CN107098908B - 一种吡咯并嘧啶类化合物的制备方法和应用 - Google Patents
一种吡咯并嘧啶类化合物的制备方法和应用 Download PDFInfo
- Publication number
- CN107098908B CN107098908B CN201610100165.5A CN201610100165A CN107098908B CN 107098908 B CN107098908 B CN 107098908B CN 201610100165 A CN201610100165 A CN 201610100165A CN 107098908 B CN107098908 B CN 107098908B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- group
- pharmaceutically acceptable
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 pyrrolopyrimidine compound Chemical class 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 102000042838 JAK family Human genes 0.000 claims description 15
- 108091082332 JAK family Proteins 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 239000012442 inert solvent Substances 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 claims description 11
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
- 230000001363 autoimmune Effects 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 5
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 claims description 5
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 claims description 5
- 108010024121 Janus Kinases Proteins 0.000 claims description 5
- 102000015617 Janus Kinases Human genes 0.000 claims description 5
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 claims description 5
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 3
- GEDFDIKDVZJSFK-UHFFFAOYSA-N 3-hydroxy-2-[1-[6-imino-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexa-2,4-dien-1-yl]ethyl]but-2-enenitrile Chemical compound OC(=C(C#N)C(C)C1C(C=C(C=C1)N(C=1C2=C(N=CN=1)NC=C2)C)=N)C GEDFDIKDVZJSFK-UHFFFAOYSA-N 0.000 claims description 3
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 3
- 206010004659 Biliary cirrhosis Diseases 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 206010012434 Dermatitis allergic Diseases 0.000 claims description 3
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 3
- 201000002481 Myositis Diseases 0.000 claims description 3
- 206010034277 Pemphigoid Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 206010046851 Uveitis Diseases 0.000 claims description 3
- 201000009961 allergic asthma Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 201000008937 atopic dermatitis Diseases 0.000 claims description 3
- 208000010668 atopic eczema Diseases 0.000 claims description 3
- 208000037979 autoimmune inflammatory disease Diseases 0.000 claims description 3
- 208000000594 bullous pemphigoid Diseases 0.000 claims description 3
- 208000037976 chronic inflammation Diseases 0.000 claims description 3
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 238000007142 ring opening reaction Methods 0.000 claims description 3
- 201000000306 sarcoidosis Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- 229940043355 kinase inhibitor Drugs 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 208000003084 Graves Ophthalmopathy Diseases 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 229960003444 immunosuppressant agent Drugs 0.000 abstract description 2
- 230000001861 immunosuppressant effect Effects 0.000 abstract description 2
- 239000003018 immunosuppressive agent Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 25
- 125000000623 heterocyclic group Chemical group 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 230000035755 proliferation Effects 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 9
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 150000007530 organic bases Chemical class 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- 239000001301 oxygen Chemical group 0.000 description 7
- 239000011593 sulfur Chemical group 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 210000004988 splenocyte Anatomy 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 5
- 229940124639 Selective inhibitor Drugs 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003226 mitogen Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002516 radical scavenger Substances 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 102000036693 Thrombopoietin Human genes 0.000 description 3
- 108010041111 Thrombopoietin Proteins 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 2
- ZKAQPVQEYCFRTK-UHFFFAOYSA-N 5-methyl-1,2-oxazole-4-carbonyl chloride Chemical compound CC=1ON=CC=1C(Cl)=O ZKAQPVQEYCFRTK-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 2
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 206010060742 Endocrine ophthalmopathy Diseases 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- YUDRVAHLXDBKSR-UHFFFAOYSA-N [CH]1CCCCC1 Chemical compound [CH]1CCCCC1 YUDRVAHLXDBKSR-UHFFFAOYSA-N 0.000 description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 2
- 238000007171 acid catalysis Methods 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- XIFJZJPMHNUGRA-UHFFFAOYSA-N n-methyl-4-nitroaniline Chemical compound CNC1=CC=C([N+]([O-])=O)C=C1 XIFJZJPMHNUGRA-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical class OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- 125000005938 2,3-dihydro-1H-isoindolyl group Chemical group 0.000 description 1
- 125000005983 2,5-diazabicyclo[2.2.1]heptan-2-yl group Chemical group 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical class NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical class OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- BYSKBKXBULSSBR-UHFFFAOYSA-N CN(C=1C2=C(N=CN=1)NC=C2)C1=CC=C(C=C1)[N+](=O)[O-] Chemical compound CN(C=1C2=C(N=CN=1)NC=C2)C1=CC=C(C=C1)[N+](=O)[O-] BYSKBKXBULSSBR-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical class [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- GCTFALKRTYVYFB-UHFFFAOYSA-N N1=CNC2=CC=NC2=C1Cl Chemical compound N1=CNC2=CC=NC2=C1Cl GCTFALKRTYVYFB-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- NVSPJDGXKBDYIZ-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]pyrazine Chemical compound C1=NC=CN2C=NN=C21 NVSPJDGXKBDYIZ-UHFFFAOYSA-N 0.000 description 1
- AYSYSOQSKKDJJY-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]pyridine Chemical compound C1=CC=CN2C=NN=C21 AYSYSOQSKKDJJY-UHFFFAOYSA-N 0.000 description 1
- YRACHDVMKITFAZ-UHFFFAOYSA-N [1,2,4]triazolo[4,3-b]pyridazine Chemical compound C1=CC=NN2C=NN=C21 YRACHDVMKITFAZ-UHFFFAOYSA-N 0.000 description 1
- XUFCBCHWTOAVAA-UHFFFAOYSA-N [1,2,4]triazolo[4,3-c]pyrimidine Chemical compound C1=CN=CN2C=NN=C21 XUFCBCHWTOAVAA-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical class [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000011095 buffer preparation Methods 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical class OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 description 1
- 125000005534 decanoate group Chemical class 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical class OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- MBVAHHOKMIRXLP-UHFFFAOYSA-N imidazo[1,2-a]pyrazine Chemical compound C1=CN=CC2=NC=CN21 MBVAHHOKMIRXLP-UHFFFAOYSA-N 0.000 description 1
- VTVRXITWWZGKHV-UHFFFAOYSA-N imidazo[1,2-b]pyridazine Chemical compound N1=CC=CC2=NC=CN21 VTVRXITWWZGKHV-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229940100601 interleukin-6 Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical class CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Chemical group 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical class OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000002491 severe combined immunodeficiency Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Emergency Medicine (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Gastroenterology & Hepatology (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种吡咯并嘧啶类化合物的制备方法和应用,具体地,本发明提供了一种式I化合物或其药学上可接受的盐,以及含有该化合物或盐的药物组合物,其制备方法及其作为免疫抑制剂的应用。
Description
技术领域
本发明涉及一种吡咯并嘧啶类化合物或其药学上可接受的盐,以及含有该化合物或盐的药物组合物,其制备方法及其作为免疫抑制剂的应用。
背景技术
JAK1在多种细胞因子和生长因子信号传导途径中具有关键作用,JAK1失调会导致或有助于产生疾病或导致炎症反应。例如,在类风湿关节炎中,白介素6的激活具有促炎效应,通过JAK1抑制直接或间接拮抗IL-6将会提供临床益处。
相对于其他JAK激酶,JAK1的选择性抑制剂对于较少选择性的抑制剂具有多种治疗益处。针对JAK2的选择性而言,多种重要的细胞因子和生长因子通过JAK2传导信号,包括例如促红细胞生成素(EPO)和促血小板生成素(TPO)。如减少的TPO信号传导将导致巨核细胞减少症,并且可能会导致血小板减少症。而对于JAK3的选择性而言,JAK3激酶缺陷的患儿则可能患有严重联合免疫缺陷病。本发明化合物是JAK抑制剂,并且大部分本发明化合物是JAK1选择性抑制剂。JAK1选择性抑制剂是相对于其他Janus激酶优选抑制JAK1活性的化合物。
因此,本领域迫切需要研发出一种具有特异性免疫抑制活性的化合物。
发明内容
本发明的目的是提供一种结构新颖的JAK1酶选择性抑制剂、及其制法和应用。
本发明第一方面,提供一种式I化合物或其药学上可接受的盐,
其中,
R1选自下组:H、取代或未取代的C1-C10烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10环烷基、取代或未取代的C4-C10杂环基、取代或未取代的C1-C10杂芳基、-RaC(O)Rb、-R1’-NRcC(O)Rb、和-R1’-N=CRcRb;且所述的取代指具有一个或多个选自下组A1的取代基:取代或未取代的C1-C10烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10环烷基、取代或未取代的C4-C10杂环基、取代或未取代的C1-C10杂芳基、卤素、-NH2、-OH和-CN;
各Ra、Rb各自独立地选自下组:氢、-CN、取代或未取代的C1-C8烷基、取代或未取代的C2-C8烯基、取代或未取代的C3-C8炔基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10环烷基、取代或未取代的C4-C10杂环基、和取代或未取代的C1-C10杂芳基,且所述的取代指具有一个或多个选自下组A2的取代基:卤素、氨基、硝基、-OH、-CN、C1-C4烷基和C1-C4卤代烷基;
Rc为H或C1-C3烷基;
R1’为苯基或环己基;
其中,所述的C4-C10杂环基和C1-C10杂芳基分别独立地具有1-3个选自N、O和S的杂原子。
在另一优选例中,Rb为取代或未取代的C1-C8烷基、取代或未取代的C2-C8烯基、或取代或未取代的C4-C10杂环基,并且所述的取代指具有一个或多个选自下组A4的取代基:卤素、-OH、-CN;所述的C4-C10杂环基具有1-3个选自N、O和S的杂原子。
在另一优选例中,所述式I化合物选自如下式I-b或I-c化合物:
在另一优选例中,所述式I化合物选自下组:
N-甲基-N-(7H-吡咯并[2,3-d]嘧啶-4-基)苯基-1,4-二胺;
5-甲基-异噁唑-{4-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-苯基}-4-酰胺;
5-甲基-异噁唑-{4-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-环己基}-胺;
2-氰基-3-羟基-2-丁烯-{4-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-苯基]-酰胺;
2-氰基-3-羟基-2-丁烯-{4-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-环己基]-酰胺;和
3-羟基-2-(1-{4-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-亚胺基苯基}-乙基)-2丁烯腈。
本发明第二方面,提供一种制备式I-b化合物的方法,包括步骤:
在惰性溶剂中,将式II化合物与式III化合物反应,得到式I-b化合物,其中,R1’的定义如上所述。
在另一优选例中,所述惰性溶剂选自下组:二氯甲烷、三氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、或其组合。
在另一优选例中,所述式II化合物与式III化合物的摩尔比为0.5-2:0.5-2;较佳地为约1:1。
在另一优选例中,所述的反应时间为1-15h,较佳地为2-10h,更佳地为0.5-5h。
在另一优选例中,所述反应在有机碱催化剂下进行。
在另一优选例中,所述有机碱催化剂选自下组:二甲基氨基吡啶(DMAP)、二异丙基乙胺(DIPEA)、或其组合。
在另一优选例中,所述反应在酸催化下进行。
在另一优选例中,所述酸催化剂为缚酸剂。
在另一优选例中,所述缚酸剂选自下组:三乙胺、吡啶、二乙胺、哌啶、或其组合。
在另一优选例中,所述方法还包括步骤(1-1):在-50~0℃下,将式II化合物、有机碱、缚酸剂溶于惰性溶剂中,滴加所述式III化合物进行反应。
在另一优选例中,所述步骤还包括步骤(1-2):将所述步骤(1-1)所得混合物升温至室温进行反应。
在另一优选例中,所述步骤还包括步骤(1-3):用水淬灭反应。
本发明第三方面,提供一种制备式I-c化合物的方法,所述方法包括步骤:
在惰性溶剂中,式I-b化合物进行开环反应,制得式I-c化合物,其中,R1’的定义如上所述。
在另一优选例中,所述惰性溶剂选自下组:甲醇、乙醇、四氢呋喃、或其组合。
在另一优选例中,所述反应在碱性条件下进行。
在另一优选例中,所述碱选自下组:碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、或其组合。
本发明第四方面,提供一种药物组合物,所述药物组合物包含治疗有效量的选自如本发明第一方面所述的化合物、或其药学上可接受的盐中的一种或多种,以及,药学上可接受的赋形剂。
本发明第五方面,提供如本发明第一方面所述的化合物或其药学上可接受的盐,或本发明第四方面所述的药物组合物在制备用于预防和治疗与JAK激酶相关的疾病和JAK激酶抑制剂的药物中的用途。
在另一优选例中,所述JAK激酶选自JAK1、JAK2和JAK3激酶。
在另一优选例中,所述疾病为自身免疫性和慢性炎症疾病。
在另一优选例中,所述疾病选自下组:系统性红斑狼疮、类风湿关节炎、多发性硬化症、II型糖尿病、炎性肠疾病、胆汁性肝硬化、葡萄膜炎、克罗恩病、溃疡性结肠炎、大疱性类天疱疮、结节病、银屑病、银屑病关节炎、自身免疫性肌炎、韦格纳肉芽肿病、格雷夫斯眼病、过敏性皮炎和哮喘。
本发明第六方面,提供一种非治疗性地抑制JAK激酶活性的方法,其特征在于,包括步骤:将本发明第一方面所述的化合物或其药学上可接受的盐与JAK激酶接触,从而抑制JAK激酶。
本发明第七方面,提供一种抑制JAK激酶活性或治疗与JAK激酶相关疾病的方法,其特征在于,包括步骤:将本发明第一方面所述的化合物或其药学上可接受的盐与JAK激酶接触,从而抑制JAK激酶。
在另一优选例中,所述方法包括对需要的哺乳动物给予治疗有效量的本发明第一方面所述的化合物或其药学上可接受的盐,或给予治疗有效量的如本发明第四方面所述的药物组合物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,首次意外地发现一种式I所示的化合物或其药学上可接受的盐,其具有免疫抑制作用,能够用于治疗免疫相关的疾病。在此基础上完成了本发明。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用,术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、氨基、硝基、C1-C4烷基。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”是指完全饱和的直链或支链的烃链基,仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个,更优选为1至6个)碳原子,且通过单键与分子的其余部分连接,例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。术语“C3~C10烷基”指具有3~10个碳原子的直链或支链烷基,例如环丙基、环丁基、环戊基、环己基或类似基团。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“炔基”是指仅由碳原子和氢原子组成、含有至少一个三键,任选含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。术语“C6~C10芳基”指具有6~10个碳原子的芳基,包括单环或二环芳基,例如苯基、萘基,或类似基团。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。术语“C1~C10杂芳基”指具有1~10个碳原子的杂芳基,例如吡咯基、吡啶基、呋喃基、噁唑基或类似基团。
术语“卤素”指F、Cl、Br和I。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
药物组合物及施用方式
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明中,术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量,或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此,预先指定准确的有效量是没用的。然而,对于某给定的状况而言,可以用常规实验来确定该有效量,临床医师是能够判断出来的。
式I化合物
如本发明所述,一种式I化合物或其药学上可接受的盐,
其中,
R1选自下组:H、取代或未取代的C1-C10烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10环烷基、取代或未取代的C4-C10杂环基、取代或未取代的C1-C10杂芳基、-RaC(O)Rb、-R1’-NRcC(O)Rb、和-R1’-N=CRcRb;且所述的取代指具有一个或多个选自下组A1的取代基:取代或未取代的C1-C10烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10环烷基、取代或未取代的C4-C10杂环基、取代或未取代的C1-C10杂芳基、卤素、-NH2、-OH和-CN;
各Ra、Rb各自独立地选自下组:氢、-CN、取代或未取代的C1-C8烷基、取代或未取代的C2-C8烯基、取代或未取代的C3-C8炔基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10环烷基、取代或未取代的C4-C10杂环基、和取代或未取代的C1-C10杂芳基,且所述的取代指具有一个或多个选自下组A2的取代基:卤素、氨基、硝基、-OH、-CN、C1-C4烷基和C1-C4卤代烷基;
Rc为H或C1-C3烷基;
R1’为苯基或环己基;
其中,所述的C4-C10杂环基和C1-C10杂芳基分别独立地具有1-3个选自N、O和S的杂原子。
式I-b化合物的制备
本发明还提供了一种制备式I化合物的代表化合物I-b的方法,所述方法包括步骤:
在惰性溶剂中,将式II化合物与式III化合物反应,得到式I-b化合物,其中,R1’的定义如上所述。
在另一优选例中,所述惰性溶剂选自下组:二氯甲烷、三氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、或其组合。
在另一优选例中,所述式II化合物与式III化合物的摩尔比为0.5-2:0.5-2;较佳地为约1:1。
在另一优选例中,所述的反应时间为1-15h,较佳地为2-10h,更佳地为0.5-5h。
在另一优选例中,所述反应在有机碱催化剂下进行。
在另一优选例中,所述有机碱催化剂选自下组:二甲基氨基吡啶(DMAP)、二异丙基乙胺(DIPEA)、或其组合。
在另一优选例中,所述反应在酸催化下进行。
在另一优选例中,所述酸催化剂为缚酸剂。
在另一优选例中,所述缚酸剂选自下组:三乙胺、吡啶、二乙胺、哌啶、或其组合。
在另一优选例中,所述方法还包括步骤(1-1):在-50~0℃下,将式II化合物、有机碱、缚酸剂溶于惰性溶剂中,滴加所述式III化合物进行反应。
在另一优选例中,所述步骤还包括步骤(1-2):将所述步骤(1-1)所得混合物升温至室温进行反应。
在另一优选例中,所述步骤还包括步骤(1-3):用水淬灭反应。
式I-c化合物的制备
本发明还提供了一种制备式I化合物的代表化合物I-c的方法,所述方法包括步骤:
在惰性溶剂中,式I-b化合物进行开环反应,制得式I-c化合物,其中,R1’的定义如上所述。
在另一优选例中,所述惰性溶剂选自下组:甲醇、乙醇、四氢呋喃、或其组合。
在另一优选例中,所述反应在碱性条件下进行。
在另一优选例中,所述碱选自下组:碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、或其组合。
用途
本发明的式I及相类结构的化合物可用于治疗和/或预防的疾病包括但并不局限于:自身免疫性和慢性炎症疾病,如系统性红斑狼疮,类风湿关节炎,多发性硬化症,II型糖尿病,炎性肠疾病,胆汁性肝硬化,葡萄膜炎和其他紊乱,如克罗恩病,溃疡性结肠炎,大疱性类天疱疮,结节病,银屑病,银屑病关节炎,自身免疫性肌炎,韦格纳肉芽肿病,格雷夫斯眼病,过敏性皮炎和哮喘。
本发明的主要优点在于:
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的特异性免疫应答抑制剂、其制备方法和应用。
3.提供了一类治疗与JAK激酶相关疾病的药物组合物。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1制备化合物1:N-甲基-N-(7H-吡咯并[2,3-d]嘧啶-4-基)苯基-1,4-二胺
称取1.53g 4-氯吡咯并嘧啶,4.6g N-甲基-对-硝基苯胺,4M HCl的二氧六环溶液于40mL二氧六环中130℃加热过夜。混合物冷却至室温,减压浓缩至干。残留物用乙酸乙酯打浆至大部分N-甲基-对-硝基苯胺消失,将所得的固体溶于甲醇和三乙胺(1.5eq)混合物中,加入硅胶,减压浓缩至干。残留物硅胶柱层析分离,二氯甲烷/甲醇=30/1体系洗脱,得到1.4g N-甲基-N-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺,收率91.5%。
将11g上述产物,10%Pd/C在装有氢气球的甲醇密闭体系中搅拌至原料反应完全,将体系过滤,滤液减压浓缩至干,残留物通过甲醇打浆得到化合物8g产物,收率为72.7%。
化合物2和化合物3的结构如下式I-b所示:
实施例 | 结构式 | R<sub>1</sub>’ |
2 | 式I-b | 苯基 |
3 | 式I-b | 环己基 |
实施例2制备化合物2:5-甲基-异噁唑-{4-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-苯基}-4-酰胺
分别称取100mg N-甲基-N-(7H-吡咯并[2,3-d]嘧啶-4-)苯基-1,4-二胺,16mgDMAP于三口烧瓶中,加入20mL二氯甲烷搅拌溶解,冷却至-20℃左右,滴加100mg三乙胺于反应液中。然后缓慢滴加103mg 5-甲基异恶唑-4-甲酰氯溶于5mL的二氯甲烷溶液,滴加完毕后,自然缓慢升至室温反应5h,TLC监测反应至结束。加20mL水淬灭反应,分液萃取,水相用二氯甲烷洗涤3次,合并有机相,无水Na2SO4干燥,硅胶柱层析分离,乙酸乙酯/正己烷=1/1体系洗脱,得72mg产物,收率为72%。
实施例3制备化合物3:5-甲基-异噁唑--{4-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-环己基}-胺
分别称取100mg N-甲基-N-(7H-吡咯并[2,3-d]嘧啶-4-)苯-1,4-二胺,16mg DMAP于三口烧瓶中,加入20mL二氯甲烷搅拌溶解,冷却至-20℃左右,滴加100mg三乙胺于反应液中。然后缓慢滴加103mg 5-甲基异恶唑-4-甲酰氯溶于5mL的二氯甲烷溶液,滴加完毕后,自然缓慢升至室温反应5h,TLC监测反应至结束。加20mL水淬灭反应,分液萃取,水相用二氯甲烷洗涤3次,合并有机相,无水Na2SO4干燥,硅胶柱层析分离,乙酸乙酯/正己烷=1/1体系洗脱,得64mg产物,收率为64%。
化合物4和化合物5的结构如下式I-c所示:
实施例 | 结构式 | R<sub>1</sub>’ |
4 | 式I-c | 苯基 |
5 | 式I-c | 环己基 |
实施例4制备化合物4:2-氰基-3-羟基-2-丁烯-{4-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-苯基]-酰胺
称取100mg化合物2于三口烧瓶中,加入30mL甲醇搅拌溶解,冷却至0℃,缓慢滴加1mL饱和碳酸氢钠水溶液,滴加完毕后,在此温度下继续搅拌反应4h,TLC跟踪反应至结束。减压蒸除甲醇,加入20mL水,分液萃取,水相用二氯甲烷洗涤3次,合并有机相,无水Na2SO4干燥,硅胶柱层析分离,二氯甲烷/甲醇=20/1体系洗脱,得到47mg产物,收率为47%。
实施例5制备化合物5:2-氰基-3-羟基-2-丁烯-{4-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-环己基]-酰胺
称取100mg化合物3于三口烧瓶中,加入30mL甲醇搅拌溶解,冷却至0℃,缓慢滴加1mL饱和碳酸氢钠水溶液,滴加完毕后,在此温度下继续搅拌反应4h,TLC跟踪反应至结束。减压蒸除甲醇,加入20mL水,分液萃取,水相用二氯甲烷洗涤3次,合并有机相,无水Na2SO4干燥,二氯甲烷/甲醇=20/1体系洗脱,得到52mg产物,收率为52%。
实施例6制备化合物6:3-羟基-2-(1-{4-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-亚胺基苯基}-乙基)-2丁烯腈
称取1g化合物5,1g 1-(5-甲基-4-异噁唑)-1-乙酮,25mL DMF,150℃加热5h。滴加75mL水,搅拌1h,过滤,滤饼溶于二氯甲烷/甲醇体系,Na2SO4干燥,硅胶柱层析分离,二氯甲烷/甲醇=60:1得到0.9g产物,收率:90%。
实施例7本发明化合物对JAK1-3酶活性的选择性抑制实验
受试化合物溶于DMSO配成10mM母液。使用前将化合物在DMSO中稀释成1mM,并做3倍梯度稀释,共11个浓度,配制缓冲液后,将JAK1、JAK2、JAK3与底物与预先稀释的不同浓度化合物混合,室温放置30分钟,每个浓度双复孔。加入ATP,室温反应90分钟,反应完毕加入抗体检测,室温孵育60分钟后Envision检测采集数据,如表1所示。
表1化合物JAK酶选择性
实施例8本发明化合物对丝裂原ConA和CD3/CD28抗体诱导的小鼠脾细胞增殖抑制能力
CD3和CD28单克隆抗体,可以特异性结合T细胞表面的CD3和CD28,导致T细胞TCR-CD3复合体的交联,诱导T细胞活化增殖,不需要第二信号的辅助。这一过程,与抗原诱导的T细胞活化类似。
CD3/CD28抗体诱导的小鼠脾细胞增殖抑制实验:每孔加入100uL细胞悬液,即5*105/孔,再加或不加入50uL浓度为2.5ug/uL的ConA和50uL不同浓度的抑制剂,阴性对照孔补足50uL完全1640培养基。培养48小时,收集细胞培养上清100uL/孔用于后续ELISA检测,加入10uL/孔CCK8试剂,检测细胞增殖情况。显微镜观察各组免疫细胞增殖情况。
丝裂原ConA诱导的小鼠脾细胞增殖抑制实验:无菌制备的C57BL/6小鼠脾细胞,以完全1640培养基调整细胞浓度为5*106/mL,向5ug/mL CD3预包板的板中每孔加入100uL细胞悬液,即5*105/孔,再加或不加入50uL浓度为8ug/mL的CD28和50uL不同浓度的抑制剂(化合物1-6),阴性对照孔补足50uL完全1640培养基。培养144小时,收集细胞培养上清100uL/孔用于后续ELISA检测,加入10uL/孔CCK8试剂,检测细胞增殖情况。显微镜观察各组免疫细胞增殖情况,计算EC50值。
各化合物对于丝裂原ConA和CD3/CD28抗体诱导的小鼠脾细胞增殖抑制能力结果如表2所示:
表2.本发明化合物对丝裂原ConA和CD3/CD28抗体诱导的小鼠脾细胞增殖抑制活性EC50
化合物编号 | ConA诱导(μM) | CD3/CD28(μM) |
1 | 53.88 | 22.73 |
2 | 40.34 | 15.09 |
3 | 90.71 | 65.67 |
4 | 61.22 | 30.85 |
5 | >200 | >100 |
6 | 93.34 | 52.79 |
对照化合物(A771726) | >200 | >200 |
以ConA为刺激源,化合物1、2、3在10uM浓度时开始出现对淋巴细胞增殖抑制作用,随着浓度增高,抑制效应更为明显。而化合物4仅在100和200uM浓度时表现出一定的抑制作用。
以抗-CD3/CD28为刺激源,化合物1、3在10uM浓度时开始出现对淋巴细胞增殖抑制作用,随着浓度增高,抑制效应增长显著;化合物2在50uM浓度时才开始出现对淋巴细胞增殖抑制作用,但随着浓度增高,抑制效应锐增;而化合物4虽然也是在50uM浓度时开始出现对淋巴细胞增殖抑制作用,但是随着浓度增高其抑制效应增长缓慢,提示维持异恶唑环及R1位置为苯基更为有利。
本实验结果表明,化合物1、3主要抑制特异性免疫,对丝裂原诱导的非特异性免疫抑制较弱。对绝大多数自身免疫病而言,特异性免疫(体液免疫和细胞免疫)紊乱在疾病发生发展中发挥了重要作用,抑制特异性免疫应答,纠正特异性免疫紊乱,可阻断疾病的进展和恶化。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (15)
2.如权利要求1所述的式I化合物或其药学上可接受的盐,其特征在于,Rb为取代或未取代的C2-C8烯基、或取代或未取代的异噁唑基,并且所述的取代指具有一个或多个选自下组A2的取代基:卤素、-OH、-CN、C1-C4烷基。
4.如权利要求1所述的式I化合物或其药学上可接受的盐,其特征在于,所述式I化合物选自下组:
5-甲基-异噁唑-{4-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-苯基}-4-酰胺;
5-甲基-异噁唑-{4-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-环己基}-胺;
2-氰基-3-羟基-2-丁烯-{4-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-苯基]-酰胺;
2-氰基-3-羟基-2-丁烯-{4-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-环己基]-酰胺;和
3-羟基-2-(1-{4-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-亚胺基苯基}-乙基)-2丁烯腈。
6.如权利要求5所述的方法,其特征在于,所述式II化合物与式III化合物的摩尔比为0.5-2:0.5-2。
7.如权利要求5所述的方法,其特征在于,所述式II化合物与式III化合物的摩尔比为1:1。
9.一种药物组合物,其特征在于,所述药物组合物包含治疗有效量的选自如权利要求1所述的化合物、或其药学上可接受的盐中的一种或多种,以及,药学上可接受的赋形剂。
10.如权利要求1所述的化合物或其药学上可接受的盐,或权利要求9所述的药物组合物在制备用于预防和治疗与JAK激酶相关的疾病和JAK激酶抑制剂的药物中的用途。
11.如权利要求10所述的用途,其特征在于,所述JAK激酶选自JAK1、JAK2和JAK3激酶。
12.如权利要求10所述的用途,其特征在于,所述疾病为自身免疫性和慢性炎症疾病。
13.如权利要求10所述的用途,其特征在于,所述疾病选自下组:系统性红斑狼疮、类风湿关节炎、多发性硬化症、II型糖尿病、炎性肠疾病、胆汁性肝硬化、葡萄膜炎、大疱性类天疱疮、结节病、银屑病、银屑病关节炎、自身免疫性肌炎、韦格纳肉芽肿病、格雷夫斯眼病、过敏性皮炎和哮喘。
14.如权利要求13所述的用途,其特征在于,所述炎性肠疾病选自下组:克罗恩病和溃疡性结肠炎。
15.一种体外非治疗性地抑制JAK激酶活性的方法,其特征在于,包括步骤:将权利要求1所述的化合物或其药学上可接受的盐与JAK激酶接触,从而抑制JAK激酶。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610100165.5A CN107098908B (zh) | 2016-02-23 | 2016-02-23 | 一种吡咯并嘧啶类化合物的制备方法和应用 |
PCT/CN2017/074446 WO2017143990A1 (zh) | 2016-02-23 | 2017-02-22 | 一种吡咯并嘧啶类化合物的制备方法和应用 |
US16/092,394 US11591333B2 (en) | 2016-02-23 | 2017-02-22 | Substituted pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
EP17755819.4A EP3421473B1 (en) | 2016-02-23 | 2017-02-22 | Method for preparing pyrrolopyrimidine compounds and application thereof |
HK19100586.9A HK1258226A1 (zh) | 2016-02-23 | 2019-01-14 | 一種吡咯並嘧啶類化合物的製備方法和應用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610100165.5A CN107098908B (zh) | 2016-02-23 | 2016-02-23 | 一种吡咯并嘧啶类化合物的制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107098908A CN107098908A (zh) | 2017-08-29 |
CN107098908B true CN107098908B (zh) | 2021-01-08 |
Family
ID=59658912
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610100165.5A Active CN107098908B (zh) | 2016-02-23 | 2016-02-23 | 一种吡咯并嘧啶类化合物的制备方法和应用 |
Country Status (5)
Country | Link |
---|---|
US (1) | US11591333B2 (zh) |
EP (1) | EP3421473B1 (zh) |
CN (1) | CN107098908B (zh) |
HK (1) | HK1258226A1 (zh) |
WO (1) | WO2017143990A1 (zh) |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3037980A (en) * | 1955-08-18 | 1962-06-05 | Burroughs Wellcome Co | Pyrrolopyrimidine vasodilators and method of making them |
PA8474101A1 (es) * | 1998-06-19 | 2000-09-29 | Pfizer Prod Inc | Compuestos de pirrolo [2,3-d] pirimidina |
AU3951899A (en) * | 1998-06-19 | 2000-01-05 | Pfizer Products Inc. | Pyrrolo(2,3-d)pyrimidine compounds |
AP1911A (en) * | 2000-06-26 | 2008-10-30 | Pfizer Prod Inc | Pyrrolo[2,3-d]pyrimidine compounds. |
KR20120083452A (ko) * | 2009-10-15 | 2012-07-25 | 화이자 인코포레이티드 | 피롤로[2,3-d]피리미딘 화합물 |
CA2782720A1 (en) * | 2009-12-18 | 2011-06-23 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US9187487B2 (en) | 2011-05-17 | 2015-11-17 | Principia Biopharma, Inc. | Azaindole derivatives as tyrosine kinase inhibitors |
KR102032934B1 (ko) * | 2011-12-21 | 2019-10-16 | 지앙수 헨그루이 메디슨 컴퍼니 리미티드 | 피롤 6원 헤테로아릴 고리 유도체, 그의 제조 방법, 및 그의 의약 용도 |
IN2015DN00370A (zh) * | 2012-07-20 | 2015-06-12 | Zoetis Llc | |
CN103896946B (zh) * | 2012-12-28 | 2018-04-03 | 浙江导明医药科技有限公司 | 用于预防及治疗多种自身免疫疾病的新化合物 |
CN105732636B (zh) * | 2014-12-30 | 2020-04-21 | 广东东阳光药业有限公司 | 杂芳化合物及其在药物中的应用 |
KR101771219B1 (ko) * | 2015-08-21 | 2017-09-05 | 양지화학 주식회사 | 야누스 키나제 1 선택적 억제제 및 그 의약 용도 |
-
2016
- 2016-02-23 CN CN201610100165.5A patent/CN107098908B/zh active Active
-
2017
- 2017-02-22 EP EP17755819.4A patent/EP3421473B1/en active Active
- 2017-02-22 US US16/092,394 patent/US11591333B2/en active Active
- 2017-02-22 WO PCT/CN2017/074446 patent/WO2017143990A1/zh active Application Filing
-
2019
- 2019-01-14 HK HK19100586.9A patent/HK1258226A1/zh unknown
Also Published As
Publication number | Publication date |
---|---|
WO2017143990A1 (zh) | 2017-08-31 |
US11591333B2 (en) | 2023-02-28 |
EP3421473A1 (en) | 2019-01-02 |
HK1258226A1 (zh) | 2019-11-08 |
US20220017522A1 (en) | 2022-01-20 |
EP3421473B1 (en) | 2022-03-30 |
EP3421473A4 (en) | 2019-10-02 |
CN107098908A (zh) | 2017-08-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112142735B (zh) | 一类稠和氰基吡啶类化合物、制备方法和用途 | |
CN112300194B (zh) | 一类稠环吡啶酮类化合物、制备方法和用途 | |
AU2014400628B2 (en) | Aminopyridazinone compounds as protein kinase inhibitors | |
JP6881879B2 (ja) | Jakキナーゼ阻害剤としてのピリミジン化合物 | |
EP4092024A1 (en) | Pyrimidine-4(3h)-ketone heterocyclic compound, preparation method therefor and use thereof in medicine and pharmacology | |
JP2018537482A (ja) | 抗癌薬として使用される複素環式化合物 | |
CN113527299B (zh) | 一类含氮稠环类化合物、制备方法和用途 | |
AU2021373162B2 (en) | Pyrazolopyridazinone compound, and pharmaceutical composition and use thereof | |
CN114195804A (zh) | 一类哌啶稠环类化合物、制备方法和用途 | |
CN112094269A (zh) | 一类饱和六元环并杂环类化合物、制备方法和用途 | |
CN115477640A (zh) | 作为parp7抑制剂的哒嗪酮类化合物 | |
CN111518100A (zh) | 环丙烯并苯并呋喃取代的氮杂芳基化合物及其应用 | |
CN111032630B (zh) | 一种化合物,其药物组合物及其用途及应用 | |
CN114516883A (zh) | 一种噻吩并嘧啶类化合物、其药物组合物及应用 | |
CN112939982A (zh) | 一种炔类杂环btk抑制剂及其制备方法和用途 | |
CN107098908B (zh) | 一种吡咯并嘧啶类化合物的制备方法和应用 | |
CN114075196B (zh) | 一类芳香环并内酰胺类化合物、其制备方法和用途 | |
CN114907350B (zh) | 一类含氮稠环类化合物、制备方法和用途 | |
WO2022240826A1 (en) | Heterocyclic derivatives as camkk2 inhibitors | |
CN118574830A (zh) | 一种哒嗪并吡啶酮类化合物、其药物组合物及应用 | |
CN114634521A (zh) | Dna-pk选择性抑制剂及其制备方法和用途 | |
CN112209925A (zh) | Ret选择性抑制剂及其制备方法和用途 | |
CN118056835A (zh) | 作为parp7抑制剂的哒嗪酮类化合物 | |
WO2024108131A1 (en) | Phthalazinone based modulators for the treatment of disease | |
CN117263950A (zh) | 一种哒嗪类化合物、其药物组合物及应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right |
Effective date of registration: 20230413 Address after: 201203 3rd floor, building 3, Lane 67, libing Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai Patentee after: CINKATE PHARMACEUTICAL INTERMEDIATES Co.,Ltd. Address before: 201203 4th floor, building 3, 67 libing Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai Patentee before: CINKATE PHARM TECH (SHANGHAI) Co.,Ltd. Patentee before: CINKATE PHARMACEUTICAL INTERMEDIATES Co.,Ltd. |
|
TR01 | Transfer of patent right |