ES2233275T3 - Intermediarios que sirven para la preparacion de inhibidores de metaloproteinasas. - Google Patents
Intermediarios que sirven para la preparacion de inhibidores de metaloproteinasas.Info
- Publication number
- ES2233275T3 ES2233275T3 ES00128719T ES00128719T ES2233275T3 ES 2233275 T3 ES2233275 T3 ES 2233275T3 ES 00128719 T ES00128719 T ES 00128719T ES 00128719 T ES00128719 T ES 00128719T ES 2233275 T3 ES2233275 T3 ES 2233275T3
- Authority
- ES
- Spain
- Prior art keywords
- formula
- benzenesulfonyl
- acid
- solution
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000002360 preparation method Methods 0.000 title abstract description 24
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 211
- 238000000034 method Methods 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims description 54
- 239000012453 solvate Substances 0.000 claims description 48
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- -1 geletinases Proteins 0.000 abstract description 115
- 239000000543 intermediate Substances 0.000 abstract description 23
- 102000002274 Matrix Metalloproteinases Human genes 0.000 abstract description 12
- 108010000684 Matrix Metalloproteinases Proteins 0.000 abstract description 12
- 102000004190 Enzymes Human genes 0.000 abstract description 9
- 108090000790 Enzymes Proteins 0.000 abstract description 9
- 210000002808 connective tissue Anatomy 0.000 abstract description 7
- 102000005741 Metalloproteases Human genes 0.000 abstract description 6
- 108010006035 Metalloproteases Proteins 0.000 abstract description 6
- 230000015556 catabolic process Effects 0.000 abstract description 5
- 238000006731 degradation reaction Methods 0.000 abstract description 5
- 102000004318 Matrilysin Human genes 0.000 abstract description 4
- 108090000855 Matrilysin Proteins 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 4
- 102000029816 Collagenase Human genes 0.000 abstract description 3
- 108060005980 Collagenase Proteins 0.000 abstract description 3
- 210000002950 fibroblast Anatomy 0.000 abstract description 3
- 239000003475 metalloproteinase inhibitor Substances 0.000 abstract description 3
- 238000007634 remodeling Methods 0.000 abstract description 3
- 108091007196 stromelysin Proteins 0.000 abstract description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 2
- 108010062466 Enzyme Precursors Proteins 0.000 abstract description 2
- 102000010911 Enzyme Precursors Human genes 0.000 abstract description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000011575 calcium Substances 0.000 abstract description 2
- 229910052791 calcium Inorganic materials 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 abstract description 2
- 210000002889 endothelial cell Anatomy 0.000 abstract description 2
- 210000002540 macrophage Anatomy 0.000 abstract description 2
- 206010061289 metastatic neoplasm Diseases 0.000 abstract description 2
- 210000001616 monocyte Anatomy 0.000 abstract description 2
- 230000028327 secretion Effects 0.000 abstract description 2
- 239000011701 zinc Substances 0.000 abstract description 2
- 229910052725 zinc Inorganic materials 0.000 abstract description 2
- 206010054094 Tumour necrosis Diseases 0.000 abstract 1
- IXKSXJFAGXLQOQ-XISFHERQSA-N WHWLQLKPGQPMY Chemical compound C([C@@H](C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CNC=N1 IXKSXJFAGXLQOQ-XISFHERQSA-N 0.000 abstract 1
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 359
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 240
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 191
- 239000000243 solution Substances 0.000 description 161
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 117
- 239000002253 acid Substances 0.000 description 96
- 238000006243 chemical reaction Methods 0.000 description 82
- 239000007787 solid Substances 0.000 description 78
- 235000019439 ethyl acetate Nutrition 0.000 description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- 239000000203 mixture Substances 0.000 description 69
- 239000002904 solvent Substances 0.000 description 63
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- 239000012044 organic layer Substances 0.000 description 53
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 229910052938 sodium sulfate Inorganic materials 0.000 description 50
- 235000011152 sodium sulphate Nutrition 0.000 description 50
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- 239000012267 brine Substances 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 35
- 125000003118 aryl group Chemical group 0.000 description 34
- 238000011282 treatment Methods 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- 125000000217 alkyl group Chemical group 0.000 description 32
- 238000001914 filtration Methods 0.000 description 29
- 239000010410 layer Substances 0.000 description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 28
- 239000002585 base Substances 0.000 description 27
- 125000000753 cycloalkyl group Chemical group 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 27
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 25
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 24
- 125000001072 heteroaryl group Chemical group 0.000 description 24
- 238000004587 chromatography analysis Methods 0.000 description 23
- 150000002148 esters Chemical class 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
- 229910052739 hydrogen Inorganic materials 0.000 description 21
- 239000001257 hydrogen Substances 0.000 description 21
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 20
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 17
- 150000003254 radicals Chemical class 0.000 description 17
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 17
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 17
- 239000003153 chemical reaction reagent Substances 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- PPNGSCRYZMXTEK-YFKPBYRVSA-N (3s)-2,2-dimethylthiomorpholine-3-carboxylic acid Chemical compound CC1(C)SCCN[C@H]1C(O)=O PPNGSCRYZMXTEK-YFKPBYRVSA-N 0.000 description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 238000010992 reflux Methods 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
- 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 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- NXBDXOHMBJGREQ-INIZCTEOSA-N (3s)-2,2-dimethyl-4-(4-pyridin-4-yloxyphenyl)sulfonylthiomorpholine-3-carboxylic acid Chemical compound OC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=NC=C1 NXBDXOHMBJGREQ-INIZCTEOSA-N 0.000 description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 150000002431 hydrogen Chemical class 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 10
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- SSUCKKNRCOFUPT-UHFFFAOYSA-N o-[tert-butyl(dimethyl)silyl]hydroxylamine Chemical compound CC(C)(C)[Si](C)(C)ON SSUCKKNRCOFUPT-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 239000008363 phosphate buffer Substances 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- 102000008186 Collagen Human genes 0.000 description 8
- 108010035532 Collagen Proteins 0.000 description 8
- 150000001412 amines Chemical group 0.000 description 8
- 239000000010 aprotic solvent Substances 0.000 description 8
- 229920001436 collagen Polymers 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 7
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 229960001639 penicillamine Drugs 0.000 description 7
- 229940124530 sulfonamide Drugs 0.000 description 7
- 239000006188 syrup Substances 0.000 description 7
- 235000020357 syrup Nutrition 0.000 description 7
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 7
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 7
- LWKYASRBLIVKFS-MRXNPFEDSA-N (2R)-1-[4-(4-chlorophenoxy)phenyl]sulfonyl-N-hydroxy-4-oxo-1,3-diazinane-2-carboxamide Chemical compound ONC(=O)[C@H]1N(CCC(N1)=O)S(=O)(=O)C1=CC=C(C=C1)OC1=CC=C(C=C1)Cl LWKYASRBLIVKFS-MRXNPFEDSA-N 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 229940125898 compound 5 Drugs 0.000 description 6
- 150000001987 diarylethers Chemical class 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 150000003456 sulfonamides Chemical class 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 6
- YQCULNLACGYFJN-MRXNPFEDSA-N (2r)-1-[4-(4-chlorophenoxy)phenyl]sulfonyl-n-hydroxypiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CNCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 YQCULNLACGYFJN-MRXNPFEDSA-N 0.000 description 5
- PPNGSCRYZMXTEK-UHFFFAOYSA-N 2,2-dimethylthiomorpholine-3-carboxylic acid Chemical compound CC1(C)SCCNC1C(O)=O PPNGSCRYZMXTEK-UHFFFAOYSA-N 0.000 description 5
- OATKXQIGHQXTDO-UHFFFAOYSA-N 4-phenoxypyridine Chemical compound C=1C=NC=CC=1OC1=CC=CC=C1 OATKXQIGHQXTDO-UHFFFAOYSA-N 0.000 description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- YKPYIPVDTNNYCN-INIZCTEOSA-N prinomastat Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=NC=C1 YKPYIPVDTNNYCN-INIZCTEOSA-N 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- XVUHQVKSXOEODI-KRWDZBQOSA-N (3s)-4-[4-(4-bromophenoxy)phenyl]sulfonyl-2,2-dimethylthiomorpholine-3-carboxylic acid Chemical compound OC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Br)C=C1 XVUHQVKSXOEODI-KRWDZBQOSA-N 0.000 description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 102000016359 Fibronectins Human genes 0.000 description 4
- 108010067306 Fibronectins Proteins 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 4
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 4
- OYKPQAHPOJHWQE-HJLWYHJMSA-N ONC(=O)C1C([S@](CCN1S(=O)(=O)C1=CC=C(C=C1)OC1=CC=NC=C1)=O)(C)C Chemical compound ONC(=O)C1C([S@](CCN1S(=O)(=O)C1=CC=C(C=C1)OC1=CC=NC=C1)=O)(C)C OYKPQAHPOJHWQE-HJLWYHJMSA-N 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000010306 acid treatment Methods 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 125000004663 dialkyl amino group Chemical group 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 4
- 239000008259 solid foam Substances 0.000 description 4
- CANFUYZXAZIOBC-XMMPIXPASA-N tert-butyl (3r)-3-[[tert-butyl(dimethyl)silyl]oxycarbamoyl]-4-[4-(4-chlorophenoxy)phenyl]sulfonylpiperazine-1-carboxylate Chemical compound CC(C)(C)[Si](C)(C)ONC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 CANFUYZXAZIOBC-XMMPIXPASA-N 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 4
- YRYAXQJXMBETAT-SSDOTTSWSA-N (2r)-4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-ium-2-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN[C@@H](C(O)=O)C1 YRYAXQJXMBETAT-SSDOTTSWSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229940124761 MMP inhibitor Drugs 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 102000016611 Proteoglycans Human genes 0.000 description 3
- 108010067787 Proteoglycans Proteins 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000011260 aqueous acid Substances 0.000 description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 150000001541 aziridines Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000007979 citrate buffer Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 150000002443 hydroxylamines Chemical class 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 3
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical compound OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 3
- 238000000638 solvent extraction Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 125000004665 trialkylsilyl group Chemical group 0.000 description 3
- 230000036269 ulceration Effects 0.000 description 3
- 229910052727 yttrium Inorganic materials 0.000 description 3
- OABISEVGEPBTEE-LJQANCHMSA-N (2r)-1-[4-(4-chlorophenoxy)phenyl]sulfonyl-4-[(2-methylpropan-2-yl)oxycarbonyl]piperazine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 OABISEVGEPBTEE-LJQANCHMSA-N 0.000 description 2
- UBKLDEGGYKOETA-QGZVFWFLSA-N (2r)-1-[4-(4-chlorophenoxy)phenyl]sulfonyl-n-hydroxy-4-methylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 UBKLDEGGYKOETA-QGZVFWFLSA-N 0.000 description 2
- IZWRTCGVRMPEFI-QGZVFWFLSA-N (2r)-1-[4-(4-chlorophenoxy)phenyl]sulfonyl-n-hydroxy-4-methylsulfonylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(S(=O)(=O)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 IZWRTCGVRMPEFI-QGZVFWFLSA-N 0.000 description 2
- KJDVIJGFTMMFFS-MRXNPFEDSA-N (3r)-4-[4-(4-chlorophenoxy)phenyl]sulfonyl-n-hydroxymorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1COCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 KJDVIJGFTMMFFS-MRXNPFEDSA-N 0.000 description 2
- MFDUVZDPDCPDEJ-MRXNPFEDSA-N (3r)-4-[4-(4-chlorophenoxy)phenyl]sulfonylmorpholine-3-carboxylic acid Chemical compound OC(=O)[C@H]1COCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 MFDUVZDPDCPDEJ-MRXNPFEDSA-N 0.000 description 2
- ZVHBVWSBTTYWDM-OAQYLSRUSA-N (3r)-n-[tert-butyl(dimethyl)silyl]oxy-4-[4-(4-chlorophenoxy)phenyl]sulfonylmorpholine-3-carboxamide Chemical compound CC(C)(C)[Si](C)(C)ONC(=O)[C@H]1COCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 ZVHBVWSBTTYWDM-OAQYLSRUSA-N 0.000 description 2
- UPRKSBKFZYPHBO-KRWDZBQOSA-N (3s)-4-[4-(4-bromophenoxy)phenyl]sulfonyl-n-hydroxy-2,2-dimethylthiomorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Br)C=C1 UPRKSBKFZYPHBO-KRWDZBQOSA-N 0.000 description 2
- JSSXHAMIXJGYCS-SCSAIBSYSA-N (R)-piperazine-2-carboxylic acid Chemical compound [O-]C(=O)[C@H]1CNCC[NH2+]1 JSSXHAMIXJGYCS-SCSAIBSYSA-N 0.000 description 2
- NXBDXOHMBJGREQ-UHFFFAOYSA-N 2,2-dimethyl-4-(4-pyridin-4-yloxyphenyl)sulfonylthiomorpholine-3-carboxylic acid Chemical compound OC(=O)C1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=NC=C1 NXBDXOHMBJGREQ-UHFFFAOYSA-N 0.000 description 2
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical class OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 2
- GOPUHTXVZGIOHN-UHFFFAOYSA-N 2,4-dihydroxybenzohydrazide Chemical compound NNC(=O)C1=CC=C(O)C=C1O GOPUHTXVZGIOHN-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- FFDRXODVUWKDNR-UHFFFAOYSA-N 2-[4-(4-bromophenoxy)phenyl]sulfonylthiomorpholine-3-carboxylic acid Chemical compound OC(=O)C1NCCSC1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Br)C=C1 FFDRXODVUWKDNR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- TYEYBOSBBBHJIV-UHFFFAOYSA-M 2-oxobutanoate Chemical compound CCC(=O)C([O-])=O TYEYBOSBBBHJIV-UHFFFAOYSA-M 0.000 description 2
- MEAAWTRWNWSLPF-UHFFFAOYSA-N 2-phenoxypyridine Chemical compound C=1C=CC=NC=1OC1=CC=CC=C1 MEAAWTRWNWSLPF-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- XGAFCCUNHIMIRV-UHFFFAOYSA-N 4-chloropyridine;hydron;chloride Chemical compound Cl.ClC1=CC=NC=C1 XGAFCCUNHIMIRV-UHFFFAOYSA-N 0.000 description 2
- FFFLYOYQSHCTRS-UHFFFAOYSA-N 4-pyridin-4-yloxybenzenesulfonyl chloride Chemical compound C1=CC(S(=O)(=O)Cl)=CC=C1OC1=CC=NC=C1 FFFLYOYQSHCTRS-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- IAHHTJKIPUPERH-SNCIIYAQSA-N BrC1=CC=C(OC2=CC=C(C=C2)S(=O)(=O)N2C(C([S@](CC2)=O)(C)C)C(=O)O)C=C1 Chemical compound BrC1=CC=C(OC2=CC=C(C=C2)S(=O)(=O)N2C(C([S@](CC2)=O)(C)C)C(=O)O)C=C1 IAHHTJKIPUPERH-SNCIIYAQSA-N 0.000 description 2
- AXDKKUJMMVUQIO-KRWDZBQOSA-N CC(C)([C@H](C(=O)O)NS(=O)(=O)C1=CC=C(C=C1)OC2=CC=C(C=C2)Br)SCCO Chemical compound CC(C)([C@H](C(=O)O)NS(=O)(=O)C1=CC=C(C=C1)OC2=CC=C(C=C2)Br)SCCO AXDKKUJMMVUQIO-KRWDZBQOSA-N 0.000 description 2
- DCXYFEDJOCDNAF-UWTATZPHSA-N D-Asparagine Chemical compound OC(=O)[C@H](N)CC(N)=O DCXYFEDJOCDNAF-UWTATZPHSA-N 0.000 description 2
- 229930182846 D-asparagine Natural products 0.000 description 2
- 102000016942 Elastin Human genes 0.000 description 2
- 108010014258 Elastin Proteins 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LWSXGYKKUKENOD-ZBXDZARASA-N ONC(=O)C1C([S@](CCN1S(=O)(=O)C1=CC=C(C=C1)OC1=CC=C(C=C1)Br)=O)(C)C Chemical compound ONC(=O)C1C([S@](CCN1S(=O)(=O)C1=CC=C(C=C1)OC1=CC=C(C=C1)Br)=O)(C)C LWSXGYKKUKENOD-ZBXDZARASA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 210000002469 basement membrane Anatomy 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 2
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
- 229920002549 elastin Polymers 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 235000015110 jellies Nutrition 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229960003151 mercaptamine Drugs 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 2
- XKSVSFLLSMFCLE-UHFFFAOYSA-N n-(3-aminopropyl)-4-(4-fluorophenoxy)benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NCCCN)=CC=C1OC1=CC=C(F)C=C1 XKSVSFLLSMFCLE-UHFFFAOYSA-N 0.000 description 2
- PWTWOGMXABHJOA-UHFFFAOYSA-N o-[tert-butyl(diphenyl)silyl]hydroxylamine Chemical compound C=1C=CC=CC=1[Si](ON)(C(C)(C)C)C1=CC=CC=C1 PWTWOGMXABHJOA-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000001012 protector Effects 0.000 description 2
- 235000004252 protein component Nutrition 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229960001922 sodium perborate Drugs 0.000 description 2
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- NBNBICNWNFQDDD-UHFFFAOYSA-N sulfuryl dibromide Chemical compound BrS(Br)(=O)=O NBNBICNWNFQDDD-UHFFFAOYSA-N 0.000 description 2
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 description 2
- UETHFTDZUAZEGC-LJQANCHMSA-N tert-butyl (3r)-4-[4-(4-chlorophenoxy)phenyl]sulfonyl-3-(hydroxycarbamoyl)piperazine-1-carboxylate Chemical compound ONC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 UETHFTDZUAZEGC-LJQANCHMSA-N 0.000 description 2
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOKIQGQOKXGHDV-UHFFFAOYSA-N thiomorpholine-3-carboxylic acid Chemical compound [O-]C(=O)C1CSCC[NH2+]1 JOKIQGQOKXGHDV-UHFFFAOYSA-N 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- PEHFQQWAINXOQG-UHFFFAOYSA-N (2-methoxyacetyl) 2-methoxyacetate Chemical compound COCC(=O)OC(=O)COC PEHFQQWAINXOQG-UHFFFAOYSA-N 0.000 description 1
- KKJLWBNLOXDPQF-UHFFFAOYSA-N (2-methylpropan-2-yl)oxycarbonyl 2-amino-3,3-dimethylpent-4-enoate Chemical compound NC(C(=O)OC(=O)OC(C)(C)C)C(C=C)(C)C KKJLWBNLOXDPQF-UHFFFAOYSA-N 0.000 description 1
- DMBCMKKNWJDRAG-MRXNPFEDSA-N (2R)-1-[4-(4-fluorophenoxy)phenyl]sulfonyl-N-hydroxy-4-oxo-1,3-diazinane-2-carboxamide Chemical compound ONC(=O)[C@H]1N(CCC(N1)=O)S(=O)(=O)C1=CC=C(C=C1)OC1=CC=C(C=C1)F DMBCMKKNWJDRAG-MRXNPFEDSA-N 0.000 description 1
- KITGVPBLWQVXJC-HXUWFJFHSA-N (2R)-1-[4-[4-(furan-2-yl)phenoxy]phenyl]sulfonyl-N-hydroxy-4-oxo-1,3-diazinane-2-carboxamide Chemical compound ONC(=O)[C@H]1N(CCC(N1)=O)S(=O)(=O)C1=CC=C(C=C1)OC1=CC=C(C=C1)C=1OC=CC=1 KITGVPBLWQVXJC-HXUWFJFHSA-N 0.000 description 1
- XZYKSXBXAYQCIY-QGZVFWFLSA-N (2R)-N-hydroxy-1-[4-(4-methoxyphenoxy)phenyl]sulfonyl-4-oxo-1,3-diazinane-2-carboxamide Chemical compound ONC(=O)[C@H]1N(CCC(N1)=O)S(=O)(=O)C1=CC=C(C=C1)OC1=CC=C(C=C1)OC XZYKSXBXAYQCIY-QGZVFWFLSA-N 0.000 description 1
- XGVJPYMYKDLKJR-QGZVFWFLSA-N (2R)-N-hydroxy-4-methyl-1-(4-phenoxyphenyl)sulfonylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 XGVJPYMYKDLKJR-QGZVFWFLSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- DKCLQMJTWKUWET-LJQANCHMSA-N (2r)-1-[4-(4-chlorophenoxy)phenyl]sulfonyl-n-hydroxy-4-(1-methylimidazol-4-yl)sulfonylpiperazine-2-carboxamide Chemical compound CN1C=NC(S(=O)(=O)N2C[C@@H](N(CC2)S(=O)(=O)C=2C=CC(OC=3C=CC(Cl)=CC=3)=CC=2)C(=O)NO)=C1 DKCLQMJTWKUWET-LJQANCHMSA-N 0.000 description 1
- BNLQWZYRKCIAAV-QGZVFWFLSA-N (2r)-1-[4-(4-fluorophenoxy)phenyl]sulfonyl-n-hydroxy-4-methylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(F)C=C1 BNLQWZYRKCIAAV-QGZVFWFLSA-N 0.000 description 1
- WKTXPBWQJVRRAX-QGZVFWFLSA-N (2r)-1-[4-(4-fluorophenoxy)phenyl]sulfonyl-n-hydroxy-4-methylsulfonylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(S(=O)(=O)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(F)C=C1 WKTXPBWQJVRRAX-QGZVFWFLSA-N 0.000 description 1
- ZHBFIBVIZZLPTB-MRXNPFEDSA-N (2r)-1-[4-(4-fluorophenoxy)phenyl]sulfonyl-n-hydroxypiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CNCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(F)C=C1 ZHBFIBVIZZLPTB-MRXNPFEDSA-N 0.000 description 1
- PELHKZRDUGLSOJ-QGZVFWFLSA-N (2r)-4-acetyl-n-hydroxy-1-(4-pyridin-4-yloxyphenyl)sulfonylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(C(=O)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=NC=C1 PELHKZRDUGLSOJ-QGZVFWFLSA-N 0.000 description 1
- XFKXZOKTTFMGQR-LJQANCHMSA-N (2r)-n-hydroxy-1-[4-[4-(1h-imidazol-2-yl)phenoxy]phenyl]sulfonyl-4-methylsulfonylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(S(=O)(=O)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(C=2NC=CN=2)C=C1 XFKXZOKTTFMGQR-LJQANCHMSA-N 0.000 description 1
- LVAKHDCLAVJQPE-LJQANCHMSA-N (2r)-n-hydroxy-4-(2-methylpropanoyl)-1-(4-phenoxyphenyl)sulfonylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(C(=O)C(C)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 LVAKHDCLAVJQPE-LJQANCHMSA-N 0.000 description 1
- JOABDOWNAKZKET-MRXNPFEDSA-N (2r)-n-hydroxy-4-methylsulfonyl-1-(4-pyridin-4-yloxyphenyl)sulfonylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(S(=O)(=O)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=NC=C1 JOABDOWNAKZKET-MRXNPFEDSA-N 0.000 description 1
- PCUOSKYWKAVURT-HXUWFJFHSA-N (2r)-n-hydroxy-4-methylsulfonyl-1-[4-[4-(1h-pyrazol-5-yl)phenoxy]phenyl]sulfonylpiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(S(=O)(=O)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(C=2NN=CC=2)C=C1 PCUOSKYWKAVURT-HXUWFJFHSA-N 0.000 description 1
- HKFOQLSPAHTQDD-GOSISDBHSA-N (3r)-3-n-hydroxy-4-[4-(4-methoxyphenoxy)phenyl]sulfonyl-1-n-methylpiperazine-1,3-dicarboxamide Chemical compound ONC(=O)[C@H]1CN(C(=O)NC)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(OC)C=C1 HKFOQLSPAHTQDD-GOSISDBHSA-N 0.000 description 1
- QUICMWBYYBMBKN-QGZVFWFLSA-N (3r)-4-[4-(4-fluorophenoxy)phenyl]sulfonyl-3-n-hydroxy-1-n-methylpiperazine-1,3-dicarboxamide Chemical compound ONC(=O)[C@H]1CN(C(=O)NC)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(F)C=C1 QUICMWBYYBMBKN-QGZVFWFLSA-N 0.000 description 1
- NAOPJAOLLMUNLT-MRXNPFEDSA-N (3r)-4-[4-(4-fluorophenoxy)phenyl]sulfonyl-n-hydroxymorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1COCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(F)C=C1 NAOPJAOLLMUNLT-MRXNPFEDSA-N 0.000 description 1
- OMVRYWZYELUBQM-OAHLLOKOSA-N (3r)-n-hydroxy-4-(4-pyridin-4-yloxyphenyl)sulfonylmorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1COCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=NC=C1 OMVRYWZYELUBQM-OAHLLOKOSA-N 0.000 description 1
- XCKAQSZAMVFIAJ-QGZVFWFLSA-N (3r)-n-hydroxy-4-[4-(4-methoxyphenoxy)phenyl]sulfonylmorpholine-3-carboxamide Chemical compound C1=CC(OC)=CC=C1OC1=CC=C(S(=O)(=O)N2[C@H](COCC2)C(=O)NO)C=C1 XCKAQSZAMVFIAJ-QGZVFWFLSA-N 0.000 description 1
- BZXLSGYZOWXWMK-GOSISDBHSA-N (3r)-n-hydroxy-4-[4-[4-(1h-imidazol-2-yl)phenoxy]phenyl]sulfonylmorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1COCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(C=2NC=CN=2)C=C1 BZXLSGYZOWXWMK-GOSISDBHSA-N 0.000 description 1
- SHZRBWPBSISAPX-IBGZPJMESA-N (3s)-4-(9h-fluoren-9-ylmethoxycarbonyl)-2,2-dimethylthiomorpholine-3-carboxylic acid Chemical compound OC(=O)[C@H]1C(C)(C)SCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 SHZRBWPBSISAPX-IBGZPJMESA-N 0.000 description 1
- HNZFMLNKCBKFQN-KRWDZBQOSA-N (3s)-4-[4-(4-chlorophenoxy)phenyl]sulfonyl-n-hydroxy-2,2-dimethylthiomorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 HNZFMLNKCBKFQN-KRWDZBQOSA-N 0.000 description 1
- HSEBQFSMKLZHPJ-INIZCTEOSA-N (3s)-n-hydroxy-2,2-dimethyl-4-(4-pyridin-2-yloxyphenyl)sulfonylthiomorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=N1 HSEBQFSMKLZHPJ-INIZCTEOSA-N 0.000 description 1
- DOXHDHZGRRHDJU-INIZCTEOSA-N (3s)-n-hydroxy-2,2-dimethyl-4-(4-pyridin-4-ylsulfanylphenyl)sulfonylthiomorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1SC1=CC=NC=C1 DOXHDHZGRRHDJU-INIZCTEOSA-N 0.000 description 1
- YVHREEZRZWNIPG-FQEVSTJZSA-N (3s)-n-hydroxy-4-[4-(4-imidazol-1-ylphenoxy)phenyl]sulfonyl-2,2-dimethylthiomorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(N2C=NC=C2)C=C1 YVHREEZRZWNIPG-FQEVSTJZSA-N 0.000 description 1
- UCQVNLQYGQSSBP-IBGZPJMESA-N (3s)-n-hydroxy-4-[4-[4-(1h-imidazol-2-yl)phenoxy]phenyl]sulfonyl-2,2-dimethylthiomorpholine-3-carboxamide Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(C=2NC=CN=2)C=C1 UCQVNLQYGQSSBP-IBGZPJMESA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- ILWJAOPQHOZXAN-UHFFFAOYSA-N 1,3-dithianyl Chemical group [CH]1SCCCS1 ILWJAOPQHOZXAN-UHFFFAOYSA-N 0.000 description 1
- KFHQOZXAFUKFNB-UHFFFAOYSA-N 1,3-oxathiolanyl Chemical group [CH]1OCCS1 KFHQOZXAFUKFNB-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- FFRBVGATVOCVAZ-UHFFFAOYSA-N 1-(4-phenylphenyl)imidazole Chemical group C1=NC=CN1C1=CC=C(C=2C=CC=CC=2)C=C1 FFRBVGATVOCVAZ-UHFFFAOYSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 1
- LOHAMFKEOQZPLB-UHFFFAOYSA-N 1-hydroxyethanesulfonamide Chemical class CC(O)S(N)(=O)=O LOHAMFKEOQZPLB-UHFFFAOYSA-N 0.000 description 1
- SSTNIXFHCIOCJI-UHFFFAOYSA-N 1-methyl-4-phenoxybenzene Chemical compound C1=CC(C)=CC=C1OC1=CC=CC=C1 SSTNIXFHCIOCJI-UHFFFAOYSA-N 0.000 description 1
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 description 1
- MBGIMCUOBVDQEO-UHFFFAOYSA-N 2,4-dihydrobenzotriazol-4-ide Chemical compound N1N=NC2=C1C=CC=[C-]2 MBGIMCUOBVDQEO-UHFFFAOYSA-N 0.000 description 1
- ZSKQDAAZMKZRKI-UHFFFAOYSA-N 2-(benzenesulfonyl)thiomorpholine-3-carboxamide Chemical compound NC(=O)C1NCCSC1S(=O)(=O)C1=CC=CC=C1 ZSKQDAAZMKZRKI-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- XSLDUNYYIOJHMP-UHFFFAOYSA-N 2-[4-[4-(furan-3-yl)phenoxy]phenyl]sulfonylthiomorpholine-3-carboxylic acid Chemical compound OC(=O)C1NCCSC1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(C2=COC=C2)C=C1 XSLDUNYYIOJHMP-UHFFFAOYSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- IULJSGIJJZZUMF-UHFFFAOYSA-N 2-hydroxybenzenesulfonic acid Chemical compound OC1=CC=CC=C1S(O)(=O)=O IULJSGIJJZZUMF-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- FVJPIFWJQUIPNO-UHFFFAOYSA-N 2-methylpropan-2-ol;oxolane Chemical compound CC(C)(C)O.C1CCOC1 FVJPIFWJQUIPNO-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- VCZWNTINWOGZMA-UHFFFAOYSA-N 2-sulfonylaziridine Chemical class O=S(=O)=C1CN1 VCZWNTINWOGZMA-UHFFFAOYSA-N 0.000 description 1
- SUFUDUDHGOHFHW-UHFFFAOYSA-N 2h-1,4-thiazine-3-carboxylic acid Chemical compound OC(=O)C1=NC=CSC1 SUFUDUDHGOHFHW-UHFFFAOYSA-N 0.000 description 1
- FPMRFGHGLLFAJZ-UHFFFAOYSA-N 3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pent-4-enoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)C(C)(C)C=C FPMRFGHGLLFAJZ-UHFFFAOYSA-N 0.000 description 1
- MJKYBKYVJLYQDF-UHFFFAOYSA-N 3-[4-(4-bromophenoxy)phenyl]sulfonyl-2,2-dimethyl-1-oxo-1,4-thiazinane-3-carboxylic acid Chemical compound CC1(C)S(=O)CCNC1(C(O)=O)S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Br)C=C1 MJKYBKYVJLYQDF-UHFFFAOYSA-N 0.000 description 1
- PLFIHRLMNDKZGJ-UHFFFAOYSA-N 4-(4-bromophenoxy)benzenesulfonyl chloride Chemical compound C1=CC(S(=O)(=O)Cl)=CC=C1OC1=CC=C(Br)C=C1 PLFIHRLMNDKZGJ-UHFFFAOYSA-N 0.000 description 1
- PDAYRCHIAPCRRD-UHFFFAOYSA-N 4-(4-fluorophenoxy)benzenesulfonyl chloride Chemical compound C1=CC(F)=CC=C1OC1=CC=C(S(Cl)(=O)=O)C=C1 PDAYRCHIAPCRRD-UHFFFAOYSA-N 0.000 description 1
- INXLITRVKMFIGU-UHFFFAOYSA-N 4-(4-methylphenoxy)benzenesulfonyl chloride Chemical compound C1=CC(C)=CC=C1OC1=CC=C(S(Cl)(=O)=O)C=C1 INXLITRVKMFIGU-UHFFFAOYSA-N 0.000 description 1
- HGTSKSHAKCGNFY-UHFFFAOYSA-N 4-acetyl-1-(4-phenoxyphenyl)sulfonylpiperazine-2-carboxylic acid Chemical compound OC(=O)C1CN(C(=O)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 HGTSKSHAKCGNFY-UHFFFAOYSA-N 0.000 description 1
- MYPXYQMABPTFFN-UHFFFAOYSA-N 4-phenoxybenzenesulfonic acid Chemical compound C1=CC(S(=O)(=O)O)=CC=C1OC1=CC=CC=C1 MYPXYQMABPTFFN-UHFFFAOYSA-N 0.000 description 1
- ILYZFHJHELGXFE-UHFFFAOYSA-N 4-pyridin-4-yloxybenzenesulfonyl chloride;hydrochloride Chemical compound Cl.C1=CC(S(=O)(=O)Cl)=CC=C1OC1=CC=NC=C1 ILYZFHJHELGXFE-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 102000043279 ADAM17 Human genes 0.000 description 1
- 108091007505 ADAM17 Proteins 0.000 description 1
- 206010048998 Acute phase reaction Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- YLMXBNACRIGGFX-UHFFFAOYSA-N C=1[C-]=NNN=1 Chemical class C=1[C-]=NNN=1 YLMXBNACRIGGFX-UHFFFAOYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 102000004266 Collagen Type IV Human genes 0.000 description 1
- 108010042086 Collagen Type IV Proteins 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- XUJNEKJLAYXESH-UWTATZPHSA-N D-Cysteine Chemical compound SC[C@@H](N)C(O)=O XUJNEKJLAYXESH-UWTATZPHSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- 229930195711 D-Serine Natural products 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- WLTCKEHCTUYJGI-UHFFFAOYSA-N Diethyl aminomalonate Chemical compound CCOC(=O)C(N)C(=O)OCC WLTCKEHCTUYJGI-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 229930195710 D‐cysteine Natural products 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 101000933374 Gallus gallus Brain-specific homeobox/POU domain protein 3 Proteins 0.000 description 1
- 108010026132 Gelatinases Proteins 0.000 description 1
- 102000013382 Gelatinases Human genes 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108030004510 Interstitial collagenases Proteins 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- VWVQUYSYXZFPHW-ZBXDZARASA-N ONC(=O)C1C([S@](CCN1S(=O)(=O)C1=CC=C(C=C1)OC1=CC=C(C=C1)F)=O)(C)C Chemical compound ONC(=O)C1C([S@](CCN1S(=O)(=O)C1=CC=C(C=C1)OC1=CC=C(C=C1)F)=O)(C)C VWVQUYSYXZFPHW-ZBXDZARASA-N 0.000 description 1
- LUGDKMAXNFNZMD-MRXNPFEDSA-N ONC(=O)[C@H]1COCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 Chemical compound ONC(=O)[C@H]1COCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 LUGDKMAXNFNZMD-MRXNPFEDSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- FXTTXRHGRZVUAG-UHFFFAOYSA-N P.Cl.Cl.Cl.Cl.Cl Chemical compound P.Cl.Cl.Cl.Cl.Cl FXTTXRHGRZVUAG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- HJPOKQICBCJGHE-UHFFFAOYSA-J [C+4].[Cl-].[Cl-].[Cl-].[Cl-] Chemical compound [C+4].[Cl-].[Cl-].[Cl-].[Cl-] HJPOKQICBCJGHE-UHFFFAOYSA-J 0.000 description 1
- LCEISKAANHGSNY-UHFFFAOYSA-N [O].ON Chemical compound [O].ON LCEISKAANHGSNY-UHFFFAOYSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- YEDHPVNPKHFZFT-UHFFFAOYSA-N benzyl 2,5-dioxopyrrolidine-1-carboperoxoate Chemical compound O=C1CCC(=O)N1C(=O)OOCC1=CC=CC=C1 YEDHPVNPKHFZFT-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- ZCILODAAHLISPY-UHFFFAOYSA-N biphenyl ether Natural products C1=C(CC=C)C(O)=CC(OC=2C(=CC(CC=C)=CC=2)O)=C1 ZCILODAAHLISPY-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- XEKAUTDWPYQNFU-UHFFFAOYSA-N chlorane Chemical compound Cl.Cl.Cl XEKAUTDWPYQNFU-UHFFFAOYSA-N 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- YVHPHQBRUPLYOS-UHFFFAOYSA-N dichloromethane;methane Chemical compound C.ClCCl YVHPHQBRUPLYOS-UHFFFAOYSA-N 0.000 description 1
- MQYQOVYIJOLTNX-UHFFFAOYSA-N dichloromethane;n,n-dimethylformamide Chemical compound ClCCl.CN(C)C=O MQYQOVYIJOLTNX-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- QRTWDLOBCCXXGN-LJQANCHMSA-N ethyl 2-[(3r)-4-[4-(4-chlorophenoxy)phenyl]sulfonyl-3-(hydroxycarbamoyl)piperazin-1-yl]acetate Chemical compound ONC(=O)[C@H]1CN(CC(=O)OCC)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 QRTWDLOBCCXXGN-LJQANCHMSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical class OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- QZOFFMRDIRXGKJ-UHFFFAOYSA-M hydron;4-pyridin-1-ium-1-ylpyridine;dichloride Chemical compound Cl.[Cl-].C1=CC=CC=[N+]1C1=CC=NC=C1 QZOFFMRDIRXGKJ-UHFFFAOYSA-M 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000010930 lactamization Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- FIXGPNLTDAUQQF-BYPYZUCNSA-N methyl (2s)-2-amino-3-methyl-3-sulfanylbutanoate Chemical compound COC(=O)[C@H](N)C(C)(C)S FIXGPNLTDAUQQF-BYPYZUCNSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- FMXOEQQPVONPBU-UHFFFAOYSA-N methylidene(dioxido)azanium Chemical compound [O-][N+]([O-])=C FMXOEQQPVONPBU-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000002864 mononuclear phagocyte Anatomy 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- YXVFYQXJAXKLAK-UHFFFAOYSA-N p-hydroxybiphenyl Natural products C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000006194 pentinyl group Chemical group 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- KLNGJOPYFVWJDS-LJQANCHMSA-N tert-butyl (3r)-4-[4-(4-fluorophenoxy)phenyl]sulfonyl-3-(hydroxycarbamoyl)piperazine-1-carboxylate Chemical compound ONC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(F)C=C1 KLNGJOPYFVWJDS-LJQANCHMSA-N 0.000 description 1
- PFUYTJUZEPQIIF-UHFFFAOYSA-N tert-butyl 2,3-dibromopropanoate Chemical compound CC(C)(C)OC(=O)C(Br)CBr PFUYTJUZEPQIIF-UHFFFAOYSA-N 0.000 description 1
- RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 0.000 description 1
- SUXHUKREMWJVSY-UHFFFAOYSA-N tert-butyl thiomorpholine-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1CSCCN1 SUXHUKREMWJVSY-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 230000008354 tissue degradation Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000002993 trophoblast Anatomy 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000007966 viscous suspension Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
- C07D239/04—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines 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
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US56976695A | 1995-12-08 | 1995-12-08 | |
| US569766 | 1995-12-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2233275T3 true ES2233275T3 (es) | 2005-06-16 |
Family
ID=24276764
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES00128719T Expired - Lifetime ES2233275T3 (es) | 1995-12-08 | 1996-12-05 | Intermediarios que sirven para la preparacion de inhibidores de metaloproteinasas. |
| ES96944229T Expired - Lifetime ES2195034T3 (es) | 1995-12-08 | 1996-12-05 | Inhibidor de metaloproteinasas, composicion farmaceutica que contiene este inhibidor y su utilizacion farmaceutica, y procedimientos que sirven para su preparacion. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES96944229T Expired - Lifetime ES2195034T3 (es) | 1995-12-08 | 1996-12-05 | Inhibidor de metaloproteinasas, composicion farmaceutica que contiene este inhibidor y su utilizacion farmaceutica, y procedimientos que sirven para su preparacion. |
Country Status (39)
Families Citing this family (114)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6500948B1 (en) * | 1995-12-08 | 2002-12-31 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof |
| EA003294B1 (ru) * | 1995-12-08 | 2003-04-24 | Агурон Фармасьютикалс, Инк. | Ингибиторы металлопротеиназы, фармацевтические композиции, их содержащие, и их фармацевтические применения |
| US6747027B1 (en) | 1996-07-22 | 2004-06-08 | Pharmacia Corporation | Thiol sulfonamide metalloprotease inhibitors |
| ATE233552T1 (de) * | 1996-07-22 | 2003-03-15 | Monsanto Co | Thiol-sulfonen als metalloproteinaseinhibitoren |
| BR9712792A (pt) * | 1996-08-28 | 1999-12-14 | Procter & Gamble | Inibidores de metaloprotease bidentada. |
| HUP0000505A3 (en) * | 1996-08-28 | 2001-12-28 | Procter & Gamble | Saturated 7-9 membered heterocyclic n-hydroxycarboxamide derivatives and pharmaceutical compositions containing them |
| US6872742B2 (en) | 1996-08-28 | 2005-03-29 | The Procter & Gamble Company | Substituted cyclic amine metalloprotease inhibitors |
| BR9713465A (pt) * | 1996-08-28 | 2000-03-28 | Procter & Gamble | Inibidores metalotprotease de amina cìclica sibstituìda |
| CN1228771A (zh) * | 1996-08-28 | 1999-09-15 | 普罗克特和甘保尔公司 | 1,3-二杂环金属蛋白酶抑制剂 |
| ATE226573T1 (de) * | 1996-08-28 | 2002-11-15 | Procter & Gamble | Heterozyklische metalloproteaseinhibitoren |
| US5929097A (en) * | 1996-10-16 | 1999-07-27 | American Cyanamid Company | Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US5962481A (en) | 1996-10-16 | 1999-10-05 | American Cyanamid Company | Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US5977408A (en) * | 1996-10-16 | 1999-11-02 | American Cyanamid Company | Preparation and use of β-sulfonamido hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| KR20000049197A (ko) * | 1996-10-16 | 2000-07-25 | 윌리암 에이취 캘넌, 에곤 이 버그 | 매트릭스 메탈로프로테이나제 및 종양 괴사 인자-α 전환 효소억제제로서의 오르토-설폰아미도 헤테로아릴 하이드록삼산의 제조 및 용도 |
| US6228869B1 (en) | 1996-10-16 | 2001-05-08 | American Cyanamid Company | Ortho-sulfonamido bicyclic hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US6548524B2 (en) | 1996-10-16 | 2003-04-15 | American Cyanamid Company | Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US6008243A (en) * | 1996-10-24 | 1999-12-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
| US6174915B1 (en) | 1997-03-25 | 2001-01-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| WO1998027069A1 (en) * | 1996-12-17 | 1998-06-25 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine compounds as inhibitors of mmp or tnf |
| US7115632B1 (en) | 1999-05-12 | 2006-10-03 | G. D. Searle & Co. | Sulfonyl aryl or heteroaryl hydroxamic acid compounds |
| IL131493A (en) | 1997-03-04 | 2004-05-12 | Monsanto Co | Aromatic compounds of the hydroxamic sulfonyl alpha-deroxamic acid and their use in the preparation of drugs for the treatment of a condition associated with pathological activity of the metalloprotease matrix |
| US6696449B2 (en) | 1997-03-04 | 2004-02-24 | Pharmacia Corporation | Sulfonyl aryl hydroxamates and their use as matrix metalloprotease inhibitors |
| US6794511B2 (en) | 1997-03-04 | 2004-09-21 | G. D. Searle | Sulfonyl aryl or heteroaryl hydroxamic acid compounds |
| US6638952B1 (en) | 1997-03-04 | 2003-10-28 | Pharmacia Corporation | Aromatic sulfonyl alpha-cycloamino hydroxamic acid compounds |
| US6087359A (en) * | 1997-03-04 | 2000-07-11 | Getman; Daniel P. | Thioaryl sulfonamide hydroxamic acid compounds |
| EP0983267B1 (en) * | 1997-03-04 | 2005-01-26 | Pharmacia Corporation | Amidoaromatic ring sulfonamide hydroxamic acid compounds |
| WO1998039316A1 (en) | 1997-03-04 | 1998-09-11 | Monsanto Company | N-hydroxy 4-sulfonyl butanamide compounds |
| US6362183B1 (en) | 1997-03-04 | 2002-03-26 | G. D. Searle & Company | Aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds |
| US5985900A (en) * | 1997-04-01 | 1999-11-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| EP0973748A1 (en) * | 1997-04-01 | 2000-01-26 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| AU7294098A (en) * | 1997-05-09 | 1998-11-27 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| JP2004137284A (ja) * | 1997-06-17 | 2004-05-13 | Kaken Pharmaceut Co Ltd | 2−スルファモイル安息香酸誘導体 |
| CN1265647A (zh) | 1997-07-31 | 2000-09-06 | 普罗克特和甘保尔公司 | 无环金属蛋白酶抑制剂 |
| US6403632B1 (en) * | 2000-03-01 | 2002-06-11 | Bristol Myers Squibb Pharma Co | Lactam metalloprotease inhibitors |
| JPH11199512A (ja) * | 1997-10-24 | 1999-07-27 | Pfizer Prod Inc | 変形性関節症および他のmmp媒介疾患の治療のためのmmp−13選択的阻害剤の使用 |
| JP2001523662A (ja) | 1997-11-14 | 2001-11-27 | ジー・ディー・サール・アンド・カンパニー | 芳香族スルホンヒドロキサム酸メタロプロテアーゼ阻害剤 |
| US20010039287A1 (en) | 1997-11-14 | 2001-11-08 | Thomas E Barta | Aromatic sulfone hydroxamic acid metalloprotease inhibitor |
| US6750228B1 (en) | 1997-11-14 | 2004-06-15 | Pharmacia Corporation | Aromatic sulfone hydroxamic acid metalloprotease inhibitor |
| CN1293663A (zh) * | 1998-01-27 | 2001-05-02 | 美国氰胺公司 | 为基质金属蛋白酶抑制剂的2,3,4,5-四氢-1h-[1,4]苯并二氮杂䓬-3-异羟肟酸 |
| US6071903A (en) * | 1998-01-27 | 2000-06-06 | American Cyanamid Company | 2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-hydroxyamic acids |
| PL342009A1 (en) | 1998-02-04 | 2001-05-07 | Novartis Ag | Sulphonylamine derivatives capable to inhibit extracellular substance degrading metaloproteinases |
| US6410580B1 (en) | 1998-02-04 | 2002-06-25 | Novartis Ag | Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases |
| US6329418B1 (en) * | 1998-04-14 | 2001-12-11 | The Procter & Gamble Company | Substituted pyrrolidine hydroxamate metalloprotease inhibitors |
| BR9910678A (pt) | 1998-05-14 | 2001-10-02 | Du Pont Pharm Co | Composto, composição farmacêutica, método para traramento ou prevenção de uma doença inflamatória, método para tratamento de uma condição ou uma doença mediada por mmps, tnf, agrecanase, ou um composto dos mesmos, em um mamìfero, método de redução de nìveis de tnf em pacientes, sem a inibição de mmps, método para tratamento de uma condição ou uma doença e uso de um novo composto |
| WO1999065867A1 (en) | 1998-06-17 | 1999-12-23 | Du Pont Pharmaceuticals Company | Cyclic hydroxamic acids as metalloproteinase inhibitors |
| EP1357109B1 (en) | 1998-06-18 | 2008-07-23 | F. Hoffmann-La Roche Ag | Process for aryl alkyl sulfide |
| FR2780402B1 (fr) * | 1998-06-30 | 2001-04-27 | Adir | Nouveaux composes acides carboxyliques et hydroxamiques inhibiteurs de metalloproteases, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| UA59453C2 (uk) * | 1998-08-12 | 2003-09-15 | Пфайзер Продактс Інк. | Похідні гідроксипіпеколат гідроксамової кислоти як інгібітори матричних металопротеїназ |
| WO2000009492A1 (en) * | 1998-08-12 | 2000-02-24 | Pfizer Products Inc. | Tace inhibitors |
| US6509337B1 (en) * | 1998-09-17 | 2003-01-21 | Pfizer Inc. | Arylsulfonyl Hydroxamic Acid derivatives as MMP and TNF inhibitors |
| US6307049B1 (en) | 1998-09-30 | 2001-10-23 | The Procter & Gamble Co. | Heterocyclic 2-substituted ketoamides |
| US6300341B1 (en) | 1998-09-30 | 2001-10-09 | The Procter & Gamble Co. | 2-substituted heterocyclic sulfonamides |
| JP2002525305A (ja) * | 1998-09-30 | 2002-08-13 | ザ、プロクター、エンド、ギャンブル、カンパニー | スルホンアミドを用いた脱毛治療の方法 |
| US6288261B1 (en) * | 1998-12-18 | 2001-09-11 | Abbott Laboratories | Inhibitors of matrix metalloproteinases |
| US6858598B1 (en) * | 1998-12-23 | 2005-02-22 | G. D. Searle & Co. | Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
| WO2000038715A2 (en) * | 1998-12-23 | 2000-07-06 | G.D. Searle & Co. | Use of an integrin antagonist and radiation in the treatment of neoplasia |
| BR0007784A (pt) | 1999-01-27 | 2002-02-05 | American Cyanamid Co | Composto, método para inibir mudanças patológicas mediadas pela enzima que converte o tnf-alfa (tace) em um mamìfero, composição farmacêutica, e, processo para preparar um composto |
| US6200996B1 (en) | 1999-01-27 | 2001-03-13 | American Cyanamid Company | Heteroaryl acetylenic sulfonamide and phosphinic acid amide hydroxamic acid tace inhibitors |
| US6753337B2 (en) | 1999-01-27 | 2004-06-22 | Wyeth Holdings Corporation | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors |
| US6277885B1 (en) | 1999-01-27 | 2001-08-21 | American Cyanamid Company | Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors |
| US6340691B1 (en) | 1999-01-27 | 2002-01-22 | American Cyanamid Company | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors |
| US6225311B1 (en) | 1999-01-27 | 2001-05-01 | American Cyanamid Company | Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors |
| US6946473B2 (en) | 1999-01-27 | 2005-09-20 | Wyeth Holdings Corporation | Preparation and use of acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors |
| AR022423A1 (es) * | 1999-01-27 | 2002-09-04 | American Cyanamid Co | Compuestos derivados de acidos 2,3,4,5-tetrahidro-1h-[1,4]benzodiazepina-3-hidroxamicos, composicion farmaceutica que los comprenden, y el uso de losmismos para la manufactura de un medicamento |
| US6313123B1 (en) | 1999-01-27 | 2001-11-06 | American Cyanamid Company | Acetylenic sulfonamide thiol tace inhibitors |
| US6326516B1 (en) | 1999-01-27 | 2001-12-04 | American Cyanamid Company | Acetylenic β-sulfonamido and phosphinic acid amide hydroxamic acid TACE inhibitors |
| US6544984B1 (en) | 1999-01-27 | 2003-04-08 | American Cyanamid Company | 2,3,4,5-tetrahydro-1H-(1,4)benzodiazepine-3-hydroxamic acids |
| US6762178B2 (en) | 1999-01-27 | 2004-07-13 | Wyeth Holdings Corporation | Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors |
| AU775701B2 (en) | 1999-02-08 | 2004-08-12 | G.D. Searle & Co. | Sulfamato hydroxamic acid metalloprotease inhibitor |
| US6800646B1 (en) | 1999-02-08 | 2004-10-05 | Pharmacia Corporation | Sulfamato hydroxamic acid metalloprotease inhibitor |
| SK12462001A3 (sk) | 1999-03-03 | 2002-04-04 | The Procter & Gamble Company | Inhibítory metaloproteáz |
| KR20010102486A (ko) | 1999-03-03 | 2001-11-15 | 데이비드 엠 모이어 | 알케닐- 및 알키닐-함유 메탈로프로테아제 저해제 |
| AUPP982399A0 (en) * | 1999-04-19 | 1999-05-13 | Fujisawa Pharmaceutical Co., Ltd. | Mmp inhibitor |
| US6583299B1 (en) | 1999-05-20 | 2003-06-24 | G.D. Searle & Co. | α-amino-β-sulfonyl hydroxamic acid compounds |
| US6869951B1 (en) | 1999-07-16 | 2005-03-22 | Pharmacia Corporation | Method of changing conformation of a matrix metalloproteinase |
| PE20010659A1 (es) | 1999-10-01 | 2001-06-20 | Hoffmann La Roche | Derivados de las pirimidin-2,4,6-trionas como inhibidores de metaloproteasas |
| IL151552A0 (en) | 2000-03-17 | 2003-04-10 | Bristol Myers Squibb Pharma Co | Cyclic beta-amino acid derivatives as inhibitors of matrix metalloproteases and tnf-alpha |
| ATE260272T1 (de) * | 2000-03-17 | 2004-03-15 | Bristol Myers Squibb Pharma Co | Beta-aminsäure-derivate zur verwendung als matrix-metalloproteasen- und tna-alpha-inhibitoren |
| EP1138680A1 (en) * | 2000-03-29 | 2001-10-04 | Pfizer Products Inc. | Gem substituted sulfonyl hydroxamic acids as MMP inhibitors |
| US6548667B2 (en) * | 2000-04-07 | 2003-04-15 | Samsung Electronics Co. Ltd. | Sulfonamide derivative as a matrix metalloproteinase inhibitor |
| US6683093B2 (en) | 2000-05-12 | 2004-01-27 | Pharmacia Corporation | Aromatic sulfone hydroxamic acids and their use as protease inhibitors |
| US6927216B2 (en) | 2000-10-03 | 2005-08-09 | Bristol-Myers Squibb Pharma Company | Cyclic sulfonyl compounds as inhibitors of metalloproteases |
| FR2819252A1 (fr) * | 2001-01-11 | 2002-07-12 | Servier Lab | Nouveaux derives d'acide hydroxamique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| US6642255B2 (en) | 2001-01-11 | 2003-11-04 | Bristol-Myers Squibb Pharma Company | 1,2,-Disubstituted cyclic inhibitors of matrix metalloproteases and TNF-alpha |
| WO2002055516A2 (en) | 2001-01-11 | 2002-07-18 | Bristol Myers Squibb Co | 1,1-DISUBSTITUTED CYCLIC INHIBITORS OF MATRIX METALLOPROTEASE AND TNF-$g(a) |
| MXPA01013326A (es) | 2001-02-14 | 2002-08-26 | Warner Lambert Co | Bifenil sulfonamidas utiles como inhibisdores de metaloproteinasa de matriz. |
| EP1373199A4 (en) | 2001-03-15 | 2004-04-07 | Bristol Myers Squibb Pharma Co | SPIROCYCLIC BETA-AMINOACID DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND THE CONVERSION ENZYME OF TNF-ALPHA (TAGE) |
| US6716845B2 (en) | 2001-03-30 | 2004-04-06 | Hoffmann-La Roche Inc. | Barbituric acid derivatives |
| JP2004530691A (ja) | 2001-05-11 | 2004-10-07 | ファルマシア・コーポレーション | 芳香族スルホンヒドロキサメートおよびプロテアーゼ阻害剤としてのそれらの使用 |
| WO2002096420A2 (en) * | 2001-05-29 | 2002-12-05 | Guilford Pharmaceuticals Inc. | Method for treating nerve injury caused by surgery |
| US6683078B2 (en) | 2001-07-19 | 2004-01-27 | Pharmacia Corporation | Use of sulfonyl aryl or heteroaryl hydroxamic acids and derivatives thereof as aggrecanase inhibitors |
| AUPR726201A0 (en) * | 2001-08-24 | 2001-09-20 | Fujisawa Pharmaceutical Co., Ltd. | New use of a cyclic compound |
| JP2003081937A (ja) * | 2001-09-07 | 2003-03-19 | Bayer Ag | ベンゼンスルホンアミド誘導体 |
| JP2005507937A (ja) | 2001-11-01 | 2005-03-24 | ワイス・ホールディングズ・コーポレイション | マトリックスメタロプロテイナーゼおよびtace阻害剤としてのアレンアリールスルホンアミドヒドロキサム酸 |
| WO2003048119A2 (en) * | 2001-11-30 | 2003-06-12 | Bristol-Myers Squibb Company | Method of producing n-[(2s)-sulfanyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-l-leucyl-l-tert-leucine n-methylamide and intermediate thereof |
| PE20030701A1 (es) | 2001-12-20 | 2003-08-21 | Schering Corp | Compuestos para el tratamiento de trastornos inflamatorios |
| CA2483314A1 (en) | 2002-04-25 | 2003-11-06 | Pharmacia Corporation | Piperidinyl-and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors |
| AU2003233154A1 (en) * | 2002-06-10 | 2003-12-22 | Pfizer Inc. | Metabolites of prinomastat and their sythesis |
| AU2003237532B2 (en) * | 2002-06-12 | 2009-07-30 | Symphony Evolution, Inc. | Human ADAM-10 inhibitors |
| US20040167182A1 (en) * | 2002-06-25 | 2004-08-26 | Becker Daniel P. | Hydroxamic acid and amide compounds and their use as protease inhibitors |
| US7199155B2 (en) | 2002-12-23 | 2007-04-03 | Wyeth Holdings Corporation | Acetylenic aryl sulfonate hydroxamic acid TACE and matrix metalloproteinase inhibitors |
| WO2004071390A2 (en) * | 2003-02-14 | 2004-08-26 | Applied Research Systems Ars Holding N.V. | Piperazine-2-carboxamide derivatives |
| JP2006517960A (ja) * | 2003-02-18 | 2006-08-03 | ファイザー インコーポレイテッド | C型肝炎ウイルスの阻害剤、それを使用する組成物および治療法 |
| ZA200507806B (en) | 2003-03-24 | 2007-03-28 | Actimis Pharmaceuticals Inc | 2-phenoxy- and 2-enysulfomamide derivatives with CCR3 antagonistic acitivity for the treatment of asthma and other inflammatory or immunolgical disorders |
| GT200500139A (es) | 2004-06-08 | 2005-07-25 | Metodo para la preparacion de acidos hidroxamicos | |
| DK2041181T3 (da) * | 2006-06-08 | 2011-08-29 | Helmholtz Zentrum Muenchen | Specifikke proteaseinhibitorer og deres anvendelse i cancerterapi |
| WO2009052200A2 (en) * | 2007-10-16 | 2009-04-23 | Symphony Evolution, Inc. | Human adam-10 inhibitors |
| EP2147684A1 (en) * | 2008-07-22 | 2010-01-27 | Bracco Imaging S.p.A | Diagnostic Agents Selective Against Metalloproteases |
| WO2011081884A1 (en) | 2009-12-14 | 2011-07-07 | Massachusetts Institute Of Technology | Systems and methods related to optical nanosensors including photoluminescent nanostructures |
| IT1401253B1 (it) | 2010-04-23 | 2013-07-18 | Uni Degli Studi Carlo Bo Urbino | Uso del sulodexide per la riduzione delle metalloproteinasi di matrice. |
| CN103998435A (zh) * | 2011-10-04 | 2014-08-20 | 法国国家健康医疗研究院 | 新型细胞凋亡诱导化合物 |
| EP3860608A1 (en) | 2018-10-04 | 2021-08-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Egfr inhibitors for treating keratodermas |
| KR102890026B1 (ko) * | 2019-04-26 | 2025-11-24 | 닛산 가가쿠 가부시키가이샤 | 아릴술폰산 에스테르 화합물의 제조 방법 |
| WO2020252439A1 (en) * | 2019-06-14 | 2020-12-17 | Loyola University Of Chicago | Carborane hydroxamic acid matrix metalloproteinase agents for boron neutron capture therapy |
Family Cites Families (48)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4032639A (en) * | 1976-03-22 | 1977-06-28 | American Home Products Corporation | 2,3,4,4A-Tetrahydro-1H-pyrazino[1,2-a,]quinoxalin-5(6H)-ones and derivatives thereof for relieving hypertension |
| ZW23187A1 (en) * | 1986-12-15 | 1988-06-29 | Hoffmann La Roche | Phosphinic acid derivatives |
| GB9000846D0 (en) * | 1990-01-15 | 1990-03-14 | Beecham Group Plc | Novel compounds |
| GB9022117D0 (en) * | 1990-10-11 | 1990-11-21 | Beecham Group Plc | Novel compounds |
| US5239078A (en) * | 1990-11-21 | 1993-08-24 | Glycomed Incorporated | Matrix metalloprotease inhibitors |
| US5189178A (en) * | 1990-11-21 | 1993-02-23 | Galardy Richard E | Matrix metalloprotease inhibitors |
| US5183900A (en) * | 1990-11-21 | 1993-02-02 | Galardy Richard E | Matrix metalloprotease inhibitors |
| JPH05503719A (ja) * | 1990-12-03 | 1993-06-17 | セルテック リミテッド | ペプチジル誘導体 |
| WO1992021360A1 (en) * | 1991-05-28 | 1992-12-10 | Merck & Co., Inc. | Substituted n-carboxyalkylpeptidyl derivatives as antidegenerative active agents |
| US5256657A (en) * | 1991-08-19 | 1993-10-26 | Sterling Winthrop, Inc. | Succinamide derivative matrix-metalloprotease inhibitors |
| GB9211706D0 (en) * | 1992-06-03 | 1992-07-15 | Celltech Ltd | Peptidyl derivatives |
| GB9211707D0 (en) * | 1992-06-03 | 1992-07-15 | Celltech Ltd | Peptidyl derivatives |
| US5376664A (en) * | 1992-07-27 | 1994-12-27 | The Du Pont Merck Pharmaceutical Company | Unsymmetrical mono-3-nitro bis-naphthalimides as anticancer agents |
| US5672583A (en) * | 1992-11-25 | 1997-09-30 | Merck & Co., Inc. | Carboxy-peptidyl derivatives as antidegenerative active agents |
| US5455258A (en) * | 1993-01-06 | 1995-10-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
| US5506242A (en) * | 1993-01-06 | 1996-04-09 | Ciba-Geigy Corporation | Arylsufonamido-substituted hydroxamic acids |
| US5552419A (en) * | 1993-01-06 | 1996-09-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
| GB9307956D0 (en) * | 1993-04-17 | 1993-06-02 | Walls Alan J | Hydroxamic acid derivatives |
| GB9308695D0 (en) * | 1993-04-27 | 1993-06-09 | Celltech Ltd | Peptidyl derivatives |
| US6013792A (en) * | 1993-08-05 | 2000-01-11 | Syntex (U.S.A.), Inc. | Matrix metalloprotease inhibitors |
| NZ271765A (en) * | 1993-08-05 | 1996-11-26 | Syntex Inc | Bridged [1,3]indolo macrocyclic lactam compounds and pharmaceutical compositions |
| US6037472A (en) * | 1993-11-04 | 2000-03-14 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
| UA48121C2 (uk) * | 1993-11-04 | 2002-08-15 | Сінтекс (С.Ш.А.) Інк. | Інгібітори матричних металопротеаз і фармацетична композиція на їх основі |
| AU678884B2 (en) * | 1994-01-22 | 1997-06-12 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
| US5514716A (en) * | 1994-02-25 | 1996-05-07 | Sterling Winthrop, Inc. | Hydroxamic acid and carboxylic acid derivatives, process for their preparation and use thereof |
| ATE181055T1 (de) * | 1994-05-28 | 1999-06-15 | British Biotech Pharm | Succinyl hydroxamsäure-, n-formyl-n-hydroxy- aminocarbonsäure- und succinsäureamid-derivate und ihre verwendung als metalloprotease- inhibitoren |
| AU690703B2 (en) * | 1994-06-22 | 1998-04-30 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
| GB9416897D0 (en) * | 1994-08-20 | 1994-10-12 | British Biotech Pharm | Metalloproteinase inhibitors |
| GB9423914D0 (en) * | 1994-11-26 | 1995-01-11 | British Biotech Pharm | Polyether derivatives as metalloproteinase inhibitors |
| US5863949A (en) * | 1995-03-08 | 1999-01-26 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
| CA2218503C (en) * | 1995-04-20 | 2001-07-24 | Pfizer Inc. | Arylsulfonyl hydroxamic acid derivatives |
| KR980009238A (ko) * | 1995-07-28 | 1998-04-30 | 우에노 도시오 | 설포닐아미노산 유도체 |
| ES2185750T3 (es) * | 1995-08-08 | 2003-05-01 | Ono Pharmaceutical Co | Derivados de acido hidroxamico utiles para la inhibicion gelatinasa. |
| TR199800849T2 (xx) * | 1995-11-13 | 1998-07-21 | Hoechst Aktiengesellschaft | Siklikle heterosiklik N-ikame edilmi� alfa-iminohidroksamla karbon asitleri |
| DE19542189A1 (de) * | 1995-11-13 | 1997-05-15 | Hoechst Ag | Cyclische N-substituierte alpha-Iminohydroxamsäuren |
| SK282833B6 (sk) * | 1995-11-17 | 2002-12-03 | Warner-Lambert Company | Sulfónamidové inhibítory matricových metaloproteináz a farmaceutická kompozícia obsahujúca tieto inhibítory |
| EA003294B1 (ru) * | 1995-12-08 | 2003-04-24 | Агурон Фармасьютикалс, Инк. | Ингибиторы металлопротеиназы, фармацевтические композиции, их содержащие, и их фармацевтические применения |
| US5753653A (en) * | 1995-12-08 | 1998-05-19 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| TW453995B (en) * | 1995-12-15 | 2001-09-11 | Novartis Ag | Certain alpha-substituted arylsulfonamido acetohydroxamic acids |
| DK0780386T3 (da) * | 1995-12-20 | 2003-02-03 | Hoffmann La Roche | Matrixmetalloproteaseinhibitorer |
| NZ323329A (en) * | 1995-12-22 | 1999-02-25 | Warner Lambert Co | 4-phenyl-piperidin-1-yl butyric acid derivatives and medicaments |
| US5837224A (en) * | 1996-01-19 | 1998-11-17 | The Regents Of The University Of Michigan | Method of inhibiting photoaging of skin |
| NZ325939A (en) * | 1996-01-23 | 2000-06-23 | Shionogi & Co | Sulphonated amino acid derivatives and matrix metalloproteinase inhibitors (MMP) containing these derivatives |
| EP0922030A1 (en) * | 1996-08-23 | 1999-06-16 | Pfizer Inc. | Arylsulfonylamino hydroxamic acid derivatives |
| BR9713465A (pt) * | 1996-08-28 | 2000-03-28 | Procter & Gamble | Inibidores metalotprotease de amina cìclica sibstituìda |
| HUP0000505A3 (en) * | 1996-08-28 | 2001-12-28 | Procter & Gamble | Saturated 7-9 membered heterocyclic n-hydroxycarboxamide derivatives and pharmaceutical compositions containing them |
| US5929097A (en) * | 1996-10-16 | 1999-07-27 | American Cyanamid Company | Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US5985900A (en) * | 1997-04-01 | 1999-11-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
-
1996
- 1996-12-05 EA EA199800541A patent/EA003294B1/ru not_active IP Right Cessation
- 1996-12-05 EP EP00128719A patent/EP1095936B1/en not_active Expired - Lifetime
- 1996-12-05 DE DE69626684T patent/DE69626684T2/de not_active Expired - Fee Related
- 1996-12-05 DE DE69633947T patent/DE69633947T2/de not_active Expired - Fee Related
- 1996-12-05 AP APAP/P/1998/001284A patent/AP1368A/en active
- 1996-12-05 PL PL96327275A patent/PL327275A1/xx unknown
- 1996-12-05 EP EP96944229A patent/EP0874830B1/en not_active Expired - Lifetime
- 1996-12-05 IL IL13802796A patent/IL138027A/en not_active IP Right Cessation
- 1996-12-05 IL IL12455996A patent/IL124559A/en not_active IP Right Cessation
- 1996-12-05 JP JP9521405A patent/JP2000502330A/ja not_active Ceased
- 1996-12-05 BR BR9611929A patent/BR9611929A/pt active Search and Examination
- 1996-12-05 AP APAP/P/2001/002270A patent/AP1288A/en active
- 1996-12-05 SI SI9630588T patent/SI0874830T1/xx unknown
- 1996-12-05 CN CNB961995831A patent/CN1207289C/zh not_active Expired - Fee Related
- 1996-12-05 CZ CZ19981733A patent/CZ292942B6/cs not_active IP Right Cessation
- 1996-12-05 WO PCT/US1996/019328 patent/WO1997020824A1/en not_active Ceased
- 1996-12-05 CA CA002238306A patent/CA2238306A1/en not_active Abandoned
- 1996-12-05 CN CNA2004100335232A patent/CN1542002A/zh active Pending
- 1996-12-05 HU HU9902092A patent/HUP9902092A3/hu unknown
- 1996-12-05 TR TR1998/00990T patent/TR199800990T2/xx unknown
- 1996-12-05 GE GEAP19964389A patent/GEP20012388B/en unknown
- 1996-12-05 PT PT96944229T patent/PT874830E/pt unknown
- 1996-12-05 AT AT96944229T patent/ATE234291T1/de not_active IP Right Cessation
- 1996-12-05 DK DK96944229T patent/DK0874830T3/da active
- 1996-12-05 ES ES00128719T patent/ES2233275T3/es not_active Expired - Lifetime
- 1996-12-05 AT AT00128719T patent/ATE283264T1/de not_active IP Right Cessation
- 1996-12-05 IL IL13481696A patent/IL134816A/xx not_active IP Right Cessation
- 1996-12-05 US US09/011,971 patent/US6153757A/en not_active Expired - Fee Related
- 1996-12-05 KR KR1019980704301A patent/KR19990072009A/ko not_active Ceased
- 1996-12-05 SK SK738-98A patent/SK73898A3/sk unknown
- 1996-12-05 AU AU14091/97A patent/AU725831C/en not_active Ceased
- 1996-12-05 NZ NZ325559A patent/NZ325559A/xx unknown
- 1996-12-05 ES ES96944229T patent/ES2195034T3/es not_active Expired - Lifetime
-
1997
- 1997-01-18 MY MYPI97000193A patent/MY117290A/en unknown
- 1997-01-22 HR HR96/019,328A patent/HRP970031A2/hr not_active Application Discontinuation
- 1997-01-23 TW TW086100726A patent/TW546293B/zh not_active IP Right Cessation
- 1997-01-29 GT GT199700015A patent/GT199700015A/es unknown
- 1997-01-29 GT GT199700015AK patent/GT199700015AA/es unknown
- 1997-02-06 SV SV1997000008A patent/SV1997000008A/es not_active Application Discontinuation
- 1997-02-12 CO CO97007169A patent/CO4790150A1/es unknown
- 1997-05-26 YU YU21597A patent/YU21597A/sr unknown
- 1997-05-27 PE PE1997000427A patent/PE69298A1/es not_active Application Discontinuation
- 1997-05-30 PA PA19978431301A patent/PA8431301A1/es unknown
- 1997-06-02 ID IDP971874A patent/ID17624A/id unknown
-
1998
- 1998-06-03 OA OA9800074A patent/OA10794A/en unknown
- 1998-06-04 MX MX9804457A patent/MX9804457A/es not_active IP Right Cessation
- 1998-06-05 NO NO19982590A patent/NO311360B1/no unknown
- 1998-06-05 BG BG102510A patent/BG64279B1/bg unknown
-
2000
- 2000-08-23 IL IL13802800A patent/IL138028A0/xx unknown
- 2000-08-23 IL IL13802700A patent/IL138027A0/xx unknown
-
2001
- 2001-06-11 IL IL14367401A patent/IL143674A0/xx unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1095936B1 (en) | Intermediates useful for the preparation of metallproteinase inhibitors | |
| US5753653A (en) | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses | |
| ES2276931T3 (es) | Derivados de compuestos heterociclicos y medicamentos. | |
| ES2213985T3 (es) | Derivados de hidroxiamida de acido 5-oxo-pirrolidin-2-carboxilico. | |
| USH1992H1 (en) | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their pharmaceutical uses | |
| ES2242402T3 (es) | Inhibidores de tace. | |
| JP2002504916A (ja) | 抗転移及び抗腫瘍活性を有するバルビツール酸誘導体 | |
| MX2013003360A (es) | Inhibidores de metaloproteinasa de matriz. | |
| US7132434B2 (en) | Metalloproteinase inhibitors | |
| AU6874498A (en) | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses | |
| US20080207608A1 (en) | 2-Propene-1-Ones As Hsp 70 Inducers | |
| ES2262248T3 (es) | Nuevos compuestos amida y medicamente que los contienen. | |
| JPWO1999025712A1 (ja) | 新規アミド化合物及びこれを含有する医薬 | |
| US6500948B1 (en) | Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof | |
| JP2003505367A (ja) | マトリックスメタロプロテイナーゼ阻害剤としての3−アリールスルホニル−2−(置換メチル)プロパン酸誘導体 | |
| CN1223636A (zh) | 基质金属蛋白酶抑制剂 | |
| HUP9903675A2 (hu) | Új acetamid-származékok és proteáz inhibitorok |