HRP980096A2 - Reverse hydroxamate derivatives as matrix metalloprotease inhibitors, metalloprotease inhibitors, and tnf alpha inhibitors - Google Patents
Reverse hydroxamate derivatives as matrix metalloprotease inhibitors, metalloprotease inhibitors, and tnf alpha inhibitorsInfo
- Publication number
- HRP980096A2 HRP980096A2 HR60/039,112A HRP980096A HRP980096A2 HR P980096 A2 HRP980096 A2 HR P980096A2 HR P980096 A HRP980096 A HR P980096A HR P980096 A2 HRP980096 A2 HR P980096A2
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- mmol
- propyl
- acid
- alkyl
- Prior art date
Links
- 239000011159 matrix material Substances 0.000 title claims description 23
- 239000003475 metalloproteinase inhibitor Substances 0.000 title description 4
- 230000002441 reversible effect Effects 0.000 title description 3
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 title 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 title 1
- -1 heterocyclylene Chemical group 0.000 claims description 295
- 125000000217 alkyl group Chemical group 0.000 claims description 138
- 150000001875 compounds Chemical class 0.000 claims description 129
- 229910052760 oxygen Inorganic materials 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 58
- 125000002947 alkylene group Chemical group 0.000 claims description 50
- 125000004450 alkenylene group Chemical group 0.000 claims description 48
- 125000004419 alkynylene group Chemical group 0.000 claims description 48
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 48
- 125000003342 alkenyl group Chemical group 0.000 claims description 47
- 125000000304 alkynyl group Chemical group 0.000 claims description 45
- 150000001408 amides Chemical class 0.000 claims description 45
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 43
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
- 150000002148 esters Chemical class 0.000 claims description 41
- 125000005724 cycloalkenylene group Chemical group 0.000 claims description 38
- 125000005549 heteroarylene group Chemical group 0.000 claims description 37
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 125000000732 arylene group Chemical group 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 29
- 239000003153 chemical reaction reagent Substances 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 239000000651 prodrug Substances 0.000 claims description 21
- 229940002612 prodrug Drugs 0.000 claims description 21
- 230000005764 inhibitory process Effects 0.000 claims description 20
- 239000012453 solvate Substances 0.000 claims description 20
- 102000005741 Metalloproteases Human genes 0.000 claims description 19
- 108010006035 Metalloproteases Proteins 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 102000018697 Membrane Proteins Human genes 0.000 claims description 12
- 108010052285 Membrane Proteins Proteins 0.000 claims description 12
- 206010012601 diabetes mellitus Diseases 0.000 claims description 9
- 206010027476 Metastases Diseases 0.000 claims description 8
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 8
- 229910005965 SO 2 Inorganic materials 0.000 claims description 7
- 230000001413 cellular effect Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 206010003246 arthritis Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 5
- 230000004614 tumor growth Effects 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 101100173726 Arabidopsis thaliana OR23 gene Proteins 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- 108091008648 NR7C Proteins 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 185
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 158
- 239000000203 mixture Substances 0.000 description 136
- 239000000243 solution Substances 0.000 description 131
- 238000005160 1H NMR spectroscopy Methods 0.000 description 117
- 235000019439 ethyl acetate Nutrition 0.000 description 117
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 104
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 100
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 92
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 88
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 85
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 235000002639 sodium chloride Nutrition 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 74
- 238000006243 chemical reaction Methods 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 72
- 239000003921 oil Substances 0.000 description 69
- 235000019198 oils Nutrition 0.000 description 69
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
- 229920006395 saturated elastomer Polymers 0.000 description 65
- 239000002904 solvent Substances 0.000 description 63
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 62
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 59
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 56
- 230000002829 reductive effect Effects 0.000 description 56
- 239000007787 solid Substances 0.000 description 56
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 55
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 54
- 229910052938 sodium sulfate Inorganic materials 0.000 description 53
- 235000011152 sodium sulphate Nutrition 0.000 description 53
- 239000011780 sodium chloride Substances 0.000 description 49
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 48
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 45
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 45
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- 239000000741 silica gel Substances 0.000 description 43
- 229910002027 silica gel Inorganic materials 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 40
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 125000001424 substituent group Chemical group 0.000 description 34
- 238000010828 elution Methods 0.000 description 32
- 238000000746 purification Methods 0.000 description 31
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 30
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 30
- 229910052717 sulfur Inorganic materials 0.000 description 29
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 27
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 27
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 27
- 235000019341 magnesium sulphate Nutrition 0.000 description 27
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 25
- 239000002585 base Substances 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 23
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- 238000006467 substitution reaction Methods 0.000 description 22
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 235000019441 ethanol Nutrition 0.000 description 20
- 239000000284 extract Substances 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- 125000003545 alkoxy group Chemical group 0.000 description 19
- 239000012043 crude product Substances 0.000 description 19
- 229910052736 halogen Inorganic materials 0.000 description 19
- 150000002367 halogens Chemical group 0.000 description 19
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 19
- 239000011368 organic material Substances 0.000 description 19
- 239000011734 sodium Substances 0.000 description 19
- 229910000029 sodium carbonate Inorganic materials 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- 125000004647 alkyl sulfenyl group Chemical group 0.000 description 17
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 17
- 125000004414 alkyl thio group Chemical group 0.000 description 17
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- 125000004093 cyano group Chemical group *C#N 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
- 238000004587 chromatography analysis Methods 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
- 125000004043 oxo group Chemical group O=* 0.000 description 16
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 14
- 108090000790 Enzymes Proteins 0.000 description 14
- 229940088598 enzyme Drugs 0.000 description 14
- 239000006260 foam Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 14
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- NLXXVSKHVGDQAT-UHFFFAOYSA-N o-(oxan-2-yl)hydroxylamine Chemical compound NOC1CCCCO1 NLXXVSKHVGDQAT-UHFFFAOYSA-N 0.000 description 12
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- VNXQBJKYPLKUST-ZCFIWIBFSA-N (2s)-2-amino-3,3-dimethyl-n-(1,3-thiazol-2-yl)butanamide Chemical compound CC(C)(C)[C@H](N)C(=O)NC1=NC=CS1 VNXQBJKYPLKUST-ZCFIWIBFSA-N 0.000 description 10
- 102100027995 Collagenase 3 Human genes 0.000 description 10
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 10
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- DYSXHOANOMCTFU-ZDUSSCGKSA-N benzyl n-[(5s)-5-amino-6-oxo-6-(1,3,4-thiadiazol-2-ylamino)hexyl]carbamate Chemical compound C([C@H](N)C(=O)NC=1SC=NN=1)CCCNC(=O)OCC1=CC=CC=C1 DYSXHOANOMCTFU-ZDUSSCGKSA-N 0.000 description 9
- 229940043279 diisopropylamine Drugs 0.000 description 9
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- PVHOFKGGCRXPBM-AWEZNQCLSA-N benzyl n-[(5s)-5-amino-6-oxo-6-(1,3-thiazol-2-ylamino)hexyl]carbamate Chemical compound C([C@H](N)C(=O)NC=1SC=CN=1)CCCNC(=O)OCC1=CC=CC=C1 PVHOFKGGCRXPBM-AWEZNQCLSA-N 0.000 description 8
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 101100422872 Arabidopsis thaliana SWEET8 gene Proteins 0.000 description 7
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- 101100118563 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPG1 gene Proteins 0.000 description 7
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- 230000004071 biological effect Effects 0.000 description 7
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- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 6
- SNDPXSYFESPGGJ-UHFFFAOYSA-N 2-aminopentanoic acid Chemical compound CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 6
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- ORWKVZNEPHTCQE-UHFFFAOYSA-N acetic formic anhydride Chemical compound CC(=O)OC=O ORWKVZNEPHTCQE-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 6
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- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
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- 238000002474 experimental method Methods 0.000 description 6
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- OMSUIQOIVADKIM-UHFFFAOYSA-N rac-3-Hydroxybutyric acid ethyl ester Natural products CCOC(=O)CC(C)O OMSUIQOIVADKIM-UHFFFAOYSA-N 0.000 description 1
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- 239000001632 sodium acetate Substances 0.000 description 1
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- 229940005550 sodium alginate Drugs 0.000 description 1
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- ABBQHOQBGMUPJH-UHFFFAOYSA-N sodium;2-hydroxybenzoic acid Chemical compound [Na+].OC(=O)C1=CC=CC=C1O ABBQHOQBGMUPJH-UHFFFAOYSA-N 0.000 description 1
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- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
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- 210000001179 synovial fluid Anatomy 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- 235000010487 tragacanth Nutrition 0.000 description 1
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- 230000037317 transdermal delivery Effects 0.000 description 1
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- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
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- 238000009736 wetting Methods 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940006486 zinc cation Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 239000011686 zinc sulphate Substances 0.000 description 1
- 235000009529 zinc sulphate Nutrition 0.000 description 1
- 230000004572 zinc-binding Effects 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- 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
- 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Detergent Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3911297P | 1997-02-26 | 1997-02-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
HRP980096A2 true HRP980096A2 (en) | 1998-12-31 |
Family
ID=21903750
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HR60/039,112A HRP980096A2 (en) | 1997-02-26 | 1998-02-24 | Reverse hydroxamate derivatives as matrix metalloprotease inhibitors, metalloprotease inhibitors, and tnf alpha inhibitors |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP1019386A1 (ja) |
JP (1) | JP2001513767A (ja) |
KR (1) | KR20000075681A (ja) |
AP (1) | AP9901631A0 (ja) |
AR (1) | AR013070A1 (ja) |
AU (1) | AU6822398A (ja) |
BR (1) | BR9807763A (ja) |
CA (1) | CA2281664A1 (ja) |
HR (1) | HRP980096A2 (ja) |
IS (1) | IS5159A (ja) |
NO (1) | NO994103L (ja) |
PE (1) | PE59199A1 (ja) |
PL (1) | PL335378A1 (ja) |
TR (1) | TR199902063T2 (ja) |
WO (1) | WO1998038179A1 (ja) |
ZA (1) | ZA981532B (ja) |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
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US6294573B1 (en) | 1997-08-06 | 2001-09-25 | Abbott Laboratories | Reverse hydroxamate inhibitors of matrix metalloproteinases |
US6235786B1 (en) | 1997-08-06 | 2001-05-22 | Abbott Laboratories | Reverse hydroxamate inhibitors of matrix metalloproteinases |
PL194240B1 (pl) | 1998-02-07 | 2007-05-31 | British Biotech Pharm | Zastosowanie pochodnych N-formylohydroksyloaminy i amidowa pochodna N-formylohydroksyloaminy |
GB9818621D0 (en) * | 1998-08-26 | 1998-10-21 | Glaxo Group Ltd | Formamide compounds as therapeutic agents |
EP1121118A4 (en) * | 1998-08-26 | 2002-09-11 | Glaxo Group Ltd | FORMAMIDE-BASED THERAPEUTIC AGENTS |
AU5688999A (en) * | 1998-08-26 | 2000-03-21 | Glaxo Group Limited | Formamide compounds as therapeutic agents |
US6288261B1 (en) | 1998-12-18 | 2001-09-11 | Abbott Laboratories | Inhibitors of matrix metalloproteinases |
US6329550B1 (en) | 1998-12-31 | 2001-12-11 | Aventis Pharmaceuticals Inc. | Amidomalonamides useful as inhibitors of MMP of matrix metalloproteinase |
GB9918869D0 (en) * | 1999-08-10 | 1999-10-13 | British Biotech Pharm | Antibacterial agents |
JP2003081838A (ja) * | 2001-09-11 | 2003-03-19 | Rohto Pharmaceut Co Ltd | グルコサミン製剤 |
EP2319518A1 (en) | 2002-02-04 | 2011-05-11 | ALFAMA-Investigacao e Desenvolvimento de Produtos Farmaceuticos Lda. | Use of CO-releasing compounds for the manufacture of a medicament for the treatment of inflammatory diseases |
CA2515534A1 (en) * | 2003-02-11 | 2004-08-26 | Boehringer Ingelheim International Gmbh | New pharmaceutical compositions based on anticholinergics and tace-inhibitors |
EP1993583A4 (en) * | 2006-02-09 | 2010-06-23 | Burnham Inst | INHIBITORS OF MEMBRANE TYPE 1 TYPE MATRIX METALLOPROTEINASE FOR THE TREATMENT OF SUGAR DIABETES DEPENDING ON INSULIN |
JP2011517313A (ja) | 2007-12-11 | 2011-06-02 | ビアメト ファーマシューティカルズ,インク. | 金属結合部分を標的化部分と組み合わせて使用する金属酵素阻害剤 |
CA2719745C (en) | 2008-03-25 | 2016-07-05 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
ATE541832T1 (de) | 2009-04-14 | 2012-02-15 | Affectis Pharmaceuticals Ag | Neuartige p2x7r-antagonisten und ihre verwendung |
WO2012110190A1 (en) | 2011-02-17 | 2012-08-23 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
PT2699242T (pt) | 2011-04-19 | 2018-01-22 | Alfama Inc | Moléculas de libertação de monóxido de carbono e utilizações das mesmas |
WO2012163792A1 (en) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
WO2012163456A1 (en) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
WO2013013179A1 (en) | 2011-07-21 | 2013-01-24 | Alfama, Inc. | Ruthenium carbon monoxide releasing molecules and uses thereof |
BR112021006407A8 (pt) | 2018-10-04 | 2022-12-06 | Inst Nat Sante Rech Med | uso de inibidores do egfr para ceratodermas |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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GB9223904D0 (en) * | 1992-11-13 | 1993-01-06 | British Bio Technology | Inhibition of cytokine production |
US6037472A (en) * | 1993-11-04 | 2000-03-14 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
EP0740652B1 (en) * | 1994-01-20 | 1998-05-06 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
GB9514867D0 (en) * | 1995-07-20 | 1995-09-20 | British Biotech Pharm | Metalloproteinase inhibitors |
HUP9903863A3 (en) * | 1995-11-23 | 2000-11-28 | British Biotech Pharm | Metalloproteinase inhibitors |
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1998
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- 1998-02-24 WO PCT/EP1998/001015 patent/WO1998038179A1/en not_active Application Discontinuation
- 1998-02-24 PL PL98335378A patent/PL335378A1/xx unknown
- 1998-02-24 AU AU68223/98A patent/AU6822398A/en not_active Abandoned
- 1998-02-24 JP JP53728498A patent/JP2001513767A/ja active Pending
- 1998-02-24 HR HR60/039,112A patent/HRP980096A2/hr not_active Application Discontinuation
- 1998-02-24 CA CA002281664A patent/CA2281664A1/en not_active Abandoned
- 1998-02-24 BR BR9807763-5A patent/BR9807763A/pt not_active Application Discontinuation
- 1998-02-24 KR KR1019997007747A patent/KR20000075681A/ko not_active Application Discontinuation
- 1998-02-24 AP APAP/P/1999/001631A patent/AP9901631A0/en unknown
- 1998-02-24 EP EP98913575A patent/EP1019386A1/en not_active Withdrawn
- 1998-02-24 TR TR1999/02063T patent/TR199902063T2/xx unknown
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- 1998-02-25 AR ARP980100842A patent/AR013070A1/es unknown
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1999
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NO994103D0 (no) | 1999-08-25 |
KR20000075681A (ko) | 2000-12-26 |
NO994103L (no) | 1999-10-25 |
PL335378A1 (en) | 2000-04-25 |
EP1019386A1 (en) | 2000-07-19 |
AR013070A1 (es) | 2000-12-13 |
PE59199A1 (es) | 1999-06-24 |
WO1998038179A1 (en) | 1998-09-03 |
ZA981532B (en) | 1999-08-24 |
CA2281664A1 (en) | 1998-09-03 |
TR199902063T2 (xx) | 1999-12-21 |
JP2001513767A (ja) | 2001-09-04 |
IS5159A (is) | 1999-08-20 |
AU6822398A (en) | 1998-09-18 |
BR9807763A (pt) | 2000-02-22 |
AP9901631A0 (en) | 1999-09-30 |
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