CZ20033558A3 - Triamid-substituované indoly, benzofurany a benzothiofeny jako inhibitory mikrozomálního proteinu přenášejícího triglyceridy (MTP) a/nebo sekrece apolipoproteinu B (APO B) - Google Patents
Triamid-substituované indoly, benzofurany a benzothiofeny jako inhibitory mikrozomálního proteinu přenášejícího triglyceridy (MTP) a/nebo sekrece apolipoproteinu B (APO B) Download PDFInfo
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- CZ20033558A3 CZ20033558A3 CZ20033558A CZ20033558A CZ20033558A3 CZ 20033558 A3 CZ20033558 A3 CZ 20033558A3 CZ 20033558 A CZ20033558 A CZ 20033558A CZ 20033558 A CZ20033558 A CZ 20033558A CZ 20033558 A3 CZ20033558 A3 CZ 20033558A3
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- Prior art keywords
- alkyl
- group
- carbon atoms
- moiety
- methyl
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- 239000003112 inhibitor Substances 0.000 title abstract description 44
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 title description 27
- 108010038232 microsomal triglyceride transfer protein Proteins 0.000 title description 24
- 150000002475 indoles Chemical class 0.000 title description 9
- 230000028327 secretion Effects 0.000 title description 9
- 150000001907 coumarones Chemical class 0.000 title description 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title description 3
- 101710095342 Apolipoprotein B Proteins 0.000 title 1
- 102100040202 Apolipoprotein B-100 Human genes 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 475
- 238000000034 method Methods 0.000 claims abstract description 175
- 230000008569 process Effects 0.000 claims abstract description 75
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 208000008589 Obesity Diseases 0.000 claims abstract description 14
- 235000020824 obesity Nutrition 0.000 claims abstract description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 217
- 125000000217 alkyl group Chemical group 0.000 claims description 181
- -1 amino, hydroxy Chemical group 0.000 claims description 176
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 78
- 125000001424 substituent group Chemical group 0.000 claims description 78
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 70
- 150000003839 salts Chemical class 0.000 claims description 68
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 229910052739 hydrogen Inorganic materials 0.000 claims description 64
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 64
- 239000001257 hydrogen Substances 0.000 claims description 63
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 125000004076 pyridyl group Chemical group 0.000 claims description 35
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 241001465754 Metazoa Species 0.000 claims description 31
- 125000005843 halogen group Chemical group 0.000 claims description 31
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 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 19
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000002950 monocyclic group Chemical group 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 14
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 12
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 150000001299 aldehydes Chemical class 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
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 8
- 239000004305 biphenyl Substances 0.000 claims description 8
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 8
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 7
- DYMRYCZRMAHYKE-UHFFFAOYSA-N n-diazonitramide Chemical compound [O-][N+](=O)N=[N+]=[N-] DYMRYCZRMAHYKE-UHFFFAOYSA-N 0.000 claims description 7
- 125000004952 trihaloalkoxy group Chemical group 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 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
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
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- 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 3
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 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 description 2
- KXRBCMNXDPKVMV-UHFFFAOYSA-N 3-chloro-1-methyl-n-[2-oxo-1-phenyl-2-(propylamino)ethyl]-5-[(2-phenylbenzoyl)amino]indole-2-carboxamide Chemical compound C=1C=CC=CC=1C(C(=O)NCCC)NC(=O)C(N(C1=CC=2)C)=C(Cl)C1=CC=2NC(=O)C1=CC=CC=C1C1=CC=CC=C1 KXRBCMNXDPKVMV-UHFFFAOYSA-N 0.000 claims description 2
- BPXYEYJNCXITEY-UHFFFAOYSA-N diazonio(trifluoromethoxy)azanide Chemical compound FC(F)(F)ON=[N+]=[N-] BPXYEYJNCXITEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052701 rubidium Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 11
- 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 1
- UWMUBZILFCWRDQ-UHFFFAOYSA-N 3-chloro-1-methyl-n-[2-oxo-1-phenyl-2-(propylamino)ethyl]-5-[[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]indole-2-carboxamide Chemical compound C=1C=CC=CC=1C(C(=O)NCCC)NC(=O)C(N(C1=CC=2)C)=C(Cl)C1=CC=2NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 UWMUBZILFCWRDQ-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
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- 102000018616 Apolipoproteins B Human genes 0.000 abstract description 3
- 108010027006 Apolipoproteins B Proteins 0.000 abstract description 3
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- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Child & Adolescent Psychology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| US30164401P | 2001-06-28 | 2001-06-28 |
Publications (1)
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| CZ20033558A3 true CZ20033558A3 (cs) | 2004-04-14 |
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Family Applications (1)
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| CZ20033558A CZ20033558A3 (cs) | 2001-06-28 | 2002-05-24 | Triamid-substituované indoly, benzofurany a benzothiofeny jako inhibitory mikrozomálního proteinu přenášejícího triglyceridy (MTP) a/nebo sekrece apolipoproteinu B (APO B) |
Country Status (46)
Families Citing this family (61)
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