KR20080043383A - Ｆａｐ 저해제 - Google Patents
Ｆａｐ 저해제 Download PDFInfo
- Publication number
- KR20080043383A KR20080043383A KR1020087007975A KR20087007975A KR20080043383A KR 20080043383 A KR20080043383 A KR 20080043383A KR 1020087007975 A KR1020087007975 A KR 1020087007975A KR 20087007975 A KR20087007975 A KR 20087007975A KR 20080043383 A KR20080043383 A KR 20080043383A
- Authority
- KR
- South Korea
- Prior art keywords
- pyrrolidine
- carbonitrile
- mmol
- methoxybenzoylamino
- alkyl
- 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- Withdrawn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 description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 51
- -1 (C 1 C 4) alkyl Compound Chemical class 0.000 claims description 27
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 206010016654 Fibrosis Diseases 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 8
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 7
- 230000035755 proliferation Effects 0.000 claims description 7
- 206010027476 Metastases Diseases 0.000 claims description 5
- 208000007502 anemia Diseases 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 210000000601 blood cell Anatomy 0.000 claims description 5
- 238000002512 chemotherapy Methods 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 230000004761 fibrosis Effects 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 230000003211 malignant effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000009401 metastasis Effects 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 208000004235 neutropenia Diseases 0.000 claims description 5
- 210000000056 organ Anatomy 0.000 claims description 5
- VEBQYHFHXCAREJ-UHFFFAOYSA-N pyrrolidin-2-ylboronic acid Chemical compound OB(O)C1CCCN1 VEBQYHFHXCAREJ-UHFFFAOYSA-N 0.000 claims description 5
- 230000029663 wound healing Effects 0.000 claims description 5
- 208000016216 Choristoma Diseases 0.000 claims description 4
- 208000034189 Sclerosis Diseases 0.000 claims description 4
- 230000007882 cirrhosis Effects 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000007634 remodeling Methods 0.000 claims description 4
- OAKKEQGCYJDXOZ-BWESVNLHSA-O CCC(C)[C@@H](C([S+](C1)CN[C@@H]1C#N)=O)NC(C1=CC=CC(OC)=C1)=O Chemical compound CCC(C)[C@@H](C([S+](C1)CN[C@@H]1C#N)=O)NC(C1=CC=CC(OC)=C1)=O OAKKEQGCYJDXOZ-BWESVNLHSA-O 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- MMEPVYJSHWWBSV-HNNXBMFYSA-N n-[2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]-2-methoxy-n-(2-methylpropyl)benzamide Chemical compound COC1=CC=CC=C1C(=O)N(CC(C)C)CC(=O)N1[C@H](C#N)CCC1 MMEPVYJSHWWBSV-HNNXBMFYSA-N 0.000 claims description 3
- JWFDLILYICVSFH-UHFFFAOYSA-N 1,1-dioxo-1,3-thiazolidine-4-carbonitrile Chemical compound O=S1(=O)CNC(C#N)C1 JWFDLILYICVSFH-UHFFFAOYSA-N 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 230000008467 tissue growth Effects 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 4
- 150000007649 L alpha amino acids Chemical class 0.000 claims 4
- 239000011159 matrix material Substances 0.000 claims 3
- RGICCULPCWNRAB-UHFFFAOYSA-N 2-[2-(2-hexoxyethoxy)ethoxy]ethanol Chemical compound CCCCCCOCCOCCOCCO RGICCULPCWNRAB-UHFFFAOYSA-N 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 125000003709 fluoroalkyl group Chemical group 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 239000001301 oxygen Substances 0.000 claims 2
- BHPWUBNBWJDBRI-GJZGRUSLSA-N (2s)-1-[(2s)-1-(3-chlorobenzoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile Chemical compound ClC1=CC=CC(C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C#N)=C1 BHPWUBNBWJDBRI-GJZGRUSLSA-N 0.000 claims 1
- VDBOVPXABUSAOH-HOCLYGCPSA-N (2s)-1-[(2s)-1-(3-methoxybenzoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbaldehyde Chemical compound COC1=CC=CC(C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C=O)=C1 VDBOVPXABUSAOH-HOCLYGCPSA-N 0.000 claims 1
- VGPPINZLYPNBTM-HOCLYGCPSA-N (2s)-1-[(2s)-1-(3-methoxybenzoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile Chemical compound COC1=CC=CC(C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C#N)=C1 VGPPINZLYPNBTM-HOCLYGCPSA-N 0.000 claims 1
- ZERXNNPHBAEGND-HOTGVXAUSA-N (2s)-1-[(2s)-1-benzoylpiperidine-2-carbonyl]pyrrolidine-2-carbonitrile Chemical compound C([C@H]1C(=O)N2[C@@H](CCC2)C#N)CCCN1C(=O)C1=CC=CC=C1 ZERXNNPHBAEGND-HOTGVXAUSA-N 0.000 claims 1
- DUAMOTNTPOWUPE-VWHLVEDXSA-N (2s)-1-[(2s)-2-(2-methoxybenzoyl)-1,3,3a,4,5,6,7,7a-octahydroindole-2-carbonyl]pyrrolidine-2-carbaldehyde Chemical compound COC1=CC=CC=C1C(=O)[C@@]1(C(=O)N2[C@@H](CCC2)C=O)NC2CCCCC2C1 DUAMOTNTPOWUPE-VWHLVEDXSA-N 0.000 claims 1
- HOGMKLFVXPLGIF-HKDCCESQSA-N (2s)-1-[(2s)-2-(4-methylbenzoyl)-1,3,3a,4,5,6,7,7a-octahydroindole-2-carbonyl]pyrrolidine-2-carbonitrile Chemical compound C1=CC(C)=CC=C1C(=O)[C@@]1(C(=O)N2[C@@H](CCC2)C#N)NC2CCCCC2C1 HOGMKLFVXPLGIF-HKDCCESQSA-N 0.000 claims 1
- DQLWFRJPQSKXMX-UWVGGRQHSA-N (2s)-2-[(2s)-2-cyano-4,4-difluoropyrrolidine-1-carbonyl]-n-ethylpyrrolidine-1-carboxamide Chemical compound CCNC(=O)N1CCC[C@H]1C(=O)N1[C@H](C#N)CC(F)(F)C1 DQLWFRJPQSKXMX-UWVGGRQHSA-N 0.000 claims 1
- HUCDGWFIFAEIHW-VSUJBEPISA-N (2s)-2-[(2s)-2-cyanopyrrolidine-1-carbonyl]-n-ethyl-1,3,3a,4,5,6,7,7a-octahydroindole-2-carboxamide Chemical compound O=C([C@@]1(NC2CCCCC2C1)C(=O)NCC)N1CCC[C@H]1C#N HUCDGWFIFAEIHW-VSUJBEPISA-N 0.000 claims 1
- HBSIJYHNQSYMFP-RYUDHWBXSA-N (2s)-2-[(2s)-2-cyanopyrrolidine-1-carbonyl]-n-propan-2-ylpyrrolidine-1-carboxamide Chemical compound CC(C)NC(=O)N1CCC[C@H]1C(=O)N1[C@H](C#N)CCC1 HBSIJYHNQSYMFP-RYUDHWBXSA-N 0.000 claims 1
- AZTYKQXGOBGTPX-RYUDHWBXSA-N (2s)-2-[(2s)-2-cyanopyrrolidine-1-carbonyl]-n-propylpyrrolidine-1-carbothioamide Chemical compound CCCNC(=S)N1CCC[C@H]1C(=O)N1[C@H](C#N)CCC1 AZTYKQXGOBGTPX-RYUDHWBXSA-N 0.000 claims 1
- FQULOSOYTBNLIJ-SHWKFHJASA-N (2s)-n-ethyl-2-[(2s)-2-formylpyrrolidine-1-carbonyl]-2,3,3a,4,5,6,7,7a-octahydroindole-1-carboxamide Chemical compound O=C([C@@H]1CC2CCCCC2N1C(=O)NCC)N1CCC[C@H]1C=O FQULOSOYTBNLIJ-SHWKFHJASA-N 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- CBEFQPARQNDBRR-UWVGGRQHSA-N 1-[(2s)-1-[(2s)-2-cyano-4,4-difluoropyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-3-ethylurea Chemical compound CCNC(=O)N[C@@H](C(C)C)C(=O)N1CC(F)(F)C[C@H]1C#N CBEFQPARQNDBRR-UWVGGRQHSA-N 0.000 claims 1
- HLNHLDNAGJUUKD-HOTGVXAUSA-N 1-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-3-propan-2-ylurea Chemical compound C([C@H](NC(=O)NC(C)C)C(=O)N1[C@@H](CCC1)C#N)C1=CC=CC=C1 HLNHLDNAGJUUKD-HOTGVXAUSA-N 0.000 claims 1
- CQPKYTAFAQYZBS-UWVGGRQHSA-N 1-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-1-oxopropan-2-yl]-3-propan-2-ylurea Chemical compound CC(C)NC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C#N CQPKYTAFAQYZBS-UWVGGRQHSA-N 0.000 claims 1
- ZSCRPXVYYFXEHH-QWRGUYRKSA-N 1-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-3-ethylurea Chemical compound CCNC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C#N ZSCRPXVYYFXEHH-QWRGUYRKSA-N 0.000 claims 1
- FTTUJTGRYWOXDJ-BEEDKBRMSA-N 1-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]-3-(2-phenylethyl)thiourea Chemical compound N([C@@H](C(C)CC)C(=O)N1[C@@H](CCC1)C#N)C(=S)NCCC1=CC=CC=C1 FTTUJTGRYWOXDJ-BEEDKBRMSA-N 0.000 claims 1
- BUNPRTJDEIFBRC-RAMGSTBQSA-N 1-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]-3-ethylurea Chemical compound CCNC(=O)N[C@@H](C(C)CC)C(=O)N1CCC[C@H]1C#N BUNPRTJDEIFBRC-RAMGSTBQSA-N 0.000 claims 1
- DNZCDLDJXZSDAH-STQMWFEESA-N 1-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]-3-ethyl-1-methylurea Chemical compound CCNC(=O)N(C)[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C#N DNZCDLDJXZSDAH-STQMWFEESA-N 0.000 claims 1
- QDPLHRWMRWAAAC-JKSUJKDBSA-N 1-benzyl-3-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]urea Chemical compound N([C@@H](C(C)(C)C)C(=O)N1[C@@H](CCC1)C#N)C(=O)NCC1=CC=CC=C1 QDPLHRWMRWAAAC-JKSUJKDBSA-N 0.000 claims 1
- RNQZZHMEFRITHS-VYIIXAMBSA-N 2-methoxy-n-[(2s)-3-methyl-1-oxo-1-pyrrolidin-1-ylpentan-2-yl]benzamide Chemical compound N([C@@H](C(C)CC)C(=O)N1CCCC1)C(=O)C1=CC=CC=C1OC RNQZZHMEFRITHS-VYIIXAMBSA-N 0.000 claims 1
- 239000004475 Arginine Substances 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims 1
- DNRDOVSZCGLLGT-TUJLOAKASA-N N([C@@H](C(C)CC)C(=O)S1(=O)C[C@H](NC1)C#N)C(=O)C1=CC=CC(OC)=C1 Chemical compound N([C@@H](C(C)CC)C(=O)S1(=O)C[C@H](NC1)C#N)C(=O)C1=CC=CC(OC)=C1 DNRDOVSZCGLLGT-TUJLOAKASA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- ANPJLJNEFJVWOO-GJZGRUSLSA-N [(2r)-1-[(2s)-2-[(2-methoxybenzoyl)amino]-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound COC1=CC=CC=C1C(=O)N[C@@H](C(C)C)C(=O)N1[C@H](B(O)O)CCC1 ANPJLJNEFJVWOO-GJZGRUSLSA-N 0.000 claims 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 1
- 235000004279 alanine Nutrition 0.000 claims 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 1
- DDHODFLDJUQHSX-SFTDATJTSA-N benzyl (4s)-4-[(4-chlorobenzoyl)amino]-5-[(2s)-2-cyanopyrrolidin-1-yl]-5-oxopentanoate Chemical compound C1=CC(Cl)=CC=C1C(=O)N[C@H](C(=O)N1[C@@H](CCC1)C#N)CCC(=O)OCC1=CC=CC=C1 DDHODFLDJUQHSX-SFTDATJTSA-N 0.000 claims 1
- QFDOFQHDZCGZJQ-ICSRJNTNSA-N benzyl n-[(2s)-3-[(2s)-2-cyanopyrrolidin-1-yl]-2-[(2-methoxybenzoyl)amino]-3-oxopropyl]carbamate Chemical compound COC1=CC=CC=C1C(=O)N[C@H](C(=O)N1[C@@H](CCC1)C#N)CNC(=O)OCC1=CC=CC=C1 QFDOFQHDZCGZJQ-ICSRJNTNSA-N 0.000 claims 1
- BAKBWMQUYIHULH-FPOVZHCZSA-N benzyl n-[(3s)-4-[(2s)-2-cyanopyrrolidin-1-yl]-3-[(2-methoxybenzoyl)amino]-4-oxobutyl]carbamate Chemical compound COC1=CC=CC=C1C(=O)N[C@H](C(=O)N1[C@@H](CCC1)C#N)CCNC(=O)OCC1=CC=CC=C1 BAKBWMQUYIHULH-FPOVZHCZSA-N 0.000 claims 1
- WBTNMOUDIQEVFC-GMAHTHKFSA-N benzyl n-[(4s)-5-[(2s)-2-cyanopyrrolidin-1-yl]-4-[(4-methoxybenzoyl)amino]-5-oxopentyl]carbamate Chemical compound C1=CC(OC)=CC=C1C(=O)N[C@H](C(=O)N1[C@@H](CCC1)C#N)CCCNC(=O)OCC1=CC=CC=C1 WBTNMOUDIQEVFC-GMAHTHKFSA-N 0.000 claims 1
- AQFRZEWKJVGQGN-UPVQGACJSA-N benzyl n-[(5s)-6-[(2s)-2-cyanopyrrolidin-1-yl]-5-[(3-methoxybenzoyl)amino]-6-oxohexyl]carbamate Chemical compound COC1=CC=CC(C(=O)N[C@@H](CCCCNC(=O)OCC=2C=CC=CC=2)C(=O)N2[C@@H](CCC2)C#N)=C1 AQFRZEWKJVGQGN-UPVQGACJSA-N 0.000 claims 1
- FAUWKACRJDTPOA-JSGCOSHPSA-N methyl (3s)-4-[(2s)-2-cyanopyrrolidin-1-yl]-3-[(2-methoxybenzoyl)amino]-4-oxobutanoate Chemical compound N([C@@H](CC(=O)OC)C(=O)N1[C@@H](CCC1)C#N)C(=O)C1=CC=CC=C1OC FAUWKACRJDTPOA-JSGCOSHPSA-N 0.000 claims 1
- VCEGEGIPEXYJAI-HKUYNNGSSA-N n-[(1s)-2-[(2s)-2-cyanopyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)N[C@H](C(=O)N1[C@@H](CCC1)C#N)C1CCCCC1 VCEGEGIPEXYJAI-HKUYNNGSSA-N 0.000 claims 1
- PWTSYTVTZMZJGD-ROUUACIJSA-N n-[(1s)-2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxo-1-phenylethyl]cyclohexanecarboxamide Chemical compound O=C([C@@H](NC(=O)C1CCCCC1)C=1C=CC=CC=1)N1CCC[C@H]1C#N PWTSYTVTZMZJGD-ROUUACIJSA-N 0.000 claims 1
- UVUCACZVILCRPP-WFASDCNBSA-N n-[(2s)-1-[(2s)-2-cyano-4,4-difluoropyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)N[C@@H](C(C)C)C(=O)N1[C@H](C#N)CC(F)(F)C1 UVUCACZVILCRPP-WFASDCNBSA-N 0.000 claims 1
- RGZBPLPCOYHYKX-XGFYENRKSA-N n-[(2s)-1-[(2s)-2-cyanoazetidin-1-yl]-3-methyl-1-oxopentan-2-yl]-2-methoxybenzamide Chemical compound N([C@@H](C(C)CC)C(=O)N1[C@@H](CC1)C#N)C(=O)C1=CC=CC=C1OC RGZBPLPCOYHYKX-XGFYENRKSA-N 0.000 claims 1
- QVOUOWQMLYUBSG-UFFKYAFASA-N n-[(2s)-1-[(2s)-2-cyanopiperidin-1-yl]-3-methyl-1-oxopentan-2-yl]-2-methoxybenzamide Chemical compound N([C@@H](C(C)CC)C(=O)N1[C@@H](CCCC1)C#N)C(=O)C1=CC=CC=C1OC QVOUOWQMLYUBSG-UFFKYAFASA-N 0.000 claims 1
- IRXQLUZQSXKQTK-PMACEKPBSA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-1-oxo-3-phenylmethoxypropan-2-yl]benzamide Chemical compound C([C@H](NC(=O)C=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C#N)OCC1=CC=CC=C1 IRXQLUZQSXKQTK-PMACEKPBSA-N 0.000 claims 1
- VJKYBUCABNMHNZ-HOTGVXAUSA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-2,2-dimethylpropanamide Chemical compound C([C@H](NC(=O)C(C)(C)C)C(=O)N1[C@@H](CCC1)C#N)C1=CC=CC=C1 VJKYBUCABNMHNZ-HOTGVXAUSA-N 0.000 claims 1
- NEKKARWFODQEBP-PMACEKPBSA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-n-methylcyclohexanecarboxamide Chemical compound C([C@H](N(C)C(=O)C1CCCCC1)C(=O)N1[C@@H](CCC1)C#N)C1=CC=CC=C1 NEKKARWFODQEBP-PMACEKPBSA-N 0.000 claims 1
- CNDNFODYJHUFBN-JSGCOSHPSA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-1-oxopropan-2-yl]-n-methylcyclohexanecarboxamide Chemical compound CN([C@@H](C)C(=O)N1[C@@H](CCC1)C#N)C(=O)C1CCCCC1 CNDNFODYJHUFBN-JSGCOSHPSA-N 0.000 claims 1
- RANABWAAQNNYCJ-XJKSGUPXSA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)N[C@@H](C(C)(C)C)C(=O)N1[C@H](C#N)CCC1 RANABWAAQNNYCJ-XJKSGUPXSA-N 0.000 claims 1
- BUMFFFVUHIJEKL-HOCLYGCPSA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)N[C@@H](C(C)C)C(=O)N2[C@@H](CCC2)C#N)=C1 BUMFFFVUHIJEKL-HOCLYGCPSA-N 0.000 claims 1
- MZHFTMRPFYCUDY-SPOOISQMSA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)N[C@@H](C(C)CC)C(=O)N1CCC[C@H]1C#N MZHFTMRPFYCUDY-SPOOISQMSA-N 0.000 claims 1
- FJGNQUANKGZDDK-UFFKYAFASA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]-2-methoxy-n-methylbenzamide Chemical compound CN([C@@H](C(C)CC)C(=O)N1[C@@H](CCC1)C#N)C(=O)C1=CC=CC=C1OC FJGNQUANKGZDDK-UFFKYAFASA-N 0.000 claims 1
- FAWMMKSJLIZZRH-HUUYTVAOSA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]-2-methoxybenzamide Chemical compound N([C@@H](C(C)CC)C(=O)N1[C@@H](CCC1)C#N)C(=O)C1=CC=CC=C1OC FAWMMKSJLIZZRH-HUUYTVAOSA-N 0.000 claims 1
- DEGBUCDMCRUTQK-QJOPWCIASA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]-3-methoxybenzamide Chemical compound N([C@@H](C(C)CC)C(=O)N1[C@@H](CCC1)C#N)C(=O)C1=CC=CC(OC)=C1 DEGBUCDMCRUTQK-QJOPWCIASA-N 0.000 claims 1
- AUPWEHXGXJUQRD-QJOPWCIASA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]-4-methoxybenzamide Chemical compound N([C@@H](C(C)CC)C(=O)N1[C@@H](CCC1)C#N)C(=O)C1=CC=C(OC)C=C1 AUPWEHXGXJUQRD-QJOPWCIASA-N 0.000 claims 1
- DMJHBAIBXDJGJI-RDJZCZTQSA-N n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)N[C@@H](CC(C)C)C(=O)N2[C@@H](CCC2)C#N)=C1 DMJHBAIBXDJGJI-RDJZCZTQSA-N 0.000 claims 1
- FWNKTVPLUJFYKD-HKUYNNGSSA-N n-[(2s)-1-[(2s)-2-formylpyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)N[C@H](C(=O)N1[C@@H](CCC1)C=O)CC1=CC=CC=C1 FWNKTVPLUJFYKD-HKUYNNGSSA-N 0.000 claims 1
- VNHAVDSIKIXKLU-BBRMVZONSA-N n-[(2s)-1-[(2s)-2-formylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)N[C@@H](C(C)C)C(=O)N1[C@H](C=O)CCC1 VNHAVDSIKIXKLU-BBRMVZONSA-N 0.000 claims 1
- PYOPMTPVNNGGLD-ZFWWWQNUSA-N n-[(2s)-5-amino-1-[(2s)-2-cyanopyrrolidin-1-yl]-1-oxopentan-2-yl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)N[C@@H](CCCN)C(=O)N1[C@H](C#N)CCC1 PYOPMTPVNNGGLD-ZFWWWQNUSA-N 0.000 claims 1
- YIJFBSOVBVNTCM-HOCLYGCPSA-N n-[(2s)-6-amino-1-[(2s)-2-cyanopyrrolidin-1-yl]-1-oxohexan-2-yl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)N[C@@H](CCCCN)C(=O)N1[C@H](C#N)CCC1 YIJFBSOVBVNTCM-HOCLYGCPSA-N 0.000 claims 1
- OQXQSKNSVJCHQM-LBPRGKRZSA-N n-[1-[(2s)-2-cyanopyrrolidin-1-yl]-2-methyl-1-oxopropan-2-yl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)NC(C)(C)C(=O)N1[C@H](C#N)CCC1 OQXQSKNSVJCHQM-LBPRGKRZSA-N 0.000 claims 1
- HSIDTMLTVRFYGR-AWEZNQCLSA-N n-[2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]naphthalene-1-carboxamide Chemical compound C=1C=CC2=CC=CC=C2C=1C(=O)NCC(=O)N1CCC[C@H]1C#N HSIDTMLTVRFYGR-AWEZNQCLSA-N 0.000 claims 1
- SPTJGQOVDKLVLF-SFHVURJKSA-N n-benzyl-n-[2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)N(CC=1C=CC=CC=1)CC(=O)N1[C@H](C#N)CCC1 SPTJGQOVDKLVLF-SFHVURJKSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 294
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 180
- 239000000243 solution Substances 0.000 description 112
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 78
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- 239000002904 solvent Substances 0.000 description 75
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 74
- 239000012267 brine Substances 0.000 description 71
- 239000011734 sodium Substances 0.000 description 71
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 71
- 239000003480 eluent Substances 0.000 description 65
- 238000003818 flash chromatography Methods 0.000 description 65
- 229920006395 saturated elastomer Polymers 0.000 description 53
- 239000012230 colorless oil Substances 0.000 description 48
- 239000011347 resin Substances 0.000 description 42
- 229920005989 resin Polymers 0.000 description 42
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 16
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- RZNHSEZOLFEFGB-UHFFFAOYSA-N 2-methoxybenzoyl chloride Chemical compound COC1=CC=CC=C1C(Cl)=O RZNHSEZOLFEFGB-UHFFFAOYSA-N 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 235000019502 Orange oil Nutrition 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000010502 orange oil Substances 0.000 description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 6
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 6
- 229960000310 isoleucine Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 238000010561 standard procedure Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- PRSDPVKGJUBIAA-UHFFFAOYSA-N 1,3-thiazolidine-4-carbonitrile Chemical compound N#CC1CSCN1 PRSDPVKGJUBIAA-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical group CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- CPFVGUFLDVAAHL-UHFFFAOYSA-N azetidine-2-carbonitrile Chemical compound N#CC1CCN1 CPFVGUFLDVAAHL-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 4
- YAVXLTMRALFZIS-UHFFFAOYSA-N piperidine-2-carbonitrile Chemical compound N#CC1CCCCN1 YAVXLTMRALFZIS-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- NDBUQNMDVALEBI-KMQXGVQRSA-N (2s)-1-[(2s)-2-amino-3-methylpentanoyl]pyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.CCC(C)[C@H](N)C(=O)N1CCC[C@H]1C#N NDBUQNMDVALEBI-KMQXGVQRSA-N 0.000 description 3
- YSLAHCILFVJJTA-ACGXKRRESA-N (2s)-2-[(2-methoxybenzoyl)amino]-3-methylpentanoic acid Chemical compound CCC(C)[C@@H](C(O)=O)NC(=O)C1=CC=CC=C1OC YSLAHCILFVJJTA-ACGXKRRESA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 3
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 108010050095 PT-100 dipeptide Proteins 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000008206 alpha-amino acids Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 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
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- XHHIPGKYPSPLHH-LURJTMIESA-N tert-butyl n-[(2s)-4,4-difluoropyrrolidine-2-carbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)[C@@H]1CC(F)(F)CN1 XHHIPGKYPSPLHH-LURJTMIESA-N 0.000 description 3
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 description 2
- KDKLQRXVEWMCCI-NSHDSACASA-N (2s)-1-[(3-methoxybenzoyl)amino]pyrrolidine-2-carboxylic acid Chemical compound COC1=CC=CC(C(=O)NN2[C@@H](CCC2)C(O)=O)=C1 KDKLQRXVEWMCCI-NSHDSACASA-N 0.000 description 2
- WTMZYKCXBXPVPT-LURJTMIESA-N (2s)-4,4-difluoro-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(O)=O WTMZYKCXBXPVPT-LURJTMIESA-N 0.000 description 2
- HMZQWWPOZADCDJ-DFWYDOINSA-N (2s)-azetidine-2-carboxamide;hydrochloride Chemical compound Cl.NC(=O)[C@@H]1CCN1 HMZQWWPOZADCDJ-DFWYDOINSA-N 0.000 description 2
- MSDJHYMGDCMMSV-JEDNCBNOSA-N (2s)-piperidine-2-carboxamide;hydrochloride Chemical compound Cl.NC(=O)[C@@H]1CCCCN1 MSDJHYMGDCMMSV-JEDNCBNOSA-N 0.000 description 2
- SWTCRXVGKJOXJA-DFWYDOINSA-N (4r)-1,3-thiazolidine-4-carboxamide;hydrochloride Chemical compound Cl.NC(=O)[C@@H]1CSCN1 SWTCRXVGKJOXJA-DFWYDOINSA-N 0.000 description 2
- RQDZKOOUQIDZOG-ZETCQYMHSA-N 1-o-tert-butyl 2-o-methyl (2s)-4,4-difluoropyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C RQDZKOOUQIDZOG-ZETCQYMHSA-N 0.000 description 2
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 2
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- KKCWBKUOPJMUQV-UHFFFAOYSA-N azetidine-2-carboxamide Chemical compound NC(=O)C1CCN1 KKCWBKUOPJMUQV-UHFFFAOYSA-N 0.000 description 2
- BPFBNQSKYIAAGF-AWEZNQCLSA-N benzyl (2s)-1-(propan-2-ylcarbamoyl)pyrrolidine-2-carboxylate Chemical compound CC(C)NC(=O)N1CCC[C@H]1C(=O)OCC1=CC=CC=C1 BPFBNQSKYIAAGF-AWEZNQCLSA-N 0.000 description 2
- YJWOGZNGMZRWCD-SFHVURJKSA-N benzyl (2s)-1-[(3-methoxybenzoyl)amino]pyrrolidine-2-carboxylate Chemical compound COC1=CC=CC(C(=O)NN2[C@@H](CCC2)C(=O)OCC=2C=CC=CC=2)=C1 YJWOGZNGMZRWCD-SFHVURJKSA-N 0.000 description 2
- NEDMOHHWRPHBAL-MERQFXBCSA-N benzyl (2s)-pyrrolidin-1-ium-2-carboxylate;chloride Chemical compound Cl.O=C([C@H]1NCCC1)OCC1=CC=CC=C1 NEDMOHHWRPHBAL-MERQFXBCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- XIMBESZRBTVIOD-UHFFFAOYSA-N piperidine-2-carboxamide Chemical compound NC(=O)C1CCCCN1 XIMBESZRBTVIOD-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- HTNIWSZFNCYNIO-CVRLYYSRSA-N tert-butyl (2s)-2-[(2-methoxybenzoyl)amino]-3-methylpentanoate Chemical compound CC(C)(C)OC(=O)[C@H](C(C)CC)NC(=O)C1=CC=CC=C1OC HTNIWSZFNCYNIO-CVRLYYSRSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- GDRUGULSUNJWLH-SPOOISQMSA-N tert-butyl n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C(C)CC)C(=O)N1CCC[C@H]1C#N GDRUGULSUNJWLH-SPOOISQMSA-N 0.000 description 2
- WUYUUWPQWVBPMP-RYUDHWBXSA-N tert-butyl n-[(2s)-2-[(2s)-2-cyanopyrrolidine-1-carbonyl]pyrrolidin-1-yl]carbamate Chemical compound CC(C)(C)OC(=O)NN1CCC[C@H]1C(=O)N1[C@H](C#N)CCC1 WUYUUWPQWVBPMP-RYUDHWBXSA-N 0.000 description 2
- HGHXDZQNWMGXCS-LURJTMIESA-N tert-butyl n-[(2s)-azetidine-2-carbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)[C@@H]1CCN1 HGHXDZQNWMGXCS-LURJTMIESA-N 0.000 description 2
- KIZBVHDOAPBRLH-QMMMGPOBSA-N tert-butyl n-[(2s)-piperidine-2-carbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)[C@@H]1CCCCN1 KIZBVHDOAPBRLH-QMMMGPOBSA-N 0.000 description 2
- OSPGNZVCVNAQOF-LBPRGKRZSA-N tert-butyl n-[2-[(2s)-2-carbamoylpyrrolidin-1-yl]-2-oxoethyl]-n-(2-methylpropyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CC(C)C)CC(=O)N1CCC[C@H]1C(N)=O OSPGNZVCVNAQOF-LBPRGKRZSA-N 0.000 description 2
- PXYMZDDBRJURCE-ZDUSSCGKSA-N tert-butyl n-[2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]-n-(2-methylpropyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CC(C)C)CC(=O)N1CCC[C@H]1C#N PXYMZDDBRJURCE-ZDUSSCGKSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QAYBEWHSDGBTFE-ZETCQYMHSA-N (2s)-1-(propan-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid Chemical compound CC(C)NC(=O)N1CCC[C@H]1C(O)=O QAYBEWHSDGBTFE-ZETCQYMHSA-N 0.000 description 1
- KWUAJLIUVZLHHF-OULXEKPRSA-N (2s)-1-[(2s)-2-amino-3,3-dimethylbutanoyl]pyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.CC(C)(C)[C@H](N)C(=O)N1CCC[C@H]1C#N KWUAJLIUVZLHHF-OULXEKPRSA-N 0.000 description 1
- CSKSDAVTCKIENY-WCCKRBBISA-N (2s)-pyrrolidine-2-carboxamide;hydrochloride Chemical compound Cl.NC(=O)[C@@H]1CCCN1 CSKSDAVTCKIENY-WCCKRBBISA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- AIOMGEMZFLRFJE-UHFFFAOYSA-N 1,3-thiazolidine-4-carboxamide Chemical compound NC(=O)C1CSCN1 AIOMGEMZFLRFJE-UHFFFAOYSA-N 0.000 description 1
- KKASGUHLXWAKEZ-UHFFFAOYSA-N 1-isothiocyanatopropane Chemical compound CCCN=C=S KKASGUHLXWAKEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- IMSVLBGSOYXVIQ-UHFFFAOYSA-N 1-oxo-1,3-thiazolidine-4-carbonitrile Chemical compound O=S1CNC(C#N)C1 IMSVLBGSOYXVIQ-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- YYVPZQADFREIFR-UHFFFAOYSA-N 3,3-difluoropyrrolidine;hydrochloride Chemical compound [Cl-].FC1(F)CC[NH2+]C1 YYVPZQADFREIFR-UHFFFAOYSA-N 0.000 description 1
- WHIHIKVIWVIIER-UHFFFAOYSA-N 3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1 WHIHIKVIWVIIER-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 208000012999 benign epithelial neoplasm Diseases 0.000 description 1
- WGNZRLMOMHJUSP-UHFFFAOYSA-N benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 WGNZRLMOMHJUSP-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000003271 compound fluorescence assay Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 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 1
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 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 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- IZJDOKYDEWTZSO-UHFFFAOYSA-N phenethyl isothiocyanate Chemical compound S=C=NCCC1=CC=CC=C1 IZJDOKYDEWTZSO-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
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- QSJTUXCBPTVKQZ-UHFFFAOYSA-N pyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.N#CC1CCCN1 QSJTUXCBPTVKQZ-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- IFRYMHOZFAPYPJ-WSZWBAFRSA-N tert-butyl (2s,3s)-2-amino-3-methylpentanoate;hydron;chloride Chemical compound Cl.CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C IFRYMHOZFAPYPJ-WSZWBAFRSA-N 0.000 description 1
- OXGKKJVYQKKOIS-LURJTMIESA-N tert-butyl (4r)-4-carbamoyl-1,3-thiazolidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)N1CSC[C@H]1C(N)=O OXGKKJVYQKKOIS-LURJTMIESA-N 0.000 description 1
- GTKKTQURDHPDOT-UHFFFAOYSA-N tert-butyl n-(1,3-thiazolidine-4-carbonyl)carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)C1CSCN1 GTKKTQURDHPDOT-UHFFFAOYSA-N 0.000 description 1
- DTCDMJMPVABQQS-SPOOISQMSA-N tert-butyl n-[(2s)-1-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C(C)CC)C(=O)N1CCC[C@H]1CO DTCDMJMPVABQQS-SPOOISQMSA-N 0.000 description 1
- DXIJZJLECZNDTH-STQMWFEESA-N tert-butyl n-[(2s)-1-[(2s)-2-cyanopyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C#N DXIJZJLECZNDTH-STQMWFEESA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no 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
- C07D207/16—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
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71332405P | 2005-09-02 | 2005-09-02 | |
| US60/713,324 | 2005-09-02 | ||
| EP05108049.7 | 2005-09-02 | ||
| EP05108049A EP1760076A1 (en) | 2005-09-02 | 2005-09-02 | FAP Inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20080043383A true KR20080043383A (ko) | 2008-05-16 |
Family
ID=38309561
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020087007975A Withdrawn KR20080043383A (ko) | 2005-09-02 | 2006-08-31 | Ｆａｐ 저해제 |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US8183280B2 (enExample) |
| EP (2) | EP1760076A1 (enExample) |
| JP (1) | JP2009507011A (enExample) |
| KR (1) | KR20080043383A (enExample) |
| AU (1) | AU2006336854A1 (enExample) |
| CA (1) | CA2627607A1 (enExample) |
| NO (1) | NO20081636L (enExample) |
| RU (1) | RU2008112683A (enExample) |
| WO (1) | WO2007085895A2 (enExample) |
| ZA (1) | ZA200802867B (enExample) |
Families Citing this family (58)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
| DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
| DE102005035891A1 (de) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| BRPI0711558A2 (pt) | 2006-05-04 | 2011-11-08 | Boeringer Ingelheim Internat Gmbh | polimorfos |
| PE20080251A1 (es) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | Usos de inhibidores de dpp iv |
| US8933201B2 (en) | 2006-06-07 | 2015-01-13 | The Board Of Regents Of The University Of Oklahoma | Substrates and inhibitors of antiplasmin cleaving enzyme and fibroblast activation protein and methods of use |
| NZ600126A (en) | 2007-08-17 | 2013-12-20 | Boehringer Ingelheim Int | Purine derivatives for use in the treatment of fap-related diseases |
| ES2372442T3 (es) * | 2007-12-10 | 2012-01-19 | F. Hoffmann-La Roche Ag | Seprasa como marcador para cáncer. |
| EP2071337A1 (en) * | 2007-12-10 | 2009-06-17 | F.Hoffmann-La Roche Ag | Seprase as a marker for cancer |
| JP5586484B2 (ja) * | 2008-03-05 | 2014-09-10 | ナショナル ヘルス リサーチ インスティテューツ | ピロリジン誘導体 |
| PE20140960A1 (es) | 2008-04-03 | 2014-08-15 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
| BRPI0916997A2 (pt) | 2008-08-06 | 2020-12-15 | Boehringer Ingelheim International Gmbh | Inibidor de dpp-4 e seu uso |
| UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
| AU2009290911A1 (en) | 2008-09-10 | 2010-03-18 | Boehringer Ingelheim International Gmbh | Combination therapy for the treatment of diabetes and related conditions |
| CN102203061A (zh) * | 2008-09-25 | 2011-09-28 | 分子制药洞察公司 | 选择性seprase抑制剂 |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| EP2382216A1 (en) | 2008-12-23 | 2011-11-02 | Boehringer Ingelheim International GmbH | Salt forms of organic compound |
| AR074990A1 (es) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina |
| EP2389176A4 (en) * | 2009-01-23 | 2012-08-01 | Univ Sydney | NEW THERAPY FOR METABOLISM DISEASE |
| EA034869B1 (ru) | 2009-11-27 | 2020-03-31 | Бёрингер Ингельхайм Интернациональ Гмбх | Лечение генотипированных пациентов с диабетом ингибиторами дпп-4, такими как линаглиптин |
| MX341025B (es) | 2010-05-05 | 2016-08-04 | Boehringer Ingelheim Int Gmbh * | Terapia de combinacion. |
| PH12012502524A1 (en) | 2010-06-24 | 2014-02-10 | Boehringer Ingelheim Int | Diabetes therapy |
| WO2012061408A2 (en) * | 2010-11-02 | 2012-05-10 | Rigel Pharmaceuticals. Inc. | Method for making macrocycles |
| US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
| WO2012076985A2 (en) * | 2010-12-06 | 2012-06-14 | The University Of British Columbia | Granzyme b inhibitor compositions, methods and uses for promoting wound healing |
| EP3517539B1 (en) | 2011-07-15 | 2022-12-14 | Boehringer Ingelheim International GmbH | Substituted dimeric quinazoline derivative, its preparation and its use in pharmaceutical compositions for the treatment of type i and ii diabetes |
| WO2013107820A1 (en) * | 2012-01-17 | 2013-07-25 | Universiteit Antwerpen | Novel fap inhibitors |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| JP6224084B2 (ja) | 2012-05-14 | 2017-11-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 糸球体上皮細胞関連障害及び／又はネフローゼ症候群の治療に用いるｄｐｐ−４阻害薬としてのキサンチン誘導体 |
| US20130303554A1 (en) | 2012-05-14 | 2013-11-14 | Boehringer Ingelheim International Gmbh | Use of a dpp-4 inhibitor in sirs and/or sepsis |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| EP2866842A1 (en) * | 2012-06-29 | 2015-05-06 | GE Healthcare UK Limited | Imaging fibrosis |
| EA021236B1 (ru) * | 2012-10-03 | 2015-05-29 | Дафот Энтерпраизес Лимитед | Nα-АЦИЛЬНЫЕ ПРОИЗВОДНЫЕ АМИНОАЦИЛ-2-ЦИАНОПИРРОЛИДИНА - ИНГИБИТОРЫ ПРОЛИЛЭНДОПЕПТИДАЗЫ И ДИПЕПТИДИЛПЕПТИДАЗЫ-IV, ОБЛАДАЮЩИЕ ГИПОГЛИКЕМИЧЕСКИМ, ПРОТИВОГИПОКСИЧЕСКИМ, НЕЙРОПРОТЕКТОРНЫМ И УЛУЧШАЮЩИМ КОГНИТИВНЫЕ ФУНКЦИИ ДЕЙСТВИЕМ |
| EP2730571A1 (en) | 2012-11-12 | 2014-05-14 | Universitat De Barcelona | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives |
| US9526728B2 (en) | 2014-02-28 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Medical use of a DPP-4 inhibitor |
| JP2017516862A (ja) * | 2014-05-30 | 2017-06-22 | ブリティッシュ コロンビア キャンサー エージェンシー ブランチ | アンドロゲン受容体調節物質及びその使用方法 |
| CN109310697A (zh) | 2016-06-10 | 2019-02-05 | 勃林格殷格翰国际有限公司 | 利格列汀和二甲双胍的组合 |
| JP7162592B2 (ja) | 2016-12-14 | 2022-10-28 | パーデュー・リサーチ・ファウンデイション | 線維芽細胞活性化タンパク質（ｆａｐ）標的イメージングおよび治療 |
| WO2018129497A1 (en) | 2017-01-09 | 2018-07-12 | Bioxcel Therapeutics, Inc. | Predictive and diagnostic methods for prostate cancer |
| AU2018386298B2 (en) * | 2017-12-15 | 2023-09-07 | Praxis Biotech LLC | Inhibitors of fibroblast activation protein |
| CN113811529A (zh) * | 2018-12-21 | 2021-12-17 | 普拉西斯生物技术有限责任公司 | 成纤维细胞激活蛋白抑制剂 |
| KR102274077B1 (ko) * | 2019-03-29 | 2021-07-09 | 보령제약 주식회사 | Fap 저해제로서의 피롤리딘 유도체 및 이를 포함하는 약학적 조성물 |
| BR112022008041A2 (pt) | 2019-11-06 | 2022-08-16 | Yuhan Corp | Compostos de pirrolidina e piperidina |
| MX2022011842A (es) * | 2020-03-24 | 2022-10-20 | Tufts College | Agentes de imagen y radiofarmacos dirigidos a fap, y usos relacionados con los mismos. |
| EP4147053B1 (en) | 2020-05-07 | 2026-01-28 | Institut Curie | Antxr1 as a biomarker of immunosuppressive fibroblast populations and its use for predicting response to immunotherapy |
| UY39569A (es) * | 2020-12-17 | 2022-07-29 | Astrazeneca Ab | N-(2-(4-cianotiazolidin-3-il)-2-oxoetil)- quinolin-4-carboxamidas |
| WO2023283256A1 (en) | 2021-07-09 | 2023-01-12 | Aligos Therapeutics, Inc. | Anti-viral compounds |
| US12065428B2 (en) | 2021-09-17 | 2024-08-20 | Aligos Therapeutics, Inc. | Anti-viral compounds |
| IL317723A (en) * | 2022-06-21 | 2025-02-01 | Astrazeneca Ab | N-(2-(3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-quinoline-4-carboxamides |
| AU2023288645A1 (en) * | 2022-06-21 | 2025-02-13 | Astrazeneca Ab | Solid-state forms of n-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)- 6-morpholinoquinoline-4-carboxamide |
| CN119562951A (zh) * | 2022-06-21 | 2025-03-04 | 阿斯利康(瑞典)有限公司 | N-(2-(4-氰基噻唑烷-3-基)-2-氧代乙基)-喹啉-4-甲酰胺 |
| AU2023303408A1 (en) | 2022-07-06 | 2024-12-19 | Aligos Therapeutics, Inc. | Anti-viral compounds |
| AU2024334645A1 (en) | 2023-08-31 | 2026-02-26 | Stichting Radboud Universitair Medisch Centrum | Endometriosis tracer |
| CN118955616B (zh) * | 2024-05-01 | 2025-09-02 | 杭州景嘉航生物医药科技有限公司 | 一种靶向结合成纤维细胞活化蛋白化合物及应用 |
| WO2026007968A1 (zh) * | 2024-07-01 | 2026-01-08 | 杭州景嘉航生物医药科技有限公司 | 一种靶向结合成纤维细胞活化蛋白的化合物及应用 |
| US20260174911A1 (en) * | 2024-12-20 | 2026-06-25 | Novartis Ag | Fap targeting compounds and conjugates thereof |
Family Cites Families (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3017929A (en) * | 1959-01-07 | 1962-01-23 | Beloit Iron Works | Head box with balanced slice body |
| US4873342A (en) | 1985-04-16 | 1989-10-10 | Suntory Limited | Dipeptide derivative and synthesis and use thereof |
| CA1320734C (en) | 1986-02-04 | 1993-07-27 | Suntory Limited | Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same |
| JPH0774193B2 (ja) | 1986-07-29 | 1995-08-09 | サントリー株式会社 | ジペプチド誘導体及びその製法並びに用途 |
| EP0280956B1 (en) | 1987-02-23 | 1992-10-21 | Ono Pharmaceutical Co., Ltd. | Thiazolidine derivatives |
| CA2004028C (en) * | 1988-12-08 | 1998-09-22 | Motoki Torizuka | Condensed benzene derivative |
| US5118811A (en) * | 1989-04-13 | 1992-06-02 | Japan Tobacco Inc. | Amino acid derivatives possessing prolyl endopeptidase-inhibitory activities |
| US5462928A (en) | 1990-04-14 | 1995-10-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type IV |
| WO1991018877A1 (en) * | 1990-06-07 | 1991-12-12 | Zeria Pharmaceutical Co., Ltd. | Novel arylalkanoylamine derivative and drug containing the same |
| FR2681864B1 (fr) * | 1991-09-27 | 1995-03-31 | Adir | Nouveaux derives bicycliques azotes, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
| WO1993023040A1 (en) * | 1992-05-20 | 1993-11-25 | Merck & Co., Inc. | 17-ethers and thioethers of 4-aza-steroids |
| KR0165704B1 (ko) * | 1992-11-20 | 1999-01-15 | 미즈노 마사루 | 프롤릴 엔도펩티다아제 억제 활성을 갖는 화합물 및 그 약학적 용도 |
| JP3810097B2 (ja) | 1993-01-15 | 2006-08-16 | 明治製菓株式会社 | ピロリジン−２−イルカルボニル複素環式化合物誘導体 |
| DE69428703T2 (de) | 1993-07-23 | 2002-05-29 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai, Tokio/Tokyo | Pyrrolidin derivate |
| JPH07126229A (ja) * | 1993-11-02 | 1995-05-16 | Yoshitomi Pharmaceut Ind Ltd | ジアリールケトン化合物およびその医薬用途 |
| US5494919A (en) | 1993-11-09 | 1996-02-27 | Merck & Co., Inc. | 2-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
| BR9408019A (pt) | 1993-11-09 | 1997-08-26 | Merck & Co Inc | Composto composição util para aumentar a produção endógena ou a liberaçao de hormonio do crescimento em ser humano ou um animal e para o tratamento da osteoporose processos para aumentar os niveis de hormônio do crescimento em um ser humano ou um animal e a eficácia de alimentação promover o crescimento aumentar a produçao de leite e melhorar a qualidade da carcaça de gado para tratar ou previnir uma condição selecionada para tratar osteoporose e para preparar um composto |
| JPH07228529A (ja) * | 1994-02-17 | 1995-08-29 | Zeria Pharmaceut Co Ltd | コリンエステラーゼ賦活剤 |
| US5574017A (en) | 1994-07-05 | 1996-11-12 | Gutheil; William G. | Antibacterial agents |
| US5863902A (en) | 1995-01-06 | 1999-01-26 | Sibia Neurosciences, Inc. | Methods of treating neurodegenerative disorders using protease inhibitors |
| PT832065E (pt) * | 1995-06-06 | 2002-02-28 | Pfizer | N-(indole-2-carbonil)-glicinamidas e seus derivados como agentes antidiabeticos |
| CA2339537A1 (en) * | 1998-08-21 | 2000-03-02 | Barbara Wallner | Regulation of substrate activity |
| EA200100972A1 (ru) | 1999-03-15 | 2002-02-28 | Аксис Фармасьютикалз, Инк. | Новые соединения и композиции как ингибиторы протеаз |
| EP1228061A4 (en) * | 1999-11-12 | 2004-12-15 | Guilford Pharm Inc | DIPEPTIDYL PEPTIDASE IV INHIBITORS; METHODS OF MANUFACTURE AND USE OF SAID INHIBITORS |
| GB9928330D0 (en) * | 1999-11-30 | 2000-01-26 | Ferring Bv | Novel antidiabetic agents |
| WO2001055105A1 (en) | 2000-01-24 | 2001-08-02 | Novo Nordisk A/S | N-substituted 2-cyanopyroles and -pyrrolines which are inhibitors of the enzyme dpp-iv |
| GB0010188D0 (en) * | 2000-04-26 | 2000-06-14 | Ferring Bv | Inhibitors of dipeptidyl peptidase IV |
| CA2424600C (en) | 2000-10-06 | 2008-12-02 | Tanabe Seiyaku Co., Ltd. | Aliphatic nitrogenous five-membered ring compounds |
| EP1363898A4 (en) | 2001-03-02 | 2004-12-08 | Bristol Myers Squibb Co | COMPOUNDS SUITABLE AS MODULATORS OF MELANOCORTIN RECEPTORS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2822826B1 (fr) | 2001-03-28 | 2003-05-09 | Servier Lab | Nouveaux derives sulfonyles d'alpha-amino-acides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| GB0115517D0 (en) | 2001-06-25 | 2001-08-15 | Ferring Bv | Novel antidiabetic agents |
| WO2003072556A1 (en) * | 2001-06-27 | 2003-09-04 | Prosidion Ltd. | Glutaminyl based dpiv inhibitors |
| FI20011466A0 (fi) * | 2001-07-04 | 2001-07-04 | Orion Corp | Prolyylioligopeptidaasia inhiboivaa aktiivisuutta omaavia yhdisteitä, niiden valmistusmenetelmiä ja käyttö |
| JP2005504766A (ja) * | 2001-08-16 | 2005-02-17 | プロバイオドラッグ アーゲー | プロリンエンドペプチダーゼ阻害剤の、細胞内シグナルカスケード依存性イノシトール（１，４，５）トリホスフェート濃度調節への使用。 |
| AU2003214534B2 (en) * | 2002-04-08 | 2006-08-31 | Torrent Pharmaceuticals Ltd. | Thiazolidine-4-carbonitriles and analogues and their use as dipeptidyl-peptidas inhibitors |
| US7691967B2 (en) * | 2002-04-30 | 2010-04-06 | Trustees Of Tufts College | Smart pro-drugs of serine protease inhibitors |
| WO2004004661A2 (en) | 2002-07-09 | 2004-01-15 | Point Therapeutics, Inc. | Boroproline compound combination therapy |
| US20060004029A1 (en) | 2002-08-30 | 2006-01-05 | Akihiko Tsuruoka | Nitrogen-containing aromatic derivatives |
| CN101247799B (zh) * | 2005-07-05 | 2013-03-27 | 塔夫茨大学信托人 | 成纤维细胞活化蛋白α的抑制剂 |
-
2005
- 2005-09-02 EP EP05108049A patent/EP1760076A1/en not_active Withdrawn
-
2006
- 2006-08-31 JP JP2008528601A patent/JP2009507011A/ja active Pending
- 2006-08-31 KR KR1020087007975A patent/KR20080043383A/ko not_active Withdrawn
- 2006-08-31 US US11/991,286 patent/US8183280B2/en not_active Expired - Fee Related
- 2006-08-31 CA CA002627607A patent/CA2627607A1/en not_active Abandoned
- 2006-08-31 EP EP06849433A patent/EP1919864A2/en not_active Withdrawn
- 2006-08-31 RU RU2008112683/04A patent/RU2008112683A/ru not_active Application Discontinuation
- 2006-08-31 AU AU2006336854A patent/AU2006336854A1/en not_active Abandoned
- 2006-08-31 WO PCT/IB2006/003512 patent/WO2007085895A2/en not_active Ceased
-
2008
- 2008-04-01 ZA ZA200802867A patent/ZA200802867B/xx unknown
- 2008-04-02 NO NO20081636A patent/NO20081636L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007085895A2 (en) | 2007-08-02 |
| US8183280B2 (en) | 2012-05-22 |
| CA2627607A1 (en) | 2007-08-02 |
| US20100081701A1 (en) | 2010-04-01 |
| AU2006336854A1 (en) | 2007-08-02 |
| NO20081636L (no) | 2008-05-29 |
| RU2008112683A (ru) | 2009-10-20 |
| EP1919864A2 (en) | 2008-05-14 |
| ZA200802867B (en) | 2008-12-31 |
| EP1760076A1 (en) | 2007-03-07 |
| JP2009507011A (ja) | 2009-02-19 |
| WO2007085895A3 (en) | 2008-04-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2009507011A (ja) | Ｆａｐ阻害剤 | |
| KR102319264B1 (ko) | Plk1의 선택적 분해를 유도하는 벤즈이미다졸 티오펜 유도체 화합물 | |
| KR101768946B1 (ko) | 프롤린 유도체 | |
| RU2660421C2 (ru) | Бензиламиновые производные | |
| EP2903998B1 (en) | Iap antagonists | |
| EP0709373B1 (en) | Pyrrolidine derivative | |
| US20050101657A1 (en) | Androgen receptor antagonists | |
| JP2002501918A (ja) | ピペリジン構造を有するファネシル転移酵素阻害剤及びその製造方法 | |
| CN114057702A (zh) | 一种新型冠状病毒主蛋白酶的抑制剂及其制备方法和用途 | |
| WO1995029892A1 (en) | Hydroxamic acid and amino acid derivatives and their use as anti-arthritic agents | |
| JP2009545613A (ja) | Ｉａｐ阻害剤として有用なｓｍａｃペプチド模倣物 | |
| JP2007532504A (ja) | Ｉａｐの阻害剤 | |
| RS52163B (sr) | Derivati bicikloestra | |
| KR20210010579A (ko) | 펩타이드 보레이트 에스테르류 화합물의 합성 및 용도 | |
| CA2218380A1 (en) | Novel hydroxamic and carbocylic acids as metalloprotease inhibitors | |
| HUT61744A (en) | Process for producing renin inhibiting alkylaminocarbonyl group-substituted heterocyclic compounds | |
| KR101469306B1 (ko) | 다이사이클로아자알칸 유도체, 이의 제조 방법 및 의학적 용도 | |
| KR20060009933A (ko) | 시아노플루오로피롤리딘 유도체 | |
| KR20070119088A (ko) | 아팝토시스 단백질 억제제 (ｉａｐ) 조절제로서의2-아미노카르보닐 치환된 피페라진 또는 디아자-시클릭화합물 | |
| WO2005073186A1 (ja) | ピロリジン誘導体 | |
| JP2004532826A (ja) | （ｓ，ｒ，ｒ）−（−）−アクチノニンおよびそのアナログの不斉合成、ならびにそれらの使用 | |
| CN102174074A (zh) | 癌细胞,t细胞和角质形成细胞增殖的抑制剂 | |
| KR102574152B1 (ko) | Plk1의 선택적 분해를 유도하는 벤즈이미다졸 티오펜 유도체 화합물 | |
| CN102010425B (zh) | 1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸衍生物类组蛋白去乙酰化酶抑制剂及其应用 | |
| JP2000502997A (ja) | レトロウイルスプロテアーゼ抑制化合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PA0105 | International application |
Patent event date: 20080402 Patent event code: PA01051R01D Comment text: International Patent Application |
|
| PG1501 | Laying open of application | ||
| N231 | Notification of change of applicant | ||
| PN2301 | Change of applicant |
Patent event date: 20081218 Comment text: Notification of Change of Applicant Patent event code: PN23011R01D |
|
| PC1203 | Withdrawal of no request for examination | ||
| WITN | Application deemed withdrawn, e.g. because no request for examination was filed or no examination fee was paid |