ES2261422T3 - Derivados de amida de acido 2-amino-3-hidroxi-4-terc-leucilamino-5-fenilpentanoico. - Google Patents
Derivados de amida de acido 2-amino-3-hidroxi-4-terc-leucilamino-5-fenilpentanoico.Info
- Publication number
- ES2261422T3 ES2261422T3 ES01943442T ES01943442T ES2261422T3 ES 2261422 T3 ES2261422 T3 ES 2261422T3 ES 01943442 T ES01943442 T ES 01943442T ES 01943442 T ES01943442 T ES 01943442T ES 2261422 T3 ES2261422 T3 ES 2261422T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- hydroxy
- formula
- compound
- radical
- 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 - Lifetime
Links
- 239000002253 acid Substances 0.000 title claims description 125
- 241000670727 Amida Species 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 162
- 241001465754 Metazoa Species 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 4
- -1 di-substituted amino Chemical group 0.000 claims description 194
- 229910052757 nitrogen Inorganic materials 0.000 claims description 73
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- YFCDKSCUZCBUJQ-LBPRGKRZSA-N (2s)-2-amino-n-[(2-hydroxy-4-methoxyphenyl)methyl]-3-methylbutanamide Chemical compound COC1=CC=C(CNC(=O)[C@@H](N)C(C)C)C(O)=C1 YFCDKSCUZCBUJQ-LBPRGKRZSA-N 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 46
- 125000004432 carbon atom Chemical group C* 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 45
- 150000002431 hydrogen Chemical class 0.000 claims description 38
- 150000002148 esters Chemical class 0.000 claims description 37
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
- 125000001589 carboacyl group Chemical group 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000001301 oxygen Chemical group 0.000 claims description 20
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 20
- 125000004414 alkyl thio group Chemical group 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 claims description 14
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 14
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 14
- 241000282414 Homo sapiens Species 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 12
- 229910052717 sulfur Chemical group 0.000 claims description 12
- 239000011593 sulfur Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 10
- 230000002062 proliferating effect Effects 0.000 claims description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 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 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 230000001012 protector Effects 0.000 claims description 3
- QDKMUWAUVPMBMF-KHQRGBKLSA-N (2r,3r,4s)-4-[[(2s)-3,3-dimethyl-2-[(2-naphthalen-1-ylacetyl)amino]butanoyl]amino]-3-hydroxy-5-phenyl-2-[(2,3,4-trimethoxyphenyl)methylamino]pentanoic acid Chemical compound COC1=C(OC)C(OC)=CC=C1CN[C@@H](C(O)=O)[C@H](O)[C@@H](NC(=O)[C@@H](NC(=O)CC=1C2=CC=CC=C2C=CC=1)C(C)(C)C)CC1=CC=CC=C1 QDKMUWAUVPMBMF-KHQRGBKLSA-N 0.000 claims description 2
- DTMIVCFTZKWUCT-RHHFKYMDSA-N (2r,3r,4s)-4-[[(2s)-3,3-dimethyl-2-[(2-naphthalen-1-ylacetyl)amino]butanoyl]amino]-3-hydroxy-5-phenyl-2-[(2,4,5-trimethoxyphenyl)methylamino]pentanoic acid Chemical compound COC1=CC(OC)=C(OC)C=C1CN[C@@H](C(O)=O)[C@H](O)[C@@H](NC(=O)[C@@H](NC(=O)CC=1C2=CC=CC=C2C=CC=1)C(C)(C)C)CC1=CC=CC=C1 DTMIVCFTZKWUCT-RHHFKYMDSA-N 0.000 claims description 2
- 241000282412 Homo Species 0.000 claims description 2
- PTVBXXOOKHBSMR-OOJKEJCUSA-N (2r,3r,4s)-4-[[(2s)-3,3-dimethyl-2-[(2-naphthalen-1-ylacetyl)amino]butanoyl]amino]-3-hydroxy-2-(naphthalen-1-ylmethylamino)-5-phenylpentanoic acid Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)CC=1C2=CC=CC=C2C=CC=1)C(C)(C)C)[C@@H](O)[C@@H](NCC=1C2=CC=CC=C2C=CC=1)C(O)=O)C1=CC=CC=C1 PTVBXXOOKHBSMR-OOJKEJCUSA-N 0.000 claims 1
- QGTBFDVWPPMKSZ-NQQZCUSYSA-N (2r,3r,4s)-4-[[(2s)-3,3-dimethyl-2-[(2-naphthalen-1-ylacetyl)amino]butanoyl]amino]-3-hydroxy-5-phenyl-2-[(3,4,5-trimethoxyphenyl)methylamino]pentanoic acid Chemical compound COC1=C(OC)C(OC)=CC(CN[C@H]([C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](NC(=O)CC=2C3=CC=CC=C3C=CC=2)C(C)(C)C)C(O)=O)=C1 QGTBFDVWPPMKSZ-NQQZCUSYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 50
- 150000003254 radicals Chemical class 0.000 description 44
- 206010028980 Neoplasm Diseases 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- 235000002639 sodium chloride Nutrition 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 27
- 239000007858 starting material Substances 0.000 description 27
- 239000000203 mixture Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 239000002904 solvent Substances 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 15
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 15
- 239000000835 fiber Substances 0.000 description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- NSVNKQLSGGKNKB-LLVKDONJSA-N (2s)-3,3-dimethyl-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CC(C)(C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 NSVNKQLSGGKNKB-LLVKDONJSA-N 0.000 description 10
- 230000008878 coupling Effects 0.000 description 10
- 238000010168 coupling process Methods 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- 239000000376 reactant Substances 0.000 description 10
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000004530 micro-emulsion Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000839 emulsion Substances 0.000 description 7
- 239000012091 fetal bovine serum Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 239000007758 minimum essential medium Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 208000026310 Breast neoplasm Diseases 0.000 description 6
- 241000208199 Buxus sempervirens Species 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 6
- 241000699660 Mus musculus Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 229960002743 glutamine Drugs 0.000 description 6
- 239000012510 hollow fiber Substances 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 238000011580 nude mouse model Methods 0.000 description 6
- 238000011894 semi-preparative HPLC Methods 0.000 description 6
- KDIWDCSQLFQETL-VLCRHTCISA-N (2r,3r,4s)-2-[(3,4-dimethoxyphenyl)methylamino]-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenylpentanoic acid Chemical compound C1=C(OC)C(OC)=CC=C1CN[C@@H](C(O)=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1=CC=CC=C1 KDIWDCSQLFQETL-VLCRHTCISA-N 0.000 description 5
- PRPINYUDVPFIRX-UHFFFAOYSA-N 1-naphthaleneacetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CC=CC2=C1 PRPINYUDVPFIRX-UHFFFAOYSA-N 0.000 description 5
- 239000005971 1-naphthylacetic acid Substances 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 5
- 235000004554 glutamine Nutrition 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- STQCJRIMCCETJZ-KSEOMHKRSA-N (2r,3r,4s)-2-[(2,4-dimethoxyphenyl)methylamino]-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenylpentanoic acid Chemical compound COC1=CC(OC)=CC=C1CN[C@@H](C(O)=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1=CC=CC=C1 STQCJRIMCCETJZ-KSEOMHKRSA-N 0.000 description 4
- PIQDXBSJADVGBC-BHDDXSALSA-N (2r,3r,4s)-2-[[4-(dimethylamino)phenyl]methylamino]-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenylpentanoic acid Chemical compound C1=CC(N(C)C)=CC=C1CN[C@@H](C(O)=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1=CC=CC=C1 PIQDXBSJADVGBC-BHDDXSALSA-N 0.000 description 4
- MGXKZDUJGHWCCF-PWRODBHTSA-N (2r,3r,4s)-3-hydroxy-2-[(3-methoxyphenyl)methylamino]-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenylpentanoic acid Chemical compound COC1=CC=CC(CN[C@H]([C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)OC(C)(C)C)C(O)=O)=C1 MGXKZDUJGHWCCF-PWRODBHTSA-N 0.000 description 4
- FEWNHAKFZOOCOX-RBZQAINGSA-N (2r,3r,4s)-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-2-(naphthalen-1-ylmethylamino)-5-phenylpentanoic acid Chemical compound C([C@H](NC(=O)OC(C)(C)C)[C@@H](O)[C@@H](NCC=1C2=CC=CC=C2C=CC=1)C(O)=O)C1=CC=CC=C1 FEWNHAKFZOOCOX-RBZQAINGSA-N 0.000 description 4
- RQGORAUXGUEPFO-VLCRHTCISA-N (2r,3r,4s)-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenyl-2-[(3,4,5-trimethoxyphenyl)methylamino]pentanoic acid Chemical compound COC1=C(OC)C(OC)=CC(CN[C@H]([C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)OC(C)(C)C)C(O)=O)=C1 RQGORAUXGUEPFO-VLCRHTCISA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
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- 230000037012 chymotrypsin-like activity Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- FUWWYSWEFMTPPH-BHDDXSALSA-N (2r,3r,4s)-2-[(3,5-dimethoxyphenyl)methylamino]-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-phenylpentanoic acid Chemical compound COC1=CC(OC)=CC(CN[C@H]([C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)OC(C)(C)C)C(O)=O)=C1 FUWWYSWEFMTPPH-BHDDXSALSA-N 0.000 description 3
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- FRJLTIFLATVTHW-IPMKNSEASA-N (2r,3r,4s)-4-amino-2-[[4-(dimethylamino)phenyl]methylamino]-3-hydroxy-5-phenylpentanoic acid Chemical compound C1=CC(N(C)C)=CC=C1CN[C@@H](C(O)=O)[C@H](O)[C@@H](N)CC1=CC=CC=C1 FRJLTIFLATVTHW-IPMKNSEASA-N 0.000 description 3
- JIFUBXRAIKRNNH-CGTJXYLNSA-N (2r,3r,4s)-4-amino-3-hydroxy-5-phenyl-2-[(2,3,4-trimethoxyphenyl)methylamino]pentanoic acid Chemical compound COC1=C(OC)C(OC)=CC=C1CN[C@@H](C(O)=O)[C@H](O)[C@@H](N)CC1=CC=CC=C1 JIFUBXRAIKRNNH-CGTJXYLNSA-N 0.000 description 3
- MTSRGQDPIRNKOG-CWFSZBLJSA-N (2r,3r,4s)-4-amino-3-hydroxy-5-phenyl-2-[(2,4,5-trimethoxyphenyl)methylamino]pentanoic acid Chemical compound COC1=CC(OC)=C(OC)C=C1CN[C@@H](C(O)=O)[C@H](O)[C@@H](N)CC1=CC=CC=C1 MTSRGQDPIRNKOG-CWFSZBLJSA-N 0.000 description 3
- IINXZGPBKVFDRJ-KFKAGJAMSA-N (2r,3r,4s)-4-amino-3-hydroxy-5-phenyl-2-[(3,4,5-trimethoxyphenyl)methylamino]pentanoic acid Chemical compound COC1=C(OC)C(OC)=CC(CN[C@H]([C@H](O)[C@@H](N)CC=2C=CC=CC=2)C(O)=O)=C1 IINXZGPBKVFDRJ-KFKAGJAMSA-N 0.000 description 3
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- 206010009944 Colon cancer Diseases 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NVSYANRBXPURRQ-UHFFFAOYSA-N naphthalen-1-ylmethanamine Chemical compound C1=CC=C2C(CN)=CC=CC2=C1 NVSYANRBXPURRQ-UHFFFAOYSA-N 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002913 oxalic acids Chemical class 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000004063 proteosomal degradation Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 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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- 238000000611 regression analysis Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229940000207 selenious acid Drugs 0.000 description 1
- MCAHWIHFGHIESP-UHFFFAOYSA-N selenous acid Chemical compound O[Se](O)=O MCAHWIHFGHIESP-UHFFFAOYSA-N 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
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- 238000010254 subcutaneous injection Methods 0.000 description 1
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- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
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- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000008521 threonine Nutrition 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 238000012090 tissue culture technique Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
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- 239000012588 trypsin Substances 0.000 description 1
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- 239000004474 valine Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
-
- 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
- A61P17/06—Antipsoriatics
-
- 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)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0012795.1A GB0012795D0 (en) | 2000-05-25 | 2000-05-25 | Organic compounds |
| GB0012795 | 2000-05-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2261422T3 true ES2261422T3 (es) | 2006-11-16 |
Family
ID=9892401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES01943442T Expired - Lifetime ES2261422T3 (es) | 2000-05-25 | 2001-05-23 | Derivados de amida de acido 2-amino-3-hidroxi-4-terc-leucilamino-5-fenilpentanoico. |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US20030166572A1 (https=) |
| EP (1) | EP1290012B1 (https=) |
| JP (1) | JP2003533541A (https=) |
| AT (1) | ATE325809T1 (https=) |
| AU (1) | AU2001266019A1 (https=) |
| CA (1) | CA2405871A1 (https=) |
| DE (1) | DE60119514T2 (https=) |
| ES (1) | ES2261422T3 (https=) |
| GB (1) | GB0012795D0 (https=) |
| PT (1) | PT1290012E (https=) |
| WO (1) | WO2001089282A2 (https=) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7351738B2 (en) * | 2002-11-27 | 2008-04-01 | Elan Pharmaceuticals, Inc. | Substituted ureas and carbamates |
| GB0504950D0 (en) * | 2005-03-10 | 2005-04-20 | Novartis Ag | Organic compositions |
| CA2604133C (en) | 2005-04-07 | 2015-12-01 | Centre National De La Recherche Scientifique | Compounds useful as modulators of the proteasome activity |
| BRPI0907805A2 (pt) * | 2008-02-28 | 2015-07-14 | Novartis Ag | Combinações para tratar dor associada à hiv |
| 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 |
| GB2523211B (en) | 2012-01-27 | 2020-03-18 | Univ Jefferson | MCT protein inhibitor-related prognostic and therapeutic methods |
| WO2014172627A1 (en) | 2013-04-19 | 2014-10-23 | Thomas Jefferson University | Caveolin-1 related methods for treating glioblastoma with temozolomide |
| CN112867706B (zh) * | 2018-05-29 | 2024-11-15 | 奥默罗斯公司 | Masp-2抑制剂和使用方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5538997A (en) * | 1993-03-12 | 1996-07-23 | Sandoz Ltd. | 2,4-diamino-3-hydroxycarboxylic acid derivatives |
| EP0982317A1 (en) * | 1998-08-26 | 2000-03-01 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Bivalent inhibitors of the proteasome |
| BR0010134A (pt) * | 1999-04-27 | 2002-01-15 | Novartis Ag | Uso de derivados de ácido 2,4-diamino-3-hidroxicarboxìlico como inibidores de proteassoma |
-
2000
- 2000-05-25 GB GBGB0012795.1A patent/GB0012795D0/en not_active Ceased
-
2001
- 2001-05-23 PT PT01943442T patent/PT1290012E/pt unknown
- 2001-05-23 WO PCT/EP2001/005952 patent/WO2001089282A2/en not_active Ceased
- 2001-05-23 US US10/258,901 patent/US20030166572A1/en not_active Abandoned
- 2001-05-23 AU AU2001266019A patent/AU2001266019A1/en not_active Abandoned
- 2001-05-23 ES ES01943442T patent/ES2261422T3/es not_active Expired - Lifetime
- 2001-05-23 CA CA002405871A patent/CA2405871A1/en not_active Abandoned
- 2001-05-23 DE DE60119514T patent/DE60119514T2/de not_active Expired - Fee Related
- 2001-05-23 EP EP01943442A patent/EP1290012B1/en not_active Expired - Lifetime
- 2001-05-23 JP JP2001585538A patent/JP2003533541A/ja active Pending
- 2001-05-23 AT AT01943442T patent/ATE325809T1/de not_active IP Right Cessation
-
2006
- 2006-05-15 US US11/434,398 patent/US20060205673A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20060205673A1 (en) | 2006-09-14 |
| DE60119514D1 (de) | 2006-06-14 |
| CA2405871A1 (en) | 2001-11-29 |
| WO2001089282A3 (en) | 2002-05-10 |
| GB0012795D0 (en) | 2000-07-19 |
| US20030166572A1 (en) | 2003-09-04 |
| AU2001266019A1 (en) | 2001-12-03 |
| EP1290012A2 (en) | 2003-03-12 |
| PT1290012E (pt) | 2006-09-29 |
| JP2003533541A (ja) | 2003-11-11 |
| ATE325809T1 (de) | 2006-06-15 |
| EP1290012B1 (en) | 2006-05-10 |
| DE60119514T2 (de) | 2006-10-05 |
| WO2001089282A2 (en) | 2001-11-29 |
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