SI9620120A - Nove makrociklične spojine kot metaloproteazni inhibitorji - Google Patents
Nove makrociklične spojine kot metaloproteazni inhibitorji Download PDFInfo
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- SI9620120A SI9620120A SI9620120A SI9620120A SI9620120A SI 9620120 A SI9620120 A SI 9620120A SI 9620120 A SI9620120 A SI 9620120A SI 9620120 A SI9620120 A SI 9620120A SI 9620120 A SI9620120 A SI 9620120A
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- SI
- Slovenia
- Prior art keywords
- alkyl
- aryl
- oxa
- hydroxycarboxamide
- oxo
- Prior art date
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- 150000002678 macrocyclic compounds Chemical class 0.000 title claims description 18
- 239000003475 metalloproteinase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 284
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 20
- 108010003059 aggrecanase Proteins 0.000 claims abstract description 18
- 239000003112 inhibitor Substances 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 232
- -1 branched Chemical group 0.000 claims description 220
- 125000003118 aryl group Chemical group 0.000 claims description 143
- 229910052739 hydrogen Inorganic materials 0.000 claims description 143
- 239000001257 hydrogen Substances 0.000 claims description 114
- 125000003545 alkoxy group Chemical group 0.000 claims description 107
- 125000001424 substituent group Chemical group 0.000 claims description 102
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 88
- 125000005843 halogen group Chemical group 0.000 claims description 87
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 86
- 125000004442 acylamino group Chemical group 0.000 claims description 85
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 85
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 70
- 125000005518 carboxamido group Chemical group 0.000 claims description 61
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 52
- 125000005110 aryl thio group Chemical group 0.000 claims description 51
- KDGKTJGPFXIBEB-UHFFFAOYSA-N n-hydroxyformamide Chemical compound ONC=O KDGKTJGPFXIBEB-UHFFFAOYSA-N 0.000 claims description 50
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 49
- 125000000753 cycloalkyl 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
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 46
- 125000004001 thioalkyl group Chemical group 0.000 claims description 46
- 125000004122 cyclic group Chemical group 0.000 claims description 45
- 150000001408 amides Chemical class 0.000 claims description 43
- 125000004432 carbon atom Chemical group C* 0.000 claims description 43
- 125000001041 indolyl group Chemical group 0.000 claims description 43
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 40
- 125000004414 alkyl thio group Chemical group 0.000 claims description 40
- 125000001769 aryl amino group Chemical group 0.000 claims description 40
- 125000004104 aryloxy group Chemical group 0.000 claims description 40
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 40
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 40
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 40
- 125000004429 atom Chemical group 0.000 claims description 36
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 229910052760 oxygen Inorganic materials 0.000 claims description 32
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 30
- 229940002612 prodrug Drugs 0.000 claims description 30
- 239000000651 prodrug Substances 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 29
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 27
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 27
- 229920006395 saturated elastomer Polymers 0.000 claims description 27
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 25
- 125000005842 heteroatom Chemical group 0.000 claims description 24
- 241000124008 Mammalia Species 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 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000002883 imidazolyl group Chemical group 0.000 claims description 20
- 229940124530 sulfonamide Drugs 0.000 claims description 20
- 150000003456 sulfonamides Chemical class 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 15
- UUYDPHCMCYSNAY-UHFFFAOYSA-N 2-amino-n-methylacetamide Chemical compound CNC(=O)CN UUYDPHCMCYSNAY-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
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 13
- 229960003104 ornithine Drugs 0.000 claims description 11
- 125000006527 (C1-C5) alkyl group Chemical group 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 10
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000003107 substituted aryl group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 230000003278 mimic effect Effects 0.000 claims description 9
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 9
- CKQYFZPCICOPMQ-VKHMYHEASA-N (2s)-2-amino-n-methylpropanamide Chemical compound CNC(=O)[C@H](C)N CKQYFZPCICOPMQ-VKHMYHEASA-N 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
- 125000005205 alkoxycarbonyloxyalkyl group Chemical group 0.000 claims description 8
- 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 claims description 8
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- CKQYFZPCICOPMQ-GSVOUGTGSA-N (2r)-2-amino-n-methylpropanamide Chemical compound CNC(=O)[C@@H](C)N CKQYFZPCICOPMQ-GSVOUGTGSA-N 0.000 claims description 6
- OOLUVSIJOMLOCB-UHFFFAOYSA-N 1633-22-3 Chemical compound C1CC(C=C2)=CC=C2CCC2=CC=C1C=C2 OOLUVSIJOMLOCB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 6
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 5
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 5
- 210000000845 cartilage Anatomy 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 5
- 229960001153 serine Drugs 0.000 claims description 5
- PZVHMLQLXAUQGY-LURJTMIESA-N (2s)-2,6-diamino-n-methylhexanamide Chemical compound CNC(=O)[C@@H](N)CCCCN PZVHMLQLXAUQGY-LURJTMIESA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-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
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 4
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- PJZBXYKLDPBGFD-GSVOUGTGSA-N (2R)-2-amino-3-hydroxy-N-methylpropanamide Chemical compound CNC(=O)[C@H](N)CO PJZBXYKLDPBGFD-GSVOUGTGSA-N 0.000 claims description 3
- PJZBXYKLDPBGFD-VKHMYHEASA-N (2s)-2-amino-3-hydroxy-n-methylpropanamide Chemical compound CNC(=O)[C@@H](N)CO PJZBXYKLDPBGFD-VKHMYHEASA-N 0.000 claims description 3
- OKTIZBDONHCJEL-YFKPBYRVSA-N (2s)-2-amino-n,3-dimethylbutanamide Chemical compound CNC(=O)[C@@H](N)C(C)C OKTIZBDONHCJEL-YFKPBYRVSA-N 0.000 claims description 3
- KNVRBEGQERGQRP-UHFFFAOYSA-N 2-amino-n,n-dimethylacetamide Chemical compound CN(C)C(=O)CN KNVRBEGQERGQRP-UHFFFAOYSA-N 0.000 claims description 3
- 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
- 239000004471 Glycine Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 3
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- KSYTYCZOPVNULI-YFKPBYRVSA-N (2s)-2,5-diamino-n-methylpentanamide Chemical compound CNC(=O)[C@@H](N)CCCN KSYTYCZOPVNULI-YFKPBYRVSA-N 0.000 claims description 2
- WUJWXVYSWIYZOV-UHFFFAOYSA-N 2-amino-n-morpholin-4-ylacetamide Chemical compound NCC(=O)NN1CCOCC1 WUJWXVYSWIYZOV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 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
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 230000002255 enzymatic effect Effects 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- RCLLXVFAYTWDIQ-UHFFFAOYSA-N n-hydroxyformamide;hydrochloride Chemical compound Cl.ONC=O RCLLXVFAYTWDIQ-UHFFFAOYSA-N 0.000 claims description 2
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 10
- 150000003857 carboxamides Chemical class 0.000 claims 2
- 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 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 238000001514 detection method Methods 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- 238000012544 monitoring process Methods 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 68
- 102000005741 Metalloproteases Human genes 0.000 abstract description 19
- 108010006035 Metalloproteases Proteins 0.000 abstract description 19
- 108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 5
- 230000008354 tissue degradation Effects 0.000 abstract description 3
- 102000003390 tumor necrosis factor Human genes 0.000 abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 234
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 231
- 239000000243 solution Substances 0.000 description 205
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 195
- 239000000047 product Substances 0.000 description 143
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 139
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 124
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 120
- 239000002253 acid Substances 0.000 description 104
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 87
- 235000019439 ethyl acetate Nutrition 0.000 description 87
- 230000002829 reductive effect Effects 0.000 description 81
- 238000006243 chemical reaction Methods 0.000 description 80
- 239000012267 brine Substances 0.000 description 74
- 239000000463 material Substances 0.000 description 74
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 74
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 74
- 238000003756 stirring Methods 0.000 description 74
- 230000008878 coupling Effects 0.000 description 72
- 238000010168 coupling process Methods 0.000 description 72
- 238000005859 coupling reaction Methods 0.000 description 72
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 72
- 239000000203 mixture Substances 0.000 description 58
- 239000007787 solid Substances 0.000 description 54
- 239000003039 volatile agent Substances 0.000 description 52
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 51
- 150000002431 hydrogen Chemical class 0.000 description 50
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 47
- 229910052763 palladium Inorganic materials 0.000 description 42
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 39
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 238000007327 hydrogenolysis reaction Methods 0.000 description 34
- 229940024606 amino acid Drugs 0.000 description 33
- 235000001014 amino acid Nutrition 0.000 description 33
- 238000005984 hydrogenation reaction Methods 0.000 description 33
- 239000003054 catalyst Substances 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 30
- 229910002027 silica gel Inorganic materials 0.000 description 30
- 150000001413 amino acids Chemical class 0.000 description 29
- 239000002904 solvent Substances 0.000 description 28
- 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 26
- 238000000746 purification Methods 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 238000005710 macrocyclization reaction Methods 0.000 description 22
- 239000012317 TBTU Substances 0.000 description 21
- 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 21
- 239000000543 intermediate Substances 0.000 description 21
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- 238000010511 deprotection reaction Methods 0.000 description 17
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 17
- 239000006260 foam Substances 0.000 description 16
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
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- 239000008346 aqueous phase Substances 0.000 description 12
- 206010003246 arthritis Diseases 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 12
- 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 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 11
- 239000004472 Lysine Substances 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 150000003141 primary amines Chemical class 0.000 description 11
- 238000004007 reversed phase HPLC Methods 0.000 description 11
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 11
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 229940124597 therapeutic agent Drugs 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 9
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- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
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- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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]
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- 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)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (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 (4)
| 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 | |
| PCT/US1996/018382 WO1997018207A2 (en) | 1995-11-14 | 1996-11-13 | Novel macrocyclic compounds as metalloprotease inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SI9620120A true SI9620120A (sl) | 1999-06-30 |
Family
ID=27358171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI9620120A SI9620120A (sl) | 1995-11-14 | 1996-11-13 | Nove makrociklične spojine kot metaloproteazni inhibitorji |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0863885A2 (cs) |
| JP (1) | JP2000502050A (cs) |
| CN (1) | CN1202161A (cs) |
| BR (1) | BR9611563A (cs) |
| CA (1) | CA2237524A1 (cs) |
| CZ (1) | CZ144798A3 (cs) |
| EE (1) | EE9800115A (cs) |
| HR (1) | HRP960533A2 (cs) |
| HU (1) | HUP0201479A2 (cs) |
| IL (1) | IL124366A0 (cs) |
| LV (1) | LV12167B (cs) |
| MX (1) | MX9803851A (cs) |
| NO (1) | NO982185L (cs) |
| PL (1) | PL326714A1 (cs) |
| SI (1) | SI9620120A (cs) |
| SK (1) | SK63498A3 (cs) |
| WO (1) | WO1997018207A2 (cs) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US6281352B1 (en) | 1995-11-14 | 2001-08-28 | Dupont Pharmaceuticals Company | Macrocyclic compounds as metalloprotease inhibitors |
| US5985911A (en) * | 1997-01-07 | 1999-11-16 | Abbott Laboratories | C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion |
| US5952320A (en) * | 1997-01-07 | 1999-09-14 | Abbott Laboratories | Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion |
| ZA9820B (en) * | 1997-01-07 | 1998-07-02 | Abbott Lab | Macrocyclic inhibitors of matrix metalloproteinases and tnf x secretion |
| US6537520B1 (en) | 1998-03-31 | 2003-03-25 | Bristol-Myers Squibb Pharma Company | Pharmaceuticals for the imaging of angiogenic disorders |
| US6548663B1 (en) | 1998-03-31 | 2003-04-15 | Bristol-Myers Squibb Pharma Company | Benzodiazepine vitronectin receptor antagonist pharmaceuticals |
| ES2241313T3 (es) | 1998-03-31 | 2005-10-16 | Bristol-Myers Squibb Pharma Company | Compuestos farmaceuticos para la formacion de imagenes de trastornos angiogenicos. |
| US6524553B2 (en) | 1998-03-31 | 2003-02-25 | Bristol-Myers Squibb Pharma Company | Quinolone vitronectin receptor antagonist pharmaceuticals |
| US6307044B1 (en) | 1998-06-11 | 2001-10-23 | Dupont Pharmaceuticals Company | Process for the preparation of macrocyclic metalloprotease inhibitors |
| 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 |
| US6569402B1 (en) | 1998-12-18 | 2003-05-27 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
| EP1140204A2 (en) | 1998-12-18 | 2001-10-10 | Du Pont Pharmaceuticals Company | Vitronectin receptor antagonist pharmaceuticals |
| US6511649B1 (en) | 1998-12-18 | 2003-01-28 | Thomas D. Harris | Vitronectin receptor antagonist pharmaceuticals |
| US6288261B1 (en) | 1998-12-18 | 2001-09-11 | Abbott Laboratories | Inhibitors of matrix metalloproteinases |
| US6794518B1 (en) | 1998-12-18 | 2004-09-21 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
| EP1140864A2 (en) | 1998-12-18 | 2001-10-10 | Du Pont Pharmaceuticals Company | Vitronectin receptor antagonist pharmaceuticals |
| 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 |
| BR0106717A (pt) | 2000-06-01 | 2002-04-16 | Bristol Myers Squibb Pharma Co | Compostos, composição farmacêutica e usos dos compostos de lactama inovadora |
| DE60235989D1 (de) | 2001-06-26 | 2010-05-27 | Amgen Fremont Inc | Antikörper gegen opgl |
| 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 |
| WO2005044780A1 (ja) * | 2003-11-10 | 2005-05-19 | Kyorin Pharmaceutical Co., Ltd. | アミノカルボン酸誘導体とその付加塩及びs1p受容体調節剤 |
| US20110015158A1 (en) | 2007-12-11 | 2011-01-20 | Viamet Pharmaceuticals, Inc. | Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties |
| TW200946105A (en) | 2008-02-07 | 2009-11-16 | Kyorin Seiyaku Kk | Therapeutic agent or preventive agent for inflammatory bowel disease containing amino alcohol derivative as active ingredient |
| EP2429290B1 (en) * | 2009-05-11 | 2014-01-01 | Purdue Research Foundation | Compounds and methods for treating aids and hiv infections |
| CA2872979C (en) * | 2011-05-19 | 2020-02-18 | Joaquin Pastor Fernandez | Macrocyclic compounds as protein kinase inhibitors |
| 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 |
| CN108752286B (zh) * | 2016-09-18 | 2021-05-11 | 广西师范大学 | 1,2,8-氧代二氮杂环壬烷衍生物及其合成方法和应用 |
| AU2019352741A1 (en) | 2018-10-04 | 2021-05-06 | Assistance Publique-Hôpitaux De Paris (Aphp) | EGFR inhibitors for treating keratodermas |
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| 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 |
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1996
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- 1996-11-13 HU HU0201479A patent/HUP0201479A2/hu unknown
- 1996-11-13 PL PL96326714A patent/PL326714A1/xx unknown
- 1996-11-13 CN CN96198327A patent/CN1202161A/zh active Pending
- 1996-11-13 CA CA002237524A patent/CA2237524A1/en not_active Abandoned
- 1996-11-13 SI SI9620120A patent/SI9620120A/sl unknown
- 1996-11-13 HR HR08/743,439A patent/HRP960533A2/hr not_active Application Discontinuation
- 1996-11-13 JP JP9519119A patent/JP2000502050A/ja active Pending
- 1996-11-13 BR BR9611563A patent/BR9611563A/pt not_active IP Right Cessation
- 1996-11-13 EP EP96943497A patent/EP0863885A2/en not_active Withdrawn
- 1996-11-13 EE EE9800115A patent/EE9800115A/xx 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
Also Published As
| Publication number | Publication date |
|---|---|
| SK63498A3 (en) | 1999-01-11 |
| EP0863885A2 (en) | 1998-09-16 |
| HRP960533A2 (en) | 1998-04-30 |
| PL326714A1 (en) | 1998-10-26 |
| CZ144798A3 (cs) | 1998-10-14 |
| IL124366A0 (en) | 1998-12-06 |
| JP2000502050A (ja) | 2000-02-22 |
| HUP0201479A2 (en) | 2002-08-28 |
| WO1997018207A3 (en) | 1997-07-24 |
| WO1997018207A2 (en) | 1997-05-22 |
| LV12167A (lv) | 1998-11-20 |
| LV12167B (en) | 1999-03-20 |
| BR9611563A (pt) | 1999-03-02 |
| CN1202161A (zh) | 1998-12-16 |
| NO982185L (no) | 1998-07-13 |
| NO982185D0 (no) | 1998-05-13 |
| EE9800115A (et) | 1998-10-15 |
| MX9803851A (es) | 1998-09-30 |
| CA2237524A1 (en) | 1997-05-22 |
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