SK132899A3 - NICOTINAMIDE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONì (54) COMPRISING THEM - Google Patents
NICOTINAMIDE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONì (54) COMPRISING THEM Download PDFInfo
- Publication number
- SK132899A3 SK132899A3 SK1328-99A SK132899A SK132899A3 SK 132899 A3 SK132899 A3 SK 132899A3 SK 132899 A SK132899 A SK 132899A SK 132899 A3 SK132899 A3 SK 132899A3
- Authority
- SK
- Slovakia
- Prior art keywords
- group
- carbon atoms
- alkyl
- hydroxy
- nicotinamide
- Prior art date
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- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical class NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 271
- 238000004260 weight control Methods 0.000 claims abstract description 19
- 208000026935 allergic disease Diseases 0.000 claims abstract description 18
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 208000023504 respiratory system disease Diseases 0.000 claims abstract description 17
- 208000006673 asthma Diseases 0.000 claims abstract description 12
- 230000002685 pulmonary effect Effects 0.000 claims abstract description 12
- 230000000241 respiratory effect Effects 0.000 claims abstract description 12
- 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 11
- 206010006895 Cachexia Diseases 0.000 claims abstract description 10
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 10
- 208000011231 Crohn disease Diseases 0.000 claims abstract description 10
- 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 10
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 10
- 206010020751 Hypersensitivity Diseases 0.000 claims abstract description 10
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 10
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 10
- 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract description 10
- 230000000172 allergic effect Effects 0.000 claims abstract description 10
- 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 10
- 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 10
- 230000004761 fibrosis Effects 0.000 claims abstract description 10
- 230000009610 hypersensitivity Effects 0.000 claims abstract description 10
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 10
- 230000035939 shock Effects 0.000 claims abstract description 10
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 10
- 230000002917 arthritic effect Effects 0.000 claims abstract description 9
- 208000030507 AIDS Diseases 0.000 claims abstract description 8
- 208000005314 Multi-Infarct Dementia Diseases 0.000 claims abstract description 5
- 201000004810 Vascular dementia Diseases 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 202
- -1 cycloalkanone Chemical group 0.000 claims description 181
- 125000000217 alkyl group Chemical group 0.000 claims description 129
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 102
- 229910052760 oxygen Inorganic materials 0.000 claims description 102
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 89
- 239000001301 oxygen Substances 0.000 claims description 89
- 229920006395 saturated elastomer Polymers 0.000 claims description 85
- 229910052739 hydrogen Inorganic materials 0.000 claims description 74
- 125000004122 cyclic group Chemical group 0.000 claims description 69
- 125000003118 aryl group Chemical group 0.000 claims description 65
- 239000001257 hydrogen Substances 0.000 claims description 63
- 229910052757 nitrogen Inorganic materials 0.000 claims description 59
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 58
- 229910052717 sulfur Inorganic materials 0.000 claims description 58
- 229910052736 halogen Inorganic materials 0.000 claims description 56
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 52
- 125000005842 heteroatom Chemical group 0.000 claims description 52
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 50
- 239000011593 sulfur Substances 0.000 claims description 50
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 41
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 33
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 125000005843 halogen group Chemical group 0.000 claims description 31
- 150000002431 hydrogen Chemical group 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 30
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 108010044467 Isoenzymes Proteins 0.000 claims description 28
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000004429 atom Chemical group 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 19
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims description 18
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 16
- 210000003979 eosinophil Anatomy 0.000 claims description 16
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 15
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 15
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 13
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 11
- 230000004913 activation Effects 0.000 claims description 11
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 125000004423 acyloxy group Chemical group 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 125000002619 bicyclic group Chemical group 0.000 claims description 10
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 208000025747 Rheumatic disease Diseases 0.000 claims description 9
- 125000004442 acylamino group Chemical group 0.000 claims description 9
- 241000282412 Homo Species 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Chemical group 0.000 claims description 4
- 229910052731 fluorine Chemical group 0.000 claims description 4
- MRPUOLUWSANGMT-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-6-yloxy)-n-[[4-(1-hydroxyethyl)cyclohexyl]methyl]pyridine-3-carboxamide Chemical compound C1CC(C(O)C)CCC1CNC(=O)C1=CC=CN=C1OC1=CC=C(OCCO2)C2=C1 MRPUOLUWSANGMT-UHFFFAOYSA-N 0.000 claims description 3
- XKCFCJYOYYBKJK-UHFFFAOYSA-N 2-(4-fluorophenoxy)-n-[[4-(3-hydroxyazetidin-1-yl)phenyl]methyl]pyridine-3-carboxamide Chemical compound C1C(O)CN1C(C=C1)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=C(F)C=C1 XKCFCJYOYYBKJK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- ZWRMYIPOBGLJIZ-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]-2-(4-fluorophenoxy)pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1OC1=NC=CC=C1C(=O)NCC1=CC=CC=C1Cl ZWRMYIPOBGLJIZ-UHFFFAOYSA-N 0.000 claims description 3
- JJISIDKWPAQXEO-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yloxy)-n-[[4-(1-hydroxyethyl)cyclohexyl]methyl]pyridine-3-carboxamide Chemical compound C1CC(C(O)C)CCC1CNC(=O)C1=CC=CN=C1OC1=CC=C(OCO2)C2=C1 JJISIDKWPAQXEO-UHFFFAOYSA-N 0.000 claims description 2
- UIWGYPGGWDGIHN-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yloxy)-n-[[4-(2-hydroxypropan-2-yl)cyclohexyl]methyl]pyridine-3-carboxamide Chemical compound C1CC(C(C)(O)C)CCC1CNC(=O)C1=CC=CN=C1OC1=CC=C(OCO2)C2=C1 UIWGYPGGWDGIHN-UHFFFAOYSA-N 0.000 claims description 2
- FYORQCRFLAGZCN-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yloxy)-n-[[4-(2-hydroxypropan-2-yl)phenyl]methyl]pyridine-3-carboxamide Chemical compound C1=CC(C(C)(O)C)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=C(OCO2)C2=C1 FYORQCRFLAGZCN-UHFFFAOYSA-N 0.000 claims description 2
- MEWIXEPIWPRGDZ-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-6-yloxy)-n-[[4-(2-hydroxypropan-2-yl)phenyl]methyl]pyridine-3-carboxamide Chemical compound C1=CC(C(C)(O)C)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=C(OCCO2)C2=C1 MEWIXEPIWPRGDZ-UHFFFAOYSA-N 0.000 claims description 2
- IJVWZYOOLAQYLO-UHFFFAOYSA-N 2-(3-acetylphenoxy)-n-[(1-hydroxy-2,3-dihydro-1h-inden-5-yl)methyl]pyridine-3-carboxamide Chemical compound CC(=O)C1=CC=CC(OC=2C(=CC=CN=2)C(=O)NCC=2C=C3CCC(O)C3=CC=2)=C1 IJVWZYOOLAQYLO-UHFFFAOYSA-N 0.000 claims description 2
- SDJFKQSWVOQKLG-UHFFFAOYSA-N 2-(3-acetylphenoxy)-n-[[2-chloro-4-(2-hydroxypropan-2-yl)phenyl]methyl]pyridine-3-carboxamide Chemical compound CC(=O)C1=CC=CC(OC=2C(=CC=CN=2)C(=O)NCC=2C(=CC(=CC=2)C(C)(C)O)Cl)=C1 SDJFKQSWVOQKLG-UHFFFAOYSA-N 0.000 claims description 2
- GRFBSCUJXIXUFR-UHFFFAOYSA-N 2-(3-acetylphenoxy)-n-[[4-(1-hydroxyethyl)cyclohexyl]methyl]pyridine-3-carboxamide Chemical compound C1CC(C(O)C)CCC1CNC(=O)C1=CC=CN=C1OC1=CC=CC(C(C)=O)=C1 GRFBSCUJXIXUFR-UHFFFAOYSA-N 0.000 claims description 2
- CSKGCQHLDROTGB-UHFFFAOYSA-N 2-(3-acetylphenoxy)-n-[[4-(2-hydroxypropan-2-yl)cyclohexyl]methyl]pyridine-3-carboxamide Chemical compound CC(=O)C1=CC=CC(OC=2C(=CC=CN=2)C(=O)NCC2CCC(CC2)C(C)(C)O)=C1 CSKGCQHLDROTGB-UHFFFAOYSA-N 0.000 claims description 2
- QEBOSQKDNQAPSQ-UHFFFAOYSA-N 2-(3-cyano-4-fluorophenoxy)-n-[[4-(2-hydroxypropan-2-yl)phenyl]methyl]pyridine-3-carboxamide Chemical compound C1=CC(C(C)(O)C)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=C(F)C(C#N)=C1 QEBOSQKDNQAPSQ-UHFFFAOYSA-N 0.000 claims description 2
- WMGMDHGSVGUHMD-UHFFFAOYSA-N 2-(3-cyanophenoxy)-n-[[4-(2-hydroxypropan-2-yl)cyclohexyl]methyl]pyridine-3-carboxamide Chemical compound C1CC(C(C)(O)C)CCC1CNC(=O)C1=CC=CN=C1OC1=CC=CC(C#N)=C1 WMGMDHGSVGUHMD-UHFFFAOYSA-N 0.000 claims description 2
- LRQBXHMVEXEFBO-UHFFFAOYSA-N 2-(4-fluorophenoxy)-n-(1-thiophen-2-ylethyl)pyridine-3-carboxamide Chemical compound C=1C=CSC=1C(C)NC(=O)C1=CC=CN=C1OC1=CC=C(F)C=C1 LRQBXHMVEXEFBO-UHFFFAOYSA-N 0.000 claims description 2
- RQACOXGAQDOEFC-UHFFFAOYSA-N 2-(4-fluorophenoxy)-n-[[4-(2-hydroxypropan-2-yl)cyclohexyl]methyl]pyridine-3-carboxamide Chemical compound C1CC(C(C)(O)C)CCC1CNC(=O)C1=CC=CN=C1OC1=CC=C(F)C=C1 RQACOXGAQDOEFC-UHFFFAOYSA-N 0.000 claims description 2
- 206010003645 Atopy Diseases 0.000 claims description 2
- 125000005055 alkyl alkoxy group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- PCBVKLULGPFYCM-UHFFFAOYSA-N n-[2-(3-acetylphenoxy)pyridin-3-yl]-2-[4-(2-hydroxypropan-2-yl)phenyl]acetamide Chemical compound CC(=O)C1=CC=CC(OC=2C(=CC=CN=2)NC(=O)CC=2C=CC(=CC=2)C(C)(C)O)=C1 PCBVKLULGPFYCM-UHFFFAOYSA-N 0.000 claims description 2
- JHFCHASTKFFTRT-UHFFFAOYSA-N n-[[2-chloro-4-(2-hydroxypropan-2-yl)phenyl]methyl]-2-(3,4-difluorophenoxy)pyridine-3-carboxamide Chemical compound ClC1=CC(C(C)(O)C)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=C(F)C(F)=C1 JHFCHASTKFFTRT-UHFFFAOYSA-N 0.000 claims description 2
- AQIVOZRZMGARTM-UHFFFAOYSA-N n-[[2-chloro-4-(2-hydroxypropan-2-yl)phenyl]methyl]-2-(3-cyano-4-fluorophenoxy)pyridine-3-carboxamide Chemical compound ClC1=CC(C(C)(O)C)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=C(F)C(C#N)=C1 AQIVOZRZMGARTM-UHFFFAOYSA-N 0.000 claims description 2
- APJBPKSPHXOFOJ-UHFFFAOYSA-N n-[[4-(2-hydroxypropan-2-yl)phenyl]methyl]-2-(3-nitrophenoxy)pyridine-3-carboxamide Chemical compound C1=CC(C(C)(O)C)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=CC([N+]([O-])=O)=C1 APJBPKSPHXOFOJ-UHFFFAOYSA-N 0.000 claims description 2
- JODSIOLAEUBBQF-UHFFFAOYSA-N n-[[4-(2-hydroxypropan-2-yl)phenyl]methyl]-2-[(3-methyl-1,2-benzoxazol-7-yl)oxy]pyridine-3-carboxamide Chemical compound C1=CC=C2C(C)=NOC2=C1OC1=NC=CC=C1C(=O)NCC1=CC=C(C(C)(C)O)C=C1 JODSIOLAEUBBQF-UHFFFAOYSA-N 0.000 claims description 2
- QHJINCSSHWJECS-UHFFFAOYSA-N n-[[4-(2-hydroxypropan-2-yl)phenyl]methyl]-2-[(4-oxo-2,3-dihydrochromen-6-yl)oxy]pyridine-3-carboxamide Chemical compound C1=CC(C(C)(O)C)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=C(OCCC2=O)C2=C1 QHJINCSSHWJECS-UHFFFAOYSA-N 0.000 claims description 2
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 claims 4
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 claims 4
- 210000003169 central nervous system Anatomy 0.000 claims 4
- WYPMCVBYRMZKMQ-UHFFFAOYSA-N 2-(3,4-difluorophenoxy)-n-[[4-(2-hydroxypropan-2-yl)phenyl]methyl]pyridine-3-carboxamide Chemical compound C1=CC(C(C)(O)C)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=C(F)C(F)=C1 WYPMCVBYRMZKMQ-UHFFFAOYSA-N 0.000 claims 1
- ZLKLSAJFFHNRIS-UHFFFAOYSA-N 2-(3-acetylphenoxy)-n-[[4-(2-hydroxypropan-2-yl)phenyl]methyl]pyridine-3-carboxamide Chemical compound CC(=O)C1=CC=CC(OC=2C(=CC=CN=2)C(=O)NCC=2C=CC(=CC=2)C(C)(C)O)=C1 ZLKLSAJFFHNRIS-UHFFFAOYSA-N 0.000 claims 1
- JBDAGDAECDLBCE-UHFFFAOYSA-N 2-(3-cyano-4-fluorophenoxy)-n-[[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]methyl]pyridine-3-carboxamide Chemical compound FC1=CC(C(C)(O)C)=CC=C1CNC(=O)C1=CC=CN=C1OC1=CC=C(F)C(C#N)=C1 JBDAGDAECDLBCE-UHFFFAOYSA-N 0.000 claims 1
- GPEKPAYXUQHZHH-UHFFFAOYSA-N 2-[3-(N-hydroxy-C-methylcarbonimidoyl)phenoxy]-N-[[4-(2-hydroxypropan-2-yl)phenyl]methyl]pyridine-3-carboxamide Chemical compound ON=C(C)C1=CC=CC(OC=2C(=CC=CN=2)C(=O)NCC=2C=CC(=CC=2)C(C)(C)O)=C1 GPEKPAYXUQHZHH-UHFFFAOYSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 claims 1
- 125000001769 aryl amino group Chemical group 0.000 claims 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical group COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims 1
- NYAZXHASVIWIRJ-UHFFFAOYSA-N nitridosulfidocarbon(.) Chemical group [S]C#N NYAZXHASVIWIRJ-UHFFFAOYSA-N 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 208000015114 central nervous system disease Diseases 0.000 abstract description 6
- 230000002757 inflammatory effect Effects 0.000 abstract description 3
- 208000010668 atopic eczema Diseases 0.000 abstract description 2
- 230000006583 body weight regulation Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 354
- 238000002360 preparation method Methods 0.000 description 340
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 232
- 239000000203 mixture Substances 0.000 description 217
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 178
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 160
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 156
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 155
- 239000000243 solution Substances 0.000 description 149
- 235000019439 ethyl acetate Nutrition 0.000 description 121
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 116
- 238000004458 analytical method Methods 0.000 description 116
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 108
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 108
- 239000007787 solid Substances 0.000 description 106
- 239000003921 oil Substances 0.000 description 96
- 235000019198 oils Nutrition 0.000 description 96
- 238000005481 NMR spectroscopy Methods 0.000 description 81
- 238000006243 chemical reaction Methods 0.000 description 76
- 239000012267 brine Substances 0.000 description 75
- 239000000284 extract Substances 0.000 description 75
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 75
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 74
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 57
- 238000002844 melting Methods 0.000 description 54
- 230000008018 melting Effects 0.000 description 54
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 54
- 239000000741 silica gel Substances 0.000 description 48
- 229910002027 silica gel Inorganic materials 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- 238000003818 flash chromatography Methods 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 238000010992 reflux Methods 0.000 description 38
- 230000035484 reaction time Effects 0.000 description 34
- 239000011734 sodium Substances 0.000 description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- 239000003880 polar aprotic solvent Substances 0.000 description 23
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- XYUXBHLZHBEDAG-UHFFFAOYSA-N tert-butyl 3-[2-(4-fluorophenoxy)pyridin-3-yl]-3-oxo-2-[(2,4,6-trifluorophenyl)methyl]propanoate Chemical compound C=1C=CN=C(OC=2C=CC(F)=CC=2)C=1C(=O)C(C(=O)OC(C)(C)C)CC1=C(F)C=C(F)C=C1F XYUXBHLZHBEDAG-UHFFFAOYSA-N 0.000 description 1
- PUEUUPFADPPJIV-UHFFFAOYSA-N tert-butyl 3-[2-(4-fluorophenoxy)pyridin-3-yl]-3-oxo-2-[[4-(trifluoromethoxy)phenyl]methyl]propanoate Chemical compound C=1C=CN=C(OC=2C=CC(F)=CC=2)C=1C(=O)C(C(=O)OC(C)(C)C)CC1=CC=C(OC(F)(F)F)C=C1 PUEUUPFADPPJIV-UHFFFAOYSA-N 0.000 description 1
- ZHMALLVTEDIEBC-UHFFFAOYSA-N tert-butyl 3-[2-(4-fluorophenoxy)pyridin-3-yl]-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]propanoate Chemical compound C=1C=CN=C(OC=2C=CC(F)=CC=2)C=1C(=O)C(C(=O)OC(C)(C)C)CC1=CC=C(C(F)(F)F)C=C1 ZHMALLVTEDIEBC-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000005306 thianaphthenyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
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- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
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- 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
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- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4340397P | 1997-04-04 | 1997-04-04 | |
| PCT/IB1998/000315 WO1998045268A1 (en) | 1997-04-04 | 1998-03-10 | Nicotinamide derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK132899A3 true SK132899A3 (en) | 2000-09-12 |
Family
ID=21927000
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK1328-99A SK132899A3 (en) | 1997-04-04 | 1998-03-10 | NICOTINAMIDE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONì (54) COMPRISING THEM |
Country Status (37)
| Country | Link |
|---|---|
| US (1) | US6380218B1 (is) |
| EP (1) | EP0971894A1 (is) |
| JP (2) | JP2000510481A (is) |
| KR (1) | KR20010005954A (is) |
| CN (1) | CN1254335A (is) |
| AP (1) | AP1388A (is) |
| AR (1) | AR012574A1 (is) |
| AU (1) | AU738037B2 (is) |
| BG (1) | BG64356B1 (is) |
| BR (1) | BR9810733A (is) |
| CA (1) | CA2285548C (is) |
| CO (1) | CO4950625A1 (is) |
| DZ (1) | DZ2457A1 (is) |
| EA (1) | EA003528B1 (is) |
| GT (1) | GT199800058A (is) |
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