KR20070008517A - 카텝신 저해물질로서 신규한 케토-옥사디아졸 유도체 - Google Patents
카텝신 저해물질로서 신규한 케토-옥사디아졸 유도체 Download PDFInfo
- Publication number
- KR20070008517A KR20070008517A KR1020067008096A KR20067008096A KR20070008517A KR 20070008517 A KR20070008517 A KR 20070008517A KR 1020067008096 A KR1020067008096 A KR 1020067008096A KR 20067008096 A KR20067008096 A KR 20067008096A KR 20070008517 A KR20070008517 A KR 20070008517A
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- difluoro
- amide
- carboxylic acid
- morpholine
- 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- Withdrawn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
- 239000003112 inhibitor Substances 0.000 title claims abstract description 13
- 102000005600 Cathepsins Human genes 0.000 title description 6
- 108010084457 Cathepsins Proteins 0.000 title description 6
- ZVTQYRVARPYRRE-UHFFFAOYSA-N oxadiazol-4-one Chemical class O=C1CON=N1 ZVTQYRVARPYRRE-UHFFFAOYSA-N 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 71
- 108090000613 Cathepsin S Proteins 0.000 claims abstract description 33
- 102100035654 Cathepsin S Human genes 0.000 claims abstract description 31
- 108090000625 Cathepsin K Proteins 0.000 claims abstract description 26
- 102000004171 Cathepsin K Human genes 0.000 claims abstract description 26
- 108090000712 Cathepsin B Proteins 0.000 claims abstract description 22
- 102000004225 Cathepsin B Human genes 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 229910052796 boron Inorganic materials 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 8
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 194
- -1 methylene, ethylene, propylene Chemical group 0.000 claims description 191
- 150000001875 compounds Chemical class 0.000 claims description 161
- 239000000203 mixture Substances 0.000 claims description 121
- 125000003118 aryl group Chemical group 0.000 claims description 97
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 59
- 125000005842 heteroatom Chemical group 0.000 claims description 55
- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 claims description 44
- 201000010099 disease Diseases 0.000 claims description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 239000000651 prodrug Substances 0.000 claims description 26
- 229940002612 prodrug Drugs 0.000 claims description 26
- 230000005764 inhibitory process Effects 0.000 claims description 25
- 230000000694 effects Effects 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 150000004677 hydrates Chemical class 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 10
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 10
- 208000001132 Osteoporosis Diseases 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 10
- 201000008482 osteoarthritis Diseases 0.000 claims description 10
- 230000007170 pathology Effects 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 150000003018 phosphorus compounds Chemical class 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 208000006673 asthma Diseases 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 7
- 239000011574 phosphorus Substances 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 206010014561 Emphysema Diseases 0.000 claims description 6
- 102000004190 Enzymes Human genes 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010039491 Sarcoma Diseases 0.000 claims description 5
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 5
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims description 5
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 201000000849 skin cancer Diseases 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 206010003246 arthritis Diseases 0.000 claims description 4
- 201000006938 muscular dystrophy Diseases 0.000 claims description 4
- QLVBPRWPCQPDFJ-GJZGRUSLSA-N n-[(2s)-1-[[(2s)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxoheptan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(F)(F)CCC)C(=O)N[C@@H](CC)C(=O)C=1ON=C(N=1)C1CC1)C(=O)N1CCOCC1 QLVBPRWPCQPDFJ-GJZGRUSLSA-N 0.000 claims description 4
- WULBHEXYVCPHPW-STQMWFEESA-N n-[(2s)-1-[[(2s)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxopentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(C)(F)F)C(=O)N[C@@H](CC)C(=O)C=1ON=C(N=1)C1CC1)C(=O)N1CCOCC1 WULBHEXYVCPHPW-STQMWFEESA-N 0.000 claims description 4
- BHKIHNVFKWTJLL-HOTGVXAUSA-N n-[(2s)-4,4-difluoro-1-[[(2s)-1-[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-1-oxobutan-2-yl]amino]-1-oxopentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(C)(F)F)C(=O)N[C@@H](CC)C(=O)C=1N=C(ON=1)C=1C=CC(F)=CC=1)C(=O)N1CCOCC1 BHKIHNVFKWTJLL-HOTGVXAUSA-N 0.000 claims description 4
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 206010006448 Bronchiolitis Diseases 0.000 claims description 3
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 3
- 206010061216 Infarction Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 230000007574 infarction Effects 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 210000004698 lymphocyte Anatomy 0.000 claims description 3
- LFTFGBYHTDEXLQ-HNNXBMFYSA-N n-[(2s)-1-(cyanomethylamino)-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(F)(F)CC=1C=CC=CC=1)C(=O)NCC#N)C(=O)N1CCOCC1 LFTFGBYHTDEXLQ-HNNXBMFYSA-N 0.000 claims description 3
- XDWXLPRVTBSUOV-LBPRGKRZSA-N n-[(2s)-1-[(1-cyanocyclopropyl)amino]-4,4-difluoro-1-oxoheptan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(F)(F)CCC)C(=O)NC1(CC1)C#N)C(=O)N1CCOCC1 XDWXLPRVTBSUOV-LBPRGKRZSA-N 0.000 claims description 3
- PGFSCNOGGUDWOG-KBPBESRZSA-N n-[(2s)-1-[[(1s)-1-cyanopropyl]amino]-4,4-difluoro-1-oxoheptan-2-yl]-1,4-oxazepane-4-carboxamide Chemical compound CCCC(F)(F)C[C@@H](C(=O)N[C@@H](CC)C#N)NC(=O)N1CCCOCC1 PGFSCNOGGUDWOG-KBPBESRZSA-N 0.000 claims description 3
- MJJFZMYUYHTJDV-DWACAAAGSA-N n-[(2s)-1-[[(2s)-1-(1,3-benzoxazol-2-yl)-2-methyl-1-oxopentan-2-yl]amino]-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical compound C([C@@H](C(=O)N[C@@](C)(CCC)C(=O)C=1OC2=CC=CC=C2N=1)NC(=O)N1CCOCC1)C(F)(F)CC1=CC=CC=C1 MJJFZMYUYHTJDV-DWACAAAGSA-N 0.000 claims description 3
- XYAWKLDLMAFDJG-OALUTQOASA-N n-[(2s)-1-[[(2s)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical compound C([C@@H](C(=O)N[C@@H](CC)C(=O)C=1ON=C(N=1)C1CC1)NC(=O)N1CCOCC1)C(F)(F)CC1=CC=CC=C1 XYAWKLDLMAFDJG-OALUTQOASA-N 0.000 claims description 3
- YKDSNKTVSUXHCQ-GGYWPGCISA-N n-[(2s)-1-[[1-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical compound C([C@@H](C(=O)NC(CC)C(=O)C=1N=C(ON=1)C1CC1)NC(=O)N1CCOCC1)C(F)(F)CC1=CC=CC=C1 YKDSNKTVSUXHCQ-GGYWPGCISA-N 0.000 claims description 3
- HTEWTMNUKYWLKX-HOTGVXAUSA-N n-[(2s)-4,4-difluoro-1-oxo-1-[[(2s)-1-oxo-1-(3-phenyl-1,2,4-oxadiazol-5-yl)butan-2-yl]amino]pentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(C)(F)F)C(=O)N[C@@H](CC)C(=O)C=1ON=C(N=1)C=1C=CC=CC=1)C(=O)N1CCOCC1 HTEWTMNUKYWLKX-HOTGVXAUSA-N 0.000 claims description 3
- TYNKEOGSAQCPOO-GJZGRUSLSA-N n-[(2s)-4,4-difluoro-1-oxo-1-[[(2s)-1-oxo-1-(3-propan-2-yl-1,2,4-oxadiazol-5-yl)butan-2-yl]amino]heptan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(F)(F)CCC)C(=O)N[C@@H](CC)C(=O)C=1ON=C(N=1)C(C)C)C(=O)N1CCOCC1 TYNKEOGSAQCPOO-GJZGRUSLSA-N 0.000 claims description 3
- UNXHAHNEDMBCRI-UHFFFAOYSA-N n-[1-[[1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical compound N=1N=C(C2CC2)OC=1C(=O)C(CC)NC(=O)C(NC(=O)N1CCOCC1)CC(F)(F)CC1=CC=CC=C1 UNXHAHNEDMBCRI-UHFFFAOYSA-N 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- NIVBSBJIXXHYFB-HNNXBMFYSA-N (2s)-n-(cyanomethyl)-4,4-difluoro-2-(2-methylpropylamino)-5-phenylpentanamide Chemical compound N#CCNC(=O)[C@@H](NCC(C)C)CC(F)(F)CC1=CC=CC=C1 NIVBSBJIXXHYFB-HNNXBMFYSA-N 0.000 claims description 2
- GFLAQUZZEJKPFG-INIZCTEOSA-N (2s)-n-(cyanomethyl)-4,4-difluoro-2-(oxan-4-ylamino)-5-phenylpentanamide Chemical compound N([C@@H](CC(F)(F)CC=1C=CC=CC=1)C(=O)NCC#N)C1CCOCC1 GFLAQUZZEJKPFG-INIZCTEOSA-N 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- BBLQXTFBLDKPJP-ADTLFGHVSA-N N([C@@H](CC(F)(F)CCC)C(=O)N[C@@H](CC)C(O)C=1OC(CC)=NN=1)C(=O)N1CCOCC1 Chemical compound N([C@@H](CC(F)(F)CCC)C(=O)N[C@@H](CC)C(O)C=1OC(CC)=NN=1)C(=O)N1CCOCC1 BBLQXTFBLDKPJP-ADTLFGHVSA-N 0.000 claims description 2
- XBKWLHLOPBYGTE-LOACHALJSA-N N-[(2S)-1-[[1-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxoheptan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(F)(F)CCC)C(=O)NC(CC)C(=O)C=1N=C(ON=1)C1CC1)C(=O)N1CCOCC1 XBKWLHLOPBYGTE-LOACHALJSA-N 0.000 claims description 2
- DJZAYJLVOWHROT-ABLWVSNPSA-N N-[(2S)-1-[[1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxopentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(C)(F)F)C(=O)NC(CC)C(=O)C=1OC(=NN=1)C1CC1)C(=O)N1CCOCC1 DJZAYJLVOWHROT-ABLWVSNPSA-N 0.000 claims description 2
- WEUBDZZIMVEGOH-ZVAWYAOSSA-N N-[(2S)-1-[[1-(5-ethyl-1,3,4-oxadiazol-2-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical compound C([C@@H](C(=O)NC(CC)C(=O)C=1OC(CC)=NN=1)NC(=O)N1CCOCC1)C(F)(F)CC1=CC=CC=C1 WEUBDZZIMVEGOH-ZVAWYAOSSA-N 0.000 claims description 2
- BHKIHNVFKWTJLL-LYKKTTPLSA-N N-[(2S)-4,4-difluoro-1-[[1-[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-1-oxobutan-2-yl]amino]-1-oxopentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(C)(F)F)C(=O)NC(CC)C(=O)C=1N=C(ON=1)C=1C=CC(F)=CC=1)C(=O)N1CCOCC1 BHKIHNVFKWTJLL-LYKKTTPLSA-N 0.000 claims description 2
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 229910000062 azane Inorganic materials 0.000 claims description 2
- 125000005872 benzooxazolyl group Chemical group 0.000 claims description 2
- VGANCOVSGCZCHC-SFHVURJKSA-N benzyl n-[(2s)-1-(cyanomethylamino)-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]carbamate Chemical compound N([C@@H](CC(F)(F)CC=1C=CC=CC=1)C(=O)NCC#N)C(=O)OCC1=CC=CC=C1 VGANCOVSGCZCHC-SFHVURJKSA-N 0.000 claims description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- JEUUAHPZPYGIFF-NSHDSACASA-N n-[(2s)-1-(cyanomethylamino)-4,4-difluoro-1-oxoheptan-2-yl]morpholine-4-carboxamide Chemical compound CCCC(F)(F)C[C@@H](C(=O)NCC#N)NC(=O)N1CCOCC1 JEUUAHPZPYGIFF-NSHDSACASA-N 0.000 claims description 2
- GFHSXGKVYPUPJB-GOTSBHOMSA-N n-[(2s)-1-[[(1s)-1-cyano-3-phenylpropyl]amino]-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(F)(F)CC=1C=CC=CC=1)C(=O)N[C@@H](CCC=1C=CC=CC=1)C#N)C(=O)N1CCOCC1 GFHSXGKVYPUPJB-GOTSBHOMSA-N 0.000 claims description 2
- DZIZVUWFJQUJHA-ZFWWWQNUSA-N n-[(2s)-1-[[(2s)-1-(1,3-benzoxazol-2-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxopentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(C)(F)F)C(=O)N[C@@H](CC)C(=O)C=1OC2=CC=CC=C2N=1)C(=O)N1CCOCC1 DZIZVUWFJQUJHA-ZFWWWQNUSA-N 0.000 claims description 2
- WWQGVDRLDMDHAP-VXKWHMMOSA-N n-[(2s)-1-[[(2s)-1-(1,3-benzoxazol-2-yl)-1-oxopentan-2-yl]amino]-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical class C([C@@H](C(=O)N[C@@H](CCC)C(=O)C=1OC2=CC=CC=C2N=1)NC(=O)N1CCOCC1)C(F)(F)CC1=CC=CC=C1 WWQGVDRLDMDHAP-VXKWHMMOSA-N 0.000 claims description 2
- MRPICXVETZLZCE-GJZGRUSLSA-N n-[(2s)-1-[[(2s)-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxoheptan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(F)(F)CCC)C(=O)N[C@@H](CC)C(=O)C=1OC(=NN=1)C1CC1)C(=O)N1CCOCC1 MRPICXVETZLZCE-GJZGRUSLSA-N 0.000 claims description 2
- MRJUWRTZHMVFNZ-GGYWPGCISA-N n-[(2s)-1-[[1-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-1-oxobutan-2-yl]amino]-4,4-difluoro-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical compound C([C@@H](C(=O)NC(CC)C(=O)C=1N=C(ON=1)C(C)(C)C)NC(=O)N1CCOCC1)C(F)(F)CC1=CC=CC=C1 MRJUWRTZHMVFNZ-GGYWPGCISA-N 0.000 claims description 2
- BHKIHNVFKWTJLL-CVEARBPZSA-N n-[(2s)-4,4-difluoro-1-[[(2r)-1-[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-1-oxobutan-2-yl]amino]-1-oxopentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(C)(F)F)C(=O)N[C@H](CC)C(=O)C=1N=C(ON=1)C=1C=CC(F)=CC=1)C(=O)N1CCOCC1 BHKIHNVFKWTJLL-CVEARBPZSA-N 0.000 claims description 2
- BSTOHWYRHZJCMX-ROUUACIJSA-N n-[(2s)-4,4-difluoro-1-[[(2s)-1-(1,3-oxazol-2-yl)-1-oxobutan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical class C([C@@H](C(=O)N[C@@H](CC)C(=O)C=1OC=CN=1)NC(=O)N1CCOCC1)C(F)(F)CC1=CC=CC=C1 BSTOHWYRHZJCMX-ROUUACIJSA-N 0.000 claims description 2
- MTEDBVQYNJJJHM-RXVVDRJESA-N n-[(2s)-4,4-difluoro-1-[[(2s)-2-methyl-1-oxopentan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]morpholine-4-carboxamide Chemical compound C([C@@H](C(=O)N[C@@](C)(CCC)C=O)NC(=O)N1CCOCC1)C(F)(F)CC1=CC=CC=C1 MTEDBVQYNJJJHM-RXVVDRJESA-N 0.000 claims description 2
- NJBRWBMLJKNQFT-LWKPJOBUSA-N n-[(2s)-4,4-difluoro-1-[[1-[5-(5-methyl-1,2-oxazol-3-yl)-1,3-oxazol-2-yl]-1-oxobutan-2-yl]amino]-1-oxoheptan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(F)(F)CCC)C(=O)NC(CC)C(=O)C=1OC(=CN=1)C1=NOC(C)=C1)C(=O)N1CCOCC1 NJBRWBMLJKNQFT-LWKPJOBUSA-N 0.000 claims description 2
- MZSHSFFLBKWTNY-HOTGVXAUSA-N n-[(2s)-4,4-difluoro-1-oxo-1-[[(2s)-1-oxo-1-(5-phenyl-1,2,4-oxadiazol-3-yl)butan-2-yl]amino]pentan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(C)(F)F)C(=O)N[C@@H](CC)C(=O)C=1N=C(ON=1)C=1C=CC=CC=1)C(=O)N1CCOCC1 MZSHSFFLBKWTNY-HOTGVXAUSA-N 0.000 claims description 2
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- ZIXNHPZETKVUEB-ROUUACIJSA-N n-[(2s)-4,4-difluoro-1-oxo-1-[[(2s)-1-oxo-1-[5-[4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butan-2-yl]amino]heptan-2-yl]morpholine-4-carboxamide Chemical compound N([C@@H](CC(F)(F)CCC)C(=O)N[C@@H](CC)C(=O)C=1OC(=NN=1)C=1C=CC(OC(F)(F)F)=CC=1)C(=O)N1CCOCC1 ZIXNHPZETKVUEB-ROUUACIJSA-N 0.000 claims description 2
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- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
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- AMWBULKKLCAABK-UHFFFAOYSA-N tert-butyl n-(1-cyano-1-hydroxybutan-2-yl)carbamate Chemical compound N#CC(O)C(CC)NC(=O)OC(C)(C)C AMWBULKKLCAABK-UHFFFAOYSA-N 0.000 description 1
- HWYBDBPRBYRUQE-UHFFFAOYSA-N tert-butyl n-(1-nitro-2-trimethylsilyloxypentan-3-yl)carbamate Chemical compound [O-][N+](=O)CC(O[Si](C)(C)C)C(CC)NC(=O)OC(C)(C)C HWYBDBPRBYRUQE-UHFFFAOYSA-N 0.000 description 1
- RKZIYBASBODWAP-RGURZIINSA-N tert-butyl n-[(2s)-1-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-1-hydroxybutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](CC)C(O)C1=NOC(C2CC2)=N1 RKZIYBASBODWAP-RGURZIINSA-N 0.000 description 1
- DFSHPCRQFPTDCX-UEWDXFNNSA-N tert-butyl n-[(2s)-1-hydroxy-1-[5-[4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butan-2-yl]carbamate Chemical compound O1C(C(O)[C@@H](NC(=O)OC(C)(C)C)CC)=NN=C1C1=CC=C(OC(F)(F)F)C=C1 DFSHPCRQFPTDCX-UEWDXFNNSA-N 0.000 description 1
- XLLWDYVSKLXNNR-UHFFFAOYSA-N tert-butyl n-[1-(5-propan-2-yl-1,2-oxazol-3-yl)-1-trimethylsilyloxybutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(CC)C(O[Si](C)(C)C)C=1C=C(C(C)C)ON=1 XLLWDYVSKLXNNR-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 238000005292 vacuum distillation Methods 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| US51437303P | 2003-10-24 | 2003-10-24 | |
| US60/514,373 | 2003-10-24 |
Publications (1)
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|---|---|
| KR20070008517A true KR20070008517A (ko) | 2007-01-17 |
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| EP (1) | EP1682524A1 (enExample) |
| JP (1) | JP4769192B2 (enExample) |
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| CN (1) | CN100543017C (enExample) |
| AU (1) | AU2004284089B2 (enExample) |
| BR (1) | BRPI0415826A (enExample) |
| CA (1) | CA2547591C (enExample) |
| IL (1) | IL175106A0 (enExample) |
| MA (1) | MA28170A1 (enExample) |
| ME (1) | MEP39608A (enExample) |
| MX (1) | MXPA06004422A (enExample) |
| NO (1) | NO20062150L (enExample) |
| NZ (1) | NZ546504A (enExample) |
| RS (1) | RS20060280A (enExample) |
| RU (1) | RU2346943C2 (enExample) |
| WO (1) | WO2005040142A1 (enExample) |
| ZA (1) | ZA200603183B (enExample) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1819667B1 (en) | 2004-12-02 | 2012-10-17 | ViroBay, Inc. | Sulfonamide compounds as cysteine protease inhibitors |
| EP1865940B1 (en) | 2005-03-21 | 2013-02-13 | Virobay, Inc. | Alpha ketoamide compounds as cysteine protease inhibitors |
| JP5215167B2 (ja) | 2005-03-22 | 2013-06-19 | ビロベイ,インコーポレイティド | システインプロテアーゼ阻害剤としてのスルホニル基含有化合物 |
| WO2007137738A1 (de) * | 2006-06-01 | 2007-12-06 | Sanofi-Aventis | Spiro-cyclische nitrile als protease-inhibitoren |
| US7893112B2 (en) | 2006-10-04 | 2011-02-22 | Virobay, Inc. | Di-fluoro containing compounds as cysteine protease inhibitors |
| CA2664878A1 (en) * | 2006-10-04 | 2008-04-10 | Virobay, Inc. | Di-fluoro containing compounds as cysteine protease inhibitors |
| MY162041A (en) | 2007-02-28 | 2017-05-31 | Sanofi Aventis | Imaging probes |
| BRPI0822420A2 (pt) * | 2008-04-01 | 2014-10-07 | Virobay Inc | Composto, composição farmaceutica, e, métodos para tratar uma doença em uma animal e para tratar um paciente que passa por uma tarepia. |
| US7741327B2 (en) | 2008-04-16 | 2010-06-22 | Hoffmann-La Roche Inc. | Pyrrolidinone glucokinase activators |
| CN102264710B (zh) * | 2008-12-19 | 2014-11-05 | 美迪维尔英国有限公司 | 半胱氨酸蛋白酶抑制剂 |
| US7893099B2 (en) * | 2009-06-11 | 2011-02-22 | Hoffman-La Roche Inc. | Cyclopentane derivatives |
| US20110021570A1 (en) | 2009-07-23 | 2011-01-27 | Nancy-Ellen Haynes | Pyridone glucokinase activators |
| US8324417B2 (en) * | 2009-08-19 | 2012-12-04 | Virobay, Inc. | Process for the preparation of (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid and alkyl esters and acid salts thereof |
| US8895497B2 (en) | 2009-12-04 | 2014-11-25 | Dcb-Usa, Llc | Cathepsin S inhibitors |
| US8500766B2 (en) * | 2009-12-18 | 2013-08-06 | Colgate-Palmolive Company | Oral care implement multiple soft tissue cleaner components |
| US8178689B2 (en) | 2010-06-17 | 2012-05-15 | Hoffman-La Roche Inc. | Tricyclic compounds |
| AU2013305759C1 (en) | 2012-08-23 | 2018-01-18 | Janssen Biopharma, Inc. | Compounds for the treatment of paramoxyvirus viral infections |
| WO2020201572A1 (en) | 2019-04-05 | 2020-10-08 | Université De Bretagne Occidentale | Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2381023A1 (fr) | 1977-02-18 | 1978-09-15 | Delalande Sa | Nouveaux oligopeptides trifluoromethyles derives de la l-alanine, leur procede de preparation et leur application en therapeutique |
| FR2605009B1 (fr) * | 1986-06-13 | 1989-06-09 | Ayi Ayicoue | Nouveaux peptides contenant un acide a-amine b-monofluore ou b,b-difluore dans leur structure dont des enkephalines et derives d'enkephalines |
| US5223485A (en) | 1989-01-31 | 1993-06-29 | Abbott Laboratories | Anaphylatoxin-receptor ligands |
| EP0456758A4 (en) * | 1989-01-31 | 1992-07-08 | Abbott Laboratories | Anaphylatoxin-receptor ligands |
| JPH0449298A (ja) * | 1990-06-19 | 1992-02-18 | Univ New York State | 新規なエンケファリン誘導体および鎮痛剤 |
| JP3605158B2 (ja) * | 1994-12-09 | 2004-12-22 | 塩野義製薬株式会社 | Hivプロテアーゼ阻害剤 |
| DE19642591A1 (de) * | 1996-10-15 | 1998-04-16 | Basf Ag | Neue Piperidin-Ketocarbonsäure-Derivate, deren Herstellung und Anwendung |
| ATE421954T1 (de) * | 1997-02-26 | 2009-02-15 | Pfizer | Heteroaryl-hexansäureamid-derivate, ihre herstellung und ihre verwendung als selektive inhibitoren der bindung von mip-1-alpha an seinen ccr1 rezeptor |
| ID20812A (id) * | 1997-07-09 | 1999-03-11 | Takeda Chemical Industries Ltd | Senyawa polyol, produk dan penggunaannya |
| KR20010041905A (ko) * | 1998-03-16 | 2001-05-25 | 시토비아 인크. | 디펩티드 카스파제 억제제 및 이의 용도 |
| GB9812523D0 (en) * | 1998-06-10 | 1998-08-05 | Angeletti P Ist Richerche Bio | Peptide inhibitors of hepatitis c virus ns3 protease |
| TW200404789A (en) | 1999-03-15 | 2004-04-01 | Axys Pharm Inc | Novel compounds and compositions as protease inhibitors |
| HRP20010738B1 (en) | 1999-03-15 | 2005-02-28 | Axys Pharmaceuticals | N-cyanomethyl amides as protease inhibitors |
| EP1372655B1 (en) | 2001-03-02 | 2008-10-01 | Merck Frosst Canada Ltd. | Cathepsin cysteine protease inhibitors |
| GB0107924D0 (en) | 2001-03-29 | 2001-05-23 | Angeletti P Ist Richerche Bio | Inhibitor of hepatitis C virus NS3 protease |
| KR20040015725A (ko) | 2001-06-01 | 2004-02-19 | 액시스 파마슈티컬스 인코포레이티드 | 카텝신 s 억제제로서의 화합물 및 약제학적 조성물 |
| US6982263B2 (en) * | 2001-06-08 | 2006-01-03 | Boehringer Ingelheim Pharmaceuticals, Inc. | Nitriles useful as reversible inhibitors of cysteine proteases |
| WO2003075836A2 (en) | 2002-03-05 | 2003-09-18 | Merck Frosst Canada & Co. | Cathepsin cysteine protease inhibitors |
| WO2003087069A2 (en) * | 2002-04-09 | 2003-10-23 | Eli Lilly And Company | Dipeptidic growth hormone secretagogues |
| WO2003097617A1 (en) * | 2002-05-14 | 2003-11-27 | Axys Pharmaceuticals, Inc. | Cysteine protease inhibitors |
-
2004
- 2004-10-22 WO PCT/US2004/035282 patent/WO2005040142A1/en not_active Ceased
- 2004-10-22 MX MXPA06004422A patent/MXPA06004422A/es active IP Right Grant
- 2004-10-22 EP EP04796294A patent/EP1682524A1/en not_active Withdrawn
- 2004-10-22 NZ NZ546504A patent/NZ546504A/en not_active IP Right Cessation
- 2004-10-22 ME MEP-396/08A patent/MEP39608A/xx unknown
- 2004-10-22 AU AU2004284089A patent/AU2004284089B2/en not_active Ceased
- 2004-10-22 BR BRPI0415826-1A patent/BRPI0415826A/pt not_active Application Discontinuation
- 2004-10-22 KR KR1020067008096A patent/KR20070008517A/ko not_active Withdrawn
- 2004-10-22 RS YUP-2006/0280A patent/RS20060280A/sr unknown
- 2004-10-22 JP JP2006536882A patent/JP4769192B2/ja not_active Expired - Fee Related
- 2004-10-22 RU RU2006117788/04A patent/RU2346943C2/ru not_active IP Right Cessation
- 2004-10-22 CA CA2547591A patent/CA2547591C/en not_active Expired - Fee Related
- 2004-10-22 CN CNB2004800389122A patent/CN100543017C/zh not_active Expired - Fee Related
-
2006
- 2006-04-20 ZA ZA200603183A patent/ZA200603183B/en unknown
- 2006-04-23 IL IL175106A patent/IL175106A0/en unknown
- 2006-04-24 US US11/409,601 patent/US7482448B2/en not_active Expired - Fee Related
- 2006-05-12 NO NO20062150A patent/NO20062150L/no unknown
- 2006-05-23 MA MA29048A patent/MA28170A1/fr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2547591A1 (en) | 2005-05-06 |
| CA2547591C (en) | 2010-08-17 |
| AU2004284089B2 (en) | 2009-11-26 |
| NO20062150L (no) | 2006-05-12 |
| NZ546504A (en) | 2009-01-31 |
| AU2004284089A1 (en) | 2005-05-06 |
| WO2005040142A1 (en) | 2005-05-06 |
| RU2006117788A (ru) | 2007-11-27 |
| US7482448B2 (en) | 2009-01-27 |
| RS20060280A (sr) | 2008-08-07 |
| HK1101871A1 (zh) | 2007-10-26 |
| ZA200603183B (en) | 2007-09-26 |
| BRPI0415826A (pt) | 2007-01-02 |
| WO2005040142B1 (en) | 2005-07-14 |
| MA28170A1 (fr) | 2006-09-01 |
| IL175106A0 (en) | 2006-09-05 |
| US20060189657A1 (en) | 2006-08-24 |
| MXPA06004422A (es) | 2006-07-03 |
| WO2005040142A9 (en) | 2005-06-09 |
| JP2007509175A (ja) | 2007-04-12 |
| JP4769192B2 (ja) | 2011-09-07 |
| CN1898219A (zh) | 2007-01-17 |
| CN100543017C (zh) | 2009-09-23 |
| EP1682524A1 (en) | 2006-07-26 |
| RU2346943C2 (ru) | 2009-02-20 |
| MEP39608A (en) | 2011-02-10 |
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