CA2603404A1 - Substituted 1,2-ethylendiamines, medicaments comprising said compound; their use and their method of manufacture - Google Patents

Info

Publication number

CA2603404A1

CA2603404A1 CA002603404A CA2603404A CA2603404A1 CA 2603404 A1 CA2603404 A1 CA 2603404A1 CA 002603404 A CA002603404 A CA 002603404A CA 2603404 A CA2603404 A CA 2603404A CA 2603404 A1 CA2603404 A1 CA 2603404A1

Authority

CA

Canada

Prior art keywords

alkyl

heteroaryl

heterocyclyl

cycloalkyl

groups

Prior art date

2005-03-30

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

• 150000001875 compounds Chemical class 0.000 title claims description 191
• 238000000034 method Methods 0.000 title claims description 45
• 239000003814 drug Chemical class 0.000 title claims description 12
• PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 title abstract description 6
• 238000004519 manufacturing process Methods 0.000 title description 5
• 238000011282 treatment Methods 0.000 claims abstract description 27
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 25
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 764
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 389
• -1 carboxy, formyl Chemical group 0.000 claims description 221
• 229910052731 fluorine Inorganic materials 0.000 claims description 187
• 239000011737 fluorine Substances 0.000 claims description 185
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 184
• 239000000460 chlorine Substances 0.000 claims description 173
• 229910052801 chlorine Inorganic materials 0.000 claims description 168
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 167
• 229910052794 bromium Inorganic materials 0.000 claims description 155
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 153
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 153
• 125000001072 heteroaryl group Chemical group 0.000 claims description 131
• 125000000623 heterocyclic group Chemical group 0.000 claims description 129
• 229910052739 hydrogen Inorganic materials 0.000 claims description 122
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 120
• 239000001257 hydrogen Substances 0.000 claims description 118
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 102
• 125000003118 aryl group Chemical group 0.000 claims description 96
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 92
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 76
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 67
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 66
• 229910052717 sulfur Inorganic materials 0.000 claims description 58
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 56
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 55
• 239000000203 mixture Substances 0.000 claims description 50
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 45
• 239000013543 active substance Substances 0.000 claims description 43
• 125000004043 oxo group Chemical group O=* 0.000 claims description 39
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
• 150000003839 salts Chemical class 0.000 claims description 32
• 125000001153 fluoro group Chemical group F* 0.000 claims description 30
• 125000004434 sulfur atom Chemical group 0.000 claims description 30
• 125000004432 carbon atom Chemical group C* 0.000 claims description 29
• 239000000126 substance Substances 0.000 claims description 29
• 101710137189 Amyloid-beta A4 protein Proteins 0.000 claims description 28
• 101710151993 Amyloid-beta precursor protein Proteins 0.000 claims description 28
• 102100022704 Amyloid-beta precursor protein Human genes 0.000 claims description 28
• 229910052757 nitrogen Inorganic materials 0.000 claims description 27
• 239000008194 pharmaceutical composition Substances 0.000 claims description 27
• 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 26
• 229910052760 oxygen Inorganic materials 0.000 claims description 26
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 22
• 125000005842 heteroatom Chemical group 0.000 claims description 22
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 21
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
• 230000000694 effects Effects 0.000 claims description 19
• 230000002401 inhibitory effect Effects 0.000 claims description 18
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 17
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
• 239000003112 inhibitor Substances 0.000 claims description 13
• 239000000556 agonist Substances 0.000 claims description 12
• 125000001544 thienyl group Chemical group 0.000 claims description 12
• 230000002265 prevention Effects 0.000 claims description 11
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 10
• 125000000217 alkyl group Chemical group 0.000 claims description 10
• 239000003085 diluting agent Substances 0.000 claims description 10
• ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 10
• ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 10
• 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 claims description 10
• 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 10
• 239000000969 carrier Substances 0.000 claims description 9
• 238000012545 processing Methods 0.000 claims description 9
• GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 8
• 102000003908 Cathepsin D Human genes 0.000 claims description 8
• 108090000258 Cathepsin D Proteins 0.000 claims description 8
• 201000010374 Down Syndrome Diseases 0.000 claims description 8
• 206010044688 Trisomy 21 Diseases 0.000 claims description 8
• 206010002022 amyloidosis Diseases 0.000 claims description 8
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
• 201000008319 inclusion body myositis Diseases 0.000 claims description 8
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 8
• 230000002159 abnormal effect Effects 0.000 claims description 7
• 230000002776 aggregation Effects 0.000 claims description 7
• 238000004220 aggregation Methods 0.000 claims description 7
• 125000004802 cyanophenyl group Chemical group 0.000 claims description 6
• 230000006806 disease prevention Effects 0.000 claims description 6
• 125000002541 furyl group Chemical group 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 6
• 230000003551 muscarinic effect Effects 0.000 claims description 6
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000000335 thiazolyl group Chemical group 0.000 claims description 6
• FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 claims description 5
• MAUMSNABMVEOGP-UHFFFAOYSA-N (methyl-$l^{2}-azanyl)methane Chemical compound C[N]C MAUMSNABMVEOGP-UHFFFAOYSA-N 0.000 claims description 5
• DUGMCDWNXXFHDE-VZYDHVRKSA-N 2-amino-2-methyl-n-[(2r)-1-(1-methylsulfonylspiro[2h-indole-3,4'-piperidine]-1'-yl)-1-oxo-3-phenylmethoxypropan-2-yl]propanamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.C([C@@H](NC(=O)C(C)(N)C)C(=O)N1CCC2(C3=CC=CC=C3N(C2)S(C)(=O)=O)CC1)OCC1=CC=CC=C1 DUGMCDWNXXFHDE-VZYDHVRKSA-N 0.000 claims description 5
• 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims description 5
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 5
• SNKZJIOFVMKAOJ-UHFFFAOYSA-N 3-Aminopropanesulfonate Chemical compound NCCCS(O)(=O)=O SNKZJIOFVMKAOJ-UHFFFAOYSA-N 0.000 claims description 5
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 5
• XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims description 5
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• KVLLHLWBPNCVNR-SKCUWOTOSA-N capromorelin Chemical compound C([C@@]12CN(CCC1=NN(C2=O)C)C(=O)[C@@H](COCC=1C=CC=CC=1)NC(=O)C(C)(C)N)C1=CC=CC=C1 KVLLHLWBPNCVNR-SKCUWOTOSA-N 0.000 claims description 5
• 229950004826 capromorelin Drugs 0.000 claims description 5
• 229960003530 donepezil Drugs 0.000 claims description 5
• 229960003980 galantamine Drugs 0.000 claims description 5
• ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 5
• 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 5
• 229940076716 ibutamoren mesylate Drugs 0.000 claims description 5
• 229960004640 memantine Drugs 0.000 claims description 5
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 5
• 229960001225 rifampicin Drugs 0.000 claims description 5
• 229960004136 rivastigmine Drugs 0.000 claims description 5
• 230000028327 secretion Effects 0.000 claims description 5
• 229960001685 tacrine Drugs 0.000 claims description 5
• YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 5
• VCVWXKKWDOJNIT-ZOMKSWQUSA-N tesofensine Chemical compound C1([C@H]2C[C@@H]3CC[C@@H](N3C)[C@@H]2COCC)=CC=C(Cl)C(Cl)=C1 VCVWXKKWDOJNIT-ZOMKSWQUSA-N 0.000 claims description 5
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
• 206010002023 Amyloidoses Diseases 0.000 claims description 4
• 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
• 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 4
• 206010012289 Dementia Diseases 0.000 claims description 4
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• 208000006011 Stroke Diseases 0.000 claims description 4
• 229930003427 Vitamin E Natural products 0.000 claims description 4
• 208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
• 125000002619 bicyclic group Chemical group 0.000 claims description 4
• 239000004305 biphenyl Substances 0.000 claims description 4
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• 208000010877 cognitive disease Diseases 0.000 claims description 4
• 230000003412 degenerative effect Effects 0.000 claims description 4
• 206010012601 diabetes mellitus Diseases 0.000 claims description 4
• WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 4
• 208000014674 injury Diseases 0.000 claims description 4
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• 208000027061 mild cognitive impairment Diseases 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• 230000002093 peripheral effect Effects 0.000 claims description 4
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 4
• 230000008733 trauma Effects 0.000 claims description 4
• 235000019165 vitamin E Nutrition 0.000 claims description 4
• 229940046009 vitamin E Drugs 0.000 claims description 4
• 239000011709 vitamin E Substances 0.000 claims description 4
• MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims description 3
• 229940124801 5-HT6 antagonist Drugs 0.000 claims description 3
• 229940082496 Adrenoreceptor antagonist Drugs 0.000 claims description 3
• 229940124638 COX inhibitor Drugs 0.000 claims description 3
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 3
• 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 claims description 3
• 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 claims description 3
• 229940127523 NMDA Receptor Antagonists Drugs 0.000 claims description 3
• 101100226116 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) esa-1 gene Proteins 0.000 claims description 3
• 230000006933 amyloid-beta aggregation Effects 0.000 claims description 3
• 239000005557 antagonist Substances 0.000 claims description 3
• 239000003242 anti bacterial agent Substances 0.000 claims description 3
• 229940088710 antibiotic agent Drugs 0.000 claims description 3
• 239000003963 antioxidant agent Substances 0.000 claims description 3
• 235000006708 antioxidants Nutrition 0.000 claims description 3
• 239000002439 beta secretase inhibitor Substances 0.000 claims description 3
• 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 claims description 3
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• 239000003395 histamine H3 receptor antagonist Substances 0.000 claims description 3
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• 239000004031 partial agonist Substances 0.000 claims description 3
• 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 claims description 3
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• 239000002464 receptor antagonist Substances 0.000 claims description 3
• 239000002469 receptor inverse agonist Substances 0.000 claims description 3
• 210000004881 tumor cell Anatomy 0.000 claims description 3
• 102000018997 Growth Hormone Human genes 0.000 claims description 2
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• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
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• 230000036961 partial effect Effects 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 30
• 125000004430 oxygen atom Chemical group O* 0.000 claims 9
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
• 229940121773 Secretase inhibitor Drugs 0.000 claims 1
• 239000000544 cholinesterase inhibitor Substances 0.000 claims 1
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims 1
• 229960003692 gamma aminobutyric acid Drugs 0.000 claims 1
• BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims 1
• BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 claims 1
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• JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims 1
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• 238000012360 testing method Methods 0.000 description 19
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
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