MXPA04004903A - Derivados de aminoacido utiles para el tratamiento de la enfermedad de alzheimer. - Google Patents

Info

Publication number

MXPA04004903A

MXPA04004903A MXPA04004903A MXPA04004903A MXPA04004903A MX PA04004903 A MXPA04004903 A MX PA04004903A MX PA04004903 A MXPA04004903 A MX PA04004903A MX PA04004903 A MXPA04004903 A MX PA04004903A MX PA04004903 A MXPA04004903 A MX PA04004903A

Authority

MX

Mexico

Prior art keywords

group

compound

lysine

beta

preparation

Prior art date

2001-11-21

Links

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• 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 72
• 238000011282 treatment Methods 0.000 title claims description 56
• 150000003862 amino acid derivatives Chemical class 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 491
• 238000000034 method Methods 0.000 claims abstract description 111
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 57
• 201000010099 disease Diseases 0.000 claims abstract description 55
• -1 9-fluorenylmethoxycarbonyl Chemical group 0.000 claims description 279
• 150000003839 salts Chemical class 0.000 claims description 66
• 239000003112 inhibitor Substances 0.000 claims description 60
• 125000004432 carbon atom Chemical group C* 0.000 claims description 43
• 206010012289 Dementia Diseases 0.000 claims description 37
• 230000000694 effects Effects 0.000 claims description 35
• 125000000217 alkyl group Chemical group 0.000 claims description 33
• 125000000623 heterocyclic group Chemical group 0.000 claims description 32
• 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 claims description 30
• 101001017818 Homo sapiens ATP-dependent translocase ABCB1 Proteins 0.000 claims description 29
• 102000004190 Enzymes Human genes 0.000 claims description 25
• 108090000790 Enzymes Proteins 0.000 claims description 25
• 229940088598 enzyme Drugs 0.000 claims description 25
• 238000004519 manufacturing process Methods 0.000 claims description 24
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
• 125000003277 amino group Chemical group 0.000 claims description 20
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
• 229910052739 hydrogen Inorganic materials 0.000 claims description 18
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 17
• 230000003412 degenerative effect Effects 0.000 claims description 16
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims description 15
• 229910052760 oxygen Inorganic materials 0.000 claims description 15
• 229910052794 bromium Inorganic materials 0.000 claims description 13
• 229910052801 chlorine Inorganic materials 0.000 claims description 13
• 125000002950 monocyclic group Chemical group 0.000 claims description 13
• 201000011240 Frontotemporal dementia Diseases 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
• 229910052731 fluorine Inorganic materials 0.000 claims description 12
• 229910052740 iodine Inorganic materials 0.000 claims description 12
• 125000005842 heteroatom Chemical group 0.000 claims description 11
• 150000003863 ammonium salts Chemical class 0.000 claims description 10
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 10
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 10
• 208000018282 ACys amyloidosis Diseases 0.000 claims description 9
• 208000028698 Cognitive impairment Diseases 0.000 claims description 9
• 208000007487 Familial Cerebral Amyloid Angiopathy Diseases 0.000 claims description 9
• 208000032849 Hereditary cerebral hemorrhage with amyloidosis Diseases 0.000 claims description 9
• 125000002619 bicyclic group Chemical group 0.000 claims description 9
• 208000010877 cognitive disease Diseases 0.000 claims description 9
• 239000001301 oxygen Chemical group 0.000 claims description 9
• 230000002265 prevention Effects 0.000 claims description 9
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
• 125000006413 ring segment Chemical group 0.000 claims description 8
• 239000011593 sulfur Chemical group 0.000 claims description 8
• 229910052717 sulfur Chemical group 0.000 claims description 8
• 208000032843 Hemorrhage Diseases 0.000 claims description 7
• 208000018737 Parkinson disease Diseases 0.000 claims description 7
• 229910052783 alkali metal Inorganic materials 0.000 claims description 7
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 7
• 230000000306 recurrent effect Effects 0.000 claims description 7
• 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 6
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• 210000004558 lewy body Anatomy 0.000 claims description 6
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
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• 125000003118 aryl group Chemical group 0.000 claims description 5
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
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• 229940079593 drug Drugs 0.000 claims description 5
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
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• 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
• 125000002785 azepinyl group Chemical group 0.000 claims description 3
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 230000006866 deterioration Effects 0.000 claims description 3
• 239000003540 gamma secretase inhibitor Substances 0.000 claims description 3
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 3
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 3
• 125000002636 imidazolinyl group Chemical group 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
• 125000002757 morpholinyl group Chemical group 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
• 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• 229940125373 Gamma-Secretase Inhibitor Drugs 0.000 claims description 2
• 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
• 230000003078 antioxidant effect Effects 0.000 claims description 2
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 2
• 239000000544 cholinesterase inhibitor Substances 0.000 claims description 2
• 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
• 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 2
• 108010091748 peptide A Proteins 0.000 claims description 2
• 125000003507 tetrahydrothiofenyl group Chemical group 0.000 claims description 2
• 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 claims description 2
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
• 125000004429 atom Chemical group 0.000 claims 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 3
• PFRUBEOIWWEFOL-UHFFFAOYSA-N [N].[S] Chemical group [N].[S] PFRUBEOIWWEFOL-UHFFFAOYSA-N 0.000 claims 2
• 125000004122 cyclic group Chemical group 0.000 claims 2
• 201000006747 infectious mononucleosis Diseases 0.000 claims 2
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
• SIGSNYAYBSJATD-UHFFFAOYSA-N Ethadione Chemical group CCN1C(=O)OC(C)(C)C1=O SIGSNYAYBSJATD-UHFFFAOYSA-N 0.000 claims 1
• QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims 1
• 241000208202 Linaceae Species 0.000 claims 1
• 235000004431 Linum usitatissimum Nutrition 0.000 claims 1
• 241000357291 Monodactylus argenteus Species 0.000 claims 1
• 206010033799 Paralysis Diseases 0.000 claims 1
• 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims 1
• 125000005343 heterocyclic alkyl group Chemical group 0.000 claims 1
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
• XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims 1
• 230000000750 progressive effect Effects 0.000 claims 1
• 208000011580 syndromic disease Diseases 0.000 claims 1
• 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 claims 1
• 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 abstract description 101
• 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 abstract description 101
• 230000002401 inhibitory effect Effects 0.000 abstract description 31
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• 241000124008 Mammalia Species 0.000 abstract description 4
• 230000008021 deposition Effects 0.000 abstract description 3
• 238000002360 preparation method Methods 0.000 description 177
• 239000004472 Lysine Substances 0.000 description 164
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• 239000000047 product Substances 0.000 description 145
• 238000005481 NMR spectroscopy Methods 0.000 description 119
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 112
• DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 90
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