CA2462875A1 - Allylamides useful in the treatment of alzheimer's disease - Google Patents

Info

Publication number

CA2462875A1

CA2462875A1 CA002462875A CA2462875A CA2462875A1 CA 2462875 A1 CA2462875 A1 CA 2462875A1 CA 002462875 A CA002462875 A CA 002462875A CA 2462875 A CA2462875 A CA 2462875A CA 2462875 A1 CA2462875 A1 CA 2462875A1

Authority

CA

Canada

Prior art keywords

substituted

hydroxy

alkyl

unsubstituted

aryl

Prior art date

2001-10-05

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 89
• 238000011282 treatment Methods 0.000 title claims description 42
• 150000001875 compounds Chemical class 0.000 claims abstract description 299
• 238000000034 method Methods 0.000 claims abstract description 126
• 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 claims abstract description 114
• 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 claims abstract description 114
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 71
• 201000010099 disease Diseases 0.000 claims abstract description 66
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 49
• 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 41
• 125000003118 aryl group Chemical group 0.000 claims description 203
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 176
• -1 amino, hydroxy Chemical group 0.000 claims description 175
• 125000005843 halogen group Chemical group 0.000 claims description 159
• 125000000217 alkyl group Chemical group 0.000 claims description 148
• 125000000623 heterocyclic group Chemical group 0.000 claims description 132
• 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 112
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• 150000001412 amines Chemical class 0.000 claims description 105
• 229910052757 nitrogen Inorganic materials 0.000 claims description 104
• 238000003776 cleavage reaction Methods 0.000 claims description 80
• 230000007017 scission Effects 0.000 claims description 80
• 239000001257 hydrogen Substances 0.000 claims description 74
• 229910052739 hydrogen Inorganic materials 0.000 claims description 74
• 239000000203 mixture Substances 0.000 claims description 74
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 62
• 239000003112 inhibitor Substances 0.000 claims description 53
• 125000005842 heteroatom Chemical group 0.000 claims description 52
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 49
• 125000002950 monocyclic group Chemical group 0.000 claims description 49
• 125000004432 carbon atom Chemical group C* 0.000 claims description 47
• 150000003839 salts Chemical class 0.000 claims description 44
• 125000003545 alkoxy group Chemical group 0.000 claims description 40
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
• 206010012289 Dementia Diseases 0.000 claims description 38
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• 238000004519 manufacturing process Methods 0.000 claims description 30
• 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 claims description 29
• 101001017818 Homo sapiens ATP-dependent translocase ABCB1 Proteins 0.000 claims description 29
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 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
• KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 claims description 24
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 24
• RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 24
• 241001465754 Metazoa Species 0.000 claims description 24
• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 24
• 125000006177 alkyl benzyl group Chemical group 0.000 claims description 24
• PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 24
• 125000004043 oxo group Chemical group O=* 0.000 claims description 24
• 210000004556 brain Anatomy 0.000 claims description 23
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• 125000004122 cyclic group Chemical group 0.000 claims description 21
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• 208000037259 Amyloid Plaque Diseases 0.000 claims description 17
• 239000003795 chemical substances by application Substances 0.000 claims description 16
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
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• 125000003342 alkenyl group Chemical group 0.000 claims description 15
• 208000018282 ACys amyloidosis Diseases 0.000 claims description 14
• 208000007487 Familial Cerebral Amyloid Angiopathy Diseases 0.000 claims description 14
• 208000032849 Hereditary cerebral hemorrhage with amyloidosis Diseases 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
• 125000001041 indolyl group Chemical group 0.000 claims description 13
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 13
• 229910052760 oxygen Inorganic materials 0.000 claims description 13
• HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 12
• RMOHQZGAPOHERV-UHFFFAOYSA-N 2-(2h-thiochromen-2-ylsulfonyl)-2h-thiochromene Chemical compound S1C2=CC=CC=C2C=CC1S(=O)(=O)C1C=CC2=CC=CC=C2S1 RMOHQZGAPOHERV-UHFFFAOYSA-N 0.000 claims description 12
• ONJRTQUWKRDCTA-UHFFFAOYSA-N 2h-thiochromene Chemical compound C1=CC=C2C=CCSC2=C1 ONJRTQUWKRDCTA-UHFFFAOYSA-N 0.000 claims description 12
• ZZQUQFZVCJWSER-UHFFFAOYSA-N 3,4-dihydro-1h-isothiochromene Chemical compound C1=CC=C2CSCCC2=C1 ZZQUQFZVCJWSER-UHFFFAOYSA-N 0.000 claims description 12
• WPWNEKFMGCWNPR-UHFFFAOYSA-N 3,4-dihydro-2h-thiochromene Chemical compound C1=CC=C2CCCSC2=C1 WPWNEKFMGCWNPR-UHFFFAOYSA-N 0.000 claims description 12
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 12
• 241000282412 Homo Species 0.000 claims description 12
• 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 12
• VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 12
• DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 12
• HEBMCVBCEDMUOF-UHFFFAOYSA-N isochromane Chemical compound C1=CC=C2COCCC2=C1 HEBMCVBCEDMUOF-UHFFFAOYSA-N 0.000 claims description 12
• 210000004558 lewy body Anatomy 0.000 claims description 12
• UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 claims description 12
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 11
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• 208000018737 Parkinson disease Diseases 0.000 claims description 10
• 230000001054 cortical effect Effects 0.000 claims description 10
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• 206010034010 Parkinsonism Diseases 0.000 claims description 8
• 230000000306 recurrent effect Effects 0.000 claims description 8
• 125000004193 piperazinyl group Chemical group 0.000 claims description 7
• 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 239000003963 antioxidant agent Substances 0.000 claims description 5
• 230000002265 prevention Effects 0.000 claims description 5
• 229940124597 therapeutic agent Drugs 0.000 claims description 5
• 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims description 4
• 125000000304 alkynyl group Chemical group 0.000 claims description 4
• 239000003540 gamma secretase inhibitor Substances 0.000 claims description 4
• VKBGWWLOSMCKMI-ZDUSSCGKSA-N (2s)-1-naphthalen-1-yloxypyrrolidine-2-carboxamide Chemical compound NC(=O)[C@@H]1CCCN1OC1=CC=CC2=CC=CC=C12 VKBGWWLOSMCKMI-ZDUSSCGKSA-N 0.000 claims description 3
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• 230000000508 neurotrophic effect Effects 0.000 claims description 2
• IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims description 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 189
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 130
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• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 30
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 30
• OHSFPKOCFVOYPQ-UHFFFAOYSA-N 2-(2h-thiochromen-2-ylsulfinyl)-2h-thiochromene Chemical compound S1C2=CC=CC=C2C=CC1S(=O)C1C=CC2=CC=CC=C2S1 OHSFPKOCFVOYPQ-UHFFFAOYSA-N 0.000 claims 10
• 125000001960 7 membered carbocyclic group Chemical group 0.000 claims 10
• 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims 9
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• 125000000041 C6-C10 aryl group Chemical group 0.000 claims 2
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
• 230000008021 deposition Effects 0.000 abstract description 3
• 241000124008 Mammalia Species 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
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