OA10764A - Protease inhibitors - Google Patents
Protease inhibitors Download PDFInfo
- Publication number
- OA10764A OA10764A OA9800049A OA9800049A OA10764A OA 10764 A OA10764 A OA 10764A OA 9800049 A OA9800049 A OA 9800049A OA 9800049 A OA9800049 A OA 9800049A OA 10764 A OA10764 A OA 10764A
- Authority
- OA
- OAPI
- Prior art keywords
- leucinyl
- benzyloxycarbonyl
- amino
- cbz
- alkyl
- Prior art date
Links
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 6
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 581
- 238000000034 method Methods 0.000 claims abstract description 301
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
- 108090000625 Cathepsin K Proteins 0.000 claims abstract description 24
- 239000011159 matrix material Substances 0.000 claims abstract description 12
- 210000000845 cartilage Anatomy 0.000 claims abstract description 8
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 7
- 208000007565 gingivitis Diseases 0.000 claims abstract description 7
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- 201000001245 periodontitis Diseases 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- 230000015556 catabolic process Effects 0.000 claims abstract 4
- 238000006731 degradation reaction Methods 0.000 claims abstract 4
- 102000004171 Cathepsin K Human genes 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 273
- -1 Het-Co Chemical group 0.000 claims description 226
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 claims description 160
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 88
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 41
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 36
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 32
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 26
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 21
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 11
- 235000001014 amino acid Nutrition 0.000 claims description 11
- 229910052786 argon Inorganic materials 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 10
- XKBQRCUXXCGCMC-UHFFFAOYSA-N 1,4-diphenylbutane-2,3-dione Chemical group C=1C=CC=CC=1CC(=O)C(=O)CC1=CC=CC=C1 XKBQRCUXXCGCMC-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 9
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000005518 carboxamido group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- OIUGPMBTYDSGBQ-INIZCTEOSA-N ethyl 2-[[[(2s)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]methyl]-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC(CNC(=O)[C@H](CC(C)C)NC(=O)OCC=2C=CC=CC=2)=N1 OIUGPMBTYDSGBQ-INIZCTEOSA-N 0.000 claims description 4
- 102200007101 rs34049451 Human genes 0.000 claims description 4
- 102200160920 rs35304565 Human genes 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- XECKTNQAABHDFZ-UHFFFAOYSA-N 1-(2-methylpropyl)-2-phenylbenzene Chemical group CC(C)CC1=CC=CC=C1C1=CC=CC=C1 XECKTNQAABHDFZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 101100516554 Caenorhabditis elegans nhr-5 gene Proteins 0.000 claims description 2
- 101100294119 Caenorhabditis elegans nhr-54 gene Proteins 0.000 claims description 2
- ZWDDBYFYFAGWGC-PVCWFJFTSA-N benzyl n-[(4s)-6-amino-2-methyl-5,7-dioxo-8-[(4-phenoxyphenyl)sulfonylamino]octan-4-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)C(N)C(=O)CNS(=O)(=O)C=1C=CC(OC=2C=CC=CC=2)=CC=1)C(=O)OCC1=CC=CC=C1 ZWDDBYFYFAGWGC-PVCWFJFTSA-N 0.000 claims description 2
- MCNNGLLIMGMEMJ-DCCUJTHKSA-N benzyl n-[(4s)-6-amino-8-(dibenzofuran-2-ylsulfonylamino)-2-methyl-5,7-dioxooctan-4-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)C(N)C(=O)CNS(=O)(=O)C=1C=C2C3=CC=CC=C3OC2=CC=1)C(=O)OCC1=CC=CC=C1 MCNNGLLIMGMEMJ-DCCUJTHKSA-N 0.000 claims description 2
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 3
- 125000003107 substituted aryl group Chemical group 0.000 claims 3
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 2
- 206010011878 Deafness Diseases 0.000 claims 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 2
- 230000010370 hearing loss Effects 0.000 claims 2
- 231100000888 hearing loss Toxicity 0.000 claims 2
- 208000016354 hearing loss disease Diseases 0.000 claims 2
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims 2
- 102200149721 rs25403 Human genes 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 125000004512 1,2,3-thiadiazol-4-yl group Chemical group S1N=NC(=C1)* 0.000 claims 1
- 125000004746 2-methylpropyloxycarbonyl group Chemical group CC(COC(=O)*)C 0.000 claims 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000006189 4-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims 1
- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 claims 1
- 125000003047 N-acetyl group Chemical group 0.000 claims 1
- FSOXYYNRYZULOL-UHFFFAOYSA-N NC(C(=O)NC(CC(C)C)C=1N=C(SC=1)C(=O)OCC)CC(C)C Chemical compound NC(C(=O)NC(CC(C)C)C=1N=C(SC=1)C(=O)OCC)CC(C)C FSOXYYNRYZULOL-UHFFFAOYSA-N 0.000 claims 1
- MJXCUCBPQOPXGU-UHFFFAOYSA-N NC(C(=O)NC(CC(C)C)C=1SC=C(N=1)C(=O)OCC)CC(C)C Chemical compound NC(C(=O)NC(CC(C)C)C=1SC=C(N=1)C(=O)OCC)CC(C)C MJXCUCBPQOPXGU-UHFFFAOYSA-N 0.000 claims 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000005037 alkyl phenyl group Chemical group 0.000 claims 1
- MVBBYHQLYRCGBR-ALLRNTDFSA-N benzyl n-[(4s)-6-amino-8-[[4-(3-chloro-2-cyanophenoxy)phenyl]sulfonylamino]-2-methyl-5,7-dioxooctan-4-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)C(N)C(=O)CNS(=O)(=O)C=1C=CC(OC=2C(=C(Cl)C=CC=2)C#N)=CC=1)C(=O)OCC1=CC=CC=C1 MVBBYHQLYRCGBR-ALLRNTDFSA-N 0.000 claims 1
- PYAGJADZMKVQBR-PMACEKPBSA-N benzyl n-[(4s,10s)-10-acetamido-6,6-diamino-2,12-dimethyl-5,7,9-trioxotridecan-4-yl]carbamate Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)CC(=O)C(N)(N)C(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 PYAGJADZMKVQBR-PMACEKPBSA-N 0.000 claims 1
- SYWULVOOUWEIMG-WPNGARGVSA-N benzyl n-[(4s,6s)-6-amino-8-(dibenzofuran-2-ylsulfonylamino)-2-methyl-5,7-dioxononan-4-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)[C@H](N)C(=O)C(C)NS(=O)(=O)C=1C=C2C3=CC=CC=C3OC2=CC=1)C(=O)OCC1=CC=CC=C1 SYWULVOOUWEIMG-WPNGARGVSA-N 0.000 claims 1
- 101150035983 str1 gene Proteins 0.000 claims 1
- 239000004365 Protease Substances 0.000 abstract description 13
- 102000035195 Peptidases Human genes 0.000 abstract description 10
- 108091005804 Peptidases Proteins 0.000 abstract description 10
- 206010065687 Bone loss Diseases 0.000 abstract description 6
- 206010003246 arthritis Diseases 0.000 abstract description 5
- 208000024693 gingival disease Diseases 0.000 abstract description 5
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 abstract description 4
- 208000029725 Metabolic bone disease Diseases 0.000 abstract description 4
- 208000010191 Osteitis Deformans Diseases 0.000 abstract description 4
- 208000027868 Paget disease Diseases 0.000 abstract description 4
- 208000027202 mammary Paget disease Diseases 0.000 abstract description 4
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 abstract description 3
- 208000008750 humoral hypercalcemia of malignancy Diseases 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 303
- 239000007787 solid Substances 0.000 description 286
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 241
- 239000000243 solution Substances 0.000 description 226
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 183
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 151
- 238000003756 stirring Methods 0.000 description 132
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 118
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 116
- 235000019439 ethyl acetate Nutrition 0.000 description 111
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 108
- USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 96
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 95
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 83
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 81
- 239000000741 silica gel Substances 0.000 description 80
- 229910002027 silica gel Inorganic materials 0.000 description 80
- 229940093499 ethyl acetate Drugs 0.000 description 77
- 239000000203 mixture Substances 0.000 description 77
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 68
- 238000005481 NMR spectroscopy Methods 0.000 description 67
- 238000006243 chemical reaction Methods 0.000 description 66
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 36
- 239000004395 L-leucine Substances 0.000 description 35
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- 239000012044 organic layer Substances 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- BIXZZSTYTJMJKS-NSHDSACASA-N (2s)-4-methyl-2-(pyridin-4-ylmethoxycarbonylamino)pentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=NC=C1 BIXZZSTYTJMJKS-NSHDSACASA-N 0.000 description 33
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- 239000012267 brine Substances 0.000 description 32
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- 239000010410 layer Substances 0.000 description 30
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- 238000010992 reflux Methods 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
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- 210000000988 bone and bone Anatomy 0.000 description 28
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- 239000000010 aprotic solvent Substances 0.000 description 26
- 229920006395 saturated elastomer Polymers 0.000 description 26
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 25
- 102100024940 Cathepsin K Human genes 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 24
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- 239000003112 inhibitor Substances 0.000 description 23
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- 239000003810 Jones reagent Substances 0.000 description 22
- 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 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 20
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 20
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
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- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical group OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
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- VXGYRCVTBHVXMZ-UHFFFAOYSA-N quinoline-6-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CC=C21 VXGYRCVTBHVXMZ-UHFFFAOYSA-N 0.000 description 1
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- 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
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- IHQKEDIOMGYHEB-UHFFFAOYSA-M sodium dimethylarsinate Chemical compound [Na+].C[As](C)([O-])=O IHQKEDIOMGYHEB-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000004905 tetrazines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
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- 125000002769 thiazolinyl group Chemical group 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Chemical class OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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- 239000004474 valine Chemical class 0.000 description 1
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- 230000003313 weakening effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C12N9/6472—Cysteine endopeptidases (3.4.22)
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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-
1996
- 1996-10-30 KR KR1019980703135A patent/KR19990067184A/ko not_active Application Discontinuation
- 1996-10-30 JP JP9517638A patent/JP2000500742A/ja not_active Ceased
- 1996-10-30 SK SK567-98A patent/SK56798A3/sk unknown
- 1996-10-30 TR TR1998/00767T patent/TR199800767T2/xx unknown
- 1996-10-30 AP APAP/P/1998/001222A patent/AP9801222A0/en unknown
- 1996-10-30 EP EP96941981A patent/EP0934291A1/en not_active Withdrawn
- 1996-10-30 HU HU9900964A patent/HUP9900964A3/hu not_active Application Discontinuation
- 1996-10-30 EA EA199800353A patent/EA199800353A1/ru unknown
- 1996-10-30 WO PCT/US1996/018000 patent/WO1997016433A1/en not_active Application Discontinuation
- 1996-10-30 CZ CZ981327A patent/CZ132798A3/cs unknown
- 1996-10-30 PL PL96326508A patent/PL326508A1/xx unknown
- 1996-10-30 AU AU11180/97A patent/AU1118097A/en not_active Abandoned
-
1998
- 1998-04-29 NO NO981938A patent/NO981938L/no unknown
- 1998-04-30 OA OA9800049A patent/OA10764A/en unknown
- 1998-05-21 BG BG102475A patent/BG102475A/xx unknown
-
1999
- 1999-04-13 US US09/290,958 patent/US5998470A/en not_active Expired - Fee Related
- 1999-06-11 US US09/330,451 patent/US6232342B1/en not_active Expired - Fee Related
- 1999-06-11 US US09/330,287 patent/US6057362A/en not_active Expired - Fee Related
-
2000
- 2000-04-19 US US09/551,968 patent/US6331542B1/en not_active Expired - Fee Related
- 2000-04-19 US US09/552,616 patent/US6284777B1/en not_active Expired - Fee Related
- 2000-12-29 NO NO20006716A patent/NO20006716D0/no not_active Application Discontinuation
- 2000-12-29 NO NO20006718A patent/NO20006718D0/no not_active Application Discontinuation
- 2000-12-29 NO NO20006717A patent/NO20006717D0/no not_active Application Discontinuation
-
2001
- 2001-02-20 CN CN01104788A patent/CN1341592A/zh active Pending
- 2001-02-20 CN CN01104787A patent/CN1341590A/zh active Pending
- 2001-02-20 CN CN01104789A patent/CN1341593A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
CZ132798A3 (cs) | 1999-02-17 |
EP0934291A4 (no) | 1999-08-11 |
US6232342B1 (en) | 2001-05-15 |
JP2000500742A (ja) | 2000-01-25 |
AU1118097A (en) | 1997-05-22 |
NO20006716L (no) | 1998-06-29 |
HUP9900964A2 (hu) | 1999-07-28 |
KR19990067184A (ko) | 1999-08-16 |
NO20006717L (no) | 1998-06-29 |
CN1341593A (zh) | 2002-03-27 |
TR199800767T2 (xx) | 1998-07-21 |
PL326508A1 (en) | 1998-09-28 |
US6284777B1 (en) | 2001-09-04 |
HUP9900964A3 (en) | 2001-02-28 |
NO981938L (no) | 1998-06-29 |
NO20006718L (no) | 1998-06-29 |
AP9801222A0 (en) | 1998-06-30 |
MX9803548A (es) | 1998-09-30 |
EP0934291A1 (en) | 1999-08-11 |
NO20006717D0 (no) | 2000-12-29 |
NO20006716D0 (no) | 2000-12-29 |
BG102475A (en) | 1999-04-30 |
US6057362A (en) | 2000-05-02 |
US5998470A (en) | 1999-12-07 |
US6331542B1 (en) | 2001-12-18 |
EA199800353A1 (ru) | 1998-12-24 |
CN1341592A (zh) | 2002-03-27 |
WO1997016433A1 (en) | 1997-05-09 |
CN1341590A (zh) | 2002-03-27 |
SK56798A3 (en) | 1998-12-02 |
NO20006718D0 (no) | 2000-12-29 |
NO981938D0 (no) | 1998-04-29 |
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