DK3119782T3 - 2,7-diazaspiro [3.5] NONANFORBINDELSER - Google Patents

Info

Publication number

DK3119782T3

DK3119782T3 DK15710486.0T DK15710486T DK3119782T3 DK 3119782 T3 DK3119782 T3 DK 3119782T3 DK 15710486 T DK15710486 T DK 15710486T DK 3119782 T3 DK3119782 T3 DK 3119782T3

Authority

DK

Denmark

Prior art keywords

diazaspiro

alkyl

sulfonyl

nonan

group

Prior art date

2014-03-17

Links

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• OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 373
• 238000011282 treatment Methods 0.000 claims abstract description 38
• 239000003814 drug Substances 0.000 claims abstract description 33
• 230000002265 prevention Effects 0.000 claims abstract description 25
• 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 13
• 208000030159 metabolic disease Diseases 0.000 claims abstract description 11
• -1 cyano, amino Chemical group 0.000 claims description 961
• 125000000623 heterocyclic group Chemical group 0.000 claims description 434
• 125000001072 heteroaryl group Chemical group 0.000 claims description 409
• 229910052739 hydrogen Inorganic materials 0.000 claims description 389
• 239000001257 hydrogen Substances 0.000 claims description 379
• 229910052799 carbon Inorganic materials 0.000 claims description 254
• 150000002431 hydrogen Chemical class 0.000 claims description 242
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 240
• 125000005843 halogen group Chemical group 0.000 claims description 189
• 229910052717 sulfur Inorganic materials 0.000 claims description 169
• 125000005842 heteroatom Chemical group 0.000 claims description 140
• 125000000217 alkyl group Chemical group 0.000 claims description 106
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 102
• 229910052757 nitrogen Inorganic materials 0.000 claims description 92
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 88
• 150000003839 salts Chemical class 0.000 claims description 83
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 75
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 72
• 125000003118 aryl group Chemical group 0.000 claims description 57
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 56
• 229920006395 saturated elastomer Polymers 0.000 claims description 56
• 239000012453 solvate Substances 0.000 claims description 45
• 125000004432 carbon atom Chemical group C* 0.000 claims description 40
• 239000008194 pharmaceutical composition Substances 0.000 claims description 39
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
• 125000004429 atom Chemical group 0.000 claims description 35
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
• SGODQWIOWBOYKT-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-phenyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1C2(CCN(CC2)S(=O)(=O)C=2C=CC=CC=2)CN1C(=O)NC1=CC=CC=C1 SGODQWIOWBOYKT-UHFFFAOYSA-N 0.000 claims description 28
• MIPCJURDXWBZGS-UHFFFAOYSA-N 7-methylsulfonyl-n-phenyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC11CN(C(=O)NC=2C=CC=CC=2)C1 MIPCJURDXWBZGS-UHFFFAOYSA-N 0.000 claims description 28
• GVNJESYLNCMALL-UHFFFAOYSA-N n-(3-cyanophenyl)-7-methylsulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC11CN(C(=O)NC=2C=C(C=CC=2)C#N)C1 GVNJESYLNCMALL-UHFFFAOYSA-N 0.000 claims description 28
• RPFCWYZXPVGZMD-UHFFFAOYSA-N n-(3-fluorophenyl)-7-methylsulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC11CN(C(=O)NC=2C=C(F)C=CC=2)C1 RPFCWYZXPVGZMD-UHFFFAOYSA-N 0.000 claims description 28
• BCYYATIMCMWEAV-UHFFFAOYSA-N n-(4-methoxyphenyl)-7-methylsulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1=CC(OC)=CC=C1NC(=O)N1CC2(CCN(CC2)S(C)(=O)=O)C1 BCYYATIMCMWEAV-UHFFFAOYSA-N 0.000 claims description 28
• LVWKQKBWFTVHLB-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-(3-fluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound FC1=CC=CC(NC(=O)N2CC3(C2)CCN(CC3)S(=O)(=O)C=2C=CC=CC=2)=C1 LVWKQKBWFTVHLB-UHFFFAOYSA-N 0.000 claims description 27
• VIFSDEIEVJLEFA-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-(4-methoxyphenyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1=CC(OC)=CC=C1NC(=O)N1CC2(CCN(CC2)S(=O)(=O)C=2C=CC=CC=2)C1 VIFSDEIEVJLEFA-UHFFFAOYSA-N 0.000 claims description 27
• BLOKECMLIIWMCH-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-propan-2-yl-2,7-diazaspiro[3.5]nonane-2-carboxamide Chemical compound C1N(C(=O)NC(C)C)CC21CCN(S(=O)(=O)C=1C=CC=CC=1)CC2 BLOKECMLIIWMCH-UHFFFAOYSA-N 0.000 claims description 27
• 125000002393 azetidinyl group Chemical group 0.000 claims description 27
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 26
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
• 229910052736 halogen Inorganic materials 0.000 claims description 24
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
• 150000002367 halogens Chemical class 0.000 claims description 23
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 22
• 208000018737 Parkinson disease Diseases 0.000 claims description 18
• 208000024827 Alzheimer disease Diseases 0.000 claims description 17
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
• 206010012601 diabetes mellitus Diseases 0.000 claims description 16
• 125000005549 heteroarylene group Chemical group 0.000 claims description 16
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
• 239000000651 prodrug Substances 0.000 claims description 13
• 229940002612 prodrug Drugs 0.000 claims description 13
• 208000000501 Lipidoses Diseases 0.000 claims description 12
• 206010024585 Lipidosis Diseases 0.000 claims description 12
• 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 11
• 201000011240 Frontotemporal dementia Diseases 0.000 claims description 11
• 102000004877 Insulin Human genes 0.000 claims description 11
• 108090001061 Insulin Proteins 0.000 claims description 11
• 230000001771 impaired effect Effects 0.000 claims description 11
• 229940125396 insulin Drugs 0.000 claims description 11
• 208000001089 Multiple system atrophy Diseases 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 7
• 208000013016 Hypoglycemia Diseases 0.000 claims description 7
• 230000002218 hypoglycaemic effect Effects 0.000 claims description 7
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
• TWKOSYIWUOMPAA-UHFFFAOYSA-N COC=1C=C(C=CC1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)(C)C Chemical compound COC=1C=C(C=CC1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)(C)C TWKOSYIWUOMPAA-UHFFFAOYSA-N 0.000 claims description 6
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
• 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 6
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 6
• 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 6
• 201000010374 Down Syndrome Diseases 0.000 claims description 6
• 208000032928 Dyslipidaemia Diseases 0.000 claims description 6
• 208000004930 Fatty Liver Diseases 0.000 claims description 6
• 208000002705 Glucose Intolerance Diseases 0.000 claims description 6
• 108700006761 Glyceraldehyde-3-phosphate dehydrogenase deficiency Proteins 0.000 claims description 6
• 206010019708 Hepatic steatosis Diseases 0.000 claims description 6
• 208000023105 Huntington disease Diseases 0.000 claims description 6
• 206010020772 Hypertension Diseases 0.000 claims description 6
• 208000031773 Insulin resistance syndrome Diseases 0.000 claims description 6
• 208000009829 Lewy Body Disease Diseases 0.000 claims description 6
• 208000017170 Lipid metabolism disease Diseases 0.000 claims description 6
• 208000008589 Obesity Diseases 0.000 claims description 6
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 6
• 230000000747 cardiac effect Effects 0.000 claims description 6
• 208000010706 fatty liver disease Diseases 0.000 claims description 6
• 208000006058 glyceraldehyde-3-phosphate dehydrogenase deficiency Diseases 0.000 claims description 6
• 201000001421 hyperglycemia Diseases 0.000 claims description 6
• 208000033510 neuroaxonal dystrophy Diseases 0.000 claims description 6
• 235000020824 obesity Nutrition 0.000 claims description 6
• 208000002593 pantothenate kinase-associated neurodegeneration Diseases 0.000 claims description 6
• 201000009104 prediabetes syndrome Diseases 0.000 claims description 6
• 102000004169 proteins and genes Human genes 0.000 claims description 6
• 108090000623 proteins and genes Proteins 0.000 claims description 6
• 231100000240 steatosis hepatitis Toxicity 0.000 claims description 6
• 208000035475 disorder Diseases 0.000 claims description 5
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
• MHRQDCKRJIRAFO-UHFFFAOYSA-N COC1=C(C=CC=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C Chemical compound COC1=C(C=CC=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C MHRQDCKRJIRAFO-UHFFFAOYSA-N 0.000 claims description 4
• OKEXLHLXTKKBHV-UHFFFAOYSA-N COC1=CC=C(C=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C Chemical compound COC1=CC=C(C=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C OKEXLHLXTKKBHV-UHFFFAOYSA-N 0.000 claims description 4
• UPGFIQGDOOBHOO-UHFFFAOYSA-N COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(=O)C2(CC2)C2=CC=CC=C2)CC1 Chemical compound COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(=O)C2(CC2)C2=CC=CC=C2)CC1 UPGFIQGDOOBHOO-UHFFFAOYSA-N 0.000 claims description 4
• GNFDJAVFXWIPJF-UHFFFAOYSA-N COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(=O)C2CCCC3=CC=CC=C23)CC1 Chemical compound COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)C(=O)C2CCCC3=CC=CC=C23)CC1 GNFDJAVFXWIPJF-UHFFFAOYSA-N 0.000 claims description 4
• QAVYZXZDDDXRSX-UHFFFAOYSA-N COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)S(=O)(=O)C2=CC=C(C=C2)OCCC)CC1 Chemical compound COC1=CC=C(C=C1)S(=O)(=O)N1CCC2(CN(C2)S(=O)(=O)C2=CC=C(C=C2)OCCC)CC1 QAVYZXZDDDXRSX-UHFFFAOYSA-N 0.000 claims description 4
• CBXZPLDWKXBERR-UHFFFAOYSA-N ClC1=CC=C(C=C1)C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound ClC1=CC=C(C=C1)C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC CBXZPLDWKXBERR-UHFFFAOYSA-N 0.000 claims description 4
• WWFKCCYTJIMGCT-UHFFFAOYSA-N ClC1=CC=C(C=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C Chemical compound ClC1=CC=C(C=C1)C(C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C WWFKCCYTJIMGCT-UHFFFAOYSA-N 0.000 claims description 4
• BMMMMMGXUXSVHE-UHFFFAOYSA-N ClC1=CC=C(C=C1)S(=O)(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC BMMMMMGXUXSVHE-UHFFFAOYSA-N 0.000 claims description 4
• FOQBYVDWBXOZNI-UHFFFAOYSA-N FC(CCC(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)(F)F Chemical compound FC(CCC(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)(F)F FOQBYVDWBXOZNI-UHFFFAOYSA-N 0.000 claims description 4
• RYEYMGSSZMPGKR-UHFFFAOYSA-N FC(OC1=CC=C(C=C1)S(=O)(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)F Chemical compound FC(OC1=CC=C(C=C1)S(=O)(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)F RYEYMGSSZMPGKR-UHFFFAOYSA-N 0.000 claims description 4
• GCHNQJRLGFWEOP-UHFFFAOYSA-N FC1=CC=C(C=C1)C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound FC1=CC=C(C=C1)C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC GCHNQJRLGFWEOP-UHFFFAOYSA-N 0.000 claims description 4
• MSNBLGNOQYMARN-UHFFFAOYSA-N FC1=CC=C(C=C1)CC(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound FC1=CC=C(C=C1)CC(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC MSNBLGNOQYMARN-UHFFFAOYSA-N 0.000 claims description 4
• LOWQVAVOFYORHV-UHFFFAOYSA-N FC1=CC=C(C=C1)CCC(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound FC1=CC=C(C=C1)CCC(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC LOWQVAVOFYORHV-UHFFFAOYSA-N 0.000 claims description 4
• MGTLXGAPIBVJJM-UHFFFAOYSA-N FC1=CC=C(C=C1)S(=O)(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound FC1=CC=C(C=C1)S(=O)(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC MGTLXGAPIBVJJM-UHFFFAOYSA-N 0.000 claims description 4
• NHDXAAZOXIDDCD-QHCPKHFHSA-N FC1=CC=C(C=C1)[C@@H](C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C(C)C Chemical compound FC1=CC=C(C=C1)[C@@H](C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC)C(C)C NHDXAAZOXIDDCD-QHCPKHFHSA-N 0.000 claims description 4
• NYKXMPTUXNPPRQ-UHFFFAOYSA-N FC=1C=C(C=CC1F)C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound FC=1C=C(C=CC1F)C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC NYKXMPTUXNPPRQ-UHFFFAOYSA-N 0.000 claims description 4
• SOVQSORWQGKPMK-UHFFFAOYSA-N O1CCC(C2=CC=CC=C12)C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC Chemical compound O1CCC(C2=CC=CC=C12)C(=O)N1CC2(C1)CCN(CC2)S(=O)(=O)C2=CC=C(C=C2)OC SOVQSORWQGKPMK-UHFFFAOYSA-N 0.000 claims description 4
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• 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
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