US20160106750A1 - Compounds for the prevention and treatment of cardiovascular diseases - Google Patents
Compounds for the prevention and treatment of cardiovascular diseases Download PDFInfo
- Publication number
- US20160106750A1 US20160106750A1 US14/922,645 US201514922645A US2016106750A1 US 20160106750 A1 US20160106750 A1 US 20160106750A1 US 201514922645 A US201514922645 A US 201514922645A US 2016106750 A1 US2016106750 A1 US 2016106750A1
- Authority
- US
- United States
- Prior art keywords
- dimethoxy
- amino
- alkyl
- alkoxy
- dimethylphenyl
- Prior art date
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 209
- 208000024172 Cardiovascular disease Diseases 0.000 title abstract description 25
- 230000002265 prevention Effects 0.000 title abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 64
- 150000002632 lipids Chemical class 0.000 claims abstract description 42
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims description 165
- 229910052739 hydrogen Inorganic materials 0.000 claims description 162
- 125000000217 alkyl group Chemical group 0.000 claims description 151
- 239000001257 hydrogen Substances 0.000 claims description 147
- 125000003545 alkoxy group Chemical group 0.000 claims description 135
- 229910052757 nitrogen Inorganic materials 0.000 claims description 107
- 125000003118 aryl group Chemical group 0.000 claims description 92
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 84
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 80
- 125000003342 alkenyl group Chemical group 0.000 claims description 78
- 125000000623 heterocyclic group Chemical group 0.000 claims description 77
- 125000000304 alkynyl group Chemical group 0.000 claims description 74
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
- -1 amino, hydroxyl Chemical group 0.000 claims description 65
- 150000003839 salts Chemical class 0.000 claims description 65
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 61
- 125000001072 heteroaryl group Chemical group 0.000 claims description 57
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 54
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 54
- 229910052721 tungsten Inorganic materials 0.000 claims description 52
- 150000001408 amides Chemical group 0.000 claims description 50
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 50
- 208000035475 disorder Diseases 0.000 claims description 49
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 40
- 125000001188 haloalkyl group Chemical group 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- PGTBXQQPHHXUIH-UHFFFAOYSA-N 2-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCN1CCOCC1 PGTBXQQPHHXUIH-UHFFFAOYSA-N 0.000 claims description 21
- 241000124008 Mammalia Species 0.000 claims description 21
- 208000029078 coronary artery disease Diseases 0.000 claims description 20
- 108010023302 HDL Cholesterol Proteins 0.000 claims description 19
- NETXMUIMUZJUTB-UHFFFAOYSA-N apabetalone Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCCO)C(C)=C1 NETXMUIMUZJUTB-UHFFFAOYSA-N 0.000 claims description 18
- KTACWZKZFWVPAU-UHFFFAOYSA-N 2-[4-[bis(2-hydroxyethyl)amino]phenyl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(N(CCO)CCO)C=C1 KTACWZKZFWVPAU-UHFFFAOYSA-N 0.000 claims description 17
- 230000001965 increasing effect Effects 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- BKRZKWKXZDDWAE-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2h-isoquinolin-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C1=CC(C)=C(O)C(C)=C1 BKRZKWKXZDDWAE-UHFFFAOYSA-N 0.000 claims description 15
- 239000007943 implant Substances 0.000 claims description 15
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 14
- UPCZAPSFBOFANL-UHFFFAOYSA-N 2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxy-3H-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(O)C(OC)=C1 UPCZAPSFBOFANL-UHFFFAOYSA-N 0.000 claims description 13
- FMIINWJKLNMTCB-UHFFFAOYSA-N 2-n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-1-n-methylbenzene-1,2-dicarboxamide Chemical compound CNC(=O)C1=CC=CC=C1C(=O)NCCOC1=C(C)C=C(C=2NC(=O)C3=C(OC)C=C(OC)C=C3N=2)C=C1C FMIINWJKLNMTCB-UHFFFAOYSA-N 0.000 claims description 13
- 206010063837 Reperfusion injury Diseases 0.000 claims description 12
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 12
- 208000031225 myocardial ischemia Diseases 0.000 claims description 12
- RVCUXKFESITCJF-UHFFFAOYSA-N 5,7-dimethoxy-2-[4-(4-methylpiperazin-1-yl)phenyl]-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1)=CC=C1N1CCN(C)CC1 RVCUXKFESITCJF-UHFFFAOYSA-N 0.000 claims description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims description 11
- QNECRDKFNQULAR-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6,7-dimethoxy-1h-quinazolin-4-one Chemical compound O1CCOC2=CC(C3=NC=4C=C(C(=CC=4C(=O)N3)OC)OC)=CC=C21 QNECRDKFNQULAR-UHFFFAOYSA-N 0.000 claims description 10
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 10
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 10
- 208000037803 restenosis Diseases 0.000 claims description 10
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 9
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 9
- JKOMAPNLTUJAPI-UHFFFAOYSA-N 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-3H-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(O)C(C)=C1 JKOMAPNLTUJAPI-UHFFFAOYSA-N 0.000 claims description 9
- SQBKNGXWWBLWCX-UHFFFAOYSA-N 2-[4-[bis(2-hydroxyethyl)amino]phenyl]-6,7-dimethoxy-1h-quinazolin-4-one Chemical compound N1C(=O)C=2C=C(OC)C(OC)=CC=2N=C1C1=CC=C(N(CCO)CCO)C=C1 SQBKNGXWWBLWCX-UHFFFAOYSA-N 0.000 claims description 9
- FVURSRKSNLWXRT-UHFFFAOYSA-N 3-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-6,8-dimethoxy-2h-isoquinolin-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C1=CC(C)=C(OCCO)C(C)=C1 FVURSRKSNLWXRT-UHFFFAOYSA-N 0.000 claims description 9
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims description 9
- 201000001881 impotence Diseases 0.000 claims description 9
- JEFZWZMTZKYAJV-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1h-quinazolin-4-one Chemical compound O1CCOC2=CC(C=3NC(C4=CC=CC=C4N=3)=O)=CC=C21 JEFZWZMTZKYAJV-UHFFFAOYSA-N 0.000 claims description 8
- MIUZDSGAZLFZFD-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound O1CCOC2=CC(C3=NC=4C(C(N3)=O)=C(OC)C=C(C=4)OC)=CC=C21 MIUZDSGAZLFZFD-UHFFFAOYSA-N 0.000 claims description 8
- BJRZXGIXBCJWHE-UHFFFAOYSA-N 2-(3,5-ditert-butyl-4-hydroxyphenyl)-5,7-dimethoxy-3H-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 BJRZXGIXBCJWHE-UHFFFAOYSA-N 0.000 claims description 8
- KPLPICKPBNUVEK-UHFFFAOYSA-N 2-(4-hydroxyphenyl)-5,7-dimethoxy-3H-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(O)C=C1 KPLPICKPBNUVEK-UHFFFAOYSA-N 0.000 claims description 8
- ZBEVYAJIDKCBPO-UHFFFAOYSA-N 2-[4-(2-aminoethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCCN)C(C)=C1 ZBEVYAJIDKCBPO-UHFFFAOYSA-N 0.000 claims description 8
- OMSFRMJNFRFNHS-UHFFFAOYSA-N 2-[4-(4-oxo-1h-quinazolin-2-yl)phenoxy]acetamide Chemical compound C1=CC(OCC(=O)N)=CC=C1C1=NC2=CC=CC=C2C(=O)N1 OMSFRMJNFRFNHS-UHFFFAOYSA-N 0.000 claims description 8
- NQBPCQCEUSKHLK-UHFFFAOYSA-N 2-[4-(4-oxo-1h-quinazolin-2-yl)phenoxy]acetic acid Chemical compound C1=CC(OCC(=O)O)=CC=C1C1=NC2=CC=CC=C2C(=O)N1 NQBPCQCEUSKHLK-UHFFFAOYSA-N 0.000 claims description 8
- TUZCEUPWNLHQFJ-UHFFFAOYSA-N 2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)phenoxy]acetic acid Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(OCC(O)=O)C=C1 TUZCEUPWNLHQFJ-UHFFFAOYSA-N 0.000 claims description 8
- VKHWXWNGILPDLU-UHFFFAOYSA-N 2-[4-(dimethylamino)naphthalen-1-yl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C1=CC=C2C(C3=NC=4C(C(N3)=O)=C(OC)C=C(C=4)OC)=CC=C(N(C)C)C2=C1 VKHWXWNGILPDLU-UHFFFAOYSA-N 0.000 claims description 8
- IXFSCCQVSKANGJ-UHFFFAOYSA-N 2-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C1CN(CC)CCN1CC1=CC=C(C=2NC(=O)C3=C(OC)C=C(OC)C=C3N=2)C=C1 IXFSCCQVSKANGJ-UHFFFAOYSA-N 0.000 claims description 8
- XWULMWWAHNKTGR-UHFFFAOYSA-N 2-[4-[bis(2-hydroxyethyl)amino]phenyl]-1h-quinazolin-4-one Chemical compound C1=CC(N(CCO)CCO)=CC=C1C1=NC2=CC=CC=C2C(=O)N1 XWULMWWAHNKTGR-UHFFFAOYSA-N 0.000 claims description 8
- COODZPZBQVVMAI-UHFFFAOYSA-N 5,7-dimethoxy-2-(4-methoxyphenyl)-1h-quinazolin-4-one Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC(OC)=CC(OC)=C2C(=O)N1 COODZPZBQVVMAI-UHFFFAOYSA-N 0.000 claims description 8
- MLNRQSOPKAOEGY-UHFFFAOYSA-N 5,7-dimethoxy-2-(4-morpholin-4-ylphenyl)-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1)=CC=C1N1CCOCC1 MLNRQSOPKAOEGY-UHFFFAOYSA-N 0.000 claims description 8
- KINIYNJVOZABGO-UHFFFAOYSA-N 5,7-dimethoxy-2-pyridin-4-yl-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=NC=C1 KINIYNJVOZABGO-UHFFFAOYSA-N 0.000 claims description 8
- 206010002383 Angina Pectoris Diseases 0.000 claims description 8
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 8
- 206010019280 Heart failures Diseases 0.000 claims description 8
- 208000008589 Obesity Diseases 0.000 claims description 8
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 8
- 206010065561 Renal artery arteriosclerosis Diseases 0.000 claims description 8
- 208000007536 Thrombosis Diseases 0.000 claims description 8
- 208000010125 myocardial infarction Diseases 0.000 claims description 8
- 235000020824 obesity Nutrition 0.000 claims description 8
- 201000011303 renal artery atheroma Diseases 0.000 claims description 8
- 230000006641 stabilisation Effects 0.000 claims description 8
- 238000011105 stabilization Methods 0.000 claims description 8
- GVFSHRSVKGNZHC-UHFFFAOYSA-N 2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxy-3H-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(O)C(Cl)=C1 GVFSHRSVKGNZHC-UHFFFAOYSA-N 0.000 claims description 7
- XAPLDZCXBLURPA-UHFFFAOYSA-N 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxy-3H-quinazolin-4-one Chemical compound N1C(=O)C=2C=C(OC)C(OC)=CC=2N=C1C1=CC(C)=C(O)C(C)=C1 XAPLDZCXBLURPA-UHFFFAOYSA-N 0.000 claims description 7
- QALMSMDJGUHAFB-UHFFFAOYSA-N 2-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-1h-quinazolin-4-one Chemical compound CC1=CC(C=2NC(=O)C3=CC=CC=C3N=2)=CC(C)=C1OCCN1CCOCC1 QALMSMDJGUHAFB-UHFFFAOYSA-N 0.000 claims description 7
- HAYKSXUTOGSILN-UHFFFAOYSA-N 2-[3-chloro-4-(2-hydroxyethoxy)phenyl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(OCCO)C(Cl)=C1 HAYKSXUTOGSILN-UHFFFAOYSA-N 0.000 claims description 7
- NDTLBDIODYIITF-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-1h-quinazolin-4-one Chemical compound CC1=C(OCCO)C(C)=CC(C=2NC(=O)C3=CC=CC=C3N=2)=C1 NDTLBDIODYIITF-UHFFFAOYSA-N 0.000 claims description 7
- SXJPKQOIKAOACM-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)-3-methoxyphenyl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(OCCO)C(OC)=C1 SXJPKQOIKAOACM-UHFFFAOYSA-N 0.000 claims description 7
- XHEDRBDXJXRRAT-UHFFFAOYSA-N 2-[4-(6,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]acetamide Chemical compound N1C(=O)C=2C=C(OC)C(OC)=CC=2N=C1C1=CC(C)=C(OCC(N)=O)C(C)=C1 XHEDRBDXJXRRAT-UHFFFAOYSA-N 0.000 claims description 7
- HDVPGLUESZTLFV-UHFFFAOYSA-N 2-[4-(dimethylamino)naphthalen-1-yl]-1h-quinazolin-4-one Chemical compound C12=CC=CC=C2C(N(C)C)=CC=C1C1=NC2=CC=CC=C2C(=O)N1 HDVPGLUESZTLFV-UHFFFAOYSA-N 0.000 claims description 7
- FVJOQHQHYHAIOC-UHFFFAOYSA-N 3-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)phenyl]propanoic acid Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(CCC(O)=O)C=C1 FVJOQHQHYHAIOC-UHFFFAOYSA-N 0.000 claims description 7
- 201000001376 Familial Combined Hyperlipidemia Diseases 0.000 claims description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 7
- 206010021024 Hypolipidaemia Diseases 0.000 claims description 7
- DMNVIUMGJXRTNI-UHFFFAOYSA-N N-[2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3H-quinazolin-6-yl]acetamide Chemical compound N1C(=O)C2=CC(NC(=O)C)=CC=C2N=C1C1=CC(C)=C(O)C(C)=C1 DMNVIUMGJXRTNI-UHFFFAOYSA-N 0.000 claims description 7
- 208000029498 hypoalphalipoproteinemia Diseases 0.000 claims description 7
- IVFBOLJNIPLCNV-UHFFFAOYSA-N n-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)phenyl]-2-hydroxyacetamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(NC(=O)CO)C=C1 IVFBOLJNIPLCNV-UHFFFAOYSA-N 0.000 claims description 7
- GFHYLMZBVPERJM-UHFFFAOYSA-N 1-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-3-phenylurea Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCNC(=O)NC1=CC=CC=C1 GFHYLMZBVPERJM-UHFFFAOYSA-N 0.000 claims description 6
- MTHYYLKKMBQEAP-UHFFFAOYSA-N 2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=NC(Cl)=C1 MTHYYLKKMBQEAP-UHFFFAOYSA-N 0.000 claims description 6
- XIBDNNSKMGUQOD-UHFFFAOYSA-N 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(N)C(C)=C1 XIBDNNSKMGUQOD-UHFFFAOYSA-N 0.000 claims description 6
- WIQXRCPVJZFZMJ-UHFFFAOYSA-N 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxy-3H-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(O)C(C)=C1 WIQXRCPVJZFZMJ-UHFFFAOYSA-N 0.000 claims description 6
- BHAJCEWFKZUIKQ-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-1h-pyrido[2,3-d]pyrimidin-4-one Chemical compound N=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCCO)C(C)=C1 BHAJCEWFKZUIKQ-UHFFFAOYSA-N 0.000 claims description 6
- RJKSYSAMNAUDLG-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-6,7-dimethoxy-1h-quinazolin-4-one Chemical compound N1C(=O)C=2C=C(OC)C(OC)=CC=2N=C1C1=CC(C)=C(OCCO)C(C)=C1 RJKSYSAMNAUDLG-UHFFFAOYSA-N 0.000 claims description 6
- SJASEOKEWBPIRK-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)-3-methylphenyl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(OCCO)C(C)=C1 SJASEOKEWBPIRK-UHFFFAOYSA-N 0.000 claims description 6
- OOQNRVSHWULSNE-UHFFFAOYSA-N 2-[4-[bis(2-hydroxyethyl)amino]phenyl]-5,7-dimethoxy-1h-pyrido[2,3-d]pyrimidin-4-one Chemical compound N=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(N(CCO)CCO)C=C1 OOQNRVSHWULSNE-UHFFFAOYSA-N 0.000 claims description 6
- UKPCBNJDWHYAQI-UHFFFAOYSA-N 4-chloro-n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]benzenesulfonamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCNS(=O)(=O)C1=CC=C(Cl)C=C1 UKPCBNJDWHYAQI-UHFFFAOYSA-N 0.000 claims description 6
- YOHOTAMJRCWPER-UHFFFAOYSA-N 5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OC)C(C)=C1 YOHOTAMJRCWPER-UHFFFAOYSA-N 0.000 claims description 6
- 208000014882 Carotid artery disease Diseases 0.000 claims description 6
- 208000002330 Congenital Heart Defects Diseases 0.000 claims description 6
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 6
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 206010022562 Intermittent claudication Diseases 0.000 claims description 6
- 102000004895 Lipoproteins Human genes 0.000 claims description 6
- 108090001030 Lipoproteins Proteins 0.000 claims description 6
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 6
- 208000005314 Multi-Infarct Dementia Diseases 0.000 claims description 6
- 208000018737 Parkinson disease Diseases 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 6
- 201000004810 Vascular dementia Diseases 0.000 claims description 6
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 6
- 230000005856 abnormality Effects 0.000 claims description 6
- 208000037876 carotid Atherosclerosis Diseases 0.000 claims description 6
- 206010008118 cerebral infarction Diseases 0.000 claims description 6
- 208000028831 congenital heart disease Diseases 0.000 claims description 6
- 230000008694 endothelial dysfunction Effects 0.000 claims description 6
- 201000001386 familial hypercholesterolemia Diseases 0.000 claims description 6
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 6
- 208000021156 intermittent vascular claudication Diseases 0.000 claims description 6
- 208000028867 ischemia Diseases 0.000 claims description 6
- 208000012947 ischemia reperfusion injury Diseases 0.000 claims description 6
- 230000000302 ischemic effect Effects 0.000 claims description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims description 6
- PIRVGPWBOGNYAH-UHFFFAOYSA-N n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]methanesulfonamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCCNS(C)(=O)=O)C(C)=C1 PIRVGPWBOGNYAH-UHFFFAOYSA-N 0.000 claims description 6
- 208000004124 rheumatic heart disease Diseases 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- PVIWIZXGEWTLOQ-UHFFFAOYSA-N 2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)phenoxy]acetamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(OCC(N)=O)C=C1 PVIWIZXGEWTLOQ-UHFFFAOYSA-N 0.000 claims description 5
- GOYUXKLVZLRPKC-UHFFFAOYSA-N 2-[4-(dimethylamino)-2h-pyridin-1-yl]-6,7-dimethoxy-1h-quinazolin-4-one Chemical compound N1C(=O)C=2C=C(OC)C(OC)=CC=2N=C1N1CC=C(N(C)C)C=C1 GOYUXKLVZLRPKC-UHFFFAOYSA-N 0.000 claims description 5
- UOZYFNTWRVDSJD-UHFFFAOYSA-N 6-bromo-2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3,5-dimethylphenyl]-1h-quinazolin-4-one Chemical compound CC1=C(OCCO[Si](C)(C)C(C)(C)C)C(C)=CC(C=2NC(=O)C3=CC(Br)=CC=C3N=2)=C1 UOZYFNTWRVDSJD-UHFFFAOYSA-N 0.000 claims description 5
- TYEWZEPXGWOXQY-UHFFFAOYSA-N 1-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-3-methylurea Chemical compound C1=C(C)C(OCCNC(=O)NC)=C(C)C=C1C1=NC2=CC(OC)=CC(OC)=C2C(=O)N1 TYEWZEPXGWOXQY-UHFFFAOYSA-N 0.000 claims description 4
- WGMFNNPODFFMLM-UHFFFAOYSA-N 2-(3,5-dimethyl-4-phenylmethoxyphenyl)-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCC1=CC=CC=C1 WGMFNNPODFFMLM-UHFFFAOYSA-N 0.000 claims description 4
- OPBWSZHIPZCHOF-UHFFFAOYSA-N 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N=2)=O)C=1N(C)C=2C1=CC(C)=C(O)C(C)=C1 OPBWSZHIPZCHOF-UHFFFAOYSA-N 0.000 claims description 4
- VVHDCWCOWMMSOC-UHFFFAOYSA-N 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one Chemical compound N=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(O)C(C)=C1 VVHDCWCOWMMSOC-UHFFFAOYSA-N 0.000 claims description 4
- RYQGDTXTAQKTGL-UHFFFAOYSA-N 2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholin-4-ylmethyl)-3H-quinazolin-4-one Chemical compound CC1=C(O)C(C)=CC(C=2NC(=O)C3=CC(CN4CCOCC4)=CC=C3N=2)=C1 RYQGDTXTAQKTGL-UHFFFAOYSA-N 0.000 claims description 4
- PQZDYFRDRHRZGF-UHFFFAOYSA-N 2-[3,5-dimethyl-4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCN1CCCC1 PQZDYFRDRHRZGF-UHFFFAOYSA-N 0.000 claims description 4
- UJQYQZYUACSONW-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethyl-1h-quinazolin-4-one Chemical compound C=1C(C)=CC(C)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCCO)C(C)=C1 UJQYQZYUACSONW-UHFFFAOYSA-N 0.000 claims description 4
- PQVHQVOOKNUBMB-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5-methoxy-1h-quinazolin-4-one Chemical compound N1C(=O)C=2C(OC)=CC=CC=2N=C1C1=CC(C)=C(OCCO)C(C)=C1 PQVHQVOOKNUBMB-UHFFFAOYSA-N 0.000 claims description 4
- NSYBXWYSRKNEDE-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-6-methoxy-1h-quinazolin-4-one Chemical compound N1C(=O)C2=CC(OC)=CC=C2N=C1C1=CC(C)=C(OCCO)C(C)=C1 NSYBXWYSRKNEDE-UHFFFAOYSA-N 0.000 claims description 4
- BDCPCEHLBBAARI-UHFFFAOYSA-N 2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]acetic acid Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCC(O)=O)C(C)=C1 BDCPCEHLBBAARI-UHFFFAOYSA-N 0.000 claims description 4
- JIYAFIZCFXYARP-UHFFFAOYSA-N 2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl n-cyclohexylcarbamate Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCOC(=O)NC1CCCCC1 JIYAFIZCFXYARP-UHFFFAOYSA-N 0.000 claims description 4
- DPSTWLDHKBPQDD-UHFFFAOYSA-N 2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl n-methylcarbamate Chemical compound C1=C(C)C(OCCOC(=O)NC)=C(C)C=C1C1=NC2=CC(OC)=CC(OC)=C2C(=O)N1 DPSTWLDHKBPQDD-UHFFFAOYSA-N 0.000 claims description 4
- VQEXPLRSSCYJEQ-UHFFFAOYSA-N 2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl n-propylcarbamate Chemical compound C1=C(C)C(OCCOC(=O)NCCC)=C(C)C=C1C1=NC2=CC(OC)=CC(OC)=C2C(=O)N1 VQEXPLRSSCYJEQ-UHFFFAOYSA-N 0.000 claims description 4
- CAWKLKXZZMFCME-UHFFFAOYSA-N 2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2-methoxyphenoxy]acetic acid Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(OCC(O)=O)C(OC)=C1 CAWKLKXZZMFCME-UHFFFAOYSA-N 0.000 claims description 4
- PMXVEHPOZWHJKR-UHFFFAOYSA-N 2-[4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy]ethanol Chemical compound N=1C2=CC(OC)=CC(OC)=C2C=NC=1C1=CC(C)=C(OCCO)C(C)=C1 PMXVEHPOZWHJKR-UHFFFAOYSA-N 0.000 claims description 4
- ZBYLVYGWTXOTIH-UHFFFAOYSA-N 2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]-5,7-dimethoxy-3H-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=C(O)C(CCO)=C1 ZBYLVYGWTXOTIH-UHFFFAOYSA-N 0.000 claims description 4
- SCCNFCOXZOFQFY-UHFFFAOYSA-N 3-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-1,1-dimethylurea Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCCNC(=O)N(C)C)C(C)=C1 SCCNFCOXZOFQFY-UHFFFAOYSA-N 0.000 claims description 4
- LFUOKUQHDNOIFT-UHFFFAOYSA-N 5,7-dichloro-2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-1h-quinazolin-4-one Chemical compound CC1=C(OCCO)C(C)=CC(C=2NC(=O)C3=C(Cl)C=C(Cl)C=C3N=2)=C1 LFUOKUQHDNOIFT-UHFFFAOYSA-N 0.000 claims description 4
- DOMIGLOJVBJZEH-UHFFFAOYSA-N 5,7-dimethoxy-2-[4-(2-methoxyethoxy)-3,5-dimethylphenyl]-1h-quinazolin-4-one Chemical compound C1=C(C)C(OCCOC)=C(C)C=C1C1=NC2=CC(OC)=CC(OC)=C2C(=O)N1 DOMIGLOJVBJZEH-UHFFFAOYSA-N 0.000 claims description 4
- VMTATHFMYBPFBD-UHFFFAOYSA-N 5,7-dimethoxy-2-[4-(morpholin-4-ylmethyl)phenyl]-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1)=CC=C1CN1CCOCC1 VMTATHFMYBPFBD-UHFFFAOYSA-N 0.000 claims description 4
- WMMXOSPJIXYOGF-UHFFFAOYSA-N 5,7-dimethoxy-2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1)=CC=C1CN1CCN(C)CC1 WMMXOSPJIXYOGF-UHFFFAOYSA-N 0.000 claims description 4
- AOJDYFWLCVYXPC-UHFFFAOYSA-N 5,7-dimethoxy-2-[4-methoxy-3-(morpholin-4-ylmethyl)phenyl]-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=1)=CC=C(OC)C=1CN1CCOCC1 AOJDYFWLCVYXPC-UHFFFAOYSA-N 0.000 claims description 4
- HUISYQXRBGYMFC-UHFFFAOYSA-N 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)-3H-quinazolin-4-one Chemical compound CC1=C(O)C(C)=CC(C=2NC(=O)C3=CC(Br)=CC=C3N=2)=C1 HUISYQXRBGYMFC-UHFFFAOYSA-N 0.000 claims description 4
- YFGXRURCWQMVKS-SSDVNMTOSA-N C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(\N=C\N(C)C)C(C)=C1 Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(\N=C\N(C)C)C(C)=C1 YFGXRURCWQMVKS-SSDVNMTOSA-N 0.000 claims description 4
- RHHHGOZXDBLBFM-UHFFFAOYSA-N n-[2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-4-oxo-1h-quinazolin-6-yl]acetamide Chemical compound N1C(=O)C2=CC(NC(=O)C)=CC=C2N=C1C1=CC(C)=C(OCCO)C(C)=C1 RHHHGOZXDBLBFM-UHFFFAOYSA-N 0.000 claims description 4
- ITRVWWNOGMNDNQ-UHFFFAOYSA-N n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-2-methylpropanamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCCNC(=O)C(C)C)C(C)=C1 ITRVWWNOGMNDNQ-UHFFFAOYSA-N 0.000 claims description 4
- PFHMVLYQAPTQRQ-UHFFFAOYSA-N n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NCCOC1=C(C)C=C(C=2NC(=O)C3=C(OC)C=C(OC)C=C3N=2)C=C1C PFHMVLYQAPTQRQ-UHFFFAOYSA-N 0.000 claims description 4
- PBGWFKIDTTYIHM-UHFFFAOYSA-N n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-4-methylbenzamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCNC(=O)C1=CC=C(C)C=C1 PBGWFKIDTTYIHM-UHFFFAOYSA-N 0.000 claims description 4
- JPXFKHCUTSMVGP-UHFFFAOYSA-N n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]acetamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCCNC(C)=O)C(C)=C1 JPXFKHCUTSMVGP-UHFFFAOYSA-N 0.000 claims description 4
- LCQCCXUNCRRWRW-UHFFFAOYSA-N n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]benzamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCNC(=O)C1=CC=CC=C1 LCQCCXUNCRRWRW-UHFFFAOYSA-N 0.000 claims description 4
- MCGGUIXJOVXSKN-UHFFFAOYSA-N n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]benzenesulfonamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCNS(=O)(=O)C1=CC=CC=C1 MCGGUIXJOVXSKN-UHFFFAOYSA-N 0.000 claims description 4
- VYQPWDNQEIHTOO-UHFFFAOYSA-N n-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenyl]-2-hydroxyacetamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(NC(=O)CO)C(C)=C1 VYQPWDNQEIHTOO-UHFFFAOYSA-N 0.000 claims description 4
- FAVQMYHCNZGIOG-UHFFFAOYSA-N 1-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-3-(4-methoxyphenyl)urea Chemical compound C1=CC(OC)=CC=C1NC(=O)NCCOC1=C(C)C=C(C=2NC(=O)C3=C(OC)C=C(OC)C=C3N=2)C=C1C FAVQMYHCNZGIOG-UHFFFAOYSA-N 0.000 claims description 3
- ZNWOWMMOOMXYMP-UHFFFAOYSA-N 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxy-3H-quinazolin-4-one Chemical compound C=1C(OC)=CC(O)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(O)C(C)=C1 ZNWOWMMOOMXYMP-UHFFFAOYSA-N 0.000 claims description 3
- HEFPIYWFMNCRPV-UHFFFAOYSA-N 6-bromo-2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-1h-quinazolin-4-one Chemical compound CC1=C(OCCO)C(C)=CC(C=2NC(=O)C3=CC(Br)=CC=C3N=2)=C1 HEFPIYWFMNCRPV-UHFFFAOYSA-N 0.000 claims description 3
- FDVCDNPTPMPVID-UHFFFAOYSA-N n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-4-methylbenzenesulfonamide Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCNS(=O)(=O)C1=CC=C(C)C=C1 FDVCDNPTPMPVID-UHFFFAOYSA-N 0.000 claims description 3
- VYGBAGCMNFMFFP-UHFFFAOYSA-N 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholin-4-ylmethyl)-3H-quinazolin-4-one Chemical compound COC1=CC=2N=C(C=3C=C(C)C(O)=C(C)C=3)NC(=O)C=2C(OC)=C1CN1CCOCC1 VYGBAGCMNFMFFP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 5
- 208000023516 stroke disease Diseases 0.000 claims 1
- 108010059886 Apolipoprotein A-I Proteins 0.000 abstract description 46
- 102000005666 Apolipoprotein A-I Human genes 0.000 abstract description 45
- 201000010099 disease Diseases 0.000 abstract description 14
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 194
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 193
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 186
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 150
- 239000000243 solution Substances 0.000 description 147
- 239000011541 reaction mixture Substances 0.000 description 141
- 239000007787 solid Substances 0.000 description 139
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 138
- 239000000203 mixture Substances 0.000 description 138
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 114
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 106
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 78
- 239000002904 solvent Substances 0.000 description 78
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 69
- 238000004440 column chromatography Methods 0.000 description 63
- 229940093499 ethyl acetate Drugs 0.000 description 59
- 235000019439 ethyl acetate Nutrition 0.000 description 59
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 44
- 239000012044 organic layer Substances 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 35
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 35
- 239000012267 brine Substances 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
- 238000001816 cooling Methods 0.000 description 28
- 150000002148 esters Chemical class 0.000 description 28
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 26
- JTBHPQAUWRGYJQ-UHFFFAOYSA-N 5,7-dimethoxy-2-pyridin-2-yl-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=CC=N1 JTBHPQAUWRGYJQ-UHFFFAOYSA-N 0.000 description 25
- 239000012043 crude product Substances 0.000 description 25
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 25
- LSDUYZHWQMMNCO-UHFFFAOYSA-N 2-amino-4,6-dimethoxybenzamide Chemical compound COC1=CC(N)=C(C(N)=O)C(OC)=C1 LSDUYZHWQMMNCO-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 23
- 238000010992 reflux Methods 0.000 description 23
- 239000003480 eluent Substances 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
- 238000001914 filtration Methods 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 229940124530 sulfonamide Drugs 0.000 description 18
- RHORCWWLDZEPTB-UHFFFAOYSA-N 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-6H-1,6-naphthyridin-5-one Chemical compound N=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C1=CC(C)=C(O)C(C)=C1 RHORCWWLDZEPTB-UHFFFAOYSA-N 0.000 description 16
- 125000004104 aryloxy group Chemical group 0.000 description 16
- 150000003456 sulfonamides Chemical class 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 235000013824 polyphenols Nutrition 0.000 description 15
- 229910000104 sodium hydride Inorganic materials 0.000 description 15
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 14
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 14
- 150000002576 ketones Chemical class 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 229910019142 PO4 Inorganic materials 0.000 description 13
- 125000004093 cyano group Chemical group *C#N 0.000 description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 13
- 239000010452 phosphate Substances 0.000 description 13
- 150000008442 polyphenolic compounds Chemical class 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 13
- UYGBSRJODQHNLQ-UHFFFAOYSA-N 4-hydroxy-3,5-dimethylbenzaldehyde Chemical compound CC1=CC(C=O)=CC(C)=C1O UYGBSRJODQHNLQ-UHFFFAOYSA-N 0.000 description 12
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 12
- 150000004677 hydrates Chemical class 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 12
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical compound SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 11
- 229940086542 triethylamine Drugs 0.000 description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
- JVLMWJSCXASRFK-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholin-4-ylmethyl)-2h-isoquinolin-1-one Chemical compound CC1=C(O)C(C)=CC(C=2NC(=O)C3=CC(CN4CCOCC4)=CC=C3C=2)=C1 JVLMWJSCXASRFK-UHFFFAOYSA-N 0.000 description 9
- PAXSRTRJTOGLAV-UHFFFAOYSA-N 3-(4-hydroxyphenyl)-2h-isoquinolin-1-one Chemical compound C1=CC(O)=CC=C1C1=CC2=CC=CC=C2C(=O)N1 PAXSRTRJTOGLAV-UHFFFAOYSA-N 0.000 description 9
- OZURCQHNZITNCL-UHFFFAOYSA-N 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol Chemical compound C=1C2=CC(OC)=CC(OC)=C2C=NC=1C1=CC(C)=C(O)C(C)=C1 OZURCQHNZITNCL-UHFFFAOYSA-N 0.000 description 9
- WFYGXOWFEIOHCZ-UHFFFAOYSA-N 4-hydroxy-3,5-dimethylbenzonitrile Chemical compound CC1=CC(C#N)=CC(C)=C1O WFYGXOWFEIOHCZ-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- 239000003937 drug carrier Substances 0.000 description 9
- 150000003840 hydrochlorides Chemical class 0.000 description 9
- 239000002480 mineral oil Substances 0.000 description 9
- 235000010446 mineral oil Nutrition 0.000 description 9
- YQCHEKKFHIGHIY-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholin-4-ylmethyl)isoquinolin-1-one Chemical compound CN1C(=O)C=2C(OC)=C(CN3CCOCC3)C(OC)=CC=2C=C1C1=CC(C)=C(O)C(C)=C1 YQCHEKKFHIGHIY-UHFFFAOYSA-N 0.000 description 8
- NGQLYAOOIQDSPO-UHFFFAOYSA-N 3-[3,5-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6,8-dimethoxy-2h-isoquinolin-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C(C=C1C)=CC(C)=C1OCCN1CCN(C)CC1 NGQLYAOOIQDSPO-UHFFFAOYSA-N 0.000 description 8
- LPPHEORVQUBKAI-UHFFFAOYSA-N 3-[4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl]-6,8-dimethoxy-2h-isoquinolin-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C1=CC(C)=C(OCC(C)(C)O)C(C)=C1 LPPHEORVQUBKAI-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- KXNBPAGNUQFBCJ-UHFFFAOYSA-N (4-isoquinolin-3-ylphenyl) 2-amino-5-(diaminomethylideneamino)pentanoate;tetrahydrochloride Chemical compound Cl.Cl.Cl.Cl.C1=CC(OC(=O)C(CCCNC(N)=N)N)=CC=C1C1=CC2=CC=CC=C2C=N1 KXNBPAGNUQFBCJ-UHFFFAOYSA-N 0.000 description 7
- JKJIPZGKICXZFZ-UHFFFAOYSA-N 2-(3,5-dimethoxyphenyl)-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound COC1=CC(OC)=CC(C=2NC(=O)C3=C(OC)C=C(OC)C=C3N=2)=C1 JKJIPZGKICXZFZ-UHFFFAOYSA-N 0.000 description 7
- ZVZWLDCQGSNBFB-UHFFFAOYSA-N 4-[2-[4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenoxy]ethyl]morpholine Chemical compound C=1C2=CC(OC)=CC(OC)=C2C=NC=1C(C=C1C)=CC(C)=C1OCCN1CCOCC1 ZVZWLDCQGSNBFB-UHFFFAOYSA-N 0.000 description 7
- VNXUAZCSHFABMS-UHFFFAOYSA-N 4-isoquinolin-3-ylphenol Chemical compound C1=CC(O)=CC=C1C1=CC2=CC=CC=C2C=N1 VNXUAZCSHFABMS-UHFFFAOYSA-N 0.000 description 7
- WLMRUOORCKEBFQ-UHFFFAOYSA-N 5,7-dimethoxy-2-pyridin-3-yl-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=CN=C1 WLMRUOORCKEBFQ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 7
- 108010010234 HDL Lipoproteins Proteins 0.000 description 7
- 102000015779 HDL Lipoproteins Human genes 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 description 7
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 7
- 230000036470 plasma concentration Effects 0.000 description 7
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 6
- RLWBNRZPIQCPFT-UHFFFAOYSA-N 2-amino-4,5-dimethoxybenzamide Chemical compound COC1=CC(N)=C(C(N)=O)C=C1OC RLWBNRZPIQCPFT-UHFFFAOYSA-N 0.000 description 6
- OOKPEGCVELIODB-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholin-4-ylmethyl)-2h-isoquinolin-1-one Chemical compound COC1=CC=2C=C(C=3C=C(C)C(O)=C(C)C=3)NC(=O)C=2C(OC)=C1CN1CCOCC1 OOKPEGCVELIODB-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- HXFAARHYVGUHOH-UHFFFAOYSA-N 3-[4-[2-(dimethylamino)ethoxy]-3,5-dimethylphenyl]-6,8-dimethoxy-2h-isoquinolin-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C1=CC(C)=C(OCCN(C)C)C(C)=C1 HXFAARHYVGUHOH-UHFFFAOYSA-N 0.000 description 6
- RXKHRQJHKYUEQR-UHFFFAOYSA-N 4-(1,6-naphthyridin-7-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CC2=NC=CC=C2C=N1 RXKHRQJHKYUEQR-UHFFFAOYSA-N 0.000 description 6
- BZVPMSKCPUPVSB-UHFFFAOYSA-N 7-(4-hydroxy-3,5-dimethylphenyl)-6H-1,6-naphthyridin-5-one Chemical compound CC1=C(O)C(C)=CC(C=2NC(=O)C3=CC=CN=C3C=2)=C1 BZVPMSKCPUPVSB-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- SHAHUVYARYRIMJ-UHFFFAOYSA-N [4-(1-oxo-2h-isoquinolin-3-yl)phenyl] 2-amino-5-(diaminomethylideneamino)pentanoate;trihydrochloride Chemical compound Cl.Cl.Cl.C1=CC(OC(=O)C(CCCNC(N)=N)N)=CC=C1C1=CC2=CC=CC=C2C(=O)N1 SHAHUVYARYRIMJ-UHFFFAOYSA-N 0.000 description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 6
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 6
- 150000002466 imines Chemical class 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- KEEFLPSUKYJVIE-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1-one Chemical compound CN1C(=O)C=2C(OC)=C(C)C(OC)=CC=2C=C1C1=CC(C)=C(O)C(C)=C1 KEEFLPSUKYJVIE-UHFFFAOYSA-N 0.000 description 5
- WGRLUDBFYJSWJG-UHFFFAOYSA-N 7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-dihydro-1,6-naphthyridine-2,5-dione Chemical compound N1C(=O)C=2C(OC)=CC(O)=NC=2C=C1C1=CC(C)=C(O)C(C)=C1 WGRLUDBFYJSWJG-UHFFFAOYSA-N 0.000 description 5
- DYZRQPAPMQNUNI-UHFFFAOYSA-N 7-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-2,4-dimethoxy-6h-1,6-naphthyridin-5-one Chemical compound N=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C(C=C1C)=CC(C)=C1OCCN1CCOCC1 DYZRQPAPMQNUNI-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- 229910019213 POCl3 Inorganic materials 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 150000001991 dicarboxylic acids Chemical class 0.000 description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
- SBOJXQVPLKSXOG-UHFFFAOYSA-N o-amino-hydroxylamine Chemical group NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 4
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 4
- OEEZSLVPEVLXSU-UHFFFAOYSA-N 3,5-dimethyl-4-phenylmethoxybenzonitrile Chemical compound CC1=CC(C#N)=CC(C)=C1OCC1=CC=CC=C1 OEEZSLVPEVLXSU-UHFFFAOYSA-N 0.000 description 4
- FOMOYRQTYWAHDJ-UHFFFAOYSA-N 4,6-dimethoxy-2-methylpyridine-3-carbonyl chloride hydrochloride Chemical compound Cl.COc1cc(OC)c(C(Cl)=O)c(C)n1 FOMOYRQTYWAHDJ-UHFFFAOYSA-N 0.000 description 4
- CLVFJLPVGFHMQK-UHFFFAOYSA-N 4,6-dimethoxy-2-methylpyridine-3-carboxylic acid Chemical compound COC1=CC(OC)=C(C(O)=O)C(C)=N1 CLVFJLPVGFHMQK-UHFFFAOYSA-N 0.000 description 4
- OMNHTTWQSSUZHO-UHFFFAOYSA-N 4-hydroxy-3,5-dimethylbenzoic acid Chemical compound CC1=CC(C(O)=O)=CC(C)=C1O OMNHTTWQSSUZHO-UHFFFAOYSA-N 0.000 description 4
- GBVVAHJALBFBOE-UHFFFAOYSA-N 7-(3,5-dimethyl-4-phenylmethoxyphenyl)-2,4-dimethoxy-6h-1,6-naphthyridin-5-one Chemical compound N=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C(C=C1C)=CC(C)=C1OCC1=CC=CC=C1 GBVVAHJALBFBOE-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 4
- 125000005110 aryl thio group Chemical group 0.000 description 4
- WYPCGKBOSFOHGU-UHFFFAOYSA-N bis(2,4,6-trichlorophenyl) propanedioate Chemical compound ClC1=CC(Cl)=CC(Cl)=C1OC(=O)CC(=O)OC1=C(Cl)C=C(Cl)C=C1Cl WYPCGKBOSFOHGU-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 4
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- WQPWRTUPFHAREU-UHFFFAOYSA-N ethyl 4-hydroxy-2-methyl-6-oxo-1h-pyridine-3-carboxylate Chemical compound CCOC(=O)C1=C(C)NC(O)=CC1=O WQPWRTUPFHAREU-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 4
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- LINPIYWFGCPVIE-UHFFFAOYSA-N 2,4,6-trichlorophenol Chemical compound OC1=C(Cl)C=C(Cl)C=C1Cl LINPIYWFGCPVIE-UHFFFAOYSA-N 0.000 description 3
- JEZXHCFBQWCWTO-UHFFFAOYSA-N 2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-6h-1,6-naphthyridin-5-one Chemical compound N=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C1=CC(C)=C(OC)C(C)=C1 JEZXHCFBQWCWTO-UHFFFAOYSA-N 0.000 description 3
- RIXVAJHMQREMMM-UHFFFAOYSA-N 2-(2-chlorophenyl)-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=CC=C1Cl RIXVAJHMQREMMM-UHFFFAOYSA-N 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- CPNJZIMFXYURFU-UHFFFAOYSA-N 2-(3,5-dimethylphenyl)-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=CC(C)=C1 CPNJZIMFXYURFU-UHFFFAOYSA-N 0.000 description 3
- JBKINHFZTVLNEM-UHFFFAOYSA-N 2-bromoethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCBr JBKINHFZTVLNEM-UHFFFAOYSA-N 0.000 description 3
- BPSZMJNQIRJYKP-UHFFFAOYSA-N 3,5-dimethyl-4-(2-morpholin-4-ylethoxy)benzaldehyde Chemical compound CC1=CC(C=O)=CC(C)=C1OCCN1CCOCC1 BPSZMJNQIRJYKP-UHFFFAOYSA-N 0.000 description 3
- DQYUTATUXSOKCS-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methylisoquinolin-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2C)=O)C=1C=C2C1=CC(C)=C(O)C(C)=C1 DQYUTATUXSOKCS-UHFFFAOYSA-N 0.000 description 3
- LENSBFXNQRMMLF-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisochromen-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(O2)=O)C=1C=C2C1=CC(C)=C(O)C(C)=C1 LENSBFXNQRMMLF-UHFFFAOYSA-N 0.000 description 3
- ZSBKNRIIPLZDND-UHFFFAOYSA-N 3-(4-hydroxyphenyl)-6,8-dimethoxy-2h-isoquinolin-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C1=CC=C(O)C=C1 ZSBKNRIIPLZDND-UHFFFAOYSA-N 0.000 description 3
- NRCBBECIFWPHJY-UHFFFAOYSA-N 3-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-6,8-dimethoxy-2h-isoquinolin-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C(C=C1C)=CC(C)=C1OCCN1CCOCC1 NRCBBECIFWPHJY-UHFFFAOYSA-N 0.000 description 3
- NFMCXWZCTMNPBM-UHFFFAOYSA-N 4-(6,8-dimethoxy-1,1-dioxo-2h-1$l^{6},2-benzothiazin-3-yl)-2,6-dimethylphenol Chemical compound C=1C(OC)=CC(OC)=C(S(N2)(=O)=O)C=1C=C2C1=CC(C)=C(O)C(C)=C1 NFMCXWZCTMNPBM-UHFFFAOYSA-N 0.000 description 3
- XCQFZIFIUMBSAO-UHFFFAOYSA-N 4-(dimethylamino)naphthalene-1-carbaldehyde Chemical compound C1=CC=C2C(N(C)C)=CC=C(C=O)C2=C1 XCQFZIFIUMBSAO-UHFFFAOYSA-N 0.000 description 3
- HLIVDDATWNATGF-UHFFFAOYSA-N 4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3,5-dimethylbenzaldehyde Chemical compound CC1=CC(C=O)=CC(C)=C1OCCO[Si](C)(C)C(C)(C)C HLIVDDATWNATGF-UHFFFAOYSA-N 0.000 description 3
- YSDDPNWGLSGZRC-UHFFFAOYSA-N 4-[bis(2-hydroxyethyl)amino]benzaldehyde Chemical compound OCCN(CCO)C1=CC=C(C=O)C=C1 YSDDPNWGLSGZRC-UHFFFAOYSA-N 0.000 description 3
- MOCXTRLLJSEBLY-UHFFFAOYSA-N 5,7-dimethoxy-2-(2-methylphenyl)-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=CC=C1C MOCXTRLLJSEBLY-UHFFFAOYSA-N 0.000 description 3
- DSPFCWXNUXTNGI-UHFFFAOYSA-N 5,7-dimethoxy-2-(6-methylpyridin-2-yl)-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC=CC(C)=N1 DSPFCWXNUXTNGI-UHFFFAOYSA-N 0.000 description 3
- GHOKTIAMZIDTEV-UHFFFAOYSA-N 5,7-dimethoxy-2-[6-(4-methylsulfanylphenyl)pyridin-2-yl]-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(N=1)=CC=CC=1C1=CC=C(SC)C=C1 GHOKTIAMZIDTEV-UHFFFAOYSA-N 0.000 description 3
- SSGYRAFYEFSSQC-UHFFFAOYSA-N 5,7-dimethoxy-2-[6-(4-methylsulfonylphenyl)pyridin-2-yl]-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(N=1)=CC=CC=1C1=CC=C(S(C)(=O)=O)C=C1 SSGYRAFYEFSSQC-UHFFFAOYSA-N 0.000 description 3
- LBIQWGNOUXLJNJ-UHFFFAOYSA-N 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-di(propan-2-yloxy)-6H-1,6-naphthyridin-5-one Chemical compound N=1C(OC(C)C)=CC(OC(C)C)=C(C(N2)=O)C=1C=C2C1=CC(C)=C(O)C(C)=C1 LBIQWGNOUXLJNJ-UHFFFAOYSA-N 0.000 description 3
- CXTSLSCHXKYMAJ-UHFFFAOYSA-N 7-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-2,4-dimethoxy-6h-1,6-naphthyridin-5-one Chemical compound N=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C1=CC(C)=C(OCCO)C(C)=C1 CXTSLSCHXKYMAJ-UHFFFAOYSA-N 0.000 description 3
- 108010087614 Apolipoprotein A-II Proteins 0.000 description 3
- 102000009081 Apolipoprotein A-II Human genes 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000002939 deleterious effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- YPMPTULBFPFSEQ-PLNGDYQASA-N ethyl (z)-3-aminobut-2-enoate Chemical compound CCOC(=O)\C=C(\C)N YPMPTULBFPFSEQ-PLNGDYQASA-N 0.000 description 3
- LNIMLSAAPISOEC-UHFFFAOYSA-N ethyl 4,6-dichloro-2-methylpyridine-3-carboxylate Chemical compound CCOC(=O)C1=C(C)N=C(Cl)C=C1Cl LNIMLSAAPISOEC-UHFFFAOYSA-N 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- AUENWDPYMGLJHA-UHFFFAOYSA-N methyl 4,6-dimethoxy-2-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=C(C)N=C(OC)C=C1OC AUENWDPYMGLJHA-UHFFFAOYSA-N 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 3
- 238000003305 oral gavage Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 235000021283 resveratrol Nutrition 0.000 description 3
- 229940016667 resveratrol Drugs 0.000 description 3
- 230000004141 reverse cholesterol transport Effects 0.000 description 3
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 2
- PRMHQIVOFKWXCI-UHFFFAOYSA-N (4-carbonochloridoyl-2,6-dimethylphenyl) acetate Chemical compound CC(=O)OC1=C(C)C=C(C(Cl)=O)C=C1C PRMHQIVOFKWXCI-UHFFFAOYSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- AFFDFWRTCGIWLL-UHFFFAOYSA-N 1-(dimethoxymethyl)-4-iodobenzene Chemical compound COC(OC)C1=CC=C(I)C=C1 AFFDFWRTCGIWLL-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- KBIAVTUACPKPFJ-UHFFFAOYSA-N 1-ethynyl-4-methoxybenzene Chemical group COC1=CC=C(C#C)C=C1 KBIAVTUACPKPFJ-UHFFFAOYSA-N 0.000 description 2
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 2
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 2
- CWKXDPPQCVWXAG-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde Chemical compound O1CCOC2=CC(C=O)=CC=C21 CWKXDPPQCVWXAG-UHFFFAOYSA-N 0.000 description 2
- AFTDJUWYIVEEJJ-UHFFFAOYSA-N 2,4-dimethoxy-6-(2-methoxy-2-oxoethyl)benzoic acid Chemical compound COC(=O)CC1=CC(OC)=CC(OC)=C1C(O)=O AFTDJUWYIVEEJJ-UHFFFAOYSA-N 0.000 description 2
- PQKFBIVPDGGROX-UHFFFAOYSA-N 2,4-dimethoxy-6-methylbenzamide Chemical compound COC1=CC(C)=C(C(N)=O)C(OC)=C1 PQKFBIVPDGGROX-UHFFFAOYSA-N 0.000 description 2
- FRBJDEWCBGUODU-UHFFFAOYSA-N 2,4-dimethoxy-6-methylbenzoic acid Chemical compound COC1=CC(C)=C(C(O)=O)C(OC)=C1 FRBJDEWCBGUODU-UHFFFAOYSA-N 0.000 description 2
- DSFRTUBFWQETRP-UHFFFAOYSA-N 2-(3,5-dimethyl-4-phenylmethoxyphenyl)ethynyl-trimethylsilane Chemical compound CC1=CC(C#C[Si](C)(C)C)=CC(C)=C1OCC1=CC=CC=C1 DSFRTUBFWQETRP-UHFFFAOYSA-N 0.000 description 2
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 2
- OYNIIKHNXNPSAG-UHFFFAOYSA-N 2-(4-formylphenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(C=O)C=C1 OYNIIKHNXNPSAG-UHFFFAOYSA-N 0.000 description 2
- FIUXJDBLSSMEHO-UHFFFAOYSA-N 2-(4-hydroxy-3,5-dimethylphenyl)-6-nitro-3H-quinazolin-4-one Chemical compound CC1=C(O)C(C)=CC(C=2NC(=O)C3=CC(=CC=C3N=2)[N+]([O-])=O)=C1 FIUXJDBLSSMEHO-UHFFFAOYSA-N 0.000 description 2
- AGUZDPQUSFEZEP-UHFFFAOYSA-N 2-(carboxymethyl)-4,6-dimethoxybenzoic acid Chemical compound COC1=CC(CC(O)=O)=C(C(O)=O)C(OC)=C1 AGUZDPQUSFEZEP-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- DXZZTORISNBNGM-UHFFFAOYSA-N 2-[2-(4-methoxyphenyl)ethynyl]pyridine-3-carbaldehyde Chemical compound C1=CC(OC)=CC=C1C#CC1=NC=CC=C1C=O DXZZTORISNBNGM-UHFFFAOYSA-N 0.000 description 2
- DWRZWESPSZTEBE-UHFFFAOYSA-N 2-[4-(dimethylamino)naphthalen-1-yl]-6,7-dimethoxy-1h-quinazolin-4-one Chemical compound C1=CC=C2C(C3=NC=4C=C(C(=CC=4C(=O)N3)OC)OC)=CC=C(N(C)C)C2=C1 DWRZWESPSZTEBE-UHFFFAOYSA-N 0.000 description 2
- PEKSAHQVDKQWST-UHFFFAOYSA-N 2-bromo-4,6-dimethoxybenzaldehyde Chemical compound COC1=CC(Br)=C(C=O)C(OC)=C1 PEKSAHQVDKQWST-UHFFFAOYSA-N 0.000 description 2
- VFZRZRDOXPRTSC-UHFFFAOYSA-N 3,5-Dimethoxybenzaldehyde Chemical compound COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 2
- DOZRDZLFLOODMB-UHFFFAOYSA-N 3,5-di-tert-Butyl-4-hydroxybenzaldehyde Chemical compound CC(C)(C)C1=CC(C=O)=CC(C(C)(C)C)=C1O DOZRDZLFLOODMB-UHFFFAOYSA-N 0.000 description 2
- RIZBLVRXRWHLFA-UHFFFAOYSA-N 3,5-dimethoxytoluene Chemical compound COC1=CC(C)=CC(OC)=C1 RIZBLVRXRWHLFA-UHFFFAOYSA-N 0.000 description 2
- VSKAIISOPCFRIG-UHFFFAOYSA-N 3-(3,5-dimethyl-4-phenylmethoxyphenyl)-6,8-dimethoxyisoquinoline Chemical compound C=1C2=CC(OC)=CC(OC)=C2C=NC=1C(C=C1C)=CC(C)=C1OCC1=CC=CC=C1 VSKAIISOPCFRIG-UHFFFAOYSA-N 0.000 description 2
- VBCFPFDUNNOWIZ-UHFFFAOYSA-N 3-(4-methoxyphenyl)isoquinoline Chemical compound C1=CC(OC)=CC=C1C1=CC2=CC=CC=C2C=N1 VBCFPFDUNNOWIZ-UHFFFAOYSA-N 0.000 description 2
- KWXHEQXDZIVEMP-UHFFFAOYSA-N 3-[4-(2-chloroethoxy)-3,5-dimethylphenyl]-6,8-dimethoxyisochromen-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(O2)=O)C=1C=C2C1=CC(C)=C(OCCCl)C(C)=C1 KWXHEQXDZIVEMP-UHFFFAOYSA-N 0.000 description 2
- VGSOCYWCRMXQAB-UHFFFAOYSA-N 3-chloro-4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1Cl VGSOCYWCRMXQAB-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- ZWIKZCIYDKPLHL-UHFFFAOYSA-N 4,6-dimethoxy-2-methylpyridine-3-carboxamide Chemical compound COC1=CC(OC)=C(C(N)=O)C(C)=N1 ZWIKZCIYDKPLHL-UHFFFAOYSA-N 0.000 description 2
- IWZOCFGSXVEJOZ-UHFFFAOYSA-N 4,6-dimethoxy-n,2-dimethylpyridine-3-carboxamide Chemical compound CNC(=O)C1=C(C)N=C(OC)C=C1OC IWZOCFGSXVEJOZ-UHFFFAOYSA-N 0.000 description 2
- GESJFWQSAZHITI-UHFFFAOYSA-N 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylbenzonitrile Chemical compound CC1=CC(C#N)=CC(C)=C1OCC(C)(C)O GESJFWQSAZHITI-UHFFFAOYSA-N 0.000 description 2
- PFODEVGLOVUVHS-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)benzaldehyde Chemical compound C1CN(C)CCN1C1=CC=C(C=O)C=C1 PFODEVGLOVUVHS-UHFFFAOYSA-N 0.000 description 2
- QTMHZBZKVJRLRM-UHFFFAOYSA-N 4-[2-[tert-butyl(dimethyl)silyl]oxy-2-methylpropoxy]-3,5-dimethylbenzonitrile Chemical compound CC1=CC(C#N)=CC(C)=C1OCC(C)(C)O[Si](C)(C)C(C)(C)C QTMHZBZKVJRLRM-UHFFFAOYSA-N 0.000 description 2
- GCZSWHFXNJVEDR-UHFFFAOYSA-N 4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3-chlorobenzaldehyde Chemical compound CC(C)(C)[Si](C)(C)OCCOC1=CC=C(C=O)C=C1Cl GCZSWHFXNJVEDR-UHFFFAOYSA-N 0.000 description 2
- PLOUOMSFVXHXOC-UHFFFAOYSA-N 4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3-methoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC=C1OCCO[Si](C)(C)C(C)(C)C PLOUOMSFVXHXOC-UHFFFAOYSA-N 0.000 description 2
- LPLVIOSKJVQVAG-UHFFFAOYSA-N 4-[4-(dimethoxymethyl)phenyl]morpholine Chemical compound C1=CC(C(OC)OC)=CC=C1N1CCOCC1 LPLVIOSKJVQVAG-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- DQEGTPQUZSCABH-UHFFFAOYSA-N 4-acetyloxy-3,5-dimethylbenzoic acid Chemical compound CC(=O)OC1=C(C)C=C(C(O)=O)C=C1C DQEGTPQUZSCABH-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- NIEBHDXUIJSHSL-UHFFFAOYSA-N 4-iodobenzaldehyde Chemical compound IC1=CC=C(C=O)C=C1 NIEBHDXUIJSHSL-UHFFFAOYSA-N 0.000 description 2
- FOAQOAXQMISINY-UHFFFAOYSA-N 4-morpholin-4-ylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1N1CCOCC1 FOAQOAXQMISINY-UHFFFAOYSA-N 0.000 description 2
- GSOXNZBHMRVUDF-UHFFFAOYSA-N 5-bromo-1,3-dimethyl-2-phenylmethoxybenzene Chemical compound CC1=CC(Br)=CC(C)=C1OCC1=CC=CC=C1 GSOXNZBHMRVUDF-UHFFFAOYSA-N 0.000 description 2
- JBROAVQZTYYRFY-UHFFFAOYSA-N 5-ethynyl-1,3-dimethyl-2-phenylmethoxybenzene Chemical compound CC1=CC(C#C)=CC(C)=C1OCC1=CC=CC=C1 JBROAVQZTYYRFY-UHFFFAOYSA-N 0.000 description 2
- UCQGXKTVLKNSOY-UHFFFAOYSA-N 6,8-dimethoxy-4h-isochromene-1,3-dione Chemical compound C1C(=O)OC(=O)C2=C1C=C(OC)C=C2OC UCQGXKTVLKNSOY-UHFFFAOYSA-N 0.000 description 2
- ZVZKFOHXQISIJS-UHFFFAOYSA-N 6-amino-2-(4-hydroxy-3,5-dimethylphenyl)-3H-quinazolin-4-one Chemical compound CC1=C(O)C(C)=CC(C=2NC(=O)C3=CC(N)=CC=C3N=2)=C1 ZVZKFOHXQISIJS-UHFFFAOYSA-N 0.000 description 2
- KFXPTJUUWVZBIW-UHFFFAOYSA-N 7-(4-methoxyphenyl)-1,6-naphthyridine Chemical compound C1=CC(OC)=CC=C1C1=CC2=NC=CC=C2C=N1 KFXPTJUUWVZBIW-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 206010034962 Photopsia Diseases 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- ZCAGHLIBKHFJDU-UHFFFAOYSA-N [4-(4-methylpiperazin-1-yl)phenyl]methanol Chemical compound C1CN(C)CCN1C1=CC=C(CO)C=C1 ZCAGHLIBKHFJDU-UHFFFAOYSA-N 0.000 description 2
- FLUKVPGBLLOGQZ-UHFFFAOYSA-N [4-(6,8-dimethoxy-1-oxoisochromen-3-yl)-2,6-dimethylphenyl] acetate Chemical compound C=1C(OC)=CC(OC)=C(C(O2)=O)C=1C=C2C1=CC(C)=C(OC(C)=O)C(C)=C1 FLUKVPGBLLOGQZ-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000001361 adipic acid Substances 0.000 description 2
- 235000011037 adipic acid Nutrition 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- KMLCMKXDMYDBMX-UHFFFAOYSA-N ethyl 3-(4-formylphenyl)propanoate Chemical compound CCOC(=O)CCC1=CC=C(C=O)C=C1 KMLCMKXDMYDBMX-UHFFFAOYSA-N 0.000 description 2
- FHKRLFLSXJAQID-UHFFFAOYSA-N ethyl 3-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)phenyl]propanoate Chemical compound C1=CC(CCC(=O)OCC)=CC=C1C1=NC2=CC(OC)=CC(OC)=C2C(=O)N1 FHKRLFLSXJAQID-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 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 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- MHWNOIUZPADXIJ-UHFFFAOYSA-N methyl 2-(2-formyl-3,5-dimethoxyphenyl)acetate Chemical compound COC(=O)CC1=CC(OC)=CC(OC)=C1C=O MHWNOIUZPADXIJ-UHFFFAOYSA-N 0.000 description 2
- CLZWNNSTRIEAMH-UHFFFAOYSA-N methyl 2-(3,5-dimethoxyphenyl)acetate Chemical compound COC(=O)CC1=CC(OC)=CC(OC)=C1 CLZWNNSTRIEAMH-UHFFFAOYSA-N 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- WVKNBCACIPKHEW-UHFFFAOYSA-N n,n-diethylethanamine;n,n-dimethylformamide Chemical compound CN(C)C=O.CCN(CC)CC WVKNBCACIPKHEW-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 2
- NCCWCZLEACWJIN-UHFFFAOYSA-N orsellinic acid methyl ester Chemical compound COC(=O)C1=C(C)C=C(O)C=C1O NCCWCZLEACWJIN-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910000065 phosphene Inorganic materials 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 235000020095 red wine Nutrition 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000011816 wild-type C57Bl6 mouse Methods 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- HSQIYOPBCOPMSS-ZETCQYMHSA-N (2s)-5-(diaminomethylideneamino)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical class CC(C)(C)OC(=O)N[C@H](C(O)=O)CCCN=C(N)N HSQIYOPBCOPMSS-ZETCQYMHSA-N 0.000 description 1
- BGOFOVHACSQSIE-ZDUSSCGKSA-N (2s)-5-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCCNC(NC(=O)OC(C)(C)C)=NC(=O)OC(C)(C)C BGOFOVHACSQSIE-ZDUSSCGKSA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FTVWIRXFELQLPI-ZDUSSCGKSA-N (S)-naringenin Chemical compound C1=CC(O)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 FTVWIRXFELQLPI-ZDUSSCGKSA-N 0.000 description 1
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- KRWRFIMBWRVMKE-UHFFFAOYSA-N 1-bromo-3,5-dimethoxybenzene Chemical compound COC1=CC(Br)=CC(OC)=C1 KRWRFIMBWRVMKE-UHFFFAOYSA-N 0.000 description 1
- JTWWWQGSFTWWDL-UHFFFAOYSA-N 1-chloro-2-iodoethane Chemical compound ClCCI JTWWWQGSFTWWDL-UHFFFAOYSA-N 0.000 description 1
- JNOZGFXJZQXOSU-UHFFFAOYSA-N 1-chloro-2-methylpropan-2-ol Chemical compound CC(C)(O)CCl JNOZGFXJZQXOSU-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 1
- FFPAFDDLAGTGPQ-UHFFFAOYSA-N 2-(3,5-dimethoxyphenyl)acetic acid Chemical compound COC1=CC(CC(O)=O)=CC(OC)=C1 FFPAFDDLAGTGPQ-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 1
- BSRAQZZEFZCJBT-UHFFFAOYSA-N 2-[2-(3,5-dimethyl-4-phenylmethoxyphenyl)ethynyl]-4,6-dimethoxybenzaldehyde Chemical compound COC1=CC(OC)=C(C=O)C(C#CC=2C=C(C)C(OCC=3C=CC=CC=3)=C(C)C=2)=C1 BSRAQZZEFZCJBT-UHFFFAOYSA-N 0.000 description 1
- RLDUQRLGSISLMK-UHFFFAOYSA-N 2-[2-(4-methoxyphenyl)ethynyl]benzaldehyde Chemical compound C1=CC(OC)=CC=C1C#CC1=CC=CC=C1C=O RLDUQRLGSISLMK-UHFFFAOYSA-N 0.000 description 1
- YHZPNGZMZXQMPV-UHFFFAOYSA-N 2-[3-(2,6-dichlorophenyl)-5-methyl-1,2-oxazol-4-yl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YHZPNGZMZXQMPV-UHFFFAOYSA-N 0.000 description 1
- CANJLKUEEMJRLN-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-oxopyridin-1-yl]-1h-quinazolin-4-one Chemical compound O=C1C=C(N(C)C)C=CN1C1=NC2=CC=CC=C2C(=O)N1 CANJLKUEEMJRLN-UHFFFAOYSA-N 0.000 description 1
- LHLWGZYYLCEIFG-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-oxopyridin-1-yl]-6,7-dimethoxy-1h-quinazolin-4-one Chemical compound N1C(=O)C=2C=C(OC)C(OC)=CC=2N=C1N1C=CC(N(C)C)=CC1=O LHLWGZYYLCEIFG-UHFFFAOYSA-N 0.000 description 1
- SOBQOVZAFJDEJI-UHFFFAOYSA-N 2-amino-5-nitrobenzamide Chemical compound NC(=O)C1=CC([N+]([O-])=O)=CC=C1N SOBQOVZAFJDEJI-UHFFFAOYSA-N 0.000 description 1
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 1
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 1
- GNFWMEFWZWXLIN-UHFFFAOYSA-N 2-bromopyridine-3-carbaldehyde Chemical compound BrC1=NC=CC=C1C=O GNFWMEFWZWXLIN-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- HNTZKNJGAFJMHQ-UHFFFAOYSA-N 2-methylpyridine-3-carboxylic acid Chemical compound CC1=NC=CC=C1C(O)=O HNTZKNJGAFJMHQ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- GHNLJDPNIAIWOQ-UHFFFAOYSA-N 2h-1$l^{6},2-benzothiazine 1,1-dioxide Chemical compound C1=CC=C2S(=O)(=O)NC=CC2=C1 GHNLJDPNIAIWOQ-UHFFFAOYSA-N 0.000 description 1
- MCIPQLOKVXSHTD-UHFFFAOYSA-N 3,3-diethoxyprop-1-ene Chemical compound CCOC(C=C)OCC MCIPQLOKVXSHTD-UHFFFAOYSA-N 0.000 description 1
- WNRGWPVJGDABME-UHFFFAOYSA-N 3,5-Dimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1 WNRGWPVJGDABME-UHFFFAOYSA-N 0.000 description 1
- NGTJBBLVOSWVNM-UHFFFAOYSA-N 3-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-6,8-dimethoxyisochromen-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(O2)=O)C=1C=C2C(C=C1C)=CC(C)=C1OCCN1CCOCC1 NGTJBBLVOSWVNM-UHFFFAOYSA-N 0.000 description 1
- ZUKUGGHRLFVGNI-UHFFFAOYSA-N 3-[4-[2-[tert-butyl(dimethyl)silyl]oxy-2-methylpropoxy]-3,5-dimethylphenyl]-6,8-dimethoxy-2h-isoquinolin-1-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1C=C2C1=CC(C)=C(OCC(C)(C)O[Si](C)(C)C(C)(C)C)C(C)=C1 ZUKUGGHRLFVGNI-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- ASFAFOSQXBRFMV-LJQANCHMSA-N 3-n-(2-benzyl-1,3-dihydroxypropan-2-yl)-1-n-[(1r)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzene-1,3-dicarboxamide Chemical compound N([C@H](C)C=1C=CC(F)=CC=1)C(=O)C(C=1)=CC(N(C)S(C)(=O)=O)=CC=1C(=O)NC(CO)(CO)CC1=CC=CC=C1 ASFAFOSQXBRFMV-LJQANCHMSA-N 0.000 description 1
- KSBGGQRDBYVDSC-UHFFFAOYSA-N 4,5-dimethoxy-2-nitrobenzamide Chemical compound COC1=CC(C(N)=O)=C([N+]([O-])=O)C=C1OC KSBGGQRDBYVDSC-UHFFFAOYSA-N 0.000 description 1
- FAMGTYWNHVETJC-UHFFFAOYSA-N 4,6-dimethoxy-1h-indole-2,3-dione Chemical compound COC1=CC(OC)=CC2=C1C(=O)C(=O)N2 FAMGTYWNHVETJC-UHFFFAOYSA-N 0.000 description 1
- PBIWVVONGPLSAJ-UHFFFAOYSA-N 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde Chemical compound CC1=CC(C=O)=CC(C)=C1OCCO PBIWVVONGPLSAJ-UHFFFAOYSA-N 0.000 description 1
- SVURWRVASLSTQJ-UHFFFAOYSA-N 4-[2-(dimethylamino)ethoxy]-3,5-dimethylbenzonitrile Chemical compound CN(C)CCOC1=C(C)C=C(C#N)C=C1C SVURWRVASLSTQJ-UHFFFAOYSA-N 0.000 description 1
- UJMKJBNUZIEAKX-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxy-3,5-dimethylbenzonitrile Chemical compound CC1=CC(C#N)=CC(C)=C1O[Si](C)(C)C(C)(C)C UJMKJBNUZIEAKX-UHFFFAOYSA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- ZLVFYUORUHNMBO-UHFFFAOYSA-N 4-bromo-2,6-dimethylphenol Chemical compound CC1=CC(Br)=CC(C)=C1O ZLVFYUORUHNMBO-UHFFFAOYSA-N 0.000 description 1
- XDJAAZYHCCRJOK-UHFFFAOYSA-N 4-methoxybenzonitrile Chemical compound COC1=CC=C(C#N)C=C1 XDJAAZYHCCRJOK-UHFFFAOYSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- CGSRJSIAGKSMHU-UHFFFAOYSA-N 4-pyrimidin-2-yloxybenzaldehyde Chemical compound C1=CC(C=O)=CC=C1OC1=NC=CC=N1 CGSRJSIAGKSMHU-UHFFFAOYSA-N 0.000 description 1
- IYLZVJSUNLUFEV-UHFFFAOYSA-N 5,7-dimethoxy-2-(1-phenyl-5-propylpyrazol-4-yl)-1h-quinazolin-4-one Chemical compound CCCC1=C(C=2NC(=O)C3=C(OC)C=C(OC)C=C3N=2)C=NN1C1=CC=CC=C1 IYLZVJSUNLUFEV-UHFFFAOYSA-N 0.000 description 1
- AMLLVLSEKJBLDP-UHFFFAOYSA-N 5-(bromomethyl)-n,2-dimethylbenzamide Chemical compound CNC(=O)C1=CC(CBr)=CC=C1C AMLLVLSEKJBLDP-UHFFFAOYSA-N 0.000 description 1
- 125000004008 6 membered carbocyclic group Chemical group 0.000 description 1
- ZIBKWGLGCZKLHZ-UHFFFAOYSA-N 6-amino-2,3-dimethoxybenzamide Chemical compound COC1=CC=C(N)C(C(N)=O)=C1OC ZIBKWGLGCZKLHZ-UHFFFAOYSA-N 0.000 description 1
- KKBVEVWKPFAYRC-UHFFFAOYSA-N 7-(3,5-dimethyl-4-phenylmethoxyphenyl)-2,4-dimethoxy-1,6-naphthyridin-5-amine Chemical compound C=1C2=NC(OC)=CC(OC)=C2C(N)=NC=1C(C=C1C)=CC(C)=C1OCC1=CC=CC=C1 KKBVEVWKPFAYRC-UHFFFAOYSA-N 0.000 description 1
- UOSULNZPRMMJLF-UHFFFAOYSA-N 7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-dihydro-1,6-naphthyridine-2,5-dione;hydrochloride Chemical compound Cl.N1C(=O)C=2C(OC)=CC(O)=NC=2C=C1C1=CC(C)=C(O)C(C)=C1 UOSULNZPRMMJLF-UHFFFAOYSA-N 0.000 description 1
- PSAHFSALJUFRIE-UHFFFAOYSA-N 7-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-2,4-diethoxy-6H-1,6-naphthyridin-5-one Chemical compound CC=1C=C(C=C(C=1OCCN1CCOCC1)C)C=1NC(C=2C(=CC(=NC=2C=1)OCC)OCC)=O PSAHFSALJUFRIE-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102100037320 Apolipoprotein A-IV Human genes 0.000 description 1
- 102100029470 Apolipoprotein E Human genes 0.000 description 1
- 101710095339 Apolipoprotein E Proteins 0.000 description 1
- 108010071619 Apolipoproteins Proteins 0.000 description 1
- 102000018616 Apolipoproteins B Human genes 0.000 description 1
- 108010027006 Apolipoproteins B Proteins 0.000 description 1
- 102000006996 Aryldialkylphosphatase Human genes 0.000 description 1
- 108010008184 Aryldialkylphosphatase Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 229940123239 Cholesterol synthesis inhibitor Drugs 0.000 description 1
- 208000022411 Cholesterol-ester transfer protein deficiency Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 101000733802 Homo sapiens Apolipoprotein A-I Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-M L-lysinate Chemical compound NCCCC[C@H](N)C([O-])=O KDXKERNSBIXSRK-YFKPBYRVSA-M 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 206010027417 Metabolic acidosis Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910004727 OSO3H Inorganic materials 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229940126033 PPAR agonist Drugs 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229920001774 Perfluoroether Polymers 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 description 1
- 108010054082 Sterol O-acyltransferase Proteins 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- QOKFSCASQKJVMB-UHFFFAOYSA-N [4-(6,8-dimethoxy-1,3-dioxo-4h-isochromene-4-carbonyl)-2,6-dimethylphenyl] acetate Chemical compound C12=CC(OC)=CC(OC)=C2C(=O)OC(=O)C1C(=O)C1=CC(C)=C(OC(C)=O)C(C)=C1 QOKFSCASQKJVMB-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000489 anti-atherogenic effect Effects 0.000 description 1
- 108010073614 apolipoprotein A-IV Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000004057 biotinyl group Chemical group [H]N1C(=O)N([H])[C@]2([H])[C@@]([H])(SC([H])([H])[C@]12[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000004202 carbamide Chemical group 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000000633 chiral stationary phase gas chromatography Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 150000001934 cyclohexanes Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical class C1(=CCCCC1)* 0.000 description 1
- 150000001941 cyclopentenes Chemical class 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 125000005303 dithiazolyl group Chemical group S1SNC(=C1)* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000678 effect on lipid Effects 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical compound Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000005027 hydroxyaryl group Chemical group 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 108010038232 microsomal triglyceride transfer protein Proteins 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- OABGZRFNYNFHCS-UHFFFAOYSA-N n,2-dimethylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1C OABGZRFNYNFHCS-UHFFFAOYSA-N 0.000 description 1
- OUQVKRKGTAUJQA-UHFFFAOYSA-N n-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]glycine Chemical compound C1=CC=CC2=C(O)C(C(=O)NCC(=O)O)=NC(Cl)=C21 OUQVKRKGTAUJQA-UHFFFAOYSA-N 0.000 description 1
- LTRKBMXZHSRQAJ-UHFFFAOYSA-N n-[2-[4-(5,7-dimethoxy-4-oxo-1h-quinazolin-2-yl)-2,6-dimethylphenoxy]ethyl]-4-methoxybenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NCCOC1=C(C)C=C(C=2NC(=O)C3=C(OC)C=C(OC)C=C3N=2)C=C1C LTRKBMXZHSRQAJ-UHFFFAOYSA-N 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- 235000007625 naringenin Nutrition 0.000 description 1
- WGEYAGZBLYNDFV-UHFFFAOYSA-N naringenin Natural products C1(=O)C2=C(O)C=C(O)C=C2OC(C1)C1=CC=C(CC1)O WGEYAGZBLYNDFV-UHFFFAOYSA-N 0.000 description 1
- 229940117954 naringenin Drugs 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical class C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 125000005460 perfluorocycloalkyl group Chemical group 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- ILJOYZVVZZFIKA-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;hydrate Chemical compound O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 ILJOYZVVZZFIKA-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- KCDXJAYRVLXPFO-UHFFFAOYSA-N syringaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1O KCDXJAYRVLXPFO-UHFFFAOYSA-N 0.000 description 1
- COBXDAOIDYGHGK-UHFFFAOYSA-N syringaldehyde Natural products COC1=CC=C(C=O)C(OC)=C1O COBXDAOIDYGHGK-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KHORERZDMJTBMR-UHFFFAOYSA-N tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(C=O)C=C1 KHORERZDMJTBMR-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- 125000006169 tetracyclic group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- DKZBBWMURDFHNE-UHFFFAOYSA-N trans-coniferylaldehyde Natural products COC1=CC(C=CC=O)=CC=C1O DKZBBWMURDFHNE-UHFFFAOYSA-N 0.000 description 1
- 238000011820 transgenic animal model Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/695—Silicon compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2420/00—Materials or methods for coatings medical devices
Definitions
- the present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use, for the treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
- ApoA-I apolipoprotein A-I
- cardiovascular disease and related disease states including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
- HDL-C appears to exert its anti-atherogenic effect by mediating reverse cholesterol transport (RCT), in which cholesterol is recruited from peripheral tissues and transported to the liver.
- RCT reverse cholesterol transport
- HDL-C also exerts anti-inflammatory and anti-oxidant effects and promotes fibrinolysis.
- HDL-C particles protect against oxidation of LDL, an important initial step in promoting cholesterol uptake by arterial macrophages.
- HDL-C exists in two main forms, one containing both apolipoprotein A-I (ApoA-I) and apolipoprotein A-II (ApoA-III), and the other containing ApoA-I without ApoA-II (Schultz et al. (1993) Nature 365, 762-764).
- the cardioprotective effect of HDL-C is mostly, but not exclusively, attributable to ApoA-I.
- ApoA-I is a critical determinant of circulating HDL-C.
- persons with familial hyperalphalipoproteinemia (elevated ApoA-I) appear to be protected from atherosclerosis, while those deficient in ApoA-I (hypoalphalipoproteinemia) show accelerated cardiovascular disease.
- various experimental manipulations to increase production of ApoA-I are associated with reduced atherogenicity.
- human ApoA-I is protective in transgenic animal models (Shah et al. (1998) Circulation 97, 780-785; Rubin et al.
- polyphenols One class of compounds that are thought to contribute to the prevention of various diseases, including cancer and cardiovascular disease, is polyphenols.
- Polyphenols are present in most food and beverages of plant origin and are the most abundant dietary antioxidants (Scalbert & Williamson (2000) J. Nutr. 130, 2073S-2085S).
- the protective properties of polyphenols have not been fully realized due to poor bioavailability (Manach et al. (2005) Am. J. Clin. Nutr. 81, 230S-242S), lack of clinical significance in various reported studies assessing them (Williamson & Manach (2005) Am. J. Clin. Nutr. 81, 243S-255S), and deleterious effects at higher dose concentrations.
- resveratrol a well known stilbene polyphenol
- red wine (Wu et. al. (2001) Int. J. Mol. Med. 8, 3-17).
- red wine cannot be consumed in therapeutically efficacious quantities on a daily basis due to the numerous well documented deleterious effects of excessive alcohol consumption.
- the effects of resveratrol may be better or safer in the absence of alcohol.
- polyphenol metabolites are known to negatively influence the biological activity of the parent compounds (Manach et al. (2005) Am. J. Clin. Nutr. 81, 230S-242S). Such metabolites often differ from the parent compound in terms of toxicity, efficacy, and length of residence in the plasma. Another limiting factor is the poor solubility of many polyphenols that limits the potential routes of administration. These and other factors have made it difficult to determine appropriate dosages of the naturally occurring polyphenols, naringenin or resveratrol, for use in humans.
- polyphenol-like compounds to be developed as therapeutic agents for the treatment and prevention of cardiovascular disease and related diseases, particularly, cholesterol- or lipid-related disorders, such as, for example, atherosclerosis. It is therefore one of the objects of the present invention to provide compounds that up-regulate the expression of ApoA-I.
- the compounds may have more favorable pharmacological properties than naturally occurring polyphenols.
- the present invention includes compounds that are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use in the treatment and prevention of cardiovascular disease and related disease states, including cholesterol- and lipid-related disorders, such as, for example, atherosclerosis.
- ApoA-I apolipoprotein A-I
- cardiovascular disease and related disease states including cholesterol- and lipid-related disorders, such as, for example, atherosclerosis.
- the methods of invention include administering to a mammal (e.g., a human) in need thereof a therapeutically effective amount of a compound of Formula I:
- X is selected from CR 11 , CR 11 R 13 , CO, CS, O, S, SO, SO 2 , N and NR 11 , wherein R 11 may be the same or different than R 13 ;
- Y is selected from CR 12 , CR 12 R 14 , CO, CS, O, S, SO, SO 2 , N and NR 12 , wherein R 12 may be the same or different than R 14 ;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 17 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;
- Z 1 , Z 2 and Z 3 are each independently selected from a single bond and a double bond;
- R 10 is not hydroxyl or ester
- the invention further includes compounds of Formula II and methods of administering a therapeutically effective amount of those compounds to a mammal (e.g., a human) in need thereof:
- X is selected from CR 11 , CR 11 R 13 , N and NR 11 , wherein R 11 may be the same or different than R 13 ;
- Y is selected from CR 12 , CR 12 R 14 , CO, CHOR 12 , CS, S, SO, and SO 2 , wherein R 12 may be the same or different than R 14 ;
- R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;
- R 1 and R 3 are each independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, hydroxyl, and hydrogen;
- R 2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;
- R 6 and R 8 are each independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, hydrogen, heterocyclyl, and cycloalkyl;
- R 5 and R 9 are each independently selected from alkyl, alkenyl, alkynyl, halogen, and hydrogen;
- R 7 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, ether, hydrogen, and hydroxyl;
- R 10 is selected from hydrogen and alkyl
- R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are connected to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each of R 5 and R 9 may independently be taken together with either R 10 or R 11 to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1 or 2;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 , Z 2 and Z 3 are each independently selected from a single bond and a double bond, wherein at least one of Z 1 or Z 2 must be a double bond;
- the methods, compounds, and compositions of the invention are useful for the prevention or treatment of diseases that benefit from raised ApoA-I or HDL, and diseases characterized by reduced ApoA-I and/or HDL-C, abnormal lipid parameters, or lipid parameters indicative of high cholesterol.
- the methods, compounds, and compositions of the invention can be used to increase expression of ApoA-I.
- Increasing expression of ApoA-I may refer to, but is not limited to, transcriptionally modulating the expression of the ApoA-I gene, thereby affecting the level of the ApoA-I protein produced (synthesized and secreted).
- An increase in ApoA-I levels may lead to an increase the levels of HDL-C and/or increase in the functionality of HDL-C particles.
- the methods, compounds, and compounds of the invention may further be used to reduce cholesterol levels. Accordingly, the methods, compounds, and compositions of the invention can be used for treatment and prevention of cardiovascular disease and related disease states, particularly, cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
- FIG. 1 depicts ApoA-I induction by 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) in HepG2 Cells (48 h).
- FIG. 2 depicts ApoA-I induction by 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) in primary human hepatocytes (48 h).
- FIG. 3 depicts plasma levels of ApoA-I in hApoA-I transgenic mice receiving 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (10, 30, and 60 mg/kg body weight) twice daily for 7 days by oral gavage.
- FIG. 4 depicts plasma levels of HDL cholesterol in hApoA-I transgenic mice receiving 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (10 and 30 mg/kg body weight) twice daily for 7 days by oral gavage.
- FIG. 5 depicts plasma levels of ApoA-I in wild-type C57BL/6 mice receiving 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (10, 30 and 60 mg/kg of body weight) twice daily for 3 days by intraperitoneal administration.
- FIG. 6 depicts plasma levels of HDL cholesterol in wild-type C57BL/6 mice receiving 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (10, 30 and 60 mg/kg of body weight) twice daily for 3 days by intraperitoneal administration.
- FIG. 7 depicts plasma levels of ApoA-I and tissue levels of ApoA-I mRNA in hApoA-I transgenic mice administered 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (30 mg/kg body weight) twice daily for 7 days by oral gavage.
- aldehyde or “formyl” as used herein refers to —CHO.
- alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms, referred to herein as (C 2 -C 22 )alkenyl, (C 2 -C 8 )alkenyl, and (C 2 -C 6 )alkenyl, respectively.
- alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, etc.
- alkoxy refers to an alkyl group attached to an oxygen (—O-alkyl-).
- Alkoxy also include an alkenyl group attached to an oxygen (“alkenyloxy”) or an alkynyl group attached to an oxygen (“alkynyloxy”) groups.
- Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-22, 1-8, or 1-6 carbon atoms, referred to herein as (C 1 -C 22 )alkoxy, (C 1 -C 8 )alkoxy, and (C 1 -C 6 )alkoxy, respectively.
- Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, etc.
- alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-22, 1-8, or 1-6 carbon atoms, referred to herein as (C 1 -C 22 )alkyl, (C 1 -C 8 )alkyl, and (C 1 -C 6 )alkyl, respectively.
- Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
- alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms, referred to herein as (C 2 -C 22 )alkynyl, (C 2 -C 8 )alkynyl, and (C 2 -C 6 )alkynyl, respectively.
- alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl, etc.
- amide refers to the form —NR 9 C(O)R b , or —C(O)NR b R c , wherein R a , R b and R c are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
- the amide can be attached to another group through R b or R c .
- the amide also may be cyclic, for example R b and R c may be joined to form a 3- to 12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-membered ring.
- amide encompasses groups such as sulfonamide, urea (ureido), carbamate, carbamic acid, and cyclic versions thereof.
- amide also encompasses an amide group attached to a carboxy group, e.g., -amide-COOH or salts such as -amide-COONa, etc, an amino group attached to a carboxy group, e.g., -amino-COOH or salts such as -amino-COONa, etc.
- amine refers to the form —NR d R e or —N(R d )R e — where R d and R e are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
- the amino can be attached to the parent molecular group through the nitrogen.
- the amino also may be cyclic, for example, R d and R e may be joined together or with the N to form a 3- to 12-membered ring, e.g., morpholino or piperidinyl.
- the term amino also includes the corresponding quaternary ammonium salt of any amino group.
- Exemplary amino groups include alkyl amino groups, wherein at least one of R d and R e is an alkyl group.
- aryl refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system.
- the aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, and heterocyclyls.
- aryl groups of this invention can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
- Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
- Exemplary aryl groups also include, but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C 6 )aryl.”
- arylalkyl refers to an alkyl group having at least one aryl substituent, e.g. -aryl-alkyl-.
- exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C 6 )arylalkyl.”
- aryloxy refers to an aryl group attached to an oxygen atom.
- exemplary aryloxy groups include, but are not limited to, aryloxys having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C 6 )aryloxy.”
- arylthio refers to an aryl group attached to an sulfur atom.
- exemplary arylthio groups include, but are not limited to, arylthios having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C 6 )arylthio.”
- arylsulfonyl refers to an aryl group attached to a sulfonyl group, e.g., —S(O) 2 -aryl-.
- exemplary arylsulfonyl groups include, but are not limited to, arylsulfonyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C 6 )arylsulfonyl.”
- benzyl refers to the group —CH 2 -phenyl.
- bicyclic aryl refers to an aryl group fused to another aromatic or non-aromatic carbocylic or heterocyclic ring.
- exemplary bicyclic aryl groups include, but are not limited to, naphthyl or partly reduced forms thereof, such as di-, tetra-, or hexahydronaphthyl.
- bicyclic heteroaryl refers to a heteroaryl group fused to another aromatic or non-aromatic carbocylic or heterocyclic ring.
- exemplary bicyclic heteroaryls include, but are not limited to, 5,6 or 6,6-fused systems wherein one or both rings contain heteroatoms.
- the term “bicyclic heteroaryl” also encompasses reduced or partly reduced forms of fused aromatic system wherein one or both rings contain ring heteroatoms.
- the ring system may contain up to three heteroatoms, independently selected from oxygen, nitrogen, or sulfur.
- the bicyclic system may be optionally substituted with one or more groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
- groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocycly
- Exemplary bicyclic heteroaryls include, but are not limited to, quinazolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, phthalazinyl, benzotriazolyl, benzopyridinyl, and benzofuranyl.
- carboxylate refers to the form —R g OC(O)N(R h )—, —R g OC(O)N(R h )R i —, or —OC(O)NR h R i , wherein R g , R h and R i are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
- Exemplary carbamates include, but are not limited to, arylcarbamates or heteroaryl carbamates, e.g., wherein at least one of R g , R h and R i are independently selected from aryl or heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine.
- carbonyl refers to —C(O)—.
- carboxy refers to —COOH or its corresponding carboxylate salts, e.g. —COONa, etc.
- carboxy also includes “carboxycarbonyl,” e.g., a carboxy group attached to a carbonyl group, e.g., —C(O)—COOH or salts such as —C(O)—COONa, etc.
- cyano refers to —CN.
- cycloalkoxy refers to a cycloalkyl group attached to an oxygen.
- cycloalkyl refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12 carbons, or 3-8 carbons, referred to herein as “(C 3 -C 8 )cycloalkyl,” derived from a cycloalkane.
- exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
- Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other cycloalkyl saturated or unsaturated, aryl, or heterocyclyl groups.
- dicarboxylic acid refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof.
- Exemplary dicarboxylic acids include alkyl dicarboxylic acids.
- Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
- Dicarboxylic acids include, but are not limited to succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/( ⁇ )-malic acid, (+)/( ⁇ ) tartaric acid, isophthalic acid, and terephthalic acid.
- Dicarboxylic acids further include carboxylic acid derivatives thereof, such as anhydrides, imides, hydrazides, etc., for example, succinic anhydride, succinimide, etc.
- esters refers to the structure —C(O)O—, —C(O)O—R j —, —R k C(O)O—R j —, or —R k C(O)O—, where O is not bound to hydrogen, and R j and R k can independently be selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, heterocyclyl.
- R k can be a hydrogen, but R j cannot be hydrogen.
- the ester may be cyclic, for example the carbon atom and R j , the oxygen atom and R k , or R j and R k may be joined to form a 3- to 12-membered ring.
- Exemplary esters include, but are not limited to, alkyl esters wherein at least one of R j or R k is alkyl, such as —O—C(O)-alkyl-, —C(O)—O-alkyl-, -alkyl-C(O)—O-alkyl-, etc.
- Exemplary esters also include aryl or heteoraryl esters, e.g.
- R j or R k is a heteroaryl group such as pyridine, pyridazine, pyrmidine and pyrazine, such as a nicotinate ester.
- exemplary esters also include reverse esters having the structure —R k C(O)O—, where the oxygen is bound to the parent molecular group.
- exemplary reverse esters include succinate, D-argininate, L-argininate, L-lysinate and D-lysinate. Esters also include carboxylic acid anhydrides and acid halides.
- ether refers to the structure —R l O—R m —, where R l and R m can independently be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, or ether.
- the ether can be attached to the parent molecular group through R l or R m .
- Exemplary ethers include, but are not limited to, alkoxyalkyl and alkoxyaryl groups.
- Ethers also includes polyethers, e.g., where one or both of R l and R m are ethers.
- halo or halogen as used herein refer to F, Cl, Br, or I.
- haloalkyl refers to an alkyl group substituted with one or more halogen atoms. “Haloalkyls” also encompass alkenyl or alkynyl groups substituted with one or more halogen atoms.
- heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
- Heteroaryls can also be fused to non-aromatic rings.
- Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl; imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl; isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
- heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as “(C 2 -C 5 )heteroaryl.”
- heterocycle refers to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.
- Heterocycles can be aromatic (heteroaryls) or non-aromatic.
- Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
- substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocycly
- Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
- Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, o
- hydroxy and “hydroxyl” as used herein refers to —OH.
- hydroxyalkyl refers to a hydroxy attached to an alkyl group.
- hydroxyaryl refers to a hydroxy attached to an aryl group.
- ketone refers to the structure —C(O)—R n —(such as acetyl, —C(O)CH 3 ) or —R n —C(O)—R o —.
- the ketone can be attached to another group through R n or R o .
- R n or R o can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R n or R o can be joined to form a 3- to 12-membered ring.
- monoester refers to an analogue of a dicarboxylic acid wherein one of the carboxylic acids is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or salt of a carboxylic acid.
- monoesters include, but are not limited to, to monoesters of succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, oxalic acid and maleic acid.
- nitro refers to the structure —NO 2 .
- perfluoroalkoxy refers to an alkoxy group in which all of the hydrogen atoms have been replaced by fluorine atoms.
- perfluoroalkyl refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluorine atoms.
- exemplary perfluroalkyl groups include, but are not limited to, (C 1-5 ) perfluoroalkyl, such as trifluoromethyl, etc.
- perfluorocycloalkyl refers to a cycloalkyl group in which all of the hydrogen atoms have been-replaced by fluorine atoms.
- phenyl refers to a 6-membered carbocyclic aromatic ring.
- the phenyl group can also be fused to a cyclohexane or cyclopentane ring.
- Phenyl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
- phosphate refers to the structure —OP(O)O 2 —, —R x OP(O)O 2 —, —OP(O)O 2 R y —, or —R x OP(O)O 2 R y —, wherein R x and R y can be selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and hydrogen.
- sulfide refers to the structure —R z S—, where R z can be selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, and heterocyclyl.
- the sulfide may be cyclic, forming a 3-12 membered ring.
- alkylsulfide refers to an alkyl group attached to a sulfur atom.
- sulfinyl refers to the structure —S(O)O—, —R p S(O)O—, —R p S(O)OR q —, or —S(O)OR q —, wherein R p and R q can be selected from alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydroxyl.
- exemplary sulfinyl groups include, but are not limited to, alkylsulfinyls wherein at least one of R p or R q is alkyl, alkenyl or alkynyl.
- sulfonamide refers to the structure —(R r )—N—S(O) 2 —R s — or —R t (R r )—N—S(O) 2 —R s , where R t , R r , and R s can be, for example, hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocyclyl.
- Exemplary sulfonamides include alkylsulfonamides (e.g., where R s is alkyl), arylsulfonamides (e.g., where R s is aryl), cycloalkyl sulfonamides (e.g., where R s is cycloalkyl), and heterocyclyl sulfonamides (e.g., where R s is heterocyclyl), etc.
- Sulfonate refers to —OSO 3 ⁇ .
- Sulfonate includes salts such as —OSO 3 Na, —OSO 3 K, etc. and the acid —OSO 3 H
- sulfonic acid refers to —SO 3 H— and its corresponding salts, e.g. —SO 3 K—, —SO 3 Na—.
- sulfonyl refers to the structure R u SO 2 —, where R u can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocyclyl, e.g., alkylsulfonyl.
- alkylsulfonyl refers to an alkyl group attached to a sulfonyl group. “Alkylsulfonyl” groups can optionally contain alkenyl or alkynyl groups.
- thioketone refers to the structure —R v —C(S)—R w —.
- the ketone can be attached to another group through R v or R w .
- R v or R w can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R v and R w can be joined to form a 3- to 12-membered ring.
- Alkyl alkenyl, alkynyl, “alkoxy,” “amino,” and “amide” groups can be substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and nitrogen.
- the substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.
- a “suitable substituent” refers to a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them.
- suitable substituents include, but are not limited to: C 1-22 , C 1-8 , and C 1-6 alkyl, alkenyl or alkynyl; C 1-6 aryl, C 2 -5 heteroaryl; C 3 -7 cycloalkyl; C 1-22 , C 1-8 , and C 1-6 alkoxy; C 6 aryloxy; —CN; —OH; oxo; halo, carboxy; amino, such as —NH(C 1-22 , C 1-8 , or C 1-6 alkyl), —N(C 1-22 , C 1-8 , and C 1-6 alkyl) 2 , —NH((C 6 )aryl), or —N((C 6 )aryl) 2 ; formyl; ketones, such as —CO(C 1-22
- compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
- composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
- prodrugs as used herein represents those prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
- a discussion is provided in Higuchi et al., “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series , Vol. 14, and in Roche, E. B., ed. Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
- pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
- Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
- the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form nontoxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.
- Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
- Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
- Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
- the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
- stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom.
- Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
- Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
- Stereoisomeric mixtures can also be resolved into their component stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
- Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
- Geometric isomers can also exist in the compounds of the present invention.
- the present invention encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
- Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards.
- structures depicting double bonds encompass both the E and Z isomers.
- Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
- the arrangement of substituents around a carbocyclic ring are designated as “cis” or “trans.”
- the term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring.
- Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
- One embodiment provides a method for increasing expression of ApoA-I in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of Formula I:
- X is selected from CR 11 , CR 11 R 13 , CO, CS, O, S, SO, SO 2 , N, and NR 11 , wherein R 11 may be the same or different than R 13 ;
- Y is selected from CR 12 , CR 12 R 14 , CO, CS, O, S, SO, SO 2 , N, and NR 12 , wherein R 12 may be the same or different than R 14 ;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 17 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;
- Z 1 , Z 2 and Z 3 are each independently selected from a single bond and a double bond;
- R 10 is not hydroxyl or ester
- Another embodiment provides a method for increasing expression of ApoA-II in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of Formula II:
- X is selected from CR 11 , CR 11 R 13 , N and NR 11 , wherein R 11 may be the same or different than R 13 ;
- Y is selected from CR 12 , CR 12 R 14 , CO, CHOR 12 , CS, S, SO, and SO 2 , wherein R 12 may be the same or different than R 14 ;
- R 11 , R 12 , R 13 , and R 14 are each independently selected from hydrogen, unsubstituted alkyl (preferably C 1-3 alkyl), unsubstituted alkenyl (preferably C 1-3 alkenyl), and unsubstituted alkynyl (preferably C 1-3 alkynyl);
- R 1 and R 3 are each independently selected from alkoxy (preferably methoxy), alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably chloride), hydroxyl, and hydrogen;
- R 2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably bromide or chloride), and hydrogen;
- R 6 and R 8 are each independently selected from alkoxy, alkyl (preferably methyl), alkenyl, alkynyl, amide, amino, halogen (preferably chloride or fluoride), hydrogen, heterocyclyl, and cycloalkyl;
- R 5 and R 9 are each independently selected from alkyl, alkenyl, alkynyl, halogen (preferably chloride), and hydrogen;
- R 7 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, ether, ester, hydrogen, and hydroxyl;
- R 10 is selected from hydrogen and alkyl (preferably methyl); or
- R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are connected to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each of R 5 and R 9 may independently be taken together with either R 10 or R 11 to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 , Z 2 and Z 3 are each independently selected from a single bond and a double bond, wherein at least one of Z 1 or Z 2 is a double bond;
- Another embodiment provides a method for increasing expression of ApoA-I in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of Formula II:
- X is selected from CH and N;
- Y is selected from CO, CS, and SO 2 ;
- R 1 and R 3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;
- R 2 is selected from alkoxy, alkyl, amino, and hydrogen
- R 6 and R 8 are each independently selected from alkoxy, amino, alkyl, hydrogen, and heterocyclyl;
- R 5 and R 9 are each hydrogen
- R 7 is selected from alkoxy, alkyl, alkynyl, amide, amino, ether, hydrogen, and hydroxyl;
- R 10 is hydrogen
- R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are connected to form group selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;
- R 5 or R 9 may be taken together with R 10 to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 , Z 2 , and Z 3 are each independently selected from a single bond and a double bond, wherein at least one of Z 1 or Z 2 is a double bond;
- X is selected from CR 11 , CR 11 R 13 , N, and NR 11 , wherein R 11 may be the same or different than R 13 ;
- Y is selected from CR 12 , CR 12 R 14 , CO, CHOR 12 , CS, S, SO, and SO 2 , wherein R 12 may be the same or different than R 14 ;
- R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, unsubstituted alkyl (preferably C 1-3 alkyl), unsubstituted alkenyl (preferably C 1-3 alkenyl), and unsubstituted alkynyl (preferably C 1-3 alkynyl);
- R 1 and R 3 are each independently selected from alkoxy (preferably methoxy), alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably chloride), hydroxyl, and hydrogen;
- R 2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably chloride and fluoride), and hydrogen;
- R 6 and R 8 are each independently selected from alkoxy, alkyl (preferably methyl), alkenyl, alkynyl, amide, amino, halogen (preferably chloride), hydrogen, heterocyclyl, and cycloalkyl;
- R 5 and R 9 are each independently selected from alkyl, alkenyl, alkynyl, halogen, and hydrogen;
- R 7 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, ether, ester, hydrogen, and hydroxyl;
- R 10 is selected from hydrogen and alkyl (preferably methyl); or
- R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are connected to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each of R 5 and R 9 may independently be taken together with R 10 or R 11 to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 , Z 2 , and Z 3 are each independently selected from a single bond and a double bond, wherein at least one of Z 1 or Z 2 is a double bond;
- R 7 is not diethylamino or an alkoxy substituted with a carboxylate group.
- At least one of R 11 , R 12 , R 13 , and R 14 is an unsubstituted (C 1-3 ) alkyl.
- Z 2 and Z 3 are each a single bond
- X is selected from N and CR 11 ;
- Y is selected from CO, SO 2 , SO, and CS.
- X is NR 11 ;
- W is N and p is 0;
- Y is selected from CO, SO 2 , SO, and CS.
- X is selected from N and CR 11 ;
- W is N, and p is 0;
- Y is selected from CR 12 , COR 12 , and SO.
- R 6 and R 8 are each independently selected from alkyl and hydrogen
- R 7 is selected from amino, hydroxyl, and alkoxy.
- W is N and R 10 is hydrogen; and Y is CO.
- W is N and R 10 is hydrogen; and Y is CO.
- R 6 and R 8 are each independently selected from alkyl and hydrogen
- R 7 is selected from amino, hydroxyl, and alkoxy.
- W is N and R 10 is hydrogen; and Y is CO.
- W is N and R 10 is hydrogen; and Y is CO.
- R 6 and R 8 are each independently selected from alkyl and hydrogen
- R 7 is selected from amino, hydroxyl, and alkoxy.
- W is N and R 10 is hydrogen; and Y is CO.
- W is N and R 10 is hydrogen; and Y is CO.
- Z 2 and Z 3 are each a single bond
- X is NR 11 ;
- X is selected from CH and N;
- W is N and p is 0;
- Y is CH.
- X is selected from CR 11 , N, and NR 11 ,
- Y is selected from CO, CS, and SO 2 ,
- R 11 is selected from hydrogen, unsubstituted alkyl (preferably C 1-3 alkyl), unsubstituted alkenyl (preferably C 1-3 alkenyl), and unsubstituted alkynyl (preferably C 1-3 alkynyl);
- R 1 and R 3 are each independently selected from alkoxy (preferably methoxy), alkyl, amino, halogen (preferably chloride), and hydrogen;
- R 2 is selected from alkoxy, alkyl, alkenyl, amide, amino, halogen (preferably bromide or chloride), and hydrogen;
- R 6 and R 8 are each independently selected from alkoxy, alkyl (preferably methyl), amino, halogen (preferably chloride and fluoride), and hydrogen;
- R 5 and R 9 are each independently selected from halogen (preferably chloride) and hydrogen;
- R 7 is selected from alkoxy, alkyl, alkenyl, amide, amino, ether, hydrogen, and hydroxyl;
- R 10 is selected from hydrogen and alkyl (preferably methyl); or
- R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 10 , and R 11 are connected to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 , Z 2 , and Z 3 are each independently selected from a single bond and a double bond, wherein at least one of Z 1 or Z 2 is a double bond;
- X is selected from N and CH;
- Y is CO
- R 1 and R 3 are each independently selected from alkoxy and hydrogen
- R 2 is selected from alkoxy, alkyl, and hydrogen
- R 6 and R 8 are each independently selected from alkyl, alkoxy, chloride, and hydrogen;
- R 5 and R 9 are each hydrogen
- R 7 is selected from amino, hydroxyl, alkoxy (preferably a substituted ethoxy group), and alkyl substituted with a heterocyclyl;
- R 10 is hydrogen
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 is a double bond, and Z 2 and Z 3 are each a single bond;
- R 7 is selected from hydroxyl and alkoxy, then at least one of R 6 and R 8 are independently selected from alkyl, alkoxy, and chloride;
- R 6 and R 8 are selected from alkyl, alkoxy, and chloride;
- X is selected from N and CR 11 ;
- Y is selected from CO and SO 2 ;
- R 11 is selected from hydrogen, unsubstituted alkyl (preferably C 1-3 alkyl), unsubstituted alkenyl (preferably C 1-3 alkenyl), and unsubstituted alkynyl (preferably C 1-3 alkynyl);
- R 1 and R 3 are each independently selected from alkoxy (preferably methoxy), alkyl, amino, halogen (preferably chloride), and hydrogen;
- R 2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably bromide or chloride), and hydrogen;
- R 6 and R 8 are each independently selected from alkyl (preferably methyl), alkoxy, amino, halogen (preferably chloride or fluoride), and hydrogen;
- R 5 and R 9 are each hydrogen
- R 7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy
- R 10 is selected from hydrogen and methyl
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- W is C and p is 1;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 is a double bond, and Z 2 and Z 3 are each a single bond;
- R 1 is selected from amino and alkoxy
- R 7 is selected from alkyl, hydroxyl, and alkoxy, then at least one of R 6 and R 8 is independently selected from alkyl, alkoxy, amino, and halogen;
- R 2 is hydrogen
- R 7 is selected from hydroxyl and alkoxy (preferably substituted with a hydroxyl.)
- R 20 is not an unsaturated cycloalkyl.
- a pharmaceutical composition comprising a compound according to embodiment 35 and a pharmaceutically acceptable carrier.
- a method of treating cardiovascular disease, or cholesterol- or lipid-related disorders comprising administering a therapeutically effective amount of a compound according to embodiment 35.
- a method of increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound according to embodiment 35.
- X is selected from N and CH;
- Y is CO
- R 1 and R 3 are each independently selected from alkoxy and hydrogen
- R 2 is selected from alkoxy, alkyl, and hydrogen
- R 6 and R 8 are each independently selected from alkyl, alkoxy, halogen (preferably chloride), and hydrogen;
- R 5 and R 9 are each hydrogen
- R 7 is selected from amino, hydroxyl, alkoxy (preferably a substituted ethoxy group), and alkyl substituted with a heterocyclyl;
- R 10 is hydrogen
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 is a double bond, and Z 2 and Z 3 are each a single bond;
- R 2 is alkoxy or hydrogen, then least one of R 1 and R 3 is alkoxy;
- R 7 is selected from hydroxyl and alkoxy, then at least one of R 6 and R 8 are independently selected from alkyl, alkoxy, and chloride;
- R 6 and R 8 are selected from alkyl, alkoxy, and chloride;
- R 20 is not an unsaturated cycloalkyl.
- a pharmaceutical composition comprising a compound according to embodiment 49 and a pharmaceutically acceptable carrier.
- a method of treating cardiovascular disease, or cholesterol- or lipid-related disorders comprising administering a therapeutically effective amount of a compound according to embodiment 49.
- a method of increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound according to embodiment 49.
- X is selected from N and CR 11 ;
- Y is selected from CO and SO 2 ;
- R 11 is selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;
- R 1 and R 3 are each independently selected from alkoxy (preferably methoxy), alkyl, amino, halogen (preferably chloride) and hydrogen;
- R 2 is selected from —N—C(O)—R 18 , —N—SO 2 —R 18 , —CH 2 —C(R 18 ) 3 , —CH 2 —N(R 18 ) 2 , and —CH 2 —O—R 18 , wherein each R 18 is independently selected from alkoxy, alkyl, alkenyl, amide, amino, aryl, arylalkyl, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, and hydrogen;
- R 6 and R 8 are each independently selected from alkyl (preferably methyl), alkoxy, amino, halogen (preferably chloride or fluoride), and hydrogen;
- R 5 and R 9 are each hydrogen
- R 7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy
- R 10 is selected from hydrogen and methyl
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- W is C and p is 1;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 is a double bond, and Z 2 and Z 3 are each a single bond;
- R 7 is selected from alkyl, hydroxyl, and alkoxy, then at least one of R 6 and R 8 is independently selected from alkyl, alkoxy, amino, and halogen;
- W is N, and p is 1; and R 10 is hydrogen.
- R 20 is not an unsaturated cycloalkyl.
- a pharmaceutical composition comprising a compound according to embodiment 56 and a pharmaceutically acceptable carrier.
- a method of treating cardiovascular disease, or cholesterol- or lipid-related disorders comprising administering a therapeutically effective amount of a compound according to embodiment 56.
- a method of increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound according to embodiment 56.
- X is selected from N and CR 11 ;
- Y is selected from CO and SO 2 ;
- R 11 is selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;
- R 1 is selected from alkoxy (preferably methoxy) or amino
- R 3 is alkoxy (preferably methoxy);
- R 2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably bromide or chloride), and hydrogen;
- R 6 and R 8 are each independently selected from alkyl, alkoxy, amino, halogen (preferably chloride or fluoride), and hydrogen;
- R 5 and R 9 are each hydrogen
- R 7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy
- R 10 is selected from hydrogen and methyl
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- W is C and p is 1;
- W is C, p is 1 and R 4 is H, or W is N and p is 0;
- Z 1 is a double bond, and Z 2 and Z 3 are each a single bond;
- R 10 is hydrogen
- R 7 is selected from hydroxyl and alkoxy.
- R 10 is hydrogen
- R 7 is selected from amide and amino.
- R 10 is hydrogen
- R 7 is alkyl
- R 20 is not an unsaturated cycloalkyl.
- a pharmaceutical composition comprising a compound according to embodiment 67 and a pharmaceutically acceptable carrier.
- a method of treating cardiovascular disease, or cholesterol- or lipid-related disorders comprising administering a therapeutically effective amount of a compound according to embodiment 67.
- a method of increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound according to embodiment 67.
- compositions comprising compounds as disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.
- These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
- Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the compound as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
- such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and the carrier or excipient (which may constitute one or more accessory ingredients).
- the carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
- the carrier may be a solid or a liquid, or both, and may be formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the active compound.
- Other pharmacologically active substances may also be present including other compounds.
- the formulations of the invention may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components.
- conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
- Liquid pharmacologically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
- suitable formulations may be prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
- a tablet may be prepared by compressing or molding a powder or granules of the compound, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
- Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a compound in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
- Formulations of the present invention suitable for parenteral administration comprise sterile aqueous preparations of the compounds, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention may contain from about 0.1 to about 5% w/w of the active compound.
- Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing the compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
- one or more conventional solid carriers for example, cocoa butter
- Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
- Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
- the active compound is generally present at a concentration of from about 0.1% to about 15% w/w of the composition, for example, from about 0.5% to about 2%.
- the amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician.
- a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 ⁇ g to about 1000 mg.
- intermittent administration such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed.
- Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect.
- physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.
- a therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound.
- the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used.
- the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration.
- Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.
- Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
- the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
- Compositions that exhibit large therapeutic indices are preferable.
- Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and Table 1 for Equivalent Surface Area Dosage Factors).
- the therapeutically effective dosage (i.e. ED 50 ) may vary with the dosage form, route of administration, the subject's age, condition, and sex, as well as the severity of the medical condition in the subject.
- the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
- a compound as disclosed herein, or a pharmaceutically acceptable salt or hydrate thereof is administered in combination with another therapeutic agent.
- the other therapeutic agent can provide additive or synergistic value relative to the administration of a compound of the present invention alone.
- the therapeutic agent can be, for example, a statin; a PPAR agonist, e.g., a thiazolidinedione or fibrate; a niacin, a RVX, FXR or LXR agonist; a bile-acid reuptake inhibitor; a cholesterol absorption inhibitor; a cholesterol synthesis inhibitor; an ion-exchange resin; an antioxidant; an inhibitor of AcylCoA cholesterol acyltransferase (ACAT inhibitor); a tyrophostine; a sulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; an apolipoprotein E regulator; a HMG-CoA reductase inhibitor,
- a method of treating or preventing cardiovascular disease, cholesterol- or lipid-related disorders comprises administering to a mammal (e.g., human) a therapeutically effective amount of a disclosed compound.
- the disclosed compound may be administered as a pharmaceutically acceptable composition, comprising a disclosed compound and a pharmaceutically acceptable carrier.
- cardiovascular disease refers to diseases and disorders of the heart and circulatory system.
- cardiovascular diseases including cholesterol- or lipid-related disorders, include, but are not limited to acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholeasterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal pulmonary embolism, pulmonary embolism,
- One embodiment provides methods for altering lipid metabolism in a patient, e.g., increasing the ratio of HDL to LDL or ApoA-I to ApoB in the blood of a patient, comprising administering to the patient a composition of the invention in an amount effective to alter lipid metabolism.
- One embodiment provides methods for elevating the levels of ApoA-I associated molecules, such as HDL, in the blood of a mammal, comprising administering to the mammal a composition comprising a disclosed compound or composition in an amount effective to elevate levels of ApoA-I and HDL associated proteins in the mammal.
- a composition comprising a disclosed compound or composition in an amount effective to elevate levels of ApoA-I and HDL associated proteins in the mammal.
- treatment refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof. In another embodiment, “treatment” or “treating” refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient. In another embodiment, “treatment” or “treating” refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both. In yet another embodiment, “treatment” or “treating” refers to delaying the onset of a disease or disorder. For example, treating a cholesterol disorder may comprise decreasing blood cholesterol levels.
- One embodiment provides a compound for administration to a patient, such as a human, as a preventative measure against cardiovascular diseases, including-cholesterol- or lipid-related disorders.
- prevention or “preventing” refers to a reduction of the risk of acquiring a given disease or disorder.
- An additional aspect of the invention provides a method for prevention of arteriosclerosis lesion development in a mammal, including the development of new arteriosclerotic lesions.
- the present invention provides a method for regressing arteriosclerosis lesions.
- the present compositions are administered as a preventative measure to a patient, such as a human having a genetic predisposition to a cardiovascular disease, including cholesterol- or lipid-related disorders, for example familial hypercholeasterolemia, familial combined hyperlipidemia, atherosclerosis, a dyslipidemia, a dyslipoproteinemia, or Alzheimer's disease.
- a cardiovascular disease including cholesterol- or lipid-related disorders, for example familial hypercholeasterolemia, familial combined hyperlipidemia, atherosclerosis, a dyslipidemia, a dyslipoproteinemia, or Alzheimer's disease.
- compositions of the invention are administered as a preventative measure to a patient having a non-genetic predisposition to a cardiovascular disease, including cholesterol- or lipid-related disorders.
- non-genetic predispositions include, but are not limited to, cardiac bypass surgery and percutaneous transluminal coronary angioplasty, which often leads to restenosis, an accelerated form of atherosclerosis; diabetes in women, which often leads to polycystic ovarian disease; and cardiovascular disease, which often leads to impotence.
- Angioplasty and open heart surgery may be required to treat cardiovascular diseases, such as atherosclerosis.
- cardiovascular diseases such as atherosclerosis.
- These surgical procedures entail using invasive surgical devices and/or implants, and are associated with a high risk of restenosis and thrombosis.
- the compounds of the invention may be used as coatings on surgical devices (e.g., catheters) and implants (e.g., stents) to reduce the risk of restenosis and thrombosis associated with invasive procedures used in the treatment of cardiovascular diseases.
- the present compositions may be used for the prevention of one disease or disorder and concurrently treating another (e.g., prevention of polycystic ovarian disease while treating diabetes; prevention of impotence while treating a cardiovascular disease).
- another e.g., prevention of polycystic ovarian disease while treating diabetes; prevention of impotence while treating a cardiovascular disease.
- Diseases and conditions associated with “diabetes mellitus” as defined herein refer to chronic metabolic disorder(s) caused by absolute or relative insulin deficiency including, but not limited to hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucose metabolism, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, ulcerative colitis, skin and connective tissue disorders, foot ulcerations, metabolic acidosis, arthritis, osteoporosis and impaired glucose tolerance.
- R a may be selected from groups including, but not limited to, alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ether, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen and hydroxyl
- R b may be selected from groups including, but not limited to, alkyl and hydrogen
- X may be selected from, e.g., CR c , N and NR c , where R c represents substituents such as alkyl, alkenyl, alkynyl, and hydrogen
- Y may be selected from, e.g., CR c , CO, CS, and SO 2 where R c is as defined above
- Z 3 may be a single or double bond; may be synthesized from readily available starting materials as outlined in the exemplary schemes below. It should be appreciated that these designations are non-limiting examples.
- Scheme 2 illustrates that condensation followed by oxidation of amide 4 and aldehyde 5 can provide quinazolinone 6.
- Condensation can occur under a variety of conditions, such as NaHSO 3 and p-TsOH in dimethylacetamide, I 2 in the presence of K 2 CO 3 , and treatment with catalytic trifluoroacetic acid followed by DDQ oxidation.
- Conversion of quinazolinone 6 into quinazoline 7 can be achieved by treatment with POCl 3 , followed by dehydration in the presence of a palladium catalyst.
- Scheme 4 provides a method for synthesizing benzothiazine-1,1-dioxide 13.
- Amide coupling of sulfonamide 11 with carboxylic acid 12 can be followed by treatment with n-BuLi to afford 13.
- acetic acid AcOH
- 2,2′-azobisisobutyronitrile AIBN
- N-bromosuccinimide N-bromosuccinimide
- Boc N-tert-butoxycarbonyl
- TDMS t-butyldimethylsilyl
- mCPBA m-chloroperoxybenzoic acid
- DMAP dimethylaminopyridine
- DCM dichloromethane
- DMF dimethylformamide
- DSO dimethylsulfoxide
- EtOH ethyl acetate
- EtOAc 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
- EHCl 1-hydroxybenzotriazole
- HOBt iodomethane
- MeI lithium hexamethyldisilazide
- MeOH methoxymethyl
- MOM methoxymethyl
- n-methyl-o-toluamide 2.0 g, 13.4 mmol
- THF THF
- n-butyl lithium 12.3 mL, 30.8 mmol, 2.5 M solution in hexane
- the mixture was stirred for 1 h at 0° C., then cooled to ⁇ 50° C. and a solution of 4-methoxy benzonitrile (2.14 g, 16.08 mmol) in THF (5 mL) was added quickly.
- the cooling bath was removed and the solution was allowed to warm to room temperature.
- n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C.
- the mixture was stirred for 1 h at 0° C., then cooled to ⁇ 50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was added quickly.
- the cooling bath was removed and the mixture was stirred at room temperature for 16 h. Saturated aqueous NH 4 Cl solution was added with cooling, and the layers were separated.
- n-butyl lithium (9.98 mL, 25.0 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling, maintaining the temperature below 20° C.
- the mixture was stirred for 1 h at 0° C., then cooled to ⁇ 50° C., and a solution of 4-O-TBDMS-3,5-dimethyl benzonitrile (2.97 g, 11.39 mmol) in THF (10 mL) was added quickly, the cooling bath was removed and the mixture was stirred for 16 h at room temperature. A saturated aqueous NH 4 Cl solution was added with cooling, and the layers were separated.
- Oxalyl chloride (1.90 mL, 21.8 mmol) was added to 2-methyl nicotinic acid (1.50 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) with triethylamine (1.6 mL, 11.5 mmol) and the reaction mixture was kept at room temperature overnight before the solvent was removed. THF was added to the residue and ammonia gas was bubbled through for 2 h. The THF was removed and the residue was dissolved into methanol and water and the pH was adjusted to 10.0 with potassium carbonate. The mixture was concentrated. After column chromatography the desired amide was isolated (1.10 g, 73.8%).
- n-Butyl lithium (2.84 mL, 7.1 mmol, 2.5 M solution in hexane) was added slowly to a solution of 2,4-dimethoxy-6-methyl benzamide (650 mg, 3.1 mmol) in THF (30 mL), under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. After completion of addition, the mixture was stirred for 1 h at 0° C., and then cooled to ⁇ 50° C. and a solution of 4-(2-tert-butyldimethyl silanyloxy)ethoxy)-3,5-dimethyl benzonitrile (the B-ring building block, above) (996 mg, 3.26 mmol) in THF (10 mL) was added quickly.
- n-Butyl lithium (4.2 mL, 10.54 mmol, 2.5 M solution in hexane) was added slowly to a solution of 2,4-dimethoxy-6-methyl benzamide (958 mg, 4.58 mmol) in THF (30 mL) under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. After completion of the addition, the mixture was stirred for 1 h at 0° C., then cooled to ⁇ 50° C. and a solution of 4-(2-dimethylamino ethoxy)-3,5-dimethyl benzonitrile (1.1 g, 5.04 mmol) (the B-ring building block) in THF (10 mL) was added quickly.
- the B-ring building block (6.93 g, 17.1 mmol) was dissolved in a mixture of methanol (50 mL) and tetrahydrofuran (50 mL). Potassium hydroxide (1.25 g, 22.2 mmol) in water (20 mL) was added. The reaction mixture was refluxed at 70° C. for 24 h. The solvent was evaporated in vacuo. Water was added and the reaction mixture was acidified with 1 N HCl (pH 4-5). The solid was filtered off, washed with water and hexane. The yield was 4.61 g (94%).
- reaction mixture was stirred at room temperature for 24 h before being washed with 1 N HCl, 2.5% NaOH and saturated sodium bicarbonate solutions.
- the organic layers were dried and evaporated in vacuo to leave a residue, which was purified by silica gel (100 g) column chromatography, employing 20-50% ethyl acetate in hexane and 5% methanol in dichloromethane as eluents. Fractions 30-66 were combined to obtain pure materials (1.35 g, 60%).
- the compound from the step above (0.105 g, 0.21 mmol) was dissolved in tetrahydrofuran under nitrogen and cooled to ⁇ 78° C.
- Methyl acetoacetate (69.67 g, 0.6 mol) in dry THF (350 mL) was cooled to ⁇ 5° C. and sodium hydride (60% in mineral oil, 24.5 g) was added at ⁇ 5 to 0° C. in 30 min.
- Diketene (50.4 g) in dry THF (80 mL) was then added drop-wise at 5° C. over 20 min. The resulting solution was allowed to stir for 1 h at ⁇ 5° C., after which it was allowed to warm to room temperature and stirred overnight.
- Acetic acid (35 mL) was added and the THF solvent was removed.
- n-BuLi (1.60 M, 3.3 mL) was added drop-wise to compound H (0.25 g, 0.81 mmol) in anhydrous THF (25 mL) at ⁇ 10° C.
- the reaction mixture was kept at 0° C. for 1 h then the cool bath was removed and the reaction mixture was further stirred for 45 min.
- Compound I (0.192 g, 0.81 mmol) in anhydrous THF (5 mL) was added drop-wise at ⁇ 10° C. and the reaction was further kept for 30 min; the reaction temperature was increased to room temperature and the reaction mixture was stirred for a further 1 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate.
- the yield was 0.36 g (35%).
- the compound 3-[4-(2-chloro-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-isochromen-1-one (0.36 g, 0.927 mmol) was dissolved in DMSO (5 mL), morpholine (0.4 mL, 4.63 mmol) and Et 3 N (0.64 mL, 4.63 mmol) were added.
- the reaction mixture was heated at 110° C. for 16 h before being cooled to room temperature. Water was added and the compound was extracted with ethyl acetate. The solvent was evaporated in vacuo to leave a residue, which was purified by chromatography.
- the yield was 0.128 g (31%).
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one can be synthesized by the following method.
- 3,5-dimethyl-4-hydroxy benzaldehyde 26.9 g, 0.179 mol
- 2-chloroethanol 87.6 g, 1.074 mol
- K 2 CO 3 99 g, 0.716 mol
- the crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na 2 SO 4 . Upon removal of solvent it gave 45 g of crude product.
- the crude product was purified by column chromatography (silica gel 230-400 mesh; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) of product.
- 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid was synthesized from 2-amino-4,6-dimethoxy-benzamide and (4-formyl phenoxy)acetic acid, using the method described for 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one.
- 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (135 mg, 21%) was isolated as an off-white solid. Selected data: MS (m/z): 357.04; MP 287-290° C.
- 5,7-Dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3-pyridine carboxaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 5,7-Dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (105 mg, 48%) was isolated as a white solid.
- 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3,5-di-tert-butyl-4-hydroxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one 130 mg, 41%) was isolated as a light yellow solid.
- 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3,5-dimethoxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one 120 mg, 46%) was isolated as a yellow solid.
- 5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-methoxy benzaldehyde, using the method described for 5,7-dimethoxy-2-(.pyridin-2-yl)quinazolin-4(3H)-one.
- 5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one (106 mg, 44%) was isolated as an off-white solid. Selected data: MS (m/z): 312.99; MP 276-277° C.
- 2-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-hydroxy-3-methoxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (90 mg, 36%) was isolated as a white solid.
- 2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3-chloro-4-hydroxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one 75 mg, 30% was isolated as a yellow solid.
- 5,7-Dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-pyridine carboxaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 5,7-Dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one (142 mg, 63%) was isolated as a pale brown solid and then converted to the corresponding hydrochloride (yellow solid).
- 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-(pyrimidin-2-yloxy)-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one 222 mg, 72%) was isolated as a light beige solid. Selected data: MS (m/z): 280.98; MP 267-268° C. (decomposed).
- 2-(4-(Dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-dimethylamino-1-naphthaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(4-(Dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one 75 mg, 26%) was isolated as a yellow solid.
- 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid was synthesized from anthranilamide and 4-formyl phenoxy acetic acid, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid 800 mg, 73%) was isolated as a white solid. Selected data: MS (m/z): 296.98; MP 285-287° C.
- 2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-dimethylamino-naphthalene-1-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one (240 mg, 69%) was isolated as a pale yellow solid.
- 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide was synthesized from anthranilamide and 2-(4-formyl-phenoxy)-acetamide, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (183 mg, 56%) was isolated as a light beige solid. Selected data: MS (m/z): 295.97; MP 277.5-278.5° C.
- 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one 120 mg, 46%) was isolated as a yellow solid.
- 2-(4-(Dimethylamino)naphthalen-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxy-benzamide and 4-Dimethylamino-naphthalene-1-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(4-(dimethylamino)naphthalen-1-yl)-6,7-dimethoxy-quinazolin-4(3H)-one (159 mg, 56%) was isolated as a white solid.
- 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxy-benzamide and 4-(N,N-bis(2-hydroxyethyl)amino)benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one 72 mg, 24%) was isolated as a yellow solid.
- 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxybenzamide and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.
- the reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight, diluted with ethyl acetate and filtered off. The solid was washed with ethyl acetate to obtain a light-yellow solid (107.7 g).
- the solid from above (107.7 g, 0.4 mol) was dissolved in POCl 3 (300 mL, 2.5 mol) and the reaction mixture was refluxed for 2 h. POCl 3 was removed and the residue was poured into water, and extracted with DCM. The solvent was removed to obtain a crude compound (73.02 g) which was used for the next step without further purification.
- the compound (73.02 g, 0.31 mol) was dissolved in methanol and sodium methoxide solution in methanol (25%) was added and the mixture was refluxed overnight ( ⁇ 14 h). The reaction mixture was quenched with acetic acid. DCM was added and the solvent was evaporated to leave a crude product (64.43 g), which was used for the next step without further purification.
- the compound (64.0 g) was dissolved in a mixture of methanol and THF. To this mixture was added lithium hydroxide (63.7 g, 1.52 mol) in water. The reaction mixture was refluxed for 3 d. The solvent was removed and conc. HCl (160 mL) was added and the mixture was concentrated. The residue was freeze dried.
- the crude salt (69.1 g) was used for the next step without further purification.
- the salt (34.6 g, 0.148 mol) was dissolved in DCM and oxalyl chloride (37.6 g, 25.8 mL) was added, followed by DMF (0.5 mL).
- the reaction mixture was stirred under nitrogen overnight.
- the solvent was evaporated in vacuo to obtain the crude acid chloride, which was used for the next step without further purification.
- the acid chloride was dissolved in DCM and ammonia gas was passed through the solution for 30 min.
- the reaction mixture was stirred overnight. Water was added and the solid was filtered off and washed with DCM.
- a small portion of pure A-ring building block (5 g) was isolated and crude materials (20 g) were saved.
- the aqueous layer was basified with 5% NaOH and saturated NaHCO 3 solution.
- the mixture was extracted with ethyl acetate and concentrated.
- the crude was dissolved in ether and hydrogen chloride in ether was added. The solvent was decanted off, dissolved in water, basified with solid NaHCO 3 and NaHCO 3 solution, extracted with ethyl acetate, and concentrated.
- the crude was purified by silica gel (100 g) column chromatography, employing 30-50% ethyl acetate in hexane as eluents to give the desired B-ring building block (0.455 g).
- the A-ring building block (0.344 g, 1.75 mmol) was dissolved in anhydrous THF (50 mL) and cooled to ⁇ 78° C.
- n-Butyllithium (3.3 mL, 5.25 mmol of 1.6 M in hexane) was added drop-wise and the temperature was increased to ⁇ 20° C. for 40 min, to ⁇ 10° C. for 1 h, and to ⁇ 5 to ⁇ 2° C. for 40 min, before the reaction mixture was cooled again to ⁇ 78° C. and the B-ring building block (0.455 g, 1.75 mmol) in acetonitrile (10 mL) was added quickly. The reaction mixture was stirred at room temperature overnight ( ⁇ 20 h).
- reaction mixture was allowed to come to room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layer was washed with water, brine and dried over Na 2 SO 4 . Then, solvent was removed to give 2.23 g of crude product in 94% yield.
- the filtrate was extracted with dichloromethane, dried over Na 2 SO 4 , purified by column chromatography, using (1) 5% methanol/dichloromethane, and (2) 10% methanol/dichloromethane as eluents.
- Acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methyl ester was obtained as a beige solid (70 mg, 43%).
- Acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methyl ester (70 mg, 0.16 mmol) was dissolved in methanol/dichloromethane (10 mL) and a solution of potassium carbonate (442 mg, 20 mmol) in water was added. The solution was stirred at room temperature for 17 h. 2 N HCl was added to adjust the reaction mixture pH to ⁇ 8. The mixture was then concentrated under reduced pressure.
- the reaction mixture was poured into a 1 M hydrochloric acid solution (60 mL), then extracted with methylene chloride (20 mL ⁇ 3) and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate.
- the crude solid (3.17 g) was purified by flash column chromatography to provide pure acetic acid (4-formyl-phenylcarbamoyl)-methyl ester (1.14 g, 62% yield) as an orange solid.
- the yellow solid was triturated with ether and methanol to provide acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methyl ester (112 mg, 37%).
- acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methyl ester (0.23 g, 0.59 mmol) in THF/methanol mixture (3.5 mL/3.5 mL) was added potassium carbonate (0.41 g, 2.95 mmol).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Surgery (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use for treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
Description
- The present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use, for the treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
- Epidemiologic data demonstrate an inverse relationship between circulating levels of high density lipoprotein cholesterol (HDL-C) and the incidence of clinically significant atherosclerosis. Each 1 mg/dl increment in the HDL-C serum level is associated with a 2-3% decrement in cardiovascular risk; a 1% reduction in LDL-C reduces coronary heart disease (CHD) risk by 2% (Gordon et al. (1997) Am. J. Med. 62, 707-714). Experimental evidence further supports the protective effect of HDL-C against cardiovascular disease. For example, in subjects with low HDL-C, administration of gemfibrozil results in a 6% increase in the HDL-C level and a corresponding 22% reduction of the CHD risk (Rubins et al. (1999) N. Engl. J. Med. 341, 410-418). Observations in genetic disorders associated with low HDL-C due to reduced ApoA-I expression, also indicate the link between elevated risk of CHD and low HDL-C.
- HDL-C appears to exert its anti-atherogenic effect by mediating reverse cholesterol transport (RCT), in which cholesterol is recruited from peripheral tissues and transported to the liver. In addition, HDL-C also exerts anti-inflammatory and anti-oxidant effects and promotes fibrinolysis. HDL-C particles protect against oxidation of LDL, an important initial step in promoting cholesterol uptake by arterial macrophages. HDL-C exists in two main forms, one containing both apolipoprotein A-I (ApoA-I) and apolipoprotein A-II (ApoA-III), and the other containing ApoA-I without ApoA-II (Schultz et al. (1993) Nature 365, 762-764). The cardioprotective effect of HDL-C is mostly, but not exclusively, attributable to ApoA-I.
- Clinical and experimental data suggest that the production of ApoA-I is a critical determinant of circulating HDL-C. For example, persons with familial hyperalphalipoproteinemia (elevated ApoA-I) appear to be protected from atherosclerosis, while those deficient in ApoA-I (hypoalphalipoproteinemia) show accelerated cardiovascular disease. In addition, various experimental manipulations to increase production of ApoA-I are associated with reduced atherogenicity. For example, human ApoA-I is protective in transgenic animal models (Shah et al. (1998) Circulation 97, 780-785; Rubin et al. (1991) Nature 353, 265-267), and treatment with ApoA-IMilano prevents atherosclerotic lesions and leads to regression of atherosclerotic plaques in human patients (Nissen et al. (2003) JAMA 290, 2292-2300). Further lines of research demonstrate that ApoA-I plays a role in enhancing reverse cholesterol transport, attenuating oxidative stress, increasing paraoxonase activity, enhancing anticoagulant activity, and increasing anti-inflammatory activity (Andersson (1997) Curr. Opin. Lipidol. 8, 225-228). Accordingly, ApoA-I is an attractive target for therapeutic intervention.
- Currently available therapeutic agents that increase the plasma concentration of ApoA-I, for example, recombinant ApoA-I or peptides that mimic ApoA-I, have potential drawbacks with respect to, e.g., stability during storage, delivery of active product, and in vivo half-life. Thus, small molecule compounds that up-regulate the production of endogenous ApoA-I, such as, for example, up-regulators of ApoA-I expression, would be very attractive as new therapeutic agents for cardiovascular disease.
- One class of compounds that are thought to contribute to the prevention of various diseases, including cancer and cardiovascular disease, is polyphenols. Polyphenols are present in most food and beverages of plant origin and are the most abundant dietary antioxidants (Scalbert & Williamson (2000) J. Nutr. 130, 2073S-2085S). However, the protective properties of polyphenols have not been fully realized due to poor bioavailability (Manach et al. (2005) Am. J. Clin. Nutr. 81, 230S-242S), lack of clinical significance in various reported studies assessing them (Williamson & Manach (2005) Am. J. Clin. Nutr. 81, 243S-255S), and deleterious effects at higher dose concentrations. For example, an abundant and available source of resveratrol, a well known stilbene polyphenol, is red wine (Wu et. al. (2001) Int. J. Mol. Med. 8, 3-17). However, red wine cannot be consumed in therapeutically efficacious quantities on a daily basis due to the numerous well documented deleterious effects of excessive alcohol consumption. The effects of resveratrol may be better or safer in the absence of alcohol.
- Several human clinical studies involving the anti-oxidant effect of various polyphenols in various foods or beverages, have failed to demonstrate an unequivocal benefit with respect to primary clinical endpoints, such as oxidative stress, lipemia, and inflammation (Williamson & Manach (2005) Am. J. Clin. Nutr. 81, 243S-255S). For example, out of twelve recent intervention studies with differing polyphenol sources; six showed no effect on lipid parameters and six showed an improvement in the lipid parameters (Manach (2005) Curr. Opin. Lipidol. 16, 77-84). Such inconclusive data has limited the potential use of polyphenols, despite their many beneficial properties.
- The use of naturally occurring polyphenols as potential therapeutics has also been impeded by the inability to achieve efficacious levels in the body, partly due to poor bioavailability (Manach et al. (2005) Am. J. Clin. Nutr. 81, 230S-242S). The bioavailability of any given polyphenol varies widely (from 1-26%) in different individuals. This variability is also seen with administration of different polyphenols to the same individual due to differences in absorption, metabolism, and excretion rates. For example, polyphenol flavonoids, such as quercetin, have been reported to have less than 1% intestinal absorption following oral administration (Gugler et al. (1975) Eur. J. Clin. Pharm. 9, 229-234). In addition, some polyphenol metabolites are known to negatively influence the biological activity of the parent compounds (Manach et al. (2005) Am. J. Clin. Nutr. 81, 230S-242S). Such metabolites often differ from the parent compound in terms of toxicity, efficacy, and length of residence in the plasma. Another limiting factor is the poor solubility of many polyphenols that limits the potential routes of administration. These and other factors have made it difficult to determine appropriate dosages of the naturally occurring polyphenols, naringenin or resveratrol, for use in humans.
- Thus, there exists a need for polyphenol-like compounds to be developed as therapeutic agents for the treatment and prevention of cardiovascular disease and related diseases, particularly, cholesterol- or lipid-related disorders, such as, for example, atherosclerosis. It is therefore one of the objects of the present invention to provide compounds that up-regulate the expression of ApoA-I. In addition, the compounds may have more favorable pharmacological properties than naturally occurring polyphenols.
- The present invention includes compounds that are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use in the treatment and prevention of cardiovascular disease and related disease states, including cholesterol- and lipid-related disorders, such as, for example, atherosclerosis.
- The methods of invention include administering to a mammal (e.g., a human) in need thereof a therapeutically effective amount of a compound of Formula I:
- wherein:
- X is selected from CR11, CR11R13, CO, CS, O, S, SO, SO2, N and NR11, wherein R11 may be the same or different than R13;
- Y is selected from CR12, CR12R14, CO, CS, O, S, SO, SO2, N and NR12, wherein R12 may be the same or different than R14;
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R17 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or
- two adjacent substituents selected from R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;
- Z1, Z2 and Z3 are each independently selected from a single bond and a double bond;
- wherein if Y is O, then X is not CO;
- wherein if X is O, then Z1 is a single bond;
- wherein if X is O and Z2 is a single bond, then R10 is not hydroxyl or ester;
- and pharmaceutically acceptable salts and hydrates thereof.
- Also included are methods of administering alternative embodiments of Formula I as set forth on pp. 27-68 and 107-139 of co-pending patent application Ser. No. 11/255,103 incorporated by reference herein.
- The invention further includes compounds of Formula II and methods of administering a therapeutically effective amount of those compounds to a mammal (e.g., a human) in need thereof:
- wherein:
- X is selected from CR11, CR11R13, N and NR11, wherein R11 may be the same or different than R13;
- Y is selected from CR12, CR12R14, CO, CHOR12, CS, S, SO, and SO2, wherein R12 may be the same or different than R14;
- R11, R12, R13 and R14 are each independently selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;
- R1 and R3 are each independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, hydroxyl, and hydrogen;
- R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;
- R6 and R8 are each independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, hydrogen, heterocyclyl, and cycloalkyl;
- R5 and R9 are each independently selected from alkyl, alkenyl, alkynyl, halogen, and hydrogen;
- R7 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, ether, hydrogen, and hydroxyl;
- R10 is selected from hydrogen and alkyl; or
- two adjacent substituents selected from R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are connected to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- wherein each of R5 and R9 may independently be taken together with either R10 or R11 to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1 or 2;
- wherein for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1, Z2 and Z3 are each independently selected from a single bond and a double bond, wherein at least one of Z1 or Z2 must be a double bond;
- and pharmaceutically acceptable salts and hydrates thereof.
- In certain embodiments, the methods, compounds, and compositions of the invention are useful for the prevention or treatment of diseases that benefit from raised ApoA-I or HDL, and diseases characterized by reduced ApoA-I and/or HDL-C, abnormal lipid parameters, or lipid parameters indicative of high cholesterol. The methods, compounds, and compositions of the invention can be used to increase expression of ApoA-I. Increasing expression of ApoA-I may refer to, but is not limited to, transcriptionally modulating the expression of the ApoA-I gene, thereby affecting the level of the ApoA-I protein produced (synthesized and secreted). An increase in ApoA-I levels may lead to an increase the levels of HDL-C and/or increase in the functionality of HDL-C particles. Thus, the methods, compounds, and compounds of the invention may further be used to reduce cholesterol levels. Accordingly, the methods, compounds, and compositions of the invention can be used for treatment and prevention of cardiovascular disease and related disease states, particularly, cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
-
FIG. 1 depicts ApoA-I induction by 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) in HepG2 Cells (48 h). -
FIG. 2 depicts ApoA-I induction by 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) in primary human hepatocytes (48 h). -
FIG. 3 depicts plasma levels of ApoA-I in hApoA-I transgenic mice receiving 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (10, 30, and 60 mg/kg body weight) twice daily for 7 days by oral gavage. -
FIG. 4 depicts plasma levels of HDL cholesterol in hApoA-I transgenic mice receiving 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (10 and 30 mg/kg body weight) twice daily for 7 days by oral gavage. -
FIG. 5 depicts plasma levels of ApoA-I in wild-type C57BL/6 mice receiving 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (10, 30 and 60 mg/kg of body weight) twice daily for 3 days by intraperitoneal administration. -
FIG. 6 depicts plasma levels of HDL cholesterol in wild-type C57BL/6 mice receiving 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (10, 30 and 60 mg/kg of body weight) twice daily for 3 days by intraperitoneal administration. -
FIG. 7 depicts plasma levels of ApoA-I and tissue levels of ApoA-I mRNA in hApoA-I transgenic mice administered 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20) (30 mg/kg body weight) twice daily for 7 days by oral gavage. - The term “aldehyde” or “formyl” as used herein refers to —CHO.
- The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms, referred to herein as (C2-C22)alkenyl, (C2-C8)alkenyl, and (C2-C6)alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, etc.
- The term “alkoxy” as used herein refers to an alkyl group attached to an oxygen (—O-alkyl-). “Alkoxy” groups also include an alkenyl group attached to an oxygen (“alkenyloxy”) or an alkynyl group attached to an oxygen (“alkynyloxy”) groups. Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-22, 1-8, or 1-6 carbon atoms, referred to herein as (C1-C22)alkoxy, (C1-C8)alkoxy, and (C1-C6)alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, etc.
- The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-22, 1-8, or 1-6 carbon atoms, referred to herein as (C1-C22)alkyl, (C1-C8)alkyl, and (C1-C6)alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
- The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms, referred to herein as (C2-C22)alkynyl, (C2-C8)alkynyl, and (C2-C6)alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl, etc.
- The term “amide” as used herein refers to the form —NR9C(O)Rb, or —C(O)NRbRc, wherein Ra, Rb and Rc are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amide can be attached to another group through Rb or Rc. The amide also may be cyclic, for example Rb and Rc may be joined to form a 3- to 12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-membered ring. The term “amide” encompasses groups such as sulfonamide, urea (ureido), carbamate, carbamic acid, and cyclic versions thereof. The term “amide” also encompasses an amide group attached to a carboxy group, e.g., -amide-COOH or salts such as -amide-COONa, etc, an amino group attached to a carboxy group, e.g., -amino-COOH or salts such as -amino-COONa, etc.
- The term “amine” or “amino” as used herein refers to the form —NRdRe or —N(Rd)Re— where Rd and Re are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amino can be attached to the parent molecular group through the nitrogen. The amino also may be cyclic, for example, Rd and Re may be joined together or with the N to form a 3- to 12-membered ring, e.g., morpholino or piperidinyl. The term amino also includes the corresponding quaternary ammonium salt of any amino group. Exemplary amino groups include alkyl amino groups, wherein at least one of Rd and Re is an alkyl group.
- The term “aryl” as used herein refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system. The aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, and heterocyclyls. The aryl groups of this invention can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C6)aryl.”
- The term “arylalkyl” as used herein refers to an alkyl group having at least one aryl substituent, e.g. -aryl-alkyl-. Exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C6)arylalkyl.”
- The term “aryloxy” as used herein refers to an aryl group attached to an oxygen atom. Exemplary aryloxy groups include, but are not limited to, aryloxys having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C6)aryloxy.”
- The term “arylthio” as used herein refers to an aryl group attached to an sulfur atom. Exemplary arylthio groups include, but are not limited to, arylthios having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C6)arylthio.”
- The term “arylsulfonyl” as used herein refers to an aryl group attached to a sulfonyl group, e.g., —S(O)2-aryl-. Exemplary arylsulfonyl groups include, but are not limited to, arylsulfonyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “(C6)arylsulfonyl.”
- The term “benzyl” as used herein refers to the group —CH2-phenyl.
- The term “bicyclic aryl” as used herein refers to an aryl group fused to another aromatic or non-aromatic carbocylic or heterocyclic ring. Exemplary bicyclic aryl groups include, but are not limited to, naphthyl or partly reduced forms thereof, such as di-, tetra-, or hexahydronaphthyl.
- The term “bicyclic heteroaryl” as used herein refers to a heteroaryl group fused to another aromatic or non-aromatic carbocylic or heterocyclic ring. Exemplary bicyclic heteroaryls include, but are not limited to, 5,6 or 6,6-fused systems wherein one or both rings contain heteroatoms. The term “bicyclic heteroaryl” also encompasses reduced or partly reduced forms of fused aromatic system wherein one or both rings contain ring heteroatoms. The ring system may contain up to three heteroatoms, independently selected from oxygen, nitrogen, or sulfur. The bicyclic system may be optionally substituted with one or more groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Exemplary bicyclic heteroaryls include, but are not limited to, quinazolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, phthalazinyl, benzotriazolyl, benzopyridinyl, and benzofuranyl.
- The term “carbamate” as used herein refers to the form —RgOC(O)N(Rh)—, —RgOC(O)N(Rh)Ri—, or —OC(O)NRhRi, wherein Rg, Rh and Ri are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include, but are not limited to, arylcarbamates or heteroaryl carbamates, e.g., wherein at least one of Rg, Rh and Ri are independently selected from aryl or heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine.
- The term “carbonyl” as used herein refers to —C(O)—.
- The term “carboxy” as used herein refers to —COOH or its corresponding carboxylate salts, e.g. —COONa, etc. The term carboxy also includes “carboxycarbonyl,” e.g., a carboxy group attached to a carbonyl group, e.g., —C(O)—COOH or salts such as —C(O)—COONa, etc.
- The term “cyano” as used herein refers to —CN.
- The term “cycloalkoxy” as used herein refers to a cycloalkyl group attached to an oxygen.
- The term “cycloalkyl” as used herein refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12 carbons, or 3-8 carbons, referred to herein as “(C3-C8)cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other cycloalkyl saturated or unsaturated, aryl, or heterocyclyl groups.
- The term “dicarboxylic acid” as used herein refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylic acids include alkyl dicarboxylic acids. Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include, but are not limited to succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(−)-malic acid, (+)/(−) tartaric acid, isophthalic acid, and terephthalic acid. Dicarboxylic acids further include carboxylic acid derivatives thereof, such as anhydrides, imides, hydrazides, etc., for example, succinic anhydride, succinimide, etc.
- The term “ester” refers to the structure —C(O)O—, —C(O)O—Rj—, —RkC(O)O—Rj—, or —RkC(O)O—, where O is not bound to hydrogen, and Rj and Rk can independently be selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, heterocyclyl. Rk can be a hydrogen, but Rj cannot be hydrogen. The ester may be cyclic, for example the carbon atom and Rj, the oxygen atom and Rk, or Rj and Rk may be joined to form a 3- to 12-membered ring. Exemplary esters include, but are not limited to, alkyl esters wherein at least one of Rj or Rk is alkyl, such as —O—C(O)-alkyl-, —C(O)—O-alkyl-, -alkyl-C(O)—O-alkyl-, etc. Exemplary esters also include aryl or heteoraryl esters, e.g. wherein at least one of Rj or Rk is a heteroaryl group such as pyridine, pyridazine, pyrmidine and pyrazine, such as a nicotinate ester. Exemplary esters also include reverse esters having the structure —RkC(O)O—, where the oxygen is bound to the parent molecular group. Exemplary reverse esters include succinate, D-argininate, L-argininate, L-lysinate and D-lysinate. Esters also include carboxylic acid anhydrides and acid halides.
- The term “ether” refers to the structure —RlO—Rm—, where Rl and Rm can independently be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, or ether. The ether can be attached to the parent molecular group through Rl or Rm. Exemplary ethers include, but are not limited to, alkoxyalkyl and alkoxyaryl groups. Ethers also includes polyethers, e.g., where one or both of Rl and Rm are ethers.
- The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.
- The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. “Haloalkyls” also encompass alkenyl or alkynyl groups substituted with one or more halogen atoms.
- The term “heteroaryl” as used herein refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryls can also be fused to non-aromatic rings. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl; imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl; isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as “(C2-C5)heteroaryl.”
- The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as used herein refer to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heterocycles can be aromatic (heteroaryls) or non-aromatic. Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.
- The terms “hydroxy” and “hydroxyl” as used herein refers to —OH.
- The term “hydroxyalkyl” as used herein refers to a hydroxy attached to an alkyl group.
- The term “hydroxyaryl” as used herein refers to a hydroxy attached to an aryl group.
- The term “ketone” as used herein refers to the structure —C(O)—Rn—(such as acetyl, —C(O)CH3) or —Rn—C(O)—Ro—. The ketone can be attached to another group through Rn or Ro. Rn or Ro can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or Rn or Ro can be joined to form a 3- to 12-membered ring.
- The term “monoester” as used herein refers to an analogue of a dicarboxylic acid wherein one of the carboxylic acids is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or salt of a carboxylic acid. Examples of monoesters include, but are not limited to, to monoesters of succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, oxalic acid and maleic acid.
- The term “nitro” as used herein refers to the structure —NO2.
- The term “perfluoroalkoxy” as used herein refers to an alkoxy group in which all of the hydrogen atoms have been replaced by fluorine atoms.
- The term “perfluoroalkyl” as used herein refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluorine atoms. Exemplary perfluroalkyl groups include, but are not limited to, (C1-5) perfluoroalkyl, such as trifluoromethyl, etc.
- The term “perfluorocycloalkyl” as used herein refers to a cycloalkyl group in which all of the hydrogen atoms have been-replaced by fluorine atoms.
- The term “phenyl” as used herein refers to a 6-membered carbocyclic aromatic ring. The phenyl group can also be fused to a cyclohexane or cyclopentane ring. Phenyl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
- The term “phosphate” as used herein refers to the structure —OP(O)O2—, —RxOP(O)O2—, —OP(O)O2Ry—, or —RxOP(O)O2Ry—, wherein Rx and Ry can be selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and hydrogen.
- The term “sulfide” as used herein refers to the structure —RzS—, where Rz can be selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, and heterocyclyl. The sulfide may be cyclic, forming a 3-12 membered ring. The term “alkylsulfide” as used herein refers to an alkyl group attached to a sulfur atom.
- The term “sulfinyl” as used herein refers to the structure —S(O)O—, —RpS(O)O—, —RpS(O)ORq—, or —S(O)ORq—, wherein Rp and Rq can be selected from alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydroxyl. Exemplary sulfinyl groups include, but are not limited to, alkylsulfinyls wherein at least one of Rp or Rq is alkyl, alkenyl or alkynyl.
- The term “sulfonamide” as used herein refers to the structure —(Rr)—N—S(O)2—Rs— or —Rt(Rr)—N—S(O)2—Rs, where Rt, Rr, and Rs can be, for example, hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocyclyl. Exemplary sulfonamides include alkylsulfonamides (e.g., where Rs is alkyl), arylsulfonamides (e.g., where Rs is aryl), cycloalkyl sulfonamides (e.g., where Rs is cycloalkyl), and heterocyclyl sulfonamides (e.g., where Rs is heterocyclyl), etc.
- The term “sulfonate” as used herein refers to —OSO3 −. Sulfonate includes salts such as —OSO3Na, —OSO3K, etc. and the acid —OSO3H
- The term “sulfonic acid” refers to —SO3H— and its corresponding salts, e.g. —SO3K—, —SO3Na—.
- The term “sulfonyl” as used herein refers to the structure RuSO2—, where Ru can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocyclyl, e.g., alkylsulfonyl. The term “alkylsulfonyl” as used herein refers to an alkyl group attached to a sulfonyl group. “Alkylsulfonyl” groups can optionally contain alkenyl or alkynyl groups.
- The term “thioketone” refers to the structure —Rv—C(S)—Rw—. The ketone can be attached to another group through Rv or Rw. Rv or Rw can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or Rv and Rw can be joined to form a 3- to 12-membered ring.
- “Alkyl,” “alkenyl,” “alkynyl,” “alkoxy,” “amino,” and “amide” groups can be substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and nitrogen. The substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.
- As used herein, a “suitable substituent” refers to a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them. Examples of suitable substituents include, but are not limited to: C1-22, C1-8, and C1-6 alkyl, alkenyl or alkynyl; C1-6 aryl, C2-5 heteroaryl; C3-7 cycloalkyl; C1-22, C1-8, and C1-6alkoxy; C6 aryloxy; —CN; —OH; oxo; halo, carboxy; amino, such as —NH(C1-22, C1-8, or C1-6 alkyl), —N(C1-22, C1-8, and C1-6 alkyl)2, —NH((C6)aryl), or —N((C6)aryl)2; formyl; ketones, such as —CO(C1-22, C1-8, and C1-6 alkyl), —CO((C6 aryl) esters, such as —CO2(C1-22, C1-8, and C1-6 alkyl) and —CO2 (C6 aryl). One of skill in art can readily choose a suitable substituent based on the stability and pharmacological and synthetic activity of the compound of the invention.
- The term “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
- The term “pharmaceutically acceptable composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
- The term “pharmaceutically acceptable prodrugs” as used herein represents those prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. A discussion is provided in Higuchi et al., “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E. B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
- The term “pharmaceutically acceptable salt(s)” refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form nontoxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
- The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
- Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
- Geometric isomers can also exist in the compounds of the present invention. The present invention encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the E and Z isomers.
- Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring are designated as “cis” or “trans.” The term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
- One embodiment provides a method for increasing expression of ApoA-I in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of Formula I:
- wherein:
- X is selected from CR11, CR11R13, CO, CS, O, S, SO, SO2, N, and NR11, wherein R11 may be the same or different than R13;
- Y is selected from CR12, CR12R14, CO, CS, O, S, SO, SO2, N, and NR12, wherein R12 may be the same or different than R14;
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, and R17 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or
- two adjacent substituents selected from R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;
- Z1, Z2 and Z3 are each independently selected from a single bond and a double bond;
- wherein if Y is O, then X is not CO;
- wherein if X is O, then Z1 is a single bond;
- wherein if X is O and Z2 is a single bond, then R10 is not hydroxyl or ester;
- and pharmaceutically acceptable salts and hydrates thereof.
- Another embodiment provides a method for increasing expression of ApoA-II in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of Formula II:
- wherein:
- X is selected from CR11, CR11R13, N and NR11, wherein R11 may be the same or different than R13;
- Y is selected from CR12, CR12R14, CO, CHOR12, CS, S, SO, and SO2, wherein R12 may be the same or different than R14;
- R11, R12, R13, and R14 are each independently selected from hydrogen, unsubstituted alkyl (preferably C1-3 alkyl), unsubstituted alkenyl (preferably C1-3 alkenyl), and unsubstituted alkynyl (preferably C1-3 alkynyl);
- R1 and R3 are each independently selected from alkoxy (preferably methoxy), alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably chloride), hydroxyl, and hydrogen;
- R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably bromide or chloride), and hydrogen;
- R6 and R8 are each independently selected from alkoxy, alkyl (preferably methyl), alkenyl, alkynyl, amide, amino, halogen (preferably chloride or fluoride), hydrogen, heterocyclyl, and cycloalkyl;
- R5 and R9 are each independently selected from alkyl, alkenyl, alkynyl, halogen (preferably chloride), and hydrogen;
- R7 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, ether, ester, hydrogen, and hydroxyl;
- R10 is selected from hydrogen and alkyl (preferably methyl); or
- two adjacent substituents selected from R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are connected to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- wherein each of R5 and R9 may independently be taken together with either R10 or R11 to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- wherein for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1, Z2 and Z3 are each independently selected from a single bond and a double bond, wherein at least one of Z1 or Z2 is a double bond;
- and pharmaceutically acceptable salts and hydrates thereof.
- Another embodiment provides a method for increasing expression of ApoA-I in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of Formula II:
- wherein:
- X is selected from CH and N;
- Y is selected from CO, CS, and SO2;
- R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;
- R2 is selected from alkoxy, alkyl, amino, and hydrogen;
- R6 and R8 are each independently selected from alkoxy, amino, alkyl, hydrogen, and heterocyclyl;
- R5 and R9 are each hydrogen;
- R7 is selected from alkoxy, alkyl, alkynyl, amide, amino, ether, hydrogen, and hydroxyl;
- R10 is hydrogen; or
- two adjacent substituents selected from R1, R2, R3, R5, R6, R7, R8, R9, and R10 are connected to form group selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;
- wherein R5 or R9 may be taken together with R10 to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- wherein for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1, Z2, and Z3 are each independently selected from a single bond and a double bond, wherein at least one of Z1 or Z2 is a double bond;
- and pharmaceutically acceptable salts and hydrates thereof.
- The following is a list of specific exemplary embodiments that are encompassed by the invention:
- 1. A method for increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound of Formula II:
- wherein:
- X is selected from CR11, CR11R13, N, and NR11, wherein R11 may be the same or different than R13;
- Y is selected from CR12, CR12R14, CO, CHOR12, CS, S, SO, and SO2, wherein R12 may be the same or different than R14;
- R11, R12, R13 and R14 are each independently selected from hydrogen, unsubstituted alkyl (preferably C1-3 alkyl), unsubstituted alkenyl (preferably C1-3 alkenyl), and unsubstituted alkynyl (preferably C1-3 alkynyl);
- R1 and R3 are each independently selected from alkoxy (preferably methoxy), alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably chloride), hydroxyl, and hydrogen;
- R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably chloride and fluoride), and hydrogen;
- R6 and R8 are each independently selected from alkoxy, alkyl (preferably methyl), alkenyl, alkynyl, amide, amino, halogen (preferably chloride), hydrogen, heterocyclyl, and cycloalkyl;
- R5 and R9 are each independently selected from alkyl, alkenyl, alkynyl, halogen, and hydrogen;
- R7 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, ether, ester, hydrogen, and hydroxyl;
- R10 is selected from hydrogen and alkyl (preferably methyl); or
- two adjacent substituents selected from R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are connected to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- wherein each of R5 and R9 may independently be taken together with R10 or R11 to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- wherein for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1, Z2, and Z3 are each independently selected from a single bond and a double bond, wherein at least one of Z1 or Z2 is a double bond;
- and pharmaceutically acceptable salts and hydrates thereof.
- In one embodiment, R7 is not diethylamino or an alkoxy substituted with a carboxylate group.
- In another embodiment, at least one of R11, R12, R13, and R14 is an unsubstituted (C1-3) alkyl.
- 2. The method according to
embodiment 1, wherein Z1 is a double bond; - Z2 and Z3 are each a single bond;
- X is selected from N and CR11;
- for W—(R10)p, W is N and p is 1; and
- Y is selected from CO, SO2, SO, and CS.
- 3. The method according to
embodiment 1, wherein Z2 is a double bond; - X is NR11;
- for W—(R10)p, W is N and p is 0; and
- Y is selected from CO, SO2, SO, and CS.
- 4. The method according to
embodiment 1, wherein Z1 and Z3 are each a double bond; - X is selected from N and CR11;
- for W—(R10)p, W is N, and p is 0; and
- Y is selected from CR12, COR12, and SO.
- 5. The method according to
embodiment 1, wherein R1 and R3 are each independently an alkoxy. - 6. The method according to
embodiment 5, wherein R6 and R8 are each independently selected from alkyl and hydrogen; and - R7 is selected from amino, hydroxyl, and alkoxy.
- 7. The method according to embodiment 6, wherein X is CR11;
- for W—(R10)p, W is N and R10 is hydrogen; and Y is CO.
- 8. The method according to embodiment 6, wherein X is N;
- for W—(R10)p, W is N and R10 is hydrogen; and Y is CO.
- 9. The method according to
embodiment 1, wherein R5 and R9 are each hydrogen. - 10. The method according to
embodiment 1, wherein at least one of R1, R2, and R3 is not hydrogen. - 11. The method according to
embodiment 10, wherein R6 and R8 are each independently selected from alkyl and hydrogen; and - R7 is selected from amino, hydroxyl, and alkoxy.
- 12. The method according to embodiment 11, wherein X is CR11;
- for W—(R10)p, W is N and R10 is hydrogen; and Y is CO.
- 13. The method according to embodiment 11, wherein X is N;
- for W—(R10)p, W is N and R10 is hydrogen; and Y is CO.
- 14. The method according to
embodiment 1, wherein at least one of R6, R7, and R8 is not hydrogen. - 15. The method according to embodiment 14, wherein R6 and R8 are each independently selected from alkyl and hydrogen; and
- R7 is selected from amino, hydroxyl, and alkoxy.
- 16. The method according to
embodiment 15, wherein X is CR11; - for W—(R10)p, W is N and R10 is hydrogen; and Y is CO.
- 17. The method according to embodiment 16, wherein the compound of Formula II is selected from:
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 7); and
- 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (Example 16).
- 18. The method according to
embodiment 15, wherein X is N; - for W—(R10)p, W is N and R10 is hydrogen; and Y is CO.
- 19. The method according to embodiment 18, wherein the compound of Formula II is selected from:
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide (Example 102);
- 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 98);
- 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 97);
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 46);
- 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 21); and
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one (Example 51).
- 20. The method according to
embodiment 1, wherein X is selected from CH, N, and NR11, and Y is selected from CH, CO, and SO2. - 21. The method according to
embodiment 20, wherein Z1 is a double bond; - Z2 and Z3 are each a single bond; and
- for W—(R10)p, W is N and p is 1.
- 22. The method according to
embodiment 20, wherein Z2 is a double bond; - X is NR11; and
- for W—(R10)p, W is N and p is 0.
- 23. The method according to
embodiment 20, wherein Z1 and Z3 are each a double bond; - X is selected from CH and N;
- for W—(R10)p, W is N and p is 0; and
- Y is CH.
- 24. The method according to
embodiment 1, wherein X is selected from CH and N, and Y is selected from CO and SO2. - 25. The method according to embodiment 24, wherein Z is a double bond, Z2 and Z3 are each a single bond, and for W—(R10)p, W is N and R10 is hydrogen.
- 26. The method according to embodiment 24, wherein Z2 is a double bond and for W—(R10)p, W is N and p is 0.
- 27. The method according to embodiment 1, wherein R7 is an amino or an alkoxy selected from the group represented by Formula III:
- wherein:
-
- A is selected from O and N;
- n is selected from 0, 1, 2, 3, 4 and 5;
- B is selected from —C(O)N(Rh)2—, —S(O)2N(Rh)2—, —C(O)—, —S(O)2—, and —C(O)O—, wherein each Rh is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and
- R20 is selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
- In another embodiment, if A is O and B is —C(O)N(Rh)2—, then R20 is not an unsaturated cycloalkyl.
- 28. The method according to embodiment 27, wherein the compound of Formula II is selected from:
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl cyclohexylcarbamate (Example 108);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide (Example 112);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide (Example 114);
- 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-phenylurea (Example 117); and
- 3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1,1-dimethylurea (Example 118).
- 29. The method according to
embodiment 1, wherein: - X is selected from CR11, N, and NR11,
- Y is selected from CO, CS, and SO2,
- R11 is selected from hydrogen, unsubstituted alkyl (preferably C1-3 alkyl), unsubstituted alkenyl (preferably C1-3 alkenyl), and unsubstituted alkynyl (preferably C1-3 alkynyl);
- R1 and R3 are each independently selected from alkoxy (preferably methoxy), alkyl, amino, halogen (preferably chloride), and hydrogen;
- R2 is selected from alkoxy, alkyl, alkenyl, amide, amino, halogen (preferably bromide or chloride), and hydrogen;
- R6 and R8 are each independently selected from alkoxy, alkyl (preferably methyl), amino, halogen (preferably chloride and fluoride), and hydrogen;
- R5 and R9 are each independently selected from halogen (preferably chloride) and hydrogen;
- R7 is selected from alkoxy, alkyl, alkenyl, amide, amino, ether, hydrogen, and hydroxyl;
- R10 is selected from hydrogen and alkyl (preferably methyl); or
- two adjacent substituents selected from R1, R2, R3, R6, R7, R8, R10, and R11 are connected to form a group selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- wherein for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1, Z2, and Z3 are each independently selected from a single bond and a double bond, wherein at least one of Z1 or Z2 is a double bond;
- and pharmaceutically acceptable salts and hydrates thereof.
- 30. The method according to embodiment 29, wherein:
- X is selected from N and CH;
- Y is CO;
- R1 and R3 are each independently selected from alkoxy and hydrogen;
- R2 is selected from alkoxy, alkyl, and hydrogen;
- R6 and R8 are each independently selected from alkyl, alkoxy, chloride, and hydrogen;
- R5 and R9 are each hydrogen;
- R7 is selected from amino, hydroxyl, alkoxy (preferably a substituted ethoxy group), and alkyl substituted with a heterocyclyl;
- R10 is hydrogen; or
- two adjacent substituents selected from R6, R7, and R8 are connected to form a heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- for W—(R10)p, W is N and p is 1;
- for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1 is a double bond, and Z2 and Z3 are each a single bond;
- with the proviso that at least one of R1 and R3 is alkoxy;
- with the proviso that if R7 is selected from hydroxyl and alkoxy, then at least one of R6 and R8 are independently selected from alkyl, alkoxy, and chloride;
- with the proviso that if R7 is an amino, then X is N;
- with the proviso that if for W—(R7)p. W is N and p is 0, then at least one of R6 and R8 is selected from alkyl, alkoxy, and chloride;
- and pharmaceutically acceptable salts and hydrates thereof.
- 31. The method according to
embodiment 30, wherein the compound of Formula II is selected from: - 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 7);
- 3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 9);
- 3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one (Example 11);
- 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 13);
- 3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 14);
- 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (Example 16);
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20);
- 3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 23);
- 2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 31);
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 46);
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one (Example 47);
- 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one (Example 48);
- 2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 67);
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (Example 70);
- 2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 89);
- 5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (Example 90);
- 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 91);
- N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide (Example 99);
- 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 99); and
- 4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide (Example 101).
- 32. The method according to
embodiment 1, wherein the compound of Formula II is selected from: - 3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one;
- 4-Isoquinolin-3-yl-phenol;
- 4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate tetrahydrochloride;
- 4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate trihydrochloride;
- 4-(1,6-naphthyridin-7-yl)phenol;
- 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methylisoquinolin-(2H)-one;
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;
- 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one;
- 3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;
- 3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;
- 3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one;
- 2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)-one;
- 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;
- 6,8-dimethoxy-3-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2-benzothiazine-1,1-dioxide;
- 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one;
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl)isoquinolin-1(2H)-one;
- 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol;
- 3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 4-(2-(4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)morpholine;
- 3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;
- 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid;
- 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one;
- 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one;
- 2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one;
- 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one;
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
- 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one;
- 2-(4-(dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide;
- 2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid;
- 2-(4-(dimethylamino)pyridinon-1-yl)quinazolin-4(3H)-one;
- 2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide;
- 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;
- 2-(4-(dimethylamino)pyridinon-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one;
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
- 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one;
- 7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-diethoxy-1,6-naphthyridin-5(6H)-one;
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one;
- 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
- 3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic acid;
- N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;
- 2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide;
- 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one
- 5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one;
- N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide;
- 7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;
- 2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one;
- 2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one;
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetic acid;
- N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide;
- 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;
- 2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;
- 5,7-dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;
- 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one;
- 2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;
- 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy-1,6-naphthyridin-5(6H)-one;
- 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol;
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one;
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;
- 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
- 5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
- 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one;
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;
- 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one;
- 5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2-yl)quinazolin-4(3H)-one;
- 2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;
- 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 5,7-dimethoxy-2-(1-phenyl-5-propyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one;
- 2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
- (E)-N′-(4-(5,7-dimeth oxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide;
- 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;
- 6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
- 6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
- 2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide;
- 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide;
- 4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide;
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)acetic acid;
- 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one;
- 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate;
- 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methylcarbamate;
- N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide;
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl cyclohexylcarbamate;
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzenesulfonamide;
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide;
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide;
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzamide;
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide;
- 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-methylurea;
- 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-(4-methoxyphenyl)urea;
- 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-phenylurea; and
- 3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1,1-dimethylurea.
- 33. The method of
embodiment 1, wherein the therapeutically effective amount of the compound of Formula II is administered with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition. - 34. The method of
embodiment 1, further comprising treating or preventing a cardiovascular diseases, or cholesterol- or lipid-related disorder. - 35. A compound of Formula II:
- wherein:
- X is selected from N and CR11;
- Y is selected from CO and SO2;
- R11 is selected from hydrogen, unsubstituted alkyl (preferably C1-3 alkyl), unsubstituted alkenyl (preferably C1-3 alkenyl), and unsubstituted alkynyl (preferably C1-3 alkynyl);
- R1 and R3 are each independently selected from alkoxy (preferably methoxy), alkyl, amino, halogen (preferably chloride), and hydrogen;
- R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably bromide or chloride), and hydrogen;
- R6 and R8 are each independently selected from alkyl (preferably methyl), alkoxy, amino, halogen (preferably chloride or fluoride), and hydrogen;
- R5 and R9 are each hydrogen;
- R7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy;
- R10 is selected from hydrogen and methyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- for W—(R10)p, W is N and p is 1;
- for W—(R7)p, W is C and p is 1;
- for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1 is a double bond, and Z2 and Z3 are each a single bond;
- with the proviso that if R1 is hydrogen, then R3 is alkoxy;
- with the proviso that if R3 is hydrogen, then R1 is selected from amino and alkoxy;
- with the proviso that if R7 is selected from alkyl, hydroxyl, and alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy, amino, and halogen;
- with the proviso that if R7 is amino, then X is N;
- and pharmaceutically acceptable salts and hydrates thereof.
- 36. The compound according to
embodiment 35, wherein X is N; for W—(R10)p, W is N and R10 is hydrogen; and R7 is amino. - 37. The compound according to embodiment 36, wherein the compound of Formula II is 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 46).
- 38. The compound according to
embodiment 35, wherein for W—(R10)p, W is N and R10 is hydrogen; and R7 is selected from hydroxyl and alkoxy. - 39. The compound according to embodiment 38, wherein the compound of Formula II is selected from:
- 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (Example 15);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide (Example 102);
- 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 98);
- 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 97);
- 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20); and
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one (Example 51).
- 40. The compound according to embodiment 38, wherein R6 and R8 are each independently alkyl;
- R2 is hydrogen; and
- R7 is selected from hydroxyl and alkoxy (preferably substituted with a hydroxyl.)
- 41. The compound according to
embodiment 40, wherein the compound of Formula II is selected from: - 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 7); and
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 19).
- 42. The compound according to embodiment 35, wherein R7 is selected from an amino or an alkoxy selected from the group represented by Formula III:
- wherein:
-
- A is selected from O and N;
- n is selected from 0, 1, 2, 3, 4 and 5;
- B is selected from —C(O)N(Rh)2—, —S(O)2N(Rh)2—, —C(O)—, —S(O)2—, —C(O)O—, wherein each Rh is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and
- R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
- In another embodiment, if A is O and B is —C(O)NH—, then R20 is not an unsaturated cycloalkyl.
- 43. The compound according to embodiment 42, wherein the compound of Formula II is selected from:
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl cyclohexylcarbamate (Example 108);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide (Example 112);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide (Example 114);
- 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-phenylurea (Example 117); and
- 3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1,1-dimethylurea (Example 118).
- 44. The compound according to
embodiment 35, wherein the compound of Formula II is selected from: - 3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 10);
- 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (Example 16);
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one (Example 17);
- 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 21);
- 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 28);
- 2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 31);
- 2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 32);
- 5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one (Example 43);
- 7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (Example 50);
- 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one (Example 52);
- 2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide (Example 55);
- 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 56);
- 2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 57);
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one (Example 58);
- N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide (Example 60);
- 7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (Example 61);
- 2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (Example 63);
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetic acid (Example 64);
- N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide (Example 65);
- 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (Example 68);
- 5,7-dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one (Example 69);
- 2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 72);
- 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 75);
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-pyrido[2,3-d]pyrimidin-4(3H)one (Example 78);
- 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (Example 79);
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one (Example 84);
- (E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide (Example 93);
- 2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 96);
- 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 99);
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)acetic acid (Example 103);
- 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate (Example 105);
- 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methylcarbamate (Example 106);
- N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide (Example 107);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide (Example 109);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzenesulfonamide (Example 110);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide (Example 111);
- N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzamide (Example 113);
- 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-methylurea (Example 115); and
- 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-(4-methoxyphenyl)urea (Example 116).
- 45. A compound selected from:
- 3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one (Example 1);
- 4-Isoquinolin-3-yl-phenol (Example 2);
- 4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate tetrahydrochloride (Example 3);
- 4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate trihydrochloride (Example 4);
- 4-(1,6-naphthyridin-7-yl)phenol (Example 5);
- 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (Example 8);
- 2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)-one (Example 12);
- 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (Example 18);
- 4-(2-(4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)morpholine (Example 22);
- 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one (Example 34);
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (Example 35);
- 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one (Example 36);
- 2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (Example 39);
- 2-(4-(dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one (Example 40);
- 2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (Example 41);
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one (Example 45);
- 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy-1,6-naphthyridin-5(6H)-one (Example 74);
- 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol (Example 76);
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one (Example 77);
- 5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (Example 80);
- 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (Example 94);
- 6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (Example 95);
- 6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (Example 95);
- 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one (Example 26);
- 5,7-dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (Example 27);
- 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 29);
- 5,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one (Example 33);
- 2-(4-(dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 37);
- 2-(4-(dimethylamino)pyridin-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one (Example 44);
- 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one (Example 71);
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one (Example 82);
- 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 83);
- 5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one (Example 85);
- 5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 86);
- 5,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin-4(3H)-one (Example 87);
- 5,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 88);
- 2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 92); and
- 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one (Example 104).
- 46. A pharmaceutical composition comprising a compound according to
embodiment 35 and a pharmaceutically acceptable carrier. - 47. A method of treating cardiovascular disease, or cholesterol- or lipid-related disorders comprising administering a therapeutically effective amount of a compound according to
embodiment 35. - 48. A method of increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound according to
embodiment 35. - 49. A compound of Formula II:
- wherein:
- X is selected from N and CH;
- Y is CO;
- R1 and R3 are each independently selected from alkoxy and hydrogen;
- R2 is selected from alkoxy, alkyl, and hydrogen;
- R6 and R8 are each independently selected from alkyl, alkoxy, halogen (preferably chloride), and hydrogen;
- R5 and R9 are each hydrogen;
- R7 is selected from amino, hydroxyl, alkoxy (preferably a substituted ethoxy group), and alkyl substituted with a heterocyclyl;
- R10 is hydrogen; or
- two adjacent substituents selected from R6, R7, and R8 are connected to form a heterocyclyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- for W—(R10)p, W is N and p is 1;
- for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1 is a double bond, and Z2 and Z3 are each a single bond;
- with the proviso that if R2 is alkoxy or hydrogen, then least one of R1 and R3 is alkoxy;
- with the proviso that if R7 is selected from hydroxyl and alkoxy, then at least one of R6 and R8 are independently selected from alkyl, alkoxy, and chloride;
- with the proviso that if R7 is an amino, then X is N;
- with the proviso that if for W—(R7)p, W is N and p is 0, then at least one of R6 and R8 is selected from alkyl, alkoxy, and chloride;
- and pharmaceutically acceptable salts and hydrates thereof.
- 50. The compound according to embodiment 49, wherein the compound of Formula II is selected from:
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 7);
- 3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 9);
- 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 13);
- 3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 14);
- 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (Example 16);
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 20);
- 3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (Example 23);
- 2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 31);
- 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 42);
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 46);
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one (Example 47);
- 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one (Example 48);
- 2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 67);
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (Example 70);
- 2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 89);
- 5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (Example 90);
- 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 91);
- N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide (Example 99);
- 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 99);
- and 4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide (Example 101).
- 51. The compound according to embodiment 49, wherein R7 is selected from an amino or an alkoxy selected from the group represented by Formula III:
- wherein:
-
- A is selected from O and N;
- n is selected from 0, 1, 2, 3, 4 and 5;
- B is selected from —C(O)N(Rh)2—, —S(O)2N(Rh)2—, —C(O)—, —S(O)2—, and —C(O)O—, wherein each Rh is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and
- R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
- In another embodiment, if A is O and B is —C(O)NH—, then R20 is not an unsaturated cycloalkyl.
- 52. The compound of embodiment 51, wherein the compound of Formula II is selected from:
- N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide (Example 99);
- 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 99); and
- 4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide (Example 101).
- 53. A pharmaceutical composition comprising a compound according to embodiment 49 and a pharmaceutically acceptable carrier.
- 54. A method of treating cardiovascular disease, or cholesterol- or lipid-related disorders comprising administering a therapeutically effective amount of a compound according to embodiment 49.
- 55. A method of increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound according to embodiment 49.
- 56. A compound of Formula II:
- wherein:
- X is selected from N and CR11;
- Y is selected from CO and SO2;
- R11 is selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;
- R1 and R3 are each independently selected from alkoxy (preferably methoxy), alkyl, amino, halogen (preferably chloride) and hydrogen;
- R2 is selected from —N—C(O)—R18, —N—SO2—R18, —CH2—C(R18)3, —CH2—N(R18)2, and —CH2—O—R18, wherein each R18 is independently selected from alkoxy, alkyl, alkenyl, amide, amino, aryl, arylalkyl, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, and hydrogen;
- R6 and R8 are each independently selected from alkyl (preferably methyl), alkoxy, amino, halogen (preferably chloride or fluoride), and hydrogen;
- R5 and R9 are each hydrogen;
- R7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy;
- R10 is selected from hydrogen and methyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- for W—(R10)p, W is N and p is 1;
- for W—(R7)p, W is C and p is 1;
- for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1 is a double bond, and Z2 and Z3 are each a single bond;
- with the proviso that if R7 is selected from alkyl, hydroxyl, and alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy, amino, and halogen;
- and pharmaceutically acceptable salts and hydrates thereof.
- 57. The compound according to embodiment 56, wherein X is N;
- for W—(R10)p, W is N, and p is 1; and R10 is hydrogen.
- 58. The compound according to embodiment 57, wherein the compound of Formula II is selected from:
- N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (Example 54);
- 2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one (Example 62);
- N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (Example 73); and
- 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morphoinomethyl)quinazolin-4(3H)-one (Example 81).
- 59. The compound according to embodiment 56, wherein X is CH; for W—(R10)p, W is N and R10 is hydrogen; and R7 is selected from hydroxyl and alkoxy.
- 60. The compound according to embodiment 59, wherein the compound of Formula II is selected from:
- 3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one (Example 11);
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl)isoquinolin-1(2H)-one (Example 17); and
- 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one (Example 51).
- 61. The compound according to embodiment 56, wherein R6 and R8 are each independently alkyl; and R7 is selected from hydroxyl and alkoxy (preferably substituted with a hydroxyl).
- 62. The compound according to embodiment 56, wherein R7 is selected from an amino or an alkoxy selected from the group represented by Formula III:
- wherein:
-
- A is selected from O and N;
- n is selected from 0, 1, 2, 3, 4 and 5;
- B is selected from —C(O)N(Rh)2—, —S(O)2N(Rh)2—, —C(O)—, —S(O)2—, —C(O)O—, wherein each Rh is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and
- R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
- In another embodiment, if A is O and B is —C(O)NH—, then R20 is not an unsaturated cycloalkyl.
- 63. The compound according to embodiment 56, wherein R6 and R8 are each independently alkyl.
- 64. A pharmaceutical composition comprising a compound according to embodiment 56 and a pharmaceutically acceptable carrier.
- 65. A method of treating cardiovascular disease, or cholesterol- or lipid-related disorders comprising administering a therapeutically effective amount of a compound according to embodiment 56.
- 66. A method of increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound according to embodiment 56.
- 67. A compound of Formula II:
- wherein:
- X is selected from N and CR11;
- Y is selected from CO and SO2;
- R11 is selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;
- R1 is selected from alkoxy (preferably methoxy) or amino;
- R3 is alkoxy (preferably methoxy);
- R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen (preferably bromide or chloride), and hydrogen;
- R6 and R8 are each independently selected from alkyl, alkoxy, amino, halogen (preferably chloride or fluoride), and hydrogen;
- R5 and R9 are each hydrogen;
- R7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy;
- R10 is selected from hydrogen and methyl;
- each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
- for W—(R10)p, W is N and p is 1;
- for W—(R7)p, W is C and p is 1;
- for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
- Z1 is a double bond, and Z2 and Z3 are each a single bond;
- with the proviso that if R7 is hydroxyl, then X is N;
- and pharmaceutically acceptable salts and hydrates thereof.
- 68. The compound according to embodiment 67, wherein X is selected from N and CH;
- R10 is hydrogen; and
- R7 is selected from hydroxyl and alkoxy.
- 69. The compound according to embodiment 68, wherein the compound of Formula II is selected from:
- 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 24);
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (Example 25);
- 5,7-dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one (Example 30); and
- 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (Example 38).
- 70. The compound according to embodiment 67, wherein X is selected from N and CH;
- R10 is hydrogen; and
- R7 is selected from amide and amino.
- 71. The compound according to embodiment 70, wherein the compound of Formula II is selected from:
- 5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one (Example 43);
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 46);
- 5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one (Example 49);
- N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide (Example 65); and
- 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-pyrido[2,3-d]pyrimidin-4(3H)one (Example 78).
- 72. The compound according to embodiment 67, wherein X is selected from N and CH;
- R10 is hydrogen; and
- R7 is alkyl.
- 73. The compound according to embodiment 72, wherein the compound of Formula II is selected from:
- 3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic acid (Example 53);
- 5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one (Example 59);
- 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one (Example 66); and
- 2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 67).
- 74. The compound according to embodiment 67, wherein R6 and R8 are each independently alkyl.
- 75. The compound according to embodiment 67, wherein R7 is selected from an amino or an alkoxy selected from the group represented by Formula III:
- wherein:
-
- A is selected from O and N;
- n is selected from 0, 1, 2, 3, 4 and 5;
- B is selected from —C(O)N(Rh)2—, —S(O)2N(Rh)2—, —C(O)—, —S(O)2—, —C(O)O—, wherein each Rh is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and
- R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
- In another embodiment, if A is O and B is —C(O)NH—, then R20 is not an unsaturated cycloalkyl.
- 76. The compound according to embodiment 75, wherein R6 and R8 are each independently alkyl.
- 77. A pharmaceutical composition comprising a compound according to embodiment 67 and a pharmaceutically acceptable carrier.
- 78. A method of treating cardiovascular disease, or cholesterol- or lipid-related disorders comprising administering a therapeutically effective amount of a compound according to embodiment 67.
- 79. A method of increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound according to embodiment 67.
- The present disclosure also provides pharmaceutical compositions comprising compounds as disclosed herein, formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
- Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the compound as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and the carrier or excipient (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and may be formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the active compound. Other pharmacologically active substances may also be present including other compounds. The formulations of the invention may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components.
- For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. In general, suitable formulations may be prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or molding a powder or granules of the compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
- Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a compound in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
- Formulations of the present invention suitable for parenteral administration comprise sterile aqueous preparations of the compounds, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention may contain from about 0.1 to about 5% w/w of the active compound.
- Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing the compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
- Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from about 0.1% to about 15% w/w of the composition, for example, from about 0.5% to about 2%.
- The amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician. For example, a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 μg to about 1000 mg. In another embodiment, intermittent administration, such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed. Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect. In accordance with standard dosing regimens, physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.
- A therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used. In one embodiment, the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration. Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.
- Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compositions that exhibit large therapeutic indices are preferable.
- Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and Table 1 for Equivalent Surface Area Dosage Factors).
-
TABLE 1 To: Mouse Rat Monkey Dog Human From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) Mouse 1 ½ ¼ ⅙ 1/12 Rat 2 1 ½ ¼ 1/7 Monkey 4 2 1 ⅗ ⅓ Dog 6 4 ⅗ 1 ½ Human 12 7 3 2 1 - The therapeutically effective dosage (i.e. ED50) may vary with the dosage form, route of administration, the subject's age, condition, and sex, as well as the severity of the medical condition in the subject. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
- In one embodiment, a compound as disclosed herein, or a pharmaceutically acceptable salt or hydrate thereof, is administered in combination with another therapeutic agent. The other therapeutic agent can provide additive or synergistic value relative to the administration of a compound of the present invention alone. The therapeutic agent can be, for example, a statin; a PPAR agonist, e.g., a thiazolidinedione or fibrate; a niacin, a RVX, FXR or LXR agonist; a bile-acid reuptake inhibitor; a cholesterol absorption inhibitor; a cholesterol synthesis inhibitor; an ion-exchange resin; an antioxidant; an inhibitor of AcylCoA cholesterol acyltransferase (ACAT inhibitor); a tyrophostine; a sulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; an apolipoprotein E regulator; a HMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein; an LDL-lowing drug; an HDL-raising drug; an HDL enhancer; a regulator of the apolipoprotein A-IV and/or apolipoprotein genes; or any cardiovascular drug.
- In one embodiment, a method of treating or preventing cardiovascular disease, cholesterol- or lipid-related disorders, comprises administering to a mammal (e.g., human) a therapeutically effective amount of a disclosed compound. The disclosed compound may be administered as a pharmaceutically acceptable composition, comprising a disclosed compound and a pharmaceutically acceptable carrier.
- As used herein, the term “cardiovascular disease” refers to diseases and disorders of the heart and circulatory system. Exemplary cardiovascular diseases, including cholesterol- or lipid-related disorders, include, but are not limited to acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholeasterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal artery atherosclerosis, rheumatic heart disease, stroke, thrombotic disorder, transitory ischemic attacks, and lipoprotein abnormalities associated with Alzheimer's disease, obesity, diabetes mellitus, syndrome X, impotence, multiple sclerosis, Parkinson's diseases and inflammatory diseases.
- One embodiment provides methods for altering lipid metabolism in a patient, e.g., increasing the ratio of HDL to LDL or ApoA-I to ApoB in the blood of a patient, comprising administering to the patient a composition of the invention in an amount effective to alter lipid metabolism.
- One embodiment provides methods for elevating the levels of ApoA-I associated molecules, such as HDL, in the blood of a mammal, comprising administering to the mammal a composition comprising a disclosed compound or composition in an amount effective to elevate levels of ApoA-I and HDL associated proteins in the mammal.
- In one embodiment, “treatment” or “treating” refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof. In another embodiment, “treatment” or “treating” refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient. In another embodiment, “treatment” or “treating” refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both. In yet another embodiment, “treatment” or “treating” refers to delaying the onset of a disease or disorder. For example, treating a cholesterol disorder may comprise decreasing blood cholesterol levels.
- One embodiment provides a compound for administration to a patient, such as a human, as a preventative measure against cardiovascular diseases, including-cholesterol- or lipid-related disorders. As used herein, “prevention” or “preventing” refers to a reduction of the risk of acquiring a given disease or disorder. An additional aspect of the invention provides a method for prevention of arteriosclerosis lesion development in a mammal, including the development of new arteriosclerotic lesions. In another aspect, the present invention provides a method for regressing arteriosclerosis lesions.
- In another embodiment, the present compositions are administered as a preventative measure to a patient, such as a human having a genetic predisposition to a cardiovascular disease, including cholesterol- or lipid-related disorders, for example familial hypercholeasterolemia, familial combined hyperlipidemia, atherosclerosis, a dyslipidemia, a dyslipoproteinemia, or Alzheimer's disease.
- In another embodiment, the compositions of the invention are administered as a preventative measure to a patient having a non-genetic predisposition to a cardiovascular disease, including cholesterol- or lipid-related disorders. Examples of such non-genetic predispositions include, but are not limited to, cardiac bypass surgery and percutaneous transluminal coronary angioplasty, which often leads to restenosis, an accelerated form of atherosclerosis; diabetes in women, which often leads to polycystic ovarian disease; and cardiovascular disease, which often leads to impotence.
- Angioplasty and open heart surgery, such as coronary bypass surgery, may be required to treat cardiovascular diseases, such as atherosclerosis. These surgical procedures entail using invasive surgical devices and/or implants, and are associated with a high risk of restenosis and thrombosis. Accordingly, the compounds of the invention may be used as coatings on surgical devices (e.g., catheters) and implants (e.g., stents) to reduce the risk of restenosis and thrombosis associated with invasive procedures used in the treatment of cardiovascular diseases.
- In another embodiment, the present compositions may be used for the prevention of one disease or disorder and concurrently treating another (e.g., prevention of polycystic ovarian disease while treating diabetes; prevention of impotence while treating a cardiovascular disease).
- Diseases and conditions associated with “diabetes mellitus” as defined herein refer to chronic metabolic disorder(s) caused by absolute or relative insulin deficiency including, but not limited to hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucose metabolism, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, ulcerative colitis, skin and connective tissue disorders, foot ulcerations, metabolic acidosis, arthritis, osteoporosis and impaired glucose tolerance.
- Exemplary compounds of the invention represented by the general formula A:
- wherein:
Ra may be selected from groups including, but not limited to, alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ether, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen and hydroxyl; Rb may be selected from groups including, but not limited to, alkyl and hydrogen; X may be selected from, e.g., CRc, N and NRc, where Rc represents substituents such as alkyl, alkenyl, alkynyl, and hydrogen; Y may be selected from, e.g., CRc, CO, CS, and SO2 where Rc is as defined above; and Z3 may be a single or double bond; may be synthesized from readily available starting materials as outlined in the exemplary schemes below. It should be appreciated that these designations are non-limiting examples. - Reaction of
aldehyde 1 with alkyne 2 in the presence of a Pd(II) catalyst, such as dichlorobis(triphenylphosphine)-palladium(II), followed by treatment with t-butylamine and Cul, can afford isoquinoline 3 as shown inScheme 1. - Scheme 2 illustrates that condensation followed by oxidation of amide 4 and
aldehyde 5 can provide quinazolinone 6. Condensation can occur under a variety of conditions, such as NaHSO3 and p-TsOH in dimethylacetamide, I2 in the presence of K2CO3, and treatment with catalytic trifluoroacetic acid followed by DDQ oxidation. Conversion of quinazolinone 6 into quinazoline 7 can be achieved by treatment with POCl3, followed by dehydration in the presence of a palladium catalyst. - Condensation of amide 8 with nitrile 9 in the presence of n-BuLi can afford
isoquinolinone 10, as shown in Scheme 3. - Scheme 4 provides a method for synthesizing benzothiazine-1,1-dioxide 13. Amide coupling of sulfonamide 11 with carboxylic acid 12 can be followed by treatment with n-BuLi to afford 13.
- Abbreviations used herein denote the following compounds, reagents and substituents: acetic acid (AcOH); 2,2′-azobisisobutyronitrile (AIBN); N-bromosuccinimide (NBS); N-tert-butoxycarbonyl (Boc); t-butyldimethylsilyl (TBDMS); m-chloroperoxybenzoic acid (mCPBA); dimethylaminopyridine (DMAP); dichloromethane (DCM); dimethylformamide (DMF); dimethylsulfoxide (DMSO); ethanol (EtOH); ethyl acetate (EtOAc); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl); 1-hydroxybenzotriazole (HOBt); iodomethane (MeI); lithium hexamethyldisilazide (LHMDS); methanol (MeOH); methoxymethyl (MOM); tetrahydrofuran (THF); triethylamine (Et3N); lithium aluminum hydride (LAH); p-toluenesulfonic acid (p-TSA); tetrabutylammonium fluoride (TBAF); N-methyl morpholine (NMM); N,N-dimethylacetamide (DMA); twice daily (BID), once daily (QD).
-
- To a solution of n-methyl-o-toluamide (2.0 g, 13.4 mmol) in THF (30 mL), n-butyl lithium (12.3 mL, 30.8 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. After completion of addition, the mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-methoxy benzonitrile (2.14 g, 16.08 mmol) in THF (5 mL) was added quickly. The cooling bath was removed and the solution was allowed to warm to room temperature. Saturated aqueous NH4Cl solution was added with cooling and the solid was isolated by filtration to give the methoxy compound (2.2 g, 65%). The methoxy compound (750 mg, 2.98 mmol) was added to a 50 mL flask and pyridinium hydrochloride (10 g) was added. The mixture was heated at 190° C. for 2 h, then cooled to room temperature, diluted with water, neutralized with NaHCO3, and the solid was isolated by filtration to give 3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (600 mg, 84%). Selected data: MS (ES) m/z: 238.92, 237.89; MP 239-241° C.
-
- To a solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) and 4-methoxyphenyl acetylene (1.58 g, 12 mmol) in 40 mL of triethylamine were added dichlorobis(triphenylphosphine)palladium(II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and the ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure. Purification of the crude compound by column chromatography (silica gel 230-400 mesh; 10% ethyl acetate in hexanes as eluent) afforded 2-(4-methoxy phenylethynyl)benzaldehyde (2.1 g, 89%). The above compound (2.06 g, 8.73 mmol) and t-butylamine (3.83 g, 52.4 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and the organic layer was dried over anhydrous Na2SO4, and concentrated to give the imine (2.4 g, 94%), which was used in the next step without further purification. To a solution of the above imine (2.39 g, 8.2 mmol) in 100 mL anhydrous DMF was added (0.156 g, 0.82 mmol) copper (I) iodide, and the solution was flushed with nitrogen. The reaction mixture was heated at 100° C. for 4 h. The mixture was cooled to room temperature, and diluted with ether (200 mL). The organic layer was washed with saturated aqueous ammonium chloride (3×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude compound as a dark colored solid. Purification by column chromatography (silica gel 230-400 mesh; 10% ethylacetate in hexanes as eluent) afforded 3-(4-methoxyphenyl)isoquinoline (1.064 g, 55%), as a white solid. The 3-(4-methoxyphenyl)isoquinoline (1.05 g, 4.47 mmol) was suspended in 30 mL hydroiodic acid and 12 mL of acetic acid was added. The reaction mixture was stirred at 110° C. for 2 h, then cooled to room temperature. The precipitate formed was filtered off, washed with acetic acid (2×5 mL) and dried under vacuum, to give a yellow solid. The crude compound was purified by triturating with 5% methanol in ether to give 4-isoquinolin-3-yl-phenol (0.83 g, 84%) as a white powder. Selected data: MS (ES) m/z: 222.89, 221.86; MP 218-219° C.
-
- To a solution of 4-isoquinolin-3-yl-phenol (0.133 g, 0.6 mmol) in anhydrous DMF (5 mL) were added HOBt (0.081 g, 0.6 mmol), Boc-Arg-(Boc)2-OH (0.285 g, 0.6 mmol), and EDCl (0.115 g, 0.6 mmol). N,N-Diisopropyl ethyl amine (0.233 g, 1.8 mmol) was added and the mixture was stirred at room temperature for 24 h. Water (15 mL) was added and the white precipitate was filtered off, washed with water and dried under vacuum to give 0.3 g (74%) of the Boc-arginine derivative. The above compound (0.3 g) was dissolved in anhydrous dichloromethane (10 mL). HCl gas was bubbled into the solution at 0° C. for 4 h. A yellow precipitate was formed. The solvent was removed and the resulting solid was dried under vacuum. Triturating with ether gave 4-(isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate tetrahydrochloride (0.2 g, 86%). Selected data: MS (ES) m/z: 222.96 (M+1-Arg), 221.99 (M-Arg); MP 198-201° C.
-
- A mixture of 3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (150 mg, 0.63 mmol) in DMF (5 mL), diisopropyl ethyl amine (245 mg, 1.89 mmol), EDCl (133 mg, 0.696 mmol), Boc-Arg (330 mg, 0.696 mmol) and HOBt (94 mg, 0.696 mmol) was stirred at room temperature for 24 h under nitrogen. The reaction mixture was diluted with water and the solid was collected by filtration. The crude product was purified by column chromatography using 5% MeOH in CH2Cl2, to give the tri-Boc ester product (375 mg 85%). HCl gas was bubbled through a solution of the tri-Boc ester (325 mg, 0.468 mmol) in CH2Cl2 (10 mL) for 6 h at 0° C. The solid was filtered off and washed with CH2Cl2 to give 4-(1-oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate trihydrochloride (170 mg, 72%). Selected data: MS (ES) m/z: 237.25 (M-Arg); 13C-NMR (DMSO-d6): δ 168.8, 163.4, 157.7, 151.0, 139.8, 139.5, 133.4, 132.8, 128.9, 127.4, 127.3, 127.25, 125.6, 122.6, 104.2, 55.6, 52.5, 27.7, 25.0.
-
- To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and 4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL) were added dichlorobis(triphenylphosphine)palladium (11) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h, then cooled to room temperature. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure leaving 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as a yellow solid. 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol) and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and dried over anhydrous Na2SO4. Removal of solvent gave the expected imine (2.72 g, 97%), which was used in next step without further purification. To a solution of the above imine (2.7 g, 9.23 mmol) in anhydrous DMF (50 mL) was added copper (I) iodide (0.190 g, 0.1 mmol). The reaction mixture was heated at 100° C. for 4 h, then cooled to room temperature and diluted with ether (200 mL). The organic layer was washed with a saturated aqueous ammonium chloride solution (3×100 mL). The organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude compound as a dark-colored solid. Purification by column chromatography (silica gel 230-400 mesh; 30% ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl) [1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of 7-(4-methoxy phenyl) [1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrous N-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol) and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture was stirred at 190° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature. The compound was purified by column chromatography to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. Selected data: MS (ES) m/z: 223.95, 222.95; MP 219-221° C.
-
- To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.3 mmol) in CH2Cl2 (30 mL), oxalyl chloride (3.62 g, 28.5 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent and excess oxalyl chloride were removed at reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine hydrochloride (1.33 g, 42.81 mmol) was added on cooling and the mixture was stirred at room temperature for 4 h. The solvent was removed and the crude product was purified by chromatography using 5% methanol in CH2Cl2, to give 1.3 g of the amide intermediate (43% yield). To a solution of the amide intermediate (1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and the mixture was stirred at room temperature for 16 h. Saturated aqueous NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give the crude intermediate, which was purified by chromatography using 5% methanol in CH2Cl2, to give two products (1) 678 mg of isoquinoline in 26% yield and (2) 780 mg of quinalone product in 27% yield. To a suspension of the above quinalone product (780 mg, 1.65 mmol) in ethanol (20 mL), conc. HCl (2 mL) was added and the mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed and purified by chromatography to give 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%). Selected data: MS (ES) m/z: 297.93; MP 245-247° C.
-
- To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.61 g, 13.1 mmol) in CH2Cl2 (50 mL), oxalyl chloride (3.38 g, 26.6 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent and excess oxalyl chloride were removed at reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine (1.24 g, 39.9 mmol) with cooling and was stirred at room temperature for 4 h. The solvent was removed and crude product was purified by chromatography by using 5% methanol in CH2Cl2 to give the amide (2.27 g, 82%). To a solution of the above amide (2.27 g, 10.9 mmol) in THF (50 mL), n-butyl lithium (9.98 mL, 25.0 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling, maintaining the temperature below 20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C., and a solution of 4-O-TBDMS-3,5-dimethyl benzonitrile (2.97 g, 11.39 mmol) in THF (10 mL) was added quickly, the cooling bath was removed and the mixture was stirred for 16 h at room temperature. A saturated aqueous NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give 3.9 g of the crude product mixture. A suspension of the crude product mixture (3.9 g) in ethanol (20 mL) was heated with conc. HCl (2 mL) at 80° C. for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed. The solid was dissolved in water and neutralized by NaHCO3, followed by extraction with CH2Cl2. The product was purified by chromatography to give two products: 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methylisoquinolin-1(2H)-one (128 mg, 5%) and 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (340 mg, 9%). Selected data for 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methylisoquinolin-1(2H)-one: MS (ES) m/z: 340.01 (M); MP 253-254° C. Selected data for 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one: MS (ES) m/z: 326.00; MP 226-227° C.
-
- Oxalyl chloride (1.90 mL, 21.8 mmol) was added to 2-methyl nicotinic acid (1.50 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) with triethylamine (1.6 mL, 11.5 mmol) and the reaction mixture was kept at room temperature overnight before the solvent was removed. THF was added to the residue and ammonia gas was bubbled through for 2 h. The THF was removed and the residue was dissolved into methanol and water and the pH was adjusted to 10.0 with potassium carbonate. The mixture was concentrated. After column chromatography the desired amide was isolated (1.10 g, 73.8%).
- NaH (0.428 g, 10.7 mmol, 60% in mineral oil) was added to 4-hydroxy-3,5-dimethylbenzonitrile (1.50 g, 10 mmol) in anhydrous DMF (8 mL). Benzyl bromide (1.83 g, 10.7 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The isolated solid was further washed with hexane to yield the desired ether building block (2.0 g, 84.3%). It was used in the next reaction without further purification. The above amide (0.65 g, 4.77 mmol) in anhydrous THF (15 mL) was added drop-wise to BuLi (7.5 mL, 1.60 M) at −20° C. The reaction mixture was kept at this temperature for 1 h and then the above ether building block (1.13 g, 4.77 mmol) in THF (20 mL) was added drop-wise at −20° C. and the reaction was stirred for 1.5 h. The reaction temperature was increased to room temperature and continued for a further 1 h. Water (20 mL) was added and the mixture was stirred for a while before the solvent was removed and the residue was purified by column chromatography to yield the desired intermediate (0.50 g, 29.4%). A 50 mL flask was charged with the above described intermediate (0.50 g, 0.0014 mol) and pyridine hydrogen chloride (2.4 g, 0.014 mol) and the mixture was heated to 180° C. for 1.5 h. The mixture was cooled and poured into methanol (4 mL), then filtered. The collected solid was further washed with ethyl acetate and dried to give 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (350 mg, 82.7%) as an HCl salt. Selected data: MS (ES) m/z: 266; MP>350° C.
-
- To a solution of 3,5-dimethyl-4-hydroxy benzonitrile (1.0 g, 6.79 mmol) in DMF (100 mL), were added a NaH (1.065 g, 26.63 mmol) and (2-bromoethoxy)-tert-butyl dimethyl silane (1.95 g, 8.15 mmol). The reaction mixture was stirred for 10 d at room temperature under nitrogen. The reaction mixture was poured into ice-water and the products were extracted with ethyl acetate. The organic layer was separated, washed with water, dried and concentrated to give crude product, which was purified by column chromatography to give 1.9 g of the B-ring building block in 92% yield.
- n-Butyl lithium (2.84 mL, 7.1 mmol, 2.5 M solution in hexane) was added slowly to a solution of 2,4-dimethoxy-6-methyl benzamide (650 mg, 3.1 mmol) in THF (30 mL), under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. After completion of addition, the mixture was stirred for 1 h at 0° C., and then cooled to −50° C. and a solution of 4-(2-tert-butyldimethyl silanyloxy)ethoxy)-3,5-dimethyl benzonitrile (the B-ring building block, above) (996 mg, 3.26 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred for 16 h at room temperature. A saturated NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give 1.2 g of crude product.
- The above crude product (1.2 g) was treated with ethanol (10 mL) and conc. HCl (2 mL) at 80° C. for 1 h. The solvent was removed and the residue was dissolved in methanol and neutralized by NaHCO3. The solvent was evaporated and crude product was purified by column chromatography to give 3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (100 mg, 11%). Selected data: MP 193-195° C.
-
- In a 250 mL round-bottomed flask were placed 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol), Ph3P (1.96 g, 7.47 mmol), diisopropylethylamine (1.75 g, 13.59 mmol) and 2-dimethylaminoethanol (660 mg, 7.47 mmol) in THF (30 mL). DEAD (1.42 g, 8.15 mmol) was added drop-wise at room temperature. The reaction mixture was stirred for 48 h at room temperature and water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4 and concentrated to give crude product. The crude product was purified by column chromatography to give 1.17 g (79%) of the B-ring building block.
- n-Butyl lithium (4.2 mL, 10.54 mmol, 2.5 M solution in hexane) was added slowly to a solution of 2,4-dimethoxy-6-methyl benzamide (958 mg, 4.58 mmol) in THF (30 mL) under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. After completion of the addition, the mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-(2-dimethylamino ethoxy)-3,5-dimethyl benzonitrile (1.1 g, 5.04 mmol) (the B-ring building block) in THF (10 mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 16 h at room temperature. A saturated NH4Cl solution was added with cooling and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give crude product. The crude product was purified by chromatography to give 3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (162 mg, 8%) as a hydrochloride. Selected data: MS (ES) m/z: 397.06; MP 261-263° C. at decomposition (HCl).
-
- Hydrogen bromide in acetic acid (13 mL, 33 wt %) was added to a mixture of 2-methyl benzoic acid (4.08 g, 30 mmol), paraformaldehyde (2.50 g, 83.0 mmol), and o-phosphoric acid (7 mL, 85%). The reaction mixture was stirred at 115° C. for 15 h. It was cooled to room temperature and poured into ice-cold water. A white precipitate was formed. The mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 6.84 g of a white solid, which was used in the next step without further purification. The above compound (6.8 g) was dissolved in anhydrous dichloromethane (150 mL). Oxalyl chloride (7.8 mL) was added drop-wise. After the addition was complete, 3 drops of anhydrous DMF were added. A vigorous reaction occurred and the stirring was continued overnight. Solvent and excess oxalylchloride were removed under reduced pressure and the residue was dried under vacuum to give 7.02 g of brown liquid, which was used in the next step without further purification. The above compound (7.02 g, 28.36 mmol) was dissolved in anhydrous THF (60 mL) and cooled to 0° C. A solution of N-methylamine (2.0 M in THF, 19 mL, 38.03 mmol) was added drop-wise under nitrogen. The stirring was continued for 15 min at 0° C. The ice-bath was removed, and the stirring was continued at room temperature for 3 h. A white precipitate was formed. Water (100 mL) was added and the mixture was extracted with ethyl acetate (150 mL). The organic layer was separated, washed with water (50 mL), saturated NaHCO3 solution (2×50 mL), water (50 mL), and brine (50 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 5.64 g of 5-bromomethyl-2,N-dimethylbenzamide as a white solid which was used in the next step without further purification. To a solution of the above compound (2.42 g, 10 mmol) in anhydrous THF was added morpholine (1.92 g, 22 mmol) at room temperature under nitrogen. A white precipitate was formed. Stirring continued overnight. Water (100 mL) was added and the mixture was extracted with ethyl acetate (150 mL). The organic layer was separated, washed with water (50 mL) and brine (50 mL) and dried (Na2SO4). Removal of solvent gave a colorless oil, which was purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent) to give the desired benzamide intermediate (yield 0.50 g, 20%). N-Butyl lithium (1.6 M solution in hexanes, 4.1 mL, 6.6 mmol) was added drop-wise to a solution of the benzamide (0.5 g, 2.0 mmol) in anhydrous THF (4 mL) at −10° C. over a period of 10 min under nitrogen. Stirring was continued at 0° C. for 1 h. The reaction mixture was cooled to −50° C. A solution of 4-(tert-butyldimethylsilanyloxy)-3,5-dimethylbenzonitrile (0.653 g, 2.5 mmol) in anhydrous THF (3 mL) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued at room temperature for 1 h. An aqueous ammonium chloride solution (5 mL) was added followed by ethyl acetate (50 mL). The organic layer was separated, washed with water (5 mL) and dried (Na2SO4). Removal of the solvent gave 1.23 g pale yellow gummy material, which was used in next step without further purification. The above compound (1.2 g) was dissolved in 10 mL anhydrous ethanol. Conc. HCl (1 mL) was added and the mixture was refluxed for 15 min, then cooled to room temperature. The solvent was removed under reduced pressure. The crude compound was basified with methanolic ammonia and purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent) to give 3-(4-hydroxy-3,5-dimethylphenyl)-7-morpholin-4-ylmethyl-2H-isoquinolin-1-one (35 mg) as a white solid (the free base). To a solution of the above compound (35 mg) in CH2Cl2 (5 mL) and MeOH (1 mL) was added drop-wise hydrogen chloride in ether (0.5 mL, 1.0 M) under nitrogen. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and dried under vacuum to give the hydrochloride of 3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one (36 mg, 93%) as a yellow solid. Selected data: MP 281-283° C. (hydrochloride).
-
- A mixture of malonic acid (20 g, 192 mmol), 2,4,6-trichlorophenol (72 g, 365 mmol), and phosphorus oxychloride (38 mL, 403.2 mmol) was stirred at reflux for 12 h. The reaction mixture was cooled to 70° C. and poured into ice water. The solid was collected by filtration, washed with water, and air-dried to give malonic acid bis-(2,4,6-trichloro-phenyl) ester (85 g, 95%). A solution of malonic acid bis-(2,4,6-trichloro-phenyl) ester (85 g, 183.6 mmol) and ethyl 3-aminocrotonate (26.1 g, 202 mmol) in bromobenzene (100 mL) was stirred at reflux for 50 min. The reaction mixture was cooled to 50° C. and diluted with EtOAc (260 mL). The solid was collected by filtration, washed with water, and air-dried, to give 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 86%).
- A solution of 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 157 mmol) in phosphorus oxychloride (60 mL, 629 mmol) was stirred at reflux for 1.5 h. The extra phosphorus oxychloride was removed and the reaction mixture was poured into ice water. The solid was removed by filtration. The filtrate was extracted with dichloromethane (3×100 mL) and concentrated. The residue was further purified by column chromatography to yield 4,6-dichloro-2-methyl nicotinic acid ethyl ester (16.9 g, 46%). A solution the ester (16.9 g, 71.3 mmol) in MeOH (60 mL) was mixed with sodium methoxide (58 mL, 257 mmol) and stirred at reflux for 12 h. The reaction was quenched by adding AcOH (50 mL), diluted with water (200 mL), extracted with dichloromethane (3×100 mL), and concentrated. The residue was purified by column chromatography to yield 4,6-dimethoxy-2-methyl nicotinic acid methyl ester (10 g, 67%). A solution of the ester (2.6 g, 12.3 mmol), lithium hydroxide (1.06 g, 44.1 mmol) in water (40 mL), MeOH (30 mL) and THF (20 mL) was stirred at reflux for 4 h. The reaction mixture was concentrated to dryness. The residue was mixed with HCl (conc., 20 mL) and was concentrated to dryness to yield crude 4,6-dimethoxy-2-methyl nicotinic acid (quantitative). To a solution of 4,6-dimethoxy-2-methyl nicotinic acid (2.5 g, 12.0 mmol) in dichloromethane (50 mL) and THF (50 mL) at room temperature was added oxalyl chloride (2.57 mL, 29.4 mmol) and DMF (3 drops). The reaction mixture was stirred at room temperature for 0.5 h, concentrated to afford 4,6-dimethoxy-2-methyl nicotinic acid chloride HCl salt (2.8 g). A solution of 4,6-dimethoxy-2-methyl nicotinic acid chloride HCl salt (8.5 g, 33.73 mmol) in dichloromethane (20 mL) and THF (20 mL) at room temperature was mixed with methylamine in THF (50 mL, 98 mmol) and stirred at 20° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (3×100 mL), and concentrated to yield 4,6-dimethoxy-2,N-dimethyl-nicotinamide (4.2 g, 66%) as a light yellow solid. A solution of 4-hydroxy-3,5-dimethylbenzonitrile (2 g, 13.6 mmol) in DMF (20 mL) at room temperature was mixed with sodium hydride (0.706 g, 17.6 mmol) and stirred for 0.5 h. Benzyl bromide (1.62 mL, 13.59 mmol) was then added and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched by adding water (200 mL), extracted with EtOAc (3×100 mL), and concentrated. The residue was purified by column chromatography to yield 4-benzyloxy-3,5-dimethylbenzonitrile (3.25 g, 100%), as a white solid. To a solution of 4,6-dimethoxy-2,N-dimethyl-nicotinamide (0.54 g, 2.57 mmol) in THF (50 mL) at −20° C. was added n-BuLi (3.54 mL, 5.67 mmol). The reaction was stirred at −20° C. to 0° C. for 2 h and then was cooled to −78° C. 4-Benzyloxy-3,5-dimethylbenzonitrile (0.49 g, 2.057 mmol) was added, the cooling bath was removed, and the reaction was allowed to warm to room temperature. After 14 h, the reaction was quenched by adding water (100 mL), extracted with dichloromethane (3×100 mL), and concentrated. The residue was purified by column chromatography to yield 7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one (0.32 g, 37%). A solution of 7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one (0.25 g, 0.6 mmol) in dichloromethane (100 mL) was mixed with BBr3 (3 mL, 3 mmol) and stirred at room temperature for 16 h. The reaction was quenched by adding water (20 mL). The resulting solid was collected by filtration, washed with water and DCM, to yield a light yellow solid. This solid was mixed with HCl in ether (10 mL, 10 mmol), stirred for 1 h, and filtered to afford 2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)-one hydrochloride (70 mg, 37%) as a light yellow solid. Selected data: MS (ES) m/z: 312; MP>330° C. (hydrochloride).
-
- A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0° C. HCl gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10° C., the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45° C. to give the hydrochloride (242.3 g, 98%), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (1700° C. external temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0° C. and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin (17.2 g, 79%) as a yellow-green solid. To a heated solution (external temp 70° C.) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40%, 1.5 L) was added H2O2(35%, 405 mL) slowly over 2 h-After the addition of each portion of H2O2, the internal reaction temperature (initially 64° C.) increased (to a maximum temp of 80° C.). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70′C, and the mixture was allowed to stir overnight while cooling to room temperature. The mixture was heated to 70° C. Additional H2O2(75 mL) was added, and the mixture was stirred at 70° C. for a further 2 h until the reaction was complete. After cooling to 10° C. (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCl (37%, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40° C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55%). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCl (89.2 g, 0.48 mol), HOBT (65 g, 0.48 mol), and NMM (51.3 mL), and the mixture was allowed to stir at room temperature for 3 h. Aqueous NH3 (83 mL, 50%) was added, and the mixture was stirred at room temperature for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2×250 mL). The combined extracts were then washed with water (2×500 mL). Concentration, formation of a slurry with ether (550 mL), filtration, and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g, 57%) as a brown solid.
- 2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80° C., for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 51%) as a white solid. Selected data: MP 291-293° C.
-
- To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.5 mmol) and 1-chloro-2-methyl propan-2-ol (8.85 g, 81.5 mmol) in ethanol (50 mL) was added potassium carbonate (7.5 g, 54 mmol) and water (5 mL). The reaction mixture was stirred at reflux for 24 h and cooled to room temperature. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.9 g, 97%) as a white solid.
- To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol) and tert-butyldimethylsilylchloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 d. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (2.24 g, 54%). N-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 mL) drop-wise at −10° C. over a period of 10 min under nitrogen. The stirring was continued at 0° C. for 1 h. The reaction mixture was cooled to −50° C. A solution of 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (1.58 g, 4.73 mmol) in anhydrous THF (5 mL) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued at room temperature for 1 h. An aqueous ammonium chloride solution (10 mL) was added followed by ethyl acetate (100 mL). The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent) to give 3-{4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylphenyl}-6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37%), as a white solid.
- The above compound (0.42 g, 0.82 mmol) was dissolved in anhydrous THF (20 mL). Tetrabutylammonium fluoride (4.1 mL, 1.0 M solution in THF) was added at 0° C. The reaction mixture was stirred at 0° C. for 10 min, then at room temperature for 2 h and then stirred at 70° C. for 24 h. The mixture was cooled to room temperature. Saturated aqueous ammonium chloride (30 mL) was added. The organic layer was separated, washed with water, brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh; 0-4% methanol in CH2Cl2 as eluent) to give 3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (0.15-g, 46%), as a white solid. Selected data: MS (ES) m/z: 397.98; MP 252-254° C. at decomposition.
-
- To a 3-necked, round-bottomed flask was added 3,5-dimethoxytoluene (6.088 g, 40 mmol) and cyclohexane (28 mL) under nitrogen. Dimethyl carbonate (30.3 g, 336 mmol) was added and the reaction mixture was heated at 60° C. Excess chlorosulfonic acid was added over a period of 15 min. The liberated HCl gas was removed by inserting a tube into solid sodium hydroxide. On completion of the addition, the reaction mixture was heated to 70-72° C. for 1 h and then cooled to room temperature. The solid was filtered off and washed with dimethyl carbonate/cyclohexane (1:1, 20 mL). The solid was dried in vacuo to obtain pure material (6.13 g, 66%). To a mixture of the sulfonic acid (product from above, 4.65 g, 20 mmol) and triethyl amine (2.03 g, 2.79 mL) in acetone (40 mL) was added 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride, 3.69 g, 20 mmol). The reaction mixture was heated under reflux for 20 h before being cooled to room temperature. The solution was passed through a Celite pad and evaporated in vacuo to leave a solid, which was filtered off and washed with hexane. The mixture of product and salt of cyanuric hydroxide and triethyl amine (7.58 g) was used for the next step without further purification.
- To a 3-necked, round-bottomed flask, equipped with a condenser (acetone-dry ice cooling), was added the mixture from the step above (7.58 g) and acetone (100 mL). The reaction mixture was cooled to −78° C. and ammonia gas was bubbled through the solution for 0.5 h. The reaction mixture was kept standing overnight, allowing slow evaporation of ammonia gas, followed by the evaporation of solvent. Water was added and the product was extracted with DCM. The solvent was dried and evaporated to leave a mixture of solid and a dense liquid. The solid was filtered off and washed with hexane to leave pure sulfonamide (3.23 g, 70%).
- To a round-bottomed flask was added 3,5-dimethyl-4-hydroxybenzoic acid (2.99 g, 18 mmol). Anhydrous DMF (20 mL) was added, followed by sodium hydride (1.8 g, 45 mmol). The reaction mixture was stirred at room temperature for 1 h. p-Methoxybenzyl chloride (6.20 g, 39.6 mmol) was added and the mixture was stirred at room temperature overnight (˜20 h). The reaction mixture was poured into water, acidified with 1 N HCl and stirred for 1 h. The precipitated solid was filtered off, washed with water and hexane to obtain pure B-ring building block (6.93 g, 95%).
- The B-ring building block (6.93 g, 17.1 mmol) was dissolved in a mixture of methanol (50 mL) and tetrahydrofuran (50 mL). Potassium hydroxide (1.25 g, 22.2 mmol) in water (20 mL) was added. The reaction mixture was refluxed at 70° C. for 24 h. The solvent was evaporated in vacuo. Water was added and the reaction mixture was acidified with 1 N HCl (pH 4-5). The solid was filtered off, washed with water and hexane. The yield was 4.61 g (94%). The product (1.932 g, 6.75 mmol) and the sulfonamide from above (1.04 g, 4.5 mmol) were taken in a 3-necked, round-bottomed flask under nitrogen. Dichloromethane (100 mL) was added with stirring. To this stirred mixture was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl. HCl, 1.36 g, 7.09 mmol), followed by N,N-dimethylaminopyridine (2.06 g, 16.9 mmol). The reaction mixture was stirred at room temperature for 24 h before being washed with 1 N HCl, 2.5% NaOH and saturated sodium bicarbonate solutions. The organic layers were dried and evaporated in vacuo to leave a residue, which was purified by silica gel (100 g) column chromatography, employing 20-50% ethyl acetate in hexane and 5% methanol in dichloromethane as eluents. Fractions 30-66 were combined to obtain pure materials (1.35 g, 60%). The compound from the step above (0.105 g, 0.21 mmol) was dissolved in tetrahydrofuran under nitrogen and cooled to −78° C. n-Butyllithium was added and the reaction mixture was allowed to warm to room temperature slowly and stirred overnight (˜14 h). TLC showed incomplete conversion. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The solvent was evaporated in vacuo to leave a residue that was purified by silica gel (15 g) column chromatography, employing 20-50% ethyl acetate in hexane as eluents. The product was not pure enough, so another column was used, employing 0.5% methanol in hexane as eluent, and finally preparative TLC was employed to purify the material. The compound from the step above (0.277 g) was dissolved in trifluoroacetic acid (10 mL) under nitrogen and the reaction mixture was refluxed (
bath temperature 80° C.) for 4 d. The solvent was evaporated in vacuo and the residue was dissolved in 0.25 N NaOH (20 mL), and acidified with acetic acid. The solid had precipitated out at this point. The solid was filtered off and washed with water, hexane and dried. From one batch, 0.005 g of pure material was isolated. From another batch, 0.060 g compound was isolated, which was not pure enough. This compound was further purified by preparative HPLC to give pure 6,8-dimethoxy-3-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2-benzothiazine-1,1-dioxide (0.010 g). Selected data: MP 246.6-247.4° C. -
- A mixture of malonic acid (20 g, 192 mmol), 2,4,6-trichlorophenol (72 g, 365 mmol), and phosphorus oxychloride (38 mL, 403.2 mmol) was stirred at reflux for 12 h. The reaction mixture was cooled to 70° C. and poured into ice water. The solid was collected by filtration, washed with water, and dried to give malonic acid bis-(2,4,6-trichloro-phenyl) ester (85 g, 95%). A solution of malonic acid bis-(2,4,6-trichloro-phenyl) ester (85 g, 184 mmol) and ethyl 3-aminocrotonate (26.08 g, 201.9 mmol) in bromobenzene (100 mL) was stirred at reflux for 50 min. The reaction mixture was cooled to 50° C. and diluted with EtOAc (260 mL). The solid was collected by filtration, washed with water, and dried to give 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 86%). A solution of 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 157 mmol) in phosphorus oxychloride (60 mL, 629 mmol) was stirred at reflux for 1.5 h. The extra phosphorus oxychloride was removed and the reaction mixture was poured into ice water. The solid was removed by filtration. The filtrate was extracted with dichloromethane (3×100 mL) and concentrated. The residue was further purified by column chromatography, to yield 4,6-dichloro-2-methyl nicotinic acid ethyl ester (16.9 g, 46%). A solution of 4,6-dichloro-2-methyl nicotinic acid ethyl ester (16.9 g, 71.3 mmol) in MeOH (60 mL) was mixed with sodium methoxide (58 mL, 256.68 mmol) and stirred at reflux for 12 h. The reaction was quenched by adding HOAc (50 mL). The mixture was diluted with water (200 mL), extracted with dichloromethane (3×100 mL), and concentrated. The residue was purified by column chromatography (SiO2, hexanes/EtOAc=6:1), to yield 4,6-dimethoxy-2-methyl nicotinic acid methyl ester (10 g, 67%). A solution of 4,6-dimethoxy-2-methyl nicotinic acid methyl ester (2.6 g, 12.3 mmol), lithium hydroxide (1.06 g, 44.08 mmol) in water (40 mL), MeOH (30 mL) and THF (20 mL) was stirred at reflux for 4 h. The reaction mixture was concentrated to dryness. The residue was mixed with HCl (conc., 20 mL) and was concentrated again on high vacuum to dryness to yield crude 4,6-dimethoxy-2-methyl nicotinic acid (quantitative yield). To a solution of 4,6-dimethoxy-2-methyl nicotinic acid (2.5 g, 12.0 mmol) in dichloromethane (50 mL) and THF (50 mL) at room temperature was added oxalyl chloride (2.57 mL, 29.4 mmol) and DMF (3 drops). The reaction mixture was stirred at room temperature for 0.5 h, concentrated to dryness using a rotary evaporator to afford crude 4,6-dimethoxy-2-methyl nicotinic acid chloride HCl salt (2.8 g, quantitative). A solution of 4,6-dimethoxy-2-methyl nicotinic acid chloride HCl salt (4.8 g, 23.5 mmol) in dichloromethane (100 mL) at room temperature was poured into a beaker of ammonium hydroxide (200 mL). The reaction mixture was stirred at room temperature for 1 h, extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator to yield 4,6-dimethoxy-2-methyl-nicotinamide (2.4 g, 52%) as a light yellow solid. A solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.59 mmol) in DMF (20 mL) at room temperature was mixed with sodium hydride (0.706 g, 17.6 mmol) and stirred for 0.5 h. Benzyl bromide (1.62 mL, 13.59 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched by adding water (200 mL), extracted with EtOAc (3×100 mL), and concentrated. The residue was purified by column chromatography to yield 4-benzyloxy-3,5-dimethylbenzonitrile (3.25 g, 100%) as a white solid. To a solution of 4,6-dimethoxy-2-methyl-nicotinamide (1 g, 5.1 mmol) in THF (120 mL) at −20° C. was added n-BuLi (9.6 mL, 15.3 mmol). The reaction was stirred at −20-0° C. for 2.5 h and then was cooled to −78° C. 4-Benzyloxy-3,5-dimethylbenzonitrile (1.21 g, 5.1 mmol) was added, the cooling bath was removed, and the reaction was allowed to warm up gradually to room temperature. After stirring at room temperature for 20 h the reaction was quenched by adding water (100 mL), extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc/MeOH=3:2:1) to yield 7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-[1,6]naphthyridin-5-ylamine (0.4 g, 19%) and 7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one (0.34 g, 16%). A solution of 7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one (0.34 g, 0.82 mmol) in DMF (100 mL) and MeOH (100 mL) was mixed with palladium/carbon (0.1 g) and subjected to hydrogenation (50 psi) for 2 h. The mixture was filtered through a Celite-pad. The filtrate was concentrated on high vacuum to afford 7-(4-hydroxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one (0.23 g, 88%). A solution of 7-(4-hydroxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one (0.23 g, 0.7 mmol) in MeOH (20 mL) and DCM (20 mL) was mixed with HCl in ether (7 mL, 7 mmol) and stirred for 0.5 h. The reaction was concentrated using a rotary evaporator to get a solid residue. The solid was rinsed with DCM, collected by filtration, washed with DCM to yield the HCl salt of 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (0.15 g, 59%) as a light yellow solid. Selected data: MS (ES) m/z: 327.06; MP>324° C. at decomposition (HCl salt).
-
- Methyl acetoacetate (69.67 g, 0.6 mol) in dry THF (350 mL) was cooled to −5° C. and sodium hydride (60% in mineral oil, 24.5 g) was added at −5 to 0° C. in 30 min. Diketene (50.4 g) in dry THF (80 mL) was then added drop-wise at 5° C. over 20 min. The resulting solution was allowed to stir for 1 h at −5° C., after which it was allowed to warm to room temperature and stirred overnight. Acetic acid (35 mL) was added and the THF solvent was removed. Water (200 mL) and ethyl acetate (300 mL) was added to the residue, pH was adjusted to 5.0 by adding HCl solution. The organic layer was separated and washed with brine and dried over sodium sulfate. After column purification and recrystalization, compound A (methyl 2,4-dihydroxy-6-methylbenzoate) was obtained (yield: 26.6 g, 24.3%). Sodium hydride (11.2 g, 0.279 mol, 60% in mineral oil) was added to compound A (24.8 g, 0.136 mol) in DMF (150 mL). The reaction temperature was cooled to −30° C. and methyl iodide (21.3 mL, 0.341 mol) was added and the reaction was kept at room temperature overnight. Sodium iodide was filtered off and DMF was removed. The residue was mixed with water (100 mL) and extracted with ethyl acetate. The organic layer was further washed with brine and dried over sodium sulfate. The crude mixture was purified by column chromatography to yield compound B (11.40 g, 39.9%). To a solution of compound B (11.4 g, 0.054 mol) in dry CCl4 (90 mL) was added N-bromosuccinimide (10.6 g, 0.0596 mol). The mixture was refluxed overnight. CCl4 was removed. Water (100 mL) was added to the residue and the solid was filtered off and washed with water and a mixture of ethyl acetate (10 mL) and hexane (30 mL) to yield compound C (13.1 g, 83.9%). Compound C (12.5 g, 0.043 mol), chloromethyl methyl ether (81.0 g) and anhydrous zinc chloride (7.0 g, 0.0513 mol) was kept at room temperature overnight. Chloromethyl methyl ether was removed and the residue was mixed with water and the pH was adjusted to 7 by adding sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over sodium sulfate. Compound D (7.39 g, 50.6%) was obtained after column chromatography. Compound D (7.39 g, 0.0218 mol), morpholine (7.62 g, 0.0875 mol), and anhydrous THF (20 mL) were stirred at room temperature overnight. The solvent was evaporated. Water and ethyl acetate were added to the residue, pH was adjusted to 9.0 with sodium bicarbonate. The organic layer was washed with brine and dried with sodium sulfate. Compound E (5.4 g, 63.8%) was obtained after column chromatography. The hydrogenation reaction was carried out at 50 psi with compound E (5.4 g, 0.0139 mol) in THF (100 mL) and triethyl amine (3.9 mL) with Pd/C (10%, 2.6 g) as a catalyst for 2 d. After the catalyst was filtered off, the organic layer was purified by column chromatography to yield compound F (3.20 g, 74.4%) and 1.1 g starting material E. Compound F (3.20 g, 0.0103 mol) was dissolved in ethanol (30 mL) and potassium hydroxide (2.31 g, 0.041 mol) in water (20 mL) was added and the reaction mixture was heated to 100° C. overnight. The solvent was removed, the pH was adjusted to 6.0 and the water was removed. The residue was further dried under high vacuum and the compound was extracted with ethanol to yield compound G (2.95 g, 99%). Compound G (2.80 g, 0.0095 mol) was mixed with thionyl chloride (7.0 mL, 0.0108 mol) and heated to reflux for 1 h. Excess thionyl chloride was removed and the residue was further dried under high vacuum and anhydrous THF (20 mL) was added and methylamine in THF (2.0 M, 30 mL) was added and the reaction was stirred for overnight. THF was removed and pH was adjusted to 8.0-9.0, the mixture was extracted with dichloromethane and dried over sodium sulfate to give compound H (2.50 g, 85.4%).
- NaH (1.14 g, 0.0285 mol, 60% in mineral oil) was added to 4-hydroxy-3,5-dimethylbenzonitrile (4.0 g, 0.027 mol) in anhydrous DMF (20 mL), followed by benzyl bromide (3.27 mL, 0.027 mol). The reaction was kept at room temperature overnight. The reaction mixture was poured into water and the solid was filtered off and washed with hexane to yield compound I (5.7 g, 89%). Compound I was used for the next step without further purification.
- n-BuLi (1.60 M, 3.3 mL) was added drop-wise to compound H (0.25 g, 0.81 mmol) in anhydrous THF (25 mL) at −10° C. The reaction mixture was kept at 0° C. for 1 h then the cool bath was removed and the reaction mixture was further stirred for 45 min. Compound I (0.192 g, 0.81 mmol) in anhydrous THF (5 mL) was added drop-wise at −10° C. and the reaction was further kept for 30 min; the reaction temperature was increased to room temperature and the reaction mixture was stirred for a further 1 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The solvent was removed and the residue was treated with acetic acid at 65° C. for 30 min then purified by column chromatography to yield compound J (0.110 g, 25.9%). Product J (300 mg) in methanol (80 mL) and 10% Pd/C (100 mg) as catalyst was stirred under H2 (50 psi) for 1 h. The catalyst was filtered off and the solvent was removed. The residue was purified by column chromatography (10% methanol in ethyl acetate) to yield 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one (60 mg, 29.8%) and 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl)isoquinolin-1(2H)-one (40 mg, 16.8%). Selected data for 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one: MP 246-248° C. Selected data for 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl)isoquinolin-1(2H)-one: MP 224-225° C.
-
- Phosphorousoxychloride (10 mL, 109.24 mmol) was added drop-wise at 0° C. to a stirred solution of 1-bromo-3,5-dimethoxy benzene (9.1 g, 41.9 mmol) in anhydrous DMF (40 mL). The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min, then at 100° C. for 4 h. The reaction mixture was cooled to room temperature, poured into ice-cold water and kept overnight. A solid precipitated and was filtered off, washed with water and dried under vacuum to give 2-bromo-4,6-dimethoxy benzaldehyde (8.67 g, 84%) as a yellow solid. To a solution of 4-bromo-2,6-dimethylphenol (6.03 g, 30 mmol) in anhydrous DMF (100 mL) was added sodium hydride (60% suspension in mineral oil, 1.26 g, 31.5 mmol) in small portions under nitrogen at room temperature. The reaction mixture was stirred for 30 min. Benzyl bromide (5.39 g, 31.5 mmol) was added slowly and stirring was continued at room temperature for 2 h. Water (200 mL) was added and the mixture was extracted with hexanes (2×200 mL). The organic layer was washed with water (3×100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 2-benzyloxy-5-bromo-1,3-dimethylbenzene (9.59 g) as a white solid which was used in the next step without further purification. (Dichloro)bis(triphenylphosphene)palladium (0.239 g, 0.34 mmol) and copper (I) iodide (0.065 g, 0.34 mmol) were added to a solution of 2-benzyloxy-5-bromo-1,3-dimethylbenzene (4.96 g, 17.03 mmol) and trimethylsilyl acetylene (1.84 g, 18.74 mmol) in triethyl amine (70 mL). The reaction mixture was stirred at reflux under nitrogen for 4 h. The mixture was cooled to room temperature. The precipitated ammonium salt was filtered off. The filtrate was concentrated under reduced pressure. The residue was dissolved in hexanes (300 mL) and washed with 2 N aqueous HCl (2×50 mL), water (50 mL), brine (50 mL), and dried over anhydrous Na2SO4. Removal of solvent gave a dark brown liquid which was purified by column chromatography (silica gel 230-400 mesh; 0-5% ethyl acetate in hexanes as eluent) to give (4-benzyloxy-3,5-dimethylphenylethynyl)trimethylsilane (4.0 g, 76% yield) of as pale yellow oil. To a degassed solution of (4-benzyloxy-3,5-dimethylphenylethynyl)trimethylsilane (3.96 g, 12.83 mmol) in anhydrous THF (60 mL) was added tetrabutylammonium fluoride (38.5 mL, 1.0M solution in THF) at 0° C. under nitrogen. Stirring continued at 0° C. for 1 h. A saturated aqueous NH4Cl solution (100 mL) was added. The reaction mixture was extracted with hexanes (300 mL). The organic layer was washed with saturated aqueous NH4Cl solution and dried over anhydrous Na2SO4. The crude compound was purified by column chromatography to give 2-benzyloxy-5-ethynyl-1,3-dimethylbenzene (2.77 g, 91% yield) as a pale yellow oil. To a degassed solution of 2-bromo-4,6-dimethoxy benzaldehyde (2.37 g, 9.68 mmol) in DMF-triethylamine (5:1, 95 mL) were added dichlorobis(triphenylphosphine)-palladium(II) (0.34 g, 0.484 mmol) and copper(I) iodide (0.553 g, 2.90 mmol). The reaction mixture was degassed. To this stirred solution, a degassed solution of 2-benzyloxy-5-ethynyl-1,3-dimethylbenzene (2.86 g, 12.1 mmol) in DMF-triethylamine (5:1, 37 mL) was added at 75° C. under nitrogen over a period of 3 h. After the completion of the addition, stirring continued at 75° C. under nitrogen for 4 h. The reaction mixture was allowed to cool to room temperature. Water (200 mL) was added. The mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (3×150 mL) and brine (150 mL), and dried over anhydrous Na2SO4. Removal of solvent gave a black gummy material, which was purified by column chromatography to give 2-(4-benzyloxy-3,5-dimethylphenylethynyl)-4,6-dimethoxybenzaldehyde (2.8 g, 72% yield) of as a brown solid. Tert-Butylamine (20 mL) was added to the above compound (2.63 g, 5.772 mmol). The reaction mixture was stirred under nitrogen for 16 h. Excess tert-butylamine was removed under reduced pressure. The mixture was dried under vacuum to give 3.11 g of imine as a brown solid. To a solution of above imine (3.07 g, 6.738 mmol) in anhydrous DMF (160 mL) was added copper (I) iodide (0.123 g, 0.674 mmol) and the reaction mixture was stirred at 100° C. for 5 h under nitrogen and cooled to room temperature. Water (200 mL) was added and the reaction mixture was extracted with ethyl acetate (2×200 mL). The organic layer was washed with water (2×100 mL), brine (150 mL), and dried over anhydrous Na2SO4. Removal of solvent gave a dark brown gummy material, which was purified by column chromatography (silica gel 230-400 mesh; 0-15% ethyl acetate in hexanes as eluent) to give 3-(4-benzyloxy-3,5-dimethylphenyl)-6,8-dimethoxy isoquinoline (0.689 g, 26%) as a brown solid. To a solution of 3-(4-benzyloxy-3,5-dimethylphenyl)-6,8-dimethoxy isoquinoline (0.68 g, 1.70 mmol) in 1:1 methanol-ethyl acetate (40 mL) was added Pd—C(10%, 200 mg) and the mixture was hydrogenated for 16 h. After reaction completion the mixture was filtered through Celite. The filtrate was concentrated and dried under vacuum to give 4-(6,8-Dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (0.51 g, 97%) as a yellow solid. To a solution of 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (25 mg, 0.081 mmol) in methanol/CH2Cl2 (1:1, 6 mL) was added a solution of hydrogen chloride in ether (1.0 M, 1 mL) and the reaction mixture was stirred at room temperature for 15 min. The solvent was removed under reduced pressure. The residue was triturated with ether to give the hydrochloride of 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (28 mg, 99%) as a yellow solid. Selected data: MP 255-256° C. (HCl salt).
-
- (3,5-Dimethoxy-phenyl)-acetic acid (10.0 g, 51 mmol) was dissolved in anhydrous methanol (100 mL) and H2SO4 (1 mL) was added drop-wise. The reaction mixture was refluxed overnight and cooled to room temperature. The solvent was removed and the residue was dissolved in ethyl acetate and washed with a NaHCO3 solution, water and dried (Na2SO4). The solvent was evaporated in vacuo to obtain (3,5-dimethoxy-phenyl)-acetic acid methyl ester in 97% (10.4 g) yield. To a solution of (3,5-dimethoxy-phenyl)-acetic acid methyl ester (10.4 g, 49.5 mmol) in dimethyl formamide (40 mL), POCl3 (5.4 mL, 59.37 mmol) was added at 55° C. After the addition, the reaction mixture was heated at 100° C. for 10 min and then stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to obtain (2-formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (10.0 g, 85%). (2-Formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (5.0 g, 21 mmol) was dissolved in CH3CN (100 mL), NaH2PO4 (0.655 g, 5.46 mmol) in water (2 mL) and 30% H2O2(2.3 mL, 21 mmol). The reaction mixture was cooled to 0° C. and a solution of NaO2Cl (2.65 g, 29.4 mmol) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 4 h before being quenched by the addition of Na2SO3 solution. The mixture was acidified with 2 N HCl and extracted with ethyl acetate. The solvent was evaporated in vacuo to obtain 2,4-dimethoxy-6-methoxycarbonylmetyl-benzoic acid (5.25 g, 98%). To a solution of 2,4-dimethoxy-6-methoxycarbonylmetyl-benzoic acid (5.25 g, 20.6 mmol) in methanol (50 mL), a solution of NaOH (4.12 g, 103 mmol) in water (20 mL) was added and the reaction mixture was allowed to stir at room temperature for 3 h. The solvent was removed, diluted with water and acidified with 2 N HCl. The compound was extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to obtain 2-carboxymethyl-4,6-dimethoxy-benzoic acid (4.65 g, 94%). To a suspension of 2-carboxymethyl-4,6-dimethoxy-benzoic acid (4.65 g, 19.4 mmol) in toluene (50 mL) was added acetic anhydride (2.01 mL, 21.3 mmol) and the reaction mixture was heated to reflux for 2 h. After cooling to 0° C., the precipitated solid was filtered off and washed with heptane and hexane to obtain 6,8-dimethoxy-isochroman-1,3-dione (3.56 g, 83%).
- To a solution of 3,5-dimethyl-4-hydroxy-benzoic acid (3.0 g, 18.05 mmol) in pyridine (7 mL) was added acetic anhydride (2.05 mL, 21.66 mmol) and the reaction mixture was stirred at room temperature for 16 h. Water was added and the mixture was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid (3.52 g, 94%). To a solution of 4-acetoxy-3,5-dimethyl-benzoic acid (6.02 g, 28.91 mmol) in CH2Cl2 (80 mL), oxalyl chloride (5.04 mL, 57.83 mmol) was added slowly, followed by a drop of dimethyl formamide. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester was dried under vacuum (6.37 g, 97%). To a solution of N,N,N,N-tetramethyl guanidine (2.77 mL, 22.078 mmol) in CH3CN (50 mL), a solution of 6,8-dimethoxy-isochroman-1,3-dione (4.46 g, 20.07 mmol) in CH3CN (100 mL) was added slowly at <0° C. (bath temperature −20° C.) in 30 min. Then, Et3N was added in one portion, followed by a solution of acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (6.37 g, 28.1 mmol) in CH3CN (50 mL) and stirred for 30 min. at <0° C. The reaction mixture was stirred at room temperature for 16 h, then heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was quenched with 1 N HCl. The precipitated solid was filtered off to give a mixture of acetic acid 4-(6,8-dimethoxy-1,3-dioxo-isochroman-4-carbonyl)-2,6-dimethyl-phenyl ester and acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester (6.0 g).
- The above mixture (6.0 g) was dissolved in H2SO4 (30%, 30 mL) and heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and the precipitated solid was filtered off to obtain a mixture of acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester and 3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one (5.5 g). The above mixture (5.5 g) was dissolved in methanol (30 mL), K2CO3 (3.09 g, 22.4 mmol) and water (10 mL) were added and the reaction mixture was stirred at room temperature for 6 h. The solvent was removed and acidified with dilute HCl. The compound was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to leave a residue which was purified by chromatography (silica gel, 230-250 mesh; 2% methanol in dichloromethane) to obtain 3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one. The yield was 1.462 g.
- To a solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one (0.875 g, 2.68 mmol) in DMF (5 mL), NaH (0.129 g, 3.22 mmol) was added and the mixture was stirred for 1 h. To the reaction mixture was added 1-chloro-2-iodo-ethane (1.23 mL, 13.4 mmol) and stirring was continued for 16 h. Then the reaction mixture was heated at 80° C. before being quenched with 1 N HCl at room temperature. The crude was purified by column chromatography (silica gel, 230-250 mesh; 2% methanol in dichloromethane). The yield was 0.36 g (35%). The compound 3-[4-(2-chloro-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-isochromen-1-one (0.36 g, 0.927 mmol) was dissolved in DMSO (5 mL), morpholine (0.4 mL, 4.63 mmol) and Et3N (0.64 mL, 4.63 mmol) were added. The reaction mixture was heated at 110° C. for 16 h before being cooled to room temperature. Water was added and the compound was extracted with ethyl acetate. The solvent was evaporated in vacuo to leave a residue, which was purified by chromatography. The yield was 0.128 g (31%). The compound 3-[3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)-phenyl]-6,8-dimethoxy-isochromen-1-one (0.128 g, 0.29 mmol) and NH3 (2.0 M solution in ethanol, 30 mL) were mixed in a steel bomb and heated at 130° C. for 16 h. The solvent was removed and the crude compound was purified by chromatography (silica gel, 230-250 mesh). The compound was then converted into the HCl salt of 3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (84 mg, 66%). Selected data: MP 196-198° C. (HCl salt).
-
- A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (0.856 g, 2.78 mmol) in N,N-dimethyl formamide (20 mL) was stirred at 70° C. for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (444 mg, 39%) as a white solid. Selected data: 229-231° C.
- Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was placed 3,5-dimethyl-4-hydroxy benzaldehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) of product. To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150° C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52%).
-
- In a 250 mL round-bottomed flask were placed 3,5-dimethyl-4-hydroxy benzaldehyde (4.0 g, 26.7 mmol), Ph3P (15.38 g, 58.66 mmol), diisopropylethylamine (13.78 g, 106.7 mmol) and 2-morpholin-4-yl-ethanol (7.69, 58.7 mmol) in THF (100 mL), then DEAD (11.1 g, 64 mmol) was added drop-wise at room temperature. The reaction mixture was stirred for 3 d at room temperature and water was added and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4 and concentrated to give crude product. The crude product was purified by column chromatography to give the B-ring building block (3.0 g, 43%).
- To a solution of 2-amino-4,6-dimethoxybenzamide (451 mg, 2.3 mmol) and 3,5-dimethyl-4-(2-morpholin-4yl-ethoxy)-benzaldehyde (550 mg, 2.09 mmol) in N,N-dimethyl formamide (20 mL), iodine (636 mg, 2.5 mmol) and potassium carbonate (288 mg, 2.09 mmol) were added and the reaction mixture was stirred at 70° C. for 48 h. The reaction mixture was poured into ice. The mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product was purified by column chromatography and converted to the hydrochloride salt of 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (40 mg, 4%) as an off-white solid. Selected data: MS (ES) m/z: 440.1; MP 185-187° C. (HCl salt).
-
- To a solution of 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (0.309 g, 1.0 mol) in anhydrous THF (20 mL), triphenyl phosphene (0.52 g, 2.0 mmol), 4-(2-hydroxyethyl)morpholine (0.262 g, 2.0 mmol) and N,N-diisopropylethylamine (0.387 g, 3.0 mmol) were added. To this stirred solution was added diethylazodicarboxylate (0.348 g, 2.0 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen, then diluted with ethyl acetate (100 mL). The organic layer was washed with water and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by column chromatography to give 3-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-6,8-dimethoxyisoquinoline (0.54 g) as a white solid.
- To a solution of the above compound (0.54 g, impure) in 1:1 ether-CH2Cl2 (10 mL), was added 1.0 M solution of hydrogen chloride in ether (2 mL) and the reaction mixture was stirred at room temperature for 30 min. Solvent was removed under reduced pressure. The residue was triturated with 10% methanol in ether to give 4-(2-(4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)morpholine (0.323 g, 70% over two steps) as a yellow solid. Selected data: MS (ES) m/z: 423.1; MP 239-240° C. (HCl salt).
-
- The compound 3-[4-(2-chloro-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-isochromen-1-one (298 mg, 0.767 mmol) was dissolved in DMSO (5 mL) and N-methyl piperazine (388 mg, 3.83 mmol) and Et3N (392 mg, 3.83 mmol) were added. The reaction mixture was heated at 110° C. for 16 h before being cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The solvent was evaporated in vacuo to leave a residue which was purified by column chromatography. The yield was 60 mg (17%). The compound 3-[3,5-dimethyl-4-(2-(4-methyl piperazin-1-yl-ethoxy)-phenyl]-6,8-dimethoxy-isochromen-1-one (60 mg, 0.13 mmol) and NH3 (2.0 M solution in ethanol, 20 mL) were mixed in a steel bomb and heated at 130° C. for 16 h. The solvent was removed and the crude compound was purified by column chromatography. The compound was then converted to the hydrochloride salt of 3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (40 mg, 62%), an off-white solid. Selected data: MS (ES) m/z: 452.1; MP 195-198° C. (HCl salt).
-
- 2-Amino-4,6-dimethoxy-benzamide (328 mg, 1.67 mmol), 4-hydroxybenzaldehyde (204 mg, 1.67 mmol), K2CO3 (231 mg, 1.67 mmol) and I2 (508 mg, 2.0 mmol) were mixed in DMF (10 mL) and the reaction mixture was heated at 70° C. for 5 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (60 mg, 12%), as an off-white solid. Selected data: MS (m/z): 299.05; MP 303-305° C.
-
- 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid was synthesized from 2-amino-4,6-dimethoxy-benzamide and (4-formyl phenoxy)acetic acid, using the method described for 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one. 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (135 mg, 21%) was isolated as an off-white solid. Selected data: MS (m/z): 357.04; MP 287-290° C.
-
- To a solution of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.764 mmol) in N,N-dimethyl acetamide (5 mL) were added 2-pyridine carboxaldehyde (0.082 g, 0.764 mmol), sodium hydrogen sulphite (58.5%, 0.15 g, 0.84 mmol), and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reaction mixture was stirred at 1500° C. overnight. The mixture was cooled to room temperature. Water (40 mL) was added and the reaction mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water and dried over anhydrous Na2SO4. The solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 1% methanol in CH2Cl2 as eluent) to give 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one (0.077 g, 36%) as a white solid. 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one was converted to the corresponding hydrochloride. Selected data: MS (m/z): 284.0; MP 215-217° C. (hydrochloride).
-
- 5,7-Dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3-pyridine carboxaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (105 mg, 48%) was isolated as a white solid. Selected data: MS (m/z): 284.0; MP 257-259° C. (hydrochloride).
-
- 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3,5-di-tert-butyl-4-hydroxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (130 mg, 41%) was isolated as a light yellow solid. Selected data: MS (m/z): 411.17; MP 229.7-230.5° C.
-
- 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3,5-dimethoxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (120 mg, 46%) was isolated as a yellow solid. Selected data: MS (m/z): 343.05; MP 270-272° C.
-
- 5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-methoxy benzaldehyde, using the method described for 5,7-dimethoxy-2-(.pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one (106 mg, 44%) was isolated as an off-white solid. Selected data: MS (m/z): 312.99; MP 276-277° C.
-
- 2-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-hydroxy-3-methoxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (90 mg, 36%) was isolated as a white solid. Selected data: MS (m/z): 329.06; MP 294-296° C.
-
- 2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3-chloro-4-hydroxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (75 mg, 30%) was isolated as a yellow solid. Selected data: MS (m/z): 333.03; MP 279-281° C.
-
- 5,7-Dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-pyridine carboxaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one (142 mg, 63%) was isolated as a pale brown solid and then converted to the corresponding hydrochloride (yellow solid). Selected data: MS (m/z): 284.06; MP 294-295° C. (hydrochloride).
-
- To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (3.0 g, 20 mmol) in anhydrous THF (100 mL), triphenyl phosphene (10.49 g, 40 mmol), 4-(2-hydroxyethyl)morpholine (5.25 g, 40 mmol) and N,N-diisopropylethylamine (7.76 g, 60 mmol) were added. To this stirred solution was added diethylazodicarboxylate (6.97 g, 40 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen and diluted with ethyl acetate (200 mL). The organic layer was washed with water and brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by column chromatography (silica gel 230-400 mesh; 0-3% methanol in CH2Cl2 as eluent) to give 3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)benzaldehyde (1.66 g, 32%) as an oil.
- To a solution of 2-amino benzamide (136 mg, 1.0 mmol) in N,N-dimethyl acetamide (5 mL) were added 3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)benzaldehyde (263 mg, 1.0 mmol), sodium hydrogen sulphite (58.5%) (196 mg, 1.1 mmol) and p-toluenesulfonic acid (19 mg, 0.1 mmol). The reaction mixture was stirred at 150° C. overnight. Water (40 mL) was added. The formed solid was filtered off, washed with water and a small amount of methanol and dried under vacuum to give the title compound (190 mg, 50%) as an off-white solid. To a solution of the above compound (174 mg, 0.458 mmol) in 2:1 anhydrous CH2Cl2-methanol (15 mL) was added 1.0 M solution of hydrogen chloride in ether (1.5 mL) and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was triturated with 10% methanol in anhydrous ether to give the hydrochloride of 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one (187 mg, 98%), as an off-white solid. Selected data: MS (ES) m/z: 380.10; MP 300-302° C. (hydrochloride).
-
- A mixture of anthranilamide (0.15 g, 1.10 mmol), 4-[2(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.340 g, 1.101 mmol), sodium hydrogensulfite (0.126 g, 1.101 mmol) and p-toluenesulfonic acid (20 mg) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The solid was collected by filtration, washed with water (10 mL×3) and dried under high vacuum to provide desired compound (328 mg, 70%), as a white solid. A solution of the above described compound (0.316 g, 0.745 mmol) in THF (3 mL) was cooled to 0° C. under nitrogen and TBAF (1.5 mL, 1.49 mmol) was added, followed by stirring at room temperature for 1 h. The reaction mixture was diluted with cold water (30 mL), the white precipitate was filtered off, washed with water (15 mL×3) and MeOH (20 mL×3) and dried under high vacuum, to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (150 mg, 65%), as a white solid. Selected data: MS (ES) m/z: 311.04; MP 260-261° C.
-
- 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-(pyrimidin-2-yloxy)-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one (222 mg, 72%) was isolated as a light beige solid. Selected data: MS (m/z): 280.98; MP 267-268° C. (decomposed).
-
- 2-(4-(Dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-dimethylamino-1-naphthaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one (75 mg, 26%) was isolated as a yellow solid. Selected data: MS (m/z): 376.07; MP 269-271° C.
-
- 2-Amino-4,6-dimethoxy-benzamide (150 mg, 0.764 mmol), 2-(4-formyl-phenoxy)-acetamide (137 mg, 0.764 mmol), sodium hydrogen sulfite (150 mg, 58.5%) and p-toluenesulfonic acid monohydrate (15 mg) in N,N-dimethyl acetamide (15 mL) were heated to 150° C. overnight. N,N-dimethyl acetamide was removed under vacuum and the residue was poured into water (50 mL). The solid was filtered off and washed with methanol to yield 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (74 mg, 27.2%). Selected data: MS (m/z): 356.09; MP 309-311° C. HPLC purity: 88.57%.
-
- 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid was synthesized from anthranilamide and 4-formyl phenoxy acetic acid, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (800 mg, 73%) was isolated as a white solid. Selected data: MS (m/z): 296.98; MP 285-287° C.
-
- 2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-dimethylamino-naphthalene-1-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one (240 mg, 69%) was isolated as a pale yellow solid. Selected data: MS (m/z): 316.08; MP 224-226° C.
-
- 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide was synthesized from anthranilamide and 2-(4-formyl-phenoxy)-acetamide, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (183 mg, 56%) was isolated as a light beige solid. Selected data: MS (m/z): 295.97; MP 277.5-278.5° C.
-
- 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one (120 mg, 46%) was isolated as a yellow solid. Selected data: MS (m/z): 341.03; MP 307.5-309.6° C.
-
- A solution of 4-(4-formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 4.47 mmol) in THF (50 mL) was mixed with LAH (0.7 g, 17.87 mmol) and stirred at reflux for 14 h. The reaction was quenched at room temperature by adding KOH aqueous (14 N, 20 mL). The supernatant was decanted and combined with DCM washings, then diluted with water (50 mL). The mixture was extracted with DCM (3×50 mL) followed by concentration using a rotary evaporator to give [4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 89%). To a solution of DMSO (0.56 mL, 7.96 mmol) in DCM (50 mL) at −78° C. was added oxalyl chloride (0.7 mL, 7.96 mmol) and the resulting mixture was stirred at −78° C. for 0.5 h. A solution of [4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 3.98 mmol) in DCM (20 mL) was slowly added. The reaction was stirred at −78° C. for 1.5 h. Triethylamine (1.7 mL, 11.94 mmol) was added and the reaction was allowed to gradually warm up to room temperature. After stirring for 4 h the reaction was quenched by adding sodium bicarbonate aqueous (1 N, 50 mL). The mixture was extracted with DCM (3×50 mL) followed by concentration to afford a residue, which was further purified by column chromatography to yield 4-(4-methyl-piperazin-1-yl)-benzaldehyde (0.5 g, 61%).
- 5,7-Dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-(4-methyl-piperazin-1-yl)-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5, 7-Dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one (120 mg, 41%) was converted to the corresponding hydrochloride (a yellow solid). Selected data: MS (m/z): 381.11; MP 252.4-254.2° C. (di-hydrochloride).
-
- A solution of 4,5-dimethoxy-2-nitrobenzamide (10 g, 44.24 mmol) in MeOH (260 mL) was mixed with palladium/carbon (2 g) and subjected to hydrogenation (50 psi) for 20 h. The reaction mixture was filtered through a Celite pad, concentrated to yield 8.7 g of 2-amino-4,5-dimethoxybenzamide (100%).
- 2-(4-(Dimethylamino)naphthalen-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxy-benzamide and 4-Dimethylamino-naphthalene-1-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(dimethylamino)naphthalen-1-yl)-6,7-dimethoxy-quinazolin-4(3H)-one (159 mg, 56%) was isolated as a white solid. Selected data: MS (m/z): 376.13; MP 235.5-236.5° C.
-
- 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-[bis-(2-hydroxy-ethyl)-amino]-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one (150 mg, 42%) was isolated as a brown solid. Selected data: MS (m/z): 326.03; MP 228-230° C.
-
- 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-[bis-(2-hydroxy-ethyl)-amino]-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-quinazolin-4(3H)-one (120 mg, 41%) was isolated as a yellow solid. Selected data: MS (m/z): 386.15; MP 249-251° C.
-
- 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxy-benzamide and 4-(N,N-bis(2-hydroxyethyl)amino)benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one (72 mg, 24%) was isolated as a yellow solid. Selected data: MS (m/z): 386.15; MP 268-270° C.
-
- 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxybenzamide and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxy-quinazolin-4(3H)-one (180 mg, 69%) was isolated as a light yellow solid. Selected data: MS (m/z): 341.03; MP 316.4-318.2° C.
-
- A solution of 4-iodobenzaldehyde (1 g, 4.31 mmol) in MeOH (50 mL) was mixed with trimethyl orthoformate (4 mL, 36.10 mmol) and p-toluenesulfonic acid (5 mg). The reaction was stirred at room temperature for 3 h and then quenched by adding excess of sodium bicarbonate solid and stirred for 1 h. The solid was removed by filtration and the filtrate was concentrated to yield 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 100%). A mixture of 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 4.31 mmol), cesium carbonate (1.4 g, 4.31 mmol), morpholine (0.375 g, 4.31 mmol), and palladium tetrakis(triphenyl) phosphine (0.25 g, 0.216 mmol) in toluene (60 mL) and tert-butanol (10 mL) was thoroughly degassed and stirred at 110° C. for 28 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), concentrated to afford a solid residue. Purification by column chromatography left 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 60%). A solution of 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 2.58 mmol) in THF (20 mL) was mixed with HCl in ether (10 mL, 10 mmol) and stirred at room temperature for 2 h. The reaction mixture was then neutralized with 1 N sodium bicarbonate aqueous to pH 9 and extracted with DCM (3×100 mL), to afford 4-morpholin-4-yl-benzaldehyde (0.37 g, 75%).
- A mixture of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.765 mmol), 4-morpholin-4-yl-benzaldehyde (0.15 g, 0.765 mmol), sodium hydrogensulfite (0.136 g, 0.765 mmol) and p-toluenesulfonic acid (10 mg) in N,N-dimethyl acetamide (10 mL) was stirred at 155° C. for 14 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The solid was collected by filtration, washed with water and MeOH to yield 5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one (0.109 g, 39%).
- A solution of 5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one (0.109 g, 0.297 mmol) in DCM (5 mL) and MeOH (5 mL) was mixed with HCl in ether (3 mL, 3 mmol), stirred for 1.5 h, concentrated. The solid formed was rinsed with Hexanes, collected by filtration and washed with hexanes and DCM to yield the hydrochloride (0.115 g, 95%) as a brown solid. Selected data: MS (m/z): 368.13; MP 217.5-219.4° C. (hydrochloride).
-
- Malonic acid (41.62 g, 0.4 mol), 2,4,6-trichlorophenol (157.96 g, 0.8 mol) and POCl3 (134.9 g, 80.6 mL) were mixed in a flask and stirred under reflux overnight. The reaction mixture was cooled to 70° C. and poured into ice-water. The solid was filtered off, washed with water and dried (183.73 g, quantitative). The compound from above (183.73 g, 0.4 mol), ethyl 3-aminocrotonate (51.7 g, 0.4 mol) and bromobenzene (200 mL) were mixed. The reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight, diluted with ethyl acetate and filtered off. The solid was washed with ethyl acetate to obtain a light-yellow solid (107.7 g). The solid from above (107.7 g, 0.4 mol) was dissolved in POCl3 (300 mL, 2.5 mol) and the reaction mixture was refluxed for 2 h. POCl3 was removed and the residue was poured into water, and extracted with DCM. The solvent was removed to obtain a crude compound (73.02 g) which was used for the next step without further purification. The compound (73.02 g, 0.31 mol) was dissolved in methanol and sodium methoxide solution in methanol (25%) was added and the mixture was refluxed overnight (˜14 h). The reaction mixture was quenched with acetic acid. DCM was added and the solvent was evaporated to leave a crude product (64.43 g), which was used for the next step without further purification. The compound (64.0 g) was dissolved in a mixture of methanol and THF. To this mixture was added lithium hydroxide (63.7 g, 1.52 mol) in water. The reaction mixture was refluxed for 3 d. The solvent was removed and conc. HCl (160 mL) was added and the mixture was concentrated. The residue was freeze dried. The crude salt (69.1 g) was used for the next step without further purification. The salt (34.6 g, 0.148 mol) was dissolved in DCM and oxalyl chloride (37.6 g, 25.8 mL) was added, followed by DMF (0.5 mL). The reaction mixture was stirred under nitrogen overnight. The solvent was evaporated in vacuo to obtain the crude acid chloride, which was used for the next step without further purification. The acid chloride was dissolved in DCM and ammonia gas was passed through the solution for 30 min. The reaction mixture was stirred overnight. Water was added and the solid was filtered off and washed with DCM. A small portion of pure A-ring building block (5 g) was isolated and crude materials (20 g) were saved.
- To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (5.04 g, 34.3 mmol) and PPh3 (18.1 g, 68.6 mmol) in anhydrous THF (200 mL), were added 4-(2-hydroxyethyl)-morpholine (9.01 g, 68.6 mmol) and isopropylethylamine. To this stirred solution was added DEAD (11.95 g, 68.6 mmol) and the reaction mixture was stirred at room temperature overnight. THF was removed and ethyl acetate was added. The mixture was washed with water and brine. The crude was dissolved in DCM and washed with 1 N HCl. The aqueous layer was basified with 5% NaOH and saturated NaHCO3 solution. The mixture was extracted with ethyl acetate and concentrated. The crude was dissolved in ether and hydrogen chloride in ether was added. The solvent was decanted off, dissolved in water, basified with solid NaHCO3 and NaHCO3 solution, extracted with ethyl acetate, and concentrated. The crude was purified by silica gel (100 g) column chromatography, employing 30-50% ethyl acetate in hexane as eluents to give the desired B-ring building block (0.455 g).
- The A-ring building block (0.344 g, 1.75 mmol) was dissolved in anhydrous THF (50 mL) and cooled to −78° C. n-Butyllithium (3.3 mL, 5.25 mmol of 1.6 M in hexane) was added drop-wise and the temperature was increased to −20° C. for 40 min, to −10° C. for 1 h, and to −5 to −2° C. for 40 min, before the reaction mixture was cooled again to −78° C. and the B-ring building block (0.455 g, 1.75 mmol) in acetonitrile (10 mL) was added quickly. The reaction mixture was stirred at room temperature overnight (˜20 h). The dark brown solution was quenched with acetic acid and refluxed for 1 h. Water was added and extracted with DCM. The crude was purified by silica gel (50 g) column chromatography, using hexane (500 mL), hexane:ethyl acetate (1:1, 750 mL), and then hexane:ethyl acetate:methanol (3:2:1) as eluents, to give 7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (100 mg, 13%) as an off-white solid. Selected data: MS (m/z): 440.28; MP 212.5-212.9° C.
-
- Methyl acetoacetate (69.67 g, 0.6 mol) in dry THF (350 mL) was cooled to −5° C. and sodium hydride in mineral oil (24.5 g, 60%) was added at −5 to 0° C. over 30 min. Diketene (50.4 g) in dry THF (80 mL) was added drop-wise at 5° C. over 20 min. The resulting solution was allowed to stir for 1.0 h at −5° C., after which it was allowed to warm to room temperature and stir overnight. Acetic acid (35 mL) was added and the THF solvent was removed. Water (200 mL) and ethyl acetate (300 mL) were added to the residue and the pH was adjusted to 5.0 by addition of HCl solution. The organic layer was separated and washed with brine and dried over sodium sulfate. After column purification and recrystalization, compound A (26.6 g, 24.3%) was obtained.
- Sodium hydride in mineral oil (11.2 g, 0.279 mol, 60%) was added to compound A (24.8 g, 0.136 mol) in DMF (150 mL). The reaction was cooled to −30° C. and methyl iodide (21.3 mL, 0.341 mol) was added and the reaction was kept at room temperature overnight. Sodium iodide was filtered off and DMF was removed. The residue was mixed with water (100 mL) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude mixture was purified by column chromatography to yield compound B (11.40 g, 39.9%). To a solution of compound B (11.4 g, 0.054 mole) in dry CCl4 (90 mL) was added N-bromosuccinimide (10.6 g, 0.0596 mol). The mixture was refluxed overnight and CCl4 solvent was removed. Water (100 mL) was added to the residue. After stirring for a while the solid was filtered off and washed with water, ethyl acetate (10 mL) and hexane (30 mL) to yield compound (13.1 g, 83.9%). Compound C (12.5 g, 0.043 mol), chloromethyl methyl ether (81.0 g) and anhydrous zinc chloride (7.0 g, 0.051 mol) were kept at room temperature overnight. Chloromethyl methyl ether was removed and the residue was mixed with water and the pH was adjusted to 7.0 using sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Compound D (7.39 g, 50.6%) was obtained after column chromatography. A solution of compound D (7.39 g, 0.022 mol), morpholine (7.62 g, 0.088 mol) and anhydrous THF (20 mL) was kept at room temperature overnight. The solvent was evaporated. Water and ethyl acetate were added to the residue, and pH was adjusted to 9.0 with sodium bicarbonate. The organic layer was washed with brine and dried over sodium sulfate, and concentrated. Compound E (5.4 g, 63.8%) was obtained after column chromatography. The hydrogenation reaction was carried out at 50 psi with compound E (5.4 g, 0.014 mol) in THF (100 mL) and triethyl amine (3.9 mL) with 10% Pd/C (2.6 g) as a catalyst for 2 d. After the catalyst was filtered off, the organic layer was purified by column chromatography to yield product F (3.20 g, 74.4%). Compound F (3.20 g, 0.0103 mol) was dissolved in ethanol (30 mL) and potassium hydroxide (2.31 g, 0.041 mol) in water (20 mL) was added and the reaction mixture was heated to 100° C. overnight. The solvent was removed, pH was adjusted to 6.0 and the water was removed. The residue was further dried under high vacuum and the compound was extracted with ethanol to yield compound G (2.95 g, 99%). Compound G (1.80 g, 6.1 mmol) with thionyl chloride (3 mL, 0.0411 mol) was refluxed for 1 h before the excess thionyl chloride was removed and the residue was dried under high vacuum. Anhydrous THF (20 mL) was added and ammonia gas was bubbled into the reaction mixture for 2 h. THF was removed and pH was adjusted to 8.0-9.0. The mixture was extracted with dichloromethane and dried over sodium sulfate to give compound H (1.30 g, 72.4%).
- NaH in mineral oil (1.14 g, 0.0285 mol, 60%) was added to 4-hydroxy-3,5-dimethylbenzonitrile (4.0 g, 0.027 mol) in anhydrous DMF (20 mL) followed by benzyl bromide (3.27 mL, 0.027 mol). The reaction was kept at room temperature overnight. The reaction mixture was poured into water and the solid was filtered off and washed with hexane to yield Compound I (5.7 g, 89%). Compound I was used for the next step reaction without further purification. BuLi (1.60 M, 10.2 mL) was added drop-wise to compound H (0.8 g, 2.72 mmol) in anhydrous THF (25 mL) at −10° C. The reaction mixture was kept at 0° C. for one h before the cooling bath was removed. The reaction mixture was stirred for 45 minutes. Compound I (0.65 g, 2.72 mmol) in anhydrous THF (5 mL) was added drop-wise at −10° C. and the reaction was continued for a further 45 min. Water (20 mL) was added. The mixture was extracted with ethyl acetate. The solvent was removed and the residue was purified by column chromatography to yield compound J (0.180 g, 12.8%). Compound J (180 mg) in methanol (80 mL) was hydrogenated at 50 psi for 3 h, using 10% Pd/C as the catalyst. The catalyst and solvent were removed and the residue was purified by column chromatography to yield 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one (28 mg, 18.8%) as a white solid. Selected data: MS (m/z): 424.21; MP 158-161° C.
-
- To a solution of 2-amino-4,5-dimethoxybenzamide (0.157 g, 0.8 mmol) in N,N-dimethylacetamide (5 mL) were added 3,5-dimethyl-4-hydroxybenzaldehyde (0.120 g, 0.8 mmol), sodium hydrogen sulphite (58.5%, 0.156 g, 0.88 mmol) and p-toluenesulfonic acid (15 mg, 0.08 mmol). The reaction mixture was stirred at 150° C. for 3 h. The reaction mixture was cooled to room temperature and water (40 mL) was added. A white precipitate was formed and filtered off, washed with water and a small amount of methanol and dried under vacuum to give 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one (0.230 g, 88% yield) as an off-white solid. Selected data: MS (ES) m/z: 327.12; MP>300° C.
-
- To a solution of 4-iodobenzaldehyde (0.116 g, 0.5 mmol), acrolein diethylacetal (0.3 mL, 1.5 mmol), tetra-n-butylammonium chloride (0.139 g, 0.5 mmol) and triethylamine in anhydrous dimethylformamide (2 mL), palladium acetate (0.003 g, 0.015 mmol) was added. The reaction mixture was heated at 90° C. and stirred for 16 h. The reaction mixture was diluted with 2 N hydrochloric acid and extracted with diethyl ether. The solvent was evaporated in vacuo to leave a residue which was purified by column chromatography (silica gel) employing 1-5% ethyl acetate in hexane as eluents to obtain 3-(4-formyl-phenyl)-propionic acid ethyl ester (0.734 g).
- To a round-bottomed flask were added 2-amino-4,6-dimethoxy-benzamide (0.161 g, 0.82 mmol), 3-(4-formyl-phenyl)-propionic acid ethyl ester (0.170 g, 0.82 mmol), sodium bisulfite (0.160 g, 0.902 mmol), p-toluenesulfonic acid (0.016 g, 0.082 mmol) and N,N-dimethylacetamide (10 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off and washed with water and methanol to obtain 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 97%). The compound 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 0.795 mmol) was taken up in a 1:1 mixture of THF and methanol (6 mL). A solution of potassium hydroxide (0.089 g, 1.59 mmol) in water (6 mL) was added to the reaction mixture and stirred at room temperature for 16 h. The solvent was removed and the reaction mixture was acidified with 1 N hydrochloric acid. The precipitated solid was filtered off and washed with water and methanol. The solid was further washed with methanol to obtain 3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic acid (0.143 g, 51%). Selected data: MS (ES) m/z: 355.0; MP 250.6-251.1° C.
-
- To a round-bottomed flask were added 2-amino-5-nitro-benzamide (0.681 g, 3.76 mmol), 4-hydroxy-3,5-dimethyl-benzaldehyde (0.565 g, 3.76 mmol), sodium bisulfite (0.747 g, 4.2 mmol), p-toluenesulfonic acid, monohydrate (0.072 g, 0.376 mmol) and N,N-dimethylacetamide (60 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off, washed with water and methanol to obtain a crude which was purified by column chromatography (silica gel (50 g) employing 1-20% methanol in dichloromethane as eluents, to obtain 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 19%). The compound 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 0.71 mmol) was hydrogenated in dimethyl formamide (20 mL) using palladium on activated carbon (0.076 g, 0.071 mmol) at room temperature for 14 h. The solvent was evaporated and the crude was purified by column chromatography (silica gel 25 g) employing 1-5% methanol in dichloromethane as eluents to obtain 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.132 g). The compound 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one was dissolved in pyridine under nitrogen. Acetic anhydride was added at room temperature and stirred for 4 h. Pyridine was removed and the residue was dried. Methanol was added to the flask and a solution of potassium carbonate in water was added and stirred for 4 h. The solvent was removed, acidified with 1 N hydrochloric acid and the precipitated solid was filtered off and dried to obtain N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (0.037 g, 17%). Selected data: MS (ES) m/z: 324.1; MP 336.5° C. (decomposed).
-
- A solution of 4-hydroxy-3,5-dimethoxybenzaldehyde (1.0 g, 6.66 mmol) in DMF (10 mL) was cooled to 0° C. under nitrogen. NaH (0.4 g, 10 mmol, 60% in oil) was added portion-wise. The reaction was stirred for 30 min; then 2-bromoacetamide (0.918 g, 6.66 mmol) was added and stirring was continued for 36 h at room temperature. The DMF was removed under reduced pressure and water (50 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with an aqueous solution of NaOH (50 mL, 10%), washed with water (50 mL) and brine solution (50 mL) and dried over MgSO4 and concentrated to give 0.6 g of crude intermediate, which was purified by flash column chromatography to provide the desired intermediate (366 mg, 26%), as a white solid. A mixture of 2-amino-4,5-dimethoxybenzamide (0.2 g, 1.019 mmol), 2-(4-formyl-2,6-dimethyl-phenoxy acetamide (0.211 g, 1.019 mmol), sodium hydrogensulfite (0.116 g, 1.121 mmol) and p-toluenesulfonic acid (20 mg) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 16 h under nitrogen. The reaction mixture was cooled to room temperature and water (50 mL) was added. The white precipitate was filtered off and washed with cold water (30 mL×2) and dried under high vacuum to provide 2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide (300 mg, 76%) as a off white solid. Selected data: MS (ES) m/z: 384.1 (M+1); MP 354-356° C.
-
- A mixture of 3-chloro-4-hydroxy-benzaldehyde (227 mg, 1.45 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (347 mg, 1.45 mmol), cesium carbonate (709 mg, 2.18 mmol) and DMSO (2 mL) was stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The resulting precipitate was filtered off, washed with water, air-dried, dissolved in a small amount of ethyl acetate and purified by column chromatography. 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde was obtained as a white solid (yield: 267 mg, 58%). To a 100 mL round-bottomed flask was added 2-amino-4,6-dimethoxy-benzamide (166 mg, 0.85 mmol), 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-benzaldehyde (267 mg, 0.85 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (216 mg, 1.2 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off, washed with water and air-dried. The crude product was purified by column chromatography to give 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (45 mg, 23%). Selected data: MS (ES) m/z: 377.03; MP 287-288° C. (decomposed).
-
- NaH (0.12 g, 0.0050 mol, 60% in mineral oil) was added to 4-hydroxy-3-methoxylbenzalde (0.636 g, 4.18 mmol) in anhydrous DMF (15 mL) and then (2-bromoethoxy)-tert-butyl-dimethylsilane (1.0 g, 4.18 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The mixture was extracted with dichloromethane and the combined organic layers were passed through a column to yield 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (170 mg, 13%). 2-Amino-4,6-dimethoxy-benzamide (101 mg, 0.515 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (160 mg, 0.515 mmol), sodium hydrogen sulfite (100 mg, 58.5%) and p-toluenesulfonic acid monohydrate (10 mg) were mixed with N,N-dimethyl acetamide (15 mL) and heated to 150° C. for 16 h. N,N-dimethyl acetamide was removed under vacuum and the residue was poured into water (50 mL). The solid was filtered off and further purified by column chromatography to yield 2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (15 mg, 7.8%). Selected data: MS (ES) m/z: 373.1; MP 246-248° C.
-
- To a solution of 2-amino-5,6-dimethoxy-benzamide (200 mg, 1.01 mmol) and 4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (314 mg, 1.01 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3(199 mg, 1.12 mmol) and p-TSA (19 mg, 0.1 mmol) were added and the reaction mixture was heated at 150° C. for 3 h, cooled to room temperature and poured into water. The solid was collected and washed with methanol to give 280 mg of mixture products. To a solution of the above mixture (280 mg, 0.578 mmol) in THF (20 mL), TBAF (150 mg, 0.578 mmol) was added at 0° C. and allowed to stir at room temperature for 3 h. The reaction mixture was quenched by addition of water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 2% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one (135 mg, 63%). Selected data: MS (ES) m/z: 371.1; MP>300° C.
-
- To a solution of 4-bromomethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), N-methyl piperazine (3.29 g, 32.92 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. Then, the reaction mixture was diluted with water and the mixture was extracted with ethyl acetate. The combined organic layers were washed well with water, brine, and dried over Na2SO4. The solvent was removed to give 4.0 g of crude product in 93% yield. Lithium aluminum hydride (0.771 g, 20.32 mmol) was taken in a 3-neck dry flask and THF was added on cooling. A solution of 4-(4-methyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (4.0 g, 15.26 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to 0° C. and 10% NaOH solution was added, followed by water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed well with water, brine and dried over Na2SO4. The solvent was removed to give 2.4 g of crude product in 67% yield.
- A 3-neck flask with anhydrous CH2Cl2 (100 mL) was cooled to the −78° C. Then, oxalyl chloride (1.66 g, 13.09 mmol) and DMSO (1.7 g, 21.8 mmol) were added at −78° C. and stirred for 15 min at −78° C. The solution of (4-(4-methyl piperazin-1-ylmethyl)phenyl)-methanol (2.4 g, 10.9 mmol) in CH2Cl2 (10 mL) was added at −78° C. and stirred at −78° C. for 1 h. Then Et3N (4.41 g, 43.63 mmol) was added at −78° C. The reaction mixture was allowed to come to room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with water, brine and dried over Na2SO4. Then, solvent was removed to give 2.23 g of crude product in 94% yield.
- To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4-(4-methyl piperazin-1-ylmethyl)benzaldehyde (166 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (149 mg, 0.84 mmol) and p-TSA (319 mg, 1.68 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. The mixture was cooled to room temperature and water was added and neutralized by addition of NaHCO3. The solvent was removed under reduced pressure to give the crude product. The crude was purified by column chromatography (silica gel 230-400 mesh; 4% NH3 in methanol/CH2Cl2 as eluent) to give the
product 5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one as a free base, which was converted to the hydrochloride salt (115 mg, 35%). Selected data: MS (ES) m/z: 395.2; MP 275-277° C. (hydrochloride). -
- A mixture of 2,6-dimethyl-phenylamine (0.62 mL, 5.0 mmol), DMSO (100 mL), conc. Aqueous HCl (36.5-38%, 5.0 mL), and dried CuCl2 was stirred at 90° C. under nitrogen for 5 h. The reaction was quenched with water. The pH of the mixture was adjusted to ˜8 using a 10% sodium hydroxide solution. The mixture was extracted with ether (3×100 mL). The solution was dried over Na2SO4 and concentrated to dryness. The resulting brown oil was dissolved in dichloromethane (anhydrous, 20 mL) and N-ethyldiisopropylamine (DIPEA, 1.0 mL, 5.8 mmol) was added. The mixture was cooled to 0° C., acetoxyacetyl chloride (0.8 mL, 7.4 mmol) was added slowly. The mixture was stirred at room temperature under nitrogen for 17 h. The mixture was concentrated to dryness and purified by column chromatography. Acetic acid (4-formyl-2,6-dimethyl-phenylcarbamoyl)-methyl ester was obtained as yellow/beige solid (96 mg). A mixture of acetic acid (4-formyl-2,6-dimethyl-phenylcarbamoyl)-methyl ester (96 mg, 0.38 mmol), 2-amino-4,6-dimethoxy-benzamide (74 mg, 0.38 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (96 mg, 0.53 mmol) and dimethylacetamide (3 mL) was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off and washed with water. The filtrate was extracted with dichloromethane, dried over Na2SO4, purified by column chromatography, using (1) 5% methanol/dichloromethane, and (2) 10% methanol/dichloromethane as eluents. Acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methyl ester was obtained as a beige solid (70 mg, 43%). Acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methyl ester (70 mg, 0.16 mmol) was dissolved in methanol/dichloromethane (10 mL) and a solution of potassium carbonate (442 mg, 20 mmol) in water was added. The solution was stirred at room temperature for 17 h. 2 N HCl was added to adjust the reaction mixture pH to ˜8. The mixture was then concentrated under reduced pressure. The resulting precipitate was filtered off, washed with water, air-dried, then washed with ether and dried, leaving N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide (30 mg, 49%) as a light brown solid. Selected data: MS (ES) m/z: 384.1; MP 190-192° C.
-
- 2-[4-(5-amino-2,4-dimethoxy-[1,6]naphthyridin-7-yl)-2,6-dimethyl-phenoxyl]-ethanol (0.302 g, 0.82 mmol) in water (5 mL) and conc. Hydrochloric acid (3 mL) were mixed with stirring. The reaction mixture was cooled to 0° C. and a solution of sodium nitrite (0.305 g, 4.42 mmol) in water (3 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 40 min. To the reaction mixture was added 1 N hydrochloric acid (10 mL) and heated at 55° C. for 50 min and then stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane and the aqueous layer was basified with aqueous 5% NaOH and saturated NaHCO3 solution. Water was evaporated and the organic compound was washed with a dichloromethane/methanol solution and concentrated to leave a crude which was purified by silica gel (50 g) column chromatography, employing 50% ethyl acetate in hexane and hexane/ethyl acetate/methanol (3:2:1) as eluent, to obtain 7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (0.080 g, 26%). Selected data: MS (ES) m/z: 371.1; MP 224.9-225.4° C.
-
- 2-Amino-5-morpholino-4-ylmethyl-benzamide hydrochloride salt (200 mg, 0.649 mmol), 4-hydroxy-3,5-dimethylbenzalde (97.4 mg, 0.649 mmol), sodium hydrogen sulfite (127 mg, 58.5%), and p-toluenesulfonic acid monohydrate (10 mg) in N,N-dimethyl acetamide (10 mL) were heated to 150° C. for 6 h. N,N-dimethyl acetamide was removed under vacuum. The residue was poured into water (50 mL) and dichloromethane was used to extract the compound, which was further purified by column chromatography to yield 30 mg free base of 2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one. The base was treated with 1.0 M HCl to give the corresponding hydrochloride (36 mg, 11.68%). Selected data: MS (ES) m/z: 366.1; mp 284-286° C. (hydrochloride).
-
- To a solution of 4,6-dimethoxy-2-methyl nicotinamide (2.0 g, 10.2 mmol) in THF (80 mL), n-butyl lithium (19.12 mL, 30.6 mmol, 1.6 M solution in hexane) was added slowly under nitrogen at −78° C. After completion of addition the mixture was stirred for 1 h at 0° C. Then cooled to −78° C. and a solution of 4-methoxy benzonitrile (1.65 g, 10.2 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 16 h at room temperature. Saturated NH4Cl solution was added with cooling. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give crude product. The crude product was purified by chromatography using 50% ethyl acetate in hexane and then 2% methanol in ethyl acetate to give 2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (410 mg, 12%), as a yellow solid. Selected data: MS (ES) m/z: 341.1; mp 262-263° C. (at decomposition).
-
- A solution of sodium hydroxide (2.53 g, 63.25 mmol) in water (65 mL) was added to a mixture of bromoacetic acid (5.27 g, 37.95 mmol) and 3,5-dimethyl-4-hydroxy-benzaldehyde (1.9 g, 12.65 mmol) in water (30 mL). The reaction mixture was stirred at 100° C. for 24 h. The solution was acidified to pH ˜2 with conc. HCl. The brown solid was filtered off, washed with water, dried under vacuum, and purified by column chromatography to give (4-formyl-2,6-dimethyl-phenoxy)-acetic acid as a light brown solid (0.40 g). To a solution of 2-amino-4,6-dimethoxybenzamide (0.150 g, 0.764 mmol) in N,N-dimethyl acetamide (5 mL) were added (4-formyl-2,6-dimethyl-phenoxy)-acetic acid (0.159 g, 0.764 mmol), sodium hydrogen sulphite (58.5%, 0.150 g, 0.84 mmol) and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reaction mixture was stirred at 150° C. for 3 h. it was then cooled to room temperature and water (40 mL) was added. A yellow precipitate was formed and filtered off, washed with water and a small amount of methanol. Triturated with 10% methanol in ether to give 0.084 g of compound, which was further purified by preparative HPLC to give 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetic acid (47 mg, 13%) as a white solid. Selected data: MS (ES) m/z: 384.0; MP 270-272° C.
-
- To a solution of 4-aminobenzaldehyde (1 g, 8.52 mmol) at 0° C. under nitrogen atmosphere were added triethylamine (2.3 mL, 16.5 mmol), 4-dimethylaminopyridine (0.1 g, 0.82 mmol) and acetoxyacetyl chloride (1.77 mL, 16.5 mmol). The reaction mixture was allowed to warm up to room temperature and was stirred for 2.5 h. Triethylamine (1.15 mL, 8.25 mmol) and acetoxyacetyl chloride (0.88 mL, 8.25 mmol) were added and the reaction mixture was stirred for 1 h more. The reaction mixture was poured into a 1 M hydrochloric acid solution (60 mL), then extracted with methylene chloride (20 mL×3) and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The crude solid (3.17 g) was purified by flash column chromatography to provide pure acetic acid (4-formyl-phenylcarbamoyl)-methyl ester (1.14 g, 62% yield) as an orange solid. A mixture of 2-amino-4,6-dimethoxy-benzamide (0.15 g, 0.76 mmol), Acetic acid (4-formyl-phenylcarbamoyl)-methyl ester (0.169 g, 0.76 mmol), sodium hydrogensulfite (0.087 g, 0.84 mmol) and p-toluenesulfonic acid (15 mg, 0.076 mmol) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 4.5 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with cold water (60 mL) to obtain a yellow solid. The yellow solid was filtered off, washed with cold water (20 mL×2), methanol and dried under vacuum to provide crude compound (230 mg, 75%).
- The yellow solid was triturated with ether and methanol to provide acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methyl ester (112 mg, 37%). To a solution of acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methyl ester (0.23 g, 0.59 mmol) in THF/methanol mixture (3.5 mL/3.5 mL) was added potassium carbonate (0.41 g, 2.95 mmol). The reaction mixture was heated at reflux overnight and the solvent was concentrated under vacuum and diluted with water (60 mL) to obtain a precipitate. The yellow solid was filtered, washed with water (20 mL), methanol and dried under vacuum to provide crude compound. The yellow solid was triturated with ether and methanol to provide the desired compound N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide (55 mg, 55%). Selected data: MS (ES) m/z: 356.1; mp 318-319° C.
-
- To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), morpholine (2.87 g, 32.92 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 3.4 g of crude product in 83% yield.
- LAH (0.571 g, 15.05 mmol) was added to a 3-neck dry flask and THF (50 mL) was added on cooling. A solution of 4-morpholin-4-ylmethyl)-benzoic acid ethyl ester (3.0 g, 12.04 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to 0° C. and a 10% NaOH solution was added carefully followed by water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give (4-morpholin-4-ylmethyl phenyl) methanol (2.0 g, 80%). To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to −78° C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at −78° C. The reaction mixture was stirred for 15 min at −78° C. A solution of (4-morpholin-4-ylmethyl phenyl) methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at −78° C. and the mixture was stirred at −78° C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude 4-morpholin-4-ylmethyl benzaldehyde (1.6 g, 81%).
- To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4-morpholin-4-ylmethyl benzaldehyde (156 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (174 mg, 0.91 mmol) were added and the reaction mixture was heated at 150° C. for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one, which was converted to the hydrochloride salt (165 mg, 51%). Selected data: MS (ES) m/z: 382.07; MP 206-208° C. (at decomposition).
-
- To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), N-ethyl piperazine (3.76 g, 32.92 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 4.61 g of crude 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (100% yield). LAH (0.792 g, 20.86 mmol) was taken up in a 3-neck dry flask and THF (60 mL) was added on cooling. A solution of 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (4.61 g, 16.69 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to 0° C., 10% NaOH solution was added, and then water was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give 2.78 g of crude (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol in 78% yield. To a 3-neck flask containing anhydrous CH2Cl2 (100 mL) cooled to the −78° C. oxalyl chloride (1.8 g, 14.25 mmol) and DMSO (1.85 g, 23.76 mmol) were added and the mixture was stirred for 15 min at −78° C. The solution of (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol (2.78 g, 11.88 mmol) in CH2Cl2 (10 mL) was added at −78° C. and stirred at −78° C. for 1 h. Then Et3N (4.8 g, 47.52 mmol) was added at −78° C. The reaction mixture was allowed to come to room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then, solvent was removed to give crude 4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (2.5 g, 91%).
- To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (177 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (319 mg, 1.68 mmol) were added and the reaction mixture was heated at 150° C. for 5 h. The reaction mixture was cooled to room temperature, Water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxy-quinazolin-4(3H)-one (87 mg, 27%), which was converted to the hydrochloride salt. Selected data: MS (ES) m/z: 409.11; MP 278-280° C. (at decomposition).
-
- A mixture of dimethyl acetone-1,3-dicarboxylate (200 g, 1.15 mol), cyanamide (48.3 g, 1.15 mol), and Ni(acac)2 (14.75 g, 0.0574 mol) in dioxane (200 mL) was heated to reflux for 16 h and then cooled to room temperature. The precipitate was filtered off, and the solid was mixed with methanol (200 mL) and stirred for 30 min and filtered again to give 93 g product (44% yield). In a 1 L flask with a reflux condenser was added the product from step one (93.0 g, 0.505 mol) and POCl3 (425 mL) and the reaction mixture was heated to reflux for 35 min. POCl3 (300 mL) was evaporated under vacuum. The residue was poured into ice and water (400 mL), which was neutralized with KOH to pH 6-7. The precipitate was filtered off and extracted with ethyl acetate (2×300 mL). The organic solution was concentrated and purified by column chromatography to give methyl 2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 20.1%). In a 500 mL flask with reflux condenser was added methyl 2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 0.101 mol) and 25 wt % sodium methoxide in methanol (88 mL, 0.407 mol), together with methanol (20 mL). The mixture was heated to reflux for 5 h then cooled to room temperature. Acetic acid (15 mL) was added to the mixture and the pH was adjusted to ˜7.0. Methanol was removed and the residue was poured into water (100 mL). The precipitated solid was filtered off and rinsed with water (3×200 mL) to give methyl 2-amino-4,6-dimethoxypyridine-3-carboxylate (18.5 g, 86.4%). In a 500 mL flask with a reflux condenser was added methyl 2-amino-4,6-dimethoxypyridine-3-carboxylate (18.5 g, 0.0872 mol), potassium hydroxide (19.5 g, 0.349 mol) in water (80 mL) and ethanol (100 mL). The mixture was heated to 80° C. for 16 h. The solvent was removed and aqueous HCl was used to adjust pH to 6.0. The water was removed by lyophilization. The obtained solid was extracted with methanol to yield 2-amino-4,6-dimethoxy-nicotinic acid in quantitative yield. 2-Amino-4,6-dimethoxy-nicotinic acid (17.2 g, 0.0872 mol) was added to THF (110 mL). 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (21.73 g, 0.113 mol), 1-hydroxybenzotriazole hydrate (12.96 g, 0.0959 mol) and 4-methyl morpholine (9.7 g, 0.0959 mol) were then added to the suspension. After stirring for 10 min at room temperature, 50% v/v ammonium hydroxide (18.3 g, 0.262 mol) was added. The reaction mixture was kept at room temperature for 16 h. THF was removed and the residue was poured into cold water (100 mL). The precipitate was filtered off and further washed with cold water to yield 5.3 g of the pure desired compound. The aqueous solution was further extracted with dichloromethane (3×150 mL) to yield 8.4 g crude product, which was further purified by column chromatography to give a total of 10.8 g (62.8%) of 2-amino-4,6-dimethoxy-nicotinamide.
- To a solution of 2-amino-4,6-dimethoxy-nicotinamide (1.40 g, 7.1 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (1.07 g, 7.1 mmol) in N,N-dimethyl acetamide (20 mL), NaHSO3 (1.39 g, 7.81 mmol) and p-TSA (0.675 g, 3.55 mmol) were added and the reaction mixture was heated at 150° C. overnight. The solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected and further washed with methanol. The crude product was purified by column chromatography (silica gel 230-400 mesh; 2% methanol in CH2Cl2 as eluent) to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (0.92 g, 39.6%). Selected data: MS (ES) m/z: 328.07; MP 297-299° C.
-
- 5,7-Dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-methoxy-3-morpholin-4-ylmethyl-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one (65 mg, 28%) was isolated as a light yellow solid. Selected data: MS (m/z): 412.07; MP 282.7-284.5° C.
-
- To a solution of 2-amino-4,6-dimethoxy-nicotinamide (1.07 g, 5.42 mmol) and 4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (1.67 g, 5.42 mmol) in N,N-dimethyl acetamide (25 mL), NaHSO3 (1.06 g, 5.97 mmol) and p-TSA (1.14 g, 5.97 mmol) were added and the reaction mixture was heated at 150° C. for 16 h, cooled to room temperature and poured into water. The solid was collected to give 3.25 g of crude product. To a solution of the crude product (3.25 g, 6.70 mmol) in THF (50 mL), TBAF (3.5 g, 13.4 mmol) was added at 0° C. and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed, and the crude was purified by column chromatography (silica gel 230-400 mesh; 2% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (132 mg, 6%). Selected data: MS (ES) m/z: 371.99; MP 255-256° C.
-
- 2-Amino-4,6-dimethoxybenzamide (0.5 g, 2.55 mmol) and methyl iodide (0.17 mL, 2.81 mmol) were mixed in a closed bomb and heated at 110° C. for 14 h. The compound was washed with a dichloromethane-methanol mixture. After removing the solvent, the crude was purified by silica gel column chromatography (40 g) employing 1-5% methanol in dichloromethane to give 2,4-dimethoxy-6-methylamino-benzamide (0.027 g, 50.4%).
- The compound 3,5-dimethyl-4-hydroxybenzoic acid (5.04 g, 30.33 mmol) was mixed with pyridine (20 mL). Acetic anhydride (3.72 g, 36.4 mmol) was added and the mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid in quantitative yield (6.33 g). The compound 4-acetoxy-3,5-dimethyl-benzoic acid (0.36 g, 1.73 mmol)) was dissolved in dichloromethane (5 mL) and oxalyl chloride (0.3 mL, 3.46 mmol) was added dropwise, followed by 1 drop of DMF. The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solvent was evaporated in vacuo to obtain acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester in quantitative yield (0.392 g).
- A solution of 2,4-dimethoxy-6-methylamino-benzamide (0.28 g, 1.33 mmol) in pyridine (10 mL) was added to acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (1.1 eq.) and stirred at room temperature for 14 h. The solvent was removed and the reaction mixture was acidified with 1 N HCl and extracted with ethyl acetate. The solvent was removed and the crude was purified by silica gel column chromatography (40 g) employing 1% methanol in dichloromethane to give acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 67%). Acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 0.89 mmol) was dissolved in ethanol (5 mL), 5% aqueous NaOH solution (10 mL) was added dropwise and the mixture was stirred at room temperature for 1.5 h. The compound was extracted with ethyl acetate and washed with ether to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one (0.13 g, 43%). Selected data: MS (ES) m/z: 340.17; MP 188.5-189.1° C.
-
- A solution of 3,5-dimethoxy-4-hydroxybenzaldehyde (3 g, 20 mmol) and 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (3.74 g, 22 mmol) in DMF (50 mL) was mixed with sodium hydride (2.24 g, 56 mmol) and potassium iodide (0.73 g, 4.4 mmol). The reaction mixture was stirred at room temperature for 2 h and then at 80° C. for an additional 2 h. The reaction was quenched with water (50 mL), extracted with EtOAc (3×100 mL), concentrated to afford an oily residue. Purification by column chromatography to yield 3.4 g of 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (70%). A mixture of 2-amino-4,6-dimethoxy-benzamide (0.2 g, 1.02 mmol), 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (0.251 g, 1.02 mmol), sodium hydrogensulfite (0.181 g, 1.02 mmol) and p-toluenesulfonic acid (0.234 g, 1.224 mmol) in N,N-dimethyl acetamide (10 mL) was stirred at 155° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (3×50 mL), and concentrated to afford a solid residue. The solid was further purified by column chromatography to yield about 40 mg impure product. This same reaction was repeated three times on the same scale and the impure product after each column was combined and subjected to one final column to yield 2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (76 mg, 4%) as a light yellow solid. Selected data: MS (ES) m/z: 424.04; MP 181.0-183.2° C.
-
- To a solution of 2-amino-5-nitro-benzamide (680 mg, 3.75 mmol) and 4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (1.16 g, 3.75 mmol) in N,N-dimethyl acetamide (35 mL), NaHSO3 (736 mg, 4.14 mmol) and p-TSA (71 mg, 0.375 mmol) were added and the reaction mixture was heated at 150° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was diluted with water and the solids were filtered off to give crude product (590 mg, 44%). To a solution of above crude product (490 mg, 1.38 mmol) in DMF (20 mL) and MeOH (20 mL), Pd—C(100 mg, 10%) was added and the reaction mixture was hydrogenated for 4 h at room temperature at 30 psi H2. The reaction mixture was filtered and the solvent was evaporated to give crude product. The crude was purified by column chromatography (silica gel 230-400 mesh; 4% methanol in CH2Cl2 as eluent) to give 6-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethylphenyl)-3H-quinazolin-4-one (190 mg, 42% yield). To a solution of 6-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethylphenyl)-3H-quinazolin-4-one (95 mg, 0.29 mmol) in pyridine (5 mL), acetic anhydride (108 mg, 0.73 mmol) was added and the mixture was stirred for 16 h at room temperature. The solvent was removed and the solids were dissolved in a mixture of MeOH (10 mL) and THF (10 mL) (compound was partially soluble). Then K2CO3 (100 mg, 0.73 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The solvent was removed and the crude was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide
- (65 mg, 60%). Selected data: MS (ES) m/z: 368.09; MP>300° C.
-
- Malonic acid (5.27 g, 51 mmol), 2,4,6-trichlorophenol (20 g, 100 mmol) and phosphorus oxychloride (17.17 g, 112 mmol) were stirred under nitrogen atmosphere at reflux for 12 h. The reaction mixture was cooled to 70° C. and poured into ice water. The formed precipitate was collected, washed with water and dried under vacuum to provide the desired malonic acid bis-(2,4,6-trichloro-phenyl) ester as a white solid (23.37 g, quantitative yield). To a mixture of malonic acid bis-(2,4,6-trichloro-phenyl) ester (23.37 g, 50.5 mmol) and ethyl-3-aminocrotonate (6.38 mL, 50.5 mmol) under nitrogen atmosphere was added bromobenzene (5 mL). The reaction mixture was heated under reflux for 2.5 h then cooled to room temperature and diluted with ethyl acetate. The formed precipitate was filtered off, washed several times with ethyl acetate and dried under vacuum to afford the desired 4,6-dihydroxy-2-methyl-nicotinic acid ethyl ester as a yellow solid (13.04 g, quantitative yield). To a mixture of 4,6-dihydroxy-2-methyl-nicotinic acid ethyl ester (12.93 g, 65.57 mmol) in N,N-dimethylformamide (550 mL) and potassium carbonate (27.18 g, 196.71 mmol) under nitrogen atmosphere was added dropwise isopropyl iodide (19.65 mL, 196.71 mmol). The resulting slurry was vigorously stirred at room temperature overnight and then filtered to remove insoluble salts. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (4×400 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to afford the desired 4,6-diisopropoxy-2-methyl-nicotinic acid ethyl ester as an oil which solidified on standing (15.24 g, 82.6%). To a solution of 4,6-diisopropoxy-2-methyl-nicotinic acid ethyl ester (15.24 g, 54.2 mmol) in methanol (70 mL) was added sodium hydroxide in water (70 mL). The reaction mixture was heated under reflux for 48 h. The solvent was removed under reduced pressure and concentrated hydrochloric acid was added (20 mL). The solvent was evaporated to provide the desired 4,6-diisopropoxy-2-methyl-nicotinic acid as a white salt (26.91 g, theoretical mass: 13.73 g). To a solution of 4,6-diisopropoxy-2-methyl-nicotinic acid salt (13.73 g, 54.2 mmol) in methylene chloride (160 mL) under nitrogen atmosphere was added oxalyl chloride (9.46 mL, 108.4 mmol) followed by N,N-dimethylformamide (1 mL). The reaction mixture was stirred overnight then the solvent was evaporated to obtain the desired crude acid chloride, which was used for the next step without further purification. To 50% v/v ammonia hydroxide (500 mL) at room temperature was added dropwise a solution of the crude 4,6-diisopropoxy-2-methyl-nicotinoyl chloride in methylene chloride (400 mL). The reaction mixture was stirred for 3.5 h. The solution was separated and the aqueous layer was extracted with methylene chloride (100 mL×8). The combined organic layers were dried over sodium sulfate and evaporated to afford a crude solid (6.94 g). The crude was purified by flash column chromatography to provide pure 4,6-diisopropoxy-2-methyl-nicotinamide as an orange solid (3.0 g, 21.9%). To a solution of 4,6-diisopropoxy-2-methyl-nicotinamide (0.3 g, 1.18 mmol) in THF (5 mL) under nitrogen was added 1.6 M n-BuLi solution in hexanes (3 mL, 4.75 mmol) at −20° C. The reaction mixture was allowed to warm-up to room temperature and left to stir for 2 h. The reaction was then cooled to −20° C. and a solution of 4-benzyloxy-3,5-dimethyl-benzonitrile in THF (5 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and was left to stir for 20 h. Water and acetic acid were added until pH ˜5. The solution was heated to 55° C. for 3 h then cooled to room temperature, diluted with ethyl acetate, separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to provide crude orange oil (1.02 g). The crude was purified by flash column chromatography to provide pure 7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-diisopropoxy-6H-[1,6]naphthyridin-5-one as a yellow solid (0.10 g, 17.9%). To a solution of 7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-diisopropoxy-[1,6]naphthyridin-5-ylamine (0.10 g, 0.21 mmol) in methanol (4 mL) was added palladium on charcoal catalyst (0.06 g, 0.54 mmol). The reaction mixture was stirred under 1 atmosphere pressure of hydrogen for 20 h and diluted with methanol and filtered through a Celite pad. The solvent was evaporated under reduced pressure to provide a crude solid (0.077 g) which was triturated with ether followed by methanol to afford the desired compound 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy-1,6-naphthyridin-5(6H)-one (35 mg, 43.2%). Selected data: MS (ES) m/z: 383.08; MP 206-208° C.
-
- To a solution of 3-bromo-4-hydroxybenzaldehyde (5 g, 2.44 mmol) in acetone (100 mL) under nitrogen atmosphere was added potassium carbonate (50 6 g, 36.6 mmol). The slurry mixture was cooled to 0° C. and chloromethyl ether (9.25 mL, 12.2 mmol) was added dropwise. The ice bath was removed and the mixture was heated at 70° C. for 2.5 h. After cooling to room temperature, excess potassium carbonate was filtered off and the acetone evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and water (100 mL) was added. The organic layer was separated, washed with 0.5 N sodium hydroxide solution (100 mL×2) followed by brine and dried over sodium sulfate and concentrated to give a crude oil (6.69 g), which was purified by Flash Column Chromatography on 230-400 mesh silica gel (40-63 μm particle size) eluted with EtOAc/hexane: 2/3 to provide pure 3-bromo-4-methoxymethoxy-benzaldehyde, as an oil (4.46 g, 73.2%). To a solution of 3-bromo-4-methoxymethoxy-benzaldehyde (4.4 g, 17.9 mmol) and vinyltributyl tin (5.8 mL, 19.7 mmol) in toluene (130 mL) under nitrogen atmosphere was added an catalytic amount of tetrakis(triphenylphosphine)palladium (0.79 mg, 0.68 mmol). The resulting mixture was heated at 100° C. overnight, cooled to room temperature and a saturated potassium fluoride solution (30 mL) was added. The solution was stirred for 30 min then diluted with ethyl acetate, separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to provide crude yellow oil (4.6 g). The crude was purified by flash column chromatography to give pure 4-methoxymethoxy-3-vinyl-benzaldehyde as a yellow oil (1.95 g, 56.5%). To a solution of 4-methoxymethoxy-3-vinyl-benzaldehyde (1.8 g, 9.46 mmol) in THF (25 mL) under nitrogen was added borane dimethyl sulfide complex at 0° C. The solution was allowed to warm to room temperature and was stirred for 18 h. The reaction mixture was quenched at 0° C. with methanol (12 mL), hydrogen peroxide solution (8 mL) and 4 N sodium hydroxide solution (12 mL). The mixture was vigorously stirred at room temperature for 12 h and was diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to provide crude oil (3.2 g). The crude was purified by flash column chromatography to give pure 2-(5-hydroxymethyl-2-methoxymethoxy-phenyl)-ethanol (1.19 g, 59.5%). The mixture of 2-(5-hydroxymethyl-2-methoxymethoxy-phenyl)-ethanol (0.78 g, 3.69 mmol) and magnesium dioxide (0.086 g, 0.99 mmol) in chloroform (12 mL) was heated at 80° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature and was diluted with chloroform and filtered through a Celite pad to give the desired 3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.63 g, 81.3%), which was used without further purification.
- A mixture of 2-amino-4,6-dimethoxy-benzamide (0.25 g, 1.27 mmol), 3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.268 g, 1.27 mmol), sodium hydrogensulfite (0.146 g, 1.4 mmol) and p-toluenesulfonic acid (0.025 g, 0.127 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent evaporated under reduced pressure. Water (70 mL) was added to obtain a solid. The yellow solid was filtered off, washed with water and dried under vacuum to provide crude 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.182 g, 36.7%) which was used as such in the next step. A solution of 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.18 g), 50% acetic acid solution (4 mL) and catalytic amount of concentrated sulfuric acid (0.02 mL) was heated at 70° C. for 2.5 h. After cooling to room temperature the reaction mixture was diluted with water (30 mL) to obtain a solid. The solid was filtered off, washed with water and dried under high vacuum to provide crude solid (0.135 g, 85%). The crude was purified by flash column chromatography to give pure 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.035 g. 8% over 2 steps). Selected data: MS (ES) m/z: 343.0; MP 249-250.3° C.
-
- To a 100 mL round bottom flask was added 2-amino-4,6-dimethoxy-benzamide (318 mg, 1.6 mmol), 4-(2-benzyloxy-ethoxy)-3,5-dimethyl-benzaldehyde (461 mg, 1.6 mmol), p-toluenesulfonic acid monohydrate (32 mg, 0.16 mmol), sodium hydrogensulfite (318 mg, 1.8 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen overnight. Water (40 mL) and ether (30 mL) were added. The precipitate was filtered off, washed with water then ether, and air-dried. The intermediate 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one was obtained as light brown/beige solid. Yield 474 mg (64%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (474 mg, 1.03 mmol) was stirred in phosphorus oxychloride (10 mL) at 100° C. for 4 h. Excess phosphorus oxychloride was removed under reduced pressure. Ice was added and the solid was collected. The solid was washed with water and ether, and air-dried. 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline was obtained as a light brown solid (yield: 356 mg, 72%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline (192 mg, 0.4 mmol) was dissolved in a small amount of THF and 10% Pd/C (dry) (66 mg) was added. Anhydrous methanol (20 mL) and ammonium formate (955 mg) were added. The mixture was stirred in a 80° C. oil bath for 5 h. The mixture was filtered through Celite, washed with MeOH/DCM, purified by column chromatography to give 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol (36 mg, 25%) as an off-white solid. Selected data: MS (ES) m/z: 355.04; mp 169-170° C.
-
- To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for 5 h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethyl benzamide (0.42 g, 95%).
- A mixture of 2-amino-4,6-dimethyl benzamide (0.2 g, 1.22 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.376 g, 1.22 mmol), sodium hydrogensulfite (0.22 g, 1.22 mmol) and p-toluenesulfonic acid (0.116 g, 0.61 mmol) in N,N-dimethyl acetamide (10 mL) was stirred at 155° C. for 14 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The solid crashed out and was collected by filtration to afford impure product. The solid was re-dissolved in THF (30 mL) and mixed with TBAF in THF (5 mL, 5 mmol). The reaction mixture was stirred at room temperature for 14 h and concentrated using a rotary evaporator to afford an oily residue. Further purification by column (SiO2, EtOAc/DCM/MeOH=12:4:1) yielded an off-white solid. This solid was diluted with MeOH (10 mL) to make a slurry. The solid was collected by filtration and washed with MeOH to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one (98 mg, 24%) as a white solid. Selected data: MS (ES) m/z: 339.10; MP 259.6-261.2° C.
-
- To a solution of 2-amino-4,6-dimethoxy-nicotinamide (300 mg, 1.52 mmol) and 4-(bis-(2-hydroxyethyl)amino)-benzaldehyde (318 mg, 1.52 mmol) in N,N-dimethylacetamide (10 mL) were added NaHSO3 (297 mg, 1.67 mmol) and p-TSA (376 mg, 1.98 mmol) and the reaction mixture was heated at 150° C. for 4 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water and the solid was filtered off to give the crude product. The crude product was purified by column chromatography to give 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (60 mg, 10%). Selected data: MS (ES) m/z: 387.05; MP 277-279° C.
-
- To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol) in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture was stirred for 1 h at room temperature. A solution of 1-bromo-2-methoxy ethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72 h at room temperature. The reaction mixture was quenched by addition of saturated NH4Cl solution and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. Upon removal of solvent, it gave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield). To a solution of 2-amino-4,6-dimethoxy-benzamide (200 mg, 1.02 mmol) and 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (199 mg, 1.12 mmol) and p-TSA (22 mg, 0.102 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. Cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the solid was collected to give the crude product. The crude product was purified by chromatography using 2% MeOH in CH2Cl2 to give 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C.
-
- To a solution of 2-amino-4,6-dichloro-benzoic acid (0.5 g, 2.43 mmol) in THF (22 mL) under nitrogen atmosphere was added successively N-(3-Dimehtylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.51 g, 2.67 mmol), N-hydroxybenzotriazole (0.36 g, 2.67 mmol) and N-methylmorpholine (0.3 mL, 2.67 mmol). The mixture was stirred for 1.5 h before a 50% ammonium hydroxide solution (1.03 mL, 14.58 mmol) was added. The mixture was stirred overnight. The solvent was evaporated under reduced pressure, water (20 mL) was added and the solution was extracted with EtOAc (50 mL×2). The combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated under reduced pressure to provide crude yellow solid (0.45 g). The crude product was triturated with ether to give pure 2-amino-4,6-dichloro-benzamide (0.41 g, 82%). A mixture of 2-amino-4,6-dichloro-benzamide (0.2 g, 0.97 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.3 g, 0.97 mmol), sodium hydrogensulfite (0.11 g, 1.05 mmol) and p-toluenesulfonic acid (0.093 g, 0.48 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, then water (70 mL) was added and the precipitate was collected, and washed with water, dried under vacuum and triturated with ether to provide the crude mixture of 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-5,7-dichloro-3H-quinazolin-4-one and 5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one (0.298 g), which was used as such in the next step. To the above described mixture (0.298 g, 0.59 mmol) in tetrahydrofurane (5 mL) was added tetrabutylammonium fluoride (2.35 mL, 2.35 mmol) under nitrogen atmosphere. The reaction mixture was stirred overnight before the solvent was evaporated under reduced pressure and water was added to obtain a precipitate. The solid was filtered off, washed with water, dried under vacuum and triturated with ether to provide crude yellow solid (0.226 g, 98%). The crude was purified twice by flash column chromatography to give pure 5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.069 g, 19%). Selected data: MS (ES) m/z: 378.92, 380.88, 382.89; MP 260.8-262.6° C.
-
- To a solution of 2,6-dimethoxytoluene (50 g, 328.5 mmol) in ether (450 mL) was added freshly prepared dioxane dibromide in ether over 0.5 h. The mixture was stirred at room temperature for an additional 1.5 h and poured into a beaker containing water (500 mL). The aqueous layer was discarded and the ether layer was washed sequentially with water (2×500 mL), sodium bicarbonate (saturated aqueous) (2×500 mL), dried over sodium sulfate, and concentrated using a rotary evaporator to afford 76 g of 3-bromo-2,6-dimethoxytoluene as a colorless oil (100%). A cooling well was used to collect 300 mL of ammonia at −78° C., which was mixed with potassium (0.5 g) and ferric nitrate (0.5 g). Additional potassium (14.2 g, 364 mmol) was added at −78° C. portion-wise. The solution was stirred at −78° C. for 15 min. To this solution was slowly added 3-bromo-2,6-dimethoxytoluene (42 g, 182 mmol) in THF (100 mL). The resulting mixture was stirred at −78° C. for 3 h and then 0° C. for 1 h. The reaction was quenched by adding water (150 mL) and extracted with DCM (3×200 mL) to get a brown oil as the crude product. It was further purified by column chromatography to yield 22.1 g of 3,5-dimethoxy-4-methylaniline (73%). A solution of 3,5-dimethoxy-4-methylaniline (22.1 g, 132.3 mmol) in dioxane (380 mL) and water (380 mL) was mixed with potassium carbonate (45.6 g, 330.8 mmol) and (Boc)2O (34.6 g 158.8 mmol) and stirred at room temperature for 14 h. The reaction mixture was then extracted with DCM (3×100 mL) and concentrated using a rotary evaporator. The resulting solid residue was purified by column chromatography. A mixture of DCM-hexanes (20 mL-300 mL) was used to make a slurry and the solid was collected by filtration and washed with hexanes to provide 28.6 g of (3,5-dimethoxy-4-methyl-phenyl)-carbamic acid tert-butyl ester (81%). A solution of (3,5-dimethoxy-4-methyl-phenyl)-carbamic acid tert-butyl ester (28.6 g, 107.1 mmol) in carbon tetrachloride (450 mL) was mixed with NBS (19.05 g, 107.1 mmol) and AIBN (1.55 g, 9.37 mmol) and the mixture was stirred at 80° C. with the light on for 2 h. The reaction was quenched by adding water (150 mL) and extracted with DCM (3×100 mL), and concentrated to afford a solid residue. Further purification by column chromatography yielded 34.9 g of (2-bromo-3,5-dimethoxy-4-methyl-phenyl)-carbamic acid tert-butyl ester (94%). A solution of (2-bromo-3,5-dimethoxy-4-methyl-phenyl)-carbamic acid tert-butyl ester (34.9 g, 100.9 mmol) in carbon tetrachloride (450 mL) was mixed with NBS (21.5 g, 121.0 mmol) and AIBN (1.55 g, 9.37 mmol) and was stirred at 80° C. with the light on for 4 h. The reaction was then quenched by adding water (150 mL) and extracted with DCM (3×100 mL), and concentrated to afford a solid residue. Further purification by column chromatography yielded 39 g of (2-bromo-4-bromomethyl-3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester (91%). A solution of (2-bromo-4-bromomethyl-3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester (39 g, 91.8 mmol) in THF (600 mL) was mixed with morpholine (45 mL, 515.0 mmol) and stirred at room temperature for 7 h. The reaction was diluted with water (300 mL), extracted with DCM (3×200 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, DCM/MeOH=20:1) to provide 35 g of (2-bromo-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (88%). A solution of (2-bromo-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (3 g, 6.94 mmol) in THF (150 mL) was mixed with NaH (0.333 g, 8.33 mmol) and stirred at room temperature for 1.5 h. The resulting mixture was cooled to −78° C. and mixed with nBuLi (3.33 mL, 8.33 mmol). The reaction was stirred for 1.5 h at −78° C. before addition of t-BuLi (8.16 mL, 13.88 mmol). The reaction was stirred at −78° C. for 1 h and carbon dioxide gas was then bubbled through for 8 h allowing the temperature to rise gradually to room temperature. The reaction was quenched by adding water (0.5 mL, 27.8 mmol) and concentrated using a rotary evaporator. The solid residue was made into slurry in minimal amount of MeOH and the solid was filtered off. The filtrate was then concentrated using a rotary evaporator and the solid was made into a slurry again in MeOH and filtered. After repeating two to three times, the filtrate was concentrated to yield 1.1 g of impure 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid (40% crude yield).
- A solution of 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid (1.8 g, 4.54 mmol), EDCl.HCl (1.31 g, 6.82 mmol), HOBt (1.23 g, 9.09 mmol), and triethylamine (3.3 mL, 23.7 mmol) in THF (50 mL) was stirred at room temperature for 1 h. Ammonium hydroxide (50% aqueous, 10 mL) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=2:1:4) to provide 0.9 g of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (50%). A solution of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (0.9 g, 2.74 mmol) in HOAc (20 mL) and 12 N HCl aqueous (20 mL) was stirred at 50° C. for 1 h and then concentrated to dryness using a rotary evaporator. The residue was mixed with saturated sodium bicarbonate aqueous (40 mL), extracted with DCM (3×100 mL), and concentrated. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=3:2:3) to provide 0.6 g of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (89%). A mixture of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (0.6 g, 2.03 mmol), 3,5-dimethyl-4-hydroxy benzaldehyde (0.61 g, 4.06 mmol), sodium hydrogensulfite (1.24 g, 7.0 mmol) and p-toluenesulfonic acid (1.14 g, 6 mmol) in N,N-dimethyl acetamide (20 mL) was stirred at 115° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc, and concentrated. Purification by column chromatography afforded a solid residue, which was made into slurry in a mixed solvent of DCM-hexanes (3 mL-20 mL). The slurry was filtered and washed with hexanes to provide 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one (56 mg, 6.6%) as a light yellow solid. Selected data: MS (ES) m/z: 426.0; MP 237.0-239.1° C.
-
- Following the method described for 6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one was made from 2-amino-5-methoxybenzamide and 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde in 4% yield and isolated as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 7.88 (s, 2H), 7.68 (d, J=8.90 Hz, 1H), 7.53 (d, J=2.95 Hz, 1H), 7.43 (dd, J=8.90, 2.98 Hz, 1H), 4.89 (t, J=5.52 Hz, 1H), 3.92-3.80 (m, 5H), 3.73 (q, J=5.09, 5.09, 4.97 Hz, 2H), 2.32 (s, 6H); MS (APCI) m/z 341 [M+H]+.
-
- A mixture of 2-chlorobenzaldehyde (0.0430 g, 306 mmol), 2-amino-4,6-dimethoxybenzamide (0.0600 g, 0.306 mmol), NaHSO3 (94%, 0.0474 g, 0.428 mmol), and p-TsOH.H2O (0.0175 g, 0.0918 mmol) in DMA (3.06 mL) was heated at 140° C. for 16 h. The mixture was cooled and chromatographed on silica gel, fractions containing the product were combined, concentrated under vacuum, diluted with EtOAc (300 mL), washed with water (3×75 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum to provide 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0377 g, 39%) as a yellow solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 7.65-7.40 (m, 4H), 6.72 (d, J=2.29 Hz, 1H), 6.59 (d, J=2.30 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H); MS (APCI) m/z 317 [M+H]+.
-
- Following the method described for 6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one, 2-(4-(2-Hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one was made from 2-amino-6-methoxybenzamide (made from the corresponding amino acid in two steps) and 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde in 77% yield and isolated as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.96 (s, 1H), 7.89 (s, 2H), 7.68 (t, J=8.20 Hz, 1H), 7.23 (d, J=7.89 Hz, 1H), 6.98 (d, J=8.19 Hz, 1H), 4.89 (t, J=5.53 Hz, 1H), 3.94-3.65 (m, 7H), 2.31 (s, 6H); MS (APCI) m/z 341 [M+H]+.
-
- A mixture of 2-amino-4,6-dimethoxybenzamide (0.060 g, 0.306 mmol), 2-methylbenzaldehyde (0.037 g, 0.306 mmol), NaHSO3 (0.032 g, 0.306 mmol), and p-TsOH.H2O (0.00370 g, 0.021 mmol) in DMA (5.00 mL) was heated at 60° C. overnight. The mixture was cooled to room temperature, water (50.0 mL) and EtOAc (50.0 mL) was added. The layers were separated and the organic layer was washed with water (2×50 mL), brine (50 mL), dried and concentrated. The crude solid was purified via CombiFlash provide 5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one (0.025 g, 28%) as yellow solid. Selected data: 1H NMR (300 MHz, CDCl3) δ 9.51 (s, 1H), 7.53 (dd, J=5.92, 3.07 Hz, 1H), 7.46-7.36 (m, 1H), 7.32 (dd, J=9.04, 4.60 Hz, 2H), 6.81 (d, J=2.29 Hz, 1H), 6.49 (d, J=2.28 Hz, 1H), 3.95 (s, J=7.48 Hz, 3H), 3.94-3.88 (s, 3H), 2.51 (s, 3H); MS (APCI) m/z 297 [M+H]+.
-
- Following the procedure described above for 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one, 5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one was made from 6-(4-(methylsulfonyl)phenyl)picolinaldehyde and 2-amino-4,6-dimethoxybenzamide in 38% as a yellow solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.69 (d, J=8.38 Hz, 2H), 8.46 (d, J=7.72 Hz, 1H), 8.33 (d, J=7.75 Hz, 1H), 8.22 (t, J=7.84 Hz, 1H), 8.08 (d, J=8.37 Hz, 2H), 6.85 (s, 1H), 6.63 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.4 (s, 3H); MS (APCI) m/z 438 [M+H]+.
-
- Following the method described for 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one, 5,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin-4(3H)-one was made from 6-methylpicolinaldehyde and 2-amino-4,6-dimethoxybenzamide in 33% yield and isolated as an off-white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.21 (d, J=7.74 Hz, 1H), 7.95 (t, J=7.75 Hz, 1H), 7.52 (d, J=7.62 Hz, 1H), 6.82 (d, J=2.33 Hz, 1H), 6.60 (d, J=2.31 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.62 (s, 3H); MS (APCI) m/z 298 [M+H]+.
-
- Following the procedure described above for 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one, 5,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2-yl)quinazolin-4(3H)-one was made from 6-(4-(methylthio)phenyl)picolinaldehyde and 2-amino-4,6-dimethoxybenzamide in 39% as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.39-8.30 (m, 3H), 8.23-8.05 (m, 2H), 7.46-7.37 (m, 2H), 6.84 (d, J=2.33 Hz, 1H), 6.62 (d, J=2.33 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 2.55 (s, 3H); MS (APCI) m/z 406 [M+H]+.
-
- Following the method described for 5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one, 2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 2-chloro-6-methylisonicotinoyl chloride in 75% yield as a white solid. Selected data: 1H NMR (300 MHz, CDCl3) δ 10.95 (s, 1H), 7.90 (s, 2H), 6.74 (d, J=2.33 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.29 (s, 3H); MS (APCI) m/z 332 [M+H]+.
-
- To a solution of 4-methoxy-3,5-dimethylbenzoic acid (0.100 g, 0.555 mmol) in CH2Cl2 (2.77 mL) cooled to 0-5° C. was added oxalyl chloride (67.8 μL, 0.777 mmol) followed by drop-wise addition of DMF (4.3 μL, 0.056 mmol). The mixture was stirred for 50 min, the volatiles were removed under vacuum, and the crude acid chloride was used immediately without further purification.
- To a mixture of 2-amino-4,6-dimethoxybenzamide (0.0990 g, 0.555 mmol) and pyridine (44.9 μL, 0.555 mmol) in THF (2.02 mL) was added dropwise a solution of the acid chloride (crude residue described above) in THF (925 μL). After 16 h, the mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (3×75 mL), saturated aqueous NaHCO3 (3×75 mL), and brine (75 mL). The insoluble yellow solid was isolated by filtration to provide the amide (0.150 g, 83%). A mixture of the amide (0.148 g, 0.413 mmol) and 2 M NaOH (7.00 mL) was heated at 85° C. for 19 h, cooled to 5° C., and neutralized with 4 M HCl in dioxanes. The white solid was filtered and rinsed with acetone to provide 5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.144 g, 100%). Selected data: 1H NMR (300 MHz, CDCl3) δ 11.00 (s, 1H), 7.90 (s, 2H), 6.74 (d, J=2.33 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.72 (s, 3H), 2.29 (s, 6H); MS (APCI) m/z 341 [M+H]+.
-
- To a solution of 3,5-dimethyl-4-nitrobenzoic acid (1.00 g, 5.12 mmol) in CH2Cl2 (25.6 mL) cooled to 0-5° C. was added oxalyl chloride (0.626 mL, 7.17 mmol) followed by dropwise addition of DMF (39.8 μL). The mixture was stirred for 2 h, the volatiles were removed under vacuum, and the crude acid chloride was used immediately without further purification. To a mixture of 2-amino-4,6-dimethoxybenzamide (0.913 g, 4.65 mmol) and pyridine (414 μL, 5.12 mmol) in THF (18.6 mL) was added dropwise a solution of the acid chloride (crude residue described above) in THF (8.53 mL). After 16 h, the mixture was diluted with EtOAc (500 mL), washed with saturated aqueous NH4Cl (3×100 mL), saturated aqueous NaHCO3 (3×100 mL), and brine (100 mL). The insoluble yellow solid was isolated by filtration to provide the amide (1.51 g, 87%). A mixture of the amide (1.50 g, 4.03 mmol) and 2 M aqueous NaOH (25.0 mL) was heated at 85° C. for 17 h, then added THF (50 mL) and stirred at reflux for 25 h. The volatiles were removed under vacuum, the mixture was cooled to 5° C., and neutralized with 4 M HCl in dioxanes. After stirring for 30 min, the white solid was filtered and lyophilized from MeCN/H2O to afford the cyclized compound (1.36 g, 95%). A mixture of the cyclized compound (0.200 g, 0.563 mmol), Na2S2O4 (0.980 g, 5.63 mmol), water (5.00 mL) and MeOH (15.0 mL) was stirred at 70° C. for 2 h. The volatiles were removed under vacuum, then diluted with EtOAc (200 mL), washed with saturated NaHCO3 (2×100 mL) and brine (75 mL). The organic layer was dried over sodium sulfate, filtered, and the volatiles were removed under vacuum to provide 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.062 g, 34%) as a yellow solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.45 (s, 1H), 7.78 (s, 2H), 6.66 (d, J=2.25 Hz, 1H), 6.42 (d, J=2.24 Hz, 1H), 5.26 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.14 (s, 6H); MS (APCI) m/z 326 [M+H]+.
-
- A mixture of 2-amino-4,6-dimethoxybenzamide (0.0700 g, 0.36 mmol) and 3,5-dimethylbenzoyl chloride (0.112 g, 0.65 mmol) in THF (5.0 mL) was placed in a microwave reactor at 80° C. for 30 min. The THF was removed under reduced pressure, and the residue was purified via CombiFlash chromatography to yield the expected amide. This material was used directly in the next step. A mixture of the amide and H2O/MeCN (2:1, 5.00 mL) was basified to pH 12 with 2 N NaOH and stirred at 80° C. for 16 h. The mixture was cooled and neutralized with 1 N HCl. The resulting precipitate was collected on a frit, washed with water (5.00 mL) and lyophilized to yield 2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0395 g, 31% over two steps) as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 7.80 (s, 2H), 7.21 (s, 1H), 6.76 (d, J=2.24 Hz, 1H), 6.53 (d, J=2.21 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.35 (s, 6H); MS (APCI) m/z 311 [M+H]+.
-
- To a solution of 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.096 g, 0.295 mmol) and diisopropylethylamine (61.7 μL, 0.354 mmol), in DMF (2.96 mL) was added dropwise methanesulfonyl chloride (25.2 μL, 0.325 mmol). After stirring at room temperature for 18 h, the mixture was diluted with EtOAc (300 mL), washed with saturated aqueous sodium bicarbonate (2×75 mL), saturated aqueous LiCl (2×75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified over silica gel (12 g, CH2Cl2/CH3OH) to provide (E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide (0.0502 g, 45%) as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.87 (s, 2H), 7.40 (s, 1H), 6.72 (d, J=2.31 Hz, 1H), 6.48 (d, J=2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.97 (s, 6H), 2.12 (s, 6H); MS (APCI) m/z 381 [M+H]+.
-
- To a solution of 4-hydroxy-3,5-dimethylbenzoic acid (2.00 g, 12.0 mmol) in CH2Cl2 (60.2 mL) cooled to 0-5° C. was added oxalyl chloride (1.47 mL, 16.8 mmol) followed by dropwise addition of DMF (93.3 μL, 1.20 mmol). The mixture was stirred for 1.25 h, the volatiles were removed under vacuum to give crude acid chloride, which was used immediately without further purification. A mixture of 2-amino-5-bromobenzamide (1.99 g, 9.23 mmol) and the acid chloride (crude residue described above) in THF (92.3 mL) was stirred at room temperature for 17 h, then heated at reflux for 4 h. The volatiles were removed under vacuum, the residue was triturated with EtOAc, and filtered to afford the amide (3.02 g, 90%) as a yellow solid. A mixture of the amide (3.01 g, 8.29 mmol), 2 M NaOH (20.0 mL), water (40.0 mL), and MeCN (20.0 mL) was heated at reflux for 15 h, cooled to 5° C., and neutralized with 2 M aqueous HCl. After stirring for 30 min, the white solid was filtered, triturated with acetone, and filtered again to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.28 g, 80%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=2.29 Hz, 1H), 7.93 (dd, J=8.72, 2.42 Hz, 1H), 7.86 (s, 2H), 7.63 (d, J=8.70 Hz, 1H), 5.75 (s, 1H), 2.24 (s, 6H); MS (APCI) m/z 346 [M+H]+.
-
- A mixture of 2-amino-5-bromobenzamide (0.100 g, 0.465 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde (0.143 g, 0.465 mmol), NaHSO3 (94%, 0.0515 g, 0.465 mmol), and p-TsOH.H2O (0.00885 g, 0.0465 mmol) in DMA (5.81 mL) was heated at reflux for 15 min, cooled to room temperature, the water (20 mL) was added. The precipitate was filtered, washed with water, triturated with acetone and filtered again. The crude solid was chromatographed on silica gel (CH2Cl2/CH3OH) to provide 6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.0395 g, 22%) and 6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.0227 g, 10%) as white solids. Selected data for 6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one: 1H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.20 (d, J=2.34 Hz, 1H), 8.01-7.80 (m, 3H), 7.66 (d, J=8.72 Hz, 1H), 4.90 (t, J=5.46 Hz, 1H), 3.85 (t, J=4.87 Hz, 2H), 3.73 (dd, J=10.06, 5.11 Hz, 2H), 2.32 (s, 6H); MS (APCI) m/z 345 [M+H]+. Selected data for 6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one: 1H NMR (300 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.20 (d, J=2.34 Hz, 1H), 7.95 (dd, J=8.71, 2.41 Hz, 1H), 7.90 (s, 2H), 7.67 (d, J=8.72 Hz, 1H), 3.90 (m, 4H), 2.32 (s, 6H), 0.90 (s, 9H), 0.09 (s, 6H); MS (APCI) m/z 503 [M+H]+.
-
- Following the method described for 2-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one, compound 2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-(benzyloxy)-3,5-dimethylbenzoyl chloride in 7% yield as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.84 (s, 1H), 7.93 (s, 2H), 7.57-7.33 (m, 5H), 6.75 (d, J=2.28 Hz, 1H), 6.52 (d, J=2.27 Hz, 1H), 4.88 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.31 (s, 6H); MS (APCI) m/z 417 [M+H]+.
-
- A mixture of 3-methyl-4-hydroxybenzaldehyde (0.200 g, 1.5 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (0.538 g, 2.25 mmol) and sodium hydride (0.061 g, 2.55 mmol) in DMF (5.00 mL) was stirred open at room temperature for 30 min in a microwave vial. The vial was then capped and heated in the microwave reactor for 1 h at 80° C. Water (55.0 mL) was added to quench. The solution was diluted with 1 N HCl (25.0 mL) and extracted with EtOAc (2×25.0 mL), dried and evaporated. The crude material was purified via CombiFlash to yield the alkylated aldehyde. A mixture of 2-amino-4,6-dimethoxybenzamide (0.167 g, 0.85 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde (0.250 g, 0.85 mmol), p-TsOH.H2O (0.016 g, 0.085 mmol) and NaHSO3 (0.088 g, 0.85 mmol) in DMA (5.00 mL) was stirred at 155° C. for 90 min. The solution was diluted with EtOAc (150 mL), washed with saturated NaHCO3 (2×50 mL), 1 N HCl (2×75 mL), brine (50 mL), dried and the solvent was removed under reduced pressure to yield the TBS protected material (0.068 g, 17%) as a tan solid. The crude material was used directly in the next step. The TBS-protected material (0.068 g, 0.144 mmol) and 1 M TBAF in THF (1.00 mL, 7 mmol) was stirred at room temperature for 1 h. The volatiles were removed under vacuum, and the residue diluted with EtOAc (100 mL). The solution was washed with water (2×50.0 mL), brine (50.0 mL), dried and the solvent was removed. The residue was purified via CombiFlash to yield 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.024 g, 47%) as an orange solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.05 (m, 2H), 7.05 (d, 1H, J=8.3 Hz), 6.72 (d, 1H, J=2.2 Hz), 6.50 (d, 1H, J=2.2 Hz), 4.87 (t, 1H, J=5.5 Hz), 4.09 (t, 2H, J=4.9 Hz), 3.89 (s, 3H), 3.84 (s, 3H), 3.76 (dd, 2H, J=5.1 Hz, J=10.0 Hz), 2.24 (s, 3H); MS (APCI) m/z 357 [M+H]+.
-
- A mixture of 4-hydroxy-3-methylbenzaldehyde (0.200 g, 1.47 mmol), 2-amino-4,6-dimethoxybenzamide (0.288 g, 1.47 mmol), NaHSO3 (94%, 0.163 g, 1.47 mmol), and p-TsOH.H2O (0.028 g, 0.147 mmol) in DMA (18.4 mL) was heated at reflux for 1 h. The mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (2×150 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with MeOH and filtered off a yellow solid, which was freeze-dried from MeCN/H2O to provide 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.161 g, 35%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.02 (s, 1H), 7.99 (d, J=1.88 Hz, 1H), 7.89 (dd, J=8.47, 2.29 Hz, 1H), 6.86 (d, J=8.50 Hz, 1H), 6.69 (d, J=2.31. Hz, 1H), 6.48 (d, J=2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.18 (s, 3H); MS (APCI) m/z 313 [M+H]+.
-
- A mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol), N-(2-bromoethyl)-phthalimide (1.22 g, 4.80 mmol), K2CO3 (0.829 g, 6.00 mmol), NaI (3.00 g, 20.0 mmol) in DMF (40.0 mL) was heated at 80° C. for 2.5 h. The reaction was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1 M NaOH (2×100 mL), 1 M HCl (2×100 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, hexanes/EtOAc) to provide the expected ether (0.300 g, 23%) as a yellow solid. A mixture of the above ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO3 (94%, 0.100 g, 0.907 mmol), and p-TsOH.H2O (0.0173 g, 0.0907 mmol) in DMA (11.3 mL) was stirred at reflux for 1.5 h then cooled to room temperature. The mixture was diluted with EtOAc (250 mL), washed with saturated aqueous ammonium chloride (3×75 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, CH2Cl2/CH3OH) to provide the expected product (0.075 g, 17%) as a light yellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and 2 M methylamine in THF (25.0 mL) was stirred at room temperature for 17 h. The volatiles were removed under vacuum and the residue was chromatographed on silica gel to provide compound N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide (0.0493 g, 22%) and compound 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0360 g, 23%) as white solids. Selected data for N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide: 1H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.51 (t, J=5.57 Hz, 1H), 8.18 (q, J=4.57 Hz, 1H), 7.89 (s, 2H), 7.53-7.42 (m, 4H), 6.74 (d, J=2.31 Hz, 1H), 6.52 (d, J=2.29 Hz, 1H), 3.96-3.80 (m, 8H), 3.61 (q, J=5.73 Hz, 2H), 2.71 (d, J=4.62 Hz, 3H), 2.32 (s, 6H); MS (APCI) m/z 531 [M+H]+. Selected data for 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one: 1H NMR (300 MHz, DMSO-d6) δ 7.90 (s, 2H), 6.74 (d, J=2.31 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.77 (t, J=5.76 Hz, 2H), 2.91 (t, J=5.75 Hz, 2H), 2.30 (s, 6H); MS (APCI) m/z 370 [M+H]+.
-
- A mixture of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.060 g, 0.162 mmol), 4-methoxybenzenesulfonyl chloride (0.044 mg, 0.211 mmol), and triethylamine (29.4 μL, 0.211 mmol) in CH2Cl2 (812 μL) was stirred at room temperature for 3 h. The mixture was chromatographed directly on silica gel to yield N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide (0.046 g, 53%) as a white solid after lyophilization from MeCN/H2O. Selected data: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 7.88 (s, 2H), 7.83-7.73 (m, 3H), 7.17-7.07 (m, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.52 (d, J=2.29 Hz, 1H), 3.91-3.75 (m, 11H), 3.12 (q, J=5.75 Hz, 2H), 2.24 (s, 6H); MS (APCI) m/z 540 [M+H]+.
-
- Following the method described for N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide, compound 4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzene-sulfonamide was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 51% yield and isolated as a white solid after lyophilization from MeCN/H2O. Selected data: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.8 (s, 1H), 8.1 (s, 1H), 7.9-7.6 (m, 6H), 6.75 (1H), 6.5 (1H), 3.9-3.7 (m, 8H), 3.15 (m, 2H), 2.2 (s, 6H); MS (APCI) m/z 544 [M+H]+.
-
- Following the method described for N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide, compound N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 42% yield and isolated as a white solid after lyophilization from MeCN/H2O. Selected data: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.82 (s, 1H), 7.90 (s, 2H), 7.33 (t, J=5.94 Hz, 1H), 6.74 (d, J=2.31 Hz, 1H), 6.52 (d, J=2.30 Hz, 1H), 3.92-3.81 (m, 8H), 3.41-3.34 (m, 2H), 2.97 (s, 3H), 2.32 (s, 6H); MS (APCI) m/z 448 [M+H]+.
-
- A mixture of NaOH (1.8 g, 0.045 mol) and 4-hydroxy-3-methoxylbenzalde (3.10 g, 0.0203 mol) in water (20 mL) was mixed with bromoacetic acid (2.82 g, 0.0203 mol) and heated to reflux for 6 h. The reaction mixture was adjusted to pH 3.0 by adding a HCl solution. The solid was filtered off and further washed with cold water and ethyl acetate (2×30 mL) to yield (4-formyl-2-methyl-phenoxy)-acetic acid (2.89 g, 67.7%). 2-Amino-4,6-dimethoxy-benzamide (150 mg, 0.764 mmol) with (4-formyl-2-methyl-phenoxy)-acetic acid (160 mg, 0.764 mmol), sodium hydrogen sulfite (150 mg, 58.5%) and p-toluenesulfonic acid monohydrate (15 mg) in N,N-dimethyl acetamide (10 mL) were heated to 150° C. for 16 h. N,N-dimethyl acetamide was removed under vacuum and the residue was poured into water (50 mL). The solid was filtered off and further purified by base/acid extractions/washes to yield 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)acetic acid (25 mg, 8.1%). Selected data: MS (ES) m/z: 387.1; MP 275-277° C.
-
- A mixture of 2-amino-4,6-dimethoxy-benzamide (0.71 g, 3.71 mmol), 3,5-dimethyl-4-benzyloxy benzaldehyde (0.94 g, 3.90 mmol), sodium hydrogensulfite (0.68 g, 3.90 mmol) and p-toluenesulfonic acid (70 mg, 0.37 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 150° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The resulting solid was collected by filtration and washed with hexanes to afford 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one as a white solid (1.2 g, 79%).
- A mixture of 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one (1.2 g, 2.92 mmol) and magnesium bromide (0.644 g, 3.5 mmol) in pyridine (50 mL) was stirred at reflux for 12 h. The mixture was concentrated and the solid residue was made into slurry with HCl (2 N, 100 mL). The solid was collected by filtration, washed with water and hexanes to yield 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-hydroxy-7-methoxy-3H-quinazolin-4-one as a white solid (0.76 g, 65%). A solution of ammonium formate (0.945 g, 15 mmol) and 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-hydroxy-7-methoxy-3H-quinazolin-4-one (0.1 g, 0.25 mmol) in DMF (50 mL) was mixed with palladium carbon (0.1 g) and stirred at 85° C. for 14 h. The resulting suspension was cooled to room temperature, passed through a Celite pad, and washed with DCM. The filtrate was concentrated and the residue was diluted with water (20 mL). The resulting solid was collected by filtration and washed with hexanes to afford 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one (57 mg, 74%) as light yellow solid. Selected data: MS (ES) m/z: 312.94; MP 291.3-293° C.
-
- A mixture of the compound of Example 20 (0.070 g, 0.19 mmol), propyl isocyanate (0.088 mL, 0.94 mmol), and TEA (0.14 g, 1.1 mmol) in THF (4.0 mL) was stirred at 70° C. for 16 h. The mixture was filtered, washed with THF, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), dried and the solvent was removed under reduced pressure. The resulting solid was chromatographed on silica gel to yield 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate (0.035 g, 41%) as an off-white solid: Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.90 (s, 2H), 7.23 (t, J=5.27 Hz, 1H), 6.74 (d, J=2.32 Hz, 1H), 6.52 (d, J=2.31 Hz, 1H), 4.27 (t, J=4.29 Hz, 2H), 3.99 (t, J=4.29 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.02-2.86 (m, 2H), 2.29 (s, 6H), 1.50-1.30 (m, 2H), 0.84 (t, J=7.33 Hz, 3H); MS (APCI) m/z 456 [M+H]+.
-
- Following the method described for 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate, compound 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methylcarbamate was made from 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 11% yield and isolated as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.90 (s, 2H), 7.08 (m, 1H), 6.74 (d, J=2.29 Hz, 1H), 6.52 (d, J=2.27 Hz, 1H), 4.27 (t, J=4.55 Hz, 2H), 3.99 (t, J=4.55 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.60 (d, J=4.57 Hz, 3H), 2.29 (s, 6H); MS (APCI) m/z 428 [M+H]+.
-
- A mixture of compound 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.060 g, 0.16 mmol), p-toluoyl chloride (0.028 mL, 0.21 mmol), and PS-DIEA (0.057 g, 0.21 mmol) in CH2Cl2 (4.0 mL) was stirred at room temperature for 16 h. The mixture was filtered, washed with CH2Cl2 and the solvent was removed under reduced pressure. The resulting residue was chromatographed on silica gel to yield N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide (0.037 g, 51%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.80-11.00 (s, 1H), 8.69 (t, J=5.43 Hz, 1H), 7.88 (s, 2H), 7.79 (d, J=8.19 Hz, 2H), 7.28 (d, J=8.00 Hz, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.51 (d, J=2.31 Hz, 1H), 3.94 (t, J=5.59 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.72-3.60 (m, 2H), 2.36 (s, 3H), 2.27 (s, 6H); MS (APCI) m/z 488 [M+H]+.
-
- A mixture of Example 18 (0.100 g, 0.270 mmol), cyclohexylisocyanate (172 μL, 1.35 mmol), and Et3N (263 μL, 1.89 mmol) in THF (1.00 mL) was stirred at reflux for 4 h then diluted with EtOAc (200 mL) and washed with saturated aqueous ammonium chloride (3×75 mL) and brine (75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (12 g, CH2Cl2/CH3OH) and the product freeze dried from MeCN/H2O to provide 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl cyclohexylcarbamate (0.0981 g, 73%) as a white solid. 1H NMR (300 MHz, DMSO-d6δ) 11.82 (s, 1H), 7.90 (s, 2H), 7.24-7.05 (m, 1H), 6.73 (d, J=2.30 Hz, 1H), 6.52 (d, J=2.31 Hz, 1H), 4.30-4.22 (m, 1H), 4.03-3.95 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.29 (s, 6H), 1.82-1.46 (m, 5H), 1.18 (m, 5H); MS (APCI) m/z 496 [M+H]+.
-
- Following the methodology described for Example 100, the title compound was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 41% yield and isolated as an off-white solid: MS (APCI) m/z 510 [M+H]+.
-
- Following the methodology described for Example 100, the title compound was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 50% yield and isolated as an off-white solid: MS (APCI) m/z 524 [M+H]+.
-
- Following the methodology described for Example 107, the title compound was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 46% yield and isolated as a white solid: MS (APCI) m/z 526 [M+Na]+.
-
- Following the methodology described for Example 107, the title compound was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 40% yield and isolated as a white solid: MS (APCI) m/z 412 [M+H]+.
-
- Following the methodology described for Example 107, the title compound was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 66% yield and isolated as a white solid: MS (APCI) m/z 474 [M+H]+.
-
- Following the methodology described for Example 107, the title compound was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 59% yield and isolated as a white solid: MS (APCI) m/z 440 [M+H]+.
-
- A mixture of compound 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.10 g, 0.27 mmol), methylisocyanate (0.020 g, 0.35 mmol), and Et3N (0.034 g, 0.35 mmol) in THF (4.0 mL) was stirred at room temperature for 16 hours. The mixture was filtered, washed with CH2Cl2 and the solvent was removed under reduced pressure. The resulting residue was chromatographed on silica gel to yield the title compound (0.082 g, 71%) as a white solid: MS (APCI) m/z 449 [M+Na]+.
-
- Following the methodology described for Example 115, the title compound was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 57% yield and isolated as a white solid: MS (APCI) m/z 541 [M+Na]+.
-
- Following the methodology described for Example 115, the title compound was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 59% yield and isolated as a light yellow solid: MS (APCI) m/z 489 [M+H]+.
-
- Following the methodology described for Example 115, the title compound was made from 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one in 59% yield and isolated as a white solid: MS (APCI) m/z 441 [M+H]+.
- In this example, ApoA-I mRNA in tissue culture cells was quantitated to measure the transcriptional up-regulation of ApoA-I when treated with a compound of the invention.
- HepG2 cells (˜2×105 per well) were placed in a 24-well plate in ˜400 μL MEM, supplemented with 0.5% (v/v) FBS, 24 h before addition of the compound of interest. At time of harvesting, the spent media was removed from the HepG2 cells and immediately placed on ice (for immediate use) or at −80° C. (for future use) in ApoA-I and albumin ELISAs. The cells remaining in the plate wells were rinsed in 200 μL PBS. PBS was carefully removed to avoid removing any loosely attached cells.
- Once the PBS was removed, 85 μL cell lysis solution was added the cells in each well and incubated for 5-10 min at room temperature, to allow for complete cell lysis and detachment. mRNA was then prepared using the “mRNA Catcher PLUS plate” from Invitrogen, according to the protocol supplied. After the last wash, as much wash buffer as possible was aspirated without allowing the wells to dry. Elution Buffer (E3, 80 μL) was then added to each well. mRNA was then eluted by incubating the mRNA Catcher PLUS plate with Elution Buffer for 5 min at 68° C. and then immediately placing the plate on ice.
- The eluted mRNA isolated was then used in a one-step real-time room temperature-PCR reaction, using components of the Ultra Sense Kit together with Applied Biosystems primer-probe mixes. Real-time PCR data was analyzed, using the Ct values, to determine the fold induction of each unknown sample, relative to the control (that is, relative to the control for each independent DMSO concentration).
- An active compound is one that causes a >15% increase in ApoA-I mRNA at a concentration less than or equal to 100 uM.
-
Effect on Ex- ApoA-I am- mRNA ple # Compound Name levels 107 N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 4-methylbenzamide 106 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2,6-dimethyl-phenoxy)ethyl methylcarbamate 105 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate 102 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)methanesulfonamide 101 4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)benzenesulfonamide 100 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 4-methoxybenzenesulfonamide 99 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 99 N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- N2-methylphthalamide 2-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Inactive dihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)isoindoline-1,3-dione 98 2-(4-hydroxy-3-methylphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 97 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 96 2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 95 6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)- Active 3,5-dimethylphenyl)quinazolin-4(3H)-one 95 6-bromo-2-(4-(2-hydroxyethoxy)-3,5- Active dimethylphenyl)quinazolin-4(3H)-one 94 6-bromo-2-(4-hydroxy-3,5- Active dimethylphenyl)quinazolin-4(3H)-one 93 (E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N- dimethylformimidamide 92 2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin- Active 4(3H)-one 5,7-dimethoxy-2-(3-nitrophenyl)quinazolin-4(3H)- Inactive one 91 2-(4-amino-3,5-dimethylphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 90 5,7-dimethoxy-2-(4-methoxy-3,5- Active dimethylphenyl)quinazolin-4(3H)-one 89 2-(2-chloro-6-methylpyridin-4-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one 88 5,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2- Active yl)quinazolin-4(3H)-one 87 5,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin- Active 4(3H)-one 86 5,7-dimethoxy-2-(6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)quinazolin- 4(3H)-one 85 5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one Active 84 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5- Active methoxyquinazolin-4(3H)-one 83 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)- Active one 82 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6- Active methoxyquinazolin-4(3H)-one 4-(4-ethoxy-5,7-dimethoxyquinazolin-2-yl)-2,6- Inactive dimethylphenol 81 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6- Active (morpholinomethyl)quinazolin-4(3H)-one 80 5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5- Active dimethylphenyl)quinazolin-4(3H)-one 79 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5- Active dimethylphenyl)quinazolin-4(3H)-one 78 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7- Active dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one 77 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- Active dimethylquinazolin-4(3H)-one 76 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6- Active dimethylphenoxy)ethanol 75 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 104 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7- Active methoxyquinazolin-4(3H)-one 74 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy- Active 1,6-naphthyridin-5(6H)-one 2-(4-(2-(benzyloxy)ethoxy)-3,5-dimethylphenyl)-5,7- Inactive dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one 73 N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4- Active oxo-3,4-dihydroquinazolin-6-yl)acetamide 72 2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)- Active 5,7-dimethoxyquinazolin-4(3H)-one 71 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1- Active methylquinazolin-4(1H)-one 70 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- Active dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one 69 5,7-dimethoxy-2-(4-methoxy-3- Active (morpholinomethyl)phenyl)quinazolin-4(3H)-one 68 2-(4-hydroxy-3,5-dimethylphenyl)-5,7- Active dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one 67 2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 66 5,7-dimethoxy-2-(4- Active (morpholinomethyl)phenyl)quinazolin-4(3H)-one 65 N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)phenyl)-2-hydroxyacetamide 64 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2,6-dimethylphenoxy)acetic acid 63 2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)- Active 1,6-naphthyridin-5(6H)-one 62 2-(4-hydroxy-3,5-dimethylphenyl)-6- Active (morpholinomethyl)quinazolin-4(3H)-one 61 7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4- Active dimethoxy-1,6-naphthyridin-5(6H)-one 60 N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2,6-dimethylphenyl)-2-hydroxyacetamide 59 5,7-dimethoxy-2-(4-((4-methylpiperazin-1- Active yl)methyl)phenyl)quinazolin-4(3H)-one 58 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7- Active dimethoxyquinazolin-4(3H)-one 103 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2-methoxyphenoxy)acetic acid 57 2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 56 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 55 2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2,6-dimethylphenoxy)acetamide 54 N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4- Active dihydroquinazolin-6-yl)acetamide 53 3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)phenyl)propanoic acid 2-(2-(4-chlorophenoxy)pyridin-3-yl)-5,7- Inactive dimethoxyquinazolin-4(3H)-one 51 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7- Active (morpholinomethyl)isoquinolin-1(2H)-one 50 7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4- Active dimethoxy-1,6-naphthyridin-5(6H)-one 49 5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin- Active 4(3H)-one 48 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7- Active dimethoxyquinazolin-4(3H)-one 47 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7- Active dimethoxyquinazolin-4(3H)-one 46 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 45 2-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin- Active 4(3H)-one 44 2-(4-(dimethylamino)pyridin-1-yl)-6,7- Active dimethoxyquinazolin-4(3H)-one 43 5,7-dimethoxy-2-(4-(4-methylpiperazin-1- Active yl)phenyl)quinazolin-4(3H)-one 42 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one 41 2-(4-(4-oxo-3,4-dihydroquinazolin-2- Active yl)phenoxy)acetamide 40 2-(4-(dimethylamino)naphthalene-1-yl)quinazolin- Active 4(3H)-one 39 2-(4-(4-oxo-3,4-dihydroquinazolin-2- Active yl)phenoxy)acetic acid 38 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)phenoxy)acetamide 37 2-(4-(dimethylamino)naphthalene-1-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one 36 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin- Active 4(3H)-one 35 2-(4-(2-hydroxyethoxy)-3,5- Active dimethylphenyl)quinazolin-4(3H)-one 34 2-(3,5-dimethyl-4-(2- Active morpholinoethoxy)phenyl)quinazolin-4(3H)-one 33 5,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one Active 32 2-(3-chloro-4-hydroxyphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 31 2-(4-hydroxy-3-methoxyphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 30 5,7-dimethoxy-2-(4-methoxyphenyl)quinazolin- Active 4(3H)-one 29 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin- Active 4(3H)-one 28 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 26 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one Active 24 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin- Active 4(3H)-one 23 3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1- Active yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)- one 22 4-(2-(4-(6,8-dimethoxyisoquinolin-3-yl)-2,6- Active dimethylphenoxy)ethyl)morpholine 21 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 5,7-dimethoxy-2-p-tolylquinazolin-4(3H)-one Inactive 20 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 19 3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8- Active dimethoxyisoquinolin-1(2H)-one 18 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6- Active dimethylphenol 17 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2- Active methyl-7-(morpholinomethyl) isoquinolin-1(2H)-one 17 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy- Active 2,7-dimethylisoquinolin-1(2H)-one 16 7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy- Active 1,6-naphthyridin-5(6H)-one 15 6,8-dimethoxy-3-(4-hydroxy-3,5-dimethylphenyl)- Active 2H-1,2-benzothiazine-1,1-dioxide 14 3-(4-(2-hydroxy-2-methylpropoxy)-3,5- Active dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)- one 13 2-(4-hydroxy-3,5-dimethylphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one 12 2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4- Active methoxy-1,6-naphthyridin-5(6H)-one 11 3-(4-hydroxy-3,5-dimethylphenyl)-7- Active (morpholinomethyl)isoquinolin-1(2H)-one 10 3-(4-(2-(dimethylamino)ethoxy)-3,5- Active dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)- one 9 3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8- Active dimethoxyisoquinolin-1(2H)-one 8 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin- Active 5(6H)-one 7 3-(4-hydroxy-3,5-dimethylphenyl)-6,8- Active dimethoxyisoquinolin-1(2H)-one 7 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2- Active methylisoquinolin-1(2H)-one 6 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin- Active 1(2H)-one 3-(3-fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin- Inactive 1(2H)-one 5 4-(1,6-naphthyridin-7-yl)phenol Active 4 4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2- Active amino-5-guanidinopentanoate 3 4-(Isoquinolin-3-yl)phenyl 2-amino-5- Active guanidinopentanoate tetrahydrochloride 2 4-Isoquinolin-3-yl-phenol Active 1 3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one Active 108 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2,6-dimethylphenoxy)ethyl cyclohexylcarbamate 109 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)benzenesulfonamide 110 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 4-methylbenzenesulfonamide 111 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 4-methoxybenzamide 112 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)acetamide 113 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)benzamide 114 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)isobutyramide 115 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 3-methylurea 116 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 3-(4-methoxyphenyl)urea 117 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 3-phenylurea 118 3-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 1,1-dimethylurea - In this example, ApoA-I mRNA and secreted protein from tissue culture cells were quantitated. The assay can be used to determine the potency for compounds of interest, including those of the present invention.
- HepG2 cells or primary human hepatocytes (BD Gentest, lot 107) (˜2×105 per well) were placed in a 24-well plate in ˜400 μL MEM, supplemented with 0.5% (v/v) FBS, 24 h before addition of the compound of interest. The compounds of interest were dissolved in DMSO at 0.05% (v/v). Appropriate volumes of the stock solutions of the compounds in DMSO were then added to appropriate volumes of MEM, supplemented with 0.5% (v/v) FBS, to achieve the desired concentration (for example, 1 μL of a compound stock into 1 mL of MEM, supplemented with 0.5% (v/v) FBS).
- Just prior to compound addition to the cells, the growth media was aspirated and replaced with 300 μL of fresh MEM, supplemented with 0.5% (v/v) FBS, followed by addition of 300 μL of the compound of interest in MEM, supplemented with 0.5% (v/v) FBS, to achieve the desired final compound concentration in a total volume of 600 μL. The final concentration of diluent (DMSO) was 0.05% (v/v).
- Cells were incubated for the desired time. The cell media was then harvested, as were the cells. ApoA-I mRNA was measured as described in Example 119. Secreted ApoA-I was measured using an ApoA-I ELISA, as described below:
- ApoA-I ELISA
- In this example, the ApoA-I secreted into the media from tissue culture cells was quantitated to assess induction of endogenous ApoA-I protein secretion from cells treated with various small molecule compounds, such as those of the present invention.
- At time of harvesting, spent media from the HepG2 cell cultures or primary cell culture was removed and stored at −80° C. in 1.5 mL microfuge tubes.
- For the human ApoA-I ELISA, an ELISA plate was coated with ˜100 μL/well human ApoA-I capture antibody diluted to ˜2 μg/mL in coating buffer for ˜1 h at room temperature. The plate was then washed three times in wash buffer. The plate was then blocked with ˜200 μL/well human ApoA-I blocking buffer for at least ˜30 min at room temperature.
- Samples for use in generating a standard curve were prepared from spent media (MEM, supplemented with 0.5% (v/v) FBS) from HepG2 or primary cells treated with DMSO for 48 h. Serial 2 fold dilutions of the media were prepared in MEM, supplemented with 0.5% (v/v) FBS. The unknown samples—from the cultures treated with the compounds of interest—were also diluted in MEM, supplemented with 0.5% (v/v) FBS. The plate was washed three times in wash buffer. The standard curve and unknown samples (100 μL/well), in triplicate, were added to the plate and it was incubated for 1.5 h at room temperature.
- The plate was washed three times in wash buffer. Human ApoA-I detection antibody, diluted 1:1000 in PBS, was added (100 μL/well) and the plate was incubated for 1 h at room temperature. The plate was washed three times in wash buffer.
- Goat anti-rabbit IgG H & L chain specific peroxidase conjugate, diluted 1:2000 in PBS, was added (100 μL/well) and the plate was incubated for 40 min at room temperature in the dark. The plate was washed six times in wash buffer.
- TMB liquid substrate was added (100 μL/well) and the plate was incubated on a shaker underneath tin foil during development. Once a sufficient “blue” color had been achieved, stop solution (50 μL/well, 1 M H2SO4) was added and mixed thoroughly on the plate shaker. Air bubbles were removed and the absorbance at 450 nm was determined, using a Molecular Devices SpectraMax 190 Plate Reader and the human ApoA-I ELISA Softmax software.
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one at 0, 2.5, 5, 10, 20, 40, 60, 80 and 100 μM in HepG2 cell culture (48 h) and assayed for ApoA-I mRNA and secreted protein (
FIG. 1 ). - 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one at 0, 2.5, 5, 10, 20, 40, 60, 80 and 100 μM in primary human hepatocytes (48 h) and assayed for ApoA-I mRNA and secreted protein (
FIG. 2 ). - To test whether the efficacy of compounds of the invention observed in vitro extended to an in vivo model, transgenic mice carrying multiple copies of the human ApoA-I gene (Bisaha et al. (1995) J. Biol. Chem. 34, 19979-88) or wild-type mice (C57BL/6 (Stock Number 000664) Jackson Laboratory (Bar Harbor, Me.)) were exposed to compounds of the invention. In the transgenic mice, the exogenous human ApoA-I gene in these mice enables them to express the human ApoA-I protein under the control of its own promoter.
- Seven to eight week old male mice were housed five per cage (10″×20″×8″ with aspen chip bedding) with pelleted Rodent chow [Purina 5001] and water available at all times. After an acclimation period of 1 week, animals were individually identified by numbering on tail and weighed. Mice were pre bled via the retro-orbital plexus, and 100 μL of blood was collected in 1.5 mL Eppendorf tube containing 5 μL of 0.5 mM EDTA and chilled on ice. Plasma was collected after centrifuging the whole blood at 14000 rpm [TOMY high speed micro-refrigerated centrifuge NTX-150] for 10 min at 4° C. and frozen at −80° C. Mice were grouped based on having an average body weight of 25 g.
- A day following pre-bleed, mice were dosed by oral gavage or i.p. daily using a 20 gauge, 11/2″ curved disposable feeding needle (Popper & Sons); when B.I.D., mice were gavaged morning and afternoon (8 am and 5 μm); when Q.D. mice were gavaged in morning (8 am). Compounds were prepared each day in vehicle. One day prior to necropsy mice were weighed and fasted overnight. On final day of dosing, mice were sacrificed post 2 h of dosing by inhalation of CO2 and blood was obtained via cardiac puncture (0.7-1.0 mL). Plasma was collected and frozen at −80° C. Samples were assayed for ApoA-I by ELISA, and HDL-C by HPLC (Polaris 200 with an auto sampler Prostar 410 from Varian on a Superose 6 10/30 column from Amersham). During necropsy, liver and enterocytes from the duodenum and jejunum of the small intestine were collected, cleaned with cold PBS and frozen at −80° C. for further analysis of compound and mRNA levels by Q-PCR.
- 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (10, 30 and 60 mg/kg of body weight, mpk) were BID administered to hApoA-I transgenic mice daily for seven days by oral gavage in 1% DMSO, 2.5% Tween-80, 10% PEG-300 QS to water. Plasma was assayed for ApoA-I (
FIG. 3 ), and HDL cholesterol (FIG. 4 ). - 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (10, 30 and 60 mg/kg of body weight) were BID administered to wild type C57BL/6 mice daily for three days by intraperitoneal administration in 1% DMSO, 2.5% Tween-80, 10% PEG-300 QS to water. Plasma was assayed for ApoA-I (
FIG. 5 ), and HDL cholesterol (FIG. 6 ). - 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (30 mg/kg of body weight) were BID administered to hApoA-I transgenic mice daily for seven days by oral gavage in 1% DMSO, 2.5% Tween-80, 10% PEG-300 QS to water. Plasma was assayed for ApoA-I and tissues were assayed for mRNA (
FIG. 7 ). - These results indicate that the compounds of the invention are useful for increasing the transcription of ApoA-I in vivo, and elevating plasma levels of ApoA-I and circulating levels of HDL-C in wild type and hApoA-I transgenic mice. These results demonstrate that compounds of the invention activate the human ApoA-I transgene in mice, leading to an increase in circulating ApoA-I.
- All references referred to herein are incorporated by reference in their entirety. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
Claims (79)
1-75. (canceled)
76. A method of treating or reducing the risk of acquiring a cardiovascular-, cholesterol-, or lipid-related disorder in a mammal suffering from or at risk of acquiring such disorder comprising administering a therapeutically effective amount of a compound via surgical device or implant, wherein the compound is selected from compounds of Formula II:
and pharmaceutically acceptable salts thereof, wherein:
X is N;
Y is CO;
R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;
R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;
R6 and R8 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
R5 and R9 are each hydrogen;
R7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy;
R10 is hydrogen;
each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
for W—(R10)p, W is N and p is 1;
for W—(R7)p, W is C and p is 1;
for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
Z1 is a double bond, and Z2 and Z3 are each a single bond;
with the proviso that if R1 is hydrogen, then R3 is alkoxy;
with the proviso that if R3 is hydrogen, then R1 is selected from amino and alkoxy;
with the proviso that if R7 is selected from alkyl, hydroxyl, and alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy, amino, and halogen.
77. The method according to claim 76 , wherein R7 is amino.
78. The method according to claim 77 , wherein the compound of Formula II is 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof.
79. The method according to claim 76 , wherein R7 is selected from hydroxyl and alkoxy.
80. The method according to claim 79 , wherein the compound of Formula II is selected from:
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide;
2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; and
pharmaceutically acceptable salts thereof.
81. The method according to claim 79 , wherein R6 and R8 are each independently alkyl;
R2 is hydrogen; and
R7 is selected from hydroxyl and alkoxy substituted with a hydroxyl.
82. The method according to claim 81 , wherein the compound of Formula II is 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof.
83. The method according to claim 76 , wherein R7 is an amino or an alkoxy selected from the group represented by Formula III:
wherein:
A is selected from O and N;
n is selected from 0, 1, 2, 3, 4 and 5;
B is selected from —C(O)N(Rh)2—, —S(O)2N(Rh)2—, —C(O)—, —S(O)2—, —C(O)O—, wherein each Rh is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and
R20, if present, is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
84. The method according to claim 83 , wherein the compound of Formula II is selected from:
2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl cyclohexylcarbamate;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide;
1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-phenylurea;
3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1,1-dimethylurea; and
pharmaceutically acceptable salts thereof.
85. The method according to claim 76 , wherein the compound of Formula II is selected from:
2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;
2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide;
2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide;
2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetic acid;
N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide;
2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;
5,7-dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;
2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-pyrido[2,3-d]pyrimidin-4(3H)one;
5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one;
(E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide;
2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)acetic acid;
2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate;
2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methylcarbamate;
N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzenesulfonamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzamide;
1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-methylurea;
1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-(4-methoxyphenyl)urea; and
pharmaceutically acceptable salts thereof.
86. A method of treating or reducing the risk of acquiring a cardiovascular-, cholesterol-, or lipid-related disorder in a mammal suffering from or at risk of acquiring such disorder comprising administering a therapeutically effective amount of a compound via surgical device or implant, wherein the compound is selected from:
2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one;
2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid;
2-(4-(dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one;
2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide;
2-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one;
2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one;
5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;
6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
5,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one;
2-(4-(dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(dimethylamino)pyridin-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one;
2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazol-4(1H)-one;
2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; and
5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one, and pharmaceutically acceptable salts thereof.
87. A method of treating or reducing the risk of acquiring a cardiovascular-, cholesterol-, or lipid-related disorder in a mammal suffering from or at risk of acquiring such disorder comprising administering a therapeutically effective amount of a compound via surgical device or implant, wherein the compound is selected from compounds of Formula II:
and pharmaceutically acceptable salts thereof, wherein:
X is N;
Y is CO;
R1 and R3 are each independently selected from alkoxy and hydrogen;
R2 is selected from alkoxy, alkyl, and hydrogen;
R6 and R8 are each independently selected from alkyl, alkoxy, chloride, and hydrogen;
R5 and R9 are each hydrogen;
R7 is selected from amino, hydroxyl, alkoxy, and alkyl substituted with a heterocyclyl;
R10 is hydrogen; or
two adjacent substituents selected from R6, R7, and R8 are connected to form a heterocyclyl;
each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
for W—(R10)p, W is N and p is 1;
for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
Z1 is a double bond, and Z2 and Z3 are each a single bond;
with the proviso that if R2 is alkoxy or hydrogen, then least one of R1 and R3 is alkoxy;
with the proviso that if R7 is selected from hydroxyl and alkoxy, then at least one of R6 and R8 are independently selected from alkyl, alkoxy, and chloride;
with the proviso that if for W—(R7)p, W is N and p is 0, then at least one of R6 and R8 is selected from alkyl, alkoxy, and chloride.
88. The method according to claim 87 , wherein the compound of Formula II is selected from:
3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;
3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;
2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one);
2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one;
2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;
2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide;
2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide; and
pharmaceutically acceptable salts thereof.
89. The method according to claim 87 , wherein R7 is selected from an amino or an alkoxy selected from the group represented by Formula III:
wherein:
A is selected from O and N;
n is selected from 0, 1, 2, 3, 4 and 5;
B is selected from —C(O)N(Rh)2—, —S(O)2N(Rh)2—, —C(O)—, —S(O)2—, and —C(O)O—, wherein each Rh is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and
R20, if present, is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
90. The method of claim 89 , wherein the compound of Formula II is selected from:
N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide;
2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide; and
pharmaceutically acceptable salts thereof.
91. A method of treating or reducing the risk of acquiring a cardiovascular-, cholesterol-, or lipid-related disorder in a mammal suffering from or at risk of acquiring such disorder comprising administering a therapeutically effective amount of a compound via surgical device or implant, wherein the compound is selected from compounds of Formula II:
and pharmaceutically acceptable salts thereof, wherein:
X is N;
Y is CO;
R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;
R2 is selected from —N—C(O)—R18, —N—SO2—R18, —CH2—C(R18)3, —CH2—N(R18)2, and —CH2—O—R18, wherein each R18 is independently selected from alkoxy, alkyl, alkenyl, amide, amino, aryl, arylalkyl, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, and hydrogen;
R6 and R8 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
R5 and R9 are each hydrogen;
R7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy;
R10 is hydrogen;
each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
for W—(R10)p, W is N and p is 1;
for W—(R7)p, W is C and p is 1;
for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
Z1 is a double bond, and Z2 and Z3 are each a single bond;
with the proviso that if R7 is selected from alkyl, hydroxyl, and alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy, amino, and halogen.
92. The method according to claim 91 , wherein the compound of Formula II is selected from:
N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;
2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one;
N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;
and
pharmaceutically acceptable salts thereof.
93. The method according to claim 91 , wherein R6 and R8 are each independently alkyl; and R7 is selected from hydroxyl and alkoxy.
94. The method according to claim 91 , wherein R7 is selected from an amino or an alkoxy selected from the group represented by Formula III:
wherein:
A is selected from O and N;
n is selected from 0, 1, 2, 3, 4 and 5;
B is selected from —C(O)N(Rh)2—, —S(O)2N(Rh)2—, —C(O)—, —S(O)2—, —C(O)O—, wherein each Rh is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and
R20, if present, is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
95. The method according to claim 91 , wherein R6 and R8 are each independently alkyl.
96. A method of treating or reducing the risk of acquiring a cardiovascular-, cholesterol-, or lipid-related disorder in a mammal suffering from or at risk of acquiring such disorder comprising administering a therapeutically effective amount of a compound via surgical device or implant, wherein the compound is selected from compounds of Formula II:
and pharmaceutically acceptable salts thereof, wherein:
X is N;
Y is CO;
R1 is selected from alkoxy or amino;
R3 is alkoxy;
R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;
R6 and R8 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
R5 and R9 are each hydrogen;
R7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy;
R10 is hydrogen;
each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
for W—(R10)p, W is N and p is 1;
for W—(R7)p, W is C and p is 1;
for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
Z1 is a double bond, and Z2 and Z3 are each a single bond.
97. The method according to claim 96 , wherein R7 is selected from hydroxyl and alkoxy.
98. The method according to claim 97 , wherein the compound of Formula II is selected from:
2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid;
5,7-dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one;
2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide; and
pharmaceutically acceptable salts thereof.
99. The method according to claim 96 , wherein R7 is selected from amide and amino.
100. The method according to claim 99 , wherein the compound of Formula II is selected from:
5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;
2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one;
N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide;
2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-pyrido[2,3-d]pyrimidin-4(3H)one; and
pharmaceutically acceptable salts thereof.
101. The method according to claim 96 , wherein R7 is alkyl.
102. The method according to claim 101 , wherein the compound of Formula II is selected from:
3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic acid;
5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one;
5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;
2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; and
pharmaceutically acceptable salts thereof.
103. The method according to claim 96 , wherein R6 and R8 are each independently alkyl.
104. The method according to claim 96 , wherein R7 is selected from an amino or an alkoxy selected from the group represented by Formula III:
wherein:
A is selected from O and N;
n is selected from 0, 1, 2, 3, 4 and 5;
B is selected from —C(O)N(Rh)2—, —S(O)2N(Rh)2—, —C(O)—, —S(O)2—, —C(O)O—, wherein each Rh is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and
R20, if present, is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
105. The method according to claim 104 , wherein R6 and R8 are each independently alkyl.
106. The method of claim 76 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is selected from acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholeasterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal artery atherosclerosis, rheumatic heart disease, stroke, thrombotic disorder, transitory ischemic attacks, lipoprotein abnormalities associated with Alzheimer's disease, diabetes mellitus, syndrome X, impotence, multiple sclerosis, and Parkinson's disease.
107. The method of claim 87 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is selected from acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholeasterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal artery atherosclerosis, rheumatic heart disease, stroke, thrombotic disorder, transitory ischemic attacks, lipoprotein abnormalities associated with Alzheimer's disease, diabetes mellitus, syndrome X, impotence, multiple sclerosis, and Parkinson's disease.
108. The method of claim 91 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is selected from acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholeasterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal artery atherosclerosis, rheumatic heart disease, stroke, thrombotic disorder, transitory ischemic attacks, lipoprotein abnormalities associated with Alzheimer's disease, diabetes mellitus, syndrome X, impotence, multiple sclerosis, and Parkinson's disease.
109. The method of claim 96 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is selected from acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholeasterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal artery atherosclerosis, rheumatic heart disease, stroke, thrombotic disorder, transitory ischemic attacks, lipoprotein abnormalities associated with Alzheimer's disease, diabetes mellitus, syndrome X, impotence, multiple sclerosis, and Parkinson's disease.
110. The method of claim 86 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is selected from acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholeasterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal artery atherosclerosis, rheumatic heart disease, stroke, thrombotic disorder, transitory ischemic attacks, lipoprotein abnormalities associated with Alzheimer's disease, diabetes mellitus, syndrome X, impotence, multiple sclerosis, and Parkinson's disease.
111. The method according to claim 76 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is selected from diabetes mellitus, myocardial infarction, coronary artery disease, coronary heart disease, familial hypercholeasterolemia, acute coronary syndrome, angina, atherosclerosis, arteriosclerosis, renal artery atherosclerosis, peripheral vascular disease, congestive heart failure, stroke, and Alzheimer's disease.
112. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is diabetes mellitus.
113. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is myocardial infarction.
114. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is coronary artery disease.
115. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is coronary heart disease.
116. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is familial hypercholeasterolemia.
117. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is acute coronary syndrome.
118. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is angina.
119. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is atherosclerosis.
120. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is arteriosclerosis.
121. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is renal artery atherosclerosis.
122. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is peripheral vascular disease.
123. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is congestive heart failure.
124. The method of claim 82 , wherein the cardiovascular-, cholesterol-, or lipid-related disorder is Alzheimer's disease.
125. A method of increasing levels of high density lipoprotein cholesterol (HDL-C) in a mammal comprising administering a therapeutically effective amount of a compound via surgical device or implant, wherein the compound is selected from compounds of Formula II:
and pharmaceutically acceptable salts thereof, wherein:
X is N;
Y is CO;
R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;
R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;
R6 and R8 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
R5 and R9 are each hydrogen;
R7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy;
R10 is hydrogen;
each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
for W—(R10)p, W is N and p is 1;
for W—(R7)p, W is C and p is 1;
for W—(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
Z1 is a double bond, and Z2 and Z3 are each a single bond;
with the proviso that if R1 is hydrogen, then R3 is alkoxy;
with the proviso that if R3 is hydrogen, then R1 is selected from amino and alkoxy;
with the proviso that if R7 is selected from alkyl, hydroxyl, and alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy, amino, and halogen.
126. The method of claim 76 , wherein the surgical device is a catheter.
127. The method of claim 126 , wherein the catheter is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
128. The method of claim 76 , wherein the implant is a stent.
129. The method of claim 128 , wherein the stent is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
130. The method of claim 86 , wherein the surgical device is a catheter.
131. The method of claim 130 , wherein the catheter is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
132. The method of claim 86 , wherein the implant is a stent.
133. The method of claim 132 , wherein the stent is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
134. The method of claim 87 , wherein the surgical device is a catheter.
135. The method of claim 134 , wherein the catheter is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
136. The method of claim 87 , wherein the implant is a stent.
137. The method of claim 136 , wherein the stent is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
138. The method of claim 91 , wherein the surgical device is a catheter.
139. The method of claim 138 , wherein the catheter is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
140. The method of claim 91 , wherein the implant is a stent.
141. The method of claim 140 , wherein the stent is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
142. The method of claim 96 , wherein the surgical device is a catheter.
143. The method of claim 142 , wherein the catheter is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
144. The method of claim 96 , wherein the implant is a stent.
145. The method of claim 144 , wherein the stent is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
146. The method of claim 125 , wherein the surgical device is a catheter.
147. The method of claim 146 , wherein the catheter is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
148. The method of claim 125 , wherein the implant is a stent.
149. The method of claim 148 , wherein the stent is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
150. The method of claim 82 , wherein the surgical device is a catheter.
151. The method of claim 150 , wherein the catheter is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
152. The method of claim 82 , wherein the implant is a stent.
153. The method of claim 152 , wherein the stent is coated with the compound of Formula II or a pharmaceutically acceptable salt thereof.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/922,645 US20160106750A1 (en) | 2007-02-01 | 2015-10-26 | Compounds for the prevention and treatment of cardiovascular diseases |
US15/710,200 US10532054B2 (en) | 2007-02-01 | 2017-09-20 | Compounds for the prevention and treatment of cardiovascular diseases |
US16/707,559 US20200352946A1 (en) | 2007-02-01 | 2019-12-09 | Compounds for the prevention and treatment of cardiovascular diseases |
US17/335,960 US20210361656A1 (en) | 2007-02-01 | 2021-06-01 | Compounds for the prevention and treatment of cardiovascular diseases |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/670,238 US8053440B2 (en) | 2007-02-01 | 2007-02-01 | Compounds for the prevention and treatment of cardiovascular diseases |
PCT/CA2007/000146 WO2008092231A1 (en) | 2007-02-01 | 2007-02-01 | Compounds for the prevention and treatment of cardiovascular diseases |
US13/243,776 US8889698B2 (en) | 2007-02-01 | 2011-09-23 | Compounds for the prevention and treatment of cardiovascular diseases |
US14/513,281 US9199990B2 (en) | 2007-02-01 | 2014-10-14 | Compounds for the prevention and treatment of cardiovascular diseases |
US14/922,645 US20160106750A1 (en) | 2007-02-01 | 2015-10-26 | Compounds for the prevention and treatment of cardiovascular diseases |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/513,281 Continuation US9199990B2 (en) | 2007-02-01 | 2014-10-14 | Compounds for the prevention and treatment of cardiovascular diseases |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/710,200 Division US10532054B2 (en) | 2007-02-01 | 2017-09-20 | Compounds for the prevention and treatment of cardiovascular diseases |
Publications (1)
Publication Number | Publication Date |
---|---|
US20160106750A1 true US20160106750A1 (en) | 2016-04-21 |
Family
ID=51894355
Family Applications (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/670,238 Active 2030-07-22 US8053440B2 (en) | 2007-02-01 | 2007-02-01 | Compounds for the prevention and treatment of cardiovascular diseases |
US13/243,776 Active US8889698B2 (en) | 2007-02-01 | 2011-09-23 | Compounds for the prevention and treatment of cardiovascular diseases |
US14/513,281 Active US9199990B2 (en) | 2007-02-01 | 2014-10-14 | Compounds for the prevention and treatment of cardiovascular diseases |
US14/922,645 Abandoned US20160106750A1 (en) | 2007-02-01 | 2015-10-26 | Compounds for the prevention and treatment of cardiovascular diseases |
US15/710,200 Active US10532054B2 (en) | 2007-02-01 | 2017-09-20 | Compounds for the prevention and treatment of cardiovascular diseases |
US16/707,559 Abandoned US20200352946A1 (en) | 2007-02-01 | 2019-12-09 | Compounds for the prevention and treatment of cardiovascular diseases |
US17/335,960 Pending US20210361656A1 (en) | 2007-02-01 | 2021-06-01 | Compounds for the prevention and treatment of cardiovascular diseases |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/670,238 Active 2030-07-22 US8053440B2 (en) | 2007-02-01 | 2007-02-01 | Compounds for the prevention and treatment of cardiovascular diseases |
US13/243,776 Active US8889698B2 (en) | 2007-02-01 | 2011-09-23 | Compounds for the prevention and treatment of cardiovascular diseases |
US14/513,281 Active US9199990B2 (en) | 2007-02-01 | 2014-10-14 | Compounds for the prevention and treatment of cardiovascular diseases |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/710,200 Active US10532054B2 (en) | 2007-02-01 | 2017-09-20 | Compounds for the prevention and treatment of cardiovascular diseases |
US16/707,559 Abandoned US20200352946A1 (en) | 2007-02-01 | 2019-12-09 | Compounds for the prevention and treatment of cardiovascular diseases |
US17/335,960 Pending US20210361656A1 (en) | 2007-02-01 | 2021-06-01 | Compounds for the prevention and treatment of cardiovascular diseases |
Country Status (17)
Country | Link |
---|---|
US (7) | US8053440B2 (en) |
EP (1) | EP2118074B1 (en) |
JP (1) | JP5236664B2 (en) |
KR (1) | KR101444489B1 (en) |
CN (1) | CN101641339B (en) |
AU (1) | AU2007345526B2 (en) |
CA (1) | CA2676984C (en) |
CY (1) | CY1115236T1 (en) |
DK (1) | DK2118074T3 (en) |
ES (1) | ES2454966T3 (en) |
HK (1) | HK1136283A1 (en) |
MX (1) | MX2009008099A (en) |
NZ (1) | NZ579355A (en) |
PL (1) | PL2118074T3 (en) |
PT (1) | PT2118074E (en) |
SI (1) | SI2118074T1 (en) |
WO (1) | WO2008092231A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9757368B2 (en) | 2009-04-22 | 2017-09-12 | Resverlogix Corp. | Anti-inflammatory agents |
US10111885B2 (en) | 2015-03-13 | 2018-10-30 | Resverlogix Corp. | Compositions and therapeutic methods for the treatment of complement-associated diseases |
US10131640B2 (en) | 2009-03-18 | 2018-11-20 | Resverlogix Corp. | Anti-inflammatory agents |
US10532054B2 (en) | 2007-02-01 | 2020-01-14 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular diseases |
Families Citing this family (88)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040033480A1 (en) * | 2002-08-15 | 2004-02-19 | Wong Norman C.W. | Use of resveratrol to regulate expression of apolipoprotein A1 |
EP2314295B1 (en) * | 2005-07-29 | 2015-01-28 | Resverlogix, Inc | Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices |
US20080255161A1 (en) * | 2007-04-11 | 2008-10-16 | Dmitry Koltun | 3-HYDROQUINAZOLIN-4-ONE DERIVATIVES FOR USE AS STEAROYL CoA DESATURASE INHIBITORS |
US20090257979A1 (en) * | 2008-04-15 | 2009-10-15 | Intermune, Inc. | Novel Inhibitors of Hepatitis C Virus Replication |
KR101629356B1 (en) * | 2008-06-26 | 2016-06-13 | 리스버로직스 코퍼레이션 | Methods of preparing quinazolinone derivatives |
CN101628913B (en) * | 2008-07-18 | 2013-01-23 | 中国科学院广州生物医药与健康研究院 | Compound as estrogen-related receptor modulator and application thereof |
JP5754568B2 (en) | 2008-08-05 | 2015-07-29 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Naphthyridine substituted with 4-dimethylamino-phenyl and its use as a medicament |
US20100267752A1 (en) * | 2008-10-15 | 2010-10-21 | Gilead Palo Alto, Inc. | 3-HYDROQUINAZOLIN-4-ONE DERIVATIVES FOR USE AS STEAROYL CoA DESATURASE INHIBITORS |
EP2377871A4 (en) | 2008-11-28 | 2012-07-25 | Chugai Pharmaceutical Co Ltd | 1-(2h)-isoquinolone derivative |
CA2747417C (en) * | 2009-01-08 | 2017-01-03 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular disease |
TW201121968A (en) * | 2009-11-09 | 2011-07-01 | Intermune Inc | Novel inhibitors of hepatitis C virus replication |
AU2011209274B8 (en) * | 2010-01-29 | 2015-08-13 | Boehringer Ingelheim International Gmbh | Substituted naphthyridines and their use as Syk kinase inhibitors |
EP2582709B1 (en) | 2010-06-18 | 2018-01-24 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
EP2590951B1 (en) | 2010-07-09 | 2015-01-07 | Pfizer Limited | Benzenesulfonamides useful as sodium channel inhibitors |
JP2013532185A (en) | 2010-07-12 | 2013-08-15 | ファイザー・リミテッド | Compound |
WO2012007883A1 (en) | 2010-07-12 | 2012-01-19 | Pfizer Limited | Sulfonamide derivatives as nav1.7 inhibitors for the treatment of pain |
US9102621B2 (en) | 2010-07-12 | 2015-08-11 | Pfizer Limited | Acyl sulfonamide compounds |
ES2525581T3 (en) | 2010-07-12 | 2014-12-26 | Pfizer Limited | N-sulfonylbenzamide derivatives useful as voltage-dependent sodium channel inhibitors |
US8772343B2 (en) | 2010-07-12 | 2014-07-08 | Pfizer Limited | Chemical compounds |
US8906943B2 (en) | 2010-08-05 | 2014-12-09 | John R. Cashman | Synthetic compounds and methods to decrease nicotine self-administration |
AU2012288969B2 (en) | 2011-07-26 | 2017-02-23 | Boehringer Ingelheim International Gmbh | Substituted quinolines and their use as medicaments |
WO2013033268A2 (en) | 2011-08-29 | 2013-03-07 | Coferon, Inc. | Bivalent bromodomain ligands, and methods of using same |
WO2013033269A1 (en) | 2011-08-29 | 2013-03-07 | Coferon, Inc. | Bioorthogonal monomers capable of dimerizing and targeting bromodomains and methods of using same |
EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
US8710064B2 (en) * | 2011-10-20 | 2014-04-29 | China Medical University | 2-aryl-4-quinazolinones and their pharmaceutical compositions |
JP5992049B2 (en) * | 2011-11-01 | 2016-09-14 | レスバーロジックス コーポレイション | Oral immediate release formulations for substituted quinazolinones |
CN102516169B (en) * | 2011-12-31 | 2014-05-28 | 清华大学 | Method for preparing polysubstituted isoquinoline and heterocyclic pyridine derivants |
WO2013132253A1 (en) | 2012-03-07 | 2013-09-12 | Institute Of Cancer Research: Royal Cancer Hospital (The) | 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use |
US9376433B2 (en) * | 2012-08-08 | 2016-06-28 | Merck Patent Gmbh | (AZA-)isoquinolinone derivatives |
PT2906531T (en) * | 2012-10-15 | 2018-02-06 | Resverlogix Corp | Compounds useful in the synthesis of benzamide compounds |
BR112015008171B1 (en) * | 2012-10-15 | 2021-01-19 | Albemarle Corporation | processes for the synthesis of 2-amino-4,6-dimethoxybenzamide and other benzamide compounds |
WO2014080290A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Cyclic amines as bromodomain inhibitors |
WO2014080291A2 (en) * | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Biaryl derivatives as bromodomain inhibitors |
WO2014096965A2 (en) | 2012-12-21 | 2014-06-26 | Rvx Therapeutics Inc. | Novel heterocyclic compounds as bromodomain inhibitors |
EP2970312B1 (en) | 2013-03-11 | 2017-11-15 | The Regents of The University of Michigan | Bet bromodomain inhibitors and therapeutic methods using the same |
NZ714669A (en) | 2013-06-21 | 2021-07-30 | Zenith Epigenetics Ltd | Novel bicyclic bromodomain inhibitors |
JP6599852B2 (en) | 2013-06-21 | 2019-10-30 | ゼニス・エピジェネティクス・リミテッド | Novel substituted bicyclic compounds as bromodomain inhibitors |
AU2014298051B2 (en) | 2013-07-31 | 2018-11-15 | Zenith Epigenetics Ltd. | Novel quinazolinones as bromodomain inhibitors |
EP3035933A4 (en) * | 2013-08-21 | 2017-04-26 | Resverlogix Corp. | Compositions and therapeutic methods for accelerated plaque regression |
CA2921985A1 (en) * | 2013-08-21 | 2015-02-26 | Resverlogix Corp. | Compositions and therapeutic methods for accelerated plaque regression |
AU2014320149A1 (en) | 2013-09-11 | 2016-04-07 | Institute Of Cancer Research: Royal Cancer Hospital (The) | 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use |
US9771333B2 (en) * | 2013-11-20 | 2017-09-26 | Signalchem Lifesciences Corp. | Quinazoline derivatives as TAM family kinase inhibitors |
CA2940554A1 (en) | 2014-02-28 | 2015-09-03 | The Regents Of The University Of Michigan | 9h-pyrimido[4,5-b]indoles and related analogs as bet bromodomain inhibitors |
SG11201609084QA (en) | 2014-05-02 | 2016-11-29 | Cerenis Therapeutics Holding Sa | Hdl therapy markers |
WO2016087936A1 (en) | 2014-12-01 | 2016-06-09 | Zenith Epigenetics Corp. | Substituted pyridinones as bromodomain inhibitors |
US10179125B2 (en) | 2014-12-01 | 2019-01-15 | Zenith Epigenetics Ltd. | Substituted pyridines as bromodomain inhibitors |
CN107207474B (en) | 2014-12-11 | 2021-05-07 | 恒翼生物医药科技(上海)有限公司 | Substituted heterocycles as bromodomain inhibitors |
EP3233846A4 (en) | 2014-12-17 | 2018-07-18 | Zenith Epigenetics Ltd. | Inhibitors of bromodomains |
US10307407B2 (en) | 2015-02-27 | 2019-06-04 | The Regents Of The University Of Michigan | 9H-pyrimido [4,5-B] indoles as BET bromodomain inhibitors |
WO2016196065A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Methods and compositions for assessing responsiveness of cancers to bet inhibitors |
JP2018526448A (en) * | 2015-09-07 | 2018-09-13 | 浙江華海薬業股▲フン▼有限公司 | Prodrug molecules capable of releasing nitric oxide |
AU2017219627B2 (en) | 2016-02-15 | 2021-08-05 | The Regents Of The University Of Michigan | Fused 1,4-oxazepines and related analogs as BET bromodomain inhibitors |
RU2021102253A (en) | 2016-04-06 | 2021-03-03 | Дзе Риджентс Оф Дзе Юниверсити Оф Мичиган | DESTRUCTORS OF MDM2 PROTEIN |
CA3020281A1 (en) | 2016-04-06 | 2017-10-12 | The Regents Of The University Of Michigan | Monofunctional intermediates for ligand-dependent target protein degradation |
AU2017250076B2 (en) | 2016-04-12 | 2021-07-22 | The Regents Of The University Of Michigan | Bet protein degraders |
AU2017326175B2 (en) | 2016-09-13 | 2022-01-27 | The Regents Of The University Of Michigan | Fused 1,4-diazepines as BET protein degraders |
WO2018052945A1 (en) | 2016-09-13 | 2018-03-22 | The Regents Of The University Of Michigan | Fused 1,4-oxazepines as bet protein degraders |
RU2016138751A (en) * | 2016-09-30 | 2018-04-02 | Общество с ограниченной ответственностью "Диборнол Девелопмент" | Cardiovascular Treatment |
EP3553058A1 (en) * | 2016-12-09 | 2019-10-16 | Crystal Pharmaceutical (Suzhou) Co., Ltd. | Crystal form of bromodomain protein inhibitor drug, preparation method and use thereof |
CA3047730A1 (en) | 2016-12-20 | 2018-06-28 | Oligomerix, Inc. | Quinazolinones that inhibit the formation of tau oligomers and their method of use |
EP3562483A4 (en) | 2016-12-20 | 2020-06-03 | Oligomerix, Inc. | Novel benzofuran, benzothiophene, and indole analogs that inhibit the formation of tau oligomers and their method of use |
US11046709B2 (en) | 2017-02-03 | 2021-06-29 | The Regents Of The University Of Michigan | Fused 1,4-diazepines as BET bromodomain inhibitors |
CN108069954B (en) * | 2017-03-03 | 2018-11-23 | 上海华汇拓医药科技有限公司 | The quinazolinones of the donor containing NO |
ES2681124B1 (en) | 2017-03-08 | 2019-06-19 | Fund Imdea Alimentacion | MEDICAL USES OF APOLIPOPROTEIN A AND ACTIVATORS OF THE SAME |
CN109384784B (en) * | 2017-08-10 | 2021-01-12 | 浙江海正药业股份有限公司 | Sulfonamide derivative, preparation method thereof and application thereof in medicine |
US11267822B2 (en) | 2017-09-13 | 2022-03-08 | The Regents Of The University Of Michigan | BET bromodomain protein degraders with cleavable linkers |
CN108484510B (en) * | 2018-05-18 | 2020-05-05 | 东南大学 | BRD4 inhibitor RVX-208-based derivative and preparation method and application thereof |
JP2021527136A (en) | 2018-06-13 | 2021-10-11 | ディブリー・アーゲー | Preparation of condensed triazepine derivatives and their use as BET inhibitors |
MX2021007152A (en) | 2018-12-17 | 2021-11-03 | Vertex Pharma | Inhibitors of apol1 and methods of using same. |
CN109776413A (en) * | 2019-01-29 | 2019-05-21 | 天津科技大学 | A kind of isoquinilone derivatives and application with hypoglycemic activity |
CN109897009B (en) * | 2019-03-15 | 2022-06-28 | 深圳晶泰科技有限公司 | Apabetalone hydrate crystal form and preparation method thereof |
CN109824608B (en) * | 2019-03-15 | 2022-06-21 | 深圳晶泰科技有限公司 | Apabetalone crystal form and preparation method thereof |
MX2022005029A (en) | 2019-11-05 | 2022-07-12 | Resverlogix Corp | Methods of treatment and/or prevention of major adverse cardiovascular events (mace) with a combination of a bet bromodomain inhibitor and a sodium dependent glucose transport 2 inhibitor. |
WO2021107657A1 (en) * | 2019-11-26 | 2021-06-03 | 주식회사 베노바이오 | Novel quinazoline redox derivative, and use as bet inhibitor |
US20230053152A1 (en) * | 2019-11-26 | 2023-02-16 | Benobio Co., Ltd. | Novel Quercetin Redox Derivative And Use Thereof As BET Inhibitor |
EP4087575A4 (en) * | 2020-01-08 | 2024-02-28 | Resverlogix Corp. | Methods of treatment and/or prevention of major adverse cardiovascular events (mace) with a combination of a bet bromodomain inhibitor and a dipeptidyl peptidase 4 inhibitor |
IL296035A (en) | 2020-03-06 | 2022-10-01 | Vertex Pharma | Methods of treating apol-1 dependent focal segmental glomerulosclerosis |
US11753413B2 (en) | 2020-06-19 | 2023-09-12 | Incyte Corporation | Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors |
US11691971B2 (en) | 2020-06-19 | 2023-07-04 | Incyte Corporation | Naphthyridinone compounds as JAK2 V617F inhibitors |
PE20231739A1 (en) | 2020-07-02 | 2023-10-31 | Incyte Corp | TRICYCLIC UREA COMPOUNDS AS JAK2 INHIBITORS V617F |
WO2022006456A1 (en) | 2020-07-02 | 2022-01-06 | Incyte Corporation | Tricyclic pyridone compounds as jak2 v617f inhibitors |
CR20230132A (en) | 2020-08-26 | 2023-06-27 | Vertex Pharma | APOL1 INHIBITORS AND METHODS FOR USING THEM |
WO2022046989A1 (en) | 2020-08-27 | 2022-03-03 | Incyte Corporation | Tricyclic urea compounds as jak2 v617f inhibitors |
WO2022140231A1 (en) | 2020-12-21 | 2022-06-30 | Incyte Corporation | Deazaguaine compounds as jak2 v617f inhibitors |
US11958861B2 (en) | 2021-02-25 | 2024-04-16 | Incyte Corporation | Spirocyclic lactams as JAK2 V617F inhibitors |
CN115710202B (en) * | 2021-08-23 | 2024-05-03 | 江西同和药业股份有限公司 | Preparation method and application of apataone key intermediate |
CN113754594A (en) * | 2021-09-16 | 2021-12-07 | 中国药科大学 | Quinazolinone compound or pharmaceutically acceptable salt and isomer thereof, preparation method, pharmaceutical composition and application thereof |
TW202334089A (en) | 2021-11-02 | 2023-09-01 | 美商夫雷爾醫療公司 | Pparg inverse agonists and uses thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9199990B2 (en) * | 2007-02-01 | 2015-12-01 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular diseases |
Family Cites Families (286)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4608A (en) * | 1846-06-27 | Netting-machine | ||
US2065593A (en) * | 1936-12-29 | Water-soluble diazoimino com | ||
US4448A (en) * | 1846-04-04 | Xjoel | ||
FR472489A (en) | 1914-02-20 | 1914-12-08 | Stas Motor Ges M B H | Metal seal ring for pistons |
FR803619A (en) | 1935-03-23 | 1936-10-05 | Ig Farbenindustrie Ag | Dihydroxystilbene-dicarboxylic acid and its preparation process |
US2065900A (en) * | 1935-03-23 | 1936-12-29 | Gen Aniline Works Inc | Dihydroxystilbene-dicarboxylic acid and a process of preparing it |
DE637259C (en) | 1935-03-24 | 1936-10-27 | I G Farbenindustrie Akt Ges | Process for the preparation of a dioxystilbene dicarboxylic acid |
FR803201A (en) | 1935-07-08 | 1936-09-25 | Ste Ind Chim Bale | Preparation of sulfonic acids |
US2071329A (en) * | 1935-08-22 | 1937-02-23 | Solvay Process Co | Method of recovering phthalic anhydride |
DE652772C (en) | 1935-11-07 | 1937-11-08 | I G Farbenindustrie Akt Ges | Process for the preparation of N-dihydroazines of the anthraquinone series |
GB728767A (en) | 1951-10-12 | 1955-04-27 | Wander Ag Dr A | 2-substituted chromone compounds, and a method of making same |
BE633049A (en) | 1962-06-06 | |||
US3251837A (en) * | 1962-09-14 | 1966-05-17 | Pfizer & Co C | Derivatives of 1, 2, 4-benzothiadiazine-1, 1-dioxides |
GB1179019A (en) | 1967-05-23 | 1970-01-28 | Produits Chimique Soc Et | Polynicotinic Esters of Flavonoids |
FR6928M (en) | 1967-11-24 | 1969-05-05 | ||
US3600394A (en) * | 1968-05-17 | 1971-08-17 | Searle & Co | 2-aminoalkyl-3-arylisocarbostyrils |
US3930024A (en) * | 1969-09-02 | 1975-12-30 | Parke Davis & Co | Pharmaceutical compositions and methods |
US3773946A (en) * | 1969-09-02 | 1973-11-20 | Parke Davis & Co | Triglyceride-lowering compositions and methods |
US3862186A (en) | 1972-12-15 | 1975-01-21 | Bristol Myers Co | Process for the production of cephalexin monohydrate |
FR2244493A1 (en) | 1973-08-09 | 1975-04-18 | Pluripharm | Flavonoid amino-acid salts - for treatment of haemorrhage, circulatory disorders and atherosclerosis |
DE2349024A1 (en) * | 1973-09-26 | 1975-04-10 | Schering Ag | 6BETA, 7BETA-EPOXY-1ALPHA, 2ALPHAMETHYLENE-D-HOMO-4-PREGNEN-3,20-DIONE |
IT1050750B (en) | 1975-12-05 | 1981-03-20 | Erba Carlo Spa | DERIVATIVES OF 3.4 OF HYDRO CHINAZOLINE |
GB1532682A (en) | 1976-04-27 | 1978-11-22 | Bristol Myers Co | Process for the preparation of cephadroxil |
US4159330A (en) | 1976-11-02 | 1979-06-26 | Carlo Erba S.P.A. | 2-Disubstituted phenyl-3,4-dihydro-4-oxo-quinazoline derivatives and process for their preparation |
US5098903A (en) | 1980-03-07 | 1992-03-24 | Board Of Regents Of The University Of Oklahoma | Diphenylcyclopropyl analogs as antiestrogenic and antitumor agents |
IL64542A0 (en) * | 1981-12-15 | 1982-03-31 | Yissum Res Dev Co | Long-chain alpha,omega-dicarboxylic acids and derivatives thereof and pharmaceutical compositions containing them |
JPS60136512A (en) * | 1983-12-26 | 1985-07-20 | Eisai Co Ltd | Remedy and preventive for hyperlipemia |
DE3423166A1 (en) * | 1984-06-22 | 1986-01-02 | Epis S.A., Zug | ALPHA, OMEGA DICARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
DE3579888D1 (en) | 1984-11-08 | 1990-10-31 | Sumitomo Pharma | CARBAPENE COMPOUNDS AND THEIR PRODUCTION. |
DE3515882A1 (en) * | 1985-05-03 | 1986-11-06 | Dr. Karl Thomae Gmbh, 7950 Biberach | MEDICINAL PRODUCTS CONTAINING PYRIDINONE WITH ANTITHROMBOTIC EFFECTS AND METHOD FOR THE PRODUCTION THEREOF |
DE3532279A1 (en) | 1985-09-11 | 1987-03-12 | Bayer Ag | 1,4-benzoxathiin derivatives |
ES2058061T3 (en) | 1985-10-25 | 1994-11-01 | Beecham Group Plc | DERIVED FROM PIPERIDINE, ITS PREPARATION AND ITS USE AS A MEDICINAL PRODUCT. |
DE3601417A1 (en) | 1986-01-20 | 1987-07-23 | Nattermann A & Cie | 2'-Alkyl(alkenyl)-substituted quercetins |
US4663345A (en) | 1986-04-17 | 1987-05-05 | American Home Products Corporation | Etodolac for treatment of gout |
EP0258190B1 (en) | 1986-08-29 | 1991-11-27 | Ciba-Geigy Ag | Process for preparing aromatic ethers and thioethers |
DE3784147T2 (en) | 1986-11-24 | 1993-06-03 | Fujisawa Pharmaceutical Co | 3-PYRROLIDINYLTHIO-1-AZABICYCLO (3.2.0) HEPT-2-EN-2-CARBONIC ACID DERIVATIVES. |
JPH07118241B2 (en) | 1987-10-21 | 1995-12-18 | 松下電器産業株式会社 | Instrument lid opening and closing device |
GB8804058D0 (en) | 1988-02-22 | 1988-03-23 | Fujisawa Pharmaceutical Co | 3-alkenyl-1-azabicyclo(3 2 0)hept-2-ene-2-carboxylic acid compounds |
US4925838A (en) | 1988-03-18 | 1990-05-15 | Fujisawa Pharmaceutical Company, Ltd. | 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds |
US4963544A (en) | 1988-05-23 | 1990-10-16 | Fujisawa Pharmaceutical Company, Ltd. | 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds |
GB8926981D0 (en) | 1988-12-23 | 1990-01-17 | Ici Plc | Heterocyclic derivatives |
JPH0741442Y2 (en) | 1989-01-31 | 1995-09-27 | シャープ株式会社 | Biological electrode holder |
EP0407217A1 (en) | 1989-07-07 | 1991-01-09 | Schering Corporation | Pharmaceutically active compounds |
FR2649612A1 (en) | 1989-07-17 | 1991-01-18 | Rhone Poulenc Sante | DRUGS BASED ON 1H-BENZOXADIAZINE DERIVATIVES-4.1.2 NOVEL DERIVATIVES AND METHODS FOR PREPARING THEM |
IE64358B1 (en) | 1989-07-18 | 1995-07-26 | Ici Plc | Diaryl ether heterocycles |
US5332832A (en) | 1989-07-26 | 1994-07-26 | Procter & Gamble Pharmaceuticals, Inc. | Nitrofurantoin crystals |
GB9018134D0 (en) | 1989-09-29 | 1990-10-03 | Ici Plc | Heterocyclic derivatives |
US5244904A (en) * | 1990-06-05 | 1993-09-14 | Toray Industries, Inc. | Indole derivatives |
JP2999579B2 (en) * | 1990-07-18 | 2000-01-17 | 武田薬品工業株式会社 | DNA and its uses |
GB9025832D0 (en) | 1990-11-28 | 1991-01-09 | Ashwell Geoffrey J | Novel films for nonlinear optical applications |
IE913866A1 (en) | 1990-11-28 | 1992-06-03 | Ici Plc | Aryl derivatives |
US5126351A (en) * | 1991-01-24 | 1992-06-30 | Glaxo Inc. | Antitumor compounds |
MX9200299A (en) | 1991-02-07 | 1992-12-01 | Roussel Uclaf | NEW NITROGENATED BICYCLE DERIVATIVES, THEIR PROCEDURE FOR PREPARING THE NEW INTERMEDIATE COMPOUNDS OBTAINED THEIR APPLICATION AS MEDICINES AND THE PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
JPH06504791A (en) | 1991-04-10 | 1994-06-02 | オクタマー,インコーポレイティド | Methods for inhibition of retrovirus replication |
US5480883A (en) * | 1991-05-10 | 1996-01-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
CA2102780C (en) * | 1991-05-10 | 2007-01-09 | Alfred P. Spada | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
US5124337A (en) * | 1991-05-20 | 1992-06-23 | Schering Corporation | N-acyl-tetrahydroisoquinolines as inhibitors of acyl-coenzyme a:cholesterol acyl transferase |
US5223506A (en) | 1991-06-04 | 1993-06-29 | Glaxo Inc. | Cyclic antitumor compounds |
PT100905A (en) | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | BICYCLE HYGIENEOUS HETEROCYCLIC COMPOUNDS CONTAINING BENZENE, CYCLOHEXAN OR PYRIDINE AND PYRIMIDINE, PYRIDINE OR IMIDAZOLE SUBSTITUTES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US5250679A (en) | 1991-10-18 | 1993-10-05 | Genentech, Inc. | Nonpeptidyl platelet aggregation inhibitors having specificity for the GPIIb III.sub. receptor |
GB9126260D0 (en) | 1991-12-11 | 1992-02-12 | Pfizer Ltd | Therapeutic agents |
US5474994A (en) | 1992-05-26 | 1995-12-12 | Recordati S.A., Chemical And Pharmaceutical Company | Bicyclic heterocyclic derivatives having α1 -adrenergic and 5HT1A |
FR2689127B1 (en) | 1992-03-31 | 1994-05-06 | Adir Cie | NEWS 3 ', 5' -DITERTBUTYL-4'-HYDROXY FLAVONES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
US7655699B1 (en) | 1992-04-22 | 2010-02-02 | Eisai Inc. | Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors |
DE4215587A1 (en) * | 1992-05-12 | 1993-11-18 | Bayer Ag | Sulfonylbenzyl-substituted benzo- and pyridopyridones |
DE4215588A1 (en) * | 1992-05-12 | 1993-11-18 | Bayer Ag | Biphenylmethyl-substituted pyridones |
GB9218334D0 (en) | 1992-08-28 | 1992-10-14 | Ici Plc | Heterocyclic compounds |
JPH0680656A (en) | 1992-09-03 | 1994-03-22 | Mitsui Petrochem Ind Ltd | Production of optically active epoxide |
AU5850894A (en) | 1992-12-23 | 1994-07-19 | Procept, Inc. | Novel agents for inhibition of hiv infectivity and use therefor |
JPH0741442A (en) | 1993-05-21 | 1995-02-10 | Sumitomo Chem Co Ltd | Acetylene alcohol derivative and its production |
JPH0761942A (en) | 1993-06-17 | 1995-03-07 | Sumitomo Chem Co Ltd | Phenol derivative and its production |
JPH0725761A (en) | 1993-07-09 | 1995-01-27 | Kureha Chem Ind Co Ltd | Agent for protecting cartilage |
EP0709373B1 (en) | 1993-07-23 | 2001-10-17 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Pyrrolidine derivative |
US5707547A (en) | 1993-08-03 | 1998-01-13 | Sumitomo Chemical Company, Limited | Trans-olefin compounds, method for production thereof, liquid crystal composition containing the same as active ingredient, and liquid crystal element using said composition |
JPH07118241A (en) | 1993-09-01 | 1995-05-09 | Sumitomo Chem Co Ltd | Phenol derivative and its production |
JPH07179380A (en) | 1993-12-22 | 1995-07-18 | Sumitomo Chem Co Ltd | Alcohol derivative and its production |
JPH07233109A (en) | 1994-02-24 | 1995-09-05 | Sumitomo Chem Co Ltd | Optically active alcohol derivative and its production |
JP4182545B2 (en) | 1994-02-25 | 2008-11-19 | 萬有製薬株式会社 | Carbapenem derivatives |
EP0749974B1 (en) * | 1994-03-08 | 2001-06-27 | Otsuka Pharmaceutical Factory, Inc. | Phosphonic diester derivative |
JPH07247289A (en) | 1994-03-11 | 1995-09-26 | Mitsui Petrochem Ind Ltd | Method for producing chromene oxide compounds |
FR2718329B1 (en) * | 1994-03-21 | 2002-09-20 | Rhone Poulenc Rorer Sa | Transgenic rabbit sensitized to dyslipoproteinemias. |
US6048903A (en) * | 1994-05-03 | 2000-04-11 | Robert Toppo | Treatment for blood cholesterol with trans-resveratrol |
US6168776B1 (en) * | 1994-07-19 | 2001-01-02 | University Of Pittsburgh | Alkyl, alkenyl and alkynyl Chrysamine G derivatives for the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition |
GB2292149A (en) | 1994-08-09 | 1996-02-14 | Ferring Res Ltd | Peptide inhibitors of pro-interleukin-1beta converting enzyme |
JP3702493B2 (en) | 1994-08-12 | 2005-10-05 | 大正製薬株式会社 | Quinazolin-4 (3H) -one derivative |
ATE190978T1 (en) | 1994-11-14 | 2000-04-15 | Warner Lambert Co | 6-ARYL-PYRIDO(2,3-D)PYRIMIDINES AND NAPHTHYRIDINES FOR INHIBITING CELL PRODUCTION CAUSED BY PROTEIN TYROSINE KINASE |
IL115256A0 (en) * | 1994-11-14 | 1995-12-31 | Warner Lambert Co | 6-Aryl pyrido (2,3-d) pyrimidines and naphthyridines and their use |
US5446071A (en) * | 1994-11-18 | 1995-08-29 | Eli Lilly And Company | Methods for lowering serum cholesterol |
JP4140981B2 (en) * | 1994-12-26 | 2008-08-27 | 東菱薬品工業株式会社 | Anti-restenosis and arteriosclerosis drug |
US5648387A (en) * | 1995-03-24 | 1997-07-15 | Warner-Lambert Company | Carboxyalkylethers, formulations, and treatment of vascular diseases |
AU5259296A (en) | 1995-04-07 | 1996-10-23 | Warner-Lambert Company | Flavones and coumarins as agents for the treatment of athero sclerosis |
DE69622472T2 (en) | 1995-06-07 | 2003-02-06 | Eli Lilly And Co., Indianapolis | Treatment of diseases by induction of BEF-1 transcription factor |
WO1997008153A1 (en) * | 1995-08-30 | 1997-03-06 | Otsuka Pharmaceutical Factory, Inc. | Process for producing quinazolin-4-one derivatives |
US5783577A (en) | 1995-09-15 | 1998-07-21 | Trega Biosciences, Inc. | Synthesis of quinazolinone libraries and derivatives thereof |
AU4858596A (en) | 1995-09-15 | 1997-04-01 | Torrey Pines Institute For Molecular Studies | Synthesis of quinazolinone libraries |
AU706262B2 (en) | 1995-10-23 | 1999-06-10 | Osteoscreen, Inc. | Compositions and methods for treating bone deficit conditions |
RU2135494C1 (en) | 1995-12-01 | 1999-08-27 | Санкио Компани Лимитед | Heterocyclic compounds and composition on said showing antagonistic effect with respect to tachykinin receptors |
US5756736A (en) * | 1996-01-26 | 1998-05-26 | Syntex (U.S.A.) Inc. | Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative |
US5739330A (en) | 1996-02-05 | 1998-04-14 | Hoechst Celanese Corporation | Process for preparing quinazolones |
WO1997028118A1 (en) | 1996-02-05 | 1997-08-07 | Hoechst Celanese Corporation | Process for preparing anthranilic acids |
US5763608A (en) | 1996-02-05 | 1998-06-09 | Hoechst Celanese Corporation | Process for preparing pyrimidine derivatives |
WO1997029106A1 (en) | 1996-02-12 | 1997-08-14 | Rutgers, The State University Of New Jersey | Coralyne analogs as topoisomerase inhibitors |
KR20000022040A (en) | 1996-06-20 | 2000-04-25 | 보오드 오브 리젠츠, 더 유니버시티 오브 텍사스 시스템 | Compounds and methods for providing pharmacologically active preparations and uses thereof |
US5854264A (en) * | 1996-07-24 | 1998-12-29 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
KR100213895B1 (en) * | 1996-10-14 | 1999-08-02 | 박원훈 | Compositions for the prevention and therapy of cardiovascular disease containing extract of citrus fruit peel hesperidin or naringin |
DE19651099A1 (en) | 1996-12-09 | 1998-06-10 | Consortium Elektrochem Ind | Multi-component system for changing, breaking down or bleaching lignin, lignin-containing materials or similar substances as well as methods for their use |
IL119971A (en) | 1997-01-07 | 2003-02-12 | Yissum Res Dev Co | Pharmaceutical compositions containing dicarboxylic acids and derivatives thereof and some novel dicarboxylic acids |
US6613722B1 (en) | 1997-03-07 | 2003-09-02 | Exxon Chemical Patents Inc. | Lubricating composition |
JPH10287678A (en) | 1997-04-11 | 1998-10-27 | Kyowa Hakko Kogyo Co Ltd | Pyrano azine derivative |
AR012634A1 (en) | 1997-05-02 | 2000-11-08 | Sugen Inc | QUINAZOLINE BASED COMPOUND, FAMACEUTICAL COMPOSITION THAT UNDERSTANDS IT, METHOD TO SYNTHESIZE IT, ITS USE, METHODS OF MODULATION OF THE DESERINE / TREONIN PROTEIN-KINASE FUNCTION AND IN VITRO METHOD TO IDENTIFY COMPOUNDS THAT MODULATE |
AU7484798A (en) | 1997-05-13 | 1998-12-08 | Octamer, Inc. | Methods for treating inflammation, inflammatory diseases, arthritis and strok e using padprt inhibitors |
US5908861A (en) * | 1997-05-13 | 1999-06-01 | Octamer, Inc. | Methods for treating inflammation and inflammatory disease using pADPRT inhibitors |
EP0988038B1 (en) | 1997-06-02 | 2002-08-14 | Janssen Pharmaceutica N.V. | (imidazol-5-yl)methyl-2-quinolinone derivatives as inhibitors of smooth muscle cell proliferation |
IL121165A0 (en) | 1997-06-26 | 1997-11-20 | Yissum Res Dev Co | Pharmaceutical compositions containing carboxylic acids and derivatives thereof |
US6294536B1 (en) | 1997-08-29 | 2001-09-25 | Takeda Schering-Plough Animal Health K.K. | Triazine derivatives, their production and use |
US20020022636A1 (en) | 1997-09-03 | 2002-02-21 | Jia-He Li | Oxo-substituted compounds, process of making, and compositions and methods for inhibiting parp activity |
US6635642B1 (en) * | 1997-09-03 | 2003-10-21 | Guilford Pharmaceuticals Inc. | PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same |
US6239114B1 (en) * | 1997-09-26 | 2001-05-29 | Kgk Synergize | Compositions and methods for treatment of neoplastic diseases with combinations of limonoids, flavonoids and tocotrienols |
DE69839887D1 (en) | 1997-10-02 | 2008-09-25 | Eisai R&D Man Co Ltd | CONDENSED PYRIDINE DERIVATIVES |
CN1124134C (en) * | 1997-10-28 | 2003-10-15 | 韩国科学技术研究院 | Naringin and naringenin as inhibitor of acyl coa-cholesterol-o-acyltransferase, ihibitor of macrophage-lipid complex accumulation on the arterial wall and preventive agent |
GB9725782D0 (en) | 1997-12-05 | 1998-02-04 | Pfizer Ltd | Therapeutic agents |
DE19756388A1 (en) * | 1997-12-18 | 1999-06-24 | Hoechst Marion Roussel De Gmbh | New 2-aryl-4-amino-6,7-di:methoxy-quinazoline derivatives useful as guanylate cyclase activators for treating cardiovascular diseases, etc. |
AU759707B2 (en) * | 1998-01-08 | 2003-04-17 | Aventis Pharmaceuticals Products Inc. | A transgenic rabbit that expresses a functional human lipoprotein (A) |
US6414037B1 (en) * | 1998-01-09 | 2002-07-02 | Pharmascience | Pharmaceutical formulations of resveratrol and methods of use thereof |
PL201461B1 (en) | 1998-03-17 | 2009-04-30 | Chugai Pharmaceutical Co Ltd | Preventives or remedies for inflammatory intestinal diseases containing as the active ingredient il-6 antagonists |
US6022901A (en) * | 1998-05-13 | 2000-02-08 | Pharmascience Inc. | Administration of resveratrol to prevent or treat restenosis following coronary intervention |
SE9802973D0 (en) | 1998-09-03 | 1998-09-03 | Astra Ab | Immediate release tablet |
KR20010079922A (en) | 1998-09-24 | 2001-08-22 | 미우라 아키라 | Hydroxyflavone Derivatives |
WO2000023075A1 (en) | 1998-10-19 | 2000-04-27 | Eisai Co., Ltd. | Analgesics |
CN1327384A (en) * | 1998-10-20 | 2001-12-19 | 韩国科学技术研究院 | Bioflavonoids as plasma high density lipoprotein level increasing agent |
US6433187B1 (en) | 1998-12-17 | 2002-08-13 | Tularik Inc. | Certain polycyclic compounds useful as tubulin-binding agents |
US6291456B1 (en) * | 1998-12-30 | 2001-09-18 | Signal Pharmaceuticals, Inc. | Compounds and methods for modulation of estrogen receptors |
US6399633B1 (en) | 1999-02-01 | 2002-06-04 | Aventis Pharmaceuticals Inc. | Use of 4-H-1-benzopryan-4-one derivatives as inhibitors of smooth muscle cell proliferation |
PL350650A1 (en) | 1999-03-15 | 2003-01-27 | Abbott Lab | 6-o-substituted macrolides having antibacterial activity |
US6969720B2 (en) * | 1999-03-17 | 2005-11-29 | Amr Technology, Inc. | Biaryl substituted purine derivatives as potent antiproliferative agents |
US6054435A (en) * | 1999-03-19 | 2000-04-25 | Abbott Laboratories | 6-O-substituted macrolides having antibacterial activity |
ES2287016T3 (en) | 1999-04-28 | 2007-12-16 | Sanofi-Aventis Deutschland Gmbh | DERIVATIVES OF DIARIL-ACID AS LIGANDS OF THE PPAR RECEIVER. |
US6835755B1 (en) | 1999-06-24 | 2004-12-28 | University Of Pretoria | Naphthoquinone derivatives and their use in the treatment and control of tuberculosis |
DE19934799B4 (en) * | 1999-07-28 | 2008-01-24 | Az Electronic Materials (Germany) Gmbh | Chiral smectic liquid crystal mixture and its use in high contrast active matrix displays |
JP2001131151A (en) | 1999-11-02 | 2001-05-15 | Shionogi & Co Ltd | New use of olefin derivative |
JP5278983B2 (en) | 1999-11-17 | 2013-09-04 | 塩野義製薬株式会社 | New uses of amide compounds |
ES2334635T3 (en) * | 1999-12-06 | 2010-03-15 | Welichem Biotech Inc. | POLYHYDROXIESTILBEN AND STILBENE OXIDES AS ANTIPSORIASIC AGENTS AND INHIBITORS OF PROTEIN KINASE. |
FR2804679B1 (en) | 2000-02-07 | 2002-04-26 | Clariant France Sa | NOVEL PHENOLIC COMPOUNDS DERIVED FROM DIALCOXYETHANALS, THEIR PREPARATION PROCESS AND THEIR APPLICATION |
WO2001060775A1 (en) | 2000-02-17 | 2001-08-23 | Appleton Papers Inc. | Process for preparing alkoxy or arylmethoxy aroxyethanes |
WO2003018008A1 (en) | 2000-02-25 | 2003-03-06 | Shionogi & Co., Ltd. | Apo ai expression accelerating agent |
DE60144322D1 (en) | 2000-04-27 | 2011-05-12 | Astellas Pharma Inc | CONDENSED HETEROARYL DERIVATIVES |
WO2001082916A2 (en) | 2000-05-03 | 2001-11-08 | Tularik Inc. | Combination therapeutic compositions and methods of use |
US6548694B2 (en) | 2000-05-23 | 2003-04-15 | Hoffman-La Roche Inc. | N-(4-carbamimidoyl-phenyl)-glycine derivatives |
JP2001335476A (en) | 2000-05-29 | 2001-12-04 | Shionogi & Co Ltd | New use of tricyclic compound |
WO2003024441A1 (en) | 2001-09-14 | 2003-03-27 | Shionogi & Co., Ltd. | Novel use of tricyclic compound |
US6479499B1 (en) | 2000-06-28 | 2002-11-12 | National Science Council | 2-phenyl-4-quinazolinone compounds, 2-phenyl-4-alkoxy-quinazoline compounds and their pharmaceutical compositions |
JP2002047283A (en) | 2000-07-04 | 2002-02-12 | Basf Ag | New flavonoid and its use in product for cosmetic or dermatological preparation |
US6541522B2 (en) * | 2000-08-16 | 2003-04-01 | Insmed Incorporated | Methods of using compositions containing hypotriglyceridemically active stilbenoids |
US7723303B2 (en) | 2000-08-24 | 2010-05-25 | The Regents Of The University Of California | Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response |
AU9650201A (en) | 2000-10-02 | 2002-04-15 | Molecular Probes Inc | Reagents for labeling biomolecules having aldehyde or ketone moieties |
CA2356544C (en) | 2000-10-03 | 2006-04-04 | Warner-Lambert Company | Pyridotriazines and pyridopyridazines |
WO2002028835A1 (en) * | 2000-10-05 | 2002-04-11 | Fujisawa Pharmaceutical Co., Ltd. | Benzamide compounds as apo b secretion inhibitors |
BR0114619A (en) * | 2000-10-11 | 2005-12-13 | Esperion Therapeutics Inc | Compound, pharmaceutical composition, methods for treating or preventing cardiovascular disease, dyslipidemia, dyslipoproteinemia, glucose metabolism disorder, thrombotic and associated with peroxisome proliferator activated receptor, alzheimer's disease, x syndrome or metabolic syndrome , septicemia, obesity, pancreatitis, hypertension, kidney disease, cancer, inflammation and impotence, in a patient and to reduce the fat content of poultry eggs and poultry meat |
CN1479721A (en) * | 2000-10-11 | 2004-03-03 | ͨ��ҽ�ƹ�˾ | Sulfoxide and bis-sulfoxide compounds and compositions for cholesterol management and related uses |
EE200300153A (en) | 2000-10-19 | 2003-06-16 | Merck & Co., Inc. | Estrogen Receptor Modulators, Pharmaceutical Composition and Method of Preparation |
KR100825182B1 (en) * | 2000-11-30 | 2008-04-24 | 캐논 가부시끼가이샤 | Luminescent Element and Display |
EP1341773A2 (en) * | 2000-12-07 | 2003-09-10 | Cv Therapeutics, Inc. | Substituted 1,3,5-triazines and pyrimidines as abca-1 elevating compounds against coronary artery disease or atherosclerosis |
KR100472694B1 (en) * | 2000-12-30 | 2005-03-07 | 한국생명공학연구원 | Flavanone derivatives and composition for preventing or treating blood lipid level-related diseases comprising same |
JP2002249483A (en) | 2001-02-21 | 2002-09-06 | Koei Chem Co Ltd | Method of producing aryl substituted heterocyclic compound |
JP4256679B2 (en) | 2001-03-16 | 2009-04-22 | ノボゲン リサーチ ピーティーワイ リミテッド | How to treat restenosis |
JP4334233B2 (en) * | 2001-04-11 | 2009-09-30 | アセロジエニクス・インコーポレイテツド | Method for increasing plasma HDL cholesterol levels and improving HDL functionality with probucol monoester |
WO2002096426A1 (en) | 2001-05-25 | 2002-12-05 | Bristol-Myers Squibb Company | Hydantion derivatives as inhibitors of matrix metalloproteinases |
WO2003007959A1 (en) | 2001-07-16 | 2003-01-30 | Fujisawa Pharmaceutical Co., Ltd. | Quinoxaline derivatives which have parp inhibitory action |
EP1430038A1 (en) * | 2001-08-13 | 2004-06-23 | Ciba SC Holding AG | Ultraviolet light absorbers |
US7429593B2 (en) * | 2001-09-14 | 2008-09-30 | Shionogi & Co., Ltd. | Utilities of amide compounds |
US8124625B2 (en) * | 2001-09-14 | 2012-02-28 | Shionogi & Co., Ltd. | Method of enhancing the expression of apolipoprotein AI using olefin derivatives |
US6835469B2 (en) * | 2001-10-17 | 2004-12-28 | The University Of Southern California | Phosphorescent compounds and devices comprising the same |
US7166368B2 (en) | 2001-11-07 | 2007-01-23 | E. I. Du Pont De Nemours And Company | Electroluminescent platinum compounds and devices made with such compounds |
US7250512B2 (en) | 2001-11-07 | 2007-07-31 | E. I. Du Pont De Nemours And Company | Electroluminescent iridium compounds having red-orange or red emission and devices made with such compounds |
US6541045B1 (en) * | 2002-01-04 | 2003-04-01 | Nutraceutical Corporation | Herbal composition and method for combating inflammation |
WO2003064399A1 (en) | 2002-01-28 | 2003-08-07 | Ube Industries, Ltd. | Process for producing quinazolin-4-one derivative |
US20040127492A1 (en) | 2002-02-19 | 2004-07-01 | Pharmacia Corporation | Cyclic pyrazoles for the inhibition of mitogen activated protein kinase-activated protein kinase-2 |
GB0206033D0 (en) | 2002-03-14 | 2002-04-24 | Pfizer Ltd | Compounds useful in therapy |
NZ556545A (en) | 2002-03-22 | 2009-03-31 | Novartis Ag | Combination comprising a beta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitor and a glucagon-like peptide-1 agonist |
MY140680A (en) | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
AU2003238157A1 (en) * | 2002-06-18 | 2003-12-31 | Sankyo Company, Limited | Fused-ring pyrimidin-4(3h)-one derivatives, processes for the preparation and uses thereof |
KR20040001144A (en) * | 2002-06-27 | 2004-01-07 | 김대경 | Novel phospholipase A2 in the cytosol of red blood cell and the antibody against it, and the use and the preparation methods thereof |
US20050080024A1 (en) * | 2002-08-15 | 2005-04-14 | Joseph Tucker | Nitric oxide donating derivatives for the treatment of cardiovascular disorders |
US20040033480A1 (en) * | 2002-08-15 | 2004-02-19 | Wong Norman C.W. | Use of resveratrol to regulate expression of apolipoprotein A1 |
US20050080021A1 (en) * | 2002-08-15 | 2005-04-14 | Joseph Tucker | Nitric oxide donating derivatives of stilbenes, polyphenols and flavonoids for the treatment of cardiovascular disorders |
CA2495903A1 (en) | 2002-08-23 | 2004-03-04 | University Of Connecticut | Novel biphenyl and biphenyl-like cannabinoids |
US20040176366A1 (en) | 2002-08-30 | 2004-09-09 | Wathen Michael W | Method of preventing or treating atherosclerosis or restenosis |
EP1398032A1 (en) | 2002-09-10 | 2004-03-17 | PheneX Pharmaceuticals AG | 4-Oxo-quinazolines as LXR nuclear receptor binding compounds |
EP1407774A1 (en) * | 2002-09-10 | 2004-04-14 | LION Bioscience AG | 2-Amino-4-quinazolinones as LXR nuclear receptor binding compounds |
EP1558581A4 (en) | 2002-10-07 | 2007-07-25 | Bristol Myers Squibb Co | Triazolone and triazolethione derivatives |
EP1553947A4 (en) | 2002-10-21 | 2006-11-29 | Bristol Myers Squibb Co | Quinazolinones and derivatives thereof as factor xa inhibitors |
WO2004039795A2 (en) | 2002-10-29 | 2004-05-13 | Fujisawa Pharmaceutical Co., Ltd. | Amide compounds for the treatment of hyperlipidemia |
EP1558260A4 (en) | 2002-11-04 | 2006-10-25 | Nps Pharma Inc | Quinazolinone compounds as calcilytics |
EP1418164A1 (en) | 2002-11-07 | 2004-05-12 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | New stilbene derivatives and their use as aryl hydrocarbon receptor ligand antagonists |
WO2004046152A1 (en) * | 2002-11-18 | 2004-06-03 | F. Hoffmann La Roche Ag | Diazinopyrimidines |
WO2004047755A2 (en) | 2002-11-22 | 2004-06-10 | Japan Tobacco Inc. | Fused bicyclic nitrogen-containing heterocycles |
CN100418954C (en) | 2002-12-13 | 2008-09-17 | 弗·哈夫曼-拉罗切有限公司 | 3h-quinazolin-4-one derivatives |
ITRM20020629A1 (en) | 2002-12-19 | 2004-06-20 | Sigma Tau Ind Farmaceuti | USE OF ALPHA-PHENYLTHIOCARBOXYL AND ACHYLPHOXYCARBOXYLIC ACIDS WITH HYPOGLYCEMY AND / OR HYPOLIPIDEMIZING ACTIVITY. |
WO2004058717A1 (en) * | 2002-12-20 | 2004-07-15 | X-Ceptor Therapeutics, Inc. | Isoquinolinone derivatives and their use as therapeutic agents |
JP2004203751A (en) | 2002-12-24 | 2004-07-22 | Pfizer Inc | Substituted 6,6-heterobicyclic derivative |
JP4500689B2 (en) * | 2002-12-26 | 2010-07-14 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Selective estrogen receptor modulator |
WO2004065392A1 (en) | 2003-01-24 | 2004-08-05 | Smithkline Beecham Corporation | Condensed pyridines and pyrimidines and their use as alk-5 receptor ligands |
WO2004072042A2 (en) | 2003-02-12 | 2004-08-26 | Carex S.A. | Quinoline derivative and their use for modulation of lxr activity |
JP2006522124A (en) * | 2003-04-03 | 2006-09-28 | バーテックス ファーマシューティカルズ インコーポレイテッド | Compositions useful as inhibitors of protein kinases |
CA2520323C (en) | 2003-04-09 | 2013-07-09 | Exelixis, Inc. | Tie-2 modulators and methods of use |
JP2004307440A (en) | 2003-04-10 | 2004-11-04 | Kyorin Pharmaceut Co Ltd | 2-amino-1,3-propanediol derivative and its addition salt |
ATE422895T1 (en) | 2003-04-16 | 2009-03-15 | Bristol Myers Squibb Co | MACROCYCLIC ISOQUINOLINE PEPTIDE INHIBITORS OF HEPATITIS C VIRUS |
KR101099409B1 (en) | 2003-06-06 | 2011-12-27 | 아렉시스 악티에볼라그 | Use of fused heterocyclic compounds as scce inhibitors for the treatment of skin conditions or cancer |
US7314939B2 (en) | 2003-06-17 | 2008-01-01 | Millennium Pharmaceuticals, Inc. | Compositions and methods for inhibiting TGF-β |
WO2004113307A1 (en) | 2003-06-18 | 2004-12-29 | Ube Industries, Ltd. | Process for producing pyrimidin-4-one compound |
US20050043300A1 (en) * | 2003-08-14 | 2005-02-24 | Pfizer Inc. | Piperazine derivatives |
MXPA06003838A (en) | 2003-10-10 | 2006-07-03 | Resverlogix Corp | Treatment of diseases associated with the egr-1 enhancer element. |
US20050096391A1 (en) | 2003-10-10 | 2005-05-05 | Per Holm | Compositions comprising fenofibrate and rosuvastatin |
EP1678157A4 (en) | 2003-10-28 | 2009-03-18 | Reddy Us Therapeutics Inc | Heterocyclic compounds and methods of making and using thereof |
WO2005065183A2 (en) | 2003-12-19 | 2005-07-21 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
WO2005066162A1 (en) | 2003-12-23 | 2005-07-21 | Human Biomolecular Research Institute | Synthetic compounds and derivatives as modulators of smoking or nicotine ingestion and lung cancer |
TW200536830A (en) | 2004-02-06 | 2005-11-16 | Chugai Pharmaceutical Co Ltd | 1-(2H)-isoquinolone derivative |
CN1960977B (en) * | 2004-05-31 | 2010-07-21 | 万有制药株式会社 | Quinazoline derivative |
GB0512324D0 (en) | 2005-06-16 | 2005-07-27 | Novartis Ag | Organic compounds |
WO2006012577A2 (en) | 2004-07-22 | 2006-02-02 | Bayer Pharmaceuticals Corporation | Quinazolinone derivatives useful for the regulation of glucose homeostasis and food intake |
US20070218155A1 (en) * | 2004-08-20 | 2007-09-20 | Kuhrts Eric H | Methods and compositions for treating dyslipidaemia |
WO2006045010A2 (en) | 2004-10-20 | 2006-04-27 | Resverlogix Corp. | Stilbenes and chalcones for the prevention and treatment of cardiovascular diseases |
JP2008526734A (en) | 2004-12-31 | 2008-07-24 | エスケー ケミカルズ カンパニー リミテッド | Quinazoline derivatives effective in preventing diabetes and obesity |
CR9465A (en) | 2005-03-25 | 2008-06-19 | Surface Logix Inc | PHARMACOCINETICALLY IMPROVED COMPOUNDS |
EP2314295B1 (en) * | 2005-07-29 | 2015-01-28 | Resverlogix, Inc | Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices |
EP1944301A4 (en) | 2005-10-27 | 2012-01-04 | Msd Kk | Novel benzoxathiin derivative |
US20070197509A1 (en) | 2005-12-21 | 2007-08-23 | Painceptor Pharma Corporation | Compositions and methods for modulating gated ion channels |
CA2621134C (en) | 2006-05-12 | 2011-07-26 | Pharmathen S.A. | Pharmaceutical formulation containing an hmg-coa reductase inhibitor and method for the preparation thereof |
US20080085911A1 (en) | 2006-10-10 | 2008-04-10 | Reliant Pharmaceuticals, Inc. | Statin and omega-3 fatty acids for reduction of apo-b levels |
US20100249161A1 (en) | 2006-11-15 | 2010-09-30 | Anders Klarskov Petersen | 2- ( 2 -hydroxyphenyl) -quinazolin-4-ones useful for treating obesity and diabetes |
CA2672373C (en) | 2006-12-19 | 2011-08-30 | Pfizer Products Inc. | Nicotinamide derivatives as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases |
ES2308916B1 (en) | 2007-03-22 | 2009-10-29 | Consejo Superior De Investigaciones Cientificas | DUAL INHIBITOR COMPOUND OF PDE7 AND / OR PDE4 ENZYMES, PHARMACEUTICAL COMPOSITIONS AND THEIR APPLICATIONS. |
EP2005941A3 (en) | 2007-06-01 | 2009-04-01 | Henkel AG & Co. KGaA | Cellular rejuvenation compounds |
WO2008152471A1 (en) | 2007-06-12 | 2008-12-18 | Coley Pharmaceutical Group, Inc. | Quinazoline derivative useful as toll-like receptor antagonist |
EP2170842A1 (en) | 2007-06-21 | 2010-04-07 | Irm, Llc | Protein kinase inhibitors and methods for using thereof |
EP2239264A4 (en) | 2007-12-28 | 2012-01-11 | Mitsubishi Tanabe Pharma Corp | Antitumor agent |
KR101629356B1 (en) | 2008-06-26 | 2016-06-13 | 리스버로직스 코퍼레이션 | Methods of preparing quinazolinone derivatives |
JP2011529932A (en) | 2008-08-05 | 2011-12-15 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Substituted naphthyridine and its use as a medicament |
US20100093636A1 (en) | 2008-10-06 | 2010-04-15 | Carolus Therapeutics, Inc. | Methods of treating inflammation |
US8569288B2 (en) | 2008-10-30 | 2013-10-29 | Circomed Llc | Thienotriazolodiazepine derivatives active on apo A |
WO2010056910A2 (en) | 2008-11-12 | 2010-05-20 | Carolus Therapeutics, Inc. | Methods of treating cardiovascular disorders |
CA2747417C (en) | 2009-01-08 | 2017-01-03 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular disease |
CA2752443A1 (en) | 2009-03-06 | 2010-09-10 | F. Hoffmann-La Roche Ag | Heterocyclic antiviral compounds |
US9238640B2 (en) | 2009-03-18 | 2016-01-19 | Resverlogix Corp. | Anti-inflammatory agents |
BRPI1014956B8 (en) | 2009-04-22 | 2021-05-25 | Resverlogix Corp | anti-inflammatory agents |
AU2010241567B2 (en) | 2009-04-29 | 2013-10-31 | Amarin Pharmaceuticals Ireland Limited | Pharmaceutical compositions comprising EPA and a cardiovascular agent and methods of using the same |
ES2353093B1 (en) | 2009-05-20 | 2012-01-03 | Consejo Superior De Investigaciones Científicas (Csic) | USE OF DERIVATIVES OF QUINAZOLINAS AND ITS PHARMACEUTICAL COMPOSITIONS IN NEURODEGENERATIVE DISEASES. |
GB201007286D0 (en) | 2010-04-30 | 2010-06-16 | Astex Therapeutics Ltd | New compounds |
DE102010048800A1 (en) | 2010-10-20 | 2012-05-10 | Merck Patent Gmbh | quinoxaline |
GB201018147D0 (en) | 2010-10-27 | 2010-12-08 | Glaxo Group Ltd | Method of treatment |
AR084070A1 (en) | 2010-12-02 | 2013-04-17 | Constellation Pharmaceuticals Inc | BROMODOMINIUM INHIBITORS AND USES OF THE SAME |
EP2675445A1 (en) | 2011-02-16 | 2013-12-25 | Pivotal Therapeutics, Inc. | Statin and omega 3 fatty acids (epa, dha and dpa) for use in cardiovascular diseases |
US9328117B2 (en) | 2011-06-17 | 2016-05-03 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
EP2748169A4 (en) | 2011-09-30 | 2015-06-17 | Kineta Inc | Anti-viral compounds |
JP5992049B2 (en) | 2011-11-01 | 2016-09-14 | レスバーロジックス コーポレイション | Oral immediate release formulations for substituted quinazolinones |
US20130281397A1 (en) | 2012-04-19 | 2013-10-24 | Rvx Therapeutics Inc. | Treatment of diseases by epigenetic regulation |
US20130281399A1 (en) | 2012-04-19 | 2013-10-24 | Rvx Therapeutics Inc. | Treatment of diseases by epigenetic regulation |
US20130281398A1 (en) | 2012-04-19 | 2013-10-24 | Rvx Therapeutics Inc. | Treatment of diseases by epigenetic regulation |
US9624244B2 (en) | 2012-06-06 | 2017-04-18 | Constellation Pharmaceuticals, Inc. | Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof |
BR112015008171B1 (en) | 2012-10-15 | 2021-01-19 | Albemarle Corporation | processes for the synthesis of 2-amino-4,6-dimethoxybenzamide and other benzamide compounds |
PT2906531T (en) | 2012-10-15 | 2018-02-06 | Resverlogix Corp | Compounds useful in the synthesis of benzamide compounds |
WO2014080290A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Cyclic amines as bromodomain inhibitors |
WO2014096965A2 (en) | 2012-12-21 | 2014-06-26 | Rvx Therapeutics Inc. | Novel heterocyclic compounds as bromodomain inhibitors |
EP2943213A4 (en) | 2013-01-08 | 2016-08-17 | Jerome Schentag | Activation of the endogenous ileal brake hormone pathway for organ regeneration and related compositions, methods of treatment, diagnostics, and regulatory systems |
WO2014134583A2 (en) | 2013-02-28 | 2014-09-04 | Washington University | Methods of treatment of human cytomegalovirus infection and diseases with bromodomain inhibitors |
EP2970312B1 (en) | 2013-03-11 | 2017-11-15 | The Regents of The University of Michigan | Bet bromodomain inhibitors and therapeutic methods using the same |
US9695179B2 (en) | 2013-03-14 | 2017-07-04 | Convergene Llc | Methods and compositions for inhibition of bromodomain-containing proteins |
EP2978859B1 (en) | 2013-03-27 | 2018-06-27 | F.Hoffmann-La Roche Ag | Genetic markers for predicting responsiveness to therapy |
TWI530499B (en) | 2013-03-28 | 2016-04-21 | 吉李德科學股份有限公司 | Benzimidazolone derivatives as bromodomain inhibitors |
CA2921985A1 (en) | 2013-08-21 | 2015-02-26 | Resverlogix Corp. | Compositions and therapeutic methods for accelerated plaque regression |
EP3035933A4 (en) | 2013-08-21 | 2017-04-26 | Resverlogix Corp. | Compositions and therapeutic methods for accelerated plaque regression |
US9814728B2 (en) | 2013-09-20 | 2017-11-14 | Saint Louis University | Inhibition of DUX4 expression using bromodomain and extra-terminal domain protein inhibitors (BETi) |
WO2015112898A1 (en) | 2014-01-23 | 2015-07-30 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Icariin derivatives |
MX2017000582A (en) | 2014-07-30 | 2017-04-27 | Hoffmann La Roche | Genetic markers for predicting responsiveness to therapy with hdl-raising or hdl mimicking agent. |
WO2016123054A2 (en) | 2015-01-26 | 2016-08-04 | The University Of North Carolina At Chapel Hill | Kinase drug combinations and methods of use thereof |
US20180104232A1 (en) | 2015-03-12 | 2018-04-19 | The University Of Chicago | Methods for determining prognosis for breast cancer patients |
JP6903585B2 (en) | 2015-03-13 | 2021-07-14 | レスバーロジックス コーポレイション | Compositions and Therapeutic Methods for the Treatment of Complement-Related Diseases |
RU2017142394A (en) | 2015-05-08 | 2019-06-10 | Президент Энд Феллоус Оф Гарвард Колледж | TARGET SELECTION OF PATIENTS FOR TREATMENT BY DERIVATIVES OF CORTISTATIN |
CA2986441A1 (en) | 2015-06-12 | 2016-12-15 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
CN106265679A (en) | 2015-06-28 | 2017-01-04 | 复旦大学 | Bromine domain protein inhibitor is preparing the purposes that anti-HIV-1 is hidden in medicine |
WO2017015027A1 (en) | 2015-07-20 | 2017-01-26 | Mayo Foundation For Medical Education And Research | Methods and materials for treating cancer |
WO2017037567A1 (en) | 2015-09-03 | 2017-03-09 | Pfizer Inc. | Regulators of frataxin |
US9896663B2 (en) | 2016-03-11 | 2018-02-20 | Peter Maccallum Cancer Institute | Leukaemia stem cell line, its method of production and uses thereof |
WO2017192691A1 (en) | 2016-05-03 | 2017-11-09 | Biogen Ma Inc. | Cell culture containing bromodomain inhibitors |
CN106176753A (en) | 2016-07-15 | 2016-12-07 | 南方医科大学 | RVX 208 is as the application of HIV 1 latent infection inversion agent |
EP3553058A1 (en) | 2016-12-09 | 2019-10-16 | Crystal Pharmaceutical (Suzhou) Co., Ltd. | Crystal form of bromodomain protein inhibitor drug, preparation method and use thereof |
-
2007
- 2007-02-01 MX MX2009008099A patent/MX2009008099A/en active IP Right Grant
- 2007-02-01 WO PCT/CA2007/000146 patent/WO2008092231A1/en active Application Filing
- 2007-02-01 KR KR1020097017716A patent/KR101444489B1/en active IP Right Grant
- 2007-02-01 CN CN2007800523498A patent/CN101641339B/en active Active
- 2007-02-01 JP JP2009547497A patent/JP5236664B2/en active Active
- 2007-02-01 AU AU2007345526A patent/AU2007345526B2/en active Active
- 2007-02-01 ES ES07710597.1T patent/ES2454966T3/en active Active
- 2007-02-01 SI SI200731438T patent/SI2118074T1/en unknown
- 2007-02-01 NZ NZ579355A patent/NZ579355A/en unknown
- 2007-02-01 PT PT77105971T patent/PT2118074E/en unknown
- 2007-02-01 US US11/670,238 patent/US8053440B2/en active Active
- 2007-02-01 CA CA2676984A patent/CA2676984C/en active Active
- 2007-02-01 EP EP07710597.1A patent/EP2118074B1/en active Active
- 2007-02-01 PL PL07710597T patent/PL2118074T3/en unknown
- 2007-02-01 DK DK07710597.1T patent/DK2118074T3/en active
-
2010
- 2010-03-22 HK HK10102977.1A patent/HK1136283A1/en unknown
-
2011
- 2011-09-23 US US13/243,776 patent/US8889698B2/en active Active
-
2014
- 2014-03-21 CY CY20141100220T patent/CY1115236T1/en unknown
- 2014-10-14 US US14/513,281 patent/US9199990B2/en active Active
-
2015
- 2015-10-26 US US14/922,645 patent/US20160106750A1/en not_active Abandoned
-
2017
- 2017-09-20 US US15/710,200 patent/US10532054B2/en active Active
-
2019
- 2019-12-09 US US16/707,559 patent/US20200352946A1/en not_active Abandoned
-
2021
- 2021-06-01 US US17/335,960 patent/US20210361656A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9199990B2 (en) * | 2007-02-01 | 2015-12-01 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular diseases |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10532054B2 (en) | 2007-02-01 | 2020-01-14 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular diseases |
US10131640B2 (en) | 2009-03-18 | 2018-11-20 | Resverlogix Corp. | Anti-inflammatory agents |
US10882828B2 (en) | 2009-03-18 | 2021-01-05 | Resverlogix Corp. | Anti-inflammatory agents |
US11407719B2 (en) | 2009-03-18 | 2022-08-09 | Resverlogix Corp. | Anti-inflammatory agents |
US9757368B2 (en) | 2009-04-22 | 2017-09-12 | Resverlogix Corp. | Anti-inflammatory agents |
US10111885B2 (en) | 2015-03-13 | 2018-10-30 | Resverlogix Corp. | Compositions and therapeutic methods for the treatment of complement-associated diseases |
US10772894B2 (en) | 2015-03-13 | 2020-09-15 | Resverlogix Corp. | Compositions and therapeutic methods for the treatment of complement-associated diseases |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210361656A1 (en) | Compounds for the prevention and treatment of cardiovascular diseases | |
US8952021B2 (en) | Compounds for the prevention and treatment of cardiovascular disease | |
US20130281397A1 (en) | Treatment of diseases by epigenetic regulation | |
US20120258975A1 (en) | Potent Small Molecule Inhibitors of Autophagy, and Methods of Use Thereof | |
JP2013500255A5 (en) | ||
US20130281398A1 (en) | Treatment of diseases by epigenetic regulation | |
CN103319408A (en) | Compounds for preventing and treating cardiovascular diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE |