DE60209227T2 - 2-((n-(2-amino-3-(heteroaryl- oder -aryl)propionyl)aminoacyl)amino)-alkylboronsäurederivate - Google Patents
2-((n-(2-amino-3-(heteroaryl- oder -aryl)propionyl)aminoacyl)amino)-alkylboronsäurederivate Download PDFInfo
- Publication number
- DE60209227T2 DE60209227T2 DE60209227T DE60209227T DE60209227T2 DE 60209227 T2 DE60209227 T2 DE 60209227T2 DE 60209227 T DE60209227 T DE 60209227T DE 60209227 T DE60209227 T DE 60209227T DE 60209227 T2 DE60209227 T2 DE 60209227T2
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- propionylamino
- formula
- trimethoxyphenyl
- ylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- -1 PROPIONYL Chemical class 0.000 title claims description 192
- 239000002253 acid Substances 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 265
- 238000000034 method Methods 0.000 claims abstract description 36
- 238000011282 treatment Methods 0.000 claims abstract description 35
- 241001465754 Metazoa Species 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 4
- 239000000460 chlorine Substances 0.000 claims description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 59
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 125000003107 substituted aryl group Chemical group 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 10
- 229910052796 boron Inorganic materials 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 230000002062 proliferating effect Effects 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 9
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 125000000524 functional group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 108010016626 Dipeptides Proteins 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000005717 substituted cycloalkylene group Chemical group 0.000 claims description 3
- RVMYSKJBWGAPPQ-DQEYMECFSA-N (2s)-2-[[(2s)-3-(3,4-dimethoxyphenyl)-2-(3-phenylanilino)propanoyl]amino]-4-methylpentanoic acid Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC1=CC=CC(C=2C=CC=CC=2)=C1 RVMYSKJBWGAPPQ-DQEYMECFSA-N 0.000 claims description 2
- VOLLGGPORYHKST-UIOOFZCWSA-N (2s)-2-[[(2s)-3-(4-methoxyphenyl)-2-(3-phenylanilino)propanoyl]amino]-4-methylpentanoic acid Chemical compound C1=CC(OC)=CC=C1C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC1=CC=CC(C=2C=CC=CC=2)=C1 VOLLGGPORYHKST-UIOOFZCWSA-N 0.000 claims description 2
- QWWDLTHXPFKTAS-DQEYMECFSA-N (2s)-4-methyl-2-[[(2s)-2-(3-phenylanilino)-3-(3,4,5-trimethoxyphenyl)propanoyl]amino]pentanoic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@H](NC=2C=C(C=CC=2)C=2C=CC=CC=2)C(=O)N[C@@H](CC(C)C)C(O)=O)=C1 QWWDLTHXPFKTAS-DQEYMECFSA-N 0.000 claims description 2
- JPHIPLCHJZGVRY-NUKCWJJBSA-N [(1r)-1-[[(2s)-2-[[(2s)-3-(4-methoxyphenyl)-2-(3-phenylanilino)propanoyl]amino]propanoyl]amino]-3-methylbutyl]boronic acid Chemical compound C1=CC(OC)=CC=C1C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B(O)O)NC1=CC=CC(C=2C=CC=CC=2)=C1 JPHIPLCHJZGVRY-NUKCWJJBSA-N 0.000 claims description 2
- LCDJPEAMOSFROR-PTJQVGQKSA-N [(1r)-3-methyl-1-[[(2s)-2-[[(2s)-2-(3-phenylanilino)-3-(2,3,4-trimethoxyphenyl)propanoyl]amino]propanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC=C1C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B(O)O)NC1=CC=CC(C=2C=CC=CC=2)=C1 LCDJPEAMOSFROR-PTJQVGQKSA-N 0.000 claims description 2
- URJILNGJEMDJRO-APTRMMRNSA-N [(1r)-3-methyl-1-[[(2s)-2-[[(2s)-2-(3-phenylpropanoylamino)-3-(2,3,4-trimethoxyphenyl)propanoyl]amino]propanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC=C1C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)CCC1=CC=CC=C1 URJILNGJEMDJRO-APTRMMRNSA-N 0.000 claims description 2
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000003981 vehicle Substances 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
- MIFUSOBKODRKPC-OLWNVYNHSA-N [(1r)-3-methyl-1-[[(2s)-4-methyl-2-[[(2s)-2-(3-phenylanilino)-3-(3,4,5-trimethoxyphenyl)propanoyl]amino]pentanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@H](NC=2C=C(C=CC=2)C=2C=CC=CC=2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)=C1 MIFUSOBKODRKPC-OLWNVYNHSA-N 0.000 claims 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims 2
- CCMMLNAYXJIYSX-NAYUSWPISA-N [(1r)-1-[[(2s)-2-[[(2s)-3-(3,4-dimethoxyphenyl)-2-(3-phenylanilino)propanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutyl]boronic acid Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)NC1=CC=CC(C=2C=CC=CC=2)=C1 CCMMLNAYXJIYSX-NAYUSWPISA-N 0.000 claims 1
- BIGIFWJGBNONPK-APGVRMINSA-N [(1r)-1-[[(2s)-2-[[(2s)-3-(3,4-dimethoxyphenyl)-2-[[2-(3-phenoxyphenyl)acetyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutyl]boronic acid Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)CC1=CC=CC(OC=2C=CC=CC=2)=C1 BIGIFWJGBNONPK-APGVRMINSA-N 0.000 claims 1
- NOCYZLFJDNEMRY-DTXPUJKBSA-N [(1r)-1-[[(2s)-2-[[(2s)-3-(4-methoxyphenyl)-2-(3-phenylanilino)propanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutyl]boronic acid Chemical compound C1=CC(OC)=CC=C1C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)NC1=CC=CC(C=2C=CC=CC=2)=C1 NOCYZLFJDNEMRY-DTXPUJKBSA-N 0.000 claims 1
- BCRCUSHGQVRUGQ-CHQNGUEUSA-N [(1r)-1-[[(2s)-2-[[(2s)-3-(4-methoxyphenyl)-2-(3-phenylanilino)propanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutyl]boronic acid Chemical compound C1=CC(OC)=CC=C1C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)NC1=CC=CC(C=2C=CC=CC=2)=C1 BCRCUSHGQVRUGQ-CHQNGUEUSA-N 0.000 claims 1
- CFKMEDWCTRYERJ-SKTSAMEXSA-N [(1r)-1-[[(2s)-3-methyl-2-[[(2s)-2-(3-phenylanilino)-3-(3,4,5-trimethoxyphenyl)propanoyl]amino]butanoyl]amino]-2-phenylethyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@H](NC=2C=C(C=CC=2)C=2C=CC=CC=2)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=2C=CC=CC=2)B(O)O)=C1 CFKMEDWCTRYERJ-SKTSAMEXSA-N 0.000 claims 1
- PZFHDQKICAUUFL-VFXRXZKFSA-N [(1r)-3-methyl-1-[[(2s)-2-[[(2s)-2-(3-phenylanilino)-3-(3,4,5-trimethoxyphenyl)propanoyl]amino]propanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@H](NC=2C=C(C=CC=2)C=2C=CC=CC=2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B(O)O)=C1 PZFHDQKICAUUFL-VFXRXZKFSA-N 0.000 claims 1
- XZXKVJSYPUKVEO-RDAHNBDFSA-N [(1r)-3-methyl-1-[[(2s)-3-methyl-2-[[(2r)-2-(3-phenylanilino)-3-(3,4,5-trimethoxyphenyl)propanoyl]amino]butanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@@H](NC=2C=C(C=CC=2)C=2C=CC=CC=2)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)=C1 XZXKVJSYPUKVEO-RDAHNBDFSA-N 0.000 claims 1
- HHKANKSMOJBZQU-BKHJTQGXSA-N [(1r)-3-methyl-1-[[(2s)-3-methyl-2-[[(2s)-2-(3-phenylanilino)-3-(2,3,4-trimethoxyphenyl)propanoyl]amino]butanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC=C1C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)NC1=CC=CC(C=2C=CC=CC=2)=C1 HHKANKSMOJBZQU-BKHJTQGXSA-N 0.000 claims 1
- XZXKVJSYPUKVEO-NAYUSWPISA-N [(1r)-3-methyl-1-[[(2s)-3-methyl-2-[[(2s)-2-(3-phenylanilino)-3-(3,4,5-trimethoxyphenyl)propanoyl]amino]butanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@H](NC=2C=C(C=CC=2)C=2C=CC=CC=2)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)=C1 XZXKVJSYPUKVEO-NAYUSWPISA-N 0.000 claims 1
- WIVSRPZCCCWNPC-KVBYWJEESA-N [(1r)-3-methyl-1-[[(2s)-3-methyl-2-[[(2s)-2-(3-phenylanilino)-3-(4-phenylmethoxyphenyl)propanoyl]amino]butanoyl]amino]butyl]boronic acid Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B(O)O)C(C)C)NC=1C=C(C=CC=1)C=1C=CC=CC=1)C(C=C1)=CC=C1OCC1=CC=CC=C1 WIVSRPZCCCWNPC-KVBYWJEESA-N 0.000 claims 1
- QXEUNGISQGCLFR-WIRXVTQYSA-N [(1r)-3-methyl-1-[[(2s)-3-methyl-2-[[(2s)-2-(3-propan-2-ylanilino)-3-(3,4,5-trimethoxyphenyl)propanoyl]amino]butanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@H](NC=2C=C(C=CC=2)C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)=C1 QXEUNGISQGCLFR-WIRXVTQYSA-N 0.000 claims 1
- NGYRVQBQNSJZRR-LVCXIWIQSA-N [(1r)-3-methyl-1-[[(2s)-3-methyl-2-[[(2s)-2-[[2-(3-phenoxyphenyl)acetyl]amino]-3-(2,3,4-trimethoxyphenyl)propanoyl]amino]butanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC=C1C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)CC1=CC=CC(OC=2C=CC=CC=2)=C1 NGYRVQBQNSJZRR-LVCXIWIQSA-N 0.000 claims 1
- RLOQPEJQOUDYSP-APGVRMINSA-N [(1r)-3-methyl-1-[[(2s)-3-methyl-2-[[(2s)-2-[[2-(3-phenoxyphenyl)acetyl]amino]-3-(3,4,5-trimethoxyphenyl)propanoyl]amino]butanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@H](NC(=O)CC=2C=C(OC=3C=CC=CC=3)C=CC=2)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)B(O)O)=C1 RLOQPEJQOUDYSP-APGVRMINSA-N 0.000 claims 1
- HPBDHYQLLUCSOT-UZGNFBRWSA-N [(1r)-3-methyl-1-[[(2s)-3-methyl-2-[[(2s)-3-(4-phenylmethoxyphenyl)-2-[[2-(3-phenylmethoxyphenyl)acetyl]amino]propanoyl]amino]butanoyl]amino]butyl]boronic acid Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B(O)O)C(C)C)NC(=O)CC=1C=C(OCC=2C=CC=CC=2)C=CC=1)C(C=C1)=CC=C1OCC1=CC=CC=C1 HPBDHYQLLUCSOT-UZGNFBRWSA-N 0.000 claims 1
- XZXKVJSYPUKVEO-VKLABOROSA-N [3-methyl-1-[[(2s)-3-methyl-2-[[(2s)-2-(3-phenylanilino)-3-(3,4,5-trimethoxyphenyl)propanoyl]amino]butanoyl]amino]butyl]boronic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@H](NC=2C=C(C=CC=2)C=2C=CC=CC=2)C(=O)N[C@@H](C(C)C)C(=O)NC(CC(C)C)B(O)O)=C1 XZXKVJSYPUKVEO-VKLABOROSA-N 0.000 claims 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 183
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 88
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 75
- 238000004128 high performance liquid chromatography Methods 0.000 description 52
- 206010028980 Neoplasm Diseases 0.000 description 40
- 238000012360 testing method Methods 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 31
- 239000000243 solution Substances 0.000 description 29
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 27
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
- CEFAGFDBTDXBRX-FQEVSTJZSA-N (2s)-2-(3-phenylanilino)-3-(3,4,5-trimethoxyphenyl)propanoic acid Chemical compound COC1=C(OC)C(OC)=CC(C[C@H](NC=2C=C(C=CC=2)C=2C=CC=CC=2)C(O)=O)=C1 CEFAGFDBTDXBRX-FQEVSTJZSA-N 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000000872 buffer Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 13
- 239000000835 fiber Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0113096A GB0113096D0 (en) | 2001-05-30 | 2001-05-30 | Organic compounds |
| GB0113096 | 2001-05-30 | ||
| GB0129394A GB0129394D0 (en) | 2001-12-07 | 2001-12-07 | Organic compounds |
| GB0129394 | 2001-12-07 | ||
| PCT/EP2002/005937 WO2002096933A1 (en) | 2001-05-30 | 2002-05-29 | 2-{[n-(2-amino-3-(heteroaryl or aryl)propionyl)-aminoacyl]-amino}-alkylboronic acid derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE60209227D1 DE60209227D1 (de) | 2006-04-20 |
| DE60209227T2 true DE60209227T2 (de) | 2006-08-17 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE60209227T Expired - Fee Related DE60209227T2 (de) | 2001-05-30 | 2002-05-29 | 2-((n-(2-amino-3-(heteroaryl- oder -aryl)propionyl)aminoacyl)amino)-alkylboronsäurederivate |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US6933290B2 (https=) |
| EP (1) | EP1399468B1 (https=) |
| JP (1) | JP4416501B2 (https=) |
| CN (1) | CN100415770C (https=) |
| AT (1) | ATE317850T1 (https=) |
| BR (1) | BR0210112A (https=) |
| CA (1) | CA2446282A1 (https=) |
| DE (1) | DE60209227T2 (https=) |
| ES (1) | ES2258149T3 (https=) |
| PT (1) | PT1399468E (https=) |
| WO (1) | WO2002096933A1 (https=) |
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| DE60209227T2 (de) * | 2001-05-30 | 2006-08-17 | Novartis Ag | 2-((n-(2-amino-3-(heteroaryl- oder -aryl)propionyl)aminoacyl)amino)-alkylboronsäurederivate |
| JP4412586B2 (ja) | 2002-01-08 | 2010-02-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | エポネマイシンおよびエポキソマイシン類似物およびそれらの用途 |
| CA2505361A1 (en) * | 2002-11-11 | 2004-05-27 | Bayer Healthcare Ag | Phenyl or heteroaryl amino alkane derivatives as ip receptor antagonist |
| US7223745B2 (en) | 2003-08-14 | 2007-05-29 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
| US7576206B2 (en) | 2003-08-14 | 2009-08-18 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
| US7468383B2 (en) | 2005-02-11 | 2008-12-23 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
| CA2618513A1 (en) | 2005-08-11 | 2007-02-22 | Ariad Pharmaceuticals, Inc. | Unsaturated heterocyclic derivatives |
| CA2629714A1 (en) | 2005-11-14 | 2007-05-24 | Ariad Gene Therapeutics, Inc. | Administration of an mtor inhibitor to treat patients with cancer |
| SI2495016T1 (sl) | 2005-12-23 | 2020-04-30 | Ariad Pharmaceuticals, Inc. | Biciklične heteroarilne spojine |
| AU2007357338B2 (en) | 2007-08-06 | 2014-03-20 | Takeda Pharmaceutical Company Limited | Proteasome inhibitors |
| PT2300013T (pt) | 2008-05-21 | 2017-10-31 | Ariad Pharma Inc | Derivados de fósforo como inibidores de cinases |
| CA2727862C (en) | 2008-06-17 | 2016-04-19 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
| AR075090A1 (es) | 2008-09-29 | 2011-03-09 | Millennium Pharm Inc | Derivados de acido 1-amino-2-ciclobutiletilboronico inhibidores de proteosoma,utiles como agentes anticancerigenos, y composiciones farmaceuticas que los comprenden. |
| EP2365809B8 (en) | 2008-11-12 | 2018-10-10 | Ariad Pharmaceuticals, Inc. | Pyrazinopyrazines and derivatives as kinase inhibitors |
| WO2010096574A1 (en) | 2009-02-20 | 2010-08-26 | Lisanti Michael P | A method of diagnosis or prognosis of a neoplasm comprising determining the level of expression of a protein in stromal cells adjacent to the neoplasm |
| AU2010341530B2 (en) | 2009-12-22 | 2016-03-10 | Cephalon, Inc. | Proteasome inhibitors and processes for their preparation, purification and use |
| CA2791651C (en) * | 2010-03-01 | 2019-08-20 | Onyx Therapeutics, Inc. | Compounds for immunoproteasome inhibition |
| WO2011133479A2 (en) | 2010-04-19 | 2011-10-27 | Niiki Pharma Inc. | Combination therapy with a proteasome inhibitor and a gallium complex |
| GB2523211B (en) | 2012-01-27 | 2020-03-18 | Univ Jefferson | MCT protein inhibitor-related prognostic and therapeutic methods |
| CN103421032B (zh) * | 2012-05-17 | 2016-01-20 | 上海创诺制药有限公司 | 一种硼替佐米中间体及其制备方法和应用 |
| WO2014172627A1 (en) | 2013-04-19 | 2014-10-23 | Thomas Jefferson University | Caveolin-1 related methods for treating glioblastoma with temozolomide |
| TN2016000492A1 (en) | 2014-05-20 | 2018-04-04 | Millennium Pharm Inc | Boron-containing proteasome inhibitors for use after primary cancer therapy. |
| CN110526912B (zh) | 2014-06-19 | 2023-02-14 | 武田药品工业株式会社 | 用于激酶抑制的杂芳基化合物 |
| MA41505A (fr) | 2015-02-11 | 2017-12-19 | Millennium Pharm Inc | Nouvelle forme cristalline d'un inhibiteur de protéasome |
| HUE064412T2 (hu) | 2016-06-21 | 2024-03-28 | Orion Ophthalmology LLC | Heterociklusos prolinamid-származékok |
| JP7164521B2 (ja) | 2016-06-21 | 2022-11-01 | オリオン・オフサルモロジー・エルエルシー | 炭素環式プロリンアミド誘導体 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4499082A (en) | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
| EP0315574A3 (de) | 1987-11-05 | 1990-08-22 | Hoechst Aktiengesellschaft | Renin-Inhibitoren |
| US5106948A (en) * | 1988-05-27 | 1992-04-21 | Mao Foundation For Medical Education And Research | Cytotoxic boronic acid peptide analogs |
| GB9017694D0 (en) | 1990-08-13 | 1990-09-26 | Sandoz Ltd | Improvements in or relating to organic chemistry |
| US5384410A (en) | 1993-03-24 | 1995-01-24 | The Du Pont Merck Pharmaceutical Company | Removal of boronic acid protecting groups by transesterification |
| US5658885A (en) | 1993-04-27 | 1997-08-19 | The Dupont Merck Pharmaceutical Company | Amidino and guanidino substituted boronic acid inhibitors of trypsin-like enzymes |
| IL109319A0 (en) | 1993-04-27 | 1994-07-31 | Du Pont Merck Pharma | Amidino and guanidino substituted boronic acid compounds |
| FR2721611B1 (fr) * | 1994-06-22 | 1996-09-27 | Adir | Nouveaux dérivés peptidiques de l'acide boronique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent . |
| US6083903A (en) * | 1994-10-28 | 2000-07-04 | Leukosite, Inc. | Boronic ester and acid compounds, synthesis and uses |
| US5614649A (en) | 1994-11-14 | 1997-03-25 | Cephalon, Inc. | Multicatalytic protease inhibitors |
| US5550262A (en) | 1994-11-14 | 1996-08-27 | Cephalon, Inc. | Multicatalytic protease inhibitors |
| CN1282242A (zh) | 1997-12-16 | 2001-01-31 | 赛福伦公司 | 多相催化蛋白酶抑制剂用作抗肿瘤剂 |
| DE60209227T2 (de) * | 2001-05-30 | 2006-08-17 | Novartis Ag | 2-((n-(2-amino-3-(heteroaryl- oder -aryl)propionyl)aminoacyl)amino)-alkylboronsäurederivate |
-
2002
- 2002-05-29 DE DE60209227T patent/DE60209227T2/de not_active Expired - Fee Related
- 2002-05-29 AT AT02743128T patent/ATE317850T1/de not_active IP Right Cessation
- 2002-05-29 CN CNB028108132A patent/CN100415770C/zh not_active Expired - Fee Related
- 2002-05-29 BR BR0210112-2A patent/BR0210112A/pt not_active IP Right Cessation
- 2002-05-29 JP JP2003500112A patent/JP4416501B2/ja not_active Expired - Fee Related
- 2002-05-29 PT PT02743128T patent/PT1399468E/pt unknown
- 2002-05-29 ES ES02743128T patent/ES2258149T3/es not_active Expired - Lifetime
- 2002-05-29 EP EP02743128A patent/EP1399468B1/en not_active Expired - Lifetime
- 2002-05-29 CA CA002446282A patent/CA2446282A1/en not_active Abandoned
- 2002-05-29 WO PCT/EP2002/005937 patent/WO2002096933A1/en not_active Ceased
- 2002-05-29 US US10/478,794 patent/US6933290B2/en not_active Expired - Fee Related
-
2005
- 2005-06-30 US US11/172,146 patent/US20050239716A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20050239716A1 (en) | 2005-10-27 |
| US20040167337A1 (en) | 2004-08-26 |
| EP1399468B1 (en) | 2006-02-15 |
| CA2446282A1 (en) | 2002-12-05 |
| CN1512999A (zh) | 2004-07-14 |
| EP1399468A1 (en) | 2004-03-24 |
| ATE317850T1 (de) | 2006-03-15 |
| US6933290B2 (en) | 2005-08-23 |
| PT1399468E (pt) | 2006-05-31 |
| BR0210112A (pt) | 2004-06-08 |
| ES2258149T3 (es) | 2006-08-16 |
| WO2002096933A1 (en) | 2002-12-05 |
| JP2005501005A (ja) | 2005-01-13 |
| JP4416501B2 (ja) | 2010-02-17 |
| DE60209227D1 (de) | 2006-04-20 |
| CN100415770C (zh) | 2008-09-03 |
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