CA2740610C - Synaptic vesicle protein 2a inhibitors for treating age-related cognitive impairment - Google Patents

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Publication number

CA2740610C

CA2740610C CA2740610A CA2740610A CA2740610C CA 2740610 C CA2740610 C CA 2740610C CA 2740610 A CA2740610 A CA 2740610A CA 2740610 A CA2740610 A CA 2740610A CA 2740610 C CA2740610 C CA 2740610C

Authority

CA

Canada

Prior art keywords

oxo

hydrogen

alkyl

butanamide

methyl

Prior art date

2008-10-16

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.)

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• 101710084141 Synaptic vesicle glycoprotein 2A Proteins 0.000 title claims abstract description 95
• 239000003112 inhibitor Substances 0.000 title claims abstract description 73
• 208000010877 cognitive disease Diseases 0.000 title claims abstract description 71
• 208000028698 Cognitive impairment Diseases 0.000 title claims abstract description 52
• HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 claims abstract description 76
• 229960004002 levetiracetam Drugs 0.000 claims abstract description 72
• 230000003920 cognitive function Effects 0.000 claims abstract description 37
• MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 claims abstract description 31
• 229960002161 brivaracetam Drugs 0.000 claims abstract description 28
• ANWPENAPCIFDSZ-BQBZGAKWSA-N seletracetam Chemical compound CC[C@@H](C(N)=O)N1C[C@@H](C=C(F)F)CC1=O ANWPENAPCIFDSZ-BQBZGAKWSA-N 0.000 claims abstract description 14
• 229950000852 seletracetam Drugs 0.000 claims abstract description 14
• 239000000203 mixture Substances 0.000 claims description 85
• 150000003839 salts Chemical class 0.000 claims description 85
• 238000013265 extended release Methods 0.000 claims description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• 239000002671 adjuvant Substances 0.000 claims description 5
• 239000002552 dosage form Substances 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 208000027061 mild cognitive impairment Diseases 0.000 abstract description 19
• 206010027175 memory impairment Diseases 0.000 abstract description 9
• 230000001149 cognitive effect Effects 0.000 abstract description 7
• -1 solubility Chemical class 0.000 description 531
• 229910052739 hydrogen Inorganic materials 0.000 description 296
• 239000001257 hydrogen Substances 0.000 description 296
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 218
• DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 190
• 125000000217 alkyl group Chemical group 0.000 description 176
• 229910052736 halogen Inorganic materials 0.000 description 176
• 150000002367 halogens Chemical class 0.000 description 142
• 150000001875 compounds Chemical class 0.000 description 120
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 119
• 125000003118 aryl group Chemical group 0.000 description 94
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 94
• 241000700159 Rattus Species 0.000 description 85
• 102100030701 Synaptic vesicle glycoprotein 2A Human genes 0.000 description 82
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 78
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 74
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 71
• 125000000623 heterocyclic group Chemical group 0.000 description 69
• 238000000034 method Methods 0.000 description 67
• 125000001424 substituent group Chemical group 0.000 description 66
• 125000004093 cyano group Chemical group *C#N 0.000 description 65
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 63
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 57
• 125000000446 sulfanediyl group Chemical group *S* 0.000 description 54
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 53
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• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 44
• 125000005843 halogen group Chemical group 0.000 description 43
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• 125000004432 carbon atom Chemical group C* 0.000 description 36
• 150000002148 esters Chemical class 0.000 description 36
• 125000003368 amide group Chemical group 0.000 description 35
• 238000012549 training Methods 0.000 description 35
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 34
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• 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 29
• NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 29
• 125000000304 alkynyl group Chemical group 0.000 description 27
• 125000004414 alkyl thio group Chemical group 0.000 description 26
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 25
• 125000000753 cycloalkyl group Chemical group 0.000 description 25
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 24
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 24
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 24
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• 238000011282 treatment Methods 0.000 description 24
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 23
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• 125000003396 thiol group Chemical class [H]S* 0.000 description 18
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• 238000012347 Morris Water Maze Methods 0.000 description 17
• 125000002541 furyl group Chemical group 0.000 description 17
• 230000014759 maintenance of location Effects 0.000 description 17
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 17
• 125000004076 pyridyl group Chemical group 0.000 description 17
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 17
• FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 16
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 16
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 16
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 15
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
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• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 15
• 230000007000 age related cognitive decline Effects 0.000 description 14
• 125000004390 alkyl sulfonyl group Chemical group 0.000 description 14
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 14
• 229940079593 drug Drugs 0.000 description 14
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 14
• 239000012453 solvate Substances 0.000 description 14
• 125000004644 alkyl sulfinyl group Chemical group 0.000 description 13
• 229910052731 fluorine Inorganic materials 0.000 description 13
• AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 13
• 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 12
• 229910052794 bromium Inorganic materials 0.000 description 12
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 12
• 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 12
• 125000000335 thiazolyl group Chemical group 0.000 description 12
• 125000001544 thienyl group Chemical group 0.000 description 12
• 229960000604 valproic acid Drugs 0.000 description 12
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 11
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
• 150000001412 amines Chemical class 0.000 description 11
• 125000004104 aryloxy group Chemical group 0.000 description 11
• 239000000460 chlorine Substances 0.000 description 11
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 11
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 11
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 11
• 229940102566 valproate Drugs 0.000 description 11
• 239000003981 vehicle Substances 0.000 description 11
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 10
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 10
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 10
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 10
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• 241000282412 Homo Species 0.000 description 10
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• 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 description 9
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 9
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 9
• 125000003282 alkyl amino group Chemical group 0.000 description 9
• 229910052801 chlorine Inorganic materials 0.000 description 9
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• MSTWYMAKOBGMBF-UHFFFAOYSA-N 1-(imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one Chemical compound O=C1CC(C=2C=CC=CC=2)CN1CN1C=CN=C1 MSTWYMAKOBGMBF-UHFFFAOYSA-N 0.000 description 8
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• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 8
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