ZA200307818B - Triamide-substituted indoles, benzofuranes and benzothiophenes as inhibitors of microsomal triglyceride transfer protein (MTP) and/or apolipoprotein B (ApoB) secretion. - Google Patents

Info

Publication number

ZA200307818B

ZA200307818B ZA200307818A ZA200307818A ZA200307818B ZA 200307818 B ZA200307818 B ZA 200307818B ZA 200307818 A ZA200307818 A ZA 200307818A ZA 200307818 A ZA200307818 A ZA 200307818A ZA 200307818 B ZA200307818 B ZA 200307818B

Authority

ZA

South Africa

Prior art keywords

alkyl

independently

methyl

phenyl

trifluoromethyl

Prior art date

2001-06-28

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• 239000003112 inhibitor Substances 0.000 title description 40
• 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 title description 23
• 108010038232 microsomal triglyceride transfer protein Proteins 0.000 title description 23
• 230000028327 secretion Effects 0.000 title description 9
• 150000002475 indoles Chemical class 0.000 title description 8
• 101710095342 Apolipoprotein B Proteins 0.000 title description 4
• 102100040202 Apolipoprotein B-100 Human genes 0.000 title description 4
• FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title description 2
• IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical class C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 348
• 125000000217 alkyl group Chemical group 0.000 claims description 244
• 238000000034 method Methods 0.000 claims description 126
• -1 nitro, azido, amino, hydroxy Chemical group 0.000 claims description 112
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 71
• 150000003839 salts Chemical class 0.000 claims description 69
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 61
• 125000003545 alkoxy group Chemical group 0.000 claims description 56
• 229910052792 caesium Inorganic materials 0.000 claims description 56
• 230000008569 process Effects 0.000 claims description 56
• 125000005843 halogen group Chemical group 0.000 claims description 53
• 150000001408 amides Chemical class 0.000 claims description 46
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 45
• 125000004076 pyridyl group Chemical group 0.000 claims description 34
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
• 241001465754 Metazoa Species 0.000 claims description 32
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 31
• 125000001475 halogen functional group Chemical group 0.000 claims description 31
• 229910052757 nitrogen Inorganic materials 0.000 claims description 28
• 229910052799 carbon Inorganic materials 0.000 claims description 27
• 125000000623 heterocyclic group Chemical group 0.000 claims description 26
• 125000001424 substituent group Chemical group 0.000 claims description 23
• 229910052684 Cerium Inorganic materials 0.000 claims description 22
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
• 125000003342 alkenyl group Chemical group 0.000 claims description 21
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
• 125000001072 heteroaryl group Chemical group 0.000 claims description 18
• 238000004519 manufacturing process Methods 0.000 claims description 18
• 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 18
• 229910052760 oxygen Inorganic materials 0.000 claims description 18
• 125000000304 alkynyl group Chemical group 0.000 claims description 16
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims description 16
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
• 125000002950 monocyclic group Chemical group 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
• 239000003085 diluting agent Substances 0.000 claims description 12
• 208000008589 Obesity Diseases 0.000 claims description 11
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
• 235000020824 obesity Nutrition 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 10
• 229910052717 sulfur Inorganic materials 0.000 claims description 10
• 125000004414 alkyl thio group Chemical group 0.000 claims description 9
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 9
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 9
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
• 125000004434 sulfur atom Chemical group 0.000 claims description 9
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 9
• 125000003118 aryl group Chemical group 0.000 claims description 8
• SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
• 150000001602 bicycloalkyls Chemical group 0.000 claims description 8
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 8
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
• 125000003282 alkyl amino group Chemical group 0.000 claims description 7
• 230000007062 hydrolysis Effects 0.000 claims description 7
• 238000006460 hydrolysis reaction Methods 0.000 claims description 7
• 229910014585 C2-Ce Inorganic materials 0.000 claims description 6
• 125000005907 alkyl ester group Chemical group 0.000 claims description 6
• TUOSYWCFRFNJBS-BHVANESWSA-N dirlotapide Chemical compound O=C([C@@H](NC(=O)C=1N(C2=CC=C(NC(=O)C=3C(=CC=CC=3)C=3C=CC(=CC=3)C(F)(F)F)C=C2C=1)C)C=1C=CC=CC=1)N(C)CC1=CC=CC=C1 TUOSYWCFRFNJBS-BHVANESWSA-N 0.000 claims description 6
• ZEJAIFHFRMTBCN-UHFFFAOYSA-N 3-chloro-1-methyl-5-[[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]indole-2-carboxylic acid Chemical compound C=1C=C2N(C)C(C(O)=O)=C(Cl)C2=CC=1NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 ZEJAIFHFRMTBCN-UHFFFAOYSA-N 0.000 claims description 5
• QCGPNKGBXUZKRV-UHFFFAOYSA-N 3-chloro-1-methyl-5-[(2-phenylbenzoyl)amino]indole-2-carboxylic acid Chemical compound C=1C=C2N(C)C(C(O)=O)=C(Cl)C2=CC=1NC(=O)C1=CC=CC=C1C1=CC=CC=C1 QCGPNKGBXUZKRV-UHFFFAOYSA-N 0.000 claims description 4
• 239000003814 drug Substances 0.000 claims description 4
• 150000002148 esters Chemical class 0.000 claims description 4
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• XDCULFDDDMBXFA-UHFFFAOYSA-N 3-chloro-1-methyl-5-[methyl-[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]indole-2-carboxylic acid Chemical compound C=1C=C2N(C)C(C(O)=O)=C(Cl)C2=CC=1N(C)C(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 XDCULFDDDMBXFA-UHFFFAOYSA-N 0.000 claims description 2
• 229920006063 Lamide® Polymers 0.000 claims description 2
• NKHQHQDDKCCGHL-UHFFFAOYSA-N 1-methyl-n-[2-(methylamino)-2-oxo-1-phenylethyl]-5-[[3-methyl-2-[4-(trifluoromethyl)phenyl]benzoyl]amino]indole-2-carboxamide Chemical compound C=1C=CC=CC=1C(C(=O)NC)NC(=O)C(N(C1=CC=2)C)=CC1=CC=2NC(=O)C1=CC=CC(C)=C1C1=CC=C(C(F)(F)F)C=C1 NKHQHQDDKCCGHL-UHFFFAOYSA-N 0.000 claims 1
• JSWATIQJRDFSBZ-UHFFFAOYSA-N CN(C(C(C1=CC=CC=C1)NC(=O)C=1N(C2=CC=C(C=C2C1)NC(=O)C=1C(=CC=CC1)C1=CC=C(C=C1)C(F)(F)F)C)=O)CC1=CC=C(C(=O)O)C=C1 Chemical compound CN(C(C(C1=CC=CC=C1)NC(=O)C=1N(C2=CC=C(C=C2C1)NC(=O)C=1C(=CC=CC1)C1=CC=C(C=C1)C(F)(F)F)C)=O)CC1=CC=C(C(=O)O)C=C1 JSWATIQJRDFSBZ-UHFFFAOYSA-N 0.000 claims 1
• 241000562429 Jamides Species 0.000 claims 1
• MBMOYBBKGIEYJX-UHFFFAOYSA-N N-(3-chloro-1-methylindol-5-yl)-N-methyl-2-[4-(trifluoromethyl)phenyl]benzamide Chemical compound ClC1=CN(C2=CC=C(C=C12)N(C(=O)C=1C(=CC=CC=1)C1=CC=C(C=C1)C(F)(F)F)C)C MBMOYBBKGIEYJX-UHFFFAOYSA-N 0.000 claims 1
• 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 124
• 239000000203 mixture Substances 0.000 description 122
• 239000000243 solution Substances 0.000 description 92
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
• 239000000047 product Substances 0.000 description 74
• 239000002904 solvent Substances 0.000 description 70
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
• 239000002253 acid Substances 0.000 description 42
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 40
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
• 239000007787 solid Substances 0.000 description 39
• 235000019439 ethyl acetate Nutrition 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• 239000011541 reaction mixture Substances 0.000 description 30
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
• 239000003795 chemical substances by application Substances 0.000 description 27
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
• 150000001412 amines Chemical class 0.000 description 26
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 25
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 24
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 24
• 238000000634 powder X-ray diffraction Methods 0.000 description 22
• 238000012360 testing method Methods 0.000 description 20
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• UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 19
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• 238000001914 filtration Methods 0.000 description 17
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• 229940093499 ethyl acetate Drugs 0.000 description 16
• 238000009472 formulation Methods 0.000 description 16
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• 239000004305 biphenyl Substances 0.000 description 15
• 239000012043 crude product Substances 0.000 description 15
• 206010012601 diabetes mellitus Diseases 0.000 description 15
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• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
• 238000010992 reflux Methods 0.000 description 14
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 13
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