PT1846424E - Inibidores de proteassomas e seus métodos de utilização - Google Patents

Info

Publication number

PT1846424E

PT1846424E PT06734698T PT06734698T PT1846424E PT 1846424 E PT1846424 E PT 1846424E PT 06734698 T PT06734698 T PT 06734698T PT 06734698 T PT06734698 T PT 06734698T PT 1846424 E PT1846424 E PT 1846424E

Authority

PT

Portugal

Prior art keywords

amino

carbonyl

methylbutyl

alkyl

hexahydro

Prior art date

2005-02-11

Links

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• Global Dossier
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• 238000000034 method Methods 0.000 title abstract description 60
• 229940079156 Proteasome inhibitor Drugs 0.000 title description 20
• 239000003207 proteasome inhibitor Substances 0.000 title description 20
• 150000001875 compounds Chemical class 0.000 claims abstract description 225
• 239000000203 mixture Substances 0.000 claims abstract description 88
• 150000002148 esters Chemical class 0.000 claims abstract description 82
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 52
• 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 claims abstract description 45
• 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 claims abstract description 45
• 230000000694 effects Effects 0.000 claims abstract description 37
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 35
• 201000011510 cancer Diseases 0.000 claims abstract description 21
• 201000010099 disease Diseases 0.000 claims abstract description 18
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 284
• -1 thiooxy Chemical group 0.000 claims description 143
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 108
• 125000000217 alkyl group Chemical group 0.000 claims description 101
• 125000003118 aryl group Chemical group 0.000 claims description 82
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 72
• 125000000623 heterocyclic group Chemical group 0.000 claims description 62
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 50
• 125000004432 carbon atom Chemical group C* 0.000 claims description 49
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 48
• 125000004122 cyclic group Chemical group 0.000 claims description 46
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 42
• 125000001072 heteroaryl group Chemical group 0.000 claims description 40
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 38
• 125000005843 halogen group Chemical group 0.000 claims description 37
• 150000003839 salts Chemical group 0.000 claims description 37
• 229910003600 H2NS Inorganic materials 0.000 claims description 34
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
• 229910052757 nitrogen Inorganic materials 0.000 claims description 34
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 31
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 30
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 30
• 125000005842 heteroatom Chemical group 0.000 claims description 30
• 125000001424 substituent group Chemical group 0.000 claims description 29
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 28
• 125000003545 alkoxy group Chemical group 0.000 claims description 27
• 125000001188 haloalkyl group Chemical group 0.000 claims description 27
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 27
• 125000003282 alkyl amino group Chemical group 0.000 claims description 26
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 26
• 229910052717 sulfur Inorganic materials 0.000 claims description 25
• 125000001041 indolyl group Chemical group 0.000 claims description 24
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 24
• 101150009274 nhr-1 gene Proteins 0.000 claims description 24
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 24
• 125000000335 thiazolyl group Chemical group 0.000 claims description 24
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 23
• 229910052801 chlorine Inorganic materials 0.000 claims description 23
• 229910052760 oxygen Inorganic materials 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
• 108090000623 proteins and genes Proteins 0.000 claims description 23
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 23
• 229910052794 bromium Inorganic materials 0.000 claims description 22
• 229910052731 fluorine Inorganic materials 0.000 claims description 22
• 125000000304 alkynyl group Chemical group 0.000 claims description 21
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
• 229910052740 iodine Inorganic materials 0.000 claims description 21
• 102000004169 proteins and genes Human genes 0.000 claims description 21
• 125000004076 pyridyl group Chemical group 0.000 claims description 21
• 125000006239 protecting group Chemical group 0.000 claims description 20
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 20
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 19
• 125000002883 imidazolyl group Chemical group 0.000 claims description 19
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 19
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 17
• 229910052799 carbon Inorganic materials 0.000 claims description 17
• 208000035475 disorder Diseases 0.000 claims description 16
• 125000004633 N-oxo-pyridyl group Chemical group 0.000 claims description 15
• 239000002253 acid Substances 0.000 claims description 15
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 15
• 229910052739 hydrogen Inorganic materials 0.000 claims description 15
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
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• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 13
• 230000002401 inhibitory effect Effects 0.000 claims description 13
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 13
• 125000002971 oxazolyl group Chemical group 0.000 claims description 12
• 125000005620 boronic acid group Chemical group 0.000 claims description 11
• 230000017854 proteolysis Effects 0.000 claims description 11
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 11
• MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 claims description 10
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
• 241000124008 Mammalia Species 0.000 claims description 10
• 150000008064 anhydrides Chemical class 0.000 claims description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 9
• 102000044159 Ubiquitin Human genes 0.000 claims description 9
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• 230000015556 catabolic process Effects 0.000 claims description 9
• 238000006731 degradation reaction Methods 0.000 claims description 9
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 8
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 8
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
• 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 claims description 8
• 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 8
• ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 8
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 7
• 239000002246 antineoplastic agent Substances 0.000 claims description 7
• 229910052796 boron Inorganic materials 0.000 claims description 7
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• 210000004072 lung Anatomy 0.000 claims description 7
• 125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims description 6
• 150000001412 amines Chemical class 0.000 claims description 6
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 6
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 210000002307 prostate Anatomy 0.000 claims description 6
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
• 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 5
• 206010025323 Lymphomas Diseases 0.000 claims description 5
• 125000003368 amide group Chemical group 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 208000015181 infectious disease Diseases 0.000 claims description 5
• 201000000050 myeloid neoplasm Diseases 0.000 claims description 5
• 210000001672 ovary Anatomy 0.000 claims description 5
• 241000725303 Human immunodeficiency virus Species 0.000 claims description 4
• 208000034578 Multiple myelomas Diseases 0.000 claims description 4
• 210000004185 liver Anatomy 0.000 claims description 4
• BLTDCIWCFCUQCB-UHFFFAOYSA-N quinoline-3-carboxamide Chemical compound C1=CC=CC2=CC(C(=O)N)=CN=C21 BLTDCIWCFCUQCB-UHFFFAOYSA-N 0.000 claims description 4
• 210000001519 tissue Anatomy 0.000 claims description 4
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• 208000023275 Autoimmune disease Diseases 0.000 claims description 2
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
• 108010057466 NF-kappa B Proteins 0.000 claims description 2
• 102000003945 NF-kappa B Human genes 0.000 claims description 2
• 201000004681 Psoriasis Diseases 0.000 claims description 2
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
• 206010003246 arthritis Diseases 0.000 claims description 2
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• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
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• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 2
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• AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 2
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• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
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• CMUOGRBIXWAAAA-KCXAZCMYSA-N [(1r)-1-[[(2s,3r)-3-hydroxy-2-(isoquinoline-1-carbonylamino)butanoyl]amino]-3-methylbutyl]boronic acid Chemical compound C1=CC=C2C(C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B(O)O)[C@@H](C)O)=NC=CC2=C1 CMUOGRBIXWAAAA-KCXAZCMYSA-N 0.000 claims 1
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• 230000000593 degrading effect Effects 0.000 claims 1
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
• HJHXYSBRTVFEDD-UHFFFAOYSA-N isoquinoline-1-carbonitrile Chemical compound C1=CC=C2C(C#N)=NC=CC2=C1 HJHXYSBRTVFEDD-UHFFFAOYSA-N 0.000 claims 1
• YZDXFUGIDTUCDA-UHFFFAOYSA-N isoquinoline-1-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=NC=CC2=C1 YZDXFUGIDTUCDA-UHFFFAOYSA-N 0.000 claims 1
• KKSZSACCVDIWIE-UHFFFAOYSA-N isoquinoline-3-carboxamide Chemical compound C1=CC=C2C=NC(C(=O)N)=CC2=C1 KKSZSACCVDIWIE-UHFFFAOYSA-N 0.000 claims 1
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• LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims 1
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• CGJMVNVWQHPASW-UHFFFAOYSA-N quinoxaline-2-carboxamide Chemical compound C1=CC=CC2=NC(C(=O)N)=CN=C21 CGJMVNVWQHPASW-UHFFFAOYSA-N 0.000 claims 1
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