ES2536841T3 - Derivados de 2H-piridazin-3-onas, su preparación y su utilización como inhibidores de la SCD-1 - Google Patents

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Publication number

ES2536841T3

ES2536841T3 ES10742811.2T ES10742811T ES2536841T3 ES 2536841 T3 ES2536841 T3 ES 2536841T3 ES 10742811 T ES10742811 T ES 10742811T ES 2536841 T3 ES2536841 T3 ES 2536841T3

Authority

ES

Spain

Prior art keywords

oxo

methyl

pyridazin

piperidin

phenoxy

Prior art date

2009-08-05

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.)

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• AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 title claims abstract description 47
• 239000003112 inhibitor Substances 0.000 title claims description 13
• AEDMQUAPBVOJNN-UHFFFAOYSA-N [3-[2-[4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl]-1,3-thiazol-5-yl]-1,2,4-oxadiazol-5-yl]methanol Chemical compound O1C(CO)=NC(C=2SC(=NC=2)N2CCC(CC2)OC=2C(=CC=CC=2)C(F)(F)F)=N1 AEDMQUAPBVOJNN-UHFFFAOYSA-N 0.000 title claims 2
• 238000002360 preparation method Methods 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 83
• 239000002585 base Substances 0.000 claims abstract description 73
• -1 nitro, trifluoromethoxy, acetyl Chemical group 0.000 claims abstract description 41
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 26
• 239000001257 hydrogen Substances 0.000 claims abstract description 26
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 26
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 19
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
• 239000000203 mixture Substances 0.000 claims abstract description 18
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 13
• 239000002253 acid Substances 0.000 claims abstract description 11
• 150000003839 salts Chemical class 0.000 claims abstract description 11
• 150000007513 acids Chemical class 0.000 claims abstract description 10
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
• 150000002367 halogens Chemical class 0.000 claims abstract description 10
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
• 239000001301 oxygen Substances 0.000 claims abstract description 8
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims abstract description 6
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 5
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 128
• 238000000034 method Methods 0.000 claims description 84
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 51
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 31
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 23
• JOKPOVVMRWSRAT-UHFFFAOYSA-N 5-[[2-[4-[2-chloro-5-(trifluoromethyl)phenoxy]piperidin-1-yl]-2-oxoethyl]amino]-1h-pyridazin-6-one Chemical compound FC(F)(F)C1=CC=C(Cl)C(OC2CCN(CC2)C(=O)CNC=2C(NN=CC=2)=O)=C1 JOKPOVVMRWSRAT-UHFFFAOYSA-N 0.000 claims description 15
• 238000011282 treatment Methods 0.000 claims description 15
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
• 229910052763 palladium Inorganic materials 0.000 claims description 13
• 229910052801 chlorine Inorganic materials 0.000 claims description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
• GZZDQWNEDXTCDL-UHFFFAOYSA-N 2-[4-[2-chloro-5-(trifluoromethyl)phenoxy]piperidin-1-yl]-n-(2-methyl-3-oxopyridazin-4-yl)-2-oxoacetamide Chemical compound O=C1N(C)N=CC=C1NC(=O)C(=O)N1CCC(OC=2C(=CC=C(C=2)C(F)(F)F)Cl)CC1 GZZDQWNEDXTCDL-UHFFFAOYSA-N 0.000 claims description 10
• 102000004190 Enzymes Human genes 0.000 claims description 10
• 108090000790 Enzymes Proteins 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 9
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 9
• 150000002632 lipids Chemical class 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• NXGURAZHMLZTAV-UHFFFAOYSA-N 2-methyl-4-[[2-oxo-2-[3-[2-(trifluoromethyl)phenoxy]azetidin-1-yl]ethyl]amino]pyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CC(OC=2C(=CC=CC=2)C(F)(F)F)C1 NXGURAZHMLZTAV-UHFFFAOYSA-N 0.000 claims description 8
• JDQCOBZYYGUZBX-UHFFFAOYSA-N 2-methyl-4-[[2-oxo-2-[4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]ethyl]amino]pyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCN(C(=O)C=2C(=CC=CC=2)C(F)(F)F)CC1 JDQCOBZYYGUZBX-UHFFFAOYSA-N 0.000 claims description 8
• YZCBCJMVTZCCPH-UHFFFAOYSA-N 2-methyl-4-[[2-oxo-2-[4-[[2-(trifluoromethyl)anilino]methyl]piperidin-1-yl]ethyl]amino]pyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(CNC=2C(=CC=CC=2)C(F)(F)F)CC1 YZCBCJMVTZCCPH-UHFFFAOYSA-N 0.000 claims description 8
• 230000000694 effects Effects 0.000 claims description 8
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 8
• PKRIRDUCIAMVKD-UHFFFAOYSA-N 2-butyl-4-[[2-[4-(2-chlorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]pyridazin-3-one Chemical compound O=C1N(CCCC)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=CC=2)Cl)CC1 PKRIRDUCIAMVKD-UHFFFAOYSA-N 0.000 claims description 7
• JPFAXYUPWWYMAR-UHFFFAOYSA-N 4-[3-[4-[2-chloro-5-(trifluoromethyl)phenoxy]piperidin-1-yl]-3-oxopropyl]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1CCC(=O)N1CCC(OC=2C(=CC=C(C=2)C(F)(F)F)Cl)CC1 JPFAXYUPWWYMAR-UHFFFAOYSA-N 0.000 claims description 7
• OLSQXUVSYNMPPV-UHFFFAOYSA-N 4-[[2-[4-(2-chlorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=CC=2)Cl)CC1 OLSQXUVSYNMPPV-UHFFFAOYSA-N 0.000 claims description 7
• OBIFWHMTCWRBOR-UHFFFAOYSA-N 4-[[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 OBIFWHMTCWRBOR-UHFFFAOYSA-N 0.000 claims description 7
• LGJQFPPLVAOGHM-UHFFFAOYSA-N 4-[[2-[4-[2-chloro-5-(trifluoromethyl)phenoxy]piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=C(C=2)C(F)(F)F)Cl)CC1 LGJQFPPLVAOGHM-UHFFFAOYSA-N 0.000 claims description 7
• ALDZGNOOEHMQOB-UHFFFAOYSA-N 5-[2-[4-(2,5-dichlorophenoxy)piperidin-1-yl]-2-oxoethoxy]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC(OCC(=O)N2CCC(CC2)OC=2C(=CC=C(Cl)C=2)Cl)=C1 ALDZGNOOEHMQOB-UHFFFAOYSA-N 0.000 claims description 7
• 208000008589 Obesity Diseases 0.000 claims description 7
• 235000020824 obesity Nutrition 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• PEBYTQYULFHAQK-UHFFFAOYSA-N 2-benzyl-4-[[2-oxo-2-[4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl]ethyl]amino]pyridazin-3-one Chemical compound FC(F)(F)C1=CC=CC=C1OC1CCN(C(=O)CNC=2C(N(CC=3C=CC=CC=3)N=CC=2)=O)CC1 PEBYTQYULFHAQK-UHFFFAOYSA-N 0.000 claims description 6
• PEJUDWTYTDPVJC-UHFFFAOYSA-N 2-methyl-4-[[2-[4-(2-methyl-5-propan-2-ylphenoxy)piperidin-1-yl]-2-oxoethyl]amino]pyridazin-3-one Chemical compound CC(C)C1=CC=C(C)C(OC2CCN(CC2)C(=O)CNC=2C(N(C)N=CC=2)=O)=C1 PEJUDWTYTDPVJC-UHFFFAOYSA-N 0.000 claims description 6
• IPKRXUODRTYICO-LBPRGKRZSA-N 4-[[(2s)-1-[4-[2-chloro-5-(trifluoromethyl)phenoxy]piperidin-1-yl]-1-oxopropan-2-yl]amino]-2-methylpyridazin-3-one Chemical compound N([C@@H](C)C(=O)N1CCC(CC1)OC=1C(=CC=C(C=1)C(F)(F)F)Cl)C1=CC=NN(C)C1=O IPKRXUODRTYICO-LBPRGKRZSA-N 0.000 claims description 6
• CEOFABJAGFEYSW-UHFFFAOYSA-N 4-[[2-[4-(2,4-dichlorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC(Cl)=CC=2)Cl)CC1 CEOFABJAGFEYSW-UHFFFAOYSA-N 0.000 claims description 6
• IKMXDVKWXNEDSY-UHFFFAOYSA-N 4-[[2-[4-(2,5-dichlorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=C(Cl)C=2)Cl)CC1 IKMXDVKWXNEDSY-UHFFFAOYSA-N 0.000 claims description 6
• YIAYWJRJENGEMD-UHFFFAOYSA-N 4-[[2-[4-(5-fluoro-2-methylphenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound CC1=CC=C(F)C=C1OC1CCN(C(=O)CNC=2C(N(C)N=CC=2)=O)CC1 YIAYWJRJENGEMD-UHFFFAOYSA-N 0.000 claims description 6
• ANOMYEAIUACIDG-UHFFFAOYSA-N 4-[[2-[4-[3-fluoro-5-(trifluoromethyl)phenoxy]piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C=C(C=C(F)C=2)C(F)(F)F)CC1 ANOMYEAIUACIDG-UHFFFAOYSA-N 0.000 claims description 6
• MCQQWKJEHAVAFC-UHFFFAOYSA-N 4-[[2-[4-[5-fluoro-2-(trifluoromethyl)phenoxy]piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=C(F)C=2)C(F)(F)F)CC1 MCQQWKJEHAVAFC-UHFFFAOYSA-N 0.000 claims description 6
• POVFQDPFRWCWRB-UHFFFAOYSA-N 4-[[2-oxo-2-[4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl]ethyl]amino]-2-propan-2-ylpyridazin-3-one Chemical compound O=C1N(C(C)C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=CC=2)C(F)(F)F)CC1 POVFQDPFRWCWRB-UHFFFAOYSA-N 0.000 claims description 6
• QNYOGSAWWWAHFR-UHFFFAOYSA-N 5-[[2-[4-(2,5-dichlorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-1h-pyridazin-6-one Chemical compound ClC1=CC=C(Cl)C(OC2CCN(CC2)C(=O)CNC=2C(NN=CC=2)=O)=C1 QNYOGSAWWWAHFR-UHFFFAOYSA-N 0.000 claims description 6
• VXOLVFMNNVJANA-UHFFFAOYSA-N 5-[[2-[4-(2-bromo-4,5-difluorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-1h-pyridazin-6-one Chemical compound C1=C(F)C(F)=CC(Br)=C1OC1CCN(C(=O)CNC=2C(NN=CC=2)=O)CC1 VXOLVFMNNVJANA-UHFFFAOYSA-N 0.000 claims description 6
• OXOAULYGMSMRHZ-UHFFFAOYSA-N 5-[[2-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-1h-pyridazin-6-one Chemical compound ClC1=CC=C(Br)C=C1OC1CCN(C(=O)CNC=2C(NN=CC=2)=O)CC1 OXOAULYGMSMRHZ-UHFFFAOYSA-N 0.000 claims description 6
• DSFQYHJOHZUZNZ-UHFFFAOYSA-N 5-[[2-oxo-2-[4-[3-(trifluoromethyl)phenoxy]piperidin-1-yl]ethyl]amino]-1h-pyridazin-6-one Chemical compound FC(F)(F)C1=CC=CC(OC2CCN(CC2)C(=O)CNC=2C(NN=CC=2)=O)=C1 DSFQYHJOHZUZNZ-UHFFFAOYSA-N 0.000 claims description 6
• 230000002265 prevention Effects 0.000 claims description 6
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• KQEBYUGMDVAMEE-UHFFFAOYSA-N 2-methyl-4-[[2-oxo-2-[4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl]ethyl]amino]pyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=CC=2)C(F)(F)F)CC1 KQEBYUGMDVAMEE-UHFFFAOYSA-N 0.000 claims description 5
• UJVYEZNLOAKEDM-UHFFFAOYSA-N 4-[[2-[3-[[2-chloro-5-(trifluoromethyl)phenoxy]methyl]azetidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CC(COC=2C(=CC=C(C=2)C(F)(F)F)Cl)C1 UJVYEZNLOAKEDM-UHFFFAOYSA-N 0.000 claims description 5
• SLEKRSNUYOJPKY-UHFFFAOYSA-N 4-[[2-[4-(2-chlorophenoxy)piperidin-1-yl]-2-oxoethyl]-methylamino]-2-methylpyridazin-3-one Chemical compound C=1C=NN(C)C(=O)C=1N(C)CC(=O)N(CC1)CCC1OC1=CC=CC=C1Cl SLEKRSNUYOJPKY-UHFFFAOYSA-N 0.000 claims description 5
• LLKVQIAGPHSNNR-UHFFFAOYSA-N 5-[2-[4-[2-chloro-5-(trifluoromethyl)phenoxy]piperidin-1-yl]-2-oxoethoxy]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC(OCC(=O)N2CCC(CC2)OC=2C(=CC=C(C=2)C(F)(F)F)Cl)=C1 LLKVQIAGPHSNNR-UHFFFAOYSA-N 0.000 claims description 5
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• JVOBCSZKFYCUCT-UHFFFAOYSA-N 4-[[2-[3-[[2-chloro-5-(trifluoromethyl)phenoxy]methyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CC(COC=2C(=CC=C(C=2)C(F)(F)F)Cl)CC1 JVOBCSZKFYCUCT-UHFFFAOYSA-N 0.000 claims description 4
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• IPKRXUODRTYICO-GFCCVEGCSA-N 4-[[(2r)-1-[4-[2-chloro-5-(trifluoromethyl)phenoxy]piperidin-1-yl]-1-oxopropan-2-yl]amino]-2-methylpyridazin-3-one Chemical compound N([C@H](C)C(=O)N1CCC(CC1)OC=1C(=CC=C(C=1)C(F)(F)F)Cl)C1=CC=NN(C)C1=O IPKRXUODRTYICO-GFCCVEGCSA-N 0.000 claims description 3
• CUTYGNLXWXOCGZ-UHFFFAOYSA-N 4-[[2-[4-(2-bromo-4,5-difluorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC(F)=C(F)C=2)Br)CC1 CUTYGNLXWXOCGZ-UHFFFAOYSA-N 0.000 claims description 3
• ZPJBXELXIIINOE-UHFFFAOYSA-N 4-[[2-[4-(2-chloro-5-fluorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=C(F)C=2)Cl)CC1 ZPJBXELXIIINOE-UHFFFAOYSA-N 0.000 claims description 3
• NFJRLVHIGFQIJF-UHFFFAOYSA-N 4-[[2-[4-(2-chloro-5-nitrophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=C(C=2)[N+]([O-])=O)Cl)CC1 NFJRLVHIGFQIJF-UHFFFAOYSA-N 0.000 claims description 3
• TVWRAPPXVROPMD-UHFFFAOYSA-N 4-[[2-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC=C1NCC(=O)N1CCC(OC=2C(=CC=C(Br)C=2)Cl)CC1 TVWRAPPXVROPMD-UHFFFAOYSA-N 0.000 claims description 3
• SMDOWEWWPQVIMX-UHFFFAOYSA-N 5-[[2-[4-(2-chloro-5-fluorophenoxy)piperidin-1-yl]-2-oxoethyl]amino]-2-methylpyridazin-3-one Chemical compound O=C1N(C)N=CC(NCC(=O)N2CCC(CC2)OC=2C(=CC=C(F)C=2)Cl)=C1 SMDOWEWWPQVIMX-UHFFFAOYSA-N 0.000 claims description 3
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• DWHIRSWNWDXFMQ-UHFFFAOYSA-N 4h-pyridazin-5-one Chemical group O=C1CC=NN=C1 DWHIRSWNWDXFMQ-UHFFFAOYSA-N 0.000 claims 1
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