NZ588589A - Novel class of spiro piperidines for the treatment of neurodegenerative diseases - Google Patents

Info

Publication number

NZ588589A

NZ588589A NZ588589A NZ58858909A NZ588589A NZ 588589 A NZ588589 A NZ 588589A NZ 588589 A NZ588589 A NZ 588589A NZ 58858909 A NZ58858909 A NZ 58858909A NZ 588589 A NZ588589 A NZ 588589A

Authority

NZ

New Zealand

Prior art keywords

methyl

thia

fluorophenyl

triazaspiro

alkyl

Prior art date

2008-05-05

Links

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• Global Dossier
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• 238000011282 treatment Methods 0.000 title claims abstract description 36
• -1 class of spiro piperidines Chemical class 0.000 title claims description 160
• 208000015122 neurodegenerative disease Diseases 0.000 title abstract description 5
• 230000004770 neurodegeneration Effects 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 140
• 125000001424 substituent group Chemical group 0.000 claims abstract description 91
• 208000012902 Nervous system disease Diseases 0.000 claims abstract description 10
• 208000025966 Neurological disease Diseases 0.000 claims abstract description 10
• 238000004519 manufacturing process Methods 0.000 claims abstract description 7
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 204
• 125000000217 alkyl group Chemical group 0.000 claims description 145
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 110
• 150000002367 halogens Chemical class 0.000 claims description 83
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 81
• 229910052736 halogen Inorganic materials 0.000 claims description 77
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 75
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 73
• 125000003118 aryl group Chemical group 0.000 claims description 60
• 229910052757 nitrogen Inorganic materials 0.000 claims description 50
• 150000003839 salts Chemical class 0.000 claims description 50
• 125000001072 heteroaryl group Chemical group 0.000 claims description 47
• 229910052799 carbon Inorganic materials 0.000 claims description 40
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 34
• 239000000203 mixture Substances 0.000 claims description 34
• 125000005843 halogen group Chemical group 0.000 claims description 28
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
• 229910052739 hydrogen Inorganic materials 0.000 claims description 24
• 239000001257 hydrogen Substances 0.000 claims description 24
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 23
• 101100134927 Gallus gallus COR8 gene Proteins 0.000 claims description 23
• 125000003386 piperidinyl group Chemical group 0.000 claims description 18
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
• 239000003814 drug Substances 0.000 claims description 14
• 125000003342 alkenyl group Chemical group 0.000 claims description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
• 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 claims description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 9
• 230000000926 neurological effect Effects 0.000 claims description 9
• 102100021257 Beta-secretase 1 Human genes 0.000 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 208000020016 psychiatric disease Diseases 0.000 claims description 7
• 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 6
• 239000003693 atypical antipsychotic agent Substances 0.000 claims description 5
• 229940127236 atypical antipsychotics Drugs 0.000 claims description 5
• 239000000544 cholinesterase inhibitor Substances 0.000 claims description 5
• 201000010099 disease Diseases 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 229940122041 Cholinesterase inhibitor Drugs 0.000 claims description 3
• 229940099433 NMDA receptor antagonist Drugs 0.000 claims description 3
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
• 125000003282 alkyl amino group Chemical group 0.000 claims description 3
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
• 230000005764 inhibitory process Effects 0.000 claims description 3
• 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 claims description 3
• CYNJHNQWUQFBEA-FDDCHVKYSA-N (5r,7s)-1-(3-fluorophenyl)-7-methyl-8-[(3-propan-2-yloxyphenyl)methyl]-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide Chemical compound CC(C)OC1=CC=CC(CN2[C@H](C[C@]3(N(S(=O)(=O)NC3)C=3C=C(F)C=CC=3)CC2)C)=C1 CYNJHNQWUQFBEA-FDDCHVKYSA-N 0.000 claims description 2
• QSOLHUVFBJBRHK-MUAVYFROSA-N (5r,7s)-1-(3-fluorophenyl)-7-methyl-8-[(3-propan-2-yloxyphenyl)methyl]-3-(pyridin-2-ylmethyl)-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide Chemical compound CC(C)OC1=CC=CC(CN2[C@H](C[C@]3(N(S(=O)(=O)N(CC=4N=CC=CC=4)C3)C=3C=C(F)C=CC=3)CC2)C)=C1 QSOLHUVFBJBRHK-MUAVYFROSA-N 0.000 claims description 2
• UZWOFKFOTAZIFO-RBISFHTESA-N (5r,7s)-1-(3-fluorophenyl)-7-methyl-8-[(3-propan-2-yloxyphenyl)methyl]-3-(pyrimidin-2-ylmethyl)-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide Chemical compound CC(C)OC1=CC=CC(CN2[C@H](C[C@]3(N(S(=O)(=O)N(CC=4N=CC=CN=4)C3)C=3C=C(F)C=CC=3)CC2)C)=C1 UZWOFKFOTAZIFO-RBISFHTESA-N 0.000 claims description 2
• IMAPVYYXLMWACS-KDYSTLNUSA-N (5r,7s)-1-(3-fluorophenyl)-7-methyl-8-[[3-(2-methylphenyl)phenyl]methyl]-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide Chemical compound C([C@@]12C[C@@H](N(CC2)CC=2C=C(C=CC=2)C=2C(=CC=CC=2)C)C)NS(=O)(=O)N1C1=CC=CC(F)=C1 IMAPVYYXLMWACS-KDYSTLNUSA-N 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 230000000052 comparative effect Effects 0.000 claims 3
• FSXGJLJJXJVZMS-KDYSTLNUSA-N (5r,7s)-1-(3-fluorophenyl)-7-methyl-3-(1,2-oxazol-3-ylmethyl)-8-[(3-propan-2-yloxyphenyl)methyl]-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide Chemical compound CC(C)OC1=CC=CC(CN2[C@H](C[C@]3(N(S(=O)(=O)N(CC4=NOC=C4)C3)C=3C=C(F)C=CC=3)CC2)C)=C1 FSXGJLJJXJVZMS-KDYSTLNUSA-N 0.000 claims 1
• CPNYKYVZIZDRFM-KDYSTLNUSA-N (5r,7s)-1-(3-fluorophenyl)-7-methyl-8-[(3-propan-2-yloxyphenyl)methyl]-3-pyrimidin-2-yl-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide Chemical compound CC(C)OC1=CC=CC(CN2[C@H](C[C@]3(N(S(=O)(=O)N(C=4N=CC=CN=4)C3)C=3C=C(F)C=CC=3)CC2)C)=C1 CPNYKYVZIZDRFM-KDYSTLNUSA-N 0.000 claims 1
• ZNJPYGAZHWKTMZ-AFMDSPMNSA-N (5r,7s)-8-[[3-(2-chlorophenyl)phenyl]methyl]-1-(3-fluorophenyl)-7-methyl-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide Chemical compound C([C@@]12C[C@@H](N(CC2)CC=2C=C(C=CC=2)C=2C(=CC=CC=2)Cl)C)NS(=O)(=O)N1C1=CC=CC(F)=C1 ZNJPYGAZHWKTMZ-AFMDSPMNSA-N 0.000 claims 1
• OSYQGIYTQMJNJN-XLNZFTOWSA-N (5r,7s)-8-[[3-[(2r)-butan-2-yl]oxyphenyl]methyl]-1-(3-fluorophenyl)-7-methyl-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide Chemical compound CC[C@@H](C)OC1=CC=CC(CN2[C@H](C[C@]3(N(S(=O)(=O)NC3)C=3C=C(F)C=CC=3)CC2)C)=C1 OSYQGIYTQMJNJN-XLNZFTOWSA-N 0.000 claims 1
• WYSAIGUNBIVZQV-CCLHPLFOSA-N 2-cyclohexyl-4-[[(5r,7s)-1-(3-fluorophenyl)-3,7-dimethyl-2,2-dioxo-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decan-8-yl]methyl]phenol Chemical compound C([C@@]12C[C@@H](N(CC2)CC=2C=C(C(O)=CC=2)C2CCCCC2)C)N(C)S(=O)(=O)N1C1=CC=CC(F)=C1 WYSAIGUNBIVZQV-CCLHPLFOSA-N 0.000 claims 1
• ZWXIZDQZWWRRNN-KSFYIVLOSA-N 2-ethoxy-4-[[(5r,7s)-1-(3-fluorophenyl)-7-methyl-2,2-dioxo-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decan-8-yl]methyl]phenol Chemical compound C1=C(O)C(OCC)=CC(CN2[C@H](C[C@]3(N(S(=O)(=O)NC3)C=3C=C(F)C=CC=3)CC2)C)=C1 ZWXIZDQZWWRRNN-KSFYIVLOSA-N 0.000 claims 1
• UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 claims 1
• UICGCQDWRACUBV-MHECFPHRSA-N 4-[[(5r,7s)-1-(3-fluorophenyl)-3,7-dimethyl-2,2-dioxo-2$l^{6}-thia-1,3,8-triazaspiro[4.5]decan-8-yl]methyl]-2-propan-2-yloxyphenol Chemical compound C1=C(O)C(OC(C)C)=CC(CN2[C@H](C[C@]3(N(S(=O)(=O)N(C)C3)C=3C=C(F)C=CC=3)CC2)C)=C1 UICGCQDWRACUBV-MHECFPHRSA-N 0.000 claims 1
• 238000002835 absorbance Methods 0.000 claims 1
• 238000011948 assay development Methods 0.000 claims 1
• JNODQFNWMXFMEV-UHFFFAOYSA-N latrepirdine Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 JNODQFNWMXFMEV-UHFFFAOYSA-N 0.000 claims 1
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• 208000024827 Alzheimer disease Diseases 0.000 abstract description 22
• 101800001718 Amyloid-beta protein Proteins 0.000 abstract description 11
• 230000000626 neurodegenerative effect Effects 0.000 abstract description 3
• 125000003003 spiro group Chemical group 0.000 abstract 1
• 238000000034 method Methods 0.000 description 70
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• 238000006243 chemical reaction Methods 0.000 description 30
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• 238000002360 preparation method Methods 0.000 description 17
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