EP0938477A4 - Benzothiazolo- und verwandte heterocyclische gruppen enthaltende cystein- und serinprotease-inhibitoren - Google Patents
Benzothiazolo- und verwandte heterocyclische gruppen enthaltende cystein- und serinprotease-inhibitorenInfo
- Publication number
- EP0938477A4 EP0938477A4 EP97949430A EP97949430A EP0938477A4 EP 0938477 A4 EP0938477 A4 EP 0938477A4 EP 97949430 A EP97949430 A EP 97949430A EP 97949430 A EP97949430 A EP 97949430A EP 0938477 A4 EP0938477 A4 EP 0938477A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- alkyl
- optionally substituted
- carbons
- groups
- 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.)
- Withdrawn
Links
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 34
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 title abstract description 16
- 235000018417 cysteine Nutrition 0.000 title abstract description 16
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 title abstract description 16
- 239000002852 cysteine proteinase inhibitor Substances 0.000 title description 7
- 239000003001 serine protease inhibitor Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 463
- 125000000217 alkyl group Chemical group 0.000 claims description 119
- 125000003118 aryl group Chemical group 0.000 claims description 58
- -1 napthyl Chemical group 0.000 claims description 54
- 125000001072 heteroaryl group Chemical group 0.000 claims description 46
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 31
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical group 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 23
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 150000001413 amino acids Chemical class 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 102000004190 Enzymes Human genes 0.000 claims description 10
- 108090000790 Enzymes Proteins 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000003435 aroyl group Chemical group 0.000 claims description 9
- 125000001589 carboacyl group Chemical group 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
- 125000006413 ring segment Chemical group 0.000 claims description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002723 alicyclic group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 3
- 125000005141 aryl amino sulfonyl group Chemical group 0.000 claims description 3
- 125000006360 carbonyl amino methylene group Chemical group [H]N(C([*:1])=O)C([H])([H])[*:2] 0.000 claims description 3
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 3
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 195
- 102000005927 Cysteine Proteases Human genes 0.000 abstract description 27
- 108010005843 Cysteine Proteases Proteins 0.000 abstract description 27
- 102000012479 Serine Proteases Human genes 0.000 abstract description 20
- 108010022999 Serine Proteases Proteins 0.000 abstract description 20
- 239000003112 inhibitor Substances 0.000 abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 206
- 230000015572 biosynthetic process Effects 0.000 description 191
- 238000003786 synthesis reaction Methods 0.000 description 190
- 239000000543 intermediate Substances 0.000 description 115
- 239000000203 mixture Substances 0.000 description 99
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 89
- 239000007787 solid Substances 0.000 description 76
- 235000019439 ethyl acetate Nutrition 0.000 description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 52
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
- 150000001299 aldehydes Chemical class 0.000 description 47
- 239000000741 silica gel Substances 0.000 description 47
- 229910002027 silica gel Inorganic materials 0.000 description 47
- 239000000243 solution Substances 0.000 description 44
- 239000000460 chlorine Substances 0.000 description 41
- FZRKAZHKEDOPNN-UHFFFAOYSA-N Nitric oxide anion Chemical compound O=[N-] FZRKAZHKEDOPNN-UHFFFAOYSA-N 0.000 description 39
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- 238000003818 flash chromatography Methods 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- 239000012267 brine Substances 0.000 description 29
- 239000011734 sodium Substances 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000010992 reflux Methods 0.000 description 14
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 13
- 208000035475 disorder Diseases 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 12
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 108010032088 Calpain Proteins 0.000 description 10
- 102000007590 Calpain Human genes 0.000 description 10
- 102000035195 Peptidases Human genes 0.000 description 10
- 108091005804 Peptidases Proteins 0.000 description 10
- 239000004365 Protease Substances 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 230000007062 hydrolysis Effects 0.000 description 10
- 238000006460 hydrolysis reaction Methods 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 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 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- XHVNXVGEFJHTMY-VIFPVBQESA-N (2s)-2-amino-4-(3-chlorophenyl)butanoic acid Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC(Cl)=C1 XHVNXVGEFJHTMY-VIFPVBQESA-N 0.000 description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 4
- KYUNTDRHCPSMOG-UHFFFAOYSA-N 2h-1,3-benzothiazole-3-carboxylic acid Chemical class C1=CC=C2N(C(=O)O)CSC2=C1 KYUNTDRHCPSMOG-UHFFFAOYSA-N 0.000 description 4
- DEGMIFWLGSEDAA-UHFFFAOYSA-N 4,5-dihydro-1,2-benzothiazepine-3-carboxylic acid Chemical class C1CC(C(=O)O)=NSC2=CC=CC=C21 DEGMIFWLGSEDAA-UHFFFAOYSA-N 0.000 description 4
- ANMVTYAYYHHSTF-UHFFFAOYSA-N 4-(4-ethylpiperazin-1-yl)-N-[6-(2-fluoro-3-methoxyphenyl)-1H-indazol-3-yl]benzamide Chemical compound CCN1CCN(CC1)c1ccc(cc1)C(=O)Nc1n[nH]c2cc(ccc12)-c1cccc(OC)c1F ANMVTYAYYHHSTF-UHFFFAOYSA-N 0.000 description 4
- WQKHERPPDYPMNX-UHFFFAOYSA-N 6-chloro-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(Cl)=CC=C21 WQKHERPPDYPMNX-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 108090000190 Thrombin Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000001594 aberrant effect Effects 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 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
- 230000001225 therapeutic effect Effects 0.000 description 3
- 229960004072 thrombin Drugs 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 2
- MQHYPURFNHOHBH-UHFFFAOYSA-N 1,1-dioxo-8,9-dihydro-4h-[1,4]dioxino[2,3-h][1,2,4]benzothiadiazine-3-carboxylic acid Chemical compound O1CCOC2=C1C=CC1=C2S(=O)(=O)N=C(C(=O)O)N1 MQHYPURFNHOHBH-UHFFFAOYSA-N 0.000 description 2
- WOHLSTOWRAOMSG-UHFFFAOYSA-N 2,3-dihydro-1,3-benzothiazole Chemical class C1=CC=C2SCNC2=C1 WOHLSTOWRAOMSG-UHFFFAOYSA-N 0.000 description 2
- BZKOZYWGZKRTIB-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-6-amine Chemical compound O1CCOC2=CC(N)=CC=C21 BZKOZYWGZKRTIB-UHFFFAOYSA-N 0.000 description 2
- GAMNINPBAOTMLA-UHFFFAOYSA-N 3-(3-chlorophenyl)propanal Chemical compound ClC1=CC=CC(CCC=O)=C1 GAMNINPBAOTMLA-UHFFFAOYSA-N 0.000 description 2
- WIAAIYJUCDAKFY-UHFFFAOYSA-N 3-(4-methoxyphenyl)-9-(prop-2-ynylamino)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=CC(OC)=CC=C1N1C(=O)C(SC=2C3=C(NCC#C)C=CN=2)=C3N=C1 WIAAIYJUCDAKFY-UHFFFAOYSA-N 0.000 description 2
- MHHMTSUMJSEJAC-UHFFFAOYSA-N 4,5-dihydro-1,2-benzothiazepine Chemical class S1N=CCCC2=CC=CC=C21 MHHMTSUMJSEJAC-UHFFFAOYSA-N 0.000 description 2
- XDCOYBQVEVSNNB-UHFFFAOYSA-N 4-[(7-naphthalen-2-yl-1-benzothiophen-2-yl)methylamino]butanoic acid Chemical compound OC(=O)CCCNCc1cc2cccc(-c3ccc4ccccc4c3)c2s1 XDCOYBQVEVSNNB-UHFFFAOYSA-N 0.000 description 2
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 description 2
- LPENFAYPZGWBEY-UHFFFAOYSA-N 7-chloro-4,5-dihydro-1,2-benzothiazepine-3-carboxylic acid Chemical compound C1CC(C(=O)O)=NSC2=CC=C(Cl)C=C21 LPENFAYPZGWBEY-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 2
- 108090000617 Cathepsin G Proteins 0.000 description 2
- 102000004173 Cathepsin G Human genes 0.000 description 2
- 102100024539 Chymase Human genes 0.000 description 2
- 108090000227 Chymases Proteins 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 108010007979 Glycocholic Acid Proteins 0.000 description 2
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 2
- 150000008575 L-amino acids Chemical class 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 102100033174 Neutrophil elastase Human genes 0.000 description 2
- 108010067372 Pancreatic elastase Proteins 0.000 description 2
- 102000016387 Pancreatic elastase Human genes 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229940125907 SJ995973 Drugs 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- DBJUEJCZPKMDPA-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O DBJUEJCZPKMDPA-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 235000012501 ammonium carbonate Nutrition 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125844 compound 46 Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 230000002132 lysosomal effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 201000006938 muscular dystrophy Diseases 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- NCNJHAHPOUUEQX-LDVROUIZSA-N n-[(2s,3r)-3-hydroxy-1-phenyl-4-[[(1r)-1-phenylethyl]amino]butan-2-yl]-4-(4-methylpiperazine-1-carbonyl)benzamide Chemical compound C([C@@H]([C@H](O)CN[C@H](C)C=1C=CC=CC=1)NC(=O)C=1C=CC(=CC=1)C(=O)N1CCN(C)CC1)C1=CC=CC=C1 NCNJHAHPOUUEQX-LDVROUIZSA-N 0.000 description 2
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- 229940100662 nasal drops Drugs 0.000 description 2
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- XYBBWMOKTFOITB-NUHJPDEHSA-N (2S)-2,6-diamino-6-(benzenesulfonyl)hexan-1-ol Chemical compound OC[C@@H](N)CCCC(N)S(=O)(=O)C1=CC=CC=C1 XYBBWMOKTFOITB-NUHJPDEHSA-N 0.000 description 1
- RLDYUMPXPLOMJB-NUHJPDEHSA-N (2S)-2,6-diamino-6-(benzenesulfonyl)hexanal Chemical compound O=C[C@@H](N)CCCC(N)S(=O)(=O)C1=CC=CC=C1 RLDYUMPXPLOMJB-NUHJPDEHSA-N 0.000 description 1
- DIXMBHMNEHPFCX-MCMMXHMISA-N (2r)-2-[5-[6-amino-5-[(1r)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol Chemical compound O([C@H](C)C=1C(=CC=C(F)C=1)N1N=CC=N1)C(C(=NC=1)N)=CC=1C=1SC([C@](C)(O)CO)=NC=1C DIXMBHMNEHPFCX-MCMMXHMISA-N 0.000 description 1
- ZXSRWZWWLPMGKO-VIFPVBQESA-N (2s)-1,1-diethoxy-4-methylpentan-2-amine Chemical compound CCOC(OCC)[C@@H](N)CC(C)C ZXSRWZWWLPMGKO-VIFPVBQESA-N 0.000 description 1
- DHCAKDKLAGTYHA-VIFPVBQESA-N (2s)-2-(aminomethyl)-3-phenylpropanamide Chemical compound NC[C@@H](C(N)=O)CC1=CC=CC=C1 DHCAKDKLAGTYHA-VIFPVBQESA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- NDWZRNAVFZPUIR-VIFPVBQESA-N (3s)-3-amino-4-phenylbutanamide Chemical compound NC(=O)C[C@@H](N)CC1=CC=CC=C1 NDWZRNAVFZPUIR-VIFPVBQESA-N 0.000 description 1
- PXRAWGHQJQMXOO-VUWPPUDQSA-N (3s)-3-amino-n-ethyl-2-hydroxy-4-phenylbutanamide Chemical compound CCNC(=O)C(O)[C@@H](N)CC1=CC=CC=C1 PXRAWGHQJQMXOO-VUWPPUDQSA-N 0.000 description 1
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 1
- LENAVORGWBTPJR-UHFFFAOYSA-N (5-pyridin-3-ylfuran-2-yl)methanamine Chemical compound O1C(CN)=CC=C1C1=CC=CN=C1 LENAVORGWBTPJR-UHFFFAOYSA-N 0.000 description 1
- JHLIGYPHPBLDDL-UHFFFAOYSA-N (5-pyridin-3-ylthiophen-2-yl)methanamine Chemical compound S1C(CN)=CC=C1C1=CC=CN=C1 JHLIGYPHPBLDDL-UHFFFAOYSA-N 0.000 description 1
- QBTROWHSMGZXCV-RQURQNPSSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecoxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QBTROWHSMGZXCV-RQURQNPSSA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- SYVYNKWQZOUOAV-UHFFFAOYSA-N 1,1-dioxo-4-propyl-2,3-dihydro-1$l^{6},2,4-benzothiadiazine-3-carboxylic acid Chemical compound C1=CC=C2N(CCC)C(C(O)=O)NS(=O)(=O)C2=C1 SYVYNKWQZOUOAV-UHFFFAOYSA-N 0.000 description 1
- JYUXDXWXTPSAEL-UHFFFAOYSA-N 1,4-dioxane;oxolane Chemical compound C1CCOC1.C1COCCO1 JYUXDXWXTPSAEL-UHFFFAOYSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- HJORCZCMNWLHMB-UHFFFAOYSA-N 1-(3-aminopropyl)pyrrolidin-2-one Chemical compound NCCCN1CCCC1=O HJORCZCMNWLHMB-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 1
- FBPDAELXSKOZAD-UHFFFAOYSA-N 2-(2-sulfamoylphenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1S(N)(=O)=O FBPDAELXSKOZAD-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- ULAYIMGRKQVQRT-UHFFFAOYSA-N 2-(3-amino-2-chloro-3-oxopropyl)-4,5-dichlorobenzenesulfonyl chloride Chemical compound NC(=O)C(Cl)CC1=CC(Cl)=C(Cl)C=C1S(Cl)(=O)=O ULAYIMGRKQVQRT-UHFFFAOYSA-N 0.000 description 1
- REIYUPHKWSOTGI-UHFFFAOYSA-N 2-(3-amino-2-chloro-3-oxopropyl)-4,5-dimethoxybenzenesulfonyl chloride Chemical compound COC1=CC(CC(Cl)C(N)=O)=C(S(Cl)(=O)=O)C=C1OC REIYUPHKWSOTGI-UHFFFAOYSA-N 0.000 description 1
- SQULRGKIKFUIRP-UHFFFAOYSA-N 2-(propylamino)benzenesulfonamide Chemical compound CCCNC1=CC=CC=C1S(N)(=O)=O SQULRGKIKFUIRP-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- YAZSBRQTAHVVGE-UHFFFAOYSA-N 2-aminobenzenesulfonamide Chemical compound NC1=CC=CC=C1S(N)(=O)=O YAZSBRQTAHVVGE-UHFFFAOYSA-N 0.000 description 1
- WZBLQMFLOFOMPP-UHFFFAOYSA-N 2-benzyl-6,7-dimethoxy-1,1-dioxo-3,4-dihydro-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound O=S1(=O)C=2C=C(OC)C(OC)=CC=2CC(C(O)=O)N1CC1=CC=CC=C1 WZBLQMFLOFOMPP-UHFFFAOYSA-N 0.000 description 1
- YLVJVWRYQNDPGP-UHFFFAOYSA-N 2-benzyl-6,7-dimethoxy-3,4-dihydro-1,2-benzothiazine Chemical compound C(C1=CC=CC=C1)N1SC2=C(CC1)C=C(C(=C2)OC)OC YLVJVWRYQNDPGP-UHFFFAOYSA-N 0.000 description 1
- FDTJZPCXJVXHRM-HXBUSHRASA-N 2-benzyl-6,7-dimethoxy-N-[(2S)-1-oxo-1-phenylpropan-2-yl]-3,4-dihydro-1,2-benzothiazine-3-carboxamide Chemical compound C(C1=CC=CC=C1)N1SC2=C(CC1C(=O)N[C@@H](C)C(=O)C1=CC=CC=C1)C=C(C(=C2)OC)OC FDTJZPCXJVXHRM-HXBUSHRASA-N 0.000 description 1
- VXJCITIMYFYBNC-UHFFFAOYSA-N 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propanenitrile Chemical compound O1CCOC2=CC(CC(Cl)C#N)=CC=C21 VXJCITIMYFYBNC-UHFFFAOYSA-N 0.000 description 1
- AJPIJOPALPIMGE-UHFFFAOYSA-N 2-chloro-3-(3,4-dichlorophenyl)propanenitrile Chemical compound N#CC(Cl)CC1=CC=C(Cl)C(Cl)=C1 AJPIJOPALPIMGE-UHFFFAOYSA-N 0.000 description 1
- IFGPEULYMHUUSF-UHFFFAOYSA-N 2-chloro-3-(3,4-dimethoxyphenyl)propanenitrile Chemical compound COC1=CC=C(CC(Cl)C#N)C=C1OC IFGPEULYMHUUSF-UHFFFAOYSA-N 0.000 description 1
- GKAYMJFBTFQFMK-UHFFFAOYSA-N 2-chloro-3-(3-fluorophenyl)propanenitrile Chemical compound FC1=CC=CC(CC(Cl)C#N)=C1 GKAYMJFBTFQFMK-UHFFFAOYSA-N 0.000 description 1
- UVNDEQREGCNWSO-UHFFFAOYSA-N 2-ethyl-1,1-dioxo-3,4,7,8-tetrahydro-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxylic acid Chemical compound O1CCOC2=C1C=C1CC(C(O)=O)N(CC)S(=O)(=O)C1=C2 UVNDEQREGCNWSO-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- SYYHMQMVOMDOAR-UHFFFAOYSA-N 2-methyl-1,1-dioxo-3,4,7,8-tetrahydro-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxylic acid Chemical compound O1CCOC2=C1C=C1CC(C(O)=O)N(C)S(=O)(=O)C1=C2 SYYHMQMVOMDOAR-UHFFFAOYSA-N 0.000 description 1
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical group C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 1
- YBRHODCMROOROS-UHFFFAOYSA-N 2h-1,2-benzothiazine-3-carboxylic acid Chemical compound C1=CC=C2SNC(C(=O)O)=CC2=C1 YBRHODCMROOROS-UHFFFAOYSA-N 0.000 description 1
- SDYWXFYBZPNOFX-UHFFFAOYSA-N 3,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C(Cl)=C1 SDYWXFYBZPNOFX-UHFFFAOYSA-N 0.000 description 1
- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 1
- KDHWOCLBMVSZPG-UHFFFAOYSA-N 3-imidazol-1-ylpropan-1-amine Chemical compound NCCCN1C=CN=C1 KDHWOCLBMVSZPG-UHFFFAOYSA-N 0.000 description 1
- UIKUBYKUYUSRSM-UHFFFAOYSA-N 3-morpholinopropylamine Chemical compound NCCCN1CCOCC1 UIKUBYKUYUSRSM-UHFFFAOYSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- LNUSRWKFCKKKPA-UHFFFAOYSA-N 4-methoxy-2-methyl-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound C1=CC=C2C(OC)=C(C(O)=O)N(C)S(=O)(=O)C2=C1 LNUSRWKFCKKKPA-UHFFFAOYSA-N 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- DKVDQNQNRFUWRX-UHFFFAOYSA-N 6-chloro-2-methyl-1,1-dioxo-3,4-dihydro-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound ClC1=CC=C2S(=O)(=O)N(C)C(C(O)=O)CC2=C1 DKVDQNQNRFUWRX-UHFFFAOYSA-N 0.000 description 1
- AXPGHBKKFUWBGY-UHFFFAOYSA-N 6-fluoro-2-methyl-1,1-dioxo-3,4-dihydro-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound FC1=CC=C2S(=O)(=O)N(C)C(C(N)=O)CC2=C1 AXPGHBKKFUWBGY-UHFFFAOYSA-N 0.000 description 1
- MHZYEEJYXSVYQT-UHFFFAOYSA-N 7-amino-2,3-dihydro-1,4-benzodioxine-6-sulfonamide;hydrochloride Chemical compound Cl.O1CCOC2=C1C=C(N)C(S(N)(=O)=O)=C2 MHZYEEJYXSVYQT-UHFFFAOYSA-N 0.000 description 1
- DJSWNINDPRRCLC-GOSISDBHSA-N 7-methyl-n-[(2r)-1-phenoxypropan-2-yl]-3-(4-propan-2-ylphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Chemical compound C([C@@H](C)NC(=O)C1=C(N2N=CC(=C2N=C1)C=1C=CC(=CC=1)C(C)C)C)OC1=CC=CC=C1 DJSWNINDPRRCLC-GOSISDBHSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002027 Amyotrophy Diseases 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- JUWCJOKPYXOPST-UCSBTNPJSA-N C([C@](C)(NC(=O)C1CC2=CC=3OCCOC=3C=C2SN1CC)C(=O)C(O)=O)C1=CC=CC=C1 Chemical compound C([C@](C)(NC(=O)C1CC2=CC=3OCCOC=3C=C2SN1CC)C(=O)C(O)=O)C1=CC=CC=C1 JUWCJOKPYXOPST-UCSBTNPJSA-N 0.000 description 1
- GSQZHKZMWWFYSZ-LBVATQBMSA-N CC(C(=O)O)([C@H](CC1=CC=CC=C1)NC(=O)C1N(SC2=C(C1)C=C1C(=C2)OCCO1)CC)O Chemical compound CC(C(=O)O)([C@H](CC1=CC=CC=C1)NC(=O)C1N(SC2=C(C1)C=C1C(=C2)OCCO1)CC)O GSQZHKZMWWFYSZ-LBVATQBMSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 102000004225 Cathepsin B Human genes 0.000 description 1
- 102000005600 Cathepsins Human genes 0.000 description 1
- 108010084457 Cathepsins Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940125761 Compound 6g Drugs 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 241000193159 Hathewaya histolytica Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- ZGULIQLMOVOTDN-CZTOGXCSSA-N N-[(2S)-1-hydroxy-1-phenylpropan-2-yl]-2-methyl-3,4,7,8-tetrahydro-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxamide Chemical compound C1OC=2C(=CC3=C(CC(N(S3)C)C(=O)N[C@@H](C)C(O)C3=CC=CC=C3)C=2)OC1 ZGULIQLMOVOTDN-CZTOGXCSSA-N 0.000 description 1
- HTSTUMZFFMJMCP-BELGNNRLSA-N N-[(2S)-1-hydroxy-1-phenylpropan-2-yl]-2-methyl-3,4-dihydro-1,2-benzothiazine-3-carboxamide Chemical compound CN1SC2=C(CC1C(=O)N[C@@H](C)C(O)C1=CC=CC=C1)C=CC=C2 HTSTUMZFFMJMCP-BELGNNRLSA-N 0.000 description 1
- VJWKYPDYCYFRKB-LYGNXSNRSA-N N-[(2S)-3-hydroxy-4-[2-(methanesulfonamido)ethylamino]-4-oxo-1-phenylbutan-2-yl]-3,4,7,8-tetrahydro-2H-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxamide Chemical compound CS(=O)(=O)NCCNC(C([C@H](CC1=CC=CC=C1)NC(=O)C1NSC2=C(C1)C=C1C(=C2)OCCO1)O)=O VJWKYPDYCYFRKB-LYGNXSNRSA-N 0.000 description 1
- OFZHDLQXFIWOBM-YVEZCHAMSA-N N-[(2S)-3-hydroxy-4-oxo-1-phenyl-4-[2-[(5-pyridin-2-ylthiophen-2-yl)sulfonylamino]ethylamino]butan-2-yl]-3,4,7,8-tetrahydro-2H-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxamide Chemical compound N1=C(C=CC=C1)C1=CC=C(S1)S(=O)(=O)NCCNC(C([C@H](CC1=CC=CC=C1)NC(=O)C1NSC2=C(C1)C=C1C(=C2)OCCO1)O)=O OFZHDLQXFIWOBM-YVEZCHAMSA-N 0.000 description 1
- WMUXHGKAWZLZMB-DJZRFWRSSA-N N1=C(C=CC=C1)C1=CC=C(S1)S(=O)(=O)NCCNC(C([C@@H](N)CC1=CC=CC=C1)O)=O Chemical compound N1=C(C=CC=C1)C1=CC=C(S1)S(=O)(=O)NCCNC(C([C@@H](N)CC1=CC=CC=C1)O)=O WMUXHGKAWZLZMB-DJZRFWRSSA-N 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001738 Nervous System Trauma Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000031165 Pseudopannota vinckei Species 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- MJSHDCCLFGOEIK-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)OCC1=CC=CC=C1 MJSHDCCLFGOEIK-UHFFFAOYSA-N 0.000 description 1
- OOMGRWNPCPICJN-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-3-yl) carbonate Chemical compound C1C(=O)NC(=O)C1OC(=O)OCC1=CC=CC=C1 OOMGRWNPCPICJN-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 238000005957 chlorosulfonylation reaction Methods 0.000 description 1
- 108090001092 clostripain Proteins 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229940009976 deoxycholate Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- POCFBDFTJMJWLG-UHFFFAOYSA-N dihydrosinapic acid methyl ester Natural products COC(=O)CCC1=CC(OC)=C(O)C(OC)=C1 POCFBDFTJMJWLG-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- WWIBVRQWNGUDTG-UHFFFAOYSA-N ethyl 1,1-dioxo-4h-1$l^{6},2,4-benzothiadiazine-3-carboxylate Chemical compound C1=CC=C2NC(C(=O)OCC)=NS(=O)(=O)C2=C1 WWIBVRQWNGUDTG-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- FXHCFPUEIDRTMR-UHFFFAOYSA-N hydron;1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;chloride Chemical compound Cl.C1=CC=C2CNC(C(=O)O)CC2=C1 FXHCFPUEIDRTMR-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 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
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- WFGNJLMSYIJWII-FJXQXJEOSA-N methyl (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WFGNJLMSYIJWII-FJXQXJEOSA-N 0.000 description 1
- NZTCVGHPDWAALP-UHFFFAOYSA-N methyl 2,2-dimethoxyacetate Chemical compound COC(OC)C(=O)OC NZTCVGHPDWAALP-UHFFFAOYSA-N 0.000 description 1
- SBQZWSNNPUWXKT-UHFFFAOYSA-N methyl 2-methyl-1,1-dioxo-7,8-dihydro-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxylate Chemical compound O1CCOC2=C1C=C1C=C(C(=O)OC)N(C)S(=O)(=O)C1=C2 SBQZWSNNPUWXKT-UHFFFAOYSA-N 0.000 description 1
- YFBYSKZROIHCFW-UHFFFAOYSA-N methyl 2-methyl-1-oxo-3,4-dihydroisoquinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)N(C)C(C(=O)OC)CC2=C1 YFBYSKZROIHCFW-UHFFFAOYSA-N 0.000 description 1
- HCBYBSNVNNNJFJ-UHFFFAOYSA-N methyl 4-hydroxy-2-methyl-1,2-benzothiazine-3-carboxylate Chemical compound C1=CC=C2SN(C)C(C(=O)OC)=C(O)C2=C1 HCBYBSNVNNNJFJ-UHFFFAOYSA-N 0.000 description 1
- OPRYTHOVRHXDSL-UHFFFAOYSA-N methyl 4-methoxy-2-methyl-1,2-benzothiazine-3-carboxylate Chemical compound C1=CC=C2SN(C)C(C(=O)OC)=C(OC)C2=C1 OPRYTHOVRHXDSL-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000002161 motor neuron Anatomy 0.000 description 1
- VVQLXCKTYMHKSH-UHFFFAOYSA-N n-(1-aminoethyl)methanesulfonamide Chemical compound CC(N)NS(C)(=O)=O VVQLXCKTYMHKSH-UHFFFAOYSA-N 0.000 description 1
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 1
- FSBLVBBRXSCOKU-UHFFFAOYSA-N n-butyl isocyanide Chemical compound CCCC[N+]#[C-] FSBLVBBRXSCOKU-UHFFFAOYSA-N 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 208000028412 nervous system injury Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004693 neuron damage Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 229940100684 pentylamine Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-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
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- VFWRGKJLLYDFBY-UHFFFAOYSA-N silver;hydrate Chemical compound O.[Ag].[Ag] VFWRGKJLLYDFBY-UHFFFAOYSA-N 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 201000005060 thrombophlebitis Diseases 0.000 description 1
- 230000008354 tissue degradation Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
- C07D327/06—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6544—Six-membered rings
- C07F9/6547—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
Definitions
- Novel benzothiazo and related heterocyclic group- containing inhibitors of cysteine or serine proteases methods for making these novel compounds, and methods for using the same are disclosed.
- cysteine and serine proteases Numerous cysteine and serine proteases have been identified in human tissues.
- a "protease” is an enzyme which degrades proteins into smaller components (peptides) .
- the terms "cysteine protease” and “serine protease” refer to proteases which are distinguished by the presence therein of a cysteine or serine residue which plays a critical role in the catalytic process.
- Mammalian systems, including humans normally degrade and process proteins via a variety of enzymes including cysteine and serine proteases. However, when present at elevated levels or when abnormally activated, cysteine and serine proteases may be involved in pathophysiological processes.
- calpains calcium-activated neutral proteases
- cysteine proteases which are ubiquitously expressed in mammalian tissues.
- Two major calpains have been identified; calpain I and calpain II. While calpain II is the predominant form in many tissues, calpain I is thought to be the predominant form in pathological conditions of nerve tissues.
- the calpain family of cysteine proteases has been implicated in many diseases and disorders, including neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, platelet aggregation, cataracts and inflammation.
- Calpain I has been implicated in excitatory amino-acid induced neurotoxicity disorders including ischemia, hypoglycemia, Huntington' s Disease, and epilepsy.
- the lysosomal cysteine protease cathepsin B has been implicated in the following disorders: arthritis, inflammation, myocardial infarction, tumor metastasis, and muscular dystrophy.
- Other lysosomal cysteine proteases include cathepsins C, H, L and S.
- Interleukin-l ⁇ converting enzyme (“ICE") is a cysteine protease which catalyzes the formation of interleukin-l ⁇ .
- Interleukin-l ⁇ is an immunoregulatory protein implicated in the following disorders: inflammation, diabetes, septic shock, rheumatoid arthritis, and Alzheimer's disease.
- ICE has also been linked to apoptotic cell death of neurons, which is implicated in a variety of neurodegenerative disorders including Parkinson's disease, ischemia, and amyotrophic lateral sclerosis (ALS) .
- ALS amyotrophic lateral sclerosis
- Cysteine proteases are also produced by various pathogens.
- the cysteine protease clostripain is produced by Clostridium histolyticum .
- Other proteases are produced by Trypanosoma cruzi , malaria parasites Plasmodiu falciparum and P . vinckei and Streptococcus .
- Hepatitis A viral protease HAV C3 is a cysteine protease essential for processing of picornavirus structural proteins and enzymes.
- Exemplary serine proteases implicated in degenerative disorders include thrombin, human leukocyte elastase, pancreatic elastase, chymase and cathepsin G.
- thrombin is produced in the blood coagulation cascade, cleaves fibrinogen to form fibrin and activates Factor VIII; thrombin is implicated in thrombophlebitis, thrombosis and asthma.
- Human leukocyte elastase is implicated in tissue degenerative disorders such as rheumatoid arthritis, osteoarthritis , atherosclerosis, bronchitis, cystic fibrosis, and emphysema.
- Pancreatic elastase is implicated in pancreatitis.
- Chymase an enzyme important in angiotensin synthesis, is implicated in hypertension, myocardial infarction, and coronary heart disease.
- Cathepsin G is implicated in abnormal connective tissue degradation, particularly in the lung.
- the present invention is directed to novel cysteine and serine protease inhibitors which contain a benzoheterocyclic group.
- Exemplary compounds are represented by the following Formula I :
- A-B represents one, two, or three carbon atoms or nitrogen atoms, optionally connected by single bonds or one double bond, optionally substituted with one or more groups selected from R 3 , R 4 , OR 3 , OR 4 , R 4a , and 0R 4a , with the proviso that the number of nitrogen atoms is 0, 1 or 2 ;
- R 1 and R 2 are each independently hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, aryl having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, heteroaralkyl , or an optionally protected natural or unnatural side chain of an amino acid, said alkyl, cycloalkyl, aryl, and heteroaryl groups being optionally substituted with one or more K groups;
- R 3 , R 4 and R 4a are each independently hydrogen, lower alkyl, or a natural or unnatural side chain of an optionally protected amino acid, said alkyl groups being optionally substituted with an aryl or heteroaryl group;
- R 5 , R 6 , R 7 and R 8 are each independently hydrogen, alkyl having from one to about 14 carbons wherein said alkyl groups are optionally substituted with one or more K groups, alkoxy having from one to about 10 carbons, halogen, alkoxycarbonyl, carboxyl, hydroxyl , heterocyclic, or amino optionally substituted with 1 to 3 aryl or lower alkyl groups; or any two adjacent R 5 , R ⁇ , R 7 and R 8 groups taken together with any intervening atoms of the benzene ring to which they are attached form an alicyclic, aromatic, heterocyclic, or heteroaryl ring having 5 to 8 ring atoms; K is halogen, lower alkyl, lower alkenyl, aryl, heterocyclic, guanidino, nitro, alkoxycarbonyl, alkoxy, hydroxyl, carboxyl, arylaminosulfonyl , heteroarylaminosulfonyl, alkylami
- Y is O, NH, NR 9 or CHR 9 ;
- R 9 is hydrogen, alkyl having from one to about 10 carbons, said alkyl groups being optionally substituted with one or more K groups, aryl having from about 6 to about 14 carbons, or aralkyl having from about 7 to about 15 carbons;
- R 10 is aryloxy, heteroaryloxy, L, halogen, or has the formula O-M, wherein M has the structure:
- R is N or CR 11 ;
- W is a double bond or a single bond
- E and F are independently R 12 , R 13 , or J; or E and F taken together comprise a joined moiety, said joined moiety being an aliphatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aromatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aliphatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, or an aromatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, said aliphatic heterocyclic ring or said aromatic heterocyclic ring each having from 1 to 4 heteroatoms;
- R 11 , R 12 , and R 13 are independently H, alkyl having from 1 to 10 carbons, heteroaryl having from 1 to 10 carbons, alkanoyl having from 1 to 10 carbons, or aroyl, wherein said alkyl, heteroaryl, alkanoyl and aroyl groups are optionally substituted with J;
- R 14 and R 15 are independently H, alkyl having from 1 to 10 carbons, aryl, or heteroaryl, wherein said alkyl, aryl and heteroaryl groups are optionally substituted with K;
- L is a phosphorus-containing enzyme reactive group having the formula:
- the compounds of the invention are useful for the inhibition of cysteine and serine proteases. Beneficially, the compounds find utility in a variety of settings.
- the claimed compounds can be used, for example, as standards to screen for natural and synthetic cysteine protease and serine protease inhibitors which have the same or similar functional characteristics as the disclosed compounds.
- the compounds of the present invention can be used to alleviate, mediate, reduce and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases and/or serine proteases.
- methods for using the subject compounds such as methods for inhibiting serine proteases or cysteine proteases comprising contacting said proteases with an inhibitory amount of a compound of the invention are disclosed.
- Methodologies for making the benzothiazine group-containing inhibitors are also disclosed.
- A-B represents one, two, or three carbon atoms or nitrogen atoms, optionally connected by single bonds or one double bond, optionally substituted with one or more groups selected from R 3 , R 4 , OR 3 , OR 4 , R 4a , and OR 4a , with the proviso that the number of nitrogen atoms is 0, 1 or 2 ;
- R 1 and R 2 are each independently hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, aryl having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, heteroaralkyl, or an optionally protected natural or unnatural side chain of an amino acid, said alkyl, cycloalkyl, aryl, and heteroaryl groups being optionally substituted with one or more K groups;
- R 3 , R 4 and R 4a are each independently hydrogen, lower alkyl, or a natural or unnatural side chain of an optionally protected amino acid, said alkyl groups being optionally substituted with an aryl or heteroaryl group;
- R 5 , R 6 , R 7 and R 8 are each independently hydrogen, alkyl having from one to about 14 carbons wherein said alkyl groups are optionally substituted with one or more K groups, alkoxy having from one to about 10 carbons, halogen, alkoxycarbonyl, carboxyl, hydroxyl, heterocyclic, or amino optionally substituted with 1 to 3 aryl or lower alkyl groups; or any two adjacent R 5 , R 6 , R 7 and R 8 groups taken together with any intervening atoms of the benzene ring to which they are attached form an alicyclic, aromatic, heterocyclic, or heteroaryl ring having 5 to 8 ring atoms; K is halogen, lower alkyl, lower alkenyl , aryl, heterocyclic, guanidino, nitro, alkoxycarbonyl, alkoxy, hydroxyl, carboxyl, arylaminosulfonyl, heteroarylaminosulfonyl , alkylaminos
- R 9 is hydrogen, alkyl having from one to about 10 carbons, said alkyl groups being optionally substituted with one or more K groups, aryl having from about 6 to about 14 carbons, or aralkyl having from about 7 to about 15 carbons;
- R 10 is aryloxy, heteroaryloxy, L, halogen, or has the formula 0-M, wherein M has the structure:
- R is N or CR 11 ;
- W is a double bond or a single bond
- E and F are independently R 12 , R 13 , or J; or E and F taken together comprise a joined moiety, said joined moiety being an aliphatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aromatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aliphatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, or an aromatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, said aliphatic heterocyclic ring or said aromatic heterocyclic ring each having from 1 to 4 heteroatoms;
- R 11 , R 12 , and R 13 are independently H, alkyl having from 1 to 10 carbons, heteroaryl having from 1 to 10 carbons, alkanoyl having from 1 to 10 carbons, or aroyl, wherein said alkyl, heteroaryl, alkanoyl and aroyl groups are optionally substituted with J;
- J is
- R 14 and R 15 are independently H, alkyl having from 1 to 10 carbons, aryl, or heteroaryl, wherein said alkyl, aryl and heteroaryl groups are optionally substituted with K;
- L is a phosphorus-containing enzyme reactive group having the formula :
- m, n, and b are each independently 0 or 1 ;
- R 2 , R 5 and R 8 are each H.
- R 1 is alkyl or aralkyl, preferably i- butyl or benzyl .
- R 6 and R 7 are independently H, alkoxy, halogen, or heterocyclic, or R 6 and R 7 taken together form -0-CH 2 -CH 2 - O- .
- R 6 and R 7 are independently H, -OCH 3 , F, Cl, or morpholin-4-yl , or R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- .
- Y is 0, NH, NR 9 or CHR 9 , where R 9 is alkyl or aralkyl.
- Y is NR 9 or CHR 9 , where R 9 is methyl ethyl, i-propyl, i-butyl or benzyl .
- R 2 , R 5 and R 8 are each H;
- R 1 is alkyl or aralkyl, with i-butyl or benzyl being preferred;
- R 6 and R 7 are independently H, alkoxy, halogen, or heterocyclic, or R 6 and R 7 taken together form -0-CH 2 -CH 2 - 0-;
- Y is O, NH, NR 9 or CHR 9
- R 6 and R 7 are preferably independently H, -0CH 3 , F, Cl, or morpholin-4-yl , or R 6 and R 7 taken together form -0-CH 2 -CH 2 - O- , and Y is preferably NR 9 or CHR 9 , where R 9 is methyl ethyl, i-propyl, i-butyl or benzyl.
- A-B is -CH 2 -CH-; Z is S0 2 ; R 2 , R 5 and R 8 are each H; and
- R 1 is alkyl, alkyl substituted with K, or aralkyl, with i-butyl, benzyl, or alkyl substituted with phenylsulfonyl -amino being preferred;
- R 6 and R 7 are independently H, alkoxy, halogen, or heterocyclic, with H, OCH 3 , F, Cl , or morpholin-4-yl being preferred, or preferably R 6 and R 7 taken together form -0-CH 2 -CH 2 -0-;
- A-B is -CH 2 - CH-; Z is S0 2 ; R 2 , R 5 and R 8 are each H; and R 1 , R 6 , R 7 , Y and Q have the values shown in Table II, infra .
- A-B is -CH 2 -CH- ;
- Z is S0 2 ;
- R 2 , R 5 and R 8 are each H;
- R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- ;
- R 1 is benzyl;
- Y is N-H or N-ethyl;
- A-B is -CH 2 - CH-; Z is S0 2 ; R 2 , R 5 and R 8 are each H; R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- ; R 1 is benzyl; and Y and Q have the values shown in Table III, infra .
- Z is S0 2 ;
- R 2 , R 5 and R 8 are each H;
- R 1 is benzyl;
- R 6 and R 7 are independently H or halogen, or R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- ;
- R 4 is H, alkoxy with methoxy being preferred, or hydroxy;
- Z is S0 2 ;
- R 2 , R 5 and R 8 are each H; and
- R 1 , R 6 , R 7 , R 4 , Y and Q have the values shown in Table IV, infra .
- A-B is -N(R 4 )-CH-; Z is S0 2 ; R 2 , R 5 and R 8 are each H; R 1 is benzyl; R 6 and R 7 are each H; Y is N-R 9 ; and R 4 , R 9 and Q have the values shown in Table V, infra .
- Z is S0 2 ;
- Y is NH;
- R 2 , R 5 and R 8 are each H;
- R 1 is benzyl and
- R 6 and R 7 are each H, or R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- ;
- Z is S0 2 ;
- Y is NH;
- R 2 , R 5 and R 8 are each H;
- R 1 is benzyl and
- R 6 , R 7 and Q have the values shown in Table VI, infra .
- compounds of the invention have the formula:
- the invention includes the bisulfite addition products of the aldehydes of Formula I, as exemplified in Example 187, infra .
- alkyl is meant to include straight -chain, branched and cyclic hydrocarbon groups such as, for example, ethyl, isopropyl and cyclopropyl groups. Preferred alkyl groups have 1 to about 10 carbon atoms. "Cycloalkyl” groups are cyclic alkyl groups. "Aryl” groups are aromatic cyclic compounds including but not limited to phenyl , naphthyl, anthracyl, phenanthryl, and pyrenyl . Also included within the definition of "aryl” are ring systems having two aromatic rings connected by a bond, such as biphenyl . Preferred aryl groups include phenyl and naphthyl.
- Carbocyclic refers to cyclic groups in which the ring portion is composed solely of carbon atoms.
- hetero denotes the presence of one or more noncarbon atoms.
- heterocyclic refers to cyclic groups in which the ring portion includes at least one heteroatom such as 0, N or S .
- Heteroalkyl groups are heterocycles containing solely single bonds within their ring portions, i.e. saturated heteroatomic ring systems.
- the term “lower alkyl” refers to alkyl groups of 1-4 carbon atoms.
- halogen refers to F, Cl, Br, and I atoms.
- aralkyl denotes alkyl groups which bear aryl groups, for example, benzyl groups.
- heteroaryl denotes aryl groups having one or more heteroatoms (e.g., 0, N, or S) contained within an aromatic ring.
- heteroarylkyl groups are aralkyl groups which have one or more heteroatoms in their aromatic ring portion. Also included within the definition of “heteroaryl” are ring systems having two aromatic rings connected by a bond, where at least one of the rings contains a hetero atom.
- alkoxy groups are alkyl groups linked through an oxygen atom. Examples of alkoxy groups include methoxy (-OCH 3 ) and ethoxy (-OCH 2 CH 3 ) groups.
- Alkoxycarbonyl groups are carbonyl groups which contain an alkoxy substituent, i.e., groups of general formula
- aroyl analogously denotes an aryl group attached through a carbonyl group.
- alkenyl is intended to include straight-chain or branched hydrocarbon chains having at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl groups and propenyl groups.
- amino acid denotes a molecule containing both an amino group and a carboxyl group.
- L-amino acid denotes an ⁇ -amino acid having the L configuration around the a>- carbon, that is, a carboxylic acid of general formula CH(COOH) (NH 2 ) - (sidechain) , having the L-configuration.
- Nonnaturally occurring amino acid sidechains are moieties that are used in place of naturally occurring amino acid sidechains in, for example, amino acid analogs. See, for example, Lehninger,
- Formula I may contain blocking groups .
- Blocking groups are known per se as chemical functional groups that can be selectively appended to functionalities, such as hydroxyl groups, amino groups, thio groups and carboxyl groups.
- Protecting groups are blocking groups that can be readily removed from functionalities. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention.
- One such protecting group is the benzyloxycarbonyl (Cbz; Z) group.
- Other protecting groups include toluenesulfonyl , t-butoxycarbonyl , methyl ester and benzyl ether groups.
- Other preferred protecting groups according to the invention may be found in Greene, T.W.
- Further blocking groups useful in the compounds of the present invention include the phthalimido group, arylcarbonyls , alkylcarbonyls , alkoxycarbonyls, aryloxycarbonyls , aralkyloxycarbonyls, alkyl- and aralkylsulfonyls, and arylsulfonyl groups such as those which have the following formulas:
- benzothiazo and related heterocyclic grou -containing components of the invention inhibit cysteine proteases and serine proteases, they can be used in both research and therapeutic settings.
- preferred compounds having defined attributes can be used to screen for natural and synthetic compounds which evidence similar characteristics in inhibiting protease activity.
- the compounds can also be used in the refinement of in vi tro and in vivo models for determining the effects of inhibition of particular proteases on particular cell types or biological conditions.
- compounds of the invention can be utilized to alleviate, mediate, reduce and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases and/or serine proteases .
- compositions are provided for inhibiting a serine protease or a cysteine protease comprising a compound of the invention.
- methods are provided for inhibiting serine proteases or cysteine proteases comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a compound of the invention.
- the disclosed compounds of the invention are useful for the inhibition of cysteine proteases and serine proteases.
- the terms “inhibit” and “inhibition” mean having an adverse effect on enzymatic activity.
- An inhibitory amount is an amount of a compound of the invention effective to inhibit a cysteine and/or serine protease .
- compositions as disclosed herein.
- pharmaceutically acceptable salts as used herein means an inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fumarate, tartrate, and citrate.
- pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt.
- pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine .
- pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine .
- compositions can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic excipients and carriers.
- compositions may be prepared for use in parenteral administration, particularly in the form of liquid solutions or suspensions; or oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, via, for example, transdermal patches; or prepared in other suitable fashions for these and other forms of administration as will be apparent to those skilled in the art .
- compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington ' s Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980) .
- Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like.
- biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds .
- parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
- Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate , or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
- Formulations for parenteral administration may also include glycocholate for buccal administration, a salicylate for rectal administration, or citric acid for vaginal administration.
- Formulations for transdermal patches are preferably lipophilic emulsions.
- the materials for this invention can be employed as the sole active agent in a pharmaceutical or can be used in combination with other active ingredients which could facilitate inhibition of cysteine and serine proteases in diseases or disorders.
- concentrations of the compounds described herein in a therapeutic composition will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) of the compounds employed, and the route of administration.
- the compounds of this invention may be provided in effective inhibitory amounts in an aqueous physiological buffer solution containing about 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from about l ⁇ g/kg to about 1 g/kg of body weight per day; a preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day.
- Such formulations typically provide inhibitory amounts of the compound of the invention.
- the preferred dosage of drug to be administered is likely, however, to depend on such variables as the type or extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
- contacting means directly or indirectly causing at least two moieties to come into physical association with each other. Contacting thus includes physical acts such as placing the moieties together in a container, or administering moieties to a patient.
- administering for example administering a compound of the invention to a human patient evidencing a disease or disorder associated with abnormal and/or aberrant activity of such proteases falls within the scope of the definition of the term "contacting".
- 2 , 3-dihydrobenzothiazole-3 -carboxylates may be prepared by treating N-alkylbenzenesulfonamides with a strong base such as butyllithium followed by glyoxylic ester by a modification of the method of robel and Dietrich, supra .
- 2- (aminosulfonyl) henyl- propanoic acid described by P. Catsoulacos and C. Camoutsis (J. Heterocycl . Chem . 1976, 13 , 1309 - 1314, incorporated by reference herein in its entirety)
- This compound was prepared according to General Procedure B. From 21 (2.5 g, 10.7 mmol) in neat chlorosulfonic acid (-10 ml) at 150°C for 1.5 hours, 3.3 g (89%) of the title compound was obtained as a yellow powder which was isolated by dropwise addition of the dark reaction mixture (cooled to ambient temperature) to a vigorously stirred slurry of ice-water (-100 g) , suction filtration of the precipitate and washing with cold water and drying to constant weight in vacuo to give analytically pure material; Anal. Calc'd for C 9 H 7 C1 4 N0 3 S : C, 30.80; H, 2.01; N, 3.99; S, 9.12; Found: C, 30.47; H, 1.92; N, 3.38; S, 9.29.
- This compound was prepared according to General Procedure B. To a dry flask equipped with a magnetic stirrer, rubber septum and drying tube was added compound 2n (5.0 g, 25.0 mmol) . Chlorosulfonic acid (17 ml) was added with stirring over 5-10 minutes at ambient temperature. An appreciable exotherm was observed along with gas evolution (HCl) that persisted for 10-15 minutes following completion of the addition. After being allowed to stir for an additional one hour, the mixture was heated to 100°C for one hour, cooled to ambient temperature, and added dropwise with vigorous stirring to an ice-water slurry ( ⁇ 500g) .
- This compound was prepared according to General Procedure C. However, the reaction was performed using concentrated aqueous ammonium hydroxide. From compound 4r (2.4 g, 7.1 mmol) and cone. NH 4 0H (50 ml) the title compound (0.87 g, 44%) was obtained following flash chromatography on silica gel (25% ethyl acetate/hexane to ethyl acetate); MS: 283 (M-H)-.
- This compound was prepared according to General Procedure F using acidic conditions (refluxing 4 N aqueous HCl in 1,4 -dioxane) rather than basic conditions. From 6k (1.0 g, 3.87 mmol) the title compound (0.43 g, 43%) was obtained following recrystallization (ether/hexanes) ; MS: 258 m/z (M-H) " ; Anal. Calc'd for C 10 H 10 FNO 4 S : C, 47.57; H, 4.55; N, 5.04; S, 11.52; F, 6.84; Found: C, 47.81; H, 4.28; N, 5.36; S, 11.62; F, 7.29.
- Procedure F acidic conditions using refluxing 4N aqueous HCl in 1,4 -dioxane. From 61 (200 mg, 0.65 mmol) the title compound (200 mg, 100%) was obtained following lyophillization of the reaction mixture; NMR (DMSO-d 6 ) ⁇ 2.64 (s, 3H) , 3.13-3.37 (m, 2H) , 4.72-4.77 (m, IH) , 7.87 (s, IH) , 7.98 (s, IH) . MS: 308, 310, 312 m/z (M+H) + (Cl 2 pattern) .
- This compound was prepared according to General Procedure G. From 8s (70 mg, 0.23 mmol) and L-N e - (benzenesulfonyl) lysinol trifluoroacetic acid salt (117 mg, 0.30 mmol) crude product (144 mg) was obtained as a mixture of diastereomers. Separation was effected by preparative tic on silica gel (5% MeOH/CH 2 Cl 2 ) :
- N- (methanesulfonyl) aminoethanamine was prepared from (JV- ( -butoxycarbonyl) amino) ethanamine and methanesulfonyl chloride according to the procudure of
- This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3 - (S) -benzyl-2- (R, S) -hydroxy-N- (3 - (4- nitrobenzenesulfonylamino) propyl) propanamide hydrochloride (59 mg, 0.12 mmol) the title compound (32 mg, 55%) was obtained following flash chromatography on silica gel (75% ethyl acetate/hexanes); MS: 732 m/z (M+H) + .
- This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3- (S) -benzyl-2- (R, S) -hydroxy-N- (2- (3 , 4- dichlorobenzenesulfonylamino) ethyl) propanamide hydrochloride (60 mg, 0.12 mmol) the title compound (58 mg, 97%) was obtained following flash chromatography on silica gel (75% ethyl acetate/hexanes); MS: 741, 743, 745 m/z (M+H) + .
- Procedure G From 8s (prepared from L-DOPA, 35 mg, 0.11 mmol) and 3 -amino-3- (S) -benzyl-2- (R, S) -hydroxy-iV- (2- (benzenesulfonylamino) ethyl) propanamide hydrochloride (60 mg, 0.15 mmol) the title compound (62 mg, 83%) was obtained following trituration with ether; MS: 673 m/z (M+H) + .
- This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3 - (S) -benzyl-2- (R, S) -hydroxy-lV- (3 - (4 - fluorobenzenesulfonylamino) propyl) propanamide hydrochloride (43 mg, 0.12 mmol) the title compound (40 mg, 59%) was obtained following preparative tic on silica gel (ethyl acetate); MS: 705 m/z (M+H) + .
- Compound 7r was prepared from compound 19 according to the procedure described for synthesis of 8s.
- Compound HAD was prepared according to General Procedure G. From compound 7r (22 mg, 0.077 mmol) and JV-butyl 2- (R, S) -hydroxy- 3 - (S) -benzyl-3-aminopropanamide, HCl salt (27.6 mg, 1.25 eq) (Harbeson, S. L., et al . ; J " . Med . Chem . , 1994, 37, 2918- 2929) the title compound (20.0 mg, 50%) was obtained; MS: 518 (M+H) + .
- the reaction was cooled to - 5 °C and 43 ml (10 eq) of Et 3 N, 733 mg (0.3 eq) of DMAP in CHC1 3 (50 ml) was added. The mixture was stirred overnight ( ⁇ 14hr) while the temperature was warmed to room temperature and then the reaction mixture was refluxed for 3 hours. After that, the reaction mixture was poured into 500 ml of ice-water and separated. The aqueous layer was extracted with CH 2 C1 2 (3x100 ml) . The combined organic layers were washed with water, 3% HCl, 5% of NaHC0 3 , brine and dried.
- Example 159 Also isolated was 118 mg (27%) of a diastereomeric mixture.
- Example 159 Also isolated was 118 mg (27%) of a diastereomeric mixture.
- This compound was prepared according to General Procedure I (in this case, isobutyl chloroformate was used in place of HOBt/BOP) . From compound 40a (25 mg, 0.11 mmol) and 3- amino- 3 - (S) -benzyl -2 -oxo-JV-butylpropanamide hydrochloride (35 mg, 0.12 mmol) the title compound (9 mg, 18%) was obtained as an off-white solid following trituration of the crude (33 mg) product with ether; MS: 455 m/z (M-H) " .
- JV-Benzoyl-1, 2,3, 4-tetrahydro-3-isoquinolinecarboxylic acid This compound was prepared according to Hein et . al . , J “ . Amer. Chem . Soc . ; 1962, 84 , 4487-4494, incorporated by reference herein in its entirety.
- a slurry of 1,2,3, 4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride (20.3 g, 95 mmol) in 2N NaOH (150 ml) was treated with benzoyl chloride (13.4 ml, 114 mmol) dropwise over 30 minutes.
- This compound was prepared according to Maeda et . al . , Chem . Phar . Bull . ; 1988, 36, 190-201, incorporated by reference herein in its entirety.
- a solution of compound 44 (15.4 g, 54.7 mmol) and potassium carbonate (7.6 g, 54.7 mmol) in water (450 ml) was treated portionwise with potassium permanganate (17.3 g, 109.5 mmol) over 10 minutes.
- the mixture was stirred for two hours, quenched with sodium bisulfite (6.5 g) and stirred for 5-10 minutes, and filtered through a bed of Celite 0 .
- the filtrate was acidified to pH 2-3 and the resulting gummy precipitate was extracted with ethyl acetate.
- assay buffer i.e., 50mM Tris, 50mM NaCl, ImM EDTA, ImM EGTA, and 5mM-mercaptoethanol , pH 7.5 including 0.2mM Succ-Leu-Tyr-MNA (Enzyme Systems Products, Dublin, CA) and 175 mL aliquoted into the same wells containing the independent inhibitor stocks as well as to positive control wells containing 5 mL DMSO, but no compound.
- assay buffer i.e., 50mM Tris, 50mM NaCl, ImM EDTA, ImM EGTA, and 5mM-mercaptoethanol , pH 7.5 including 0.2mM Succ-Leu-Tyr-MNA (Enzyme Systems Products, Dublin, CA) and 175 mL aliquoted into the same wells containing the independent inhibitor stocks as well as to positive control wells containing 5 mL DMSO, but no compound.
- Inhibition of calpain I activity was calculated as the percent decrease in the rate of substrate hydrolysis in the presence of inhibitor relative to the rate in its absence. Comparison between the inhibited and control rates was made within the linear range for substrate hydrolysis. For screening, compounds were tested at 10 mM. Compounds having 50% inhibition at 10 mM were considered active. The IC50s of inhibitors (concentration yielding 50% inhibition) were determined from the percent decrease in the rates of substrate hydrolysis in the presence of five to seven different concentrations of the test compound. The results were plotted as percent inhibition versus log inhibitor concentration, and the IC50 was calculated from linear regression of the data. Results are presented in Tables II- VII and in Example 187.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Emergency Medicine (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Neurosurgery (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3052696P | 1996-11-13 | 1996-11-13 | |
US30526P | 1996-11-13 | ||
US968035 | 1997-11-12 | ||
US08/968,035 US5952328A (en) | 1997-11-12 | 1997-11-12 | Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors |
PCT/US1997/020782 WO1998021186A1 (en) | 1996-11-13 | 1997-11-13 | Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0938477A1 EP0938477A1 (de) | 1999-09-01 |
EP0938477A4 true EP0938477A4 (de) | 1999-12-29 |
Family
ID=26706137
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97949430A Withdrawn EP0938477A4 (de) | 1996-11-13 | 1997-11-13 | Benzothiazolo- und verwandte heterocyclische gruppen enthaltende cystein- und serinprotease-inhibitoren |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0938477A4 (de) |
JP (1) | JP2002514192A (de) |
AU (1) | AU7179598A (de) |
CA (1) | CA2271116A1 (de) |
NO (1) | NO992315L (de) |
WO (1) | WO1998021186A1 (de) |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69808266D1 (de) * | 1997-04-16 | 2002-10-31 | Arqule Inc | Herstellung und verwendung von alpha-ketoamid derivate und anordnunge |
US6143931A (en) * | 1997-04-16 | 2000-11-07 | Arqule, Inc. | Synthesis and use of α-ketoamide derivatives and arrays |
US6150378A (en) * | 1997-10-07 | 2000-11-21 | Cephalon, Inc. | Peptidyl-containing α-ketoamide cysteine and serine protease inhibitors |
CA2319173A1 (en) * | 1998-02-11 | 1999-08-19 | Jingwu Duan | Novel cyclic sulfonamide derivatives as metalloproteinase inhibitors |
EP1068191A1 (de) * | 1998-03-31 | 2001-01-17 | Warner-Lambert Company Llc | Benzoxazinone/benzothiazinone als serin-protease inhibitoren |
AU3731400A (en) | 1999-03-05 | 2000-09-21 | Trustees Of University Technology Corporation, The | Methods and compositions useful in inhibiting apoptosis |
FR2818641B1 (fr) * | 2000-12-21 | 2004-03-05 | Servier Lab | Nouveaux derives de 1,1-dioxo-2h-1,2-benzothiazine 3-carboxamides, leur procede de preparation et les compositions pharmaceutiques que les contiennent |
EP3192872A1 (de) | 2003-08-26 | 2017-07-19 | The Regents of the University of Colorado, a body corporate | Inhibitoren der serinproteaseaktivität und deren verwendung in verfahren und zusammensetzungen zur behandlung bakterieller infektionen |
CA2563038C (en) | 2004-04-02 | 2013-10-29 | Gaik Beng Kok | Neurologically-active compounds |
UA95454C2 (uk) | 2005-07-15 | 2011-08-10 | Амр Текнолоджи, Інк. | Арил- і гетероарилзаміщені тетрагідробензазепіни і їх застосування для блокування зворотного захоплення норепінефрину, допаміну і серотоніну |
WO2009015917A2 (en) | 2007-05-14 | 2009-02-05 | F. Hoffmann-La Roche Ag | Dihydroquinone and dihydronaphthridine inhibitors of jnk |
US8236798B2 (en) * | 2009-05-07 | 2012-08-07 | Abbott Gmbh & Co. Kg | Carboxamide compounds and their use as calpain inhibitors |
WO2017156071A1 (en) | 2016-03-09 | 2017-09-14 | Blade Therapeutics, Inc. | Cyclic keto-amide compounds as calpain modulators and methods of production and use thereof |
EP3481835A4 (de) | 2016-07-05 | 2020-02-26 | Blade Therapeutics, Inc. | Calpain-modulatoren und therapeutische verwendungen davon |
CN110062753A (zh) * | 2016-09-13 | 2019-07-26 | 哈普洛根有限责任公司 | 抗病毒化合物 |
KR20190063473A (ko) | 2016-09-28 | 2019-06-07 | 블레이드 테라퓨틱스, 인크. | 칼페인 조정자 및 그 치료학적 용도 |
GB201713962D0 (en) * | 2017-08-31 | 2017-10-18 | Ctxt Pty Ltd | Compounds |
GB201810581D0 (en) | 2018-06-28 | 2018-08-15 | Ctxt Pty Ltd | Compounds |
EP3986890B1 (de) | 2019-06-18 | 2023-11-15 | Pfizer Inc. | Benzisoxazol-sulfonamid-derivate |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS58225076A (ja) * | 1982-06-23 | 1983-12-27 | Mitsui Toatsu Chem Inc | ベンゾチアジンカルボキシアミド誘導体およびそれを含有する医薬組成物 |
EP0134582A2 (de) * | 1983-09-07 | 1985-03-20 | Tanabe Seiyaku Co., Ltd. | Peptide, Verfahren zur deren Herstellung und pharmazeutische Zusammensetzungen |
WO1997003679A1 (en) * | 1995-07-17 | 1997-02-06 | Cephalon, Inc. | Phosphorous-containing cysteine and serine protease inhibitors |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3960854A (en) * | 1972-03-20 | 1976-06-01 | Merck & Co., Inc. | 7-Mercapto(or thio)-benzothiadiazine products |
US4585793A (en) * | 1983-05-09 | 1986-04-29 | Georgia Tech Research Institute | Thioester inhibitors of serine proteases |
US4889851A (en) * | 1986-11-21 | 1989-12-26 | Fujisawa Pharmaceutical Co, Ltd. | Benzothiadiazine compounds, and pharmaceutical composition comprising the same |
JPH0629271B2 (ja) * | 1988-03-09 | 1994-04-20 | 株式会社日本ハイポックス | ベンゾチアジン―1,1―ジオキシド誘導体及びそれを含有する医薬組成物 |
US5384411A (en) * | 1991-06-20 | 1995-01-24 | Hewlett-Packard Company | Immobilization of PH-sensitive dyes to solid supports |
PT590455E (pt) * | 1992-09-28 | 2001-04-30 | Hoechst Ag | 1(2h)-isoquinolinas substituidas anti-arritmicas e cardioprotectoras processo para a sua preparacao medicamento contendo estes compostos e sua utilizacao para a preparacao de um medicamento para o combate de falhas cardiacas |
-
1997
- 1997-11-13 JP JP52284598A patent/JP2002514192A/ja active Pending
- 1997-11-13 AU AU71795/98A patent/AU7179598A/en not_active Abandoned
- 1997-11-13 CA CA002271116A patent/CA2271116A1/en not_active Abandoned
- 1997-11-13 EP EP97949430A patent/EP0938477A4/de not_active Withdrawn
- 1997-11-13 WO PCT/US1997/020782 patent/WO1998021186A1/en not_active Application Discontinuation
-
1999
- 1999-05-12 NO NO992315A patent/NO992315L/no not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS58225076A (ja) * | 1982-06-23 | 1983-12-27 | Mitsui Toatsu Chem Inc | ベンゾチアジンカルボキシアミド誘導体およびそれを含有する医薬組成物 |
EP0134582A2 (de) * | 1983-09-07 | 1985-03-20 | Tanabe Seiyaku Co., Ltd. | Peptide, Verfahren zur deren Herstellung und pharmazeutische Zusammensetzungen |
WO1997003679A1 (en) * | 1995-07-17 | 1997-02-06 | Cephalon, Inc. | Phosphorous-containing cysteine and serine protease inhibitors |
Non-Patent Citations (2)
Title |
---|
GOMMAA A M ET AL: "Synthesis of some substituted indane-amino acid derivatives", ASIAN J. CHEM. (AJCHEW,09707077);1992; VOL.4 (3); PP.634-40, Al-Azhar Univ.;Fac. Sci.; Nasr; Egypt (EG), XP002120460 * |
See also references of WO9821186A1 * |
Also Published As
Publication number | Publication date |
---|---|
NO992315L (no) | 1999-06-11 |
WO1998021186A1 (en) | 1998-05-22 |
AU7179598A (en) | 1998-06-03 |
NO992315D0 (no) | 1999-05-12 |
CA2271116A1 (en) | 1998-05-22 |
JP2002514192A (ja) | 2002-05-14 |
EP0938477A1 (de) | 1999-09-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1998021186A1 (en) | Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors | |
JP4199309B2 (ja) | 新規アセトアミド誘導体およびプロテアーゼ阻害 | |
EP0910564B1 (de) | Aus d-aminosäuren abgeleitete cystein- und serinproteasehemmer | |
US6288231B1 (en) | Peptide-containing α-ketoamide cysteine and serine protease inhibitors | |
CA2304204C (en) | Quinoline-containing .alpha.-ketoamide cysteine and serine protease inhibitors | |
JPH10501803A (ja) | チアゾリジン誘導体、それらの製造及びそれらを含有する薬物 | |
US5952328A (en) | Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors | |
WO2000016767A1 (en) | Hydroxamate-containing cysteine and serine protease inhibitors | |
WO1993017003A1 (en) | Retroviral protease inhibitors | |
HUT68710A (en) | Process for preparing benzoxazepine and benzothiazepine derivatives | |
US5744339A (en) | Thiomethylene group-containing aldehyde cysteine and serine protease inhibitors | |
JP2002521367A (ja) | ウロキナーゼ阻害剤としてのイソキノリン類 | |
KR0163671B1 (ko) | N-아릴술포닐-알파-프로파길글리신아미드 유도체 | |
KR100551944B1 (ko) | 신규에폭시숙신아미드유도체또는그의염 | |
MXPA00003431A (en) | QUINOLINE-CONTAINING&agr;-KETOAMIDE CYSTEINE AND SERINE PROTEASE INHIBITORS | |
MXPA01002977A (en) | Hydroxamate-containing cysteine and serine protease inhibitors | |
MXPA00003419A (en) | PEPTIDE-CONTAINING&agr;-KETOAMIDE CYSTEINE AND SERINE PROTEASE INHIBITORS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19990518 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI NL PT SE |
|
RIC1 | Information provided on ipc code assigned before grant |
Free format text: 6C 07D 217/12 A, 6C 07D 279/02 B, 6C 07D 285/20 B, 6C 07D 285/24 B, 6C 07D 471/04 B, 6C 07D 497/00 B, 6C 07D 497/04 B, 6C 07D 513/04 B, 6C 07D 217/26 B, 6C 07D 327/06 B, 6C 07D 417/12 B, 6C 07D 417/14 B, 6A 61K 31/54 B, 6A 61K 31/535 B, 6C 07D 513/04 J, 6C 07D 319:00 J, 6C 07D 279:00 J |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 19991111 |
|
AK | Designated contracting states |
Kind code of ref document: A4 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI NL PT SE |
|
17Q | First examination report despatched |
Effective date: 20011001 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20020212 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1022152 Country of ref document: HK |