JP2000502050A - メタロプロテアーゼ阻害剤としての新規なマクロ環状化合物 - Google Patents
メタロプロテアーゼ阻害剤としての新規なマクロ環状化合物Info
- Publication number
- JP2000502050A JP2000502050A JP9519119A JP51911997A JP2000502050A JP 2000502050 A JP2000502050 A JP 2000502050A JP 9519119 A JP9519119 A JP 9519119A JP 51911997 A JP51911997 A JP 51911997A JP 2000502050 A JP2000502050 A JP 2000502050A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- aryl
- oxa
- oxo
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000002678 macrocyclic compounds Chemical class 0.000 title description 6
- 239000003475 metalloproteinase inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 299
- 238000000034 method Methods 0.000 claims abstract description 95
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 29
- 108010003059 aggrecanase Proteins 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- -1 branched Chemical group 0.000 claims description 245
- 125000000217 alkyl group Chemical group 0.000 claims description 156
- 125000003118 aryl group Chemical group 0.000 claims description 140
- 229910052739 hydrogen Inorganic materials 0.000 claims description 131
- 239000001257 hydrogen Substances 0.000 claims description 123
- 229910052736 halogen Inorganic materials 0.000 claims description 120
- 150000002367 halogens Chemical class 0.000 claims description 120
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 103
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 91
- 125000003545 alkoxy group Chemical group 0.000 claims description 88
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 78
- 125000004442 acylamino group Chemical group 0.000 claims description 73
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 60
- ATHHXGZTWNVVOU-UHFFFAOYSA-N monomethyl-formamide Natural products CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims description 57
- 150000001408 amides Chemical class 0.000 claims description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 49
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 49
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 47
- 125000004122 cyclic group Chemical group 0.000 claims description 46
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- 150000003857 carboxamides Chemical class 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 42
- SOWBFZRMHSNYGE-UHFFFAOYSA-N oxamic acid Chemical compound NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 claims description 41
- 125000005110 aryl thio group Chemical group 0.000 claims description 40
- 125000004104 aryloxy group Chemical group 0.000 claims description 40
- 241001024304 Mino Species 0.000 claims description 38
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
- 125000004429 atom Chemical group 0.000 claims description 36
- KDGKTJGPFXIBEB-UHFFFAOYSA-N n-hydroxyformamide Chemical compound ONC=O KDGKTJGPFXIBEB-UHFFFAOYSA-N 0.000 claims description 36
- 125000001769 aryl amino group Chemical group 0.000 claims description 35
- 150000003839 salts Chemical group 0.000 claims description 35
- 229920006395 saturated elastomer Polymers 0.000 claims description 35
- 125000004414 alkyl thio group Chemical group 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 125000004432 carbon atom Chemical group C* 0.000 claims description 33
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 28
- 229940124530 sulfonamide Drugs 0.000 claims description 27
- 150000003456 sulfonamides Chemical class 0.000 claims description 27
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 26
- 125000002883 imidazolyl group Chemical group 0.000 claims description 25
- 239000000651 prodrug Chemical group 0.000 claims description 24
- 229940002612 prodrug Drugs 0.000 claims description 24
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 24
- 241000124008 Mammalia Species 0.000 claims description 23
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- 125000001041 indolyl group Chemical group 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 125000003107 substituted aryl group Chemical group 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 238000006467 substitution reaction Methods 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 16
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 14
- 229960003104 ornithine Drugs 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 13
- OOLUVSIJOMLOCB-UHFFFAOYSA-N 1633-22-3 Chemical compound C1CC(C=C2)=CC=C2CCC2=CC=C1C=C2 OOLUVSIJOMLOCB-UHFFFAOYSA-N 0.000 claims description 12
- 125000004001 thioalkyl group Chemical group 0.000 claims description 12
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 10
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 210000000845 cartilage Anatomy 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- UUYDPHCMCYSNAY-UHFFFAOYSA-N 2-amino-n-methylacetamide Chemical compound CNC(=O)CN UUYDPHCMCYSNAY-UHFFFAOYSA-N 0.000 claims description 8
- 239000004471 Glycine Substances 0.000 claims description 8
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 8
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 8
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 8
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- MMNTZXRQPVRSSO-UHFFFAOYSA-N sulfamoylformic acid Chemical compound NS(=O)(=O)C(O)=O MMNTZXRQPVRSSO-UHFFFAOYSA-N 0.000 claims description 8
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 241000257303 Hymenoptera Species 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 5
- VGWQYIYHHIAZNH-UHFFFAOYSA-N Cl.C1CCCCCCCCCCCCC1 Chemical compound Cl.C1CCCCCCCCCCCCC1 VGWQYIYHHIAZNH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052770 Uranium Inorganic materials 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 4
- 230000015271 coagulation Effects 0.000 claims description 4
- 238000005345 coagulation Methods 0.000 claims description 4
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- FWHFRDUWGWUPOC-UHFFFAOYSA-N 2-amino-n-pyridin-2-ylacetamide Chemical compound NCC(=O)NC1=CC=CC=N1 FWHFRDUWGWUPOC-UHFFFAOYSA-N 0.000 claims description 3
- BFJOJIJWHRDGQO-UHFFFAOYSA-N 3-amino-n-methylpropanamide Chemical compound CNC(=O)CCN BFJOJIJWHRDGQO-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 3
- 229960001153 serine Drugs 0.000 claims description 3
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 claims description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-O guanidinium Chemical compound NC(N)=[NH2+] ZRALSGWEFCBTJO-UHFFFAOYSA-O 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 20
- 239000003937 drug carrier Substances 0.000 claims 10
- 102100036601 Aggrecan core protein Human genes 0.000 claims 1
- 108010067219 Aggrecans Proteins 0.000 claims 1
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 claims 1
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 claims 1
- 101000823100 Homo sapiens Putative alpha-1-antitrypsin-related protein Proteins 0.000 claims 1
- 102100022709 Putative alpha-1-antitrypsin-related protein Human genes 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 229940054066 benzamide antipsychotics Drugs 0.000 claims 1
- 150000003936 benzamides Chemical class 0.000 claims 1
- 125000004965 chloroalkyl group Chemical group 0.000 claims 1
- 230000001112 coagulating effect Effects 0.000 claims 1
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- 238000007689 inspection Methods 0.000 claims 1
- 238000012544 monitoring process Methods 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- 102000005741 Metalloproteases Human genes 0.000 abstract description 23
- 108010006035 Metalloproteases Proteins 0.000 abstract description 23
- 108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 20
- 239000003112 inhibitor Substances 0.000 abstract description 14
- 230000006378 damage Effects 0.000 abstract description 10
- 102000003390 tumor necrosis factor Human genes 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 245
- 239000000243 solution Substances 0.000 description 216
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 187
- 239000000047 product Substances 0.000 description 158
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 157
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 144
- 239000002253 acid Substances 0.000 description 121
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 117
- 235000019439 ethyl acetate Nutrition 0.000 description 91
- 238000003756 stirring Methods 0.000 description 91
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 89
- 230000002829 reductive effect Effects 0.000 description 76
- 238000010168 coupling process Methods 0.000 description 75
- 238000005859 coupling reaction Methods 0.000 description 75
- 239000012267 brine Substances 0.000 description 74
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 74
- 230000008878 coupling Effects 0.000 description 72
- 239000000463 material Substances 0.000 description 72
- 239000000203 mixture Substances 0.000 description 71
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
- 239000011541 reaction mixture Substances 0.000 description 67
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 61
- 239000007787 solid Substances 0.000 description 55
- 239000003039 volatile agent Substances 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 53
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 52
- 150000002431 hydrogen Chemical class 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 229910052763 palladium Inorganic materials 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- 238000010511 deprotection reaction Methods 0.000 description 38
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 36
- 238000005984 hydrogenation reaction Methods 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 33
- 229910002027 silica gel Inorganic materials 0.000 description 33
- 239000003054 catalyst Substances 0.000 description 32
- 238000004587 chromatography analysis Methods 0.000 description 32
- 229940024606 amino acid Drugs 0.000 description 31
- 235000001014 amino acid Nutrition 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 30
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 30
- 150000001413 amino acids Chemical class 0.000 description 29
- 239000003480 eluent Substances 0.000 description 28
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 27
- 239000002904 solvent Substances 0.000 description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 25
- 239000012317 TBTU Substances 0.000 description 24
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 238000000746 purification Methods 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 239000004472 Lysine Substances 0.000 description 22
- 239000000543 intermediate Substances 0.000 description 22
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 21
- 239000012298 atmosphere Substances 0.000 description 21
- 235000008504 concentrate Nutrition 0.000 description 21
- 239000012141 concentrate Substances 0.000 description 21
- 125000003396 thiol group Chemical class [H]S* 0.000 description 21
- 238000005710 macrocyclization reaction Methods 0.000 description 20
- 238000010898 silica gel chromatography Methods 0.000 description 20
- 239000006260 foam Substances 0.000 description 18
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 16
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 206010003246 arthritis Diseases 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 14
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 238000007327 hydrogenolysis reaction Methods 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 238000004007 reversed phase HPLC Methods 0.000 description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 10
- 230000029936 alkylation Effects 0.000 description 10
- 238000005804 alkylation reaction Methods 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 9
- 125000002619 bicyclic group Chemical group 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 235000018977 lysine Nutrition 0.000 description 9
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 9
- 150000003141 primary amines Chemical class 0.000 description 9
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 150000003951 lactams Chemical class 0.000 description 8
- 125000004076 pyridyl group Chemical group 0.000 description 8
- 150000003335 secondary amines Chemical class 0.000 description 8
- 239000012265 solid product Substances 0.000 description 8
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 7
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
- C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
- C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D419/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US668495P | 1995-11-14 | 1995-11-14 | |
US64690296A | 1996-05-08 | 1996-05-08 | |
US74343996A | 1996-11-01 | 1996-11-01 | |
US08/743,439 | 1996-11-01 | ||
US60/646,902 | 1996-11-01 | ||
US60/006,684 | 1996-11-01 | ||
PCT/US1996/018382 WO1997018207A2 (fr) | 1995-11-14 | 1996-11-13 | Nouveaux composes macrocycliques tenant lieu d'inhibiteurs de la metalloprotease |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2000502050A true JP2000502050A (ja) | 2000-02-22 |
Family
ID=27358171
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP9519119A Pending JP2000502050A (ja) | 1995-11-14 | 1996-11-13 | メタロプロテアーゼ阻害剤としての新規なマクロ環状化合物 |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP0863885A2 (fr) |
JP (1) | JP2000502050A (fr) |
CN (1) | CN1202161A (fr) |
BR (1) | BR9611563A (fr) |
CA (1) | CA2237524A1 (fr) |
CZ (1) | CZ144798A3 (fr) |
EE (1) | EE9800115A (fr) |
HR (1) | HRP960533A2 (fr) |
HU (1) | HUP0201479A2 (fr) |
IL (1) | IL124366A0 (fr) |
LV (1) | LV12167B (fr) |
MX (1) | MX9803851A (fr) |
NO (1) | NO982185L (fr) |
PL (1) | PL326714A1 (fr) |
SI (1) | SI9620120A (fr) |
SK (1) | SK63498A3 (fr) |
WO (1) | WO1997018207A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005044780A1 (fr) * | 2003-11-10 | 2005-05-19 | Kyorin Pharmaceutical Co., Ltd. | Derive d'acide aminocarboxylique, son sel d'addition et agent de regulation du recepteur s1p |
US8476305B2 (en) | 2008-02-07 | 2013-07-02 | Kyorin Pharmaceutical Co., Ltd. | Therapeutic agent or prophylactic agent for inflammatory bowel disease comprising amino alcohol derivative as active ingredient |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6281352B1 (en) * | 1995-11-14 | 2001-08-28 | Dupont Pharmaceuticals Company | Macrocyclic compounds as metalloprotease inhibitors |
ZA9820B (en) * | 1997-01-07 | 1998-07-02 | Abbott Lab | Macrocyclic inhibitors of matrix metalloproteinases and tnf x secretion |
US5952320A (en) * | 1997-01-07 | 1999-09-14 | Abbott Laboratories | Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion |
US5985911A (en) * | 1997-01-07 | 1999-11-16 | Abbott Laboratories | C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion |
SK13952000A3 (sk) | 1998-03-31 | 2001-12-03 | Dupont Pharmaceuticals Company | Farmaceutické zlúčeniny na zobrazovanie porúch angiogenézy |
US6548663B1 (en) | 1998-03-31 | 2003-04-15 | Bristol-Myers Squibb Pharma Company | Benzodiazepine vitronectin receptor antagonist pharmaceuticals |
US6537520B1 (en) | 1998-03-31 | 2003-03-25 | Bristol-Myers Squibb Pharma Company | Pharmaceuticals for the imaging of angiogenic disorders |
US6524553B2 (en) | 1998-03-31 | 2003-02-25 | Bristol-Myers Squibb Pharma Company | Quinolone vitronectin receptor antagonist pharmaceuticals |
WO1999064406A1 (fr) | 1998-06-11 | 1999-12-16 | Du Pont Pharmaceuticals Company | Procede de preparation d'inhibiteurs macrocycliques des metalloproteases |
NZ525513A (en) | 1998-08-07 | 2004-09-24 | Pont Pharmaceuticals Du | Succinoylamino lactams as inhibitors of Abeta protein production |
HRP990246A2 (en) | 1998-08-07 | 2000-06-30 | Du Pont Pharm Co | Succinoylamino benzodiazepines as inhibitors of a beta protein production |
US6511649B1 (en) | 1998-12-18 | 2003-01-28 | Thomas D. Harris | Vitronectin receptor antagonist pharmaceuticals |
US6569402B1 (en) | 1998-12-18 | 2003-05-27 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
BR9917079A (pt) | 1998-12-18 | 2001-10-30 | Du Pont Pharm Co | Compostos antagonistas de receptor devitronectina, kit, composição metalofarmacêuticade diagnóstico ou terapêutica, composição deagente de contraste para ultra-som, composiçãoradiofarmacêutica terapêutica, composiçãofarmacêutica de diagnóstico, método detratamento da artrite reumatóide, do cancêr e darestenose em um paciente, método de formação deimagem da angiogênese terapêutica, do câncer, denovos vasos sanguìneos, da arteriosclerose, darestenose, da isquemia e da lesão por reperfusãodo miocárdio em um paciente |
US6794518B1 (en) | 1998-12-18 | 2004-09-21 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6288261B1 (en) | 1998-12-18 | 2001-09-11 | Abbott Laboratories | Inhibitors of matrix metalloproteinases |
CA2349333A1 (fr) | 1998-12-18 | 2000-06-22 | Du Pont Pharmaceuticals Company | Medicaments antagonistes du recepteur de la vitronectine |
US6649377B1 (en) | 1999-05-10 | 2003-11-18 | Syntex (U.S.A.) Llc | Human aggrecanase and nucleic acid compositions encoding the same |
US6808902B1 (en) | 1999-11-12 | 2004-10-26 | Amgen Inc. | Process for correction of a disulfide misfold in IL-1Ra Fc fusion molecules |
US6989139B2 (en) * | 2000-02-15 | 2006-01-24 | Bristol-Myers Squibb Pharma Company | Matrix metalloproteinase inhibitors |
EP1268450A1 (fr) | 2000-06-01 | 2003-01-02 | Bristol-Myers Squibb Pharma Company | Lactames substitues par des succinates cycliques en tant qu'inhibiteurs de la production de la proteine beta |
TR201809008T4 (tr) | 2001-06-26 | 2018-07-23 | Amgen Fremont Inc | Opgl ye karşi antikorlar. |
PE20030701A1 (es) | 2001-12-20 | 2003-08-21 | Schering Corp | Compuestos para el tratamiento de trastornos inflamatorios |
US7491794B2 (en) | 2003-10-14 | 2009-02-17 | Intermune, Inc. | Macrocyclic compounds as inhibitors of viral replication |
EP2543368A1 (fr) | 2007-12-11 | 2013-01-09 | Viamet Pharmaceuticals, Inc. | Inhibiteurs de métalloenzymes utilisant des fractions de liaison à un métal en combinaison avec des fractions de ciblage |
WO2010132494A1 (fr) * | 2009-05-11 | 2010-11-18 | Ghosh Arun K | Composés et méthodes utilisables dans le cadre du traitement du sida et des infections par le vih |
PL2710018T3 (pl) | 2011-05-19 | 2022-04-04 | Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) | Związki makrocykliczne jako inhibitory kinaz białkowych |
CN102276546B (zh) * | 2011-05-31 | 2014-06-25 | 中国科学院广州生物医药与健康研究院 | 用作蛋白聚糖酶调节剂的化合物及其应用 |
CN108623530B (zh) * | 2016-09-18 | 2021-05-11 | 广西师范大学 | 1,2,8-氧代二氮杂环壬-9-硫酮衍生物及其合成方法和应用 |
JP2022512584A (ja) | 2018-10-04 | 2022-02-07 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 角皮症を処置するためのegfrインヒビター |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9102635D0 (en) * | 1991-02-07 | 1991-03-27 | British Bio Technology | Compounds |
US5427954A (en) * | 1992-04-29 | 1995-06-27 | Shriner's Hospitals For Crippled Children | Compositions and methods for detection and treatment of human osteoarthritis |
-
1996
- 1996-11-13 SI SI9620120A patent/SI9620120A/sl unknown
- 1996-11-13 CN CN96198327A patent/CN1202161A/zh active Pending
- 1996-11-13 BR BR9611563A patent/BR9611563A/pt not_active IP Right Cessation
- 1996-11-13 EP EP96943497A patent/EP0863885A2/fr not_active Withdrawn
- 1996-11-13 CZ CZ981447A patent/CZ144798A3/cs unknown
- 1996-11-13 SK SK634-98A patent/SK63498A3/sk unknown
- 1996-11-13 CA CA002237524A patent/CA2237524A1/fr not_active Abandoned
- 1996-11-13 JP JP9519119A patent/JP2000502050A/ja active Pending
- 1996-11-13 PL PL96326714A patent/PL326714A1/xx unknown
- 1996-11-13 HR HR08/743,439A patent/HRP960533A2/hr not_active Application Discontinuation
- 1996-11-13 WO PCT/US1996/018382 patent/WO1997018207A2/fr not_active Application Discontinuation
- 1996-11-13 IL IL12436696A patent/IL124366A0/xx unknown
- 1996-11-13 EE EE9800115A patent/EE9800115A/xx unknown
- 1996-11-13 HU HU0201479A patent/HUP0201479A2/hu unknown
-
1998
- 1998-05-13 NO NO982185A patent/NO982185L/no unknown
- 1998-05-14 MX MX9803851A patent/MX9803851A/es unknown
- 1998-07-07 LV LVP-98-104A patent/LV12167B/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005044780A1 (fr) * | 2003-11-10 | 2005-05-19 | Kyorin Pharmaceutical Co., Ltd. | Derive d'acide aminocarboxylique, son sel d'addition et agent de regulation du recepteur s1p |
US8476305B2 (en) | 2008-02-07 | 2013-07-02 | Kyorin Pharmaceutical Co., Ltd. | Therapeutic agent or prophylactic agent for inflammatory bowel disease comprising amino alcohol derivative as active ingredient |
Also Published As
Publication number | Publication date |
---|---|
MX9803851A (es) | 1998-09-30 |
NO982185D0 (no) | 1998-05-13 |
IL124366A0 (en) | 1998-12-06 |
BR9611563A (pt) | 1999-03-02 |
EE9800115A (et) | 1998-10-15 |
CZ144798A3 (cs) | 1998-10-14 |
NO982185L (no) | 1998-07-13 |
SI9620120A (sl) | 1999-06-30 |
HUP0201479A2 (en) | 2002-08-28 |
EP0863885A2 (fr) | 1998-09-16 |
LV12167A (lv) | 1998-11-20 |
HRP960533A2 (en) | 1998-04-30 |
WO1997018207A3 (fr) | 1997-07-24 |
CN1202161A (zh) | 1998-12-16 |
SK63498A3 (en) | 1999-01-11 |
CA2237524A1 (fr) | 1997-05-22 |
PL326714A1 (en) | 1998-10-26 |
WO1997018207A2 (fr) | 1997-05-22 |
LV12167B (en) | 1999-03-20 |
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