CN105143208A - 作为激酶抑制剂的喹唑啉 - Google Patents
作为激酶抑制剂的喹唑啉 Download PDFInfo
- Publication number
- CN105143208A CN105143208A CN201480009917.6A CN201480009917A CN105143208A CN 105143208 A CN105143208 A CN 105143208A CN 201480009917 A CN201480009917 A CN 201480009917A CN 105143208 A CN105143208 A CN 105143208A
- Authority
- CN
- China
- Prior art keywords
- disease
- compound
- illness
- treatment
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940043355 kinase inhibitor Drugs 0.000 title description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 150000003246 quinazolines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 164
- 102100022502 Receptor-interacting serine/threonine-protein kinase 2 Human genes 0.000 claims abstract description 57
- 101001109137 Homo sapiens Receptor-interacting serine/threonine-protein kinase 2 Proteins 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims description 78
- -1 butylsulfonyl Chemical group 0.000 claims description 64
- 238000011282 treatment Methods 0.000 claims description 57
- 201000010099 disease Diseases 0.000 claims description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 claims description 39
- 108091000080 Phosphotransferase Proteins 0.000 claims description 32
- 102000020233 phosphotransferase Human genes 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 24
- 230000001404 mediated effect Effects 0.000 claims description 23
- 208000009766 Blau syndrome Diseases 0.000 claims description 22
- 230000002757 inflammatory effect Effects 0.000 claims description 14
- 208000011231 Crohn disease Diseases 0.000 claims description 11
- 201000000306 sarcoidosis Diseases 0.000 claims description 11
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 10
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 10
- 206010046851 Uveitis Diseases 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 102000004190 Enzymes Human genes 0.000 claims description 8
- 108090000790 Enzymes Proteins 0.000 claims description 8
- 210000000936 intestine Anatomy 0.000 claims description 8
- 210000000056 organ Anatomy 0.000 claims description 8
- 206010037660 Pyrexia Diseases 0.000 claims description 7
- 208000011580 syndromic disease Diseases 0.000 claims description 7
- 201000004624 Dermatitis Diseases 0.000 claims description 5
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 claims description 4
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 4
- 206010016262 Fatty liver alcoholic Diseases 0.000 claims description 4
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 4
- 206010063837 Reperfusion injury Diseases 0.000 claims description 4
- 206010039361 Sacroiliitis Diseases 0.000 claims description 4
- 206010069351 acute lung injury Diseases 0.000 claims description 4
- 208000026594 alcoholic fatty liver disease Diseases 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 208000010706 fatty liver disease Diseases 0.000 claims description 4
- 208000024908 graft versus host disease Diseases 0.000 claims description 4
- 206010025135 lupus erythematosus Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 4
- 230000009885 systemic effect Effects 0.000 claims description 4
- 238000002054 transplantation Methods 0.000 claims description 4
- 101000733257 Homo sapiens Rho guanine nucleotide exchange factor 28 Proteins 0.000 claims 6
- 230000002596 correlated effect Effects 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 description 57
- 238000009472 formulation Methods 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 238000001144 powder X-ray diffraction data Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000003513 alkali Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 108010079933 Receptor-Interacting Protein Serine-Threonine Kinase 2 Proteins 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 230000008859 change Effects 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 6
- 101001125026 Homo sapiens Nucleotide-binding oligomerization domain-containing protein 2 Proteins 0.000 description 6
- 102100029441 Nucleotide-binding oligomerization domain-containing protein 2 Human genes 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 6
- 229960004963 mesalazine Drugs 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 108010042708 Acetylmuramyl-Alanyl-Isoglutamine Proteins 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- 101001125032 Homo sapiens Nucleotide-binding oligomerization domain-containing protein 1 Proteins 0.000 description 5
- 102100029424 Nucleotide-binding oligomerization domain-containing protein 1 Human genes 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- BSOQXXWZTUDTEL-ZUYCGGNHSA-N muramyl dipeptide Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O BSOQXXWZTUDTEL-ZUYCGGNHSA-N 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 230000001629 suppression Effects 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000002260 anti-inflammatory agent Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000013016 damping Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 4
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 241000238631 Hexapoda Species 0.000 description 3
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 3
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 3
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- 230000002052 anaphylactic effect Effects 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000037396 body weight Effects 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
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 230000004068 intracellular signaling Effects 0.000 description 3
- 229940054136 kineret Drugs 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 3
- 229960001940 sulfasalazine Drugs 0.000 description 3
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- MJZJYWCQPMNPRM-UHFFFAOYSA-N 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine Chemical compound CC1(C)N=C(N)N=C(N)N1OCCCOC1=CC(Cl)=C(Cl)C=C1Cl MJZJYWCQPMNPRM-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000011594 Autoinflammatory disease Diseases 0.000 description 2
- 108091008875 B cell receptors Proteins 0.000 description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 2
- 229940124292 CD20 monoclonal antibody Drugs 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 102100026888 Mitogen-activated protein kinase kinase kinase 7 Human genes 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 2
- CLDKAKLHMYILJA-UHFFFAOYSA-N [S].C1=NC=C2NC=NC2=N1 Chemical compound [S].C1=NC=C2NC=NC2=N1 CLDKAKLHMYILJA-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229960002964 adalimumab Drugs 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229960004436 budesonide Drugs 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000008148 cardioplegic solution Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002447 crystallographic data Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229950009760 epratuzumab Drugs 0.000 description 2
- 238000011067 equilibration Methods 0.000 description 2
- 229960000403 etanercept Drugs 0.000 description 2
- 238000002875 fluorescence polarization Methods 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 229960001731 gluceptate Drugs 0.000 description 2
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229920000591 gum Polymers 0.000 description 2
- 230000012447 hatching Effects 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 2
- 229960004171 hydroxychloroquine Drugs 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 102000006495 integrins Human genes 0.000 description 2
- 108010044426 integrins Proteins 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000005240 left ventricle Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229960005027 natalizumab Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229940035567 orencia Drugs 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229940061969 rheumatrex Drugs 0.000 description 2
- 229960001886 rilonacept Drugs 0.000 description 2
- 108010046141 rilonacept Proteins 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 229960004540 secukinumab Drugs 0.000 description 2
- 208000013223 septicemia Diseases 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229950010077 sifalimumab Drugs 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- CBPNZQVSJQDFBE-HGVVHKDOSA-N temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CCC2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-HGVVHKDOSA-N 0.000 description 2
- 229960000235 temsirolimus Drugs 0.000 description 2
- 108091008743 testicular receptors 4 Proteins 0.000 description 2
- 229960003989 tocilizumab Drugs 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
- 230000009466 transformation Effects 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 229960003824 ustekinumab Drugs 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- GMKMEZVLHJARHF-UHFFFAOYSA-N (2R,6R)-form-2.6-Diaminoheptanedioic acid Natural products OC(=O)C(N)CCCC(N)C(O)=O GMKMEZVLHJARHF-UHFFFAOYSA-N 0.000 description 1
- FKHUGQZRBPETJR-RXSRXONKSA-N (2r)-2-[[(4r)-4-[[(2s)-2-[[(2r)-2-[(3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxypropanoyl]amino]propanoyl]amino]-5-amino-5-oxopentanoyl]amino]-6-(octadecanoylamino)hexanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@@H]1NC(C)=O FKHUGQZRBPETJR-RXSRXONKSA-N 0.000 description 1
- OBSLWIKITOYASJ-AZEWMMITSA-N (2r,3s,4s,5r,6s)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical compound CN[C@@H]1[C@H](O)O[C@@H](CO)[C@H](O)[C@H]1O OBSLWIKITOYASJ-AZEWMMITSA-N 0.000 description 1
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical class C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 1
- WMPTYRGXBUYONY-UHFFFAOYSA-N 2-chloroquinazoline Chemical compound C1=CC=CC2=NC(Cl)=NC=C21 WMPTYRGXBUYONY-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-HOSYLAQJSA-N 2-oxopentanedioic acid Chemical class OC(=O)CCC(=O)[13C](O)=O KPGXRSRHYNQIFN-HOSYLAQJSA-N 0.000 description 1
- IYTJRMRETHPZAC-UHFFFAOYSA-N 4,4-dibenzylpiperidine Chemical class C1CNCCC1(CC=1C=CC=CC=1)CC1=CC=CC=C1 IYTJRMRETHPZAC-UHFFFAOYSA-N 0.000 description 1
- QCXJEYYXVJIFCE-UHFFFAOYSA-N 4-acetamidobenzoic acid Chemical class CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical class NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- GHGZJUIEJLXZAT-UHFFFAOYSA-N 6-iodo-1h-quinazolin-2-one Chemical compound O=C1NC=C2C=C(I)C=CC2=N1 GHGZJUIEJLXZAT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100032220 Calcium and integrin-binding family member 2 Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 102100035904 Caspase-1 Human genes 0.000 description 1
- 108090000426 Caspase-1 Proteins 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101000943456 Homo sapiens Calcium and integrin-binding family member 2 Proteins 0.000 description 1
- 101000944365 Homo sapiens Cyclin-dependent kinase inhibitor 1C Proteins 0.000 description 1
- 108060006678 I-kappa-B kinase Proteins 0.000 description 1
- 102000001284 I-kappa-B kinase Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000013264 Interleukin-23 Human genes 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 108010014632 NF-kappa B kinase Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000256259 Noctuidae Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 229920003110 Primojel Polymers 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 108010052160 Site-specific recombinase Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 241000256251 Spodoptera frugiperda Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229950005953 camsilate Drugs 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 238000003391 densitometric scan Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-M dichloroacetate Chemical compound [O-]C(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-M 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 231100000284 endotoxic Toxicity 0.000 description 1
- 230000002346 endotoxic effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 229950000206 estolate Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- GKDRMWXFWHEQQT-UHFFFAOYSA-N fostamatinib Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C(NC=3N=C4N(COP(O)(O)=O)C(=O)C(C)(C)OC4=CC=3)C(F)=CN=2)=C1 GKDRMWXFWHEQQT-UHFFFAOYSA-N 0.000 description 1
- 229950005309 fostamatinib Drugs 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- GMKMEZVLHJARHF-SYDPRGILSA-N meso-2,6-diaminopimelic acid Chemical compound [O-]C(=O)[C@@H]([NH3+])CCC[C@@H]([NH3+])C([O-])=O GMKMEZVLHJARHF-SYDPRGILSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002062 molecular scaffold Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- DKJCUVXSBOMWAV-PCWWUVHHSA-N naltrindole Chemical compound N1([C@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC2=C3[CH]C=CC=C3N=C25)O)CC1)O)CC1CC1 DKJCUVXSBOMWAV-PCWWUVHHSA-N 0.000 description 1
- 229950005216 napadisilate Drugs 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 210000004493 neutrocyte Anatomy 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 239000011049 pearl Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 238000012510 peptide mapping method Methods 0.000 description 1
- 238000000955 peptide mass fingerprinting Methods 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002336 repolarization Effects 0.000 description 1
- 108700033545 romurtide Proteins 0.000 description 1
- 229950003733 romurtide Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 229940075466 undecylenate Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Virology (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Communicable Diseases (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
Abstract
本文公开了作为RIP2激酶抑制剂的化合物,及其制备和使用方法。
Description
发明领域
本发明涉及抑制RIP2激酶的喹唑啉及其制备和使用方法。
发明背景
受体相互作用蛋白-2(RIP2)激酶,其也被称为CARD3、RICK、CARDIAK或RIPK2,是参与先天性免疫信号传导的TKL家族丝氨酸/苏氨酸蛋白激酶。RIP2激酶由通过过渡(IM)区域连接的N-末端激酶域和C-末端半胱天冬酶-募集域(CARD)组成((1998)J.Biol.Chem.273,12296-12300;(1998)CurrentBiology8,885-889;和(1998)J.Biol.Chem.273,16968-16975)。RIP2激酶的CARD域介导与其它含CARD的蛋白(例如NOD1和NOD2)间的相互作用((2000)J.Biol.Chem.275,27823-27831和(2001)EMBOreports2,736-742)。NOD1和NOD2为细胞质受体,其在先天性免疫监视中起到重要作用。它们识别出革兰氏阳性菌和革兰氏阴性菌病原体并分别通过特定的肽聚糖基序、二氨基庚二酸(即DAP)和胞壁酰基二肽(MDP)激活((2007)JImmunol178,2380-2386)。
激活后,RIP2激酶结合NOD1或NOD2,并且表现为主要地起到分子支架的功能,以将参与NF-κB和分裂素激活蛋白激酶的活化的其它激酶(TAK1,IKKα/β/γ)连接在一起((2006)NatureReviewsImmunology6,9-20)。RIP2激酶经历了赖氨酸-209上的K63-连接的多聚泛素化,其促进了TAK1的募集((2008)EMBOJournal27,373-383)。这种翻译后修饰是信号传导所必需的,因为该残基突变阻止NOD1/2介导的NF-kB的激活。RIP2激酶还在丝氨酸-176和其它可能的残基上发生自磷酸化作用((2006)CellularSignalling18,2223-2229)。使用激酶失活突变体(K47A)和非选择性小分子抑制剂的研究已经证明了RIP2激酶的活性对调节RIP2激酶表达和信号传导的稳定性是重要的((2007)BiochemJ404,179-190和(2009)J.Biol.Chem.284,19183-19188)。
RIP2-依赖性信号传导的失调已经与自身炎症性疾病相关联。在NOD2的NACHT-域中的功能增强(Gain-of-function)突变引起Blau综合征、早发性结节病、特征在于葡萄膜炎、皮炎和关节炎的儿科肉芽肿病((2001)NatureGenetics29,19-20;(2005)JournalofRheumatology32,373-375;(2005)CurrentRheumatologyReports7,427-433;(2005)Blood105,1195-1197;(2005)EuropeanJournalofHumanGenetics13,742-747;(2006)AmericanJournalofOphthalmology142,1089-1092;(2006)Arthritis&Rheumatism54,3337-3344;(2009)Arthritis&Rheumatism60,1797-1803;和(2010)Rheumatology49,194-196)。在NOD2的LRR-域中的突变已经与节段性回肠炎的易感性密切相关((2002)Am.J.Hum.Genet.70,845-857;(2004)EuropeanJournalofHumanGenetics12,206-212;(2008)MucosalImmunology(2008)1(Suppl1),S5–S9.1,S5-S9;(2008)InflammatoryBowelDiseases14,295-302;(2008)ExperimentalDermatology17,1057-1058;(2008)BritishMedicalBulletin87,17-30;(2009)InflammatoryBowelDiseases15,1145–1154和(2009)MicrobesandInfection11,912-918)。NOD1中的突变已经与哮喘((2005)Hum.Mol.Genet.14,935-941)、早发性和肠外炎性肠病相关((2005)Hum.Mol.Genet.14,1245-1250)。遗传和功能学研究也已经指出RIP2-依赖性信号传导在多种其它肉芽肿病,例如结节病((2009)JournalofClinicalImmunology29,78-89和(2006)SarcoidosisVasculitisandDiffuseLungDiseases23,23-29)和韦格纳肉芽肿((2009)DiagnosticPathology4,23)中的作用。
RIP2激酶活性的强效性、选择性小分子抑制剂将阻断RIP2-依赖的促炎性信号传导,从而在特征在于RIP2激酶活性增加和/或失调的自身炎症性疾病和/或自身免疫性疾病中提供治疗益处。
发明概述
本发明涉及选自以下的化合物:
6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-(2-甲氧基乙氧基)喹唑啉-4-胺,其具有式:
6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,其具有式:
6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-丙氧基喹唑啉-4-胺,其具有式:
和6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-((四氢呋喃-2-基)甲氧基)喹唑啉-4-胺,其具有式:
或其盐,尤其是其药学上可接受的盐。
因此,本发明涉及一种抑制RIP2激酶的方法,该方法包括将本发明化合物或其盐,尤其是药学上可接受的盐与细胞接触。
本发明还涉及一种治疗RIP2激酶介导的疾病或病症的方法,其包括对有需要的患者(人或其他哺乳动物,尤其是人)给药治疗有效量的本发明化合物或其盐,尤其是药学上可接受的盐。本发明还涉及本发明化合物或包含本发明化合物的药物组合物用以抑制RIP2激酶和/或治疗RIP2激酶介导的疾病或病症的用途。
RIP2激酶介导的疾病或病症的实例包括葡萄膜炎、节段性回肠炎、溃疡性结肠炎、早发性和肠外炎性肠病和肉芽肿病,例如结节病、Blau综合征、早发性结节病和韦格纳肉芽肿病。
本发明还涉及药物组合物,其包含本发明化合物或其盐,尤其是药学上可接受的盐,以及药学上可接受的赋形剂。具体地,本发明涉及治疗RIP2激酶介导的疾病或病症的药物组合物,其中所述组合物包含本发明化合物或其盐,尤其是药学上可接受的盐,以及一种或多种药学上可接受的赋形剂。
附图说明
图1是结晶形式的6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺(游离碱)的粉末X射线衍射(PXRD)图案。
图2显示对大鼠预先给药6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺的化合物,接着给药L18-MDP之后,在大鼠全血样品中获得的组合的IL8细胞因子响应。
发明详述
本文所用术语“本发明化合物”或“该发明化合物”表示如此处所定义的任何化合物,其为任何形式,即,任何盐或非盐形式(例如游离酸或碱的形式,或盐的形式,尤其是药学上可接受的盐)以及其任一物理形式(例如包括非固体形式(例如液体或半固体形式),以及固体形式(例如无定形或晶体形式,尤其是多晶形式),溶剂合物形式,包括水合物形式(例如单水合物、二水合物和半水合物)),以及各种形式的混合物(盐的水合物)。具体地,应该理解的是,本发明包括作为游离碱和其盐的本发明化合物,例如作为其药学上可接受的盐。在一个实施方案中,本发明涉及游离碱形式的本发明化合物。在另一个实施方案中,本发明涉及盐形式的本发明化合物,特别是药学上可接受的盐。
本领域技术人员还应当理解,本发明的化合物中的吡唑基部分可作为存在互变的吡唑基异构体,其表示为式(I-A)和式(I-B):
应理解,得到的吡唑基部分可命名为3,4-二甲基-1H-吡唑-5-基部分或4,5-二甲基-1H-吡唑-3-基部分。应理解,任何提及本发明的命名化合物意在包括命名化合物的所有互变异构体和命名化合物的互变异构体的任何混合物。例如,化合物名称6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺意在包括化合物6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺和6-(叔丁基磺酰基)-N-(3,4-二甲基-1H-吡唑-5-基)-7-乙氧基喹唑啉-4-胺,及其混合物。本文描述的化合物的所有互变异构形式意在被包括于被本发明的范围内。
本发明化合物可含有一个或多个不对称中心(也称为手性中心),因此可以各种对映异构体、非对映异构体或其它立体异构体的形式或以其混合物的形式存在。手性中心,例如手性碳,也可存在于本发明化合物中。当存在于本发明化合物(例如,化合物名称)或本文所说明的任何化学结构中的手性中心的立体化学未指明时,该化合物、化合物名称或结构包含所有单独的立体异构体及其所有的混合物。因此,含有一个或多个手性中心的本发明化合物可以以外消旋混合物、对映异构体富集混合物或对映异构体纯的单独立体异构体存在。
含有一个或多个不对称中心的根据本发明的化合物的各种立体异构体可以通过本领域技术人员已知的方法拆分。例如,可如下进行所述拆分:(1)通过形成非对映异构体盐、复合物或其他衍生物;(2)通过与立体异构体特异性试剂的选择性反应,例如通过酶促氧化或还原;或(3)通过在手性环境中的气-液色谱或液相色谱,所述手性环境例如在手性载体(例如连接有手性配体的硅胶)或在手性溶剂存在下。本领域技术人员将会理解,当将所需立体异构体通过上述分离方法之一转化成另一化学实体时,需要其他步骤来释放所需形式。或者,特异性立体异构体可通过使用光学活性试剂、底物、催化剂或溶剂的不对称合成法来合成,或通过不对称转化将一种对映异构体转化成另一种异构体。
应理解本发明化合物的固体形式可以晶型、非晶型或其混合物存在。所述晶型也可显示多晶型(即出现不同晶型的能力)。这些不同晶型,通常称为“多晶型体”。多晶型体有相同的化学组成,但是不同的堆积(packing)、几何排列和其他可描述的晶体固态的性质。因此,多晶型体可具有不同的物理性质,例如形状、密度、硬度、可变形性、稳定性和溶解性质。多晶型体通常具有不同的熔点、IR光谱和X-射线粉末衍射图,其可用于鉴定。本领域一般技术人员将会理解,可制备不同多晶型体,例如,通过改变或调整在结晶/重结晶所述化合物中所用的条件。
本领域技术人员众所周知且应理解,采用的仪器、湿度、温度、粉末晶体的取向,以及在获得粉末X射线衍射(PXRD)图案时涉及的其他参数可能导致衍射图案的外观、强度、和在线的位置的一些变化。粉末X射线衍射图案,其与本文所提供的图“基本上一致”,是本领域技术人员将认为是代表其具有与图中的PXRD图案提供的化合物相同的晶体形式的PXRD图案。例如,所述PXRD图案可以与图1的是相同的,或更可能它可能有些不同。这样的PXRD图案可能不必需显示本文中所呈现的衍射图案的每条线,和/或可以表现出在外观、强度、或线的位置偏移的轻微的变化,这些变化是源自获得数据时条件的差异。本领域技术人员能够确定,结晶化合物的样品是否与本文公开的形式有相同的形式,或不同的形式,这通过比较它们的PXRD图案来确定。例如,本领域的技术人员可以将6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺(游离碱)的晶型的样品的PXRD图案与图1的PXRD图案叠加,并使用本领域中的经验和知识,容易地确定样品的PXRD图案是否基本上与图1的PXRD图案一致。如果样品的PXRD图案基本上与图1一致,则样品晶型可被容易地和准确地识别为具有与本文描述的6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺(游离碱)的相同晶型。类似地,本领域技术人员能够确定PXRD图案中获得的给定的衍射角(以°2θ表达)是否是在大约相同的位置作为记载的值。
由于其在药物中潜在的用途,式(I)化合物的盐优选为药学上可接受的盐。合适的药学上可接受的盐包括酸加成盐或碱加成盐,例如在Berge,BighleyandMonkhouseJ.Pharm.Sci(1977)66,pp1-19和"PharmaceuticalSalts: Properties,Selection,andUse,2ndRevisedEdition,"P.H.StahlandC.G.Wermuth(eds.),Wiley,Hoboken,NJ,US(2011)中所描述的那些。
术语“药学上可接受的”是指那些化合物、材料、组合物和剂型,其在合理的医学判断范围内,适用于与人类和动物组织接触而没有过度的毒性、刺激,或其他的问题或并发症,与合理的利益/风险比相称。
“药学上可接受的盐”是指适合于药物用途的化合物。适合于在药物中使用的本发明的化合物的盐和溶剂化物(例如水合物和盐的水合物)形式,是其中的平衡离子或相关溶剂是药学上可接受的那些。然而,具有非药学上可接受的平衡离子或相关溶剂的盐和溶剂化物也在本发明的范围之内,例如,用作本发明的其他化合物及其盐和溶剂化物制备过程中的中间体。
当本发明化合物为碱(含有碱性部分)时,所需盐形式可通过本领域已知的任一适当方法制备,包括用酸处理游离碱。药学上可接受的酸加成盐的实例包括乙酸盐、己二酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、樟脑酸盐、樟脑磺酸盐(camsylate)、癸酸盐(decanoate)、己酸盐(hexanoate)、辛酸盐(octanoate)、碳酸盐、碳酸氢盐、肉桂酸盐、柠檬酸盐、环己氨基磺酸盐、十二烷基硫酸盐(estolate)、乙烷-1,2-二磺酸盐(乙二磺酸盐)、乙磺酸盐(esylate)、甲酸盐、富马酸盐、粘酸盐(galactarate或mucate)、龙胆酸盐(2,5-二羟基苯甲酸盐)、葡庚糖酸盐(gluceptate)、葡糖酸盐、葡糖醛酸盐、谷氨酸盐、戊二酸盐、甘油磷酸盐、乙醇酸盐、马尿酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、异丁酸盐、乳酸盐、乳糖醛酸盐、月桂酸盐、马来酸盐、苹果酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐(mesylate)、萘-1,5-二磺酸盐(萘二磺酸盐)、萘磺酸盐(napsylate)、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐、二磷酸盐、丙酸盐、焦谷氨酸盐、水杨酸盐、癸二酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一碳烯酸盐、1-羟基-2-萘甲酸盐、2,2-二氯乙酸盐、2-羟基乙磺酸盐(羟乙基磺酸盐)、2-氧代戊二酸盐、4-乙酰氨基苯甲酸盐和4-氨基水杨酸盐。可使用非药学上可接受的盐例如三氟乙酸盐,例如在分离本发明化合物时,并且所述盐也包括在本发明的范围内。
当本发明化合物为酸(含有酸性部分)时,所需盐可通过本领域已知的任一适当方法制备,包括用无机或有机碱处理游离酸。药学上可接受的碱加成盐的实例包括铵盐、锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、锌盐、三甲胺、三乙胺、吗啉、吡啶、哌啶、皮考啉、二环己胺、N,N'-二苄基乙二胺、2-羟基乙胺、双-(2-羟乙基)胺、三-(2-羟乙基)胺、普鲁卡因、二苄基哌啶、去氢枞胺、葡糖胺、N-甲基葡糖胺、可力丁、奎宁、喹啉、赖氨酸和精氨酸。在一个实施方案中,药学上可接受的碱加成盐是钠盐。
本发明一些化合物可与一个或多个当量的酸(如果化合物含有碱性部分)或碱(如果化合物含有酸性部分)形成盐。本发明在其范围内包含所有可能的化学计量和非化学计量盐形式。
本发明还提供本发明化合物药学上可接受的盐向本发明化合物的另一种药学上可接受的盐的转化。
如果碱性化合物被分离为盐,该化合物的相应的游离酸或游离碱形式可通过本领域已知的任何合适的方法来制备。
对于本发明化合物的溶剂合物,包括以晶体形式存在的本发明化合物的盐的溶剂合物,本领域技术人员将理解可形成药学上可接受的溶剂合物,其中在结晶时溶剂分子被掺入晶格中。溶剂合物可包含非水溶剂例如乙醇、异丙醇、DMSO、乙酸、乙醇胺和EtOAc,或者它们可包含水作为溶剂(该溶剂被掺入到晶格中)。其中水为溶剂(该溶剂被并入晶格中)的溶剂合物通常称为“水合物”。水合物包括化学计量量的水合物以及含有可变量水的水合物(compositions)。本发明包括所有该类溶剂合物,特别是水合物。
由于本发明化合物用于药物组合物,将容易理解其各自优选以基本上纯的形式提供,例如至少60%的纯度,更合适为至少75%的纯度,以及优选为至少85%,尤其至少98%的纯度(%指重量百分比)。所述化合物的不纯的制备品可用于制备药物组合物中使用的更纯的形式。
一般合成方法
本发明化合物可通过使用下列方案中描述的合成方法或通过有机化学技术人员的知识来获得。这些方案提供的合成方法适用于应用合适前体制备具有多种不同取代基的本发明化合物,如果需要则将其适当地保护,来与本文概括的反应实现相容。需要的话,随后进行脱保护,得到通常公开的实际化合物。尽管仅显示了通式化合物的方案,但其说明了用于制备本发明化合物的方法。
可以在吡唑基装配之前装配在C6上的取代。硫醇与6-碘代喹唑酮的钯催化的偶联可生成硫化物,其可随后被氧化成砜。用POCl3或SOCl2氯化可生成4-氯喹唑啉。
方案1
苯胺/胺可在碱或酸的条件下与4-氯-喹唑啉反应,以生成4-氨基喹唑啉,其可为最终化合物或用作进一步合成的中间体。
方案2
本发明的一些化合物的制备或者可通过6-溴-7-氟代喹唑啉-4-酚与合适的醇类在碱的存在下反应并伴随加热,以生成合适的6-溴-7-烷氧基喹唑啉-4-酚。用胺/苯胺进行随后的氯化和置换将生成4-氨基-6-溴-7-烷氧基喹啉。这些化合物与硫醇或硫醇盐,在钯催化剂、配体和碱的合适的组合的存在下并伴随加热,进一步反应,以生成4-氨基-6-烷基硫基-7-烷氧基喹唑啉。氧化作用将生成4-氨基-6-磺酰基-7-烷氧基喹唑啉,其可为最终化合物或用作进一步反应的中间体。
方案3
本发明的一些化合物的制备可从7-氟代-6-磺酰基-4-喹唑酮完成。中间体的合成开始于4-氟代-2-氨基苯甲酸的溴化,然后用醋酸甲脒在原位缩合。与硫醇的钯催化的偶联可生成硫化物,其随后氧化成砜。
方案4
用氟取代基取代烷氧基,可通过用适当的醇与叔丁醇钾处理来实现。
方案5
本发明的具体化合物为6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺(作为游离碱)。在另一个实施方案中,本发明的具体化合物为6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺或其盐。在另一个实施方案中,本发明的具体化合物为6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺或其药学上可接受的盐。在另一个实施方案中,本发明的具体化合物为结晶形式的6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,其特征在于图1的PXRD图案。在另一个实施方案中,本发明的具体化合物为结晶形式的6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,其特征在于表1的衍射数据。
本发明的化合物是RIP2激酶的抑制剂。因此,在一个实施方案中,本发明涉及抑制RIP2激酶的方法,其包括将细胞与本发明的化合物接触。在另一个实施方案中,本发明涉及治疗RIP2激酶介导的疾病或病症的方法,其包括给药治疗有效量的化合物于有此需要的人。
在另一个具体实施方案中,本发明涉及治疗RIP2激酶介导的疾病或病症的方法,其包括给药治疗有效量的6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,或其药学上可接受的盐,于有此需要的人。
本发明化合物尤其可用于治疗RIP2激酶介导的疾病或病症,特别是RIP2激酶将提供益处的疾病或病症。这样的KIP2激酶介导的疾病或病症的实例包括葡萄膜炎、白介素-1转换酶(ICE,也被称为胱天蛋白酶-1)相关的发热综合征(ICE发热)、皮炎、急性肺损伤、2型糖尿病、关节炎(特别是类风湿性关节炎)、炎性肠病(例如溃疡性结肠炎和节段性回肠炎)、早发性炎性肠病和肠外炎性肠病、预防响应于心脏手术、器官移植、败血病和其它损伤导致的缺血在实体器官(特别是肾)中的缺血再灌注损伤、肝脏疾病(非酒精性脂肪肝、酒精性脂肪肝和自身免疫性肝炎)、过敏性疾病(例如哮喘)、移植反应(例如移植物抗宿主疾病)、自身免疫性疾病(例如系统性红斑狼疮和多发性硬化症)和肉芽肿病(例如结节病、Blau综合征、早发性结节病、韦格纳肉芽肿病以及间质性肺疾病)。
本发明化合物尤其可用于治疗葡萄膜炎、ICE发热、Blau综合征、早发性结节病、溃疡性结肠炎、节段性回肠炎、韦格纳肉芽肿病以及结节病。治疗RIP2激酶介导的疾病或病症,或更广泛地,治疗免疫介导的疾病包括但不限于,过敏性疾病、自身免疫性疾病、移植排异反应的预防等,可使用本发明化合物以单一治疗或双重或多重组合治疗来实现,尤其是用于治疗顽固性病例,例如与其它抗炎药物和/或抗TNF药物的组合,其可根据本领域已知的治疗有效量进行给药。
本发明的化合物可以单独使用或与其它治疗剂结合使用。本发明的组合疗法因而包括给药至少一种本发明的化合物,以及使用至少一种其它治疗活性剂。优选地,本发明的组合疗法包括给药至少一种本发明的化合物,和至少一种其它治疗活性剂。
一种或多种本发明的化合物和一种或多种其它治疗活性剂可以以单一药物组合物给药或分开给药,且当分开给药时,可以同时给药或按任何顺序给药。一种或多种本发明的化合物和一种或多种其它治疗活性剂的量和给药的相对时间会以实现所需的组合治疗效果来选择。因此,在另一方面,提供了一种包含本发明化合物连同一种或多种其它治疗活性剂的组合。进一步,提供了一种组合,其包含6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,或其药学上可接受的盐,连同一种或多种其它治疗活性剂。
因此,在本发明的一个方面中,本发明化合物和包含本发明化合物的药物组合物可与一种或多种治疗剂组合使用,或使用时包括一种或多种其他治疗剂,所述治疗剂例如抗炎剂和/或抗TNF剂。
本发明化合物可以与皮质激素和/或抗TNF药物组合给药治疗Blau综合征、早发性结节病;或与抗TNF生物制剂或其他抗炎性生物制剂组合给药治疗节段性回肠炎;或与5-ASA(美沙拉嗪)或柳氮磺吡啶组合给药治疗溃疡性结肠炎;或与低剂量皮质激素和/或甲氨喋呤组合给药治疗韦格纳肉芽肿病或结节病或间质性肺疾病;或与生物制剂(例如抗TNF药物、抗IL-6药物等)组合给药治疗类风湿性关节炎;或与抗IL6剂和/或甲氨喋呤组合给药治疗ICE发热。
合适的抗炎剂的实例包括5-氨基水杨酸和美沙拉嗪制剂、柳氮磺胺吡啶、羟氯喹、硫嘌呤(硫唑嘌呤、巯嘌呤)、甲氨蝶呤、环磷酰胺、环孢菌素、JAK抑制剂(托法替尼)、皮质激素,特别是低剂量的皮质激素(如泼尼松和布地奈德)和抗炎生物制剂如抗IL6R单克隆抗体((tocilizumab))、抗IL6生物制剂、抗IL1或IL12或IL23生物制剂(ustekinumab)、抗整联蛋白试剂(那他珠单抗)、抗CD20单克隆抗体(利妥昔单抗和奥法木单抗)、以及其他试剂,如阿巴西普阿那白滞素和贝利单抗CD4生物制剂和T细胞或B细胞受体或白细胞介素的其它细胞因子抑制剂或生物制剂。合适的抗TNF药物的实例包括抗TNF生物制剂如(依那西普)、(阿达木单抗)、(英夫利昔单抗)、(赛妥珠单抗)和(戈利木单抗)。
合适的抗炎剂的其他实例包括5-氨基水杨酸和美沙拉嗪制剂、柳氮磺胺吡啶、羟氯喹、硫嘌呤(硫唑嘌呤、巯嘌呤)、甲氨蝶呤、环磷酰胺、环孢菌素、钙调磷酸酶抑制剂(环孢霉素、吡美莫司、他克莫司)、霉酚酸mTOR抑制剂(坦罗莫司(temsirolimus)、依维莫司)、JAK抑制剂(托法替尼)、)、Syk抑制剂(fostamatinib)、皮质激素,特别是低剂量的皮质激素(如泼尼松和布地奈德)和抗炎生物制剂如抗IL6R单克隆抗体((tocilizumab))、抗IL6生物制剂、抗IL1(阿那白滞素卡那单抗利洛纳塞)、抗IL12或抗IL23和生物制剂(ustekinumab)、抗IL17生物制剂(secukinumab)、抗CD22(依帕珠单抗)、抗整联蛋白试剂(那他珠单抗)、维多珠单抗)、抗IFNa(sifalimumab)、抗-CD20单克隆抗体(利妥昔单抗和奥法木单抗)、和其他试剂,例如阿巴西普阿那白滞素卡那单抗利洛纳塞secukinumab、依帕珠单抗、sifalimumab和贝利单抗CD4生物制剂和T细胞或B细胞受体或白细胞介素的其它细胞因子抑制剂或生物制剂。合适的抗TNF药物的实例包括抗TNF生物制剂(例如(依那西普))、(阿达木单抗)、(英夫利昔单抗)、(赛妥珠单抗)和(戈利木单抗))。本发明还提供了用于治疗用途的本发明化合物。具体地,本发明提供本文所述的化合物,或其药学上可接受的盐,其用于治疗中。更具体地,本发明提供了6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,或其药学上可接受的盐,其用于在治疗。
在另一个实施方案中,本发明提供本发明化合物用于治疗RIP2激酶介导的疾病或病症。具体地,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗RIP2激酶介导的疾病或病症。
在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗葡萄膜炎、白介素-1转换酶相关的发热综合征、皮炎、急性肺损伤、2型糖尿病、关节炎(特别是类风湿性关节炎)、炎性肠病(例如溃疡性结肠炎和节段性回肠炎)、早发性炎性肠病和肠外炎性肠病、预防响应于心脏手术、器官移植、败血病和其它损伤导致的缺血在实体器官(特别是肾)中的缺血再灌注损伤、肝脏疾病(非酒精性脂肪肝、酒精性脂肪肝和自身免疫性肝炎)、过敏性疾病(例如哮喘)、移植反应(例如移植物抗宿主疾病)、自身免疫性疾病(例如系统性红斑狼疮和多发性硬化症)和肉芽肿病(例如结节病、Blau综合征、早发性结节病、韦格纳肉芽肿病或间质性肺疾病)。
在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗葡萄膜炎。在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗白介素-1转换酶相关的发热综合征。在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗Blau综合征。在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗早发性结节病。在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗溃疡性结肠炎。在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗节段性回肠炎。在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗早发性炎性肠病。在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗肠外炎性肠病。在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗韦格纳肉芽肿病。在另一个实施方案中,本发明提供本文所述化合物,或其药学上可接受的盐,用于治疗结节病。
本发明还提供本发明化合物在制备用于治疗RIP2激酶介导的疾病或病症的药物中的用途,例如本文中记载的各种疾病和病症。具体地,本发明提供本文所述化合物,或其药学上可接受的盐,在制备用于治疗RIP2激酶介导的疾病或病症的药物中的用途。更具体地,本发明提供6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,或其药学上可接受的盐,在制备用于治疗RIP2激酶介导的疾病或病症的药物中的用途。
本发明还提供本文所述化合物或其药学上可接受的盐,在制备用于治疗患有RIP2激酶介导的疾病或病症的有此需要的人中的用途。在治疗上的“有效量”是指如上文所定义,当给予有此需要该类治疗的患者时,足够达到治疗效果的化合物的量。因此,例如,本发明化合物或其药学上可接受的盐的治疗有效量是:当给予有此需要的人时,足以调节或抑制RIP2激酶活性,使该活性介导的疾病症状降低、减缓或受阻的活性试剂的量。给定化合物的量依据多种因素而改变,例如具体化合物(例如,效能(pIC50)、有效性(EC50)和具体化合物的生物半衰期)、疾病症状及其严重程度、所需治疗患者的本性(例如,年龄、体型和体重),但是本领域技术人员仍可以按常规决定。同样地,所述化合物治疗的持续时间和给药的时间期限(给药间的时间期限和给药时机,例如,饭前/随餐/饭后)根据需治疗的哺乳动物的本性(例如,体重)、具体化合物及其性质(例如,药学特性)、疾病或病症及其严重程度和特定的药物组合物及其使用方法而变化,但是本领域技术人员仍可以决定。
“治疗”或“疗法”是指患者的疾病或病症至少有所减轻。减轻疾病或病症的治疗方法包括本发明化合物在任一常规可接受方法中的使用,例如用于阻止、阻滞、预防、治疗或治愈所介导的疾病或病症。使用本发明化合物可容易治疗的具体的疾病和病症在本文中描述。
本发明化合物可以以任一合适的给药途径给药,包括全身给药和局部给药。全身给药包括口服给药、肠胃外给药、透皮给药、直肠给药和吸入给药。肠胃外给药表示除肠内、透皮或吸入以外的给药途径,通常为注射或输注。肠胃外给药包括静脉、肌内和皮下注射或输注。吸入表示给药至患者肺部,无论是通过嘴或是鼻通道吸入。局部给药包括施于皮肤。
在给定时间内,本发明化合物可给药一次或根据给药方案以不同的时间间隔给药多次剂量。例如,剂量可以每天给药一、二、三或四次。剂量可以给药直到实现所需治疗效果,或无限期给药以维持所需治疗效果。本发明化合物的合适给药方案取决于化合物的药代动力学性质,例如吸收、分布和半衰期,其可由本领域技术人员确定。此外,本发明化合物的合适的给药方案(包括该给药方案的持续时间)取决于待治疗的疾病或病症、待治疗的疾病或病症的严重程度、待治疗的患者的年龄和身体状况、待治疗的患者的病史、并行治疗的性质、所需治疗效果和本领域技术人员知识和专业内的类似因素。该技术人员还将理解,合适的给药方案可根据个别患者对于给药方案的反应或由于个别患者需要随时间变化来进行调整。
对于治疗用途而言,本发明化合物通常(但不必须)在给药患者前配制成药物组合物。因此,本发明也涉及药物组合物,其包含本发明化合物以及一种或多种药学上可接受的赋形剂。
在一个实施方案中,本文提供药物组合物,其包含6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,或其药学上可接受的盐,和一种或多种药学上可接受的赋形剂。在另一个实施方案中,本文提供药物组合物,其包含6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺(作为游离碱)和一种或多种药学上可接受的赋形剂。在另一个实施方案中,本文提供药物组合物,其包含结晶形式的6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺(其特征在于图1的PXRD图案)和一种或多种药学上可接受的赋形剂。本发明的药物组合物可以制备和包装为散装形式,其中本发明的化合物的有效量可以被提取,然后将其给药于患者如以粉剂、糖浆和注射液形式。或者,本发明的药物组合物可以制备和包装为单位剂型。对于口服施用,例如,可给药一个或多个片剂或胶囊剂。所述药物组合物的剂量含有至少治疗有效量的本发明的化合物。当以单位剂型制备时,该药物组合物可含有1mg至1000mg的本发明的化合物。
如本文所提供,包含1mg至1000mg的本发明的化合物的单位剂型(药物组合物)可被给药每天1、2、3或4次,优选每天1、2或3次,更优选地,每天一次或两次,以治疗RIP2介导的疾病或病症。
本发明的药物组合物通常包含一种本发明化合物。但是,在一些实施方案中,本发明的药物组合物包含多于一种本发明化合物。此外,本发明的药物组合物还可任选地包含一种或多种其他的药学活性化合物。
本文所用“药学上可接受的赋形剂”表示在给药形式中涉及的或与组合物相容的物质、组合物或载体。当混合时,各赋形剂必须与药物组合物的其他成分相容,使得避免对患者给药时将基本上降低本发明化合物的功效的相互作用和将导致药物组合物成为药学上不可接受的相互作用。此外,各赋形剂的纯度当然必须足够高,使其为药学上可接受。
本发明化合物和药学上可接受的赋形剂通常被配制成通过所需给药途径适于给药患者的剂型。常规的剂型包括(1)适于口服给药的剂型,例如片剂、胶囊剂、小胶囊剂、丸剂、锭剂、粉末、糖浆、酏剂、悬浮液、溶液、乳剂、囊剂和扁囊剂;(2)适于肠胃外给药的剂型,例如无菌溶液、悬浮液和用于重构(reconstitution)的粉末;(3)适于透皮给药的剂型,例如透皮贴剂;(4)适于直肠给药的剂型,例如栓剂;(5)适于吸入的剂型,例如气雾剂和溶液;和(6)适于局部给药的剂型,例如乳膏、软膏、洗剂、溶液、糊剂、喷雾剂、泡沫剂和凝胶剂。
合适的药学上可接受的赋形剂将根据所选具体的剂型而变化。此外,可根据在组合物中的具体功能来选择合适的药学上可接受的赋形剂。例如,可根据促进制备均一剂型的能力来选择某些药学上可接受的赋形剂。可根据促进制备稳定的剂型的能力来选择某些药学上可接受的赋形剂。可根据在给药患者后促进本发明化合物从一个器官或身体部分携带或运输至另一器官或身体部分的能力来选择某些药学上可接受的赋形剂。某些药学上可接受的赋形剂可根据其提高患者顺应性的能力进行选择。
合适的药学上可接受的赋形剂包括下列赋形剂类型:稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、粒化剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、增甜剂、调味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。本领域技术人员将理解,某些药学上可接受的赋形剂可以以多于一种功能和以替代性功能来使用,取决于所述赋形剂在制剂中存在多少和在制剂中存在何种其他成分。
具有本领域的知识和技术的技术人员能够选择出以适当量用于本发明的合适的药学上可接受的赋形剂。此外,有许多本领域技术人员可用的资源,这些资源描述了药学上可接受的赋形剂且其可用于选择合适的药学上可接受的赋形剂。实例包括Remington'sPharmaceuticalSciences(MackPublishingCompany),TheHandbookofPharmaceuticalAdditives(GowerPublishingLimited),和TheHandbookofPharmaceuticalExcipients(theAmericanPharmaceuticalAssociationandthePharmaceuticalPress)。
本发明的药物组合物使用本领域技术人员已知的技术和方法制备。通常用于本领域的一些方法描述在Remington'sPharmaceuticalSciences(MackPublishingCompany)中。
一方面,本发明涉及固体口服剂型,例如片剂或胶囊剂,其包含有效量的本发明化合物以及稀释剂或填充剂。合适的稀释剂和填充剂包括乳糖、蔗糖、右旋糖、甘露醇、山梨醇、淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、纤维素及其衍生物(例如微晶纤维素)、硫酸钙和磷酸氢钙。口服固体给药剂型还可包含粘合剂。合适的粘合剂包括淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、明胶、阿拉伯胶、海藻酸钠、海藻酸、西黄蓍胶、瓜尔胶、聚维酮和纤维素及其衍生物(例如微晶纤维素)。口服固体给药剂型还可包含崩解剂。合适的崩解剂包括交聚维酮、淀粉羟乙酸钠、交联羧甲基纤维素、海藻酸和羧甲基纤维素钠。口服固体给药剂型还可包含润滑剂。合适的润滑剂包括硬脂酸、硬脂酸镁、硬脂酸钙和滑石。
实施例
用下列实施例说明本发明。这些实施例不是用于限制本发明的范围,而是为本领域技术人员提供关于制备和使用的本发明化合物、组合物和方法的指导。虽然本发明所描述了具体的实施方案,本领域技术人员将理解,在不脱离本发明精神和范围的情况下,可作出各种变化和修改。
本发明也包括本发明化合物的各种氘化形式。连接到碳原子的各可用的氢原子可独立地用氘原子替换。本领域普通技术人员将知晓如何合成本发明化合物的氘化形式。
使用软件命名程序ACD/NameProV6.02(可获自AdvancedChemistryDevelopment,Inc.,110YongeStreet,14thFloor,Toronto,Ontario,Canada,M5C1T4(http://www.acdlabs.com/))或ChemDraw中的命名程序,Struct=NamePro12.0,作为ChemBioDrawUltra的部分,可获自CambridgeSoft.100CambridgeParkDrive,Cambridge,MA02140USA(www.cambridgesoft.com)得到本文所述的中间体和最终化合物的名称。
在下列实验说明中,可使用下列缩写:
制备1
6-(叔丁基磺酰基)-7-氟代喹唑啉-4-酚
步骤1:6-(叔丁基硫基)-7-氟代喹唑啉-4-酚:将6-溴-7-氟代喹唑啉-4-酚(69g,285mmol)、四(三苯膦)-钯(0)(20g,17mmol)和碳酸钠(60g,570mmol)的混合物在DMF(1L)中搅拌同时通氮气5分钟。将2-甲基丙烷-2-硫醇(64ml,570mmol)加入其中并将反应混合物在100℃于回流冷凝器中加热6小时。将反应混合物冷却并通过玻璃滤纸过滤,然后将其缓慢倒入1500ml搅拌的水中。将所得的红色沉淀物过滤并研磨于200mL的EtOAc中。将固体过滤,并依次用110mL己烷,150mL的90:10的己烷:EtOAc洗涤,得到6-(叔丁基硫基)-7-氟代喹唑啉-4-酚(44.5g,61.9%产率),为褐色固体。LC/MS:M+H=253.21HNMR(400MHz,DMSO-d6)δppm12.23-12.72(m,1H),8.24(d,J=8.1Hz,1H),8.19(s,1H),7.58(d,J=9.6Hz,1H),1.28(s,9H)。
步骤2:6-(叔丁基磺酰基)-7-氟代喹唑啉-4-酚:将6-(叔丁基硫基)-7-氟代喹唑啉-4-酚(45g,124mmol)和Oxone(过硫酸氢钾制剂)(191g,311mmol)在乙酸乙酯(1220ml)、甲醇(1220ml)和水(1220ml)中的悬浮液在25℃搅拌4h,同时再添加另外的25g(共2.8eq)的Oxone。将反应混合物通过顶置式搅拌器搅拌12h。将反应混合物过滤,并将滤液用饱和碳酸氢钠水溶液、然后用固体碳酸氢钠,缓慢碱化至pH~7.5。将该混合物用额外的1.25L的EtOAc、然后用500mlEtOAc萃取。将合并的有机物用盐水洗涤,然后用MgSO4干燥,过滤,并真空浓缩。通过研磨于200mL的EtOAc,将少量杂质去除。所需的6-(叔丁基磺酰基)-7-氟代喹唑啉-4-酚(33.2g,94%产率)作为黄色固体滤出。LC/MS:M+H=285.21HNMR(400MHz,DMSO-d6)δppm12.48-13.03(m,br.s,1H),8.47(d,J=7.8Hz,1H),8.32(s,1H),7.73(d,J=11.1Hz,1H),1.17-1.40(s,9H)。
制备2
6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-氟代喹唑啉-4-胺
向6-(叔丁基磺酰基)-7-氟代喹唑啉-4-酚(4.14g,14.56mmol)在乙腈(42.7ml)中的溶液中,加入POCl3(2.036ml,21.84mmol)和DIEA(3.81ml,21.84mmol)。将反应混合物加热至80℃并过夜16h。加入额外的POCl3(500uL)并将反应混合物在80℃搅拌18h。通过LCMS得到氯化物的完全转化。加入4,5-二甲基-1H-吡唑-3-胺(1.942g,17.47mmol)并将反应混合物在80℃搅拌1h。将沉淀物过滤,用乙腈洗涤并干燥以获得6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-氟代喹唑啉-4-胺,盐酸盐(4.15g,9.93mmol,68.2%产率)。1HNMR(400MHz,DMSO-d6)δppm9.10-9.44(m,1H)8.88(br.s.,1H)7.94(d,J=10.36Hz,1H)2.23(s,3H)1.82(s,3H)1.24-1.45(m,9H).MS(m\z)378(M+H)+。
实施例1
6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-(2-甲氧基乙氧基)喹唑啉-4-胺
将6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-氟代喹唑啉-4-胺,盐酸盐(300mg,0.73mmol)、2-甲氧基乙醇(5.7ml,73mmol)和KOtBu(410mg,3.6mmol)的混合物在90℃加热4天。将反应混合物浓缩至干,干法上样到硅胶上并通过柱色谱法纯化(ISCO-Rf,0-25%甲醇(w/1%NH4OH)/乙酸乙酯,得到6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-(2-甲氧基乙氧基)喹唑啉-4-胺(230mg,0.531mmol,73.2%产率),为黄色固体。1HNMR(400MHz,DMSO-d6)δppm12.19(s,1H),10.36(s,1H),8.99(s,1H),8.45(s,1H),7.34(s,1H),4.26-4.42(m,2H),3.73(t,J=4.4Hz,2H),3.34(s,3H),2.18(s,3H),1.74(s,3H),1.33(s,9H).MS(m/z)434。
实施例2
6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺
步骤1:6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-氟代喹唑啉-4-胺:向6-(叔丁基磺酰基)-7-氟代喹唑啉-4-酚(5.50g,19.35mmol)在乙腈(48ml)中的悬浮液中加入POCl3(2.70ml,29.0mmol)和TEA(4.0ml,29mmol)。将反应混合物在80℃搅拌过夜。将4,5-二甲基-1H-吡唑-3-胺(2.58g,23.2mmol)加至溶液,并将反应混合物继续在80℃搅拌1小时。固体开始沉淀出来。将反应混合物冷却至室温。滤出固体并用冷乙腈洗涤。将固体在真空烘箱中干燥,得到6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-氟代喹唑啉-4-胺,盐酸盐(4.91g,11.86mmol,61.3%产率)。(M+H)+378.2。
步骤2:6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺:将乙醇钠(24ml,65.6mmol,21%/EtOH)和6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-氟代喹唑啉-4-胺,盐酸盐(4.80g,11.60mmol)合并,并将悬浮液在80℃加热2小时。将反应混合物冷却至室温。蒸发EtOH,将残留物溶解在25ml水中。通过加入1N盐酸将溶液中和至pH~9。浅黄色固体沉淀出来。将固体过滤,用水洗涤和在真空烘箱中干燥过夜,得到6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺(3.90g,9.67mmol,83%产率)。(M+H)+404.1;1HNMR(DMSO-d6,400MHz):δ=12.20(s,1H),10.36(s,1H),8.99(s,1H),8.46(s,1H),7.30(s,1H),4.134.34(m,2H),2.18(s,3H),1.74(s,3H),1.40(t,J=6.9Hz,3H),1.33ppm(s,9H)。
将6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺(120g)的样品悬浮于EtOH(2000ml),然后加热至70℃。加入额外的EtOH(2000ml),并将所得混合物加热至回流。大多数的固体溶解在溶剂中。将热悬浮液过滤,并将溶液倾入12L冷水中。将此混合物搅拌约60分钟,然后将浴温热至室温,静置过夜。将浅黄色沉淀物通过过滤分离并在真空烘箱中干燥,得到105.9g(261mmol,88%回收率)6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺的结晶,其特征在于图1的PXRD图案和表1的衍射数据。
所述PXRD分析在如下仪器进行:Rigaku台式X射线衍射仪,型号MiniflexII,序列号DD02652,使用闪烁体NaI(TI)检测器。采集条件包括:CuKα辐射发电机电压:30kV,发电机电流:15mA,开始角:3.0°2θ,终止角:40.0°2θ,步长:0.04°2θ,每步时间:0.5秒。将样品用零背景(正面辅助光(frontfill))技术制备。
表1.
实施例3
6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-丙氧基喹唑啉-4-胺
将6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-氟代喹唑啉-4-胺(1.5g,3.97mmol),丙烷-1醇(17.85ml,238mmol)和KOtBu(2.230g,19.87mmol)的混合物在90℃加热21h。将反应混合物倾入乙醚中-溶液变混浊-无沉淀。将该混合物用柠檬酸中和并用EtOAc(1x)和2-MeTHF(1x)萃取。将合并的有机物用盐水洗涤,经Na2SO4干燥并浓缩至干,得到了粗产物,将粗产物通过HPLC(10-50%的ACN/水,0.1%TFA)纯化。将含产物的级分在EtOAc和饱和碳酸氢钠之间分配,用盐水洗涤,经Na2SO4干燥并浓缩至干。将所得的残余物用EtOAc研磨并过滤,得到6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-丙氧基喹唑啉-4-胺(280mg,0.671mmol,16.87%产率),为白色固体。1HNMR(400MHz,DMSO-d6)δppm12.19(s,1H)10.36(s,1H)8.99(s,1H)8.45(s,1H)7.29(s,1H)4.17(t,J=6.19Hz,2H)2.18(s,3H)1.76-1.84(m,2H)1.74(s,3H)1.26-1.37(m,9H)1.07(t,J=7.45Hz,3H)。MS(m/z)418.3(M+H)+。
实施例4
6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-((四氢呋喃-2-基)甲氧基)喹唑啉-4-胺
向(四氢呋喃-2-基)甲醇(148mg,1.45mmol)在DMF(1mL)的溶液中加入KOtBu(163mg,1.45mmol)。将溶液在室温搅拌5分钟。然后加入6-(叔丁基磺酰基)-7-氯-N-(4,5-二甲基-1H吡唑-3-基)喹唑啉-4-胺(30mg,0.076mmol),并将反应混合物在80℃搅拌过夜。大部分DMF在真空中除去。将粗物质经Biotage柱(0至16%MeOH/DCM)纯化,得到6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-((四氢呋喃-2-基)甲氧基)喹唑啉-4-胺(40mg,0.084mmol,35%产率)。1HNMR(DMSO-d6)δ:12.19(br.s.,1H),10.36(br.s.,1H),8.99(s,1H),8.45(s,1H),7.34(s,1H),4.21(m,3H),3.77-3.87(m,1H),3.65-3.76(m,1H),2.18(s,3H),2.00(m,2H),1.79-1.90(m,2H),1.75(s,3H),1.32(s,9H)。MS(m/z)460。
药物组合物
实施例A
片剂使用常规方法制备,并配制如下:
实施例B
胶囊使用常规方法制备,并配制如下:
生物测定:
开发基于荧光偏振的结合测定法用于通过与荧光标记的ATP竞争性配体竞争,来定量新的测试化合物在RIPK2的ATP结合口袋的相互作用。将全长FLAGHis标记的RIPK2从杆状病毒表达系统中纯化,以两倍于表观KD的浓度将其用于最终测定。将荧光标记的配体(5-({[2-({[3-({4-[(5-羟基-2-甲基苯基)氨基]-2-嘧啶基}氨基)苯基]羰基}氨基)乙基]氨基}羰基)-2-(6-羟基-3-氧代-3H-夹氧杂蒽-9-基)苯甲酸,其按照WO2011/120025中描述的方法制备)用于最终测定,其最终测定浓度为5nM。酶和配体在50mMHEPESpH7.5、150mMNaCl、10mMMgCl2、1mMDTT和1mMCHAPS的溶液中制备。用100%DMSO制备测试化合物的溶液,向多孔板的各孔中加入100nL。之后,将5ulRIPK2加至测试化合物(浓度为最终测试浓度的两倍)中,在室温孵育10分钟。孵育之后,将5ul荧光标记的配体溶液加至各反应中,以两倍于最终测定浓度,室温孵育至少10分钟。最终,样品在能够测量荧光偏振的仪器上读取。测试化合物的抑制表示为相对于内部测定对照的抑制百分比(%)。
对于浓度/剂量响应实验,将标准化数据拟合,使用常规技术确定pIC50。求出pIC50的平均值以确定至少两个实验的平均值。
实施例编号 | pIC50 |
1 | 7.4 |
2 | 7.8 |
3 | 7.9 |
4 | 8.0 |
连续的测试导致实施例1(7.5)和实施例3(8.1)的化合物的pIC50的报告的平均值有轻微的改变。
FLAGHis标记的RIPK2的制备:
全长人RIPK2(受体-相互作用的丝氨酸-苏氨酸激酶2)cDNA购于Invitrogen(Carlsbad,California,USA,克隆编号:IOH6368,RIPK2-pENTR221)。根据Invitrogen描述的实验方案,将LR克隆用于位点特异性重组RIPK2下游至包含在目标载体pDEST8-FLAG-His6的N-末端的FLAG-6His。根据制造商的实验方案,利用(Invitrogen)实现转染入草地贪夜蛾(Spodopterafrugiperda,Sf9)昆虫细胞。
在27℃,80rpm,在摇瓶中,使Sf9细胞在Excell420(SAFCBiosciences,Lenexa,Kansas,US;Andover,HampshireUK)生长培养基中生长,直到有足够的体积来接种到生物反应器中。在27℃,30%溶解氧和60-140rpm搅动速率下,使细胞在50升工作容积的生物反应器(Applikon,FosterCity,California,US;Schiedam,Netherlands)中生长,直至达到所需的体积,其细胞浓度约为3.7xe6细胞/mL。用杆状病毒以12.7的感染复数(MOI)感染昆虫细胞。继续孵育43个小时的表达时相。利用Viafuge(Carr)以80升/小时的流速连续离心(以2500g),将感染的细胞从生长培养基中移出。将细胞沉淀物立即冷冻,之后用于纯化。
纯化操作I:将9.83x1010个昆虫细胞再悬浮于1.4L溶胞缓冲液(50mMTris(pH8.0)、150mMNaCl、0.5mMNaF、0.1%TritonX-100、1mL/升蛋白酶抑制剂组合物(ProteaseInhibitorCocktail)SetIII(购于EMDGroup;CalBiochem/MerckBiosciences,Gibbstown,NewJersey,US;Damstadt,Germany)并在冰上用Dounce匀浆法加工。然后将悬浮液在47,900g,4℃离心2小时使之变澄清。从不溶沉淀物中倾倒出细胞裂解物,并以线性流速16cm/h载样至55mLFLAG-M2亲和柱(2.6x10.4cm)上,其已用10个柱体积的缓冲液A(50mMTris(pH8.0)、150mMNaCl、0.5mMNaF、1mL/升蛋白酶抑制剂组合物SetIII)进行预平衡。然后将该柱用15个柱体积的缓冲液A洗涤,用6个柱体积的缓冲液B(缓冲液A+150μg/mL3XFLAG肽)以线性流速57cm/h进行洗脱。对于通过SDS-PAGE鉴定为含有目标蛋白的级分,利用10kDaMWCOSnakeSkinPleatedDialysisTubing用5L缓冲液A(不包含蛋白酶抑制剂组合物)进行透析过夜,从制品中除去3XFLAG肽。由纯化过程得到11.3mg的总蛋白,其通过凝胶光密度扫描法测得RIPK2以40%的纯度存在,并用肽质量指纹图谱确认。制品的主要污染蛋白鉴定为较低分子量的RIPK2降解产物。
纯化操作II:将100g细胞(10升的发酵规模)冷冻、解冻、再悬浮于1L溶胞缓冲液(50mMTrisHCLpH7.5、250mMNaCl、0.1mMTCEP、3ml蛋白酶抑制剂组合物)中并通过以10,000psi高压匀浆一次(Avestin)来溶胞。然后将悬浮液以35,000g在4℃离心45分钟以使之澄清。离心法收集上清液,用5ml抗FLAG-M2树脂孵育,该树脂用缓冲液A(50mMTrisHCLpH7.5、250mMNaCl、0.1mMTCEP)预平衡。在4℃进行蛋白结合1小时后,将树脂填充到两个一次性25ml柱中。每个柱用25ml缓冲液A进行洗涤,用10ml(缓冲液A+200ug/mlFlag肽)洗脱。将洗脱液浓缩至1ml,上样至superdex200(16/60)尺寸排阻色谱柱。根据SDS-PAGE分析结果,收集含全长RIPK2的级分。该纯化过程得到1.36mg/L80%纯度的RIPK2蛋白,并通过肽质量指纹谱进行确认。
生物测定:
开发胞壁酰二肽(MDP)刺激的人全血细胞因子,这是为了评价新试验化合物的细胞效力和效能。将从健康人类志愿者得到的肝素化血液(160μL)分配到多孔板的各个孔中。将试验化合物溶解于100%DMSO中并稀释于无钙的和无镁的D-PBS以制备10x操作母液。将20微升稀释的试验化合物加入每孔,并将板置于板振荡器(500rpm)上并在加湿的培养箱(37℃,5%CO2)中孵育30分钟。MDP的10倍操作母液制备于含有1%DMSO的无菌的,无内毒素的水中。将20微升的MDP母液加入每孔(终浓度=100ng/ml)以刺激RIP2激酶依赖性细胞因子的产生。DMSO的最终浓度在所有孔中为0.1%(v/v)。将板孵育另外6小时(如上所述)。然后将另外100μL的DPBS(Dulbecco氏磷酸盐缓冲盐水)加入孔,将板离心,回收上清液。使用市售免疫测定(MesoScaleDiscovery)定量上清液中的TNFα水平。将试验化合物抑制表示为内部检测对照的抑制的百分比(%)。对于浓度/剂量响应实验,拟合标准化数据,并使用常规技术测定pIC50。将pIC50平均以确定平均值,至少需2次实验。
实施例编号 | pIC50 |
1 | 7.4 |
2 | 7.2 |
3 | 7.0 |
4 | 7.2 |
体内生物测定-诱导的炎性响应的抑制
RIP2抑制剂的有效性也可在啮齿类动物体内进行评估。已证实小鼠腹膜内(i.p.)或静脉内(i.v.)给药L18-MDP可经过激活NOD2信号传导通路诱导炎性响应(Rosenweig,H.L.等,2008.JournalofLeukocyteBiology84:529-536)。利用常规技术,通过测量一种或多种细胞因子(IL8、TNFα、IL6和IL-1β)在血清和/或腹膜灌洗液中含量的增加和/或测量流入腹膜空间的中性粒细胞(当腹膜内给药L18-MDP时),监测经L18-MDP治疗的小鼠/大鼠的炎性响应水平。可通过以下证明在经治疗的大鼠中抑制L18-MDP诱导的炎性响应:对测试的化合物进行口服预先给药,然后利用常规技术测量并比较在血清中的一种或多种细胞因子水平(IL8、TNFα、IL6和IL-1β)以与经治疗的动物进行对照。
例如,对大鼠口服预先给药实施例2的化合物,6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,剂量为0、0.04、0.4和4mg/kg,之后给药L18-MDP(50μg/只大鼠)0.25h/min。从本研究所用大鼠体内采取的全血样品中,利用基于抗体的检测(Meso-ScaleDiscoveryplatform)对IL8细胞因子水平进行测量。IL8细胞因子响应计算为相对于媒介物治疗的小鼠观察到的响应而言对各剂量水平显示的平均响应,并且如附图2中所示,作为平均值±平均值的标准差(n=8只大鼠/组)。
体内生物测定-兔子心脏楔形制品
将体重2.2-3kg的雌兔用肝素抗凝并用戊巴比妥麻醉(50mg/kg,i.v.)。其胸部经由左侧开胸术打开,并将心脏离体,并放置于由冷的(4℃)标准台氏液组成的的心脏停搏液。跨壁楔具有约1.5cm宽,2-3cm长的尺寸,并从左心室解剖。
将楔形组织经左前降动脉或旋动脉插管并灌注心脏停搏液。然后,将制品放置于小的组织浴和动脉灌注台氏液中(T:35.7±0.1℃,灌注压:30-45mmHg)。心室楔形被允许平衡于组织浴中,直到电稳定,通常是一小时。使用在除了尖端都绝缘的双极银电极,在1000和2000毫秒的基础循环时间(BCL),刺激该制品,并将其施用于心内膜表面。
使用放置于台式液中的胞外银/氯化银电极对从心外膜表面和心内膜表面开始的制剂的1.0至1.5cm进行镀液(bathing),在所有实验中记录跨壁心电图(ECG),沿着相同的向量作为跨膜记录(外膜:“+”极)。在ECG上,跨壁复极离散度(TDR)可通过T波(Tp-e)的顶点与终点的间距定义。QT间期被定义为从QRS波开始到使T波的最终下坡越过等电位线的点的时间。QRS、QT和Tp-e持续时间通过10次扫描测量,且每次处理时,都将其平均。每次处理时,都平均动物的总群体数量的数据,并与平均对照值比较。等长收缩力产生(%ICF)通过10次扫描测量,且每次处理时,都将其平均。每次处理时,都平均动物的总群体数量的数据,并与平均对照值比较。
各试验化合物均制备于100%DMSO母液,浓度为30mM。将化合物稀释至在台氏缓冲液中测试的最高浓度(台式缓冲液含有(以mM计):29NaCl、4KCl、0.9NaH2PO4、20NaHCO3、1.8CaCl2、0.5MgSO4、和5.5葡萄糖,当用95%O2和5%CO2缓冲时,pH为7.4),至此制备后续系列稀释溶液。
各试验化合物在1-30μM的4种浓度测试。在将楔形制品灌注标准台氏液并在1000毫秒的BCL刺激一小时后,在记录其基线ECG和等长收缩力(ICF)后,刺激频率降低到2000毫秒的BCL,稳定5分钟。然后,将该制品返回至1000毫秒的BCL并灌注含有试验化合物的台氏液。对于每个测试化合物的浓度,楔形制品在1000毫秒的BCL灌注20分钟,然后在2000毫秒的BCL灌注5分钟,在其间记录ECG和ICF。实施例2的化合物(6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺)在兔子心脏楔形制品中评估。
楔形制品的四个主要示值读数包括QT间期延长、torsadogenicity(源自QT、Tp-e和早期后除极的TdP的分数)、脉冲传导(QRS相关)和收缩力,这些示于表2中。
将评分系统用于使用分离的兔左心室楔形制品估计化合物的相对TdP风险:QT间期的点、Tp-e/QT比值。TdP的分数是通过首先将QT间期和Tp-e/QT比值转化为从基线的%变化产生的。这些值被分别基于以下系统指定TdP的分数:-5%=-1、-5%至10%=0、10%至20%=1、20%至30%=2、>30%=3。总评分系统范围为-2至14,在BCL=2000ms的情况下。
表2.总结数据(平均值,n=2)。
对照 | 1μM | 3μM | 10μM | 30μM | |
QT(毫秒) | 335.5 | 346.4 | 351.9 | 348.8 | 348.8 |
ΔQT% | 3 | 4.8 | 4.0 | 4.0 | |
Tp-e(毫秒) | 70.8 | 71.9 | 73.2 | 68.4 | 69.1 |
QRS(毫秒) | 40.1 | 39.6 | 39.2 | 39.4 | 39.7 |
ICF(%变化) | -4.4 | -5.3 | -15.1 | -20.7 | |
致心律失常 | 0/2 | 0/2 | 0/2 | 0/2 | 0/2 |
TdP分数 | 0 | -0.50 | 0.00 | -0.50 | -0.50 |
QT=QT间期,Tp-e=跨壁离散度,ICF=收缩力。
激酶组选择性
实施例2的化合物(6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺)的激酶组选择性(通过ReactionBiologyCorporation,OneGreatValleyParkway,Malvern,PA,USA,19355,http://www.reactionbiology.com实施)通过针对含337个成员的激酶组(337memberkinasepanel)的体外概括确定。在1μM的浓度,实施例2的化合物表现出对337种测试的激酶中的1种的>70%抑制和对337种测试的激酶的4种的>50%抑制。
参考文献:WO2011/120025、WO2011/120026、WO2011/123609、WO2011/140442、WO2012/021580、WO2012/122011、WO2013/025958。
Claims (17)
1.化合物,其具有式:
或其盐。
2.化合物,其为6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺。
3.化合物,其为6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,或其药学上可接受的盐。
4.药物组合物,其包含6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺,或其药学上可接受的盐,和一种或多种药学上可接受的赋形剂。
5.药物组合物,其包含6-(叔丁基磺酰基)-N-(4,5-二甲基-1H-吡唑-3-基)-7-乙氧基喹唑啉-4-胺和一种或多种药学上可接受的赋形剂。
6.治疗RIP2激酶介导的疾病或病症的方法,其包含给药治疗有效量的权利要求2的化合物或其药学上可接受的盐于有此需要的人。
7.治疗RIP2激酶介导的疾病或病症的方法,其包含给药治疗有效量的权利要求3的化合物于有此需要的人。
8.权利要求2的化合物,或其药学上可接受的盐,用于治疗。
9.权利要求3的化合物,用于治疗。
10.权利要求2的化合物,或其药学上可接受的盐,用于治疗RIP2激酶介导的疾病或病症。
11.权利要求3的化合物,用于治疗RIP2激酶介导的疾病或病症。
12.权利要求2的化合物或其药学上可接受的盐在制备用于治疗RIP2激酶介导的疾病或病症的药物中的用途。
13.权利要求3的化合物在制备用于治疗RIP2激酶介导的疾病或病症的药物中的用途。
14.权利要求6或7的方法,其中所述疾病或病症选自葡萄膜炎、白介素-1转换酶相关的发热综合征、皮炎、急性肺损伤、2型糖尿病、关节炎、类风湿性关节炎、溃疡性结肠炎、节段性回肠炎、早发性炎性肠病、肠外炎性肠病、预防在实体器官移植中的缺血再灌注损伤、非酒精性脂肪肝、酒精性脂肪肝、自身免疫性肝炎、哮喘、移植物抗宿主疾病、系统性红斑狼疮、多发性硬化症、结节病、Blau综合征、早发性结节病、韦格纳肉芽肿病和间质性肺疾病。
15.权利要求10或11中任一项的化合物,或其药学上可接受的盐,其中所述疾病或病症选自葡萄膜炎、白介素-1转换酶相关的发热综合征、皮炎、急性肺损伤、2型糖尿病、关节炎、类风湿性关节炎、溃疡性结肠炎、节段性回肠炎、早发性炎性肠病、肠外炎性肠病、预防在实体器官移植中的缺血再灌注损伤、非酒精性脂肪肝、酒精性脂肪肝、自身免疫性肝炎、哮喘、移植物抗宿主疾病、系统性红斑狼疮、多发性硬化症、结节病、Blau综合征、早发性结节病、韦格纳肉芽肿病和间质性肺疾病。
16.权利要求6或7的方法,其中所述疾病或病症选自葡萄膜炎、白介素-1转换酶相关的发热综合征、Blau综合征、早发性结节病、溃疡性结肠炎、节段性回肠炎、韦格纳肉芽肿病和结节病。
17.权利要求10或11中任一项的化合物,或其药学上可接受的盐,其中所述疾病或病症选自葡萄膜炎、白介素-1转换酶相关的发热综合征、Blau综合征、早发性结节病、溃疡性结肠炎、节段性回肠炎、韦格纳肉芽肿病和结节病。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361767423P | 2013-02-21 | 2013-02-21 | |
US61/767,423 | 2013-02-21 | ||
PCT/IB2014/059094 WO2014128622A1 (en) | 2013-02-21 | 2014-02-19 | Quinazolines as kinase inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105143208A true CN105143208A (zh) | 2015-12-09 |
CN105143208B CN105143208B (zh) | 2017-09-26 |
Family
ID=50238430
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480009917.6A Expired - Fee Related CN105143208B (zh) | 2013-02-21 | 2014-02-19 | 作为激酶抑制剂的喹唑啉 |
Country Status (13)
Country | Link |
---|---|
US (1) | US9650364B2 (zh) |
EP (1) | EP2958911B1 (zh) |
JP (1) | JP6301374B2 (zh) |
KR (1) | KR20150118152A (zh) |
CN (1) | CN105143208B (zh) |
AR (1) | AR094707A1 (zh) |
AU (1) | AU2014220300B2 (zh) |
BR (1) | BR112015019624A2 (zh) |
CA (1) | CA2902132C (zh) |
ES (1) | ES2654100T3 (zh) |
RU (1) | RU2662810C2 (zh) |
TW (1) | TWI630203B (zh) |
WO (1) | WO2014128622A1 (zh) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2609578T3 (es) | 2011-03-04 | 2017-04-21 | Glaxosmithkline Intellectual Property Development Limited | Amino-quinolinas como inhibidores de quinasa |
TWI547494B (zh) | 2011-08-18 | 2016-09-01 | 葛蘭素史克智慧財產發展有限公司 | 作為激酶抑制劑之胺基喹唑啉類 |
TW201425307A (zh) | 2012-09-13 | 2014-07-01 | Glaxosmithkline Llc | 作為激酶抑制劑之胺基-喹啉類 |
AR092529A1 (es) | 2012-09-13 | 2015-04-22 | Glaxosmithkline Llc | Compuesto de aminoquinazolina, composicion farmaceutica que lo comprende y uso de dicho compuesto para la preparacion de un medicamento |
BR112015019624A2 (pt) | 2013-02-21 | 2017-07-18 | Glaxosmithkline Ip Dev Ltd | quinazolinas como inibidores de quinase |
GB201506872D0 (en) | 2015-04-22 | 2015-06-03 | Ge Oil & Gas Uk Ltd | Novel compounds |
GB201516243D0 (en) | 2015-09-14 | 2015-10-28 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
US10781205B2 (en) * | 2016-04-20 | 2020-09-22 | Glaxosmithkline Intellectual Property Development Limited | Conjugates comprising RIPK2 inhibitors |
CN112638905A (zh) * | 2018-08-28 | 2021-04-09 | 南京明德新药研发有限公司 | 作为rip2激酶抑制剂的喹唑啉类衍生物 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995015758A1 (en) * | 1993-12-10 | 1995-06-15 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit csf-1r receptor tyrosine kinase |
CN1620296A (zh) * | 2001-12-24 | 2005-05-25 | 阿斯特拉曾尼卡有限公司 | 作为Aurora激酶抑制剂的取代喹唑啉衍生物 |
CN101074227A (zh) * | 2002-12-24 | 2007-11-21 | 阿斯利康(瑞典)有限公司 | 膦酰氧基喹唑啉衍生物及其药物用途 |
US20120053183A1 (en) * | 2010-08-27 | 2012-03-01 | University Of The Pacific | Piperazinylpyrimidine analogues as protein kinase inhibitors |
WO2013025958A1 (en) * | 2011-08-18 | 2013-02-21 | Glaxo Group Limited | Amino quinazolines as kinase inhibitors |
Family Cites Families (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4916135A (en) | 1989-05-08 | 1990-04-10 | Hoechst Roussel Pharmaceuticals Inc. | N-heteroaryl-4-quinolinamines |
PT100905A (pt) | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | Compostos heterociclicos azotados biciclicos contendo aneis de benzeno, ciclo-hexano ou piridina e de pirimidina, piridina ou imidazol substituidos e composicoes farmaceuticas que os contem |
GB9300059D0 (en) | 1992-01-20 | 1993-03-03 | Zeneca Ltd | Quinazoline derivatives |
GB9510757D0 (en) | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
US6046206A (en) | 1995-06-07 | 2000-04-04 | Cell Pathways, Inc. | Method of treating a patient having a precancerous lesions with amide quinazoline derivatives |
ID19609A (id) | 1996-07-13 | 1998-07-23 | Glaxo Group Ltd | Senyawa-senyawa heterosiklik |
WO1998005647A1 (en) | 1996-08-01 | 1998-02-12 | Dow Agrosciences Llc | Quinolinium derivatives having fungicidal activity |
US6809097B1 (en) | 1996-09-25 | 2004-10-26 | Zeneca Limited | Quinoline derivatives inhibiting the effect of growth factors such as VEGF |
UA73073C2 (uk) | 1997-04-03 | 2005-06-15 | Уайт Холдінгз Корпорейшн | Заміщені 3-ціанохіноліни, спосіб їх одержання та фармацевтична композиція |
GB9800569D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
CN1158266C (zh) | 1998-10-01 | 2004-07-21 | 阿斯特拉曾尼卡有限公司 | 化合物 |
GB2345486A (en) | 1999-01-11 | 2000-07-12 | Glaxo Group Ltd | Heteroaromatic protein tyrosine kinase inhibitors |
ES2334879T3 (es) | 1999-09-21 | 2010-03-17 | Astrazeneca Ab | Derivados de quinazolina y su uso como productos farmaceuticos. |
US6977259B2 (en) | 2000-01-28 | 2005-12-20 | Astrazeneca Ab | Quinoline derivatives and their use as aurora 2 kinase inhibitors |
MXPA02007957A (es) | 2000-02-17 | 2002-11-29 | Amgen Inc | Inhibidores de cinasas. |
US6521618B2 (en) | 2000-03-28 | 2003-02-18 | Wyeth | 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors |
US6589758B1 (en) | 2000-05-19 | 2003-07-08 | Amgen Inc. | Crystal of a kinase-ligand complex and methods of use |
BR0113056A (pt) | 2000-08-09 | 2003-07-08 | Astrazeneca Ab | Composto, processo papa a preparação do mesmo, composição farmacêutica, e, método para produzir um efeito antiangiogênico e/ou redutor da permeabilidade vascular em um animal de sangue quente, e, uso de um composto |
US6548508B2 (en) | 2000-10-20 | 2003-04-15 | Pfizer, Inc. | Use of PDE V inhibitors for improved fecundity in mammals |
GB0104422D0 (en) | 2001-02-22 | 2001-04-11 | Glaxo Group Ltd | Quinoline derivative |
ATE325795T1 (de) | 2001-03-23 | 2006-06-15 | Bayer Corp | Rho-kinase inhibitoren |
JP4320705B2 (ja) | 2001-03-23 | 2009-08-26 | バイエル コーポレイション | Rhoキナーゼ阻害剤 |
SE0101675D0 (sv) | 2001-05-11 | 2001-05-11 | Astrazeneca Ab | Novel composition |
US7115617B2 (en) | 2001-08-22 | 2006-10-03 | Amgen Inc. | Amino-substituted pyrimidinyl derivatives and methods of use |
WO2003026665A1 (en) | 2001-09-26 | 2003-04-03 | Bayer Pharmaceuticals Corporation | 2-phenylamino-4-(5-pyrazolylamino)-pyrimidine derivatives as kinase inhibitors, in particular, src kinase inhibitors |
US7645878B2 (en) | 2002-03-22 | 2010-01-12 | Bayer Healthcare Llc | Process for preparing quinazoline Rho-kinase inhibitors and intermediates thereof |
TWI275390B (en) | 2002-04-30 | 2007-03-11 | Wyeth Corp | Process for the preparation of 7-substituted-3- quinolinecarbonitriles |
AU2003255482A1 (en) * | 2002-10-02 | 2004-04-23 | Merck Patent Gmbh | Use of 4 amino-quinazolines as anti cancer agents |
AU2003286711A1 (en) | 2002-10-25 | 2004-05-13 | Vertex Pharmaceuticals Incorporated | Indazolinone compositions useful as kinase inhibitors |
US20040122161A1 (en) | 2002-12-21 | 2004-06-24 | Paul Charles W. | Hot melt adhesive based on acrylic block copolymers |
ATE438644T1 (de) * | 2002-12-24 | 2009-08-15 | Astrazeneca Ab | Chinazolinderivate |
TWI328009B (en) | 2003-05-21 | 2010-08-01 | Glaxo Group Ltd | Quinoline derivatives as phosphodiesterase inhibitors |
MXPA05012839A (es) | 2003-05-27 | 2006-05-17 | Pfizer Prod Inc | Quinazolinas y pirido[3,4-d] pirimidinas como inhibidores de receptores tirosina quinasa. |
NZ544472A (en) | 2003-07-03 | 2009-04-30 | Myriad Genetics Inc | Compounds and therapeutical use thereof |
SI1667991T1 (sl) | 2003-09-16 | 2008-10-31 | Astrazeneca Ab | Kinazolinski derivati kot inhibitorji tirozin kinaze |
SI2392564T1 (sl) | 2003-09-26 | 2014-02-28 | Exelixis, Inc. | c-Met modulatorji in postopki uporabe |
AU2004309166B2 (en) | 2003-12-23 | 2008-02-21 | Pfizer Inc. | Novel quinoline derivatives |
JPWO2005090332A1 (ja) | 2004-03-23 | 2008-01-31 | 萬有製薬株式会社 | 置換キナゾリン又はピリドピリミジン誘導体 |
WO2005115145A2 (en) | 2004-05-20 | 2005-12-08 | Wyeth | Quinone substituted quinazoline and quinoline kinase inhibitors |
CA2567080A1 (en) | 2004-05-27 | 2005-12-15 | Vertex Pharmaceuticals Incorporated | Ice inhibitors for the treatment of autoinflammatory diseases |
CA2569404A1 (en) | 2004-06-04 | 2005-12-22 | Amphora Discovery Corporation | Quinoline- and isoquinoline-based compounds exhibiting atp-utilizing enzyme inhibitory activity, and compositions, and uses thereof |
FR2873695A1 (fr) | 2004-07-30 | 2006-02-03 | Palumed Sa | Molecules hybrides qa ou q est une aminoquinoleine et a est un antibiotique ou un inhibiteur de resistance), leur synthese et leurs utilisations en tant qu'agent antibacterien |
MX2007005408A (es) * | 2004-11-09 | 2007-05-16 | Hoffmann La Roche | Compuestos de aminoquinazolinas. |
JP4988592B2 (ja) | 2004-12-22 | 2012-08-01 | バイエル ファーマ アクチエンゲゼルシャフト | キノリン誘導体、その使用、製造およびそれを含む医薬剤 |
US8258145B2 (en) | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
WO2006108059A1 (en) | 2005-04-06 | 2006-10-12 | Exelixis, Inc. | C-met modulators and methods of use |
JO2787B1 (en) | 2005-04-27 | 2014-03-15 | امجين إنك, | Alternative amide derivatives and methods of use |
EP1746096A1 (en) | 2005-07-15 | 2007-01-24 | 4Sc Ag | 2-Arylbenzothiazole analogues and uses thereof in the treatment of cancer |
ITMI20052008A1 (it) | 2005-10-21 | 2007-04-22 | Ctg Pharma S R L | Nuovi antimalarici derivati della 4-aminochinolina |
FR2902100A1 (fr) | 2006-06-13 | 2007-12-14 | Sanofi Aventis Sa | Molecules duales contenant un derive peroxydique, leur synthese et leurs applications en therapeutique |
US7511063B2 (en) | 2006-08-16 | 2009-03-31 | Schering Corporation | High affinity quinoline-based kinase ligands |
JP2008063278A (ja) | 2006-09-07 | 2008-03-21 | Fujifilm Finechemicals Co Ltd | 1−ピリジン−4−イル−インドール類の製造方法 |
WO2008033749A2 (en) | 2006-09-11 | 2008-03-20 | Curis, Inc. | Quinazoline based egfr inhibitors containing a zinc binding moiety |
AU2007296745B2 (en) | 2006-09-11 | 2011-12-01 | Curis, Inc. | Quinazoline based EGFR inhibitors |
JP2010502743A (ja) | 2006-09-11 | 2010-01-28 | キュリス,インコーポレイテッド | 抗増殖薬剤としての多機能性低分子 |
TW200829555A (en) | 2006-11-10 | 2008-07-16 | Astrazeneca Ab | Chemical compounds |
US8163923B2 (en) | 2007-03-14 | 2012-04-24 | Advenchen Laboratories, Llc | Spiro substituted compounds as angiogenesis inhibitors |
US8148532B2 (en) | 2007-03-14 | 2012-04-03 | Guoqing Paul Chen | Spiro substituted compounds as angiogenesis inhibitors |
US20080234267A1 (en) | 2007-03-20 | 2008-09-25 | Karen Elizabeth Lackey | Compounds and Methods of Treatment |
WO2008119771A2 (en) | 2007-03-30 | 2008-10-09 | Clanotech Ab | Quinoline-s-carboxylic acid derivatives as tyrosine kinase inhibitors |
MY153427A (en) | 2007-04-23 | 2015-02-13 | Sanofi Aventis | Quinoline-carboxamide derivatives as p2y12 antagonists |
PE20090717A1 (es) | 2007-05-18 | 2009-07-18 | Smithkline Beecham Corp | Derivados de quinolina como inhibidores de la pi3 quinasa |
EP2777704A3 (en) | 2007-06-01 | 2015-01-21 | Wyeth LLC | Treatment of imatinib resistant leukemia using 4-aminoquinoline-3-carbonitriles |
CN101362719B (zh) | 2007-08-06 | 2012-04-18 | 北京师范大学 | 喹啉类衍生物以及包含其的组合物 |
US7939546B2 (en) | 2007-10-12 | 2011-05-10 | Supergen, Inc. | Quinoline derivatives for modulating DNA methylation |
US7790746B2 (en) | 2007-10-12 | 2010-09-07 | Supergen, Inc. | Quinoline derivatives for modulating DNA methylation |
EP2072502A1 (de) | 2007-12-20 | 2009-06-24 | Bayer Schering Pharma Aktiengesellschaft | Sulfoximid-substituierte Chinolin- und Chinazolinderivate als Kinase-Inhibitoren |
GB0801416D0 (en) | 2008-01-25 | 2008-03-05 | Piramed Ltd | Pharmaceutical compounds |
TW200940064A (en) | 2008-03-06 | 2009-10-01 | Genentech Inc | Combination therapy with C-MET and EGFR antagonists |
CA2739302A1 (en) | 2008-10-17 | 2010-04-22 | Brendan C. Bender | Treatment method |
DE102008062566A1 (de) | 2008-12-16 | 2010-06-17 | Bayer Schering Pharma Aktiengesellschaft | Aminosäureester-Prodrugs und ihre Verwendung |
PH12012500097A1 (en) | 2009-07-21 | 2011-01-27 | Shanghai Inst Organic Chem | Potent small molecule inhibitors of autophagy, and methods of use thereof |
WO2011112588A2 (en) | 2010-03-08 | 2011-09-15 | Case Western Reserve University | Compositions and methods for treating inflammatory disorders |
EP2552214A4 (en) * | 2010-03-26 | 2013-10-16 | Glaxo Group Ltd | PYRAZOLYL-PYRIMIDINES AS KINASE INHIBITORS |
WO2011120025A1 (en) | 2010-03-26 | 2011-09-29 | Glaxo Group Limited | Indazolyl-pyrimidines as kinase inhibitors |
JP2013523766A (ja) | 2010-03-31 | 2013-06-17 | グラクソ グループ リミテッド | キナーゼ阻害剤としてのイミダゾリル‐イミダゾール |
EP2566477B1 (en) | 2010-05-07 | 2015-09-02 | GlaxoSmithKline Intellectual Property Development Limited | Amino-quinolines as kinase inhibitors |
UY33549A (es) | 2010-08-10 | 2012-01-31 | Glaxo Group Ltd | Quinolil aminas como agentes inhibidores de las quinasas |
AU2012223639B2 (en) | 2011-02-28 | 2015-03-19 | Sunshine Lake Pharma Co., Ltd. | Substituted quinoline compounds and methods of use |
ES2609578T3 (es) | 2011-03-04 | 2017-04-21 | Glaxosmithkline Intellectual Property Development Limited | Amino-quinolinas como inhibidores de quinasa |
AR092529A1 (es) | 2012-09-13 | 2015-04-22 | Glaxosmithkline Llc | Compuesto de aminoquinazolina, composicion farmaceutica que lo comprende y uso de dicho compuesto para la preparacion de un medicamento |
TW201425307A (zh) | 2012-09-13 | 2014-07-01 | Glaxosmithkline Llc | 作為激酶抑制劑之胺基-喹啉類 |
BR112015019624A2 (pt) | 2013-02-21 | 2017-07-18 | Glaxosmithkline Ip Dev Ltd | quinazolinas como inibidores de quinase |
-
2014
- 2014-02-19 BR BR112015019624A patent/BR112015019624A2/pt not_active Application Discontinuation
- 2014-02-19 TW TW103105395A patent/TWI630203B/zh not_active IP Right Cessation
- 2014-02-19 EP EP14708681.3A patent/EP2958911B1/en active Active
- 2014-02-19 AR ARP140100520A patent/AR094707A1/es unknown
- 2014-02-19 RU RU2015139758A patent/RU2662810C2/ru not_active IP Right Cessation
- 2014-02-19 CN CN201480009917.6A patent/CN105143208B/zh not_active Expired - Fee Related
- 2014-02-19 KR KR1020157022263A patent/KR20150118152A/ko not_active Application Discontinuation
- 2014-02-19 CA CA2902132A patent/CA2902132C/en not_active Expired - Fee Related
- 2014-02-19 WO PCT/IB2014/059094 patent/WO2014128622A1/en active Application Filing
- 2014-02-19 AU AU2014220300A patent/AU2014220300B2/en not_active Ceased
- 2014-02-19 JP JP2015558582A patent/JP6301374B2/ja not_active Expired - Fee Related
- 2014-02-19 US US14/762,905 patent/US9650364B2/en active Active
- 2014-02-19 ES ES14708681.3T patent/ES2654100T3/es active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995015758A1 (en) * | 1993-12-10 | 1995-06-15 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit csf-1r receptor tyrosine kinase |
CN1620296A (zh) * | 2001-12-24 | 2005-05-25 | 阿斯特拉曾尼卡有限公司 | 作为Aurora激酶抑制剂的取代喹唑啉衍生物 |
CN101074227A (zh) * | 2002-12-24 | 2007-11-21 | 阿斯利康(瑞典)有限公司 | 膦酰氧基喹唑啉衍生物及其药物用途 |
US20120053183A1 (en) * | 2010-08-27 | 2012-03-01 | University Of The Pacific | Piperazinylpyrimidine analogues as protein kinase inhibitors |
WO2013025958A1 (en) * | 2011-08-18 | 2013-02-21 | Glaxo Group Limited | Amino quinazolines as kinase inhibitors |
Also Published As
Publication number | Publication date |
---|---|
ES2654100T3 (es) | 2018-02-12 |
CA2902132C (en) | 2020-09-22 |
AR094707A1 (es) | 2015-08-19 |
CA2902132A1 (en) | 2014-08-28 |
WO2014128622A1 (en) | 2014-08-28 |
RU2015139758A (ru) | 2017-03-24 |
BR112015019624A2 (pt) | 2017-07-18 |
TWI630203B (zh) | 2018-07-21 |
EP2958911A1 (en) | 2015-12-30 |
AU2014220300A1 (en) | 2015-08-06 |
CN105143208B (zh) | 2017-09-26 |
AU2014220300B2 (en) | 2016-10-13 |
US20150361069A1 (en) | 2015-12-17 |
JP6301374B2 (ja) | 2018-03-28 |
US9650364B2 (en) | 2017-05-16 |
TW201444824A (zh) | 2014-12-01 |
RU2662810C2 (ru) | 2018-07-31 |
JP2016509051A (ja) | 2016-03-24 |
KR20150118152A (ko) | 2015-10-21 |
EP2958911B1 (en) | 2017-10-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105143208A (zh) | 作为激酶抑制剂的喹唑啉 | |
KR102483876B1 (ko) | 아미노 피리미딘 ssao 억제제 | |
CN105121432B (zh) | 作为激酶抑制剂的杂环酰胺 | |
BRPI0609650A2 (pt) | inibidores heterobicìlicos de hvc | |
EA035116B1 (ru) | 7-(тиазол-5-ил)пирролопиримидин в качестве агониста рецептора tlr7 | |
BR112014030577B1 (pt) | Dihidronaftiridinas e compostos relacionados, bem como composições farmacêuticas compreendendo os mesmos | |
CN103857288A (zh) | 作为激酶抑制剂的氨基-喹啉 | |
CN104854101A (zh) | Alk激酶抑制剂 | |
CN104302292A (zh) | 表现出抗癌和抗增殖活性的吡啶酮酰胺以及类似物 | |
US10231973B2 (en) | Salts of quinazoline derivative and method for preparing the same | |
EP0443568A1 (en) | Fused thiophene derivatives, their production and use | |
CN109516999A (zh) | 用作蛋白质激酶调节剂的化合物及其应用 | |
CN104797581A (zh) | 杂芳基炔烃化合物及其应用 | |
CN104619327A (zh) | 作为激酶抑制剂的氨基喹唑啉的前药 | |
KR102418211B1 (ko) | 일시적 수용체 전위 a1 이온 채널의 억제 | |
EP3661935B1 (en) | Substituted pyrazolopyrimidines useful as kinases inhibitors | |
CN1893944B (zh) | 具有抗增殖活性的3-氰基喹啉衍生物 | |
WO2018157737A1 (zh) | 一种多靶点激酶抑制剂 | |
AU2015263980A1 (en) | NAMPT inhibitors and methods | |
CN111362924B (zh) | 氘代的嘧啶衍生物及其用途 | |
CN104788423B (zh) | 一种新的囊性纤维化跨膜传导调节因子抑制剂 | |
CN111566102B (zh) | 作为激活素受体样激酶抑制剂的取代的吡咯并吡啶 | |
EP3632912B1 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
WO2024055994A1 (zh) | 萘并呋喃取代的戊二酰亚胺类化合物的晶型、制备方法及其应用 | |
CN110092799B (zh) | 一种环状化合物、其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170926 Termination date: 20220219 |