TW201940475A - 製備jak抑制劑之方法及中間物 - Google Patents
製備jak抑制劑之方法及中間物 Download PDFInfo
- Publication number
- TW201940475A TW201940475A TW108103234A TW108103234A TW201940475A TW 201940475 A TW201940475 A TW 201940475A TW 108103234 A TW108103234 A TW 108103234A TW 108103234 A TW108103234 A TW 108103234A TW 201940475 A TW201940475 A TW 201940475A
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- formula
- reaction
- salt
- sodium
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 98
- 230000008569 process Effects 0.000 title abstract description 11
- 239000000543 intermediate Substances 0.000 title abstract description 10
- 229940122245 Janus kinase inhibitor Drugs 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 151
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 135
- 238000006243 chemical reaction Methods 0.000 claims description 93
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 70
- 150000003839 salts Chemical class 0.000 claims description 68
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 63
- 239000002904 solvent Substances 0.000 claims description 37
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- 239000003638 chemical reducing agent Substances 0.000 claims description 21
- 230000001590 oxidative effect Effects 0.000 claims description 18
- 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 16
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical group ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 14
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 229950009390 symclosene Drugs 0.000 claims description 14
- 230000003647 oxidation Effects 0.000 claims description 13
- 238000007254 oxidation reaction Methods 0.000 claims description 13
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 8
- 229960005091 chloramphenicol Drugs 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical group [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 6
- 150000003512 tertiary amines Chemical class 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 claims description 3
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 claims description 3
- GJQNVZVOTKFLIU-UHFFFAOYSA-N piperidin-1-ium-4-one;chloride Chemical compound Cl.O=C1CCNCC1 GJQNVZVOTKFLIU-UHFFFAOYSA-N 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 55
- 201000010099 disease Diseases 0.000 abstract description 54
- 102000015617 Janus Kinases Human genes 0.000 abstract description 50
- 108010024121 Janus Kinases Proteins 0.000 abstract description 50
- 206010028980 Neoplasm Diseases 0.000 abstract description 29
- 230000000694 effects Effects 0.000 abstract description 21
- 201000011510 cancer Diseases 0.000 abstract description 19
- 208000027866 inflammatory disease Diseases 0.000 abstract description 13
- 238000011282 treatment Methods 0.000 abstract description 10
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 8
- KTBSXLIQKWEBRB-UHFFFAOYSA-N 2-[1-[1-[3-fluoro-2-(trifluoromethyl)pyridine-4-carbonyl]piperidin-4-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile Chemical compound C1=CN=C(C(F)(F)F)C(F)=C1C(=O)N1CCC(N2CC(CC#N)(C2)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CC1 KTBSXLIQKWEBRB-UHFFFAOYSA-N 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 73
- 239000000243 solution Substances 0.000 description 73
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 70
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 65
- 239000007787 solid Substances 0.000 description 59
- 239000011541 reaction mixture Substances 0.000 description 57
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- 230000002829 reductive effect Effects 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 35
- 239000011734 sodium Chemical group 0.000 description 32
- 229910052757 nitrogen Inorganic materials 0.000 description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 21
- 239000000047 product Substances 0.000 description 20
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000012267 brine Substances 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 102000004127 Cytokines Human genes 0.000 description 15
- 108090000695 Cytokines Proteins 0.000 description 15
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 15
- 108010000837 Janus Kinase 1 Proteins 0.000 description 15
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 14
- 229910052708 sodium Inorganic materials 0.000 description 14
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 13
- 206010013774 Dry eye Diseases 0.000 description 12
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 201000004681 Psoriasis Diseases 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 206010028537 myelofibrosis Diseases 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 9
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- 230000004054 inflammatory process Effects 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
- ZQGYIMCJYKMORF-UHFFFAOYSA-N 1,4-dioxa-8-azaspiro[4.5]decan-8-yl-[3-fluoro-2-(trifluoromethyl)pyridin-4-yl]methanone Chemical compound C1=CN=C(C(F)(F)F)C(F)=C1C(=O)N1CCC2(OCCO2)CC1 ZQGYIMCJYKMORF-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 208000017733 acquired polycythemia vera Diseases 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 208000037244 polycythemia vera Diseases 0.000 description 8
- 230000011664 signaling Effects 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 7
- 201000004624 Dermatitis Diseases 0.000 description 7
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 230000009885 systemic effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 208000014767 Myeloproliferative disease Diseases 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 241000283984 Rodentia Species 0.000 description 6
- 206010046851 Uveitis Diseases 0.000 description 6
- IRJYGOFHHMEPAW-UHFFFAOYSA-N acetonitrile hexanedioic acid Chemical compound C(C)#N.C(CCCCC(=O)O)(=O)O IRJYGOFHHMEPAW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 206010003246 arthritis Diseases 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 210000003491 skin Anatomy 0.000 description 6
- JGPYLNFYLAFBTC-UHFFFAOYSA-N 2-[3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile Chemical compound C1=C(C=2C=3C=CNC=3N=CN=2)C=NN1C1(CC#N)CNC1 JGPYLNFYLAFBTC-UHFFFAOYSA-N 0.000 description 5
- 206010012442 Dermatitis contact Diseases 0.000 description 5
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 5
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- 108010063738 Interleukins Proteins 0.000 description 5
- 102000015696 Interleukins Human genes 0.000 description 5
- 102000042838 JAK family Human genes 0.000 description 5
- 108091082332 JAK family Proteins 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 229910004298 SiO 2 Inorganic materials 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 208000010668 atopic eczema Diseases 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000003102 growth factor Substances 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000010926 purge Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 210000002345 respiratory system Anatomy 0.000 description 5
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 5
- PNFXHELBYLWWLZ-UHFFFAOYSA-N (4-iodopyrazol-1-yl)-trimethylsilane Chemical compound C[Si](C)(C)N1C=C(I)C=N1 PNFXHELBYLWWLZ-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- GOJNFUXEBVBARW-UHFFFAOYSA-N 4-amino-6-chloropyrimidine-5-carbaldehyde Chemical compound NC1=NC=NC(Cl)=C1C=O GOJNFUXEBVBARW-UHFFFAOYSA-N 0.000 description 4
- WVGCPEDBFHEHEZ-UHFFFAOYSA-N 4-bromo-1h-pyrazole Chemical compound BrC=1C=NNC=1 WVGCPEDBFHEHEZ-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- 206010010741 Conjunctivitis Diseases 0.000 description 4
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 4
- 230000004163 JAK-STAT signaling pathway Effects 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- 208000009525 Myocarditis Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- 206010039705 Scleritis Diseases 0.000 description 4
- 229940124639 Selective inhibitor Drugs 0.000 description 4
- 206010070834 Sensitisation Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- PBINVYFFOPHLQR-UHFFFAOYSA-N [3-fluoro-2-(trifluoromethyl)pyridin-4-yl]-(4-hydroxypiperidin-1-yl)methanone Chemical compound OC1CCN(CC1)C(=O)c1ccnc(c1F)C(F)(F)F PBINVYFFOPHLQR-UHFFFAOYSA-N 0.000 description 4
- ZFYVPANOOXNHIW-UHFFFAOYSA-N acetonitrile;dihydrochloride Chemical compound Cl.Cl.CC#N ZFYVPANOOXNHIW-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 4
- 210000000845 cartilage Anatomy 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 208000010247 contact dermatitis Diseases 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 201000005962 mycosis fungoides Diseases 0.000 description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 208000003476 primary myelofibrosis Diseases 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000008313 sensitization Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- PBKONEOXTCPAFI-UHFFFAOYSA-N 1,2,4-trichlorobenzene Chemical compound ClC1=CC=C(Cl)C(Cl)=C1 PBKONEOXTCPAFI-UHFFFAOYSA-N 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 3
- SNBYDHCSBZIOQL-UHFFFAOYSA-N 3-hydroxyazetidine-1-carboxylic acid Chemical compound OC1CN(C(O)=O)C1 SNBYDHCSBZIOQL-UHFFFAOYSA-N 0.000 description 3
- XQSJHQXYQAUDFC-UHFFFAOYSA-N 4,6-dichloropyrimidine-5-carbaldehyde Chemical compound ClC1=NC=NC(Cl)=C1C=O XQSJHQXYQAUDFC-UHFFFAOYSA-N 0.000 description 3
- DUFGYCAXVIUXIP-UHFFFAOYSA-N 4,6-dihydroxypyrimidine Chemical compound OC1=CC(O)=NC=N1 DUFGYCAXVIUXIP-UHFFFAOYSA-N 0.000 description 3
- IOYBCQUZINUXEI-UHFFFAOYSA-N 4-bromo-1-(2-ethoxyethyl)pyrazole Chemical compound CCOCCN1C=C(Br)C=N1 IOYBCQUZINUXEI-UHFFFAOYSA-N 0.000 description 3
- LLNQWPTUJJYTTE-UHFFFAOYSA-N 4-iodopyrazole Chemical compound IC=1C=NNC=1 LLNQWPTUJJYTTE-UHFFFAOYSA-N 0.000 description 3
- JLTOEABHOGMVTH-UHFFFAOYSA-N 6-chloro-5-(2-methoxyethenyl)pyrimidin-4-amine Chemical compound COC=CC1=C(N)N=CN=C1Cl JLTOEABHOGMVTH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 206010012438 Dermatitis atopic Diseases 0.000 description 3
- 206010058314 Dysplasia Diseases 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- 206010070835 Skin sensitisation Diseases 0.000 description 3
- 239000005708 Sodium hypochlorite Substances 0.000 description 3
- LCKIEQZJEYYRIY-UHFFFAOYSA-N Titanium ion Chemical compound [Ti+4] LCKIEQZJEYYRIY-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000001361 adipic acid Substances 0.000 description 3
- 235000011037 adipic acid Nutrition 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000000172 allergic effect Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- 230000037182 bone density Effects 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 239000002024 ethyl acetate extract Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 201000004614 iritis Diseases 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 206010025135 lupus erythematosus Diseases 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 3
- 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 3
- 239000000376 reactant Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 206010039083 rhinitis Diseases 0.000 description 3
- 208000017520 skin disease Diseases 0.000 description 3
- 231100000370 skin sensitisation Toxicity 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 2
- LCHTWRWPHBRTNO-UHFFFAOYSA-N 1-benzhydrylazetidin-3-ol;hydrochloride Chemical compound Cl.C1C(O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 LCHTWRWPHBRTNO-UHFFFAOYSA-N 0.000 description 2
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- XELKWDFNWRGTLX-UHFFFAOYSA-N 2-(azetidin-3-ylidene)acetonitrile;hydrochloride Chemical compound Cl.N#CC=C1CNC1 XELKWDFNWRGTLX-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- NJVBRQCIRKXSEC-UHFFFAOYSA-N 2-[1-[1-[[3-fluoro-2-(trifluoromethyl)pyridin-4-yl]methyl]piperidin-4-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile Chemical compound C1=CN=C(C(F)(F)F)C(F)=C1CN1CCC(N2CC(CC#N)(C2)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CC1 NJVBRQCIRKXSEC-UHFFFAOYSA-N 0.000 description 2
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- GOYPFNAZTPCXGS-UHFFFAOYSA-N 3-fluoro-2-(trifluoromethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(F)(F)F)=C1F GOYPFNAZTPCXGS-UHFFFAOYSA-N 0.000 description 2
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 2
- IUKMFDRZLSINSM-UHFFFAOYSA-N C1CN(CCC1=O)C2=C(C=CC=N2)CC3=C(C(=NC=C3)C(F)(F)F)F Chemical compound C1CN(CCC1=O)C2=C(C=CC=N2)CC3=C(C(=NC=C3)C(F)(F)F)F IUKMFDRZLSINSM-UHFFFAOYSA-N 0.000 description 2
- FEYXNXSWKWGYQZ-UHFFFAOYSA-N C1CN(CCC1=O)CCC2=C(C(=NC=C2)C(F)(F)F)F Chemical compound C1CN(CCC1=O)CCC2=C(C(=NC=C2)C(F)(F)F)F FEYXNXSWKWGYQZ-UHFFFAOYSA-N 0.000 description 2
- QURMUUDZQGNREA-UHFFFAOYSA-N C1CN(CCC1N2CC(C2)(CC#N)N3C=C(C=N3)C4=C5C=CNC5=NC=N4)C6=C(C=CC7=C6CC8=CC=CC=C87)CC9=C(C(=NC=C9)C(F)(F)F)F Chemical compound C1CN(CCC1N2CC(C2)(CC#N)N3C=C(C=N3)C4=C5C=CNC5=NC=N4)C6=C(C=CC7=C6CC8=CC=CC=C87)CC9=C(C(=NC=C9)C(F)(F)F)F QURMUUDZQGNREA-UHFFFAOYSA-N 0.000 description 2
- 206010006895 Cachexia Diseases 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- GATVIKZLVQHOMN-UHFFFAOYSA-N Chlorodibromomethane Chemical compound ClC(Br)Br GATVIKZLVQHOMN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000002691 Choroiditis Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 108010062580 Concanavalin A Proteins 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 108010075944 Erythropoietin Receptors Proteins 0.000 description 2
- 102100036509 Erythropoietin receptor Human genes 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- 208000009386 Experimental Arthritis Diseases 0.000 description 2
- 108010091824 Focal Adhesion Kinase 1 Proteins 0.000 description 2
- 102100037813 Focal adhesion kinase 1 Human genes 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- 208000029462 Immunodeficiency disease Diseases 0.000 description 2
- 208000004575 Infectious Arthritis Diseases 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- 206010028561 Myeloid metaplasia Diseases 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- 206010034277 Pemphigoid Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 208000008601 Polycythemia Diseases 0.000 description 2
- 208000003971 Posterior uveitis Diseases 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 206010038910 Retinitis Diseases 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 2
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 102000000887 Transcription factor STAT Human genes 0.000 description 2
- 108050007918 Transcription factor STAT Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000010072 bone remodeling Effects 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 208000019664 bone resorption disease Diseases 0.000 description 2
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 208000000594 bullous pemphigoid Diseases 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000001886 ciliary effect Effects 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 125000005265 dialkylamine group Chemical group 0.000 description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 210000005069 ears Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- ZQBFAOFFOQMSGJ-UHFFFAOYSA-N hexafluorobenzene Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1F ZQBFAOFFOQMSGJ-UHFFFAOYSA-N 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000002991 immunohistochemical analysis Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229940047122 interleukins Drugs 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 210000003593 megakaryocyte Anatomy 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- PKVRJCUKSNFIBN-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 PKVRJCUKSNFIBN-UHFFFAOYSA-N 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 159000000001 potassium salts Chemical group 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000011808 rodent model Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 201000001223 septic arthritis Diseases 0.000 description 2
- 201000009890 sinusitis Diseases 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- QUERMGFVJPRMJL-UHFFFAOYSA-N tert-butyl azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC1 QUERMGFVJPRMJL-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 206010043554 thrombocytopenia Diseases 0.000 description 2
- 206010043778 thyroiditis Diseases 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- FRXOYYBDUSFAGK-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane Chemical compound ClN1CN(Cl)CN(Cl)C1 FRXOYYBDUSFAGK-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- KPKNTUUIEVXMOH-UHFFFAOYSA-N 1,4-dioxa-8-azaspiro[4.5]decane Chemical compound O1CCOC11CCNCC1 KPKNTUUIEVXMOH-UHFFFAOYSA-N 0.000 description 1
- VXBPZOLCIITMPB-UHFFFAOYSA-N 1,4-dioxa-8-azaspiro[4.5]decane;hydrochloride Chemical compound Cl.O1CCOC11CCNCC1 VXBPZOLCIITMPB-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- CJYZRVRNCDOPKI-UHFFFAOYSA-N 1-[[3-fluoro-2-(trifluoromethyl)pyridin-4-yl]methyl]piperidin-4-one Chemical compound FC1=C(CN2CCC(CC2)=O)C=CN=C1C(F)(F)F CJYZRVRNCDOPKI-UHFFFAOYSA-N 0.000 description 1
- JDCSQLCLIAJBBK-UHFFFAOYSA-N 1-benzylazetidin-1-ium-3-ol;chloride Chemical compound Cl.C1C(O)CN1CC1=CC=CC=C1 JDCSQLCLIAJBBK-UHFFFAOYSA-N 0.000 description 1
- JOXQHYFVXZZGQZ-UHFFFAOYSA-N 1-benzylazetidin-3-ol Chemical compound C1C(O)CN1CC1=CC=CC=C1 JOXQHYFVXZZGQZ-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical class CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- BJWNKFVWHPJKQZ-UHFFFAOYSA-N 2,3-dimethylbut-2-enenitrile Chemical compound CC(C)=C(C)C#N BJWNKFVWHPJKQZ-UHFFFAOYSA-N 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- OWMAUILZJRKPBN-UHFFFAOYSA-N 2-(azetidin-3-ylidene)acetonitrile Chemical compound N#CC=C1CNC1 OWMAUILZJRKPBN-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical group FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- KIPMDPDAFINLIV-UHFFFAOYSA-N 2-nitroethanol Chemical compound OCC[N+]([O-])=O KIPMDPDAFINLIV-UHFFFAOYSA-N 0.000 description 1
- NIJDLMFDTGNKRK-UHFFFAOYSA-N 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidine-1-carboxylic acid Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(C2(CC#N)CN(C2)C(O)=O)N=C1 NIJDLMFDTGNKRK-UHFFFAOYSA-N 0.000 description 1
- TWCMZOCNJQYFJV-UHFFFAOYSA-N 3-(cyanomethylidene)azetidine-1-carboxylic acid Chemical compound OC(=O)N1CC(=CC#N)C1 TWCMZOCNJQYFJV-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- JAARRMAXWFHZJM-UHFFFAOYSA-N 3-oxoazetidine-1-carboxylic acid Chemical compound OC(=O)N1CC(=O)C1 JAARRMAXWFHZJM-UHFFFAOYSA-N 0.000 description 1
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- RUKDVLFJSMVBLV-UHFFFAOYSA-N 5-iodo-1h-pyrazole Chemical compound IC1=CC=NN1 RUKDVLFJSMVBLV-UHFFFAOYSA-N 0.000 description 1
- DUKKRSPKJMHASP-UHFFFAOYSA-N 6-chloropyrimidin-4-amine Chemical compound NC1=CC(Cl)=NC=N1 DUKKRSPKJMHASP-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 206010001557 Albinism Diseases 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 244000036975 Ambrosia artemisiifolia Species 0.000 description 1
- 235000003129 Ambrosia artemisiifolia var elatior Nutrition 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- XHUXWZPBAWJIRN-UHFFFAOYSA-N B(O)(O)O.COCC(O)(C)C(C)(C)O Chemical compound B(O)(O)O.COCC(O)(C)C(C)(C)O XHUXWZPBAWJIRN-UHFFFAOYSA-N 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- LBFFRGJOHFMFPF-UHFFFAOYSA-N C(CCC)C1N(CC1)C(=O)O Chemical group C(CCC)C1N(CC1)C(=O)O LBFFRGJOHFMFPF-UHFFFAOYSA-N 0.000 description 1
- PIMMPEGPGOYDMI-UHFFFAOYSA-N C(CCC)C1N(CC1O)C(=O)O Chemical compound C(CCC)C1N(CC1O)C(=O)O PIMMPEGPGOYDMI-UHFFFAOYSA-N 0.000 description 1
- IVTIIJPBAOFMEE-UHFFFAOYSA-N C(CCCCC(=O)O)(=O)O.N1=CN=C(C2=C1NC=C2)C=2C=NN(C2)C2(CN(C2)C2CCN(CC2)CC2=C(C(=NC=C2)C(F)(F)F)F)CC#N Chemical compound C(CCCCC(=O)O)(=O)O.N1=CN=C(C2=C1NC=C2)C=2C=NN(C2)C2(CN(C2)C2CCN(CC2)CC2=C(C(=NC=C2)C(F)(F)F)F)CC#N IVTIIJPBAOFMEE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010007279 Carcinoid tumour of the gastrointestinal tract Diseases 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 208000005024 Castleman disease Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 206010058112 Chondrolysis Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 206010011219 Costochondritis Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 102100038497 Cytokine receptor-like factor 2 Human genes 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010014025 Ear swelling Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 241001326189 Gyrodactylus prostae Species 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical compound ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000956427 Homo sapiens Cytokine receptor-like factor 2 Proteins 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 238000000023 Kugelrohr distillation Methods 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 241001237732 Microtia Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101100346764 Mus musculus Mtln gene Proteins 0.000 description 1
- 101100095974 Mus musculus Smc3 gene Proteins 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108091008611 Protein Kinase B Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 201000008736 Systemic mastocytosis Diseases 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 102000036693 Thrombopoietin Human genes 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 208000026317 Tietze syndrome Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 1
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- PWUBONDMIMDOQY-UHFFFAOYSA-N acetonitrile;hydrochloride Chemical compound Cl.CC#N PWUBONDMIMDOQY-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- TVJORGWKNPGCDW-UHFFFAOYSA-N aminoboron Chemical compound N[B] TVJORGWKNPGCDW-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 235000003484 annual ragweed Nutrition 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 208000026764 autoimmune bullous skin disease Diseases 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 201000004982 autoimmune uveitis Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000004888 barrier function Effects 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
- 238000012742 biochemical analysis Methods 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- YLCRSZMKPIXDDD-UHFFFAOYSA-N boric acid 2,3,5-trimethylhexane-2,3-diol Chemical compound OB(O)O.CC(C)CC(C)(O)C(C)(C)O YLCRSZMKPIXDDD-UHFFFAOYSA-N 0.000 description 1
- QHXLIQMGIGEHJP-UHFFFAOYSA-N boron;2-methylpyridine Chemical compound [B].CC1=CC=CC=N1 QHXLIQMGIGEHJP-UHFFFAOYSA-N 0.000 description 1
- VPEPQDBAIMZCGV-UHFFFAOYSA-N boron;5-ethyl-2-methylpyridine Chemical compound [B].CCC1=CC=C(C)N=C1 VPEPQDBAIMZCGV-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- NNTOJPXOCKCMKR-UHFFFAOYSA-N boron;pyridine Chemical compound [B].C1=CC=NC=C1 NNTOJPXOCKCMKR-UHFFFAOYSA-N 0.000 description 1
- 229950005228 bromoform Drugs 0.000 description 1
- 235000006263 bur ragweed Nutrition 0.000 description 1
- VSCMKGSHVUPBEE-UHFFFAOYSA-N butyl 3-oxoazetidine-1-carboxylate Chemical compound CCCCOC(=O)N1CC(=O)C1 VSCMKGSHVUPBEE-UHFFFAOYSA-N 0.000 description 1
- DFPYOQLZOOMYLN-UHFFFAOYSA-N butyl cyclobutanecarboxylate Chemical group CCCCOC(=O)C1CCC1 DFPYOQLZOOMYLN-UHFFFAOYSA-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
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 235000003488 common ragweed Nutrition 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- UQHKFADEQIVWID-UHFFFAOYSA-N cytokinin Natural products C1=NC=2C(NCC=C(CO)C)=NC=NC=2N1C1CC(O)C(CO)O1 UQHKFADEQIVWID-UHFFFAOYSA-N 0.000 description 1
- 239000004062 cytokinin Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 230000002327 eosinophilic effect Effects 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000006589 gland dysfunction Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000011554 guinea pig model Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid group Chemical group C(CCCCCC)(=O)O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid group Chemical group C(CCCCC)(=O)O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 102000049918 human JAK1 Human genes 0.000 description 1
- 238000013415 human tumor xenograft model Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000011824 leiomyosarcoma of the corpus uteri Diseases 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000012423 maintenance Methods 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
- 230000036244 malformation Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- MIKKOBKEXMRYFQ-WZTVWXICSA-N meglumine amidotrizoate Chemical compound C[NH2+]C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I MIKKOBKEXMRYFQ-WZTVWXICSA-N 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910001509 metal bromide Inorganic materials 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- MBHINSULENHCMF-UHFFFAOYSA-N n,n-dimethylpropanamide Chemical compound CCC(=O)N(C)C MBHINSULENHCMF-UHFFFAOYSA-N 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
- DYFFAVRFJWYYQO-UHFFFAOYSA-N n-methyl-n-phenylaniline Chemical compound C=1C=CC=CC=1N(C)C1=CC=CC=C1 DYFFAVRFJWYYQO-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 229940092253 ovalbumin Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000009038 pharmacological inhibition Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 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 1
- 230000003334 potential effect Effects 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000007112 pro inflammatory response Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 235000009736 ragweed Nutrition 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- ATMQILXYOUZQKX-UHFFFAOYSA-N sodium N,N-diethylethanamine Chemical compound [Na+].CCN(CC)CC ATMQILXYOUZQKX-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000009996 subepithelial mucinous corneal dystrophy Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 230000004489 tear production Effects 0.000 description 1
- JBOTYFLJTLOKTI-UHFFFAOYSA-N tert-butyl 3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 JBOTYFLJTLOKTI-UHFFFAOYSA-N 0.000 description 1
- BESFCRTTXQYNBW-UHFFFAOYSA-N tert-butyl 3-(cyanomethylidene)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=CC#N)C1 BESFCRTTXQYNBW-UHFFFAOYSA-N 0.000 description 1
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 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
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- 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
- 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
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
Abstract
本發明係關於製備{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之方法及中間物,其可用於治療與Janus激酶(JAK)活性相關之疾病,包括發炎性病症、自體免疫病症、癌症及其他疾病。
Description
本發明係關於製備{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之方法及中間物,其可用於治療與Janus激酶(JAK)活性相關之疾病,包括發炎性病症、自體免疫病症、癌症及其他疾病。
蛋白激酶(Protein kinase,PK)調控各種生物過程,尤其包括細胞生長、存活、分化、器官形成、形態發生、新血管形成、組織修復及再生。蛋白激酶亦在包括癌症之許多人類疾病中起專門作用。細胞介素、低分子量多肽或糖蛋白調控與宿主對敗血症之發炎反應相關的許多路徑。細胞介素影響細胞分化、增殖及活化,且可調節促炎反應與消炎反應以允許宿主對病原體適當地反應。大量細胞介素之信號傳導涉及蛋白酪胺酸激酶之Janus激酶家族(JAK)及信號傳導與轉錄活化因子(STAT)。存在四種已知之哺乳動物JAK:JAK1 (Janus激酶-1)、JAK2、JAK3 (亦稱Janus激酶,白血球;JAKL;及L-JAK)及TYK2 (蛋白酪胺酸激酶2)。
細胞介素刺激之免疫及發炎反應引起疾病之發病機理:諸如嚴重合併性免疫缺失病(SCID)之病理由免疫系統受到遏制產生,而過度活性或不適當免疫/發炎反應引起自體免疫疾病(例如氣喘、全身性紅斑狼瘡、甲狀腺炎、心肌炎)及諸如硬皮病及骨關節炎之疾病的病理(Ortmann, R. A., T. Cheng等人(2000)Arthritis Res
2(1): 16-32)。
JAK表現之缺乏與許多疾病病況有關。舉例而言,Jak1-/-小鼠在出生時矮小,無法餵奶且在圍產期死亡(Rodig, S. J., M. A. Meraz等人, (1998)Cell
93(3): 373-83)。Jak2-/-小鼠胚胎貧血且在交配後約12.5天由於缺乏定向型紅血球生成而死亡。咸信JAK/STAT路徑及尤其所有四種JAK在氣喘反應、慢性阻塞性肺病、支氣管炎及下呼吸道之其他相關發炎疾病之發病機理中起作用。經由JAK傳導信號之多種細胞介素與上呼吸道之發炎疾病/病狀相關聯,諸如影響鼻及鼻竇之疾病(例如鼻炎及鼻竇炎),無論是否在傳統上為過敏反應。JAK/STAT路徑亦與眼睛之發炎疾病/病狀及慢性過敏反應相關。
癌症中JAK/STAT可藉由刺激細胞介素(例如IL-6或GM-CSF)或藉由減少諸如SOCS (細胞介素信號傳導之遏制因子)或PIAS (活化STAT之蛋白抑制因子)的JAK信號傳導之內源性抑制因子而活化(Boudny, V.及Kovarik, J.,Neoplasm
. 49:349-355, 2002)。STAT信號傳導以及JAK下游之其他路徑(例如Akt)的活化與許多癌症類型中之不良預後相關(Bowman, T.等人,Oncogene
19:2474-2488, 2000)。升高水準之經由JAK/STAT傳導信號之循環細胞介素係惡病質及/或慢性疲勞之起因。因而,JAK抑制可因延伸超過潛在抗腫瘤活性之原因而有益於癌症患者。JAK2酪胺酸激酶可有益於患有骨髓增生性病症,例如真性紅血球增多症(PV)、特發性血小板增多症(ET)、伴有骨髓纖維化之髓樣化生(MMM)的患者(Levin等人,Cancer Cell
, 第7卷, 2005: 387-397)。JAK2V617F激酶之抑制減少造血細胞之增殖,此表明JAK2為PV、ET及MMM之患者中藥理學抑制之潛在標靶。
JAK之抑制可有益於罹患皮膚免疫病症,諸如牛皮癬及皮膚敏化之患者。咸信除其中多者經由JAK傳導信號(Adv Pharmacol.
2000;47:113-74)之多種趨化介素及生長因子外,牛皮癬之維持視許多發炎細胞介素而定(JCI, 113:1664-1675)。
JAK1在失調時可引起或造成疾病病況之許多細胞介素及生長因子信號傳導路徑中起重要作用。舉例而言,在類風濕性關節炎中IL-6水準升高,類風濕性關節炎係一種已表明具有不利影響之疾病(Fonesca, J.E.等人, Autoimmunity Reviews, 8:538-42, 2009)。因為IL-6至少部分經由JAK1傳導信號,所以預期直接或間接經由抑制JAK1對抗IL-6可提供臨床益處(Guschin, D., N.等人, Embo J 14:1421, 1995;Smolen, J. S.等人, Lancet 371:987, 2008)。此外,在一些癌症中,JAK1突變,引起組成性不希望之腫瘤細胞生長及存活(Mullighan CG, Proc Natl Acad Sci U S A.106:9414-8, 2009;Flex E.等人, J Exp Med. 205:751-8, 2008)。在其他自體免疫疾病及癌症中,升高的全身水準之活化JAK1之發炎細胞介素亦可引起該疾病及/或相關症狀。因此,此類疾病之患者可得益於JAK1抑制。JAK1之選擇性抑制劑可為有效的,同時避免抑制其他JAK激酶之不必要及可能不良之作用。
相對於其他JAK激酶,JAK1之選擇性抑制劑與較低選擇性抑制劑相比可具有多個治療優點。關於針對JAK2之選擇性,許多重要細胞介素及生長因子經由JAK2傳導信號,包括例如促紅細胞生成素(Epo)及血小板生成素(Tpo) (Parganas E等人, Cell. 93:385-95, 1998)。Epo為紅血球產生之關鍵生長因子;因此,缺乏Epo依賴性信號傳導可引起紅血球數目減少及貧血(Kaushansky K, NEJM 354:2034-45, 2006)。Tpo為JAK2依賴性生長因子之另一實例,其在控制巨核細胞,亦即產生血小板之細胞的增殖及成熟中起重要作用(Kaushansky K, NEJM 354:2034-45, 2006)。因而,Tpo信號傳導減少將降低巨核細胞數目(巨核細胞減少症),且降低循環血小板計數(血小板減少症)。此可引起不希望及/或無法控制之出血。諸如JAK3及Tyk2之其他JAK之抑制減少亦可為合乎需要的,因為缺乏此等激酶之功能型式之人類已顯示罹患許多病,諸如嚴重合併性免疫缺失病或高免疫球蛋白E症候群(Minegishi, Y等人, Immunity 25:745-55, 2006;Macchi P等人, Nature. 377:65-8, 1995)。因此,對其他JAK之親和力降低之JAK1抑制劑與較低選擇性抑制劑相比,在減少涉及免疫抑制、貧血及血小板減少症之副作用方面將具有顯著優點。
由於JAK抑制劑有用,所以需要發展新的用於製備JAK抑制劑之方法。本發明係針對此需要及其他需要。
JAK抑制劑描述於以引用之方式整體併入本文中之US 2011/0224190中,其包括{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈,其在下文描繪為式I。
I
I
本發明尤其提供用於製備式I化合物之方法及中間物。
詳言之,本發明提供一種方法,其包括使式III化合物:
III
或其鹽與4-羥基哌啶反應,形成式IV化合物:
IV
或其鹽。
III
或其鹽與4-羥基哌啶反應,形成式IV化合物:
IV
或其鹽。
本文所述之方法可進一步包括使式IV化合物或其鹽在氧化條件下反應,形成式V化合物:
V
或其鹽。
V
或其鹽。
本發明亦提供一種方法,其包括使式III化合物:
III
或其鹽與4-哌啶酮或其鹽反應,形成式V化合物:
V
或其鹽。
III
或其鹽與4-哌啶酮或其鹽反應,形成式V化合物:
V
或其鹽。
在一些實施例中,本文所述之方法進一步包括使式V化合物與式VI化合物:
VI
或其鹽在還原劑存在下反應,形成式I化合物:
I
或其鹽;
其中Z1 為H或保護基。
VI
或其鹽在還原劑存在下反應,形成式I化合物:
I
或其鹽;
其中Z1 為H或保護基。
本發明亦提供式III化合物:
III
或其鹽。
III
或其鹽。
應瞭解,為簡單起見,在分開實施例之上下文中描述的本發明之某些特徵亦可組合提供於單個實施例中。相反地,為簡便起見,在單個實施例之上下文中描述的本發明之多種特徵亦可分開或呈任何合適子組合提供。
本文所述之方法可根據本領域中已知之任何合適方法監測。舉例而言,產物形成可藉由光譜手段監測,諸如核磁共振譜法(例如1
H或13
C)、紅外光譜法或分光光度測定法(例如UV-可見光);或藉由層析法監測,諸如高效液相層析法(HPLC)或薄層層析法(TLC)或其他相關技術。
如本文所用,術語「反應」如本領域中已知使用,且一般係指將化學試劑以允許其在分子層面相互作用,從而實現化學或物理轉化之方式聚集。在一些實施例中,反應涉及兩種試劑,其中相對於第一試劑,使用一或多個當量之第二試劑。本文所述之方法之反應步驟可在適合於製備所鑑別產物之條件下進行適合於製備所鑑別產物的時間。
化合物之製備可涉及多種化學基團之保護及脫除保護基。對保護及脫除保護基之需要及適當保護基之選擇容易由本領域之技術人員確定。保護基之化學可見於例如Greene等人, Protective Groups in Organic Synthesis, 第4版, Wiley & Sons, 2007,其以引用之方式整體併入本文中。本文所述之對保護基之調整及形成及裂解方法可按需要根據多種取代基調整。
本文所述之方法之反應可在有機合成領域之技術人員容易選擇的合適溶劑中進行。合適溶劑可實質上不與起始物質(反應物)、中間物或產物在進行反應之溫度,例如可在溶劑冷凍溫度至溶劑沸點溫度範圍內的溫度下反應。既定反應可在一種溶劑中或超過一種溶劑之混合物中進行。視具體反應步驟而定,可針對具體反應步驟選擇合適溶劑。在一些實施例中,可在缺少溶劑下,諸如當至少一種試劑為液體或氣體時進行反應。
合適溶劑可包括鹵化溶劑,諸如四氯化碳、溴二氯甲烷、二溴氯甲烷、溴仿、氯仿、溴氯甲烷、二溴甲烷、丁基氯、二氯甲烷、四氯乙烯、三氯乙烯、1,1,1-三氯乙烷、1,1,2-三氯乙烷、1,1-二氯乙烷、2-氯丙烷、α,α,α-三氟甲苯、1,2-二氯乙烷、1,2-二溴乙烷、六氟苯、1,2,4-三氯苯、1,2-二氯苯、氯苯、氟苯、其混合物及其類似物。
合適醚溶劑包括:二甲氧基甲烷、四氫呋喃、1,3-二噁烷、1,4-二噁烷、呋喃、***、乙二醇二甲醚、乙二醇二***、二乙二醇二甲醚、二乙二醇二***、三乙二醇二甲醚、苯甲醚、第三丁基甲基醚、其混合物及其類似物。
合適質子溶劑可包括例如且不限於水、甲醇、乙醇、2-硝基乙醇、2-氟乙醇、2,2,2-三氟乙醇、乙二醇、1-丙醇、2-丙醇、2-甲氧基乙醇、1-丁醇、2-丁醇、異丁醇、第三丁醇、2-乙氧基乙醇、二乙二醇、1-戊醇、2-戊醇或3-戊醇、新戊醇、第三戊醇、二乙二醇單甲醚、二乙二醇單***、環己醇、苯甲醇、苯酚或丙三醇。
合適非質子溶劑可包括例如且不限於四氫呋喃(THF)、N,N-二甲基甲醯胺(DMF)、N,N-二甲基乙醯胺(DMA)、1,3-二甲基-3,4,5,6-四氫-2(1H)-嘧啶酮(DMPU)、1,3-二甲基-2-咪唑啶酮(DMI)、N-甲基吡咯啶酮(NMP)、甲醯胺、N-甲基乙醯胺、N-甲基甲醯胺、乙腈、二甲亞碸、丙腈、甲酸乙酯、乙酸甲酯、六氯丙酮、丙酮、乙基甲基酮、乙酸乙酯、環丁碸、N,N-二甲基丙醯胺、四甲基脲、硝基甲烷、硝基苯或六甲基磷醯胺。
合適烴溶劑包括苯、環己烷、戊烷、己烷、甲苯、環庚烷、甲基環己烷、庚烷、乙苯、間二甲苯、鄰二甲苯或對二甲苯、辛烷、茚滿、壬烷或萘。
本文所述之方法之反應可在熟練技術人員容易確定之適當溫度下進行。反應溫度將視例如以下而定:試劑及溶劑(若存在)之熔點及沸點;反應熱力學(例如劇烈放熱反應可能需要在降低溫度下進行);及反應動力學(例如高活化能量障壁可能需要高溫)。「高溫」係指超過室溫(約22℃)之溫度。本文所述之方法之反應可在空氣中或在惰性氛圍下進行。通常,含有實質上與空氣反應之試劑或產物的反應可使用熟練技術人員熟知之空氣敏感性合成技術進行。
在一些實施例中,化合物之製備可涉及酸或鹼之添加以實現例如所需反應之催化或諸如酸加成鹽之鹽形式的形成。
示例酸可為無機酸或有機酸。無機酸包括鹽酸、氫溴酸、硫酸、磷酸及硝酸。有機酸包括甲酸、乙酸、丙酸、丁酸、苯甲酸、4-硝基苯甲酸、甲烷磺酸、對甲苯磺酸、苯磺酸、酒石酸、三氟乙酸、丙炔酸、丁酸、2-丁炔酸、乙烯基乙酸、戊酸、己酸、庚酸、辛酸、壬酸及癸酸。
示例鹼包括氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸鋰、碳酸鈉、碳酸鉀及碳酸氫鈉。一些示例強鹼包括(但不限於)氫氧化物、烷氧化物、金屬醯胺、金屬氫化物、金屬二烷基醯胺及芳基胺,其中烷氧化物包括甲基、乙基及第三丁基氧化物之鋰鹽、鈉鹽及鉀鹽;金屬醯胺包括胺基鈉、胺基鉀及胺基鋰;金屬氫化物包括氫化鈉、氫化鉀及氫化鋰;且金屬二烷基醯胺包括甲基、乙基、正丙基、異丙基、正丁基、第三丁基、三甲基矽烷基及經環己基取代之醯胺的鈉鹽及鉀鹽。
中間物及產物亦可包括本文揭示之化合物之鹽。如本文所用,術語「鹽」係指由可接受之酸或鹼添加至本文揭示之化合物所形成的鹽。在一些實施例中,鹽為醫藥學上可接受之鹽。如本文所用,短語「醫藥學上可接受」係指自毒物學觀點可接受用於醫藥應用中且不會不利地與活性成分相互作用的物質。包括單鹽及雙鹽之醫藥學上可接受之鹽包括(但不限於)衍生自有機酸及無機酸之鹽,該等酸諸如但不限於乙酸、乳酸、檸檬酸、肉桂酸、酒石酸、琥珀酸、反丁烯二酸、順丁烯二酸、丙二酸、扁桃酸、蘋果酸、草酸、丙酸、鹽酸、氫溴酸、磷酸、硝酸、硫酸、乙醇酸、丙酮酸、甲烷磺酸、乙烷磺酸、甲苯磺酸、水楊酸、苯甲酸及類似已知之可接受之酸。合適鹽之清單見於Remington's Pharmaceutical Sciences, 第17版, Mack Publishing Company, Easton, Pa., 1985, 第1418頁及Journal of Pharmaceutical Science, 66, 2 (1977),各以引用之方式整體併入本文中。
在根據本文所述之方法製備化合物之後,可使用通常分離及純化操作,諸如濃縮、過濾、萃取、固相萃取、再結晶、層析及其類似操作,以分離所需產物。
在一些實施例中,本文所述之化合物及其鹽實質上分離。「實質上分離」意謂化合物至少部分或實質上與形成或偵測到其之環境分離。部分分離可包括例如富集本發明化合物之組合物。實質上分離可包括含有至少約50重量%、至少約60重量%、至少約70重量%、至少約80重量%、至少約90重量%、至少約95重量%、至少約97重量%或至少約99重量%之本發明化合物或其鹽的組合物。分離化合物及其鹽之方法為本領域中之常規方法。
用於製備一些中間物之方法可見於2015年3月24日頒予之美國專利第8,987,443號;2016年11月8日頒予之美國專利第9,487,521號;2013年4月2日頒予之美國專利第8,410,265號及2014年7月1日頒予之美國專利第8,765,734號,各以引用之方式整體併入本文中。
方法及中間物
方法及中間物
本發明尤其提供用於製備式I化合物之方法及中間物。因此,在一個態樣中,本文提供一種方法,其包括使式III化合物:
III
或其鹽與4-羥基哌啶反應,形成式IV化合物:
IV
或其鹽。
III
或其鹽與4-羥基哌啶反應,形成式IV化合物:
IV
或其鹽。
在一些實施例中,與4-羥基哌啶之反應在鹼存在下進行。
在一些實施例中,鹼為三級胺。
在一些實施例中,三級胺為N,N
-二異丙基乙胺。
在一些實施例中,與4-羥基哌啶之反應在包含二氯甲烷之溶劑組分中進行。
在一些實施例中,與4-羥基哌啶之反應在約25℃至約35℃之溫度下進行。
在一些實施例中,式III化合物由如下方法形成,該方法包括使式II化合物:
II
或其鹽與草醯氯反應,形成式III化合物或其鹽。
II
或其鹽與草醯氯反應,形成式III化合物或其鹽。
在一些實施例中,式II化合物與草醯氯之反應在催化量之二甲基甲醯胺(DMF)存在下進行。在一些實施例中,DMF以相對於式II化合物介於約0.010與0.03莫耳當量之間存在。
在一些實施例中,式II化合物與草醯氯之反應在包含二氯甲烷之溶劑組分中進行。
在一些實施例中,式II化合物與草醯氯之反應在約15℃至約25℃之溫度下進行。
本文所述之方法可進一步包括使式IV化合物或其鹽在氧化條件下反應,形成式V化合物:
V
或其鹽。
V
或其鹽。
在一些實施例中,氧化條件包含至少一種氧化劑(亦即第一氧化劑)。在一些實施例中,氧化條件包含第二氧化劑。
在一些實施例中,氧化劑為三氯異氰尿酸(TCIC)。在一些實施例中,TCIC以相對於式IV化合物介於約0.5與約0.7莫耳當量之間存在。
在一些實施例中,氧化劑為2,2,6,6-四甲基-1-哌啶基氧基(TEMPO)。在一些實施例中,TEMPO以相對於式IV化合物介於約0.005與約0.05莫耳當量之間存在。在一些實施例中,TEMPO以相對於式IV化合物介於約0.015與約0.025莫耳當量之間存在。在一些實施例中,TEMPO以相對於式IV化合物約0.020莫耳當量存在。
在一些實施例中,氧化條件包含至少TCIC (第一氧化劑)及TEMPO (第二氧化劑)。在一些實施例中,氧化條件包含金屬溴化物,例如溴化鈉。在一些實施例中,溴化鈉以相對於式IV化合物介於約0.005與約0.015莫耳當量之間存在。在一些實施例中,溴化鈉以相對於式IV化合物約0.01當量存在。
在一些實施例中,氧化條件進一步包含鹼。在一些實施例中,鹼為碳酸氫鈉及/或碳酸鈉。在一些實施例中,碳酸氫鈉以相對於式IV化合物介於約1與約10莫耳當量之間存在。在一些實施例中,碳酸氫鈉以相對於式IV化合物約5莫耳當量存在。在一些實施例中,碳酸鈉以相對於式IV化合物介於約0.1與約1莫耳當量之間存在。在一些實施例中,碳酸鈉以相對於式IV化合物約0.5莫耳當量存在。
在一些實施例中,式IV化合物在氧化條件下之反應進一步包含碳酸氫鈉、碳酸鈉及溴化鈉中之一或多者。在一些實施例中,式IV化合物在氧化條件下之反應進一步包含碳酸氫鈉、碳酸鈉及溴化鈉。
在一些實施例中,式IV化合物在氧化條件下之反應進一步包含包括二氯甲烷之溶劑組分。在一些實施例中,溶劑組分進一步包含水。
在一些實施例中,氧化條件包含在約0℃至約5℃之溫度下將三氯異氰尿酸(TCIC)添加至包含式IV化合物及TEMPO之溶液。在一些實施例中,三氯異氰尿酸之添加包含以至少兩部分添加三氯異氰尿酸。在一些實施例中,在該添加後在約0℃至約5℃之溫度下攪拌溶液約30分鐘。在一些實施例中,該方法進一步包括在該攪拌後將該溶液升溫至約20℃至約25℃之溫度,歷時約一小時至約兩小時之時間。
在一些實施例中,氧化條件產生純度超過約99%之式V化合物。
在一些實施例中,本文所述之方法進一步包括使式V化合物與式VI化合物:
VI
或其鹽在還原劑存在下反應,形成式I化合物:
I
或其鹽;
其中Z1 為H或保護基。
VI
或其鹽在還原劑存在下反應,形成式I化合物:
I
或其鹽;
其中Z1 為H或保護基。
在一些實施例中,Z1
為H。
在一些實施例中,還原劑為氰基硼氫化鈉或三乙醯氧基硼氫化鈉。在一些實施例中,還原劑為三乙醯氧基硼氫化鈉。在一些實施例中,使用基於式VI化合物超過1當量(例如2當量)之三乙醯氧基硼氫化鈉。
還原劑可為適用於還原胺化之任何還原劑,包括多種硼氫化物及硼烷還原劑,諸如以下中之彼等還原劑:Ellen W. Baxter及Allen B. Reitz, Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents, Organic Reactions, 第1章, 第1-57頁 (Wiley, 2002),其以引用之方式整體併入本文中。非限制性類別之適當還原劑包括硼氫化物、氰基硼氫化物、三((C1-4
醯基)氧基硼氫化物(例如三乙醯氧基硼氫化物衍生物)、9-硼雜雙環[3.3.1]壬烷氫化物、三(C1-4
烷基)硼氫化物及二異松蒎基氰基硼氫化物衍生物、胺基硼烷、硼烷-吡啶複合物及烷基胺硼烷。適當還原劑之非限制性實例包括氰基硼氫化鈉、三乙醯氧基硼氫化鈉、氰基-9-硼雜雙環[3.3.1]壬烷氫化鈉、氰基硼氫化四丁銨、固體支撐物上氰基硼氫化物、三乙醯氧基硼氫化四甲銨、三乙醯氧基硼氫化鈉、三乙基硼氫化鋰、三(第二丁基)硼氫化鋰、二異松蒎基氰基硼氫化鈉、兒茶酚硼烷、硼烷四氫呋喃、硼氫化鈉、硼氫化鉀、硼氫化鋰、在氫氣存在下之鈀、5-乙基-2-甲基吡啶硼烷(PEMB)、2-甲基吡啶硼烷或聚合物支撐之三乙醯氧基硼氫化物。在一些實施例中,上述中之任一者及較佳氰基硼氫化鈉與鈦(IV)添加劑、脫水劑或鹵化鋅添加劑組合使用。在一些實施例中,還原劑為氰基硼氫化四(C1-4
烷基)銨或三乙醯氧基硼氫化四(C1-4
烷基)銨、鹼金屬氰基硼氫化物或三乙醯氧基硼氫化物或者鹼土金屬氰基硼氫化物或三乙醯氧基硼氫化物。在一些實施例中,還原劑為鹼金屬氰基硼氫化物。在一些實施例中,還原劑係選自氰基硼氫化鈉及三乙醯氧基硼氫化鈉。在一些實施例中,還原劑為三乙醯氧基硼氫化鈉。如本文所用,鈦(IV)添加劑為含有鈦(IV)金屬之路易斯酸(例如四氯化鈦、異丙氧化鈦、乙氧化鈦及其類似物)。
在一些實施例中,式VI化合物或其鹽為2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)氮雜環丁烷-3-基)乙腈二鹽酸鹽。在一些實施例中,反應在至少兩當量第二鹼存在下進行。在一些實施例中,第二鹼為三級胺(例如三乙胺)。如本文所用,短語「第二鹼」中之「第二」用於區分該鹼與該方法之初期或後面步驟中所用之其他鹼且並非指示兩種鹼均必須存在。
在一些實施例中,使用基於式VI化合物或其鹽超過1當量式V化合物。
在一些實施例中,式VI化合物或其鹽與式V化合物之反應在二氯甲烷溶劑中進行。
在一些實施例中,該方法進一步包括使式I化合物與己二酸反應,形成式I化合物之己二酸鹽。
在另一個態樣中,本文提供一種方法,其包括使式III化合物:
III
或其鹽與4-哌啶酮或其鹽反應,形成式V化合物:
V
或其鹽。
III
或其鹽與4-哌啶酮或其鹽反應,形成式V化合物:
V
或其鹽。
在一些實施例中,4-哌啶酮或其鹽為4-哌啶酮鹽酸鹽。在一些實施例中,4-哌啶酮或其鹽為4-哌啶酮鹽酸鹽單水合物。
在一些實施例中,式III化合物與4-哌啶酮之反應進一步包括鹼。在一些實施例中,鹼為碳酸鈉。
在一些實施例中,式III化合物與4-哌啶酮之反應在包含二氯甲烷之溶劑組分中進行。
在一些實施例中,式III化合物與4-哌啶酮之反應在約0℃至約5℃之溫度下進行。
在一些實施例中,式III化合物由如下方法形成,該方法包括使式II化合物:
II
或其鹽與草醯氯反應,形成式III化合物或其鹽。
II
或其鹽與草醯氯反應,形成式III化合物或其鹽。
在一些實施例中,式II化合物與草醯氯之反應在催化量之二甲基甲醯胺(DMF)存在下進行。在一些實施例中,DMF以相對於式II化合物介於約0.010與0.03莫耳當量之間存在。
在一些實施例中,式II化合物與草醯氯之反應在包含二氯甲烷之溶劑組分中進行。
在一些實施例中,式II化合物與草醯氯之反應在約15℃至約25℃之溫度下進行。
在一些實施例中,在式III化合物與4-哌啶酮反應前不分離式III化合物。
在一些實施例中,式II化合物與草醯氯之反應及式III化合物與4-哌啶酮之反應在單個反應器中進行。
在一些實施例中,本文所述之方法進一步包括使式V化合物與式VI化合物:
VI
或其鹽在還原劑存在下反應,形成式I化合物:
I
或其鹽;
其中Z1 為H或保護基。
VI
或其鹽在還原劑存在下反應,形成式I化合物:
I
或其鹽;
其中Z1 為H或保護基。
在一些實施例中,Z1
為H。
在一些實施例中,還原劑為氰基硼氫化鈉或三乙醯氧基硼氫化鈉。在一些實施例中,還原劑為三乙醯氧基硼氫化鈉。在一些實施例中,使用基於式VI化合物超過1當量(例如2當量)之三乙醯氧基硼氫化鈉。
在一些實施例中,式VI化合物或其鹽為2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)氮雜環丁烷-3-基)乙腈二鹽酸鹽。在一些實施例中,反應在至少兩當量第二鹼存在下進行。在一些實施例中,第二鹼為三級胺(例如三乙胺)。
在一些實施例中,使用基於式VI化合物或其鹽超過1當量之式V化合物。
在一些實施例中,式VI化合物或其鹽與式V化合物之反應在二氯甲烷溶劑中進行。
在一些實施例中,該方法進一步包括使式I化合物與己二酸反應,形成式I化合物之己二酸鹽。
在一態樣中,本文提供一種式III化合物:
III
或其鹽。
用途
III
或其鹽。
用途
式I化合物{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈為JAK (例如JAK1、JAK2)抑制劑。JAK抑制劑可用於治療多種JAK相關疾病或病症。JAK相關疾病之實例包括涉及免疫系統之疾病,包括例如器官移植排斥反應(例如同種異體移植排斥及移植物抗宿主疾病)。JAK相關疾病之其他實例包括自體免疫疾病,諸如多發性硬化、類風濕性關節炎、幼年型關節炎、牛皮癬性關節炎、I型糖尿病、狼瘡、牛皮癬、發炎性腸病、潰瘍性結腸炎、克羅恩氏病(Crohn's disease)、重症肌無力、免疫球蛋白腎病、心肌炎、自體免疫性甲狀腺病、慢性阻塞性肺病(COPD)及其類似疾病。在一些實施例中,自體免疫疾病為自體免疫性大皰皮膚病,諸如尋常天疱瘡(PV)或大皰性類天疱瘡(BP)。
JAK相關疾病之進一步實例包括過敏病狀,諸如氣喘、食物過敏、濕疹性皮炎、接觸性皮炎、異位性皮炎(異位性濕疹)及鼻炎。JAK相關疾病之進一步實例包括病毒疾病,諸如艾伯斯坦巴爾病毒(Epstein Barr Virus,EBV)、B型肝炎、C型肝炎、HIV、HTLV 1、水痘-帶狀疱疹病毒(VZV)及人類乳頭狀瘤病毒(HPV)。JAK相關疾病之進一步實例包括與軟骨翻轉有關之疾病,例如痛風性關節炎、膿毒性關節炎或傳染性關節炎、反應性關節炎、反射***感神經失養症、痛性營養不良、白化病症候群(Tietze syndrome)、肋營養不良、地方性變形性骨關節炎(osteoarthritis deformans endemica)、姆塞雷尼病(Mseleni disease)、海地病(Handigodu disease)、由纖維肌痛引起之變性、全身性紅斑狼瘡、硬皮病或強直性脊椎炎。
JAK相關疾病之進一步實例包括先天性軟骨畸形,包括遺傳性軟骨溶解症、軟骨發育不良及假性軟骨發育不良(例如小耳、無耳及幹骺端軟骨發育不良)。JAK相關疾病或病狀之進一步實例包括皮膚病,諸如牛皮癬(例如尋常性牛皮癬)、異位性皮炎、皮疹、皮膚刺激、皮膚致敏(例如接觸性皮炎或過敏性接觸性皮炎)。舉例而言,當局部塗敷時包括一些醫藥之某些物質可引起皮膚致敏。在一些實施例中,至少一種本發明之JAK抑制劑與引起不必要致敏之藥劑一起共同投與或相繼投與可幫助治療此類不必要之致敏或皮炎。在一些實施例中,皮膚病藉由局部投與至少一種本發明之JAK抑制劑而治療。
JAK相關疾病或病狀之進一步實例包括特徵在於實體腫瘤(例如***癌、腎癌、肝癌、胰臟癌、胃癌、乳癌、肺癌、頭頸部癌、甲狀腺癌、膠質母細胞瘤、卡波西氏肉瘤(Kaposi's sarcoma)、卡斯特曼病(Castleman's disease)、子宮平滑肌肉瘤、黑色素瘤等)、血液學癌症(例如淋巴瘤、白血病,諸如急性淋巴母細胞性白血病(ALL)、急性髓細胞性白血病(AML)或多發性骨髓瘤)及皮膚癌(諸如皮膚T細胞淋巴瘤(CTCL)及皮膚B細胞淋巴瘤)之疾病或病狀。示例CTCL包括塞紮萊症候群(Sezary syndrome)及蕈樣真菌病。JAK相關疾病或病狀之其他實例包括肺動脈高壓。
JAK相關疾病或病狀之其他實例包括炎症相關癌症。在一些實施例中,癌症與炎症性腸病有關。在一些實施例中,炎症性腸病為潰瘍性結腸炎。在一些實施例中,炎症性腸病為克羅恩氏病。在一些實施例中,炎症相關癌症為結腸炎相關癌症。在一些實施例中,炎症相關癌症為結腸癌或結腸直腸癌。在一些實施例中,癌症為胃癌、胃腸道類癌腫瘤、胃腸道間質瘤(GIST)、腺癌、小腸癌或直腸癌。
JAK相關疾病可進一步包括特徵為以下突變體表現之疾病:JAK2突變體,諸如在偽激酶結構域中具有至少一個突變之JAK2突變體(例如JAK2V617F);在偽激酶結構域外具有至少一個突變之JAK2突變體;JAK1突變體;JAK3突變體;促紅細胞生成素受體(EPOR)突變體;或CRLF2之表現失調。
JAK相關疾病可進一步包括骨髓增生性病症(MPD),諸如真性紅血球增多症(PV)、特發性血小板增多症(ET)、伴有骨髓纖維化之髓樣化生(MMM)、原發性骨髓纖維化(PMF)、慢性骨髓性白血病(CML)、慢性骨髓單核球性白血病(CMML)、嗜伊紅性白血球增多症候群(HES)、全身性肥大細胞病(SMCD)及其類似疾病。在一些實施例中,骨髓增生性病症為骨髓纖維化(例如原發性骨髓纖維化(PMF)或真性紅血球增多症/特發性血小板增多繼發性骨髓纖維化(PV繼發性/ET繼發性MF))。在一些實施例中,骨髓增生性疾病為特發性血小板增多繼發性骨髓纖維化(ET繼發性MF)。在一些實施例中,骨髓增生性疾病為真性紅血球增多症繼發性骨髓纖維化(PV繼發性MF)。
JAK相關疾病或病狀之其他實例包括藉由投與本發明之化合物改善其他醫藥之皮膚副作用。舉例而言,許多藥劑引起不必要之過敏反應,該等過敏反應可表現為痤瘡樣皮疹或相關皮炎。具有此類不良副作用之示例藥劑包括抗癌藥物,諸如吉非替尼(gefitinib)、西妥昔單抗(cetuximab)、埃羅替尼(erlotinib)及其類似藥物。本發明之化合物可與具有不良皮膚副作用之藥劑組合(例如同時或相繼)全身或局部投與(例如侷限於皮炎附近)。在一些實施例中,本發明之化合物可與一或多種其他醫藥一起局部投與,其中其他醫藥在缺乏本發明之化合物下局部塗敷時引起接觸性皮炎、過敏性接觸性致敏或類似皮膚病。因此,本發明之組合物包括含有本發明之化合物及可引起皮炎、皮膚病或相關副作用之其他藥劑的局部調配物。
其他JAK相關疾病包括炎症及發炎疾病。示例發炎疾病包括結節病、眼睛發炎疾病(例如虹膜炎、葡萄膜炎、鞏膜炎、結膜炎或相關疾病)、呼吸道發炎疾病(例如上呼吸道,包括鼻及鼻竇,諸如鼻炎或鼻竇炎,或下呼吸道,包括支氣管炎、慢性阻塞性肺病及其類似疾病)、發炎肌病(諸如心肌炎)及其他發炎疾病。在一些實施例中,眼睛發炎疾病為瞼炎。
其他JAK相關疾病包括缺血再灌注損傷或與發炎缺血事件相關之疾病或病狀(諸如中風或心動停止)、內毒素驅動之疾病病況(例如繞道手術之後的併發症或引起慢性心臟衰竭之慢性內毒素病況)、厭食、惡病質、諸如由癌症引起或與癌症有關之疲勞、再狹窄、硬化性皮炎纖維化、與缺氧或星形膠質細胞增生有關之病狀(諸如糖尿病性視網膜病、癌症或神經變性)及諸如全身性發炎反應症候群(SIRS)及敗血性休克之其他發炎疾病。其他JAK相關疾病包括痛風及由於例如良性***肥厚或良性***肥大而增加之***尺寸;以及骨吸收疾病,諸如骨質疏鬆症或骨關節炎;與激素不平衡及/或激素療法有關之骨吸收疾病、自體免疫疾病(例如骨結節病)或癌症(例如骨髓瘤)。
其他JAK相關疾病包括乾眼症。如本文所用,「乾眼症」意欲涵蓋在乾眼病工作組(Dry Eye Workshop,DEWS)之近期官方報告中概述之疾病病況,其定義乾眼為「引起不適、視力障礙及淚膜不穩定性之症狀且對視角面具有潛在損害的眼淚及視角面之多因子疾病。其伴隨有淚膜之滲透性增加及視角面發炎。」 Lemp, 「The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop」,The Ocular Surface
, 5(2), 75-92 2007年4月,以引用之方式整體併入本文中。在一些實施例中,乾眼症係選自淚液缺乏性乾眼(ADDE)或蒸發性乾眼症或其適當組合。在一些實施例中,乾眼症為休格連氏症候群乾眼(Sjogren syndrome dry eye,SSDE)。在一些實施例中,乾眼症為非休格連氏症候群乾眼(NSSDE)。
進一步JAK相關疾病包括結膜炎、葡萄膜炎(包括慢性葡萄膜炎)、脈絡膜炎、視網膜炎、睫狀體炎、鞏膜炎、鞏膜表層炎或虹膜炎。其他JAK相關疾病包括與諸如流感及SARS之病毒感染相關之呼吸功能障礙或衰竭。
實例
實例
本發明將藉助於特定實例更詳細地描述。提供以下實例以達成說明之目的,且不意欲以任何方式限制本發明。本領域技術人員將容易識別多個非關鍵參數,此等參數可變化或修改,得到基本上相同結果。
實例 1. 合成 2-(3-(4-(7H - 吡咯并 [2,3-d ] 嘧啶 -4- 基 )-1H - 吡唑 -1- 基 )-1-(1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 基 ) 氮雜環丁烷 -3- 基 ) 乙腈己二酸鹽 (9)
流程 I
實例 1. 合成 2-(3-(4-(7H - 吡咯并 [2,3-d ] 嘧啶 -4- 基 )-1H - 吡唑 -1- 基 )-1-(1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 基 ) 氮雜環丁烷 -3- 基 ) 乙腈己二酸鹽 (9)
流程 I
3-( 氰基甲基 )-3-(4-(4,4,5,5- 四甲基 -1,3,2- 二氧硼戊烷 -2- 基 )-1H
- 吡唑 -1- 基 ) 氮雜環丁烷 -1- 甲酸第三丁酯 (3).
在周圍溫度下向1 L裝備有氮氣入口、熱電偶及機械攪拌器之燒瓶依序添加異丙醇(IPA,200 mL)、1,8-二氮雜雙環[5,4,0]十一-烯(DBU,9.8 g,64.4 mmol,0.125當量)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H
-吡唑(1
,101 g,520.51 mmol,1.01當量)及3-(氰基亞甲基)氮雜環丁烷-1-甲酸第三丁酯(2
,100 g,514.85 mmol),產生呈懸浮液形式之反應混合物。在30分鐘內將所得反應混合物加熱至回流,得到均質溶液且混合物維持於回流下,再保持2-3小時。在如藉由HPLC監測,反應完成後,在45分鐘內將正庚烷(400 mL)逐漸添加至反應混合物,同時維持混合物在回流下。在添加正庚烷期間固體沈澱。一旦正庚烷添加結束,則使混合物逐漸冷卻至周圍溫度且在周圍溫度下再攪拌1小時。藉由過濾來收集固體,用正庚烷(200 mL)洗滌,且在氮氣吹掃下在真空下在50℃下乾燥至恆重,得到呈白色至淺黃色固體狀之3-(氰基甲基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H
-吡唑-1-基)氮雜環丁烷-1-甲酸第三丁酯(3
,181 g,199.9 g理論值,90.5%)。3
:1
H NMR (400 MHz, DMSO-d 6
) δ 8.31 (s, 1H), 7.74 (s, 1H), 4.45 - 4.23 (m, 2H), 4.23 - 4.03 (m, 2H), 3.56 (s, 2H), 1.38 (s, 9H), 1.25 (s, 12H) ppm;13
C NMR (101 MHz, DMSO-d 6
) δ 155.34, 145.50, 135.88, 116.88, 107.08 (br), 83.15, 79.36, 58.74 (br), 56.28, 27.96, 26.59, 24.63 ppm;C19
H29
BN4
O4
(MW 388.27), LCMS (EI)m
/e
389 (M+
+ H)。
3-(4-(7H
- 吡咯并 [2,3-d
] 嘧啶 -4- 基 )-1H
- 吡唑 -1- 基 )-3-( 氰基甲基 )- 氮雜環丁烷 -1- 甲酸第三丁酯 (5).
在周圍溫度下向1 L裝備有氮氣入口、熱電偶及機械攪拌器之燒瓶添加4-氯-7H
-吡咯并[2,3-d
]嘧啶(4
,39.6 g,257.6 mmol)、3-(氰基甲基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H
-吡唑-1-基)氮雜環丁烷-1-甲酸第三丁酯(3
,100 g,257.6 mmol,1.0當量)、氟化銫(136.9 g,901.4 mmol,3.5當量)、第三丁醇(250 mL)、水(250 mL)及[1,1′-雙(二環己基膦基)二茂鐵]二氯鈀(II) (Pd-127,351.4 mg,0.46 mmol,0.0018當量)。將所得反應混合物脫氣且用氮氣再填充,進行3次,接著加熱至回流且維持在回流下氮氣下20-24小時。當HPLC顯示反應結束時,使反應混合物在30分鐘內冷卻至45-55℃,分離兩相,且棄去水相。在45-55℃下在30分鐘內向有機相添加正庚烷(125 mL)。所得混合物在一小時內緩慢冷卻至周圍溫度且在周圍溫度下再攪拌2小時。藉由過濾來收集固體,用正庚烷(100 mL)洗滌,且在氮氣吹掃下在真空下在50℃下乾燥至恆重,得到呈淺黃色固體狀之3-(4-(7H
-吡咯并[2,3-d
]嘧啶-4-基)-1H
-吡唑-1-基)-3-(氰基甲基)-氮雜環丁烷-1-甲酸第三丁酯(5
,96.8 g,97.7 g理論值,99%)。 5
:1
H NMR (400 MHz, DMSO-d 6
) δ 8.89 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.60 (d,J
= 3.5 Hz, 1H), 7.06 (d,J
= 3.6 Hz, 1H), 4.62 - 4.41 (m, 2H), 4.31 - 4.12 (m, 2H), 3.67 (s, 2H), 1.39 (s, 9H) ppm;13
C NMR (101 MHz, DMSO-d 6
) δ 155.40, 152.60, 150.63, 149.15, 139.76, 129.53, 127.65, 122.25, 116.92, 113.21, 99.71, 79.45, 58.34 (br), 56.80, 27.99, 26.83 ppm;C19
H21
N7
O2
(MW 379.4), LCMS (EI)m
/e
380 (M+
+ H)。
2-(3-(4-(7H
- 吡咯并 [2,3-d
] 嘧啶 -4- 基 )-1H
- 吡唑 -1- 基 ) 氮雜環丁烷 -3- 基 ) 乙腈二鹽酸鹽 (6).
在室溫下向0.5 L裝備有氮氣入口、熱電偶、加料漏斗及機械攪拌器之燒瓶添加3-(4-(7H
-吡咯并[2,3-d
]嘧啶-4-基)-1H
-吡唑-1-基)-3-(氰基甲基)氮雜環丁烷-1-甲酸第三丁酯(5
,15 g,39.5 mmol)、水(7.5 mL,416 mmol)及二氯甲烷(75 mL)。將混合物在室溫下攪拌,產生懸浮液。在5分鐘內向懸浮液添加5 M氯化氫(HCl)於異丙醇(55 mL,275 mmol,7.0當量)中之溶液。接著將所得反應混合物加熱至緩緩回流且維持於回流下3-4小時。在如藉由HPLC監測,反應完成後,將第三丁基甲基醚(TBME,45 mL)添加至反應懸浮液。混合物逐漸冷卻至室溫且再攪拌一小時。藉由過濾來收集固體,用第三丁基甲基醚(TBME,45 mL)洗滌且在氮氣吹掃下在真空下在50℃下乾燥至恆重,得到呈灰白色至淡黃色固體狀之2-(3-(4-(7H
-吡咯并[2,3-d
]嘧啶-4-基)-1H
-吡唑-1-基)氮雜環丁烷-3-基)乙腈二鹽酸鹽(6
,13.6 g,13.9 g理論值,98%)。6
:1
H NMR (400 MHz, D2
O) δ 8.96 (s, 1H), 8.81 (s, 1H), 8.49 (s, 1H), 7.78 (d,J
= 3.8 Hz, 1H), 7.09 (d,J
= 3.7 Hz, 1H), 4.93 (d,J
= 12.8 Hz, 2H), 4.74 (d,J
= 12.5 Hz, 2H), 3.74 (s, 2H) ppm;13
C NMR (101 MHz, D2
O) δ 151.35, 143.75, 143.33, 141.33, 132.03, 131.97, 115.90, 114.54, 113.85, 103.18, 59.72, 54.45 (2C), 27.02 ppm;C14
H15
Cl2
N7
(游離鹼C14
H13
N7
, MW 279.30), LCMS (EI)m
/e
280 (M+
+ H)。
2-(3-(4-(7H
- 吡咯并 [2,3-d
] 嘧啶 -4- 基 )-1H
- 吡唑 -1- 基 )-1-(1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 基 ) 氮雜環丁烷 -3- 基 ) 乙腈 (8 ,游離鹼 ).
在周圍溫度下向0.5 L裝備有氮氣入口、熱電偶、加料漏斗及機械攪拌器之燒瓶添加2-(3-(4-(7H
-吡咯并[2,3-d
]嘧啶-4-基)-1H
-吡唑-1-基)氮雜環丁烷-3-基)乙腈二鹽酸鹽(6
,20 g,56.78 mmol)、二氯甲烷(200 mL)及三乙胺(TEA,16.62 mL,119.2 mmol,2.1當量)。將混合物在周圍溫度下攪拌30分鐘,接著添加1-(3-氟-2-(三氟甲基)-異菸鹼醯基)哌啶-4-酮(7
,17.15 g,57.91 mmol,1.02當量)至混合物。接著在5分鐘內在周圍溫度下(低於26℃)將混合物用三乙醯氧基硼氫化鈉(25.34 g,113.6 mmol,2.0當量)處理。將所得反應混合物在周圍溫度下攪拌2小時。在如藉由HPLC監測,反應完成後,將反應混合物用飽和NaHCO3
水溶液(200 mL)淬滅。分離兩相且將水相用二氯甲烷(200 mL)萃取。將合併之有機相用4%鹽水(100 mL)洗滌,接著藉由蒸餾使溶劑自二氯甲烷交換為丙酮。所需粗產物(8
)於丙酮中之所得溶液直接用於隨後己二酸鹽形成。一小部分溶液藉由管柱層析法(SiO2
,EtOAc中0-10% MeOH梯度溶離)來純化,得到呈灰白色固體狀之分析純之2-(3-(4-(7H
-吡咯并[2,3-d
]嘧啶-4-基)-1H
-吡唑-1-基)-1-(1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-基)氮雜環丁烷-3-基)乙腈(8 ,
游離鹼)。8
:1
H NMR (400 MHz, DMSO-d 6
) δ 12.17 (d,J
= 2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t,J
= 4.7 Hz, 1H), 7.63 (dd,J
= 3.6, 2.3 Hz, 1H), 7.09 (dd,J
= 3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d,J
= 7.9 Hz, 2H),
3.61 (t,J
= 7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t,J
= 10.5 Hz, 1H), 3.09 (ddd,J
= 13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83 - 1.75 (m, 1H), 1.70 - 1.63 (m, 1H), 1.35 - 1.21 (m, 2H) ppm;13
C NMR (101 MHz, DMSO-d 6
) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm;C26
H23
F4
N9
O(MW, 553.51), LCMS (EI)m
/e
554.1 (M+
+ H)。
2-(3-(4-(7H
- 吡咯并 [2,3-d
] 嘧啶 -4- 基 )-1H
- 吡唑 -1- 基 )-1-(1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 基 ) 氮雜環丁烷 -3- 基 ) 乙腈己二酸鹽 (9).
在周圍溫度下向0.5 L裝備有機械攪拌器、熱電偶、加料漏斗及氮氣入口之燒瓶添加粗2-(3-(4-(7H
-吡咯并[2,3-d
]嘧啶-4-基)-1H
-吡唑-1-基)-1-(1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-基)氮雜環丁烷-3-基)乙腈(8
,游離鹼,31.38 g,56.7 mmol)於丙酮(220 mL)及己二酸(8.7 g,59.53 mmol,1.05當量)中之溶液。接著反應混合物加熱至回流,得到溶液。在40-50℃下在一小時內將正庚烷(220 mL)逐漸添加至反應混合物。在一小時內所得混合物逐漸冷卻至周圍溫度且在周圍溫度下再攪拌16小時。藉由過濾來收集固體,用正庚烷(2×60 mL)洗滌,且在氮氣吹掃下在真空下在50℃下乾燥至恆重,得到呈白色至灰白色固體狀之2-(3-(4-(7H
-吡咯并[2,3-d
]嘧啶-4-基)-1H
-吡唑-1-基)-1-(1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-基)氮雜環丁烷-3-基)乙腈己二酸鹽(9
,34.0 g,39.7 g理論值,兩步85.6%)。9
:1
H NMR (400 MHz, DMSO-d 6
) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H),8.69 (d,J
= 4.7 Hz, 1H), 8.45 (s, 1H), 7.93 (t,J
= 4.7 Hz, 1H), 7.63 (dd,J
= 3.6, 2.3 Hz, 1H), 7.09 (dd,J
= 3.6, 1.7 Hz, 1H), δ 4.11 (dt,J
= 11.0, 4.4 Hz, 1H), 3.77 (d,J
= 7.8 Hz, 2H), 3.60 (t,J
= 7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt,J
= 14.4, 4.6 Hz, 1H), 3.28 (t,J
= 10.4 Hz, 1H), 3.09 (ddd,J
= 13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt,J
= 8.6, 3.5 Hz, 1H), 2.28 - 2.17 (m, 4H), 1.83 - 1.74 (m, 1H), 1.67 (d,J
= 11.0 Hz, 1H), 1.59 - 1.46 (m, 4H), 1.37 - 1.21 (m, 2H) ppm;13
C NMR (101 MHz, DMSO-d 6
) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm;C32
H33
F4
N9
O5
(MW 699.66;游離鹼C26
H23
F4
N9
O, MW, 553.51), LCMS (EI)m
/e
554.0 (M+
+ H)。
實例 2 : 2-(3-(4-(7H- 吡咯并 [2,3-d] 嘧啶 -4- 基 )-1H- 吡唑 -1- 基 )-1-(1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 基 ) 氮雜環丁烷 -3- 基 ) 乙腈之替代合成
流程 II
實例 2 : 2-(3-(4-(7H- 吡咯并 [2,3-d] 嘧啶 -4- 基 )-1H- 吡唑 -1- 基 )-1-(1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 基 ) 氮雜環丁烷 -3- 基 ) 乙腈之替代合成
流程 II
2-( 氮雜環丁烷 -3- 亞基 ) 乙腈鹽酸鹽 (2a).
在周圍溫度下向0.5 L裝備有氮氣入口、熱電偶及機械攪拌器之燒瓶添加3-(氰基亞甲基)氮雜環丁烷-1-甲酸第三丁酯(2
,30 g,154.46 mmol)及二氯甲烷(300 mL)。接著在周圍溫度下溶液用5 M氯化氫(HCl)之異丙醇溶液(294.2 mL,1.54 mol,10當量)處理且所得反應混合物在周圍溫度下攪拌18小時。在如藉由HPLC監測,反應完成後,向懸浮液添加第三丁基甲基醚(TBME,150 mL),且將混合物在周圍溫度下攪拌2小時。固體藉由過濾來收集,用正庚烷(2×100 mL)洗滌,且在周圍溫度下在過濾漏斗上乾燥3小時,得到呈白色固體狀之2-(氮雜環丁烷-3-亞基)乙腈鹽酸鹽(2a
,13.7 g,20.2 g理論值,67.8%)。2a
:1
H NMR (500 MHz, DMSO-d 6
) δ 9.99 (s, 2H), 5.94 (p,J
= 2.5 Hz, 1H), 4.85 - 4.80 (m, 2H), 4.77 - 4.71 (m, 2H) ppm;13
C NMR (126 MHz, DMSO-d 6
) δ 155.65, 114.54, 94.78, 55.26, 54.63 ppm;C5
H7
ClN2
(MW 130.58;游離鹼C5
H6
N2
, MW 94.11), LCMS (EI)m
/e
95 (M+
+ H)。
2-(1-(1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 基 ) 氮雜環丁烷 -3- 亞基 ) 乙腈 (10).
在周圍溫度下向0.25 L裝備有氮氣入口、熱電偶及磁力攪拌器之燒瓶添加2-(氮雜環丁烷-3-亞基)乙腈鹽酸鹽(2a
,4.5 g,34.46 mmol)、1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-酮(7
,10 g,34.46 mmol,1.0當量)及二氯甲烷(100 mL)且接著在周圍溫度下所得混合物用三乙醯氧基硼氫化鈉(14.6 g,68.93 mmol,2.0當量)處理。將反應混合物在周圍溫度下攪拌2小時,接著用飽和碳酸氫鈉(NaHCO3
)水溶液(50 mL)淬滅。分離兩相且將水相用二氯甲烷(200 mL)萃取。合併之有機相用水(50 mL)及鹽水(50 mL)洗滌且在減壓下濃縮,得到粗所需產物(10
),其藉由管柱層析法(SiO2
,己烷中0-10%乙酸乙酯梯度溶離)來純化,得到呈白色固體狀之2-(1-(1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-基)氮雜環丁烷-3-亞基)乙腈(10
,9.5 g,12.7 g理論值,74.8%)。10
:1
H NMR (400 MHz, CDCl3
) δ 8.57 (d,J
= 4.7 Hz, 1H), 7.54 (t,J
= 4.6 Hz, 1H), 5.29 (p,J
= 2.4 Hz, 1H), 4.18 - 4.08 (m, 1H), 4.08 - 4.03 (m, 2H), 3.98 - 3.94 (m, 2H), 3.57 - 3.39 (m, 2H), 3.17 - 3.04 (m, 1H), 2.56 (tt,J
= 7.4, 3.5 Hz, 1H), 1.86 - 1.77 (m, 1H), 1.75 - 1.64 (m, 1H), 1.54 - 1.43 (m, 1H), 1.43 - 1.31 (m, 1H) ppm;13
C NMR (101 MHz, CDCl3
) δ 161.34, 160.73, 152.62 (d,J
= 269.1 Hz), 145.75 (d,J
= 6.1 Hz), 136.73 (qd,J
= 36.1, 12.0 Hz), 134.56 (d,J
= 16.9 Hz), 126.89, 120.58 (qd,J
= 275.0, 4.9 Hz), 115.11, 92.04, 62.05, 60.57 (2C), 44.47, 39.42, 29.38, 28.47 ppm;C17
H16
F4
N4
O (MW 368.33), LCMS (EI)m
/e
369 (M+
+ H)。
2-(1-(1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 基 )-3-(4-(4,4,5,5- 四甲基 -1,3,2- 二氧硼戊烷 -2- 基 )-1H
- 吡唑 -1- 基 ) 氮雜環丁烷 -3- 基 ) 乙腈 (11).
在周圍溫度下向25 mL裝備有氮氣入口、熱電偶及磁力攪拌器之燒瓶添加4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H
-吡唑(1
,210 mg,1.08 mmol,1.08當量)、2-(1-(1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-基)氮雜環丁烷-3-亞基)乙腈(10
,370 mg,1.0 mmol)及乙腈(3 mL)。接著在周圍溫度下溶液用1,8-二氮雜雙環[5,4,0]十一-烯(DBU,173 mg,0.17 mL,1.12 mmol,1.12當量)處理且所得反應混合物升溫至50℃且在50℃下攪拌隔夜。當如藉由HPLC監測,反應完成時,反應混合物直接負載在矽膠(SiO2
)管柱上進行層析純化(乙酸乙酯中0-2.5% MeOH梯度溶離),得到呈白色固體狀之2-(1-(1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H
-吡唑-1-基)氮雜環丁烷-3-基)乙腈(11
,263 mg,562.4 mg理論值,46.7%)。11
:1
H NMR (400 MHz, DMSO-d 6
) δ 8.64 (d,J
= 4.7 Hz, 1H), 8.22 (d,J
= 0.6 Hz, 1H), 7.88 (dd,J
= 4.7 Hz, 1H), 7.69 (s, 1H), 4.10 - 3.99 (m, 1H), 3.58 (d,J
= 7.8 Hz, 2H), 3.52 - 3.42 (m, 2H), 3.44 (s, 2H), 3.41 - 3.33 (m, 1H), 3.28 - 3.15 (m, 1H), 3.03 (ddd,J
= 12.9, 9.2, 3.2 Hz, 1H), 2.51 - 2.44 (m, 1H), 1.77 - 1.66 (m, 1H), 1.64 - 1.54 (m, 1H), 1.28 - 1.17 (m, 2H), 1.24 (s, 12H) ppm;13
C NMR (101 MHz, DMSO-d 6
) δ 160.22, 152.13 (d,J
= 265.8 Hz), 146.23 (d,J
= 5.7 Hz), 145.12, 135.41, 134.66 (d,J
= 16.9 Hz), 134.43 (qd,J
= 35.0, 11.7 Hz), 127.58, 120.61 (qd,J
= 274.4, 4.6 Hz), 117.35, 106.59 (br), 83.10, 61.40, 60.53 (2C), 56.49, 44.17, 38.99, 28.55, 27.82, 27.02, 24.63 ppm;C26
H31
BF4
N6
O3
(MW 562.37), LCMS (EI)m
/e
563 (M+
+ H)。
2-(3-(4-(7H
- 吡咯并 [2,3-d
] 嘧啶 -4- 基 )-1H
- 吡唑 -1- 基 )-1-(1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 基 ) 氮雜環丁烷 -3- 基 ) 乙腈 (8).
在周圍溫度下向25 mL裝備有氮氣入口、熱電偶、加料漏斗及磁力攪拌器之燒瓶添加2-(1-(1-(3-氟-2-(三氟甲基)-異菸鹼醯基)哌啶-4-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H
-吡唑-1-基)氮雜環丁烷-3-基)乙腈(11
,307 mg,0.546 mmol)、4-氯-7H
-吡咯并[2,3-d
]嘧啶(4
,84.8 mg,0.548 mmol,1.0當量)、碳酸氫鈉(NaHCO3
,229 mg,2.72 mmol,5.0當量)、水(1.6 mL)及1,4-二噁烷(1.6 mL)。接著在周圍溫度下混合物用肆(三苯基膦)鈀(0) (12.8 mg,0.011 mmol,0.02當量)處理且將所得反應混合物脫氣且用氮氣再填充3次,接著加熱至85℃。將反應混合物在85℃下在氮氣下攪拌隔夜。當如藉由HPLC監測,反應完成時,反應混合物在減壓下濃縮至乾且藉由直接矽膠(SiO2
)管柱層析法(己烷中0-10%乙酸乙酯梯度溶離)純化乾燥之反應混合物,獲得呈灰白色固體狀之所需產物,2-(3-(4-(7H
-吡咯并[2,3-d
]嘧啶-4-基)-1H
-吡唑-1-基)-1-(1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-基)氮雜環丁烷-3-基)乙腈(8
,游離鹼,135 mg,302.2 mg理論值,44.6%)。藉由此合成方法獲得之化合物在每個可比較態樣中與藉由如以上實例1中所述之合成方法製造的化合物8一致。
實例 3. 合成 1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 酮 (7)
流程 III
實例 3. 合成 1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 酮 (7)
流程 III
(3- 氟 -2-( 三氟甲基 ) 吡啶 -4- 基 )(1,4- 二氧雜 -8- 氮雜螺 [4,5] 癸烷 -8- 基 ) 甲酮 (14).
向30 L裝備有磁力攪拌器、加料漏斗及隔片之反應器饋入氫氧化鈉(NaOH,1.4 kg,35 mol,2.0當量)及水(7 L)且在周圍溫度下將所得溶液用1,4-二氧雜-8-氮雜螺[4.5]癸烷鹽酸鹽(3.13 kg,17.43 mol)處理。接著將所得混合物在周圍溫度下攪拌30分鐘,接著用固體氯化鈉(1.3 kg)飽和且用2-甲基-四氫呋喃(3×7 L)萃取。合併之有機相經無水硫酸鈉(Na2
SO4
,1.3 kg)乾燥且在藉由過濾移除乾燥試劑硫酸鈉(Na2
SO4
)後,在減壓(70 mmHg)下在50℃下濃縮。將由此獲得之黃色油狀物在減壓(80 mmHg,bp 115至120℃)下蒸餾,得到呈澄清油狀之1,4-二氧雜-8-氮雜螺[4.5]癸烷(2.34 kg,2.496 kg理論值,93.8%),其直接用於隨後偶合反應。
在周圍溫度下向乾燥之裝備有磁力攪拌器、加料漏斗、溫度計及真空出口之100 L反應器饋入3-氟-2-(三氟甲基)異菸鹼酸(13
,3.0 kg,14.35 mol)、六氟磷酸苯并***-1-基氧基參(二甲基胺基)鏻(BOP試劑,7.6 kg,17.2 mol,1.2當量)、1,4-二氧雜-8-氮雜螺[4.5]癸烷(2.34 kg,16.36 mol,1.14當量)及N
,N
-二甲基甲醯胺(DMF,18 L)。接著將所得溶液在周圍溫度下攪拌20分鐘,接著冷卻至5至10℃。接著三乙胺(Et3
N,4 L,28.67 mol,2.0當量)經1小時添加至反應混合物且在添加三乙胺期間內部溫度保持在5℃與10℃之間。在周圍溫度(約20℃)下將由此獲得之深棕色溶液攪拌12小時且接著冷卻至大約10℃。在劇烈攪拌下,18 L飽和碳酸氫鈉(NaHCO3
)水溶液及36 L水依序添加至冷卻之反應混合物且內部溫度保持在15℃下。由此獲得之沈澱(濾餅)藉由過濾來收集。接著用12 kg固體氯化鈉(NaCl)使水相飽和且用EtOAc (2×18 L)萃取。將合併之有機層依序用飽和碳酸氫鈉(NaHCO3
)水溶液(18 L)及水(2×18 L)洗滌。所收集之濾餅接著溶回在有機相中且所得深棕色溶液用水(2×18 L)洗滌,接著在減壓下濃縮(40-50℃,30 mm Hg),得到約5.0 kg呈棕色黏性油狀之粗所需產物(14
)。接著在50℃下使以上獲得之粗產物溶於EtOH (8.15 L)中且在大約0℃下經30分鐘用水(16.3 L)處理所得溶液。棕色溶液進行接種,接著在攪拌下經3小時逐漸冷卻至周圍溫度(約20℃)且在周圍溫度下攪拌12小時。藉由過濾來收集固體,用EtOH與水之混合物(EtOH:H2
O = 1:20,2 L)洗滌且在約60℃下在減壓(50 mmHg)下乾燥24小時,得到呈白色固體狀之(3-氟-2-(三氟甲基)吡啶-4-基)(1,4-二氧雜-8-氮雜螺[4,5]癸烷-8-基)甲酮(14
,3.98 kg,4.797 kg理論值,83.0%)。14
:1
H NMR (300 MHz, DMSO-d 6
) d 8.64 (d,3 J HH
= 4.68 Hz, 1H, 吡啶中NCH), 7.92 (dd,3 J HH
= 4.68 Hz,4 J HF
= 4.68 Hz, 1H, 吡啶中NCCH), 3.87 - 3.91 (m, 4H, OCH2
CH2
O), 3.70 (br s, 2H, 吡啶環中一個NCH2
, 吡啶環中另一NCH2
, 均處於軸向位), 3.26 (t,3 J HH
= 5.86 Hz, 2H, 吡啶環中一個NCH2
, 吡啶環中另一NCH2
, 均處於赤道位), 1.67 (d,3 J HH
= 5.86 Hz, 2H, 吡啶環中一個NCCH2
, 吡啶環中另一NCCH2
, 均處於赤道位), 1.58 (br s, 2H, 吡啶環中一個NCCH2
, 吡啶環中另一NCCH2
, 均處於軸向位) ppm;13
C NMR (75 MHz, DMSO-d 6
) d 161.03 (N-C=O), 151.16 (d,1 J CF
= 266.03 Hz, C-F), 146.85 (d,4 J CF
= 4.32 Hz, 吡啶中NCH), 135.24 (d,2 J CF
= 11.51 Hz,C
-C=O), 135.02 (四重峰,2 J CF
= 34.57 Hz, NC
CF3
), 128.24 (d,4 J CF
= 7.48 Hz, 吡啶中NCC
H), 119.43 (d × 四重峰,1 J CF
= 274.38 Hz,3 J CF
= 4.89 Hz, CF3
), 106.74 (OC
O), 64.60 (OCC
O), 45.34 (吡啶環中NC), 39.62(吡啶環中NC), 34.79(吡啶環中NCC
), 34.10 (吡啶環中NCC
) ppm;19
F NMR (282 MHz, DMSO-d 6
) d -64.69 (d,4 J FF
= 15.85 Hz, F3
C), -129.26 (d × 四重峰,4 J FF
= 15.85 Hz,4 J FH
= 3.96 Hz, FC) ppm;C14
H14
F4
N2
O3
(MW, 334.27), LCMS (EI)m/e
335.1 (M+
+ H)。
1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 酮 ( 7).
在周圍溫度下在5 L裝備有機械攪拌器、熱電偶、加料漏斗及氮氣入口之4頸圓底燒瓶中饋入含(3-氟-2-(三氟甲基)吡啶-4-基)(1,4-二氧雜-8-氮雜螺[4,5]癸烷-8-基)甲酮(14
,100 g,0.299 mol)之乙腈(ACN,400 mL)。所得溶液冷卻至低於10℃,接著用6.0 N鹽酸(HCl)水溶液(450 mL,2.70 mol,9.0當量)處理,同時內部溫度保持低於10℃。接著所得反應混合物逐漸升溫至室溫且在周圍溫度下經8小時經由加料漏斗將額外量之6.0 N鹽酸(HCl)水溶液(1050 mL,6.30 mol,21.0當量)緩慢引入反應混合物。當如藉由HPLC監測,反應完成時,反應混合物接著冷卻至0℃,接著用30%氫氧化鈉水溶液(NaOH,860 mL,8.57 mmol,28.6當量)處理,同時內部溫度保持低於10℃。隨後所得反應混合物升溫至周圍溫度,接著經1小時添加固體碳酸氫鈉(NaHCO3
,85.0 g,1.01 mol,3.37當量)。混合物接著用EtOAc (2×1.2 L)萃取,且合併之有機相用16%氯化鈉水溶液(2×800 mL)洗滌且藉由真空蒸餾濃縮至約1.0 L。將正庚烷(2.1 L)添加至殘餘物,且所得混合物藉由真空蒸餾濃縮至1.0 L。向濃縮混合物添加正庚烷(2.1 L)。接著所得白色漿狀物藉由真空蒸餾濃縮至1.0 L。接著向白色漿狀物添加甲基第三丁基醚(MTBE,1.94 L)。將白色混濁物加熱至40℃,獲得澄清溶液。所得溶液藉由真空蒸餾濃縮至約1.0 L。將混合物在室溫下攪拌1小時。白色沈澱藉由過濾來收集,用正庚烷(400 mL)洗滌且在抽真空下在氮氣下在濾紙上乾燥,得到呈灰白色固體狀之1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-酮(7
,78.3 g,86.8 g理論值,產生90.2%產率,及如藉由HPLC量測,98%純度)。7
:1
H NMR (300 MHz, DMSO-d 6
) d 8.68 (d,3 J HH
= 4.69 Hz, 1H, 吡啶中NCH), 7.97 (dd,3 J HH
= 4.69 Hz,4 J HF
= 4.69 Hz, 1H, 吡啶中NCCH), 3.92 (br s, 2H, 吡啶環中一個NCH2
, 吡啶環中另一個NCH2
, 均處於軸向位), 3.54 (t,3 J HH
= 6.15 Hz, 2H, 吡啶環中一個NCH2
, 吡啶環中另一個NCH2
, 均處於赤道位), 2.48 (t,3 J HH
= 6.44 Hz, 2H, NCCH2
), 2.34 (t,3 J HH
= 6.15 Hz, 2H, NCCH2
) ppm;13
C NMR (75 MHz, DMSO-d 6
) d 207.17 (C=O), 161.66 (N-C=O), 151.26 (d,1 J CF
= 266.89 Hz, C-F), 146.90 (d,4 J CF
= 6.05 Hz, 吡啶中NCH), 135.56 (C
-C=O), 134.78 -135.56 (m, NC
CF3
), 128.27 (d,3 J CF
= 7.19 Hz, 吡啶中NCC
H), 119.52 (d× 四重峰,1 J CF
= 274.38 Hz,3 J CF
= 4.89 Hz, CF3
), 45.10 (吡啶環中NC) ppm, 一個碳(吡啶環中NCC
)由於與(CD3
)2
SO重疊而遺漏;19
F NMR (282 MHz, DMSO-d 6
) d -64.58 (d,4 J FF
= 15.85 Hz, F3
C), -128.90 (d × 四重峰,4 J FF
=1 5.85 Hz,4 J FH
= 4.05 Hz, FC) ppm;C12
H10
F4
N2
O2
(MW, 290.21), LCMS (EI)m/e
291.1 (M+
+ H)。
實例 4. 合成 3-( 氰基亞甲基 ) 氮雜環丁烷 -1- 甲酸第三丁酯
流程 IV
實例 4. 合成 3-( 氰基亞甲基 ) 氮雜環丁烷 -1- 甲酸第三丁酯
流程 IV
1- 二苯甲基氮雜環丁 -3- 醇鹽酸鹽 (16).
在周圍溫度下將二苯基甲胺(2737 g,15.0 mol,1.04當量)於甲醇(MeOH,6 L)中之溶液用來自加料漏斗之2-(氯甲基)環氧乙烷(1330 g,14.5 mol)處理。在初始加料期間注意到輕微吸熱。將所得反應混合物在室溫下攪拌3天,接著升溫至回流,再歷時3天。當TLC顯示反應似乎完成時,首先使反應混合物冷卻至室溫且接著在冰浴中冷卻至0-5℃。藉由過濾來收集固體且用丙酮(4 L)洗滌,得到第一批粗所需產物(1516 g)。將濾液在減壓下濃縮且所得半固體用丙酮(1 L)稀釋。接著此固體藉由過濾來收集,得到第二批粗所需產物(221 g);發現粗產物1-二苯甲基氮雜環丁-3-醇鹽酸鹽(1737 g,3998.7 g理論值,43.4%產率)足夠純而無需進一步純化即用於後續反應。1
HNMR (300 MHz, DMSO-d 6
) d 12.28 (br. d, 1H), 7.7 (m, 5H), 7.49 (m, 5H), 6.38 (d, 1H), 4.72 (br. s, 1H), 4.46 (m, 1H), 4.12 (m, 2H), 3.85 (m, 2H) ppm;C16
H18
ClNO(MW 275.77; 游離鹼C16
H17
NO, MW, 239.31), LCMS (EI)m
/e
240 (M+
+ H)。
3- 羥基氮雜環丁烷 -1- 甲酸第三丁酯 (17).
將1-二苯甲基氮雜環丁-3-醇鹽酸鹽(625 g,2.27 mol)於碳酸鈉水溶液(Na2
CO3
,5 L)及二氯甲烷(CH2
Cl2
,5 L)之10%溶液中之懸浮液在室溫下攪拌直至所有固體均溶解。分離兩層,且將水層用二氯甲烷(CH2
Cl2
,2 L)萃取。合併之有機萃取物經硫酸鈉(Na2
SO4
)乾燥且在減壓下濃縮。接著所得粗1-二苯甲基氮雜環丁-3-醇游離鹼溶於THF (6 L)中且將溶液置於大帕爾彈(Parr bomb)中。將二碳酸二第三丁酯(BOC2
O,545 g,2.5 mol,1.1當量)及20%鈀(Pd)/碳(125 g,50%濕)添加至帕爾彈。用氫氣(H2
)將容器充至30 psi且在穩定氫氣氛圍下在室溫下攪拌(容器再充氣三次以維持壓力在30 psi下) 18小時。當HPLC顯示反應完成時(不再吸收氫氣),反應混合物經Celite墊過濾且Celite墊用THF (4 L)洗滌。將濾液在減壓下濃縮以移除溶劑且殘餘物負載至具有最少量之二氯甲烷(CH2
Cl2
)的Biotage 150管柱上。管柱用正庚烷中20-50%乙酸乙酯溶離且收集含有純所需產物3-羥基氮雜環丁烷-1-甲酸第三丁酯之溶離份且合併。溶劑在減壓下移除,得到呈無色油狀之3-羥基氮雜環丁烷-1-甲酸第三丁酯(357 g,393.2 g理論值,90.8%產率),其在周圍溫度下在真空中靜置後固化。1
HNMR (300 MHz, CDCl3
), d 4.56 (m 1H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm。
3- 側氧基氮雜環丁烷 -1- 甲酸第三丁酯 (18).
使3-羥基氮雜環丁烷-1-甲酸第三丁酯(50 g,289 mmol)於乙酸乙酯(400 mL)中之溶液冷卻至0℃。接著在0-5℃下將所得溶液用固體TEMPO (0.5 g,3.2 mmol,0.011當量)及溴化鉀(KBr,3.9 g,33.2 mmol,0.115當量)於水(60 mL)中之溶液處理。在保持反應溫度在0-5℃之間的同時,添加飽和碳酸氫鈉水溶液(NaHCO3
,450 mL)及次氯酸鈉水溶液(NaClO,10-13%可用氯,450 mL)。一旦添加次氯酸鈉溶液,反應混合物顏色立即改變。當添加額外量之次氯酸鈉溶液時,反應混合物顏色逐漸褪色。當TLC顯示所有起始物質耗盡時,反應混合物顏色不再改變。接著反應混合物用乙酸乙酯(EtOAc,500 mL)稀釋且分離兩層。有機層用水(500 mL)及飽和氯化鈉水溶液(500 mL)洗滌且經硫酸鈉(Na2
SO4
)乾燥。接著溶劑在減壓下移除 ,得到粗產物3-側氧基氮雜環丁烷-1-甲酸第三丁酯(48 g,49.47 g理論值,97%產率),發現其足夠純且無需進一步純化直接用於後續反應。1
HNMR (CDCl3
, 300 MHz) d 4.65 (s, 4H), 1.42 (s, 9H) ppm。
3-( 氰基亞甲基 ) 氮雜環丁烷 -1- 甲酸第三丁酯 (2)
. 在室溫下將磷酸二乙酯氰基甲酯(745 g,4.20 mol,1.20當量)及無水四氫呋喃(THF,9 L)添加至裝備有熱電偶、加料漏斗及氮氣保護管之四頸燒瓶。溶液用冰-甲醇浴冷卻至-14℃且經20分鐘添加1.0 M第三丁醇鉀(t
-BuOK)於無水四氫呋喃(THF,3.85 L,3.85 mol,1.1當量)中之溶液,保持反應溫度低於-5℃。將所得反應混合物在-10℃下攪拌3小時且經2小時添加1-第三丁氧羰基-3-氮雜環丁酮(600 g,3.50 mol)於無水四氫呋喃(THF,2 L)中之溶液,保持內部溫度低於-5℃。經1小時將反應混合物自-5℃攪拌至-10℃且接著緩慢升溫至室溫且在室溫下攪拌隔夜。接著反應混合物用水(4.5 L)及飽和氯化鈉水溶液(NaCl,4.5 L)稀釋且用乙酸乙酯(EtOAc,2×9 L)萃取。合併之有機層用鹽水(6 L)洗滌且經無水硫酸鈉(Na2
SO4
)乾燥。溶劑在減壓下移除且殘餘物用二氯甲烷(CH2
Cl2
,4 L)稀釋,接著吸收至矽膠(SiO2
,1.5 Kg)上。吸收在矽膠上之粗產物藉由急驟管柱層析法(SiO2
,3.5 Kg,0-25% EtOAc/己烷梯度溶離)純化,得到呈白色固體狀之3-(氰基亞甲基)氮雜環丁烷-1-甲酸第三丁酯(2
,414.7 g,679.8 g理論值,61%產率)
。2
:1
H NMR (300MHz, CDCl3
) d 5.40 (m, 1H), 4.70 (m, 2H), 4.61 (m, 2H), 1.46 (s, 9H) ppm;C10
H14
N2
O2
(MW, 194.23), LCMS (EI)m
/e
217 (M+
+ Na)。
實例 5. 合成 4-(4,4,5,5- 四甲基 -1,3,2- 二氧硼戊烷 -2- 基 )-1H- 吡唑
流程 V
實例 5. 合成 4-(4,4,5,5- 四甲基 -1,3,2- 二氧硼戊烷 -2- 基 )-1H- 吡唑
流程 V
4- 碘吡唑 (20).
在周圍溫度下向裝備有氮氣入口、加料漏斗、熱電偶及機械攪拌器之燒瓶饋入吡唑(1
,450 g,6.62 mol)及四氫呋喃(THF,5 L)。接著混合物冷卻至10℃且在約10℃下將N
-碘代丁二醯亞胺(NIS,1490 g,6.62 mol,1.0當量)呈固體分部分添加至混合物。接著將所得反應混合物在周圍溫度下攪拌1小時(可能需要更長反應時間,視周圍溫度而定)。接著過濾混合物且在減壓下移除THF。殘餘物懸浮於乙酸乙酯(6 L)中且過濾不溶物。深色濾液依序用飽和硫代硫酸鈉水溶液(2×3 L) (有機層變淡至淺黃色)、水(2×3 L)及鹽水(2 L)洗滌。接著所得有機層經硫酸鈉乾燥,過濾,且在減壓下濃縮,在真空烘箱中在約30℃下乾燥隔夜後得到呈白色至淺黃色固體狀之4-碘吡唑(1138 g,1284.1 g理論值,88.6%)。1
H NMR (400 MHz, DMSO-d 6
) δ 13.17 (bs, 1H), 7.93 (bs,1H), 7.55 (bs,1H) ppm;C3
H3
IN2
(MW, 193.97), LCMS (EI)m
/e
195 (M+
+ H)。
1- 三甲基矽烷基 -4- 碘 吡唑 (21).
在周圍溫度下向裝備有回流冷凝器、氮氣入口、機械攪拌器及熱電偶之燒瓶饋入4-碘吡唑(200 g,1.03 mol)及THF (2 L)。向此溶液添加三乙胺(TEA,158 mL,1.13 mol,1.1當量)且所得溶液在冰-鹽水浴中冷卻至0℃。在劇烈攪拌下向此溶液添加氯三甲基矽烷(TMS-Cl,137 mL,1.08 mol,1.05當量),使溫度達至18℃。(反應物變得極稠且難以攪拌,但隨著時間過去變得易管理)。當放熱過程平息時,移除冷卻浴,且使反應升溫至室溫。藉由GC追蹤反應,且發現在約1小時之後似乎完成(反應取樣必須在缺乏空氣下進行且用無水溶劑稀釋以防TMS水解)。接著反應混合物用正庚烷(2 L)稀釋,接著在氮氣下過濾。用氮氣使旋轉蒸發儀通風,在減壓下自濾液移除溶劑。殘餘油狀物用正庚烷(1 L)稀釋且再濃縮。若在添加正庚烷後形成固體,則需要第二次過濾。接著使用Kugelohr在減壓下(在約0.5托下70-90℃)蒸餾殘餘物,得到呈無色油狀之1-三甲基矽烷基-4-碘吡唑(263 g,274.1 g理論值,96%)。此物質必須一直保持在氮氣下,因為TMS基團迅速水解。隨後,發現1-三甲基矽烷基-4-碘吡唑可藉由加熱碘吡唑與2當量六甲基二矽氮烷1小時來製備。
4-(4,4,5,5- 四甲基 -1,3,2- 二氧硼戊烷 -2- 基 )-1H
- 吡唑 (1).
在周圍溫度下向裝備有機械攪拌器、氮氣入口、加料漏斗及熱電偶之燒瓶饋入1-三甲基矽烷基-4-碘吡唑(225.1 g,0.85 mol)及THF (2200 mL)。此混合物在冰/鹽/鹽水浴中冷卻至約-6℃,接著按使內部溫度不超過0℃之速率添加氯化異丙基鎂於THF中之溶液(2 M THF溶液,510 mL,1.02 mol,1.2當量)。金屬/鹵素交換程度藉由GC監測且發現在約10分鐘之後完成。然後最初向橙棕色溶液緩慢添加2-異丙氧基-4,4,5,5-四甲基-1,3,2-二氧硼戊烷(異丙基頻哪醇硼酸酯,347 mL,1.7 mol,2.0當量),保持溫度低於0℃,接著在添加約一半化合物之後相當迅速地添加,使溫度達至5℃(反應物變得相當稠,接著緩慢變稀)。接著將反應在0℃下攪拌10分鐘,接著經1小時升溫至周圍溫度,且在周圍溫度下再攪拌1小時。使反應混合物冷卻至約6℃且添加飽和氯化銨水溶液(NH4
Cl,2.2 L),溫度升至25℃。將混合物攪拌5分鐘,接著用甲苯(10 L)稀釋。分離各層(大量固體存在於水層中)且有機層依序用水(6×2.2 L)及鹽水(2×2.2 L)洗滌,接著經硫酸鈉(Na2
SO4
)乾燥。藉由過濾移除乾燥試劑硫酸鈉(Na2
SO4
),且在減壓下濃縮溶液。殘餘甲苯與正庚烷共蒸發,得到呈白色固體狀之4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H
-吡唑(1
,90.3 g,164.9 g理論值,54.8%)。1
:1
H NMR (400 MHz, DMSO-d 6
) δ 13.08 (bs, 1H), 7.94 (s,1H), 7.62 (s,1H), 1.23 (s, 12H) ppm;C9
H15
BN2
O2
(MW, 194.04), LCMS (EI)m
/e
195 (M+
+ H)。
實例 6. 4-(4,4,5,5- 四甲基 -1,3,2- 二氧硼戊烷 -2- 基 )-1H- 吡唑之替代合成
流程 VI
實例 6. 4-(4,4,5,5- 四甲基 -1,3,2- 二氧硼戊烷 -2- 基 )-1H- 吡唑之替代合成
流程 VI
4- 溴吡唑 (22).
在周圍溫度下使吡唑(19
,34.0 g,0.5 mol)及NBS (89.0 g,0.5 mol,1.0當量)懸浮於水(625 ml)中。將所得懸浮液在周圍溫度下攪拌隔夜。接著反應混合物用EtOAc (2×100 mL)萃取。將合併之EtOAc萃取物用Na2
S2
O3
水溶液及鹽水洗滌,經Na2
SO4
乾燥,且在減壓下濃縮,得到呈白色固體狀之粗4-溴吡唑(72.0 g,73.5 g理論值,98%產率)(GC純度:>98%),其未經進一步純化直接用於後續反應。
4- 溴 -1-( 乙氧基乙基 ) -1H
- 吡唑 (23)
. 在周圍溫度下向4-溴吡唑(70.0 g,0.476 mol)於CH2
Cl2
(600 mL)中之溶液添加3.1 M HCl之二噁烷溶液(4 mL)及乙基乙烯基醚(41 g,0.569 mol,1.2當量)中之溶液。將所得反應混合物在周圍溫度下攪拌3小時。將反應用NaHCO3
水溶液淬滅且分離兩層。有機層用水洗滌,經Na2
SO4
乾燥,且在減壓下濃縮至乾,得到呈油狀之4-溴-1-(乙氧基乙基)-1H
-吡唑(113 g,104.3 g理論值,97%產率) (GC純度:89%),其未經進一步純化直接用於後續反應。
1-( 乙氧基乙基 ) -4-(4,4,5,5- 四甲基 [1,3,2] 二氧硼戊烷 -2- 基 )-1H
- 吡唑 (24)
. 在周圍溫度下向100 mli
PrMgCl.LiCl (50 mmol,1.8當量)於THF中之溶液添加4-溴-1-(乙氧基乙基)-1H
-吡唑(6.15 g,28 mmol)。將所得反應混合物在周圍溫度下攪拌12小時且接著冷卻至-20℃。接著在-20℃下將甲氧基頻哪醇硼酸酯(10.6 g,67 mmol,2.4當量)添加至反應混合物。將所得混合物在0-10℃下攪拌1小時。添加NH4
Cl水溶液以淬滅反應。接著將混合物用石油醚(PE)萃取。合併之PE萃取物用飽和NaHCO3
洗滌,經Na2
SO4
乾燥且在減壓下濃縮。粗產物在PE中結晶,得到呈白色至灰白色固體狀之1-(乙氧基乙基)-4-(4,4,5,5-四甲基[1,3,2]二氧硼戊烷-2-基)-1H
-吡唑(24
,4.2 g,7.45 g理論值,56.4%產率) (GC純度:99%)。24
:1
H NMR (DMSO-d 6
, 400 MHz) δ 8.09 (s, 1H), 8.58 (s,1H), 7.62 (s,1H), 5.55 (q, 1H,J
= 6.1 Hz), 3.37 (dq, 1H,J
= 7.1, 9.6 Hz), 3.12 (dq, 1H,J
= 7.0, 9.7 Hz), 1.56 (d, 3H,J
= 6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H,J
= 7.0 Hz) ppm;C13
H23
BN2
O3
(MW, 266.14), LCMS (EI)m
/e
267 (M+
+ H)。
4-(4,4,5,5- 四甲基 -1,3,2- 二氧硼戊烷 -2- 基 )-1H
- 吡唑 (1).
在0-5℃下向2,3-二甲基丁-2,3-二醇(25.0 kg,211.6 mol)及1-(1-乙氧基乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H
-吡唑(24
,55.0 kg,206.7 mol)於1,2-二氯乙烷(750 kg)中之混合物緩慢添加HCl之MTBE溶液(25.0 kg,20-30% HCl)。接著將所得反應混合物在10-20℃下攪拌3-5小時。在如藉由HPLC監測,選擇性脫除保護基反應完成後(1
:低於1%),反應混合物脫氣且用氮氣再填充,接著冷卻至-15℃。接著向冷卻之反應混合物添加三乙胺(TEA,30.0 kg,296.5 mol)以調整pH值至7-8。接著混合物逐漸升溫至周圍溫度,接著用水(150 kg)處理。分離兩相且有機層用鹽水(60 kg)洗滌且經硫酸鈉(Na2
SO4
)乾燥。乾燥試劑硫酸鈉(Na2
SO4
)藉由過濾來移除且所得溶液在40-50℃下在減壓下濃縮成黏稠油狀物。殘餘物升溫至60-70℃且在相同溫度下用石油醚(100 kg)稀釋。所得混合物接著逐漸冷卻至周圍溫度且隨後冷卻至-5℃且在相同溫度下攪拌3小時。固體藉由濃縮來收集且在50-60℃下在真空下乾燥,得到粗所需產物(1
,33.75 kg,40.11 kg理論值,84.1%)。接著粗所需產物懸浮於1,2-二氯乙烷(30 kg)中且將所得混合物加熱至回流直至形成澄清溶液。接著在相同溫度下向熱溶液添加石油醚(150 kg)。接著所得混合物逐漸冷卻至周圍溫度且隨後冷卻至-5℃且在相同溫度下攪拌3小時。固體藉由濃縮來收集且在真空下在50-60℃下乾燥,得到呈灰白色固體狀之4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H
-吡唑(1
,31.0 kg,40.11 kg理論值,77.3%),其在每個可比較態樣中與藉由如以上實例5中所述之合成方法合成的物質一致。
實例 7. 合成 4- 氯 -7H-[ 吡咯并 [2,3-d] 嘧啶
流程 VII
實例 7. 合成 4- 氯 -7H-[ 吡咯并 [2,3-d] 嘧啶
流程 VII
4,6- 二氯嘧啶 -5- 甲醛 (26).
向5 L裝備有機械攪拌器、加料漏斗、冷凝器、熱電偶及N2
吹掃之4頸燒瓶饋入NaOH洗氣水溶液、氯氧化磷(POCl3
,1 L,10.572 mol,4.82當量)且在冰/鹽浴中冷卻。接著在0 ± 2℃下N
,N
-二甲基甲醯胺(DMF,320 mL,4.138 mol,1.85當量)逐滴添加至燒瓶。在經約0.5小時添加約100 mL DMF之後,發生結晶且反應溫度自0℃增加至10℃。停止添加且使混合物再冷卻至約2℃。在低於8℃下經2.5小時添加剩餘DMF。懸浮液變得極稠,使得攪拌困難。當完成DMF添加時,在3-5℃下攪拌混合物0.5小時。4,6-二羥基嘧啶(250 g,2.232 mol)呈固體逐份添加。在添加約三分之一4,6-二羥基嘧啶之後,反應混合物變得更流動,且發生緩慢放熱現象,經0.5小時反應溫度增加至約12℃。剩餘4,6-二羥基嘧啶經0.25小時逐份添加,反應溫度自12℃增加至27℃。維持反應溫度在25-27℃下,間歇性冷卻,在此時間期間黃色懸浮液變稀,接著再次變稠。在放熱現象在約1小時內平息之後,緩慢加熱反應混合物。在約55℃下,反應混合物變得極稠,且發生第二次輕度放熱現象。移除加熱套,同時反應溫度繼續增加至約63℃且在滴下前保持在此溫度下若干分鐘。重新開始加熱混合物,直至獲得緩緩回流(約100℃)。在約95℃下,HCl氣體開始穩定、相當快速放出,且反應混合物逐漸變稀且變黑。在約0.5小時之後,顯現澄清棕色溶液,經1.25小時回流溫度緩慢增加至115℃。在回流下總共2.5小時後,反應混合物冷卻至周圍溫度且在周圍溫度下攪拌隔夜。在減壓下(浴溫45-50℃)移除過量POCl3
(儘可能)。將稠殘餘棕色油狀物極慢傾倒至20 L分離漏斗中之冷H2
O (5 L)中,按需要添加冰以維持混合物水溶液靠近室溫。將混合物水溶液用EtOAc (2×3 L,接著1×2 L)萃取。將合併之EtOAc萃取物用H2
O (2×2.5 L)、飽和NaHCO3
水溶液(1 L)、鹽水(1 L)洗滌,經Na2
SO4
乾燥,過濾,且在減壓下濃縮(浴溫在35℃下),得到呈黃橙色固體狀之粗4,6-二氯嘧啶-5-甲醛(270 g,395 g理論值,68.4%)。藉由Kugelrohr蒸餾(烘箱溫度在90-100℃下,225毫托)來純化此粗物質之20 g部分,得到15.3 g呈白色固體狀之純4,6-二氯嘧啶-5-甲醛,其在室溫下靜置時變黃。1
H NMR (300 MHz, CDCl3
) δ 10.46 (s, 1H), 8.89 (s,1H) ppm。
4- 胺基 -6- 氯嘧啶 -5- 甲醛 (27)
. 在周圍溫度下7 M NH3
之MeOH溶液(265 mL,1.855 mol,2.0當量)經1.25小時添加至4,6-二氯嘧啶-5-甲醛(163.7 g,0.9301 mol)於甲苯(3 L)中之溶液。反應溫度自20℃緩慢增加至26℃且形成黃色懸浮液。輕度冷卻以維持反應溫度低於26℃。在周圍溫度下攪拌懸浮液3.5小時,接著藉由過濾來收集固體。固體用EtOAc (1 L)洗滌。在減壓下濃縮濾液,且固體用甲苯及正庚烷(2:1 v/v,600 mL)濕磨,過濾且乾燥,得到71.1 g呈黃色固體狀之4-胺基-6-氯嘧啶-5-甲醛。自反應混合物過濾之原始固體含有額外量之4-胺基-6-氯嘧啶-5-甲醛。藉由在EtOAc (1.25 L)中攪拌1.5小時,過濾,接著在THF (750 mL)中攪拌1小時且再次過濾,自過濾之固體萃取產物。在減壓下濃縮EtOAc與THF濾液,且所得固體用甲苯及正庚烷(2:1 v/v,450 mL)濕磨,過濾且乾燥,得到額外44.1 g呈黃色固體狀之4-胺基-6-氯嘧啶-5-甲醛。4-胺基-6-氯嘧啶-5-甲醛(115.2 g,146.5 g理論)之合併產率為78.6%。1
HNMR (300 MHz, DMSO-d 6
) δ 10.23 (s, 1H), 8.71 (bs,1H), 8.55 (bs, 1H), 8.39 (s, 1H) ppm;C5
H4
ClN3
O(MW, 157.56), LCMS (EI)m
/e
158 (M+
+ H)。
6- 氯 -5-(2- 甲氧基乙烯基 ) 嘧啶 -4- 基胺 (28).
氯化(甲氧基甲基)三苯基鏻(276.0 g,0.807 mol,1.1當量)於THF (1.5 L)中之懸浮液在冰/鹽浴中冷卻至-2℃且在-2至-3℃下經1.5小時添加1 M第三丁醇鉀(KO t
Bu)之THF溶液(807 mL,0.807 mol,1.1當量)。將深紅橙色混合物在-2至-3℃下攪拌1小時。接著4-胺基-6-氯嘧啶-5-甲醛(115.2 g,0.7338 mol,1.0當量)呈固體形式逐份添加至反應混合物,使用THF (200 mL)清洗容器及漏斗。在添加期間,反應溫度自-3℃增加至13℃且顯現棕色。當反應溫度降低至10℃時,移除冷卻浴且使反應混合物升溫至周圍溫度且在周圍溫度下攪拌42小時。反應混合物冷卻至-2℃,接著藉由緩慢添加飽和NH4
Cl水溶液(750 mL)淬滅。在減壓下濃縮混合物,移除大部分THF。殘餘物分配於EtOAc (3 L)與H2
O (1 L)之間。過濾有機相以移除界面處之不溶物,接著用2 N HCl (4×250 mL)、接著3 N HCl (2×250 mL)萃取。合併之HCl萃取物用EtOAc (500 mL)反萃取,接著經Celite過濾,移除不溶物。濾液在冰/鹽水浴中冷卻,用6 N NaOH水溶液調至pH 8,且用EtOAc (3×1 L)萃取。合併之EtOAc萃取物用鹽水 (1 L)洗滌,經Na2
SO4
乾燥,與木炭(10 g)及矽膠(10 g)一起攪拌1小時。混合物經Celite過濾,用EtOAc (1 L)洗滌Celite墊。濃縮濾液,殘餘EtOAc與正庚烷(500 mL)共蒸發。所得棕褐色固體在高真空下抽吸2小時,得到粗6-氯-5-(2-甲氧基乙烯基)嘧啶-4-基胺(72.3 g,136.2 g理論值,53.1%)。粗所需產物未經進一步純化即用於以下反應。粗產物之樣品(2.3 g)藉由矽膠管柱層析,用0-35% EtOAc/正庚烷溶離來純化,得到 1.7 g呈白色固體狀之純6-氯-5-(2-甲氧基乙烯基)嘧啶-4-基胺,發現其為E/Z
異構體之1:2混合物。1
H NMR (300 MHz, DMSO-d 6
):E
-異構體: δ 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H,J
= 13.1), 5.35 (d, 1H,J
= 13.0 Hz), 3.68 (s, 3H) ppm及Z
-異構體: δ 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H,J
= 6.8 Hz), 5.02 (d, 1H,J
= 6.7 Hz), 3.69 (s, 3H) ppm;C7
H8
ClN3
O(MW, 185.61), LCMS (EI)m
/e
186/188 (M+
+ H)。
4- 氯 -7H
-[ 吡咯并 [2,3-d
] 嘧啶 (4)
. 將濃HCl (5 mL)添加至粗6-氯-5-(2-甲氧基乙烯基)嘧啶-4-基胺(70.0 g,0.3784 mol)於THF (700 mL)中之溶液且將所得反應混合物加熱至回流,保持7.5小時。升溫後,形成淡色懸浮液,其逐漸再溶解。當如藉由HPLC監測,認為反應完成時,反應混合物冷卻至周圍溫度且在周圍溫度下攪拌隔夜。固體NaHCO3
(15 g)添加至反應混合物且所得混合物在周圍溫度下攪拌1小時。添加木炭(7 g)、矽膠(7 g)及Na2
SO4
(20 g)且將混合物加熱至40℃,保持1小時。接著混合物冷卻至周圍溫度且經Celite過濾,用THF (1 L)洗滌Celite墊。在減壓下濃縮濾液且所得固體在減壓下乾燥,得到呈黃棕色固體狀之粗4-氯-7H
-[吡咯并[2,3-d
]嘧啶(4
,58.1 g,58.1 g理論值,100%)。在50-55℃下此粗所需產物溶於EtOAc (1 L)中且用活性木炭(3 g)處理。混合物過濾,同時穿過Celite升溫且Celite墊用溫EtOAc (250 mL)洗滌。濾液濃縮至約500 mL且使懸浮液在周圍溫度下靜置隔夜。懸浮液隨後冷卻至0-5℃,保持2小時,接著固體藉由過濾來收集。固體乾燥,得到呈黃棕色晶體狀之純4-氯-7H
-[吡咯并[2,3-d
]嘧啶(4
,54.5 g,58.1 g理論值,94%)。1
H NMR (400 MHz, DMSO-d 6
) δ 12.58 (bs, 1H), 8.58 (s,1H), 7.69 (d,1H,J
= 3.5 Hz), 6.59 (d, 1H,J
= 3.5 Hz) ppm;LCMS (EI)m/e
154/156 (M+
+H)。
實例 8. 1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 酮 (7) 之替代合成
流程 VIII
實例 8. 1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 酮 (7) 之替代合成
流程 VIII
步驟 1 : (3- 氟 -2-( 三氟甲基 ) 吡啶 -4- 基 )(4- 羥基哌啶 -1- 基 ) 甲酮 (30).
在室溫下向3-氟-2-(三氟甲基)異菸鹼酸(13
) (54.01 g,258.3 mmol)於二氯甲烷(270 mL)中之溶液添加N,N
-二甲基甲醯胺(0.34 g,4.65 mmol)。經由加料漏斗經30分鐘向此溶液添加含乙二醯氯(34.41 g,271.2 mmol)之二氯甲烷(81 ml),同時內部溫度維持於15至25℃下。將加料漏斗用二氯甲烷(27 mL)清洗。將混合物在室溫下攪拌兩小時,得到棕色溶液。二氯甲烷在30℃之溫度下在減壓下蒸餾。殘餘物溶於二氯甲烷(270 mL)中且溶劑在30℃下在減壓下餾出。所得殘餘物溶於二氯甲烷(270 mL)中,得到3-氟-2-(三氟甲基)異菸鹼醯基氯(29
)之二氯甲烷溶液。向另一燒瓶添加4-羥基哌啶(33.18 g,328 mmol)、二氯甲烷(270 mL)及N,N
-二異丙基乙胺(108 mL,619.9 mmol)。將混合物加熱至33℃,形成溶液。混合物冷卻至室溫。在25至35℃之溫度下向溶液添加含3-氟-2-(三氟甲基)異菸鹼醯基氯(29)之二氯甲烷。添加後,將混合物在25至35℃下再攪拌一小時。向容器添加水(430 mL)及37%鹽酸(62.4 g,633 mmol)。在低於25℃之內部溫度下將稀釋之鹽酸添加至反應混合物。在攪拌混合物30分鐘後,有機相藉由分離來收集。有機相用9.5%鹽水(210 g)洗滌。合併水相且用二氯甲烷(430 mL)萃取。合併有機相且用4.5%鹽水(210 ml)及水(215 mL)洗滌。二氯甲烷藉由溶劑交換成2-甲氧基-2-甲基丙烷(TBME)而移除。將含殘餘物之TBME (135 mL)加熱至60°C,保持1小時。混合物逐漸冷卻至0°C,以使(3-氟-2-(三氟甲基)吡啶-4-基)(4-羥基哌啶-1-基)甲酮結晶。將混合物過濾且濕餅用TBME (27 mL)洗滌。固體在50°C下乾燥,得到呈淡棕色固體狀之(3-氟-2-(三氟甲基)吡啶-4-基)(4-羥基哌啶-1-基)甲酮(30
) (69.95 g,92%)。HPLC-MS: 293.0 (M+H)。1
H NMR (400 MHz, DMSO-d 6
) δ 3.09 - 3.99 (m, 4H); 1,37 - 1.80 (m, 4H); 3.75 (m, 1H); 4,84 (d, 1H (b)); 8.65 (d, 1H, J = 4.7Hz); 7.89 (dd, 1H, J = 4,7, J = 4.7 Hz)。13
C NMR (101 MHz, DMSO-d 6
) δ 33,5, 34,3, 38.9, 44.0, 65.0, 120.6, 127.6, 134.5, 134.7, 146.2, 152.2; 160.2。C12
H12
F4
N2
O2
(MW 292.23), LCMS (EI)m
/e
293.0 (M+
+ H)。如藉由HPLC量測,測得經由此方法之化合物30之純度超過約98%。
步驟 2 : 1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 酮 (7).
在15至25℃下向燒瓶添加(3-氟-2-(三氟甲基)吡啶-4-基)(4-羥基哌啶-1-基)甲酮(30
) (50 g,171.1 mmol)、二氯甲烷(733 mL)、水(766 mL)、碳酸氫鈉(71.4 g,849.7)、碳酸鈉(99.1 g,85.2 mmol)、溴化鈉(1.76 g,17.1 mmol)及2,2,6,6-四甲基-1-哌啶基氧基(TEMPO) (0.535 g,3.42 mmol)。混合物冷卻至0至5℃。以四部分經10分鐘向混合物添加1,3,5-三氯-1,3,5-三嗪烷
-4,4,6-三酮(23.8 g,102 mmol)。將混合物在0至5℃下攪拌30分鐘且接著混合物在30分鐘內升溫至20至25℃。在20至25℃下再攪拌混合物一小時後,在20至25℃下藉由添加甲醇(26.23 mL,647.5 mmol)淬滅反應。將混合物攪拌20分鐘且經Celite床過濾。Celite (20 g)床用二氯甲烷(50 mL)洗滌。分離有機相。將有機相依序用6%鹽水(266 g)及水(250 mL)洗滌。活性木炭(3.5 g)添加至有機相。在室溫下攪拌混合物30分鐘後,其經Celite (20 g)床過濾。濾床用二氯甲烷(50 mL)洗滌。二氯甲烷藉由溶劑交換成2-甲氧基-2-甲基丙烷(TBME)而移除且將含殘餘物之TBME (180 mL)加熱至50至60℃。庚烷(500 mL)逐漸添加至溫混合物(500 mL),同時內部溫度維持超過50℃以使產物結晶。混合物逐漸冷卻至10℃且過濾。濕餅用庚烷(2×75 mL)洗滌。固體在減壓下乾燥,得到呈灰白色至棕色固體狀之1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-酮(7
) (49.7 g,87.9%產率)。1
H NMR (300 MHz, DMSO-d 6
) d 8.68 (d,3 J HH
= 4.69 Hz, 1H, 吡啶中NCH), 7.97 (dd,3 J HH
= 4.69 Hz,4 J HF
= 4.69 Hz, 1H, 吡啶中NCCH), 3.92 (br s, 2H, 哌啶環中一個NCH2
, 吡啶環中另一個NCH2
, 均處於軸向位), 3.54 (t,3 J HH
= 6.15 Hz, 2H, 哌啶環中一個NCH2
, 吡啶環中另一個NCH2
, 均處於赤道位), 2.48 (t,3 J HH
= 6.44 Hz, 2H, NCCH2
), 2.34 (t,3 J HH
= 6.15 Hz, 2H, NCCH2
) ppm;13
C NMR (75 MHz, DMSO-d 6
) d 207.17 (C=O), 161.66 (N-C=O), 151.26 (d,1 J CF
= 266.89 Hz, C-F), 146.90 (d,4 J CF
= 6.05 Hz, 吡啶中NCH), 135.56 (C
-C=O), 134.78 -135.56 (m, NC
CF3
), 128.27 (d,3 J CF
= 7.19 Hz, 吡啶中NCC
H), 119.52 (d× 四重峰,1 J CF
= 274.38 Hz,3 J CF
= 4.89 Hz, CF3
), 45.10 (吡啶環中NC) ppm, 一個碳(吡啶環中NCC
) 由於與(CD3
)2
SO重疊而遺漏;19
F NMR (282 MHz, DMSO-d 6
) d -64.58 (d,4 J FF
= 15.85 Hz, F3
C), -128.90 (d × 四重峰,4 J FF
=1 5.85 Hz,4 J FH
= 4.05 Hz, FC) ppm;C12
H10
F4
N2
O2
(MW, 290.21), LCMS (EI)m/e
291.1 (M+
+ H)。如藉由HPLC量測,測得經由此方法之化合物7之純度介於約90%與約96%之間。
注意到增加之氧化劑(例如TEMPO)之使用可增加雜質形成及降低分離產率。更長氧化時間亦可增加雜質形成及降低分離產率。
實例 9. 1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 酮 (7) 之 替代合成
流程 IX
實例 9. 1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 酮 (7) 之 替代合成
流程 IX
1-(3- 氟 -2-( 三氟甲基 ) 異菸鹼醯基 ) 哌啶 -4- 酮 (7).
在室溫下向3-氟-2-(三氟甲基)異菸鹼酸(13
) (20 g,96.65 mmol)於二氯甲烷(150 mL)中之溶液添加N,N
-二甲基甲醯胺(0.13 g,1.72 mmol)。經由加料漏斗經30分鐘向此溶液添加含乙二醯氯(12.75 g,100.4 mmol)之二氯甲烷(40 ml),同時內部溫度維持於15至25℃下。將加料漏斗用二氯甲烷(10 mL)清洗。將混合物在室溫下攪拌2小時,得到中間物3-氟-2-(三氟甲基)異菸鹼醯基氯之棕色溶液。向溶液饋入4-哌啶酮單水合物鹽酸鹽(19.1 g,124.3 mmol)。混合物冷卻至0至5℃且添加碳酸鈉(20.28 g,191.3 mmol)於水(200 mL)中之溶液。在添加後,混合物升溫至室溫且攪拌2小時。分離有機相且依序用6%鹽水(110 g)及水(100 mL)洗滌。向有機相添加活性木炭(1.4 g)。在室溫下攪拌混合物60分鐘後,混合物經Celite (5 g)床過濾。濾床用二氯甲烷(40 mL)洗滌。二氯甲烷藉由溶劑交換成2-甲氧基-2-甲基丙烷(TBME)而移除且將含殘餘物之TBME (100 mL)加熱至50至60℃。將庚烷(250 mL)逐漸添加至溫混合物,同時維持內部溫度超過50℃以使產物結晶。混合物逐漸冷卻至10℃且過濾。濕餅用庚烷 (2×40 mL)洗滌。固體在減壓下乾燥,得到呈灰白色至棕色固體狀之1-(3-氟-2-(三氟甲基)異菸鹼醯基)哌啶-4-酮(7
) (25.8 g,92.7%產率)。1
H NMR (300 MHz, DMSO-d 6
) d 8.68 (d,3 J HH
= 4.69 Hz, 1H, 吡啶中NCH), 7.97 (dd,3 J HH
= 4.69 Hz,4 J HF
= 4.69 Hz, 1H, 吡啶中NCCH), 3.92 (br s, 2H, 哌啶環中一個NCH2
, 吡啶環中另一個NCH2
, 均處於軸向位), 3.54 (t,3 J HH
= 6.15 Hz, 2H, 哌啶環中一個NCH2
, 吡啶環中另一個NCH2
, 均處於赤道位), 2.48 (t,3 J HH
= 6.44 Hz, 2H, NCCH2
), 2.34 (t,3 J HH
= 6.15 Hz, 2H, NCCH2
) ppm;13
C NMR (75 MHz, DMSO-d 6
) d 207.17 (C=O), 161.66 (N-C=O), 151.26 (d,1 J CF
= 266.89 Hz, C-F), 146.90 (d,4 J CF
= 6.05 Hz, 吡啶中NCH), 135.56 (C
-C=O), 134.78 -135.56 (m, NC
CF3
), 128.27 (d,3 J CF
= 7.19 Hz, 吡啶中NCC
H), 119.52 (d× 四重峰,1 J CF
= 274.38 Hz,3 J CF
= 4.89 Hz, CF3
), 45.10 (吡啶環中NC) ppm, 一個碳(吡啶環中NCC
) 由於與(CD3
)2
SO重疊而遺漏;19
F NMR (282 MHz, DMSO-d 6
) d -64.58 (d,4 J FF
= 15.85 Hz, F3
C), -128.90 (d × 四重峰,4 J FF
=1 5.85 Hz,4 J FH
= 4.05 Hz, FC) ppm;C12
H10
F4
N2
O2
(MW, 290.21), LCMS (EI)m/e
291.1 (M+
+ H)。如藉由HPLC量測,測得經由此方法之化合物7之純度超過約99%。
實例 A : 活體外 JAK 激酶分析
實例 A : 活體外 JAK 激酶分析
根據Park等人,Analytical Biochemistry 1999
,269
, 94-104中描述之以下活體外分析測試式I化合物對JAK標靶之抑制活性。在昆蟲細胞中使用桿狀病毒表現具有N端His標籤之人類JAK1 (a.a. 837-1142)及JAK2 (a.a. 828-1132)之催化結構域且純化。藉由量測生物素化肽之磷酸化來分析JAK1及JAK2之催化活性。磷酸化肽藉由均相時差式螢光(HTRF)偵測。在40 μL反應物中量測各激酶情況下化合物之IC50
,反應物在具有100 mM NaCl、5 mM DTT及0.1 mg/mL (0.01%) BSA之50 mM Tris (pH 7.8)緩衝液中含有該酶、ATP及500 nM肽。對於1 mM IC50
量測,反應物中之ATP濃度為1 mM。反應在室溫下進行1小時,接著在分析緩衝液(Perkin Elmer, Boston, MA)中用20 μL 45 mM EDTA、300 nM SA-APC、6 nM Eu-Py20終止。結合於銪標記之抗體進行40分鐘,且在Fusion盤式讀數器(Perkin Elmer, Boston, MA)上量測HTRF信號。式I化合物及己二酸鹽在JAK1下IC50
≤5 nM (在1 mM ATP下量測),其中JAK2/JAK1比率> 10 (在1 mM ATP下量測)。
實例 B :細胞分析
實例 B :細胞分析
生長依賴於細胞介素且因此依賴於JAK/STAT信號轉導之癌細胞株可以6000個細胞/孔(96孔盤格式)塗鋪在RPMI 1640、10% FBS及1 nG/mL適當細胞介素中。化合物可添加至DMSO/培養基(最終濃度0.2% DMSO)中之細胞中且在37℃、5% CO2
下培育72小時。化合物對細胞活力之作用使用CellTiter-Glo發光細胞活力分析(Promega),接著TopCount (Perkin Elmer, Boston, MA)定量來評定。使用非JAK驅動之細胞株,利用相同分析讀取,同時量測化合物之潛在脫靶作用。所有實驗通常一式兩份進行。
以上細胞株亦可用於檢查化合物對JAK激酶或潛在下游受質,諸如STAT蛋白、Akt、Shp2或Erk之磷酸化的作用。此等實驗可在細胞介素饑餓隔夜後進行,接著與化合物進行短暫預先培育(2小時或更少)且細胞介素刺激約1小時或更少。接著自細胞提取蛋白質且藉由本領域之技術人員熟悉之技術,包括西方點墨法或ELISA,使用可區分磷酸化蛋白與總蛋白之抗體分析。此等實驗可利用正常細胞或癌細胞來研究化合物對腫瘤細胞存活生物學或對發炎疾病之介體的活性。舉例而言,關於後者,諸如IL-6、IL-12、IL-23或IFN之細胞介素可用於刺激JAK活化,引起STAT蛋白磷酸化,及可能轉錄概況(藉由陣列或qPCR技術評定)或諸如IL-17之蛋白質之產生及/或分泌。化合物抑制此等細胞介素介導之作用的能力可使用本領域之技術人員常用之技術量測。
亦可在細胞模型中測試本文中之化合物,該等細胞模型經設計以評估其針對突變JAK,例如在髓樣增生性病症中發現之JAK2V617F突變的效力及活性。此等實驗常常利用野生型或突變JAK激酶在其中異位表現之細胞介素依賴性血液學譜系細胞(例如BaF/3) (James, C.等人,Nature
434:1144-1148;Staerk, J.等人, JBC 280:41893-41899)。終點包括化合物對細胞存活、增殖及磷酸化JAK、STAT、Akt或Erk蛋白質之作用。
可評估本文中之某些化合物抑制T細胞增殖之活性。可考慮此類分析為第二細胞介素(亦即JAK)驅動之增殖分析以及免疫活化之免疫遏制或抑制之簡單化分析。以下為如何進行此類實驗之簡要概述。使用Ficoll Hypaque分離方法自人類全血樣品製備外周血單核細胞(PBMC),且可藉由淘洗自PBMC獲得T細胞(部分2000)。新鮮分離之人類T細胞可以2×106
個細胞/毫升之密度在37℃下供養在培養基(RPMI 1640,補充有10%胎牛血清、100 U/ml青黴素、100 μg/ml鏈黴素)中長達2天。對於IL-2刺激之細胞增殖分析,首先用植物凝集素(PHA)以10 μg/mL之最終濃度處理T細胞72小時。在用PBS洗滌一次後,將6000個細胞/孔塗鋪在96孔盤中且在培養基中在100 U/mL人類IL-2 (ProSpec-Tany TechnoGene; Rehovot, Israel)存在下用化合物以不同濃度處理。將盤在37℃下培育72小時且使用CellTiter-Glo發光試劑按照製造商提議之方案(Promega; Madison, WI)評定增殖指數。
實例 C :活體內抗腫瘤功效
實例 C :活體內抗腫瘤功效
可在人類腫瘤異種移植模型中在免疫受損小鼠中評估本文中之化合物。舉例而言,INA-6漿細胞瘤細胞株之致瘤變異體可用於皮下接種SCID小鼠(Burger, R.等人,Hematol
J. 2:42-53, 2001)。接著載有腫瘤之動物隨機化至藥物或媒劑處理組且可藉由許多通常途徑,包括經口、腹膜內或使用可植入泵連續輸注來投與不同劑量之化合物。隨著時間過去,使用測徑規追蹤腫瘤生長。此外,可在針對如上所述(實例B)之分析開始處理之後的任何時候收穫腫瘤樣品以評估化合物對JAK活性及下游信號傳導路徑之作用。另外,可使用其他已知激酶(例如Bcr-Abl)驅動之異種移植腫瘤模型,諸如K562腫瘤模型評定化合物之選擇性。
實例 D :鼠科皮膚接觸遲發型過敏反應測試
實例 D :鼠科皮膚接觸遲發型過敏反應測試
亦可在T細胞驅動之鼠科遲發型過敏測試模型中測試本文中之化合物的功效(抑制JAK標靶)。認為鼠科皮膚接觸延遲型過敏(DTH)反應為臨床接觸性皮炎及其他T-淋巴細胞介導之皮膚免疫病症,諸如牛皮癬之有效模型(Immunol Today
. 1998年1月;19(1):37-44)。鼠科DTH共享牛皮癬之多種特徵,包括免疫浸潤、伴隨發炎細胞介素之增加及角化細胞過度增殖。此外,在臨床中有效治療牛皮癬之許多類別藥劑亦為小鼠中DTH反應之有效抑制劑(Agents Actions. 1993年1月;38(1-2):116-21)。
在第0天及第1天,藉由向剃毛之腹部局部施用抗原2,4-二硝基-氟苯(DNFB),敏化Balb/c小鼠。在第5天,使用工程師之測微計量測耳朵之厚度。記錄此量測且用作基線。接著藉由以0.2%之濃度局部施用總共20 μL(10 μL在內耳廓上及10 μL在外耳廓上) DNFB來激發動物之兩個耳朵。在激發之後二十四至七十二小時,再次量測耳朵。在整個敏化及激發期(第-1天至第7天)或在激發期前及整個激發期(通常第4天下午至第7天)用測試化合物處理。全身或者局部(局部施用處理至耳朵)投與測試化合物(不同濃度)之處理。測試化合物之功效藉由與無處理時之情況相比耳腫減少來指示。引起20%或更多之減少的化合物視為有效的。在一些實驗中,激發小鼠而非敏化(陰性對照)。
測試化合物之抑制作用(抑制JAK-STAT路徑之活化)可藉由免疫組織化學分析證實。JAK-STAT路徑之活化引起功能轉錄因子之形成及移位。此外,免疫細胞之流入及增加之角化細胞增殖亦應提供可進行研究及定量之耳朵之獨特表現概況變化。使用與磷酸化STAT3特異性相互作用之抗體(純系58E12, Cell Signaling Technologies),經福馬林固定及石蠟包埋之耳朵切片(在DTH模型中激發期之後收穫)進行免疫組織化學分析。將小鼠耳朵用測試化合物、媒劑或***(dexamethasone)(臨床上有效的對牛皮癬之治療)處理或在DTH模型中無任何處理以進行比較。測試化合物及***可在品質與數量上產生類似的轉錄改變,且測試化合物與***可減少浸潤細胞數目。全身與局部投與測試化合物可產生抑制作用,亦即減少浸潤細胞數目及抑制轉錄變化。
實例 E :活體內消炎活性
實例 E :活體內消炎活性
可在經設計以複製單一或複雜發炎反應之囓齒類動物或非囓齒類動物模型中評估本文中之化合物。舉例而言,囓齒類動物關節炎模型可用於評估預防或治療劑量之化合物的治療潛能。此等模型包括但不限於小鼠或大鼠膠原蛋白誘發之關節炎、大鼠佐劑誘發之關節炎及膠原蛋白抗體誘發之關節炎。包括(但不限於)多發性硬化、I型糖尿病、葡萄膜視網膜炎、甲狀腺炎、重症肌無力、免疫球蛋白腎病、心肌炎、氣道敏感(氣喘)、狼瘡或結腸炎的自體免疫疾病亦可用於評估本文中之化合物之治療潛能。此等模型在研究團體中成功建立且為本領域之技術人員所熟悉(Current Protocols in Immunology, 第3卷, Coligan, J.E.等人, Wiley Press.;Methods in Molecular Biology
: 第225卷, Inflammation Protocols., Winyard, P.G.及Willoughby, D.A., Humana Press, 2003.)。
實例 F :乾眼、葡萄膜炎及結膜炎治療之動物模型
實例 F :乾眼、葡萄膜炎及結膜炎治療之動物模型
藥劑可在本領域之技術人員已知的一或多種乾眼臨床前模型中評估,該等模型包括(但不限於)兔伴刀豆凝集素A (ConA)淚腺模型、東莨菪鹼小鼠模型(皮下或經皮)、肉毒菌小鼠淚腺模型或引起眼腺功能障礙之許多自發囓齒類動物自體免疫模型(例如NOD-SCID、MRL/lpr或NZB/NZW)中之任一者(Barabino等人, Experimental Eye Research 2004, 79, 613-621及Schrader等人, Developmental Opthalmology, Karger 2008, 41, 298-312,各以引用之方式整體併入本文中)。此等模型中之終點可包括眼腺及眼睛(角膜等)之組織病理學且可能包括量測眼淚產生之經典希爾默測試(Schirmer test)或其修改型式(Barabino等人)。活性可藉由多種投與途徑(例如全身或局部)給藥來評定,此可在可量測之疾病存在之前或之後開始。
藥劑可在本領域之技術人員已知之一或多種葡萄膜炎臨床前模型中評估。此等模型包括(但不限於)實驗自體免疫葡萄膜炎(EAU)及內毒素誘發之葡萄膜炎(EIU)模型。EAU實驗可在兔、大鼠或小鼠中進行且可涉及被動或主動免疫。舉例而言,多種視網膜抗原中之任一者可用於使動物對相關免疫原敏感,此後可用相同抗原經眼激發動物。EIU模型更急性且涉及脂多醣以低於致死劑量局部或全身投與。EIU與EAU模型之終點可尤其包括眼底鏡檢查、組織病理學。此等模型由Smith等人(Immunology and Cell Biology 1998, 76, 497-512,其以引用之方式整體併入本文中)評述。活性可藉由多種投與途徑(例如全身或局部)給藥來評定,此可在可量測之疾病存在之前或之後開始。上列一些模型亦可顯現鞏膜炎/鞏膜表層炎、脈絡膜炎、睫狀體炎或虹膜炎,因此可用於研究化合物治療性治療此等疾病之潛在活性。
藥劑亦可在本領域之技術人員已知之一或多種結膜炎臨床前模型中評估。此等模型包括(但不限於)利用豚鼠、大鼠或小鼠之囓齒類動物模型。豚鼠模型包括利用主動免疫或被動免疫及/或利用諸如卵白蛋白或豚草進行免疫激發方案之模型(Groneberg, D.A等人, Allergy 2003, 58, 1101-1113,其以引用之方式整體併入本文中)。大鼠及小鼠模型在綜合設計上與豚鼠中之模型相似(亦由Groneberg評述)。活性可藉由多種投與途徑(例如全身或局部)給藥來評定,此可在可量測之疾病存在之前或之後開始。此類研究之終點可包括例如諸如結膜之眼睛組織之組織學、免疫學、生物化學或分子分析。
實例 G :骨骼之活體內保護
實例 G :骨骼之活體內保護
化合物可在本領域之技術人員已知之骨質缺乏症、骨質疏鬆症或骨吸收之多種臨床前模型中評估。舉例而言,切除卵巢之囓齒類動物可用於評估化合物影響骨骼重塑及/或密度之徵象及標記物的能力(W.S.S. Jee及W. Yao, J Musculoskel. Nueron. Interact., 2001, 1(3), 193-207,其以引用之方式整體併入本文中)。可替代地,骨骼密度及構造可在療法(例如糖皮質素)誘發之骨質缺乏症之模型中在對照或化合物處理之囓齒類動物中評估(Yao等人, Arthritis and Rheumatism, 2008, 58(6), 3485-3497;及同前58(11), 1674-1686,兩者均以引用之方式整體併入本文中)。另外,化合物對骨吸收及密度之作用可在上文論述之囓齒類動物關節炎模型(實例E)中評估。雖然所有此等模型之終點可變化,但常常包括組織學及放射學評定以及骨骼重塑之免疫組織學及適當生物化學標記物。
已描述本發明之許多實施例。然而,應瞭解在不脫離本發明之精神及範疇下可進行多種修改。因此,其他實施例在以下申請專利範圍之範疇內。
無
Claims (44)
- 一種方法,其包括使式III化合物: III 或其鹽與4-羥基哌啶反應,形成式IV化合物: IV 或其鹽。
- 如申請專利範圍第1項之方法,其中與4-羥基哌啶之該反應在鹼存在下進行。
- 如申請專利範圍第2項之方法,其中該鹼為三級胺。
- 如申請專利範圍第3項之方法,其中該三級胺為N ,N -二異丙基乙胺。
- 如申請專利範圍第1項至第4項中任一項之方法,其中與4-羥基哌啶之該反應在包含二氯甲烷之溶劑組分中進行。
- 如申請專利範圍第1項至第5項中任一項之方法,其中與4-羥基哌啶之該反應在約25℃至約35℃之溫度下進行。
- 如申請專利範圍第1項至第6項中任一項之方法,其中該式III化合物由如下方法形成,該方法包括使式II化合物: II 或其鹽與草醯氯反應,形成該式III化合物或其鹽。
- 如申請專利範圍第7項之方法,其中該式II化合物與草醯氯之該反應在催化量之二甲基甲醯胺(DMF)存在下進行。
- 如申請專利範圍第7項或第8項之方法,其中該式II化合物與草醯氯之該反應在包含二氯甲烷之溶劑組分中進行。
- 如申請專利範圍第7項至第9項中任一項之方法,其中該式II化合物與草醯氯之該反應在約15℃至約25℃之溫度下進行。
- 如申請專利範圍第1項至第10項中任一項之方法,其進一步包括使該式IV化合物或其鹽在氧化條件下反應,形成式V化合物: V 或其鹽。
- 如申請專利範圍第11項之方法,其中該等氧化條件包含第一氧化劑。
- 如申請專利範圍第12項之方法,其中該等氧化條件包含第二氧化劑。
- 如申請專利範圍第12項或第13項之方法,其中該第一氧化劑為三氯異氰尿酸(TCIC)。
- 如申請專利範圍第14項之方法,其中該TCIC以相對於該式IV化合物約0.5與約0.7莫耳當量之間存在。
- 如申請專利範圍第13項至第15項中任一項之方法,其中該第二氧化劑為2,2,6,6-四甲基-1-哌啶基氧基(TEMPO)。
- 如申請專利範圍第16項之方法,其中該TEMPO以相對於該式IV化合物約0.015與約0.025莫耳當量之間存在。
- 如申請專利範圍第11項至第17項中任一項之方法,其中該式IV化合物在氧化條件下之該反應進一步包含碳酸氫鈉、碳酸鈉及溴化鈉中之一或多者。
- 如申請專利範圍第11項至第18項中任一項之方法,其中該式IV化合物在氧化條件下之該反應進一步包含包括二氯甲烷之溶劑組分。
- 如申請專利範圍第19項之方法,其中該溶劑組分進一步包含水。
- 如申請專利範圍第11項中任一項之方法,其中該等氧化條件包含在約0℃至約5℃之溫度下將三氯異氰尿酸添加至包含該式IV化合物及TEMPO之溶液。
- 如申請專利範圍第21項之方法,其中三氯異氰尿酸之該添加包括以至少兩部分添加該三氯異氰尿酸。
- 如申請專利範圍第21項或第22項之方法,其中在該添加後在約0℃至約5℃之溫度下攪拌該溶液約30分鐘。
- 如申請專利範圍第23項之方法,該方法進一步包括在該攪拌後將該溶液升溫至約20℃至約25℃之溫度,歷時約一小時至約兩小時之時間。
- 如申請專利範圍第11項至第24項中任一項之方法,其進一步包括使式V化合物與式VI化合物: VI 或其鹽在還原劑存在下反應,形成式I化合物: I 或其鹽; 其中Z1 為H或保護基。
- 如申請專利範圍第25項之方法,其中Z1 為H。
- 如申請專利範圍第25項或第26項之方法,其中該還原劑為氰基硼氫化鈉或三乙醯氧基硼氫化鈉。
- 一種方法,其包括使式III化合物: III 或其鹽與4-哌啶酮或其鹽反應,形成式V化合物: V 或其鹽。
- 如申請專利範圍第28項之方法,其中該4-哌啶酮或其鹽為4-哌啶酮鹽酸鹽。
- 如申請專利範圍第28項之方法,其中該4-哌啶酮或其鹽為4-哌啶酮鹽酸鹽單水合物。
- 如申請專利範圍第28項至第30項中任一項之方法,其中該反應進一步包含鹼。
- 如申請專利範圍第31項之方法,其中該鹼為碳酸鈉。
- 如申請專利範圍第28項至第32項中任一項之方法,其中該式III化合物與該4-哌啶酮之該反應在包含二氯甲烷之溶劑組分中進行。
- 如申請專利範圍第28項至第33項中任一項之方法,其中該式III化合物與該4-哌啶酮之該反應在約0℃至約5℃之溫度下進行。
- 如申請專利範圍第28項至第34項中任一項之方法,其中該式III化合物由如下方法形成,該方法包括使式II化合物: II 或其鹽與草醯氯反應,形成該式III化合物或其鹽。
- 如申請專利範圍第35項之方法,其中該式II化合物與草醯氯之該反應在催化量之二甲基甲醯胺(DMF)存在下進行。
- 如申請專利範圍第35項或第36項之方法,其中該式II化合物與草醯氯之該反應在包含二氯甲烷之溶劑組分中進行。
- 如申請專利範圍第35項至第37項中任一項之方法,其中該式II化合物與草醯氯之該反應在約15℃至約25℃之溫度下進行。
- 如申請專利範圍第35項至第38項中任一項之方法,其中在該式III化合物與4-哌啶酮反應前不分離該式III化合物。
- 如申請專利範圍第35項至第39項中任一項之方法,其中該式II化合物與草醯氯之該反應及該式III化合物與4-哌啶酮之該反應在單一反應器中進行。
- 如申請專利範圍第28項至第40項中任一項之方法,其進一步包括使式V化合物與式VI化合物: VI 或其鹽在還原劑存在下反應,形成式I化合物: I 或其鹽; 其中Z1 為H或保護基。
- 如申請專利範圍第41項之方法,其中Z1 為H。
- 如申請專利範圍第41項或第42項之方法,其中該還原劑為氰基硼氫化鈉或三乙醯氧基硼氫化鈉。
- 一種式III化合物, III 或其鹽。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862623664P | 2018-01-30 | 2018-01-30 | |
US62/623,664 | 2018-01-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201940475A true TW201940475A (zh) | 2019-10-16 |
TWI797242B TWI797242B (zh) | 2023-04-01 |
Family
ID=65409599
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW108103234A TWI797242B (zh) | 2018-01-30 | 2019-01-29 | 製備jak抑制劑之方法及中間物 |
Country Status (32)
Country | Link |
---|---|
US (1) | US10899736B2 (zh) |
EP (2) | EP3746429B1 (zh) |
JP (2) | JP7393348B2 (zh) |
KR (1) | KR20200129099A (zh) |
CN (1) | CN112105608B (zh) |
AR (1) | AR114810A1 (zh) |
AU (1) | AU2019213665B2 (zh) |
BR (1) | BR112020015470A2 (zh) |
CA (1) | CA3089832A1 (zh) |
CL (1) | CL2020001983A1 (zh) |
CO (1) | CO2020009994A2 (zh) |
CR (1) | CR20200379A (zh) |
DK (1) | DK3746429T3 (zh) |
EA (1) | EA202091830A1 (zh) |
ES (1) | ES2912469T3 (zh) |
HR (1) | HRP20220510T1 (zh) |
IL (1) | IL276302B2 (zh) |
LT (1) | LT3746429T (zh) |
MA (1) | MA51771B1 (zh) |
MD (1) | MD3746429T2 (zh) |
MX (1) | MX2020007973A (zh) |
PE (1) | PE20211310A1 (zh) |
PH (1) | PH12020551145A1 (zh) |
PL (1) | PL3746429T3 (zh) |
PT (1) | PT3746429T (zh) |
RS (1) | RS63312B1 (zh) |
SG (1) | SG11202007164UA (zh) |
SI (1) | SI3746429T1 (zh) |
TW (1) | TWI797242B (zh) |
UA (1) | UA127488C2 (zh) |
WO (1) | WO2019152374A1 (zh) |
ZA (1) | ZA202004692B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112105608B (zh) | 2018-01-30 | 2023-07-14 | 因赛特公司 | 制备(1-(3-氟-2-(三氟甲基)异烟碱基)哌啶-4-酮)的方法 |
PE20212186A1 (es) | 2018-02-16 | 2021-11-11 | Incyte Corp | Inhibidores de la via de jak1 para el tratamiento de trastornos relacionados con citoquinas |
US11584961B2 (en) | 2018-03-30 | 2023-02-21 | Incyte Corporation | Biomarkers for inflammatory skin disease |
CA3097025A1 (en) | 2018-04-13 | 2019-10-17 | Incyte Corporation | Biomarkers for graft-versus-host disease |
EA202191170A1 (ru) | 2018-10-31 | 2021-07-27 | Инсайт Корпорейшн | Комбинированная терапия для лечения гематологических заболеваний |
MA55201A (fr) | 2019-03-05 | 2022-01-12 | Incyte Corp | Inhibiteurs de la voie jak1 pour le traitement d'un dysfonctionnement chronique de l'allogreffe pulmonaire |
US11992490B2 (en) | 2019-10-16 | 2024-05-28 | Incyte Corporation | Use of JAK1 inhibitors for the treatment of cutaneous lupus erythematosus and Lichen planus (LP) |
CN110683978A (zh) * | 2019-10-30 | 2020-01-14 | 西安医学院 | 一种3-腈基亚甲基氮杂环丁烷-1-碳酸叔丁酯的制备方法 |
AU2021329301A1 (en) | 2020-08-18 | 2023-04-13 | Incyte Corporation | Process and intermediates for preparing a JAK1 inhibitor |
CA3192099A1 (en) | 2020-08-18 | 2022-02-24 | Incyte Corporation | Process and intermediates for preparing a jak inhibitor |
MX2023006542A (es) | 2020-12-08 | 2023-08-25 | Incyte Corp | Inhibidores de la vía cinasa jano 1 (jak1) para el tratamiento del vitiligo. |
CN112625030A (zh) * | 2020-12-25 | 2021-04-09 | 杭州澳赛诺生物科技有限公司 | 一种一锅法合成n-保护3-溴代吡唑的合成方法 |
Family Cites Families (283)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2985589A (en) | 1957-05-22 | 1961-05-23 | Universal Oil Prod Co | Continuous sorption process employing fixed bed of sorbent and moving inlets and outlets |
US3832460A (en) | 1971-03-19 | 1974-08-27 | C Kosti | Anesthetic-vasoconstrictor-antihistamine composition for the treatment of hypertrophied oral tissue |
US4140755A (en) | 1976-02-13 | 1979-02-20 | Hoffmann-La Roche Inc. | Sustained release tablet formulations |
DE3036390A1 (de) | 1980-09-26 | 1982-05-13 | Troponwerke GmbH & Co KG, 5000 Köln | Neue pyrrolo-pyrimidine, verfahren zu ihrer herstellung und ihre verwendung bei der herstellung von biologischen wirkstoffen |
DE3220113A1 (de) | 1982-05-28 | 1983-12-01 | Basf Ag, 6700 Ludwigshafen | Difluormethoxiphenylthiophosphorsaeureester |
US4402832A (en) | 1982-08-12 | 1983-09-06 | Uop Inc. | High efficiency continuous separation process |
US4548990A (en) | 1983-08-15 | 1985-10-22 | Ciba-Geigy Corporation | Crosslinked, porous polymers for controlled drug delivery |
US4498991A (en) | 1984-06-18 | 1985-02-12 | Uop Inc. | Serial flow continuous separation process |
NL8403224A (nl) | 1984-10-24 | 1986-05-16 | Oce Andeno Bv | Dioxafosforinanen, de bereiding ervan en de toepassing voor het splitsen van optisch actieve verbindingen. |
CA1306260C (en) | 1985-10-18 | 1992-08-11 | Shionogi & Co., Ltd. | Condensed imidazopyridine derivatives |
US5378700A (en) | 1989-10-11 | 1995-01-03 | Teijin Limited | Fused pyrimidine derivative, process for preparation of same and pharmaceutical preparation comprising same as active ingredient |
IT1258781B (it) | 1992-01-16 | 1996-02-29 | Zambon Spa | Composizione farmaceutica oftalmica contenente n-acetilcisteina e polivinilalcol |
US5521184A (en) | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
AU671491B2 (en) | 1992-12-18 | 1996-08-29 | F. Hoffmann-La Roche Ag | N-oxycarbonyl substituted 5'-deoxy-5-fluorcytidines |
JPH0710876A (ja) | 1993-06-24 | 1995-01-13 | Teijin Ltd | 4位に環状アミノ基を有するピロロ[2,3―d]ピリミジン |
EP0727217A3 (en) | 1995-02-10 | 1997-01-15 | Suntory Ltd | Pharmaceutical and cosmetic compositions containing God-type ellagitannin as an active ingredient |
US5856326A (en) | 1995-03-29 | 1999-01-05 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
IL117580A0 (en) | 1995-03-29 | 1996-07-23 | Merck & Co Inc | Inhibitors of farnesyl-protein transferase and pharmaceutical compositions containing them |
KR19990028709A (ko) | 1995-07-05 | 1999-04-15 | 미리암 디. 메코너헤이 | 살진균 피리미디논 |
US5630943A (en) | 1995-11-30 | 1997-05-20 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Discontinuous countercurrent chromatographic process and apparatus |
TW531537B (en) * | 1995-12-27 | 2003-05-11 | Janssen Pharmaceutica Nv | 1-(1,2-disubstituted piperidinyl)-4-substituted piperidine derivatives |
GB9604361D0 (en) | 1996-02-29 | 1996-05-01 | Pharmacia Spa | 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors |
JP2000504023A (ja) | 1996-04-03 | 2000-04-04 | メルク エンド カンパニー インコーポレーテッド | 癌治療方法 |
WO1997038664A2 (en) | 1996-04-18 | 1997-10-23 | Merck & Co., Inc. | A method of treating cancer |
US5795909A (en) | 1996-05-22 | 1998-08-18 | Neuromedica, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
AU3215197A (en) | 1996-05-30 | 1998-01-05 | Merck & Co., Inc. | A method of treating cancer |
US6624138B1 (en) | 2001-09-27 | 2003-09-23 | Gp Medical | Drug-loaded biological material chemically treated with genipin |
WO1998044797A1 (en) | 1997-04-07 | 1998-10-15 | Merck & Co., Inc. | A method of treating cancer |
US6060038A (en) | 1997-05-15 | 2000-05-09 | Merck & Co., Inc. | Radiolabeled farnesyl-protein transferase inhibitors |
US6063284A (en) | 1997-05-15 | 2000-05-16 | Em Industries, Inc. | Single column closed-loop recycling with periodic intra-profile injection |
US5908841A (en) | 1997-08-11 | 1999-06-01 | Boehringer Ingelheim Pharmaceuticals, Inc. | 5,11-dihydro-6H-dipyrido 3,2-b:2',3'-e!azepine-6-ones and their use in the prevention of treatment of HIV infection |
US6075056A (en) | 1997-10-03 | 2000-06-13 | Penederm, Inc. | Antifungal/steroid topical compositions |
US6025366A (en) | 1998-04-02 | 2000-02-15 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
US6232320B1 (en) | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
SK18542000A3 (sk) | 1998-06-04 | 2001-12-03 | Abbott Laboratories | Protizápalové zlúčeniny inhibujúce bunkovú adhéziu |
PA8474101A1 (es) | 1998-06-19 | 2000-09-29 | Pfizer Prod Inc | Compuestos de pirrolo [2,3-d] pirimidina |
JP4516690B2 (ja) | 1998-08-11 | 2010-08-04 | ノバルティス アーゲー | 血管形成阻害活性を有するイソキノリン誘導体 |
JP2000119271A (ja) | 1998-08-12 | 2000-04-25 | Hokuriku Seiyaku Co Ltd | 1h―イミダゾピリジン誘導体 |
ES2190241T3 (es) | 1998-09-10 | 2003-07-16 | Nycomed Danmark As | Compuestos farmaceuticos de liberacion rapida de substancias medicamentosas. |
US6375839B1 (en) | 1998-10-29 | 2002-04-23 | Institut Francais Du Petrole | Process and device for separation with variable-length chromatographic zones |
US6413419B1 (en) | 1998-10-29 | 2002-07-02 | Institut Francais Du Petrole | Process and device for separation with variable-length chromatographic |
FR2785196B1 (fr) | 1998-10-29 | 2000-12-15 | Inst Francais Du Petrole | Procede et dispositif de separation avec des zones chromatographiques a longueur variable |
US6133031A (en) | 1999-08-19 | 2000-10-17 | Isis Pharmaceuticals Inc. | Antisense inhibition of focal adhesion kinase expression |
EP1165084A4 (en) | 1999-03-03 | 2002-05-15 | Merck & Co Inc | PRENYL PROTEIN TRANSFERASES INHIBITORS |
GB9905075D0 (en) | 1999-03-06 | 1999-04-28 | Zeneca Ltd | Chemical compounds |
US6217895B1 (en) | 1999-03-22 | 2001-04-17 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
US6239113B1 (en) | 1999-03-31 | 2001-05-29 | Insite Vision, Incorporated | Topical treatment or prevention of ocular infections |
AU3565999A (en) | 1999-04-16 | 2000-11-02 | Coelacanth Chemical Corporation | Synthesis of azetidine derivatives |
US6921763B2 (en) | 1999-09-17 | 2005-07-26 | Abbott Laboratories | Pyrazolopyrimidines as therapeutic agents |
WO2001027104A1 (fr) | 1999-10-13 | 2001-04-19 | Banyu Pharmaceutical Co., Ltd. | Derives d'imidazolidinone a substitution |
AP1905A (en) | 1999-12-10 | 2008-10-20 | Pfizer Prod Inc | Pyrrolo[2,3-d] Pyrimidine Compounds. |
CZ301750B6 (cs) | 1999-12-24 | 2010-06-09 | Aventis Pharma Limited | Bicyklický pyrrolový derivát, jeho použití pri výrobe léciva, farmaceutická kompozice tento derivát obsahující a pro použití pri lécení |
GB0004890D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
US7235551B2 (en) | 2000-03-02 | 2007-06-26 | Smithkline Beecham Corporation | 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases |
ES2206363T3 (es) | 2000-04-07 | 2004-05-16 | Laboratoire Medidom S.A. | Formulaciones oftalmicas a base de ciclosporina, de acido hialuronico y de polisorbato. |
AU4878601A (en) | 2000-04-20 | 2001-11-07 | Mitsubishi Corporation | Aromatic amide compounds |
ATE502941T1 (de) | 2000-04-25 | 2011-04-15 | Icos Corp | Hemmer der menschlichen phosphatidyl-inositol-3- kinase delta |
AU7549501A (en) | 2000-06-16 | 2002-01-02 | Biogen Inc | Angiogenesis-modulating compositions and uses |
US7498304B2 (en) | 2000-06-16 | 2009-03-03 | Curis, Inc. | Angiogenesis-modulating compositions and uses |
US6335342B1 (en) | 2000-06-19 | 2002-01-01 | Pharmacia & Upjohn S.P.A. | Azaindole derivatives, process for their preparation, and their use as antitumor agents |
WO2001097849A1 (fr) | 2000-06-23 | 2001-12-27 | Mitsubishi Pharma Corporation | Potentialisateurs d'effet antitumoral |
UA74370C2 (uk) | 2000-06-26 | 2005-12-15 | Пфайзер Продактс Інк. | Піроло(2,3-d)піримідинові сполуки як імуносупресори |
AU1560802A (en) | 2000-06-28 | 2002-01-08 | Smithkline Beecham Plc | Wet milling process |
EP1343781B1 (en) | 2000-12-05 | 2008-09-03 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases |
GB0100622D0 (en) | 2001-01-10 | 2001-02-21 | Vernalis Res Ltd | Chemical compounds V111 |
WO2002055496A1 (en) | 2001-01-15 | 2002-07-18 | Glaxo Group Limited | Aryl piperidine and piperazine derivatives as inducers of ldl-receptor expression |
EP1363702A4 (en) | 2001-01-30 | 2007-08-22 | Cytopia Pty Ltd | PROCESS FOR INHIBITING KINASES |
JP4316893B2 (ja) | 2001-05-16 | 2009-08-19 | バーテックス ファーマシューティカルズ インコーポレイテッド | Srcおよび他のプロテインキナーゼのインヒビター |
US7301023B2 (en) | 2001-05-31 | 2007-11-27 | Pfizer Inc. | Chiral salt resolution |
GB0115109D0 (en) | 2001-06-21 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
GB0115393D0 (en) | 2001-06-23 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
EP1414443B1 (en) | 2001-08-01 | 2006-11-15 | Merck & Co., Inc. | BENZIMIDAZO 4,5-f|ISOQUINOLINONE DERIVATIVES |
MXPA04002243A (es) | 2001-09-19 | 2004-06-29 | Aventis Pharma Sa | Compuestos quimicos. |
US6429231B1 (en) | 2001-09-24 | 2002-08-06 | Bradley Pharmaceuticals, Inc. | Compositions containing antimicrobials and urea for the treatment of dermatological disorders and methods for their use |
CN1582150B (zh) | 2001-10-30 | 2011-09-07 | 诺瓦提斯公司 | 作为flt3受体酪氨酸激酶活性抑制剂的星形孢菌素衍生物 |
JP2003155285A (ja) | 2001-11-19 | 2003-05-27 | Toray Ind Inc | 環状含窒素誘導体 |
CN1582272A (zh) | 2001-11-30 | 2005-02-16 | 帝人株式会社 | 制备5-(3-氰基苯基)-3-甲酰基苯甲酸化合物的方法 |
GT200200234A (es) | 2001-12-06 | 2003-06-27 | Compuestos cristalinos novedosos | |
US6995144B2 (en) | 2002-03-14 | 2006-02-07 | Eisai Co., Ltd. | Nitrogen containing heterocyclic compounds and medicines containing the same |
TW200403058A (en) | 2002-04-19 | 2004-03-01 | Bristol Myers Squibb Co | Heterocyclo inhibitors of potassium channel function |
AU2003237121A1 (en) | 2002-04-26 | 2003-11-10 | Vertex Pharmaceuticals Incorporated | Pyrrole derivatives as inhibitors of erk2 and uses thereof |
CA2483084A1 (en) | 2002-05-02 | 2003-11-13 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
AU2003234439A1 (en) | 2002-05-07 | 2003-11-11 | Control Delivery Systems, Inc. | Processes for forming a drug delivery device |
CA2486183C (en) | 2002-05-23 | 2012-01-10 | Cytopia Pty Ltd. | Protein kinase inhibitors |
TW200406374A (en) | 2002-05-29 | 2004-05-01 | Novartis Ag | Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases |
EP1535934A4 (en) | 2002-06-26 | 2005-11-02 | Idemitsu Kosan Co | HYDROGEN COPOLYMER, PROCESS FOR PRODUCING THE SAME, AND THERMOFUSIBLE ADHESIVE COMPOSITION CONTAINING SAME |
GB0215676D0 (en) | 2002-07-05 | 2002-08-14 | Novartis Ag | Organic compounds |
GB0215844D0 (en) | 2002-07-09 | 2002-08-14 | Novartis Ag | Organic compounds |
EP1541563A4 (en) | 2002-07-10 | 2007-11-07 | Ono Pharmaceutical Co | ANTAGONIST OF CCR4 AND CORRESPONDING MEDICINAL USE |
KR20050057175A (ko) | 2002-09-20 | 2005-06-16 | 알콘, 인코퍼레이티드 | 안구건조증 치료용 사이토카인 합성 저해제의 용도 |
US20040204404A1 (en) | 2002-09-30 | 2004-10-14 | Robert Zelle | Human N-type calcium channel blockers |
AU2003295396B2 (en) | 2002-11-04 | 2009-02-26 | Vertex Pharmaceuticals Incorporated | Heteroaryl-pyramidine derivatives as JAK inhibitors |
CL2003002353A1 (es) | 2002-11-15 | 2005-02-04 | Vertex Pharma | Compuestos derivados de diaminotriazoles, inhibidores d ela proteina quinasa; composicion farmaceutica; procedimiento de preparacion; y su uso del compuesto en el tratamiento de enfermedades de desordenes alergicos, proliferacion, autoinmunes, condic |
US20040099204A1 (en) | 2002-11-25 | 2004-05-27 | Nestor John J. | Sheet, page, line, position marker |
BR0316487A (pt) | 2002-11-26 | 2005-10-11 | Pfizer Prod Inc | Método todo de tratamento da rejeição de transplantes |
UA80767C2 (en) | 2002-12-20 | 2007-10-25 | Pfizer Prod Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
UY28126A1 (es) | 2002-12-24 | 2004-06-30 | Alcon Inc | Uso de glucocorticoides selectivos para la superficie ocular en el tratamiento de la sequedad ocular |
TW200418806A (en) | 2003-01-13 | 2004-10-01 | Fujisawa Pharmaceutical Co | HDAC inhibitor |
US7444183B2 (en) | 2003-02-03 | 2008-10-28 | Enteromedics, Inc. | Intraluminal electrode apparatus and method |
EP1611125A1 (en) | 2003-02-07 | 2006-01-04 | Vertex Pharmaceuticals Incorporated | Heteroaryl substituted pyrolls useful as inhibitors of protein kinases |
GB0305929D0 (en) | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
JP2006522124A (ja) | 2003-04-03 | 2006-09-28 | バーテックス ファーマシューティカルズ インコーポレイテッド | プロテインキナーゼのインヒビターとして有用な組成物 |
SE0301373D0 (sv) | 2003-05-09 | 2003-05-09 | Astrazeneca Ab | Novel compounds |
SE0301372D0 (sv) | 2003-05-09 | 2003-05-09 | Astrazeneca Ab | Novel compounds |
FR2857454B1 (fr) | 2003-07-08 | 2006-08-11 | Aventis Pasteur | Dosage des acides techoiques des bacteries gram+ |
US20050043346A1 (en) | 2003-08-08 | 2005-02-24 | Pharmacia Italia S.P.A. | Pyridylpyrrole derivatives active as kinase inhibitors |
WO2005020921A2 (en) | 2003-08-29 | 2005-03-10 | Exelixis, Inc. | C-kit modulators and methods of use |
WO2005026129A1 (en) | 2003-09-15 | 2005-03-24 | Gpc Biotech Ag | Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases |
PE20050952A1 (es) | 2003-09-24 | 2005-12-19 | Novartis Ag | Derivados de isoquinolina como inhibidores de b-raf |
SI1679074T1 (sl) | 2003-10-24 | 2011-04-29 | Santen Pharmaceutical Co Ltd | Terapevtsko sredstvo za keratokonjuktivno motnjo |
MY141220A (en) | 2003-11-17 | 2010-03-31 | Astrazeneca Ab | Pyrazole derivatives as inhibitors of receptor tyrosine kinases |
EP1689407A1 (en) | 2003-11-25 | 2006-08-16 | Pfizer Products Inc. | Method of treatment of atherosclerosis |
EP1734967A2 (en) | 2003-12-17 | 2006-12-27 | Pfizer Products Incorporated | Pyrrolo [2,3-d] pyrimidine compounds for treating transplant rejection |
EP1694659B8 (en) | 2003-12-19 | 2008-10-08 | Schering Corporation | Thiadiazoles as cxc- and cc- chemokine receptor ligands |
PT1696920E (pt) | 2003-12-19 | 2015-01-14 | Plexxikon Inc | Compostos e métodos para o desenvolvimento de moduladores de ret |
AU2004303602C1 (en) | 2003-12-23 | 2009-05-28 | Astex Therapeutics Limited | Pyrazole derivatives as protein kinase modulators |
WO2005067546A2 (en) | 2004-01-13 | 2005-07-28 | Ambit Biosciences Corporation | Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases |
EP1744751A4 (en) | 2004-03-18 | 2010-03-10 | Brigham & Womens Hospital | TREATMENT OF SYNUCLEINOPATHIES |
RU2403252C2 (ru) | 2004-03-30 | 2010-11-10 | Вертекс Фармасьютикалз Инкорпорейтед | Азаиндолы, полезные в качестве ингибиторов jak и других протеинкиназ |
AU2005249380C1 (en) | 2004-04-23 | 2012-09-20 | Exelixis, Inc. | Kinase modulators and methods of use |
US7558717B2 (en) | 2004-04-28 | 2009-07-07 | Vertex Pharmaceuticals Incorporated | Crystal structure of human JAK3 kinase domain complex and binding pockets thereof |
US20060106020A1 (en) | 2004-04-28 | 2006-05-18 | Rodgers James D | Tetracyclic inhibitors of Janus kinases |
AU2005237254B2 (en) | 2004-05-03 | 2010-02-04 | Novartis Ag | Combinations comprising a S1P receptor agonist and a JAK3 kinase inhibitor |
EP1753428A4 (en) | 2004-05-14 | 2010-09-15 | Abbott Lab | INHIBITORS OF KINASES AS THERAPEUTIC AGENTS |
PE20060426A1 (es) | 2004-06-02 | 2006-06-28 | Schering Corp | DERIVADOS DE ACIDO TARTARICO COMO INHIBIDORES DE MMPs, ADAMs, TACE Y TNF-alfa |
CN1960988B (zh) | 2004-06-10 | 2012-01-25 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
JP5315611B2 (ja) | 2004-06-23 | 2013-10-16 | 小野薬品工業株式会社 | S1p受容体結合能を有する化合物およびその用途 |
CA2572058A1 (en) | 2004-06-30 | 2006-01-12 | Vertex Pharmaceuticals Incorporated | Azaindoles useful as inhibitors of protein kinases |
US7138423B2 (en) | 2004-07-20 | 2006-11-21 | Bristol-Myers Squibb Company | Arylpyrrolidine derivatives as NK-1 /SSRI antagonists |
FR2873691B1 (fr) | 2004-07-29 | 2006-10-06 | Sanofi Synthelabo | Derives d'amino-piperidine, leur preparation et leur application en therapeutique |
WO2006013114A1 (en) | 2004-08-06 | 2006-02-09 | Develogen Aktiengesellschaft | Use of a timp-2 secreted protein product for preventing and treating pancreatic diseases and/or obesity and/or metabolic syndrome |
WO2006022459A1 (en) | 2004-08-23 | 2006-03-02 | Mogam Biotechnology Institute | Primer and probe for detection of sars coronavirus, kit comprising the primer and/or the probe, and detection method thereof |
US20070054916A1 (en) | 2004-10-01 | 2007-03-08 | Amgen Inc. | Aryl nitrogen-containing bicyclic compounds and methods of use |
BRPI0518152A (pt) | 2004-10-13 | 2008-11-04 | Hoffmann La Roche | pirazolbenzodiazepinas dissubstituìdas úteis como inibidores para cdk2 e angiogênese e para o tratamento de cánceres de mama, cólon, pulmão e próstata |
MY179032A (en) | 2004-10-25 | 2020-10-26 | Cancer Research Tech Ltd | Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors |
UY29177A1 (es) | 2004-10-25 | 2006-05-31 | Astex Therapeutics Ltd | Derivados sustituidos de purina, purinona y deazapurina, composiciones que los contienen métodos para su preparación y sus usos |
ES2354824T3 (es) | 2004-11-04 | 2011-03-18 | Vertex Pharmaceuticals, Inc. | Pirazolo[1,5-a]pirimidinas útiles como inhibidores de proteínas cinasas. |
RU2007123675A (ru) | 2004-11-24 | 2008-12-27 | Новартис АГ (CH) | Комбинации ингибиторов jak |
US7517870B2 (en) | 2004-12-03 | 2009-04-14 | Fondazione Telethon | Use of compounds that interfere with the hedgehog signaling pathway for the manufacture of a medicament for preventing, inhibiting, and/or reversing ocular diseases related with ocular neovascularization |
US20060128803A1 (en) | 2004-12-14 | 2006-06-15 | Alcon, Inc. | Method of treating dry eye disorders using 13(S)-HODE and its analogs |
AR054416A1 (es) | 2004-12-22 | 2007-06-27 | Incyte Corp | Pirrolo [2,3-b]piridin-4-il-aminas y pirrolo [2,3-b]pirimidin-4-il-aminas como inhibidores de las quinasas janus. composiciones farmaceuticas. |
WO2006067445A2 (en) | 2004-12-22 | 2006-06-29 | Astrazeneca Ab | Csf-1r kinase inhibitors |
WO2006077499A1 (en) | 2005-01-20 | 2006-07-27 | Pfizer Limited | Chemical compounds |
ZA200707342B (en) | 2005-02-03 | 2009-03-25 | Vertex Pharma | Pyrrolopyrimidines useful as inhibitors of protein kinase |
WO2007044050A2 (en) | 2005-02-04 | 2007-04-19 | Bristol-Myers Squibb Company | 1h-imidazo[4,5-d]thieno[3,2-b]pyridine based tricyclic compounds and pharmaceutical compositions comprising same |
WO2006101783A2 (en) | 2005-03-15 | 2006-09-28 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
RU2007140903A (ru) | 2005-04-05 | 2009-05-20 | Фармакопия, Инк. (Us) | Производные пурина и имидазопиридина для иммуносупрессии |
GB0510139D0 (en) | 2005-05-18 | 2005-06-22 | Addex Pharmaceuticals Sa | Novel compounds B1 |
GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
US8921376B2 (en) | 2005-05-20 | 2014-12-30 | Vertex Pharmaceuticals Incorporated | Pyrrolopyridines useful as inhibitors of protein kinase |
WO2006133426A2 (en) | 2005-06-08 | 2006-12-14 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
WO2006136823A1 (en) | 2005-06-21 | 2006-12-28 | Astex Therapeutics Limited | Heterocyclic containing amines as kinase b inhibitors |
MY153898A (en) | 2005-06-22 | 2015-04-15 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
CN102127078A (zh) | 2005-07-14 | 2011-07-20 | 安斯泰来制药株式会社 | Janus激酶3的杂环类抑制剂 |
FR2889662B1 (fr) | 2005-08-11 | 2011-01-14 | Galderma Res & Dev | Emulsion de type huile-dans-eau pour application topique en dermatologie |
WO2007025090A2 (en) | 2005-08-25 | 2007-03-01 | Kalypsys, Inc. | Heterobicyclic and - tricyclic inhibitors of mapk/erk kinase |
EP1926735A1 (en) | 2005-09-22 | 2008-06-04 | Incyte Corporation | Tetracyclic inhibitors of janus kinases |
RU2008117151A (ru) | 2005-09-30 | 2009-11-10 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | Деазапурины, пригодные в качестве ингибиторов янус-киназ |
WO2007044894A2 (en) | 2005-10-11 | 2007-04-19 | Chembridge Research Laboratories, Inc. | Cell-free protein expression systems and methods of use thereof |
BRPI0617221B1 (pt) | 2005-10-14 | 2016-07-12 | Sumitomo Chemical Co | composto de hidrazida, seu uso, pesticida e método de controlar uma peste |
AU2006305271B2 (en) * | 2005-10-19 | 2011-11-17 | Kissei Pharmaceutical Co., Ltd. | Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof |
PT1945631E (pt) | 2005-10-28 | 2012-10-15 | Astrazeneca Ab | Derivados de 4-(3-aminopirazole)pirimidina para utilização como inibidores da tirosina-cinase no tratamento do cancro |
RU2589878C2 (ru) | 2005-11-01 | 2016-07-10 | Таргеджен, Инк. | Би-арил-мета-пиримидиновые ингибиторы киназ |
WO2007062459A1 (en) | 2005-11-29 | 2007-06-07 | Cytopia Research Pty Ltd | Selective kinase inhibitors based on pyridine scaffold |
LT2474545T (lt) | 2005-12-13 | 2017-02-27 | Incyte Holdings Corporation | Heteroarilu pakeisti pirolo[2,3-b]piridinai ir pirolo[2,3-b]pirimidinai kaip janus kinazės inhibitoriai |
US20130137681A1 (en) | 2005-12-13 | 2013-05-30 | Incyte Corporation | HETEROARYL SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AND PYRROLO[2,3-b]PYRIMIDINES AS JANUS KINASE INHIBITORS |
WO2007076423A2 (en) | 2005-12-22 | 2007-07-05 | Smithkline Beecham Corporation | INHIBITORS OF Akt ACTIVITY |
PT1962830E (pt) | 2005-12-23 | 2013-05-29 | Glaxosmithkline Llc | Inibidores azaindólicos de cinases aurora |
NZ601687A (en) | 2006-01-17 | 2014-03-28 | Vertex Pharma | Azaindoles useful as inhibitors of janus kinases |
US20070208053A1 (en) | 2006-01-19 | 2007-09-06 | Arnold Lee D | Fused heterobicyclic kinase inhibitors |
JP2009525350A (ja) | 2006-02-01 | 2009-07-09 | スミスクライン ビーチャム コーポレーション | Rafキナーゼ阻害薬として有用なピロロ[2,3,b]ピリジン誘導体 |
US7745477B2 (en) | 2006-02-07 | 2010-06-29 | Hoffman-La Roche Inc. | Heteroaryl and benzyl amide compounds |
CN101443322A (zh) | 2006-03-10 | 2009-05-27 | 小野药品工业株式会社 | 含氮杂环衍生物及含有该衍生物作为活性成分的药物 |
MX2008012738A (es) | 2006-04-03 | 2009-02-06 | Astellas Pharma Inc | Heterocompuesto. |
JP2009532475A (ja) | 2006-04-05 | 2009-09-10 | バーテックス ファーマシューティカルズ インコーポレイテッド | ヤヌスキナーゼの阻害剤として有用なデアザプリン |
EP2059515A2 (en) | 2006-04-12 | 2009-05-20 | Pfizer Limited | Pyrrolidine derivatives as modulators of chemokine ccr5 receptors |
WO2007129195A2 (en) | 2006-05-04 | 2007-11-15 | Pfizer Products Inc. | 4-pyrimidine-5-amino-pyrazole compounds |
WO2007135461A2 (en) | 2006-05-18 | 2007-11-29 | Bayer Healthcare Ag | Pharmaceutical compositions comprising implitapide and methods of using same |
US7691811B2 (en) | 2006-05-25 | 2010-04-06 | Bodor Nicholas S | Transporter-enhanced corticosteroid activity and methods and compositions for treating dry eye |
JO3235B1 (ar) | 2006-05-26 | 2018-03-08 | Astex Therapeutics Ltd | مركبات بيررولوبيريميدين و استعمالاتها |
AU2007275221A1 (en) | 2006-07-20 | 2008-01-24 | Allen J. Borchardt | Benzothiophene inhibitors of RHO kinase |
WO2008013622A2 (en) | 2006-07-27 | 2008-01-31 | E. I. Du Pont De Nemours And Company | Fungicidal azocyclic amides |
US8492378B2 (en) | 2006-08-03 | 2013-07-23 | Takeda Pharmaceutical Company Limited | GSK-3β inhibitor |
WO2008022164A2 (en) | 2006-08-16 | 2008-02-21 | Boehringer Ingelheim International Gmbh | Pyrazine compounds, their use and methods of preparation |
WO2008028937A1 (en) | 2006-09-08 | 2008-03-13 | Novartis Ag | N-biaryl (hetero) arylsulphonamide derivatives useful in the treatment of diseases mediated by lymphocytes interactions |
WO2008035376A2 (en) | 2006-09-19 | 2008-03-27 | Council Of Scientific & Industrial Research | A novel bio-erodible insert for ophthalmic applications and a process for the preparation thereof |
WO2008043031A1 (en) | 2006-10-04 | 2008-04-10 | Pharmacopeia, Inc. | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
US7915268B2 (en) | 2006-10-04 | 2011-03-29 | Wyeth Llc | 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression |
US20120225057A1 (en) | 2006-10-11 | 2012-09-06 | Deciphera Pharmaceuticals, Llc | Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases |
CA2667487C (en) | 2006-11-06 | 2017-04-04 | Supergen, Inc. | Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitors |
US20080119496A1 (en) | 2006-11-16 | 2008-05-22 | Pharmacopeia Drug Discovery, Inc. | 7-Substituted Purine Derivatives for Immunosuppression |
LT3034075T (lt) | 2006-11-22 | 2018-11-26 | Incyte Holdings Corporation | Imidazotriazinai ir imidazopirimidinai kaip kinazės inhibitoriai |
WO2008067119A2 (en) | 2006-11-27 | 2008-06-05 | Smithkline Beecham Corporation | Novel compounds |
NZ577111A (en) | 2006-12-15 | 2012-05-25 | Abbott Lab | Novel oxadiazole compounds |
CA2672903C (en) | 2006-12-20 | 2012-10-23 | Amgen Inc. | Heterocyclic compounds and their use in treating inflammation, angiogenesis and cancer |
US7687522B2 (en) | 2006-12-20 | 2010-03-30 | Amgen Inc. | Substituted pyridines and pyrimidines and their use in treatment of cancer |
MX2009005644A (es) | 2006-12-22 | 2009-06-08 | Sigma Tau Ind Farmaceuti | Gel util para el suministro de farmacos oftalmicos. |
WO2008079965A1 (en) | 2006-12-22 | 2008-07-03 | Incyte Corporation | Substituted heterocycles as janus kinase inhibitors |
JP2008179621A (ja) * | 2006-12-28 | 2008-08-07 | Taisho Pharmaceutical Co Ltd | 含窒素飽和複素環化合物 |
KR20080062876A (ko) | 2006-12-29 | 2008-07-03 | 주식회사 대웅제약 | 신규한 항진균성 트리아졸 유도체 |
WO2008082839A2 (en) | 2006-12-29 | 2008-07-10 | Abbott Laboratories | Pim kinase inhibitors as cancer chemotherapeutics |
WO2008082840A1 (en) | 2006-12-29 | 2008-07-10 | Abbott Laboratories | Pim kinase inhibitors as cancer chemotherapeutics |
EA019951B1 (ru) | 2007-03-01 | 2014-07-30 | Новартис Аг | Ингибиторы киназы pim и способы их применения |
WO2008124323A1 (en) | 2007-04-03 | 2008-10-16 | Array Biopharma Inc. | Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors |
GB0709031D0 (en) | 2007-05-10 | 2007-06-20 | Sareum Ltd | Pharmaceutical compounds |
US8653262B2 (en) | 2007-05-31 | 2014-02-18 | Boehringer Ingelheim International Gmbh | CCR2 receptor antagonists and uses thereof |
GB0710528D0 (en) | 2007-06-01 | 2007-07-11 | Glaxo Group Ltd | Novel compounds |
CL2008001709A1 (es) | 2007-06-13 | 2008-11-03 | Incyte Corp | Compuestos derivados de pirrolo [2,3-b]pirimidina, moduladores de quinasas jak; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como cancer, psoriasis, artritis reumatoide, entre otras. |
CA2689663C (en) | 2007-06-13 | 2016-08-09 | Incyte Corporation | Salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
RU2445098C2 (ru) | 2007-07-11 | 2012-03-20 | Пфайзер Инк. | Фармацевтические композиции и способы лечения сухих кератитов |
WO2009016460A2 (en) | 2007-08-01 | 2009-02-05 | Pfizer Inc. | Pyrazole compounds and their use as raf inhibitors |
WO2009049028A1 (en) | 2007-10-09 | 2009-04-16 | Targegen Inc. | Pyrrolopyrimidine compounds and their use as janus kinase modulators |
WO2009064486A2 (en) | 2007-11-15 | 2009-05-22 | Musc Foundation For Research Development | Inhibitors of pim protein kinases, compositions, and methods for treating cancer |
BRPI0820544A2 (pt) | 2007-11-16 | 2015-06-16 | Incyte Corp | 4-pirazolil-n-arilpirimidin-2-aminas e pirazolil-n-heteroarilpirimidin-2-aminas como inibidores de janus cinase |
GB0723815D0 (en) | 2007-12-05 | 2008-01-16 | Glaxo Group Ltd | Compounds |
ES2598503T3 (es) | 2008-01-18 | 2017-01-27 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Nuevos citostáticos nucleósidos 7-deazapurina |
EA019309B1 (ru) | 2008-02-04 | 2014-02-28 | Меркьюри Терапьютикс, Инк. | Модуляторы ampk (амф-активируемой протеинкиназы) |
UY31679A1 (es) | 2008-03-03 | 2009-09-30 | Inhibidores de cinasa pim y metodos para su uso | |
RS55263B1 (sr) | 2008-03-11 | 2017-02-28 | Incyte Holdings Corp | Derivati azetidina i ciklobutana kao jak inhibitori |
EP2274300A2 (en) | 2008-03-21 | 2011-01-19 | Novartis AG | Novel heterocyclic compounds and uses therof |
KR102080429B1 (ko) | 2008-06-26 | 2020-02-21 | 안테리오스, 인코퍼레이티드 | 경피 운반 |
UY31952A (es) | 2008-07-02 | 2010-01-29 | Astrazeneca Ab | 5-metilideno-1,3-tiazolidina-2,4-dionas sustituidas como inhibidores de quinasa pim |
FR2933409B1 (fr) | 2008-07-03 | 2010-08-27 | Centre Nat Rech Scient | NOUVEAUX PYRROLO °2,3-a! CARBAZOLES ET LEUR UTILISATION COMME INHIBITEURS DES KINASES PIM |
TWI496779B (zh) | 2008-08-19 | 2015-08-21 | Array Biopharma Inc | 作為pim激酶抑制劑之***吡啶化合物 |
WO2010022081A1 (en) | 2008-08-19 | 2010-02-25 | Array Biopharma Inc. | Triazolopyridine compounds as pim kinase inhibitors |
PT2384326E (pt) | 2008-08-20 | 2014-06-09 | Zoetis Llc | Compostos de pirrolo[2,3-d]pirimidina |
BRPI0918496A2 (pt) | 2008-09-02 | 2019-09-24 | Novartis Ag | composto inibidor bicíclico de quinase, uso do mesmo, composição farmacêutica e método para inibir a atividade da quinase pim em uma célula |
MX2011002365A (es) | 2008-09-02 | 2011-04-04 | Novartis Ag | Derivados de picolinamida como inhibidres de cinasa. |
JP5584215B2 (ja) | 2008-09-02 | 2014-09-03 | ノバルティス アーゲー | ヘテロ環pimキナーゼ阻害剤 |
CL2009001884A1 (es) | 2008-10-02 | 2010-05-14 | Incyte Holdings Corp | Uso de 3-ciclopentil-3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)propanonitrilo, inhibidor de janus quinasa, y uso de una composición que lo comprende para el tratamiento del ojo seco. |
US20110183958A1 (en) | 2008-10-17 | 2011-07-28 | Merck Frosst Canada Ltd. | Azetidine derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
JOP20190231A1 (ar) | 2009-01-15 | 2017-06-16 | Incyte Corp | طرق لاصلاح مثبطات انزيم jak و المركبات الوسيطة المتعلقة به |
EP2210890A1 (en) | 2009-01-19 | 2010-07-28 | Almirall, S.A. | Oxadiazole derivatives as S1P1 receptor agonists |
US8263601B2 (en) | 2009-02-27 | 2012-09-11 | Concert Pharmaceuticals, Inc. | Deuterium substituted xanthine derivatives |
BRPI1012159B1 (pt) | 2009-05-22 | 2022-01-25 | Incyte Holdings Corporation | Compostos derivados de n-(hetero)aril-pirrolidina de pirazol-4-il-pirrolo[2,3-d] pirimidinas e pirrol-3-il-pirrolo[2,3-d] pirimidinas como inibidores de janus cinase, composições farmacêuticas compreendendo os referidos compostos e usos dos mesmos |
DK2432472T3 (da) | 2009-05-22 | 2019-11-18 | Incyte Holdings Corp | 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octan- eller heptan-nitril som jak-inhibitorer |
UA110324C2 (en) | 2009-07-02 | 2015-12-25 | Genentech Inc | Jak inhibitory compounds based on pyrazolo pyrimidine |
US20120157500A1 (en) | 2009-08-24 | 2012-06-21 | Weikang Tao | Jak inhibition blocks rna interference associated toxicities |
TW201111385A (en) | 2009-08-27 | 2011-04-01 | Biocryst Pharm Inc | Heterocyclic compounds as janus kinase inhibitors |
TW201113285A (en) | 2009-09-01 | 2011-04-16 | Incyte Corp | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
JP5567136B2 (ja) | 2009-09-08 | 2014-08-06 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 4−置換ピリジン−3−イル−カルボキサミド化合物及び使用方法 |
EP2305660A1 (en) | 2009-09-25 | 2011-04-06 | Almirall, S.A. | New thiadiazole derivatives |
CA2777114C (en) | 2009-10-09 | 2018-10-23 | Incyte Corporation | Hydroxyl, keto, and glucuronide derivatives of 3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
CA2775009A1 (en) | 2009-10-20 | 2011-04-28 | Cellzome Limited | Heterocyclyl pyrazolopyrimidine analogues as jak inhibitors |
EP2332917B1 (en) | 2009-11-11 | 2012-08-01 | Sygnis Bioscience GmbH & Co. KG | Compounds for PIM kinase inhibition and for treating malignancy |
WO2011066369A2 (en) | 2009-11-24 | 2011-06-03 | Alder Biopharmaceuticals, Inc. | Antagonists of il-6 to raise albumin and/or lower crp |
EP2506852A4 (en) | 2009-12-04 | 2013-06-19 | Univ Texas | INTERFERONTHERAPIES IN COMBINATION WITH BLOCKING OF STAT3 ACTIVATION |
CN102712640A (zh) | 2010-01-12 | 2012-10-03 | 弗·哈夫曼-拉罗切有限公司 | 三环杂环化合物、其组合物和应用方法 |
SA111320200B1 (ar) | 2010-02-17 | 2014-02-16 | ديبيوفارم اس ايه | مركبات ثنائية الحلقة واستخداماتها كمثبطات c-src/jak مزدوجة |
AU2011217961B2 (en) | 2010-02-18 | 2016-05-05 | Incyte Holdings Corporation | Cyclobutane and methylcyclobutane derivatives as Janus kinase inhibitors |
KR20220015492A (ko) | 2010-03-10 | 2022-02-08 | 인사이트 홀딩스 코포레이션 | Jak1 저해제로서의 피페리딘4일 아제티딘 유도체 |
EP2554866B1 (en) * | 2010-03-30 | 2018-11-21 | NTN Corporation | Anti-friction bearing |
RU2012148246A (ru) | 2010-04-14 | 2014-05-20 | Эррэй Биофарма Инк. | 5, 7- замещенные-имидазо[1, 2-с]пиримидины как ингибиторы jak-киназ |
EP2390252A1 (en) | 2010-05-19 | 2011-11-30 | Almirall, S.A. | New pyrazole derivatives |
PL2574168T3 (pl) | 2010-05-21 | 2016-10-31 | Preparaty inhibitora kinazy janusowej do stosowania miejscowego | |
US8637529B2 (en) | 2010-06-11 | 2014-01-28 | AbbYie Inc. | Pyrazolo[3,4-d]pyrimidine compounds |
WO2012003457A1 (en) | 2010-07-01 | 2012-01-05 | Mtm Research Llc | Anti-fibroblastic fluorochemical emulsion therapies |
WO2012045020A1 (en) | 2010-09-30 | 2012-04-05 | Portola Pharmaceuticals, Inc. | Combinations of 4-(cyclopropylamino)-2-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenylamino)pyrimidine-5-carboxamide and fludarabine |
ES2536415T3 (es) | 2010-11-19 | 2015-05-25 | Incyte Corporation | Pirrolopiridinas y pirrolopirimidinas sustituidas heterocíclicas como inhibidores de JAK |
CA2818542A1 (en) | 2010-11-19 | 2012-05-24 | Incyte Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors |
KR20130137011A (ko) | 2010-12-03 | 2013-12-13 | 와이엠 바이오사이언시즈 오스트레일리아 피티와이 엘티디 | Jak-2 매개 병태의 치료 방법 |
ES2547916T3 (es) | 2011-02-18 | 2015-10-09 | Novartis Pharma Ag | Terapia de combinación de inhibidores de mTOR/JAK |
EP2721028B1 (en) | 2011-06-20 | 2015-11-04 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
US9358229B2 (en) | 2011-08-10 | 2016-06-07 | Novartis Pharma Ag | JAK PI3K/mTOR combination therapy |
TW201313721A (zh) | 2011-08-18 | 2013-04-01 | Incyte Corp | 作為jak抑制劑之環己基氮雜環丁烷衍生物 |
UA111854C2 (uk) * | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки для отримання інгібіторів jak |
WO2013173720A1 (en) * | 2012-05-18 | 2013-11-21 | Incyte Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors |
US10155987B2 (en) | 2012-06-12 | 2018-12-18 | Dana-Farber Cancer Institute, Inc. | Methods of predicting resistance to JAK inhibitor therapy |
JP2015526520A (ja) | 2012-08-31 | 2015-09-10 | プリンシピア バイオファーマ インコーポレイテッド | Itk阻害剤としてのベンズイミダゾール誘導体 |
NZ707495A (en) | 2012-11-01 | 2019-01-25 | Incyte Holdings Corp | Tricyclic fused thiophene derivatives as jak inhibitors |
PE20200175A1 (es) | 2012-11-15 | 2020-01-24 | Incyte Holdings Corp | Formas de dosificacion de ruxolitinib de liberacion sostenida |
UA120162C2 (uk) | 2013-03-06 | 2019-10-25 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки при отриманні інгібітора jak |
TWI599567B (zh) * | 2013-03-14 | 2017-09-21 | 健生藥品公司 | P2x7調節劑 |
HUE033587T2 (hu) | 2013-05-17 | 2017-12-28 | Incyte Corp | Bipirazol-származékok mint JAK inhibitorok |
CA3155500A1 (en) | 2013-08-07 | 2015-02-12 | Incyte Corporation | Sustained release dosage forms for a jak1 inhibitor |
CA2921568A1 (en) | 2013-08-20 | 2015-02-25 | Incyte Corporation | Survival benefit in patients with solid tumors with elevated c-reactive protein levels |
MX2016011103A (es) | 2014-02-28 | 2017-02-28 | Incyte Corp | Inhibidores de cinasa janus 1 (jak1) para el tratamiento de sindromes mielodisplasicos. |
CA3158254C (en) | 2014-04-08 | 2024-05-21 | Incyte Corporation | Treatment of b-cell malignancies by a combination jak and pi3k inhibitors |
SG10201809518QA (en) | 2014-04-30 | 2018-11-29 | Incyte Corp | Processes of preparing a jak1 inhibitor and new forms thereto |
EP3148545B1 (en) | 2014-05-28 | 2023-03-15 | Onco Tracker, Inc. | Anti-cancer effects of jak2 inhibitors in combination with thalidomide derivatives and glucocorticoids |
US9498467B2 (en) | 2014-05-30 | 2016-11-22 | Incyte Corporation | Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1 |
CN105524067A (zh) * | 2014-09-28 | 2016-04-27 | 江苏柯菲平医药股份有限公司 | 4-取代吡咯并[2,3-d]嘧啶化合物及其用途 |
CN112105608B (zh) | 2018-01-30 | 2023-07-14 | 因赛特公司 | 制备(1-(3-氟-2-(三氟甲基)异烟碱基)哌啶-4-酮)的方法 |
-
2019
- 2019-01-29 CN CN201980014286.XA patent/CN112105608B/zh active Active
- 2019-01-29 JP JP2020562089A patent/JP7393348B2/ja active Active
- 2019-01-29 ES ES19705025T patent/ES2912469T3/es active Active
- 2019-01-29 CA CA3089832A patent/CA3089832A1/en active Pending
- 2019-01-29 EA EA202091830A patent/EA202091830A1/ru unknown
- 2019-01-29 SG SG11202007164UA patent/SG11202007164UA/en unknown
- 2019-01-29 US US16/260,578 patent/US10899736B2/en active Active
- 2019-01-29 DK DK19705025.5T patent/DK3746429T3/da active
- 2019-01-29 PE PE2020001131A patent/PE20211310A1/es unknown
- 2019-01-29 MD MDE20201229T patent/MD3746429T2/ro unknown
- 2019-01-29 PL PL19705025T patent/PL3746429T3/pl unknown
- 2019-01-29 LT LTEPPCT/US2019/015582T patent/LT3746429T/lt unknown
- 2019-01-29 TW TW108103234A patent/TWI797242B/zh active
- 2019-01-29 EP EP19705025.5A patent/EP3746429B1/en active Active
- 2019-01-29 HR HRP20220510TT patent/HRP20220510T1/hr unknown
- 2019-01-29 BR BR112020015470-9A patent/BR112020015470A2/pt unknown
- 2019-01-29 AU AU2019213665A patent/AU2019213665B2/en active Active
- 2019-01-29 IL IL276302A patent/IL276302B2/en unknown
- 2019-01-29 RS RS20220525A patent/RS63312B1/sr unknown
- 2019-01-29 MA MA51771A patent/MA51771B1/fr unknown
- 2019-01-29 SI SI201930247T patent/SI3746429T1/sl unknown
- 2019-01-29 UA UAA202005585A patent/UA127488C2/uk unknown
- 2019-01-29 WO PCT/US2019/015582 patent/WO2019152374A1/en unknown
- 2019-01-29 EP EP22157237.3A patent/EP4086245A1/en not_active Withdrawn
- 2019-01-29 CR CR20200379A patent/CR20200379A/es unknown
- 2019-01-29 MX MX2020007973A patent/MX2020007973A/es unknown
- 2019-01-29 AR ARP190100197A patent/AR114810A1/es unknown
- 2019-01-29 KR KR1020207024908A patent/KR20200129099A/ko not_active Application Discontinuation
- 2019-01-29 PT PT197050255T patent/PT3746429T/pt unknown
-
2020
- 2020-07-29 PH PH12020551145A patent/PH12020551145A1/en unknown
- 2020-07-29 CL CL2020001983A patent/CL2020001983A1/es unknown
- 2020-07-29 ZA ZA2020/04692A patent/ZA202004692B/en unknown
- 2020-08-13 CO CONC2020/0009994A patent/CO2020009994A2/es unknown
-
2023
- 2023-10-11 JP JP2023175953A patent/JP2024023173A/ja active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI797242B (zh) | 製備jak抑制劑之方法及中間物 | |
US9714233B2 (en) | Processes and intermediates for making a JAK inhibitor |