所有培养基。
2)加入新鲜细胞培养基(37℃预热)(100mm皿加10mL或150mm皿加入20mL)。
4.冻存细胞
1)重复传代培养步骤1-4。
2)细胞1000转离心5分钟。
3)吸去上清液,用冻存液重新悬浮,计数并稀释到(2-3)×10
6个/mL。每个细胞冷冻管中加入1mL悬浮细胞。
4)把冻存管放入冻存盒中,然后将冻存盒转移到-80℃冰箱中并过夜。
5)将冻存管转移到到液氮中(-196℃)。
5.接种细胞
1)小心吸出所有培养基,用适量DPBS轻轻冲洗细胞层,然后吸出。
2)加适量的0.05%Typsine EDTA置于CO
2培养箱孵育在3-5分钟消化细胞。
3)用适量的细胞培养基重新悬浮细胞。
4)计算所需的细胞量,细胞浓度为4×10
3个/孔。
5)用适当的细胞培养液稀释细胞悬浮液。
6)细胞悬浮液分装到一次性无菌加样槽中。
7)30μL每孔接种到384孔板中。
8)细胞板放置在37℃5%CO
2培养箱培养18-24小时。
化合物配制
1.地塞米松(Dexamethasone):
用DMSO稀释溶解到30mM,避光分装保存在-80℃冰箱中备用。
2.4倍浓度化合物配制:
试验化合物用DMSO稀释到30mM,分装保存在-80℃冰箱中备用。
用DMSO稀释化合物到1mM,0.25mM,0.0625mM,0.015625mM,0.0039mM,0.0009765mM,0.000244mM,0.000061mM,0.00001526mM和0.0000038125mM,然后用含活性炭处理血清培养基稀释25倍,最后得到4×浓度化合物实验板,使用前配制。
最终DMSO实验浓度为0.1%。
MMTV_GR转录激活活性试验
1)接种细胞:新鲜细胞以4×10
3个/30μL/孔接种到384白色透明底实验板中,在37℃5%CO
2培养箱中培养24小时。
2)化合物配制:在实验开始前配置好化合物板,准备好4×浓度的参照化合物(地塞米松)和受试化合物,最后得到4×浓度化合物实验板。
3)加入化合物:用Bravo转移10μL 4×化合物并加入到细胞板中。在37℃5%CO
2培养箱中培养18小时。
4)30μL Bright-Glo荧光检测试剂转入到细胞板中。
5)离心孵育2分钟
6)用Envision读板机测定荧光数值。
数据处理及分析
阳性对照:1000nM地塞米松(0.1%DMSO)
阴性对照:0.1%DMSO
试验化合物:最高浓度1000nM,4倍稀释,共10个孔,重复。
地塞米松:最高浓度1000nM,4倍稀释,共10个孔,重复。
利用作图软件GraphPad Prism5制作受试化合物浓度曲线,计算IC
50值。
实验结果见表1。
表1 本发明化合物体外筛选测试结果
注:N/A代表未检测;IC
50为绝对IC
50,EC
50为绝对EC
50;Effect代表最大效应值。
结论:本发明化合物展现了很好的转录抑制活性,及相当的转录激活活性。
实验例3:体外检测化合物对人外周血单核细胞TNF-α的抑制活性
实验目的:根据人外周血单核细胞(hPBMC)中TNF-α的水平来表达测试化合物细胞水平的抗炎活性。
培养基及试剂:
PRMI 1640培养基(Invitrogen-11875093,lot 2003787)
双抗(PS)(Invitrogen-15140122,lot 2019317)
胎牛血清(FBS)(Gibco-10091148,lot 1989478)
台盼蓝(Gibco-15250061,lot 1311086)
TNF-αElisa试剂盒Set A(BD-555212,lot 7171693),
TNF-αElisa试剂盒Set B(BD-550534,lot 9095783)
PBMC细胞(AllCells,Cat.PB006F-C,lot LP190225B):RPMI 1640+10%FBS(Gibico)+1%PS
方法
实验步骤:
1.PBMC实验
1.1复苏细胞
1)在37℃水浴锅中连续搅拌,快速解冻冷冻细胞.
2)在50ml离心管中加入25ml新鲜的预热解冻培养基。然后轻轻一点一滴地加入细胞。
3)将细胞以2000rpm离心10min(升速9,降速0)。
4)丢弃上清液,将细胞颗粒重新悬浮于25ml新鲜预热的RPMI 1640培养基中。
1.2在96孔板中种细胞
5)解冻复苏重悬细胞后,计数细胞数,计算实验所需细胞总数。
6)用适当体积的细胞培养基稀释细胞悬液。
7)将细胞悬液倒入无菌的一次性容器中。
8)转移100000细胞/(100μl)的细胞悬液到96孔板每个孔中。
9)将细胞板放入加湿的空气中,5%CO
2培养箱,37℃,放置2小时。
2.化合物剂量梯度稀释
第一步将化合物从储藏浓度10mM用100%DMSO稀释到1mM,作为第一个点用100%DMSO 3倍稀释8个点。第二步用不含有血清的培养基125倍稀释,此时DMSO的浓度是0.8%。然后转16.8μL已经用培养基稀释好的化合物到100μL的细胞板里,此时DMSO的浓度是0.114%。
加好化合物后将细胞板放入37℃,5%CO
2培养箱中孵育1个小时。
3.LPS稀释
第一步将LPS用超纯水稀释到储藏浓度1mg/ml。第二步储藏浓度的LPS用不含血清的培养基稀释到1ug/mL。第三步用不含有血清的培养基1666.666倍稀释。然后转16.8μL已经用培养基稀释好的LPS到116.8μL的细胞板里,此时DMSO终浓度是0.1%,加好LPS后将细胞板放入37℃,5%CO
2培养箱中孵育18个小时。
ELISA实验
第一天:
1.将TNF-a抗体在包被液中稀释至1×,然后每孔100μL加到96孔高结合性能的板子中,板子用膜封住放到4℃18个小时。
2.配制2000ml清洗缓冲液至1×备用。
第二天:
3.包被的板子过夜后,将包被液倒掉,用清洗缓冲液每孔300μL/孔清洗3遍。
4.板子清洗过后加每孔200μL的封闭缓冲液,板子用膜封住。放到25℃孵育箱中孵育一个小时。
5.将孵育18个小时的细胞板子放到离心机中离心,温度:25℃,转速:2000转,时间:10分钟,升速:9,降速:1。离心后取每孔100μL细胞上清到3599细胞板中,后放到4℃冰箱备用。
6.将细胞上清用封闭缓冲液稀释40倍放到4℃冰箱待用,后配制标准品也放置4℃冰箱备用。
7.封闭完成后,将封闭液倒掉,用清洗缓冲液每孔300μL清洗3遍。
8.将稀释好的细胞上清样品以及标准品加到ELISA板子中,板子用膜封住。后放到25℃孵育箱中孵育两个小时。
9.将板中液体倒掉,用清洗缓冲液每孔300μL清洗5遍。
10.配制抗体,并每孔加入100μL,用封板膜封板。后放到25℃孵育箱中孵育一个小时。
11.将板中液体倒掉,用清洗缓冲液每孔300μL清洗7遍。
12.配制显色液,每孔加100μL。后避光放到25℃孵育箱中孵育半个小时。
13.每孔加50μL终止液,离心,温度:25℃,转速:1000转,时间:1分钟,升速:9,降速:9。
14.离心后30分钟内在Envision上读数,设置为吸收光450减去吸收光570的值为最终的原始数据使用值。
数据处理:
根据原始数据计算抑制率,抑制率计算公式为:
抑制率=(1-(原始值-HPE平均值)/(ZPE平均值-HPE平均值))×100%
其中ZPE为:0%抑制(75pg/ml LPS,0.1%DMSO),HPE为:100%抑制(不含LPS,0.1%DMSO)。
S/B:ZPE平均值/HPE平均值
Z-factor:Z factor=1-(3×(ZPE标准差+HPE标准差)/(ZPE平均值–HPE平均值))
用×Lfit统计软件中的Model 205进行数据分析。以浓度为横坐标,抑制率为纵坐标,IC
50的计算公式为:用4参数logistic剂量响应方程,绘制了被测化合物的浓度和抑制率(%),并确定了50%抑制所需的化合物浓度(IC
50)。
将标准曲线的原始值输入到GraphPad Prism中,绘制出标准曲线,计算化合物抑制TNF-α的IC
50及最高效应值。
实验结果见表2。
表2 本发明化合物体外检测对人外周血单核细胞TNF-α的抑制结果
注:***测试Top浓度100nM,3倍稀释,8浓度;**测试Top浓度500nM,3倍稀释,8浓度;*测试Top浓度1000nM,3倍稀释,8浓度;其余测试Top浓度10000nM,3倍稀释,8浓度;IC
50为绝对IC
50;Top(%)代表最大效应值。
结论:本发明化合物展现了很好的细胞水平的抗炎活性。
实验例4:人肝微粒体CYP抑制实验
研究项目的目的是采用CYP同工酶的5合1探针底物来评价供试品对人肝微粒体细胞色素P450同工酶(CYP3A4)的抑制性。
混合人肝微粒体(HLM)购自Corning Inc.(Steuben,New York,USA)或者其他的供应商,使用前都储存在低于-70℃条件下。
将稀释好的系列浓度的供试品工作液加入到含有人肝微粒体、探针底物和循环体系的辅助因子的孵育体系中,不含供试品而含有溶剂的对照作为酶活性对照(100%)。探针底物生成的代谢产物在样品中的浓度采用液相色谱-串联质谱(LC-MS/MS)方法进行测定。使用SigmaPlot(V.11)对供试品平均百分比活性对浓度作非线性回归分析。通过三参数或四参数反曲对数方程来计算IC
50值。测试结果如表3:
表3 本发明化合物体外检测对CYP3A4的抑制
测试化合物 | AZD9567 | WX019 | WX053 |
CYP3A4(IC50,μM) | 2.95 | 9.12 | 15.7 |
结论:AZD9567对CYP3A4有中强度抑制。化合物WX019,WX053明显改善了对CYP3A4的抑制。
实验例5:体内药代动力学性质研究
实验目的:该研究的目的是为了测定化合物在雄性SD大鼠中的药代动力学参数。
实验方法:该项目使用两只雄性SD大鼠,进行静脉注射给药,给药剂量为2mg/kg,给药浓度0.4mg/mL,收集0h(给药前)和给药后0.0833、0.25、0.5、1、2、4、6、8、24h的血浆样品,然后对收集的样品进行LC-MS/MS分析并采集数据。采集的分析数据用Phoenix WinNonlin 6.3软件计算相关药代动力学参数。
实验结果如表4:
表4 体内药代动力学实验结果
结论:本发明化合物具有较好的表观分布容积和半衰期。
Claims (16)
- 式(I)所示化合物或其药学上可接受的盐,其中,X选自NH和O;T 1选自CH 2和O;T 2、T 3和T 4分别独立地选自CH和N;T 5选自NH和O;T 6选自CH和N;环B选自苯基;R 1选自H和C 1-3烷氧基,所述C 1-3烷氧基任选被1、2或3个R b取代;各R 2分别独立地选自H、F、Cl、Br和CH 3;R 3选自C 1-6烷基,所述C 1-6烷基任选被1、2或3个R c取代;m选自0、1和2;n选自1和2;R a分别独立地选自H和C 1-3烷基,所述C 1-3烷基任选被1、2或3个R取代;R b分别独立地选自H、F、Cl、Br和I;R c分别独立地选自H、F、Cl、Br、I和OH;R分别独立地选自F和OCH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R a分别独立地选自H、CH 3、CF 3、CH 2CH 3、C(CH 3) 2和CH 2CH 2OCH 3。
- 根据权利要求1或2所述化合物或其药学上可接受的盐,其中,R 1选自H和OCH 3,所述OCH 3任选被1、2或3个R b取代。
- 根据权利要求9所述化合物或其药学上可接受的盐,其中,R 1选自H和OCH 3。
- 根据权利要求1或2所述化合物或其药学上可接受的盐,其中,R 3选自C 1-3烷基,所述C 1- 3烷基任选被1、2或3个R c取代。
- 根据权利要求11所述化合物或其药学上可接受的盐,其中,R 3选自CH 3、CH 2CH 3和C(CH 3) 2。
- 根据权利要求1~14任意一项所述的化合物或其药学上可接受的盐在制备与糖皮质激素受体相关疾病的药物中的应用。
- 根据权利要求15所述的应用,所述的与糖皮质激素受体相关疾病是指类风湿关节炎。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101611015A (zh) * | 2006-12-21 | 2009-12-23 | 阿斯利康(瑞典)有限公司 | 用于治疗糖皮质激素受体所介导紊乱的吲唑基酯和吲唑基酰胺衍生物 |
CN102112449A (zh) * | 2008-05-20 | 2011-06-29 | 阿斯利康(瑞典)有限公司 | 苯基或吡啶基取代的吲唑衍生物 |
CN107001320A (zh) * | 2014-09-26 | 2017-08-01 | 阿斯利康(瑞典)有限公司 | 1‑烷基‑6‑氧代‑1,6‑二氢吡啶‑3‑基化合物及其用途 |
WO2019010491A1 (en) * | 2017-07-07 | 2019-01-10 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | COMBINATIONS OF MEDICINES FOR THE PROTECTION AGAINST THE DEATH OF NEURONAL CELLS |
CN109415348A (zh) * | 2016-03-23 | 2019-03-01 | 阿斯利康(瑞典)有限公司 | Sgr调节剂的新的物理形式 |
-
2020
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101611015A (zh) * | 2006-12-21 | 2009-12-23 | 阿斯利康(瑞典)有限公司 | 用于治疗糖皮质激素受体所介导紊乱的吲唑基酯和吲唑基酰胺衍生物 |
CN102112449A (zh) * | 2008-05-20 | 2011-06-29 | 阿斯利康(瑞典)有限公司 | 苯基或吡啶基取代的吲唑衍生物 |
CN107001320A (zh) * | 2014-09-26 | 2017-08-01 | 阿斯利康(瑞典)有限公司 | 1‑烷基‑6‑氧代‑1,6‑二氢吡啶‑3‑基化合物及其用途 |
CN109415348A (zh) * | 2016-03-23 | 2019-03-01 | 阿斯利康(瑞典)有限公司 | Sgr调节剂的新的物理形式 |
WO2019010491A1 (en) * | 2017-07-07 | 2019-01-10 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | COMBINATIONS OF MEDICINES FOR THE PROTECTION AGAINST THE DEATH OF NEURONAL CELLS |
Non-Patent Citations (5)
Title |
---|
HEMMERLING MARTIN, NILSSON STINABRITT, EDMAN KARL, EIREFELT STEFAN, RUSSELL WAYNE, HENDRICKX RAMON, JOHNSSON ESKIL, KÄRRMAN MÅRDH : "Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 60, no. 20, 26 October 2017 (2017-10-26), pages 8591 - 8605, XP055825954, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b01215 * |
HEMMERLING MARTIN; EDMAN KARL; LEPISTÖ MATTI; ERIKSSON ANDERS; IVANOVA SVETLANA; DAHMÉN JAN; REHWINKEL HARTMUT; BERGER MARKUS; HEN: "Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 26, no. 23, 19 October 2016 (2016-10-19), AMSTERDAM, NL, pages 5741 - 5748, XP029815435, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2016.10.052 * |
LENAROPA, J. MED. CHEM., vol. 61, 2018, pages 1785 - 1799 |
RIPA LENA, EDMAN KARL, DEARMAN MATTHEW, EDENRO GORAN, HENDRICKX RAMON, ULLAH VICTORIA, CHANG HUI-FANG, LEPISTÖ MATTI, CHAPMAN DAVE: "Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 61, no. 5, 8 March 2018 (2018-03-08), pages 1785 - 1799, XP055825952, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b01690 * |
See also references of EP4086247A4 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023274040A1 (zh) * | 2021-06-28 | 2023-01-05 | 南京明德新药研发有限公司 | 一种三唑并吡啶取代的吲唑类化合物的晶型及其制备方法 |
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CN114929684A (zh) | 2022-08-19 |
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EP4086247A1 (en) | 2022-11-09 |
CN114929684B (zh) | 2023-08-18 |
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