JP2004527511A - メタロプロテイナーゼ阻害剤 - Google Patents
メタロプロテイナーゼ阻害剤 Download PDFInfo
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- JP2004527511A JP2004527511A JP2002573759A JP2002573759A JP2004527511A JP 2004527511 A JP2004527511 A JP 2004527511A JP 2002573759 A JP2002573759 A JP 2002573759A JP 2002573759 A JP2002573759 A JP 2002573759A JP 2004527511 A JP2004527511 A JP 2004527511A
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- Prior art keywords
- alkyl
- apci
- methyl
- heteroaryl
- nmr
- Prior art date
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- 239000003475 metalloproteinase inhibitor Substances 0.000 title claims description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 315
- 102000005741 Metalloproteases Human genes 0.000 claims abstract description 75
- 108010006035 Metalloproteases Proteins 0.000 claims abstract description 75
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 66
- 201000010099 disease Diseases 0.000 claims abstract description 66
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 66
- 230000001404 mediated effect Effects 0.000 claims abstract description 43
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 42
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 35
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 33
- 238000011282 treatment Methods 0.000 claims abstract description 29
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 21
- 229910052751 metal Inorganic materials 0.000 claims abstract description 21
- 239000002184 metal Substances 0.000 claims abstract description 21
- 230000027455 binding Effects 0.000 claims abstract description 20
- -1 heteroalkyl-aryl Chemical group 0.000 claims description 147
- 238000000034 method Methods 0.000 claims description 90
- 238000006243 chemical reaction Methods 0.000 claims description 52
- 150000003839 salts Chemical class 0.000 claims description 46
- 229910052757 nitrogen Inorganic materials 0.000 claims description 41
- 150000002148 esters Chemical class 0.000 claims description 37
- 238000001727 in vivo Methods 0.000 claims description 31
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 claims description 30
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 125000006413 ring segment Chemical group 0.000 claims description 22
- 102100027995 Collagenase 3 Human genes 0.000 claims description 21
- 102000004190 Enzymes Human genes 0.000 claims description 20
- 108090000790 Enzymes Proteins 0.000 claims description 20
- 101000577887 Homo sapiens Collagenase 3 Proteins 0.000 claims description 20
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 20
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000000524 functional group Chemical group 0.000 claims description 17
- 150000003573 thiols Chemical class 0.000 claims description 17
- 102100030416 Stromelysin-1 Human genes 0.000 claims description 16
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 102100030411 Neutrophil collagenase Human genes 0.000 claims description 14
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 13
- 241001465754 Metazoa Species 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000002619 bicyclic group Chemical group 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 101000990908 Homo sapiens Neutrophil collagenase Proteins 0.000 claims description 9
- 125000006168 tricyclic group Chemical group 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- 101000990915 Homo sapiens Stromelysin-1 Proteins 0.000 claims description 8
- 101710170181 Metalloproteinase inhibitor Proteins 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229940126170 metalloproteinase inhibitor Drugs 0.000 claims description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 102100027998 Macrophage metalloelastase Human genes 0.000 claims description 6
- 102000035195 Peptidases Human genes 0.000 claims description 6
- 108091005804 Peptidases Proteins 0.000 claims description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 6
- 150000001356 alkyl thiols Chemical class 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 229940124530 sulfonamide Drugs 0.000 claims description 6
- 150000003457 sulfones Chemical class 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 5
- 235000013877 carbamide Nutrition 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 150000003456 sulfonamides Chemical class 0.000 claims description 5
- QPRATAOCXWOIPO-UHFFFAOYSA-N 2-nitroethene-1,1-diamine Chemical compound NC(N)=C[N+]([O-])=O QPRATAOCXWOIPO-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims description 4
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 4
- 125000005362 aryl sulfone group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 150000007942 carboxylates Chemical class 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 235000019833 protease Nutrition 0.000 claims description 4
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004001 thioalkyl group Chemical group 0.000 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000004422 alkyl sulphonamide group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 150000001504 aryl thiols Chemical class 0.000 claims description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims description 2
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 101000577881 Homo sapiens Macrophage metalloelastase Proteins 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 466
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 429
- 229910052739 hydrogen Inorganic materials 0.000 description 354
- 238000005160 1H NMR spectroscopy Methods 0.000 description 287
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 166
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 149
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 134
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 132
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 130
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 126
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 106
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 103
- 239000000203 mixture Substances 0.000 description 87
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 64
- 235000019439 ethyl acetate Nutrition 0.000 description 62
- 239000000243 solution Substances 0.000 description 62
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 61
- 239000007787 solid Substances 0.000 description 61
- 239000002904 solvent Substances 0.000 description 53
- 230000015572 biosynthetic process Effects 0.000 description 48
- 238000003786 synthesis reaction Methods 0.000 description 48
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 47
- 238000005882 aldol condensation reaction Methods 0.000 description 46
- 239000000047 product Substances 0.000 description 46
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical group O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- VMAQYKGITHDWKL-UHFFFAOYSA-N 5-methylimidazolidine-2,4-dione Chemical compound CC1NC(=O)NC1=O VMAQYKGITHDWKL-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- 239000007858 starting material Substances 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 27
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 239000000377 silicon dioxide Substances 0.000 description 26
- 239000012043 crude product Substances 0.000 description 25
- 239000003921 oil Substances 0.000 description 25
- 235000019198 oils Nutrition 0.000 description 25
- 239000012074 organic phase Substances 0.000 description 24
- 230000000694 effects Effects 0.000 description 23
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000012267 brine Substances 0.000 description 21
- 239000003480 eluent Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 150000001412 amines Chemical class 0.000 description 20
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 19
- 229940088598 enzyme Drugs 0.000 description 19
- 150000002576 ketones Chemical class 0.000 description 19
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 16
- 201000006417 multiple sclerosis Diseases 0.000 description 15
- 238000002390 rotary evaporation Methods 0.000 description 15
- 239000007832 Na2SO4 Substances 0.000 description 14
- 150000001299 aldehydes Chemical class 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- 238000004821 distillation Methods 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 230000014759 maintenance of location Effects 0.000 description 14
- 239000002002 slurry Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 229940091173 hydantoin Drugs 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 238000002953 preparative HPLC Methods 0.000 description 13
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 12
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000001099 ammonium carbonate Substances 0.000 description 12
- 235000012501 ammonium carbonate Nutrition 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
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- 239000002244 precipitate Substances 0.000 description 12
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 11
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 11
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- 229920006395 saturated elastomer Polymers 0.000 description 10
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 10
- 229940124761 MMP inhibitor Drugs 0.000 description 9
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- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 8
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
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- WYURNTSHIVDZCO-SVYQBANQSA-N oxolane-d8 Chemical compound [2H]C1([2H])OC([2H])([2H])C([2H])([2H])C1([2H])[2H] WYURNTSHIVDZCO-SVYQBANQSA-N 0.000 description 8
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- 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 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
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- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 101710108790 Stromelysin-1 Proteins 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- 201000008482 osteoarthritis Diseases 0.000 description 7
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 7
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
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- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
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- 230000015556 catabolic process Effects 0.000 description 6
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- 238000006731 degradation reaction Methods 0.000 description 6
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- 102000004169 proteins and genes Human genes 0.000 description 6
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- 210000001519 tissue Anatomy 0.000 description 6
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- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 5
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- DMMXLTYIKKMKIU-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CCC(O)CC1 DMMXLTYIKKMKIU-UHFFFAOYSA-N 0.000 description 1
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- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- NCZIHTFUQIAOLW-UHFFFAOYSA-N tert-butyl n-[5-[4-(5-chloropyridin-2-yl)oxypiperidin-1-yl]sulfonyl-4-oxopentyl]carbamate Chemical compound C1CN(S(=O)(=O)CC(=O)CCCNC(=O)OC(C)(C)C)CCC1OC1=CC=C(Cl)C=N1 NCZIHTFUQIAOLW-UHFFFAOYSA-N 0.000 description 1
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- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 1
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- XPARCVGSTPKNNR-UHFFFAOYSA-M zinc;ethyl butanoate;bromide Chemical compound [Zn+2].[Br-].CCOC(=O)CC[CH2-] XPARCVGSTPKNNR-UHFFFAOYSA-M 0.000 description 1
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Classifications
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Applications Claiming Priority (3)
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| SE0100903A SE0100903D0 (sv) | 2001-03-15 | 2001-03-15 | Compounds |
| SE0100902A SE0100902D0 (sv) | 2001-03-15 | 2001-03-15 | Compounds |
| PCT/SE2002/000475 WO2002074750A1 (en) | 2001-03-15 | 2002-03-13 | Metalloproteinase inhibitors |
Publications (2)
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| JP2004527511A true JP2004527511A (ja) | 2004-09-09 |
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| CZ (1) | CZ20032502A3 (https=) |
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| RU (1) | RU2003127732A (https=) |
| SK (1) | SK10932003A3 (https=) |
| WO (1) | WO2002074750A1 (https=) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2008513499A (ja) * | 2004-09-20 | 2008-05-01 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | ステアロイル−CoAデサチュラーゼ酵素によって媒介される疾患の処置のための複素環誘導体 |
| JP2009531313A (ja) * | 2006-03-16 | 2009-09-03 | アストラゼネカ・アクチエボラーグ | (5s)−5−[4−(5−クロロ−ピリジン−2−イルオキシ)−ピペリジン−1−スルホニルメチル]−5−メチル−イミダゾリジン−2,4−ジオン(i)の新規結晶形gおよびその中間体 |
| JP2014503529A (ja) * | 2010-12-17 | 2014-02-13 | ファーマハンガリー 2000 ケイエフティー. | 新規マトリックスメタロプロテアーゼ阻害薬 |
| JP2021523240A (ja) * | 2018-05-15 | 2021-09-02 | フォアシー ファーマシューティカルズ ユーエスエー,インコーポレーテッド | マトリックスメタロプロテイナーゼ(mmp)阻害剤及びその使用方法 |
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| SE0100902D0 (sv) | 2001-03-15 | 2001-03-15 | Astrazeneca Ab | Compounds |
| SE0100903D0 (sv) * | 2001-03-15 | 2001-03-15 | Astrazeneca Ab | Compounds |
| US6890915B2 (en) | 2001-05-25 | 2005-05-10 | Bristol-Myers Squibb Pharma Company | Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE) |
| SE0103710D0 (sv) | 2001-11-07 | 2001-11-07 | Astrazeneca Ab | Compounds |
| US20050119251A1 (en) * | 2001-12-21 | 2005-06-02 | Jian-Min Fu | Nicotinamide derivatives and their use as therapeutic agents |
| JP4485941B2 (ja) * | 2002-06-05 | 2010-06-23 | 株式会社カネカ | 光学活性α−メチルシステイン誘導体の製造方法 |
| SE0202539D0 (sv) * | 2002-08-27 | 2002-08-27 | Astrazeneca Ab | Compounds |
| SE0202692D0 (sv) * | 2002-09-11 | 2002-09-11 | Astrazeneca Ab | Compounds |
| SE0202693D0 (sv) * | 2002-09-11 | 2002-09-11 | Astrazeneca Ab | Compounds |
| GB0221246D0 (en) * | 2002-09-13 | 2002-10-23 | Astrazeneca Ab | Compounds |
| GB0221250D0 (en) * | 2002-09-13 | 2002-10-23 | Astrazeneca Ab | Compounds |
| JP4866610B2 (ja) * | 2003-08-18 | 2012-02-01 | 富士フイルムファインケミカルズ株式会社 | ピリジルテトラヒドロピリジン類およびピリジルピペリジン類 |
| US20050203156A1 (en) * | 2004-03-12 | 2005-09-15 | Wyeth | Hydantoins having RNase modulatory activity |
| US7648992B2 (en) | 2004-07-05 | 2010-01-19 | Astrazeneca Ab | Hydantoin derivatives for the treatment of obstructive airway diseases |
| SE0401763D0 (sv) * | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Compounds |
| SE0401762D0 (sv) * | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Novel compounds |
| US7488745B2 (en) | 2004-07-16 | 2009-02-10 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
| US7504424B2 (en) | 2004-07-16 | 2009-03-17 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
| ATE478864T1 (de) | 2004-07-16 | 2010-09-15 | Schering Corp | Hydantoinderivate zur behandlung von entzündlichen erkrankungen |
| EP1827438B2 (en) * | 2004-09-20 | 2014-12-10 | Xenon Pharmaceuticals Inc. | Piperazin derivatives for inhibiting human stearoyl-coa-desaturase |
| AU2005286648A1 (en) * | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
| JP5080256B2 (ja) * | 2004-09-20 | 2012-11-21 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | 二環式複素環誘導体およびステアロイル−CoAデサチュラーゼ(SCD)のインヒビターとしてのそれらの使用 |
| CA2580857A1 (en) * | 2004-09-20 | 2006-09-28 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| US7829712B2 (en) * | 2004-09-20 | 2010-11-09 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase |
| AR051091A1 (es) * | 2004-09-20 | 2006-12-20 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores de la estearoil-coa desaturasa |
| EP1807085B1 (en) | 2004-09-20 | 2013-08-21 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| CA2580762A1 (en) * | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as therapeutic agents |
| SE0403085D0 (sv) * | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Novel componds |
| SE0403086D0 (sv) * | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Compounds |
| AU2006343359A1 (en) * | 2005-06-03 | 2007-11-15 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors |
| AR059036A1 (es) | 2006-01-17 | 2008-03-12 | Schering Corp | Compuestos para el tratamiento de trastornos inflamatorios |
| TW200740769A (en) * | 2006-03-16 | 2007-11-01 | Astrazeneca Ab | Novel process |
| TW200831488A (en) * | 2006-11-29 | 2008-08-01 | Astrazeneca Ab | Novel compounds |
| WO2009007747A2 (en) * | 2007-07-11 | 2009-01-15 | Astrazeneca Ab | Hydantoin derivatives used as mmp12 inhibitors |
| EP2346857B1 (en) | 2008-09-24 | 2019-11-27 | Merck Sharp & Dohme Corp. | Compounds for the treatment of inflammatory disorders |
| TW201024304A (en) | 2008-09-24 | 2010-07-01 | Schering Corp | Compounds for the treatment of inflammatory disorders |
| US8569336B2 (en) | 2008-11-10 | 2013-10-29 | Ling Tong | Compounds for the treatment of inflammatory disorders |
| EP2356111A1 (en) | 2008-11-10 | 2011-08-17 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
| EP2941423B1 (en) | 2013-01-07 | 2021-06-09 | University of Southern California | Deoxyuridine triphosphatase inhibitors |
| CN105531270B (zh) * | 2013-06-07 | 2017-09-05 | 科研制药株式会社 | (+)-5-(3,4-二氟苯基)-5-[(3-甲基-2-氧吡啶-1(2h)-基)甲基]咪唑烷-2,4-二酮及含有该化合物的药物 |
| WO2017006283A1 (en) | 2015-07-08 | 2017-01-12 | Cv6 Therapeutics (Ni) Limited | Deoxyuridine triphosphatase inhibitors containing cyclopropano linkage |
| US10577321B2 (en) | 2015-07-08 | 2020-03-03 | University Of Southern California | Deoxyuridine triphosphatase inhibitors |
| SI3319939T1 (sl) | 2015-07-08 | 2025-04-30 | Cv6 Therapeutics (Ni) Limited | Zaviralci deoksiuridin trifosfataze, ki vsebujejo hidantoin |
| WO2017006271A1 (en) | 2015-07-08 | 2017-01-12 | University Of Southern California | Deoxyuridine triphosphatase inhibitors containing amino sulfonyl linkage |
| US11168059B2 (en) | 2016-11-23 | 2021-11-09 | Cv6 Therapeutics (Ni) Limited | Amino sulfonyl compounds |
| US10858344B2 (en) | 2016-11-23 | 2020-12-08 | Cv6 Therapeutics (Ni) Limited | Hydantoin containing deoxyuridine triphosphatase inhibitors |
| WO2018098207A1 (en) | 2016-11-23 | 2018-05-31 | Cv6 Therapeutics (Ni) Limited | Hydantoin containing deoxyuridine triphosphatase inhibitors |
| WO2018098204A1 (en) | 2016-11-23 | 2018-05-31 | Cv6 Therapeutics (Ni) Limited | 6-membered uracil isosteres |
| WO2018098208A1 (en) | 2016-11-23 | 2018-05-31 | Cv6 Therapeutics (Ni) Limited | Nitrogen ring linked deoxyuridine triphosphatase inhibitors |
| WO2018128720A1 (en) | 2017-01-05 | 2018-07-12 | Cv6 Therapeutics (Ni) Limited | Uracil containing compounds |
| AR110963A1 (es) | 2017-02-07 | 2019-05-22 | Dae Woong Pharma | Compuestos heterocíclicos, su método de preparación y composición farmacéutica que los comprende |
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| US3529019A (en) * | 1968-04-23 | 1970-09-15 | Colgate Palmolive Co | Alkylaryloxy alanines |
| CS151744B1 (https=) * | 1971-01-19 | 1973-11-19 | ||
| US3849574A (en) * | 1971-05-24 | 1974-11-19 | Colgate Palmolive Co | Alpha-substituted-beta-arylthioalkyl amino-acids,for increasing heart rate |
| US5268291A (en) * | 1983-01-19 | 1993-12-07 | Genentech, Inc. | Human t-PA production using vectors coding for DHFR protein |
| EP0640594A1 (en) * | 1993-08-23 | 1995-03-01 | Fujirebio Inc. | Hydantoin derivative as metalloprotease inhibitor |
| NZ501166A (en) * | 1997-07-31 | 2001-12-21 | Abbott Lab | Reverse hydroxamate-containing compounds and their use as inhibitors of matrix metalloproteinases |
| DE69811111T2 (de) * | 1997-11-12 | 2003-07-24 | Darwin Discovery Ltd., Cambridge | Hydroxamsäure- und carbonsäurederivate mit mmp und tnf hemmender wirkung |
| EP1150975A1 (en) * | 1998-12-31 | 2001-11-07 | Aventis Pharmaceuticals Inc. | 1-carboxymethyl-2-oxo-azepan derivatives useful as selective inhibitors of mmp-12 |
| US6294694B1 (en) * | 1999-06-04 | 2001-09-25 | Wisconsin Alumni Research Foundation | Matrix metalloproteinase inhibitors and method of using same |
| GB9916562D0 (en) * | 1999-07-14 | 1999-09-15 | Pharmacia & Upjohn Spa | 3-Arylsulfonyl-2-(substituted-methyl) propanoic acid derivatives as matrix metalloproteinase inhibitora |
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- 2003-09-10 IS IS6944A patent/IS6944A/is unknown
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008513499A (ja) * | 2004-09-20 | 2008-05-01 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | ステアロイル−CoAデサチュラーゼ酵素によって媒介される疾患の処置のための複素環誘導体 |
| JP2009531313A (ja) * | 2006-03-16 | 2009-09-03 | アストラゼネカ・アクチエボラーグ | (5s)−5−[4−(5−クロロ−ピリジン−2−イルオキシ)−ピペリジン−1−スルホニルメチル]−5−メチル−イミダゾリジン−2,4−ジオン(i)の新規結晶形gおよびその中間体 |
| JP2014503529A (ja) * | 2010-12-17 | 2014-02-13 | ファーマハンガリー 2000 ケイエフティー. | 新規マトリックスメタロプロテアーゼ阻害薬 |
| JP2021523240A (ja) * | 2018-05-15 | 2021-09-02 | フォアシー ファーマシューティカルズ ユーエスエー,インコーポレーテッド | マトリックスメタロプロテイナーゼ(mmp)阻害剤及びその使用方法 |
| JP7344959B2 (ja) | 2018-05-15 | 2023-09-14 | フォアシー ファーマシューティカルズ ユーエスエー,インコーポレーテッド | マトリックスメタロプロテイナーゼ(mmp)阻害剤及びその使用方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0400206A2 (hu) | 2004-08-30 |
| HUP0400206A3 (en) | 2004-10-28 |
| MXPA03008180A (es) | 2003-12-12 |
| RU2003127732A (ru) | 2005-03-20 |
| EE200300439A (et) | 2003-12-15 |
| WO2002074750A1 (en) | 2002-09-26 |
| CA2440632A1 (en) | 2002-09-26 |
| IS6944A (is) | 2003-09-10 |
| US20040147573A1 (en) | 2004-07-29 |
| PL364714A1 (en) | 2004-12-13 |
| EP1370536A1 (en) | 2003-12-17 |
| KR20030082990A (ko) | 2003-10-23 |
| BR0208105A (pt) | 2004-03-09 |
| NO20034025L (no) | 2003-11-13 |
| IL157570A0 (en) | 2004-03-28 |
| NO20034025D0 (no) | 2003-09-11 |
| CN1509275A (zh) | 2004-06-30 |
| CZ20032502A3 (cs) | 2004-01-14 |
| SK10932003A3 (sk) | 2004-04-06 |
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