CA2477585A1 - Amino acid derivatives useful for the treatment of alzheimer's disease - Google Patents

Info

Publication number

CA2477585A1

CA2477585A1 CA002477585A CA2477585A CA2477585A1 CA 2477585 A1 CA2477585 A1 CA 2477585A1 CA 002477585 A CA002477585 A CA 002477585A CA 2477585 A CA2477585 A CA 2477585A CA 2477585 A1 CA2477585 A1 CA 2477585A1

Authority

CA

Canada

Prior art keywords

group

formula

carbon atoms

heterocycle

compound

Prior art date

2001-11-21

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 84
• 238000011282 treatment Methods 0.000 title claims description 56
• 150000003862 amino acid derivatives Chemical class 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 551
• 238000000034 method Methods 0.000 claims abstract description 117
• 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 claims abstract description 112
• 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 claims abstract description 112
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 70
• 201000010099 disease Diseases 0.000 claims abstract description 65
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 47
• 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 39
• -1 9-fluorenylmethoxycarbonyl Chemical group 0.000 claims description 139
• 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 claims description 105
• 125000004432 carbon atom Chemical group C* 0.000 claims description 104
• 101710137189 Amyloid-beta A4 protein Proteins 0.000 claims description 98
• 102100022704 Amyloid-beta precursor protein Human genes 0.000 claims description 98
• 101710151993 Amyloid-beta precursor protein Proteins 0.000 claims description 98
• 239000000203 mixture Substances 0.000 claims description 93
• 125000000217 alkyl group Chemical group 0.000 claims description 80
• 238000003776 cleavage reaction Methods 0.000 claims description 77
• 230000007017 scission Effects 0.000 claims description 77
• 150000003839 salts Chemical class 0.000 claims description 68
• 229910052739 hydrogen Inorganic materials 0.000 claims description 61
• 125000000623 heterocyclic group Chemical group 0.000 claims description 60
• 239000003112 inhibitor Substances 0.000 claims description 55
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
• 230000000694 effects Effects 0.000 claims description 39
• 125000003277 amino group Chemical group 0.000 claims description 33
• 210000004027 cell Anatomy 0.000 claims description 32
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 31
• 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 claims description 30
• 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 30
• 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 30
• 101001017818 Homo sapiens ATP-dependent translocase ABCB1 Proteins 0.000 claims description 30
• 229910052760 oxygen Inorganic materials 0.000 claims description 29
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 29
• 238000004519 manufacturing process Methods 0.000 claims description 28
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
• 125000006413 ring segment Chemical group 0.000 claims description 28
• 230000005764 inhibitory process Effects 0.000 claims description 27
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• 229940088598 enzyme Drugs 0.000 claims description 26
• 208000027061 mild cognitive impairment Diseases 0.000 claims description 26
• 206010012289 Dementia Diseases 0.000 claims description 25
• 150000003863 ammonium salts Chemical class 0.000 claims description 25
• 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 25
• 229910052757 nitrogen Inorganic materials 0.000 claims description 24
• 241001465754 Metazoa Species 0.000 claims description 22
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• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 21
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 19
• 229910052783 alkali metal Inorganic materials 0.000 claims description 18
• 230000003412 degenerative effect Effects 0.000 claims description 18
• 125000005842 heteroatom Chemical group 0.000 claims description 18
• 229910052717 sulfur Chemical group 0.000 claims description 18
• 208000037259 Amyloid Plaque Diseases 0.000 claims description 17
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 17
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 17
• 239000011593 sulfur Chemical group 0.000 claims description 17
• 150000001340 alkali metals Chemical class 0.000 claims description 16
• 125000003118 aryl group Chemical group 0.000 claims description 16
• 239000001301 oxygen Chemical group 0.000 claims description 16
• 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 15
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 14
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 14
• 201000010374 Down Syndrome Diseases 0.000 claims description 13
• 206010044688 Trisomy 21 Diseases 0.000 claims description 13
• 150000001342 alkaline earth metals Chemical class 0.000 claims description 13
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
• 239000003795 chemical substances by application Substances 0.000 claims description 13
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 13
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
• 208000018282 ACys amyloidosis Diseases 0.000 claims description 12
• 208000007487 Familial Cerebral Amyloid Angiopathy Diseases 0.000 claims description 12
• 208000032849 Hereditary cerebral hemorrhage with amyloidosis Diseases 0.000 claims description 12
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 12
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
• 239000003937 drug carrier Substances 0.000 claims description 11
• 241000282412 Homo Species 0.000 claims description 10
• 239000003814 drug Substances 0.000 claims description 10
• 210000004558 lewy body Anatomy 0.000 claims description 10
• 230000001225 therapeutic effect Effects 0.000 claims description 10
• 230000002792 vascular Effects 0.000 claims description 9
• 208000018737 Parkinson disease Diseases 0.000 claims description 8
• 208000027089 Parkinsonian disease Diseases 0.000 claims description 8
• 206010034010 Parkinsonism Diseases 0.000 claims description 8
• 230000001054 cortical effect Effects 0.000 claims description 8
• 230000007850 degeneration Effects 0.000 claims description 8
• 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 8
• 208000032843 Hemorrhage Diseases 0.000 claims description 7
• 230000000306 recurrent effect Effects 0.000 claims description 7
• 229910052708 sodium Inorganic materials 0.000 claims description 7
• 239000003963 antioxidant agent Substances 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
• 229940124597 therapeutic agent Drugs 0.000 claims description 5
• 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims description 4
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
• 239000003540 gamma secretase inhibitor Substances 0.000 claims description 4
• 230000002265 prevention Effects 0.000 claims description 4
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 3
• 210000004102 animal cell Anatomy 0.000 claims description 3
• 125000002785 azepinyl group Chemical group 0.000 claims description 3
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
• 229910052792 caesium Inorganic materials 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
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
• 210000004962 mammalian cell Anatomy 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
• 229910052700 potassium Inorganic materials 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
• 125000003718 tetrahydrofuranyl 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
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
• QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
• 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
• 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 2
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
• 239000000544 cholinesterase inhibitor Substances 0.000 claims description 2
• 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
• 230000000508 neurotrophic effect Effects 0.000 claims description 2
• 125000001422 pyrrolinyl group Chemical group 0.000 claims description 2
• 125000005493 quinolyl group Chemical group 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
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 12
• 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims 10
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 4
• 241000124008 Mammalia Species 0.000 abstract description 4
• 230000008021 deposition Effects 0.000 abstract description 3
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• 235000002639 sodium chloride Nutrition 0.000 description 71
• 239000000243 solution Substances 0.000 description 69
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
• 238000005481 NMR spectroscopy Methods 0.000 description 53
• 235000019439 ethyl acetate Nutrition 0.000 description 53
• 239000000758 substrate Substances 0.000 description 51
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
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• 238000003556 assay Methods 0.000 description 38
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