TWI245762B - Pyridazinone aldose reductase inhibitors - Google Patents

Info

Publication number

TWI245762B

TWI245762B TW091106386A TW91106386A TWI245762B TW I245762 B TWI245762 B TW I245762B TW 091106386 A TW091106386 A TW 091106386A TW 91106386 A TW91106386 A TW 91106386A TW I245762 B TWI245762 B TW I245762B

Authority

TW

Taiwan

Prior art keywords

group

compound

methyl

chloro

benzofuran

Prior art date

2001-03-30

Links

• Espacenet
• Global Dossier
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• 239000003288 aldose reductase inhibitor Substances 0.000 title abstract description 14
• AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 title abstract description 12
• 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 349
• 239000003795 chemical substances by application Substances 0.000 claims abstract description 42
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
• 241000124008 Mammalia Species 0.000 claims abstract description 28
• 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 13
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 12
• 206010012655 Diabetic complications Diseases 0.000 claims abstract description 10
• -1 pyridopyridinyl Chemical group 0.000 claims description 228
• 150000003839 salts Chemical class 0.000 claims description 90
• 125000000217 alkyl group Chemical group 0.000 claims description 85
• 229940002612 prodrug Drugs 0.000 claims description 81
• 239000000651 prodrug Substances 0.000 claims description 81
• 125000001424 substituent group Chemical group 0.000 claims description 78
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 60
• 125000001153 fluoro group Chemical group F* 0.000 claims description 53
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 41
• 125000003545 alkoxy group Chemical group 0.000 claims description 41
• 239000001257 hydrogen Substances 0.000 claims description 40
• 229910052739 hydrogen Inorganic materials 0.000 claims description 40
• 239000002253 acid Substances 0.000 claims description 38
• 239000003814 drug Substances 0.000 claims description 33
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
• 229940079593 drug Drugs 0.000 claims description 28
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 25
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
• 125000005843 halogen group Chemical group 0.000 claims description 22
• 125000002971 oxazolyl group Chemical group 0.000 claims description 20
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 19
• 125000004076 pyridyl group Chemical group 0.000 claims description 19
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
• 239000004575 stone Substances 0.000 claims description 18
• IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 17
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 16
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 16
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 15
• PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 15
• 125000001246 bromo group Chemical group Br* 0.000 claims description 14
• 208000028867 ischemia Diseases 0.000 claims description 14
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 14
• 239000002243 precursor Substances 0.000 claims description 14
• 125000000335 thiazolyl group Chemical group 0.000 claims description 14
• 125000002883 imidazolyl group Chemical group 0.000 claims description 13
• 125000001624 naphthyl group Chemical group 0.000 claims description 13
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 13
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
• 239000003085 diluting agent Substances 0.000 claims description 12
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 11
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 11
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 11
• 150000002576 ketones Chemical class 0.000 claims description 11
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 11
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 11
• 125000001544 thienyl group Chemical group 0.000 claims description 11
• 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 10
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 9
• 125000002541 furyl group Chemical group 0.000 claims description 9
• 210000005003 heart tissue Anatomy 0.000 claims description 9
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
• 239000000460 chlorine Substances 0.000 claims description 8
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 8
• 125000001425 triazolyl group Chemical group 0.000 claims description 8
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
• 125000005605 benzo group Chemical group 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 6
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
• 125000005554 pyridyloxy group Chemical group 0.000 claims description 6
• 239000008186 active pharmaceutical agent Substances 0.000 claims description 5
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
• 125000006365 alkylene oxy carbonyl group Chemical group 0.000 claims description 4
• 125000003118 aryl group Chemical group 0.000 claims description 4
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
• 159000000000 sodium salts Chemical class 0.000 claims description 4
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
• 241001465754 Metazoa Species 0.000 claims description 3
• 239000007983 Tris buffer Substances 0.000 claims description 3
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 3
• 125000000304 alkynyl group Chemical group 0.000 claims description 3
• OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 claims description 3
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 238000006467 substitution reaction Methods 0.000 claims description 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
• ZRXHLJNBNWVNIM-UHFFFAOYSA-N 3-methyl-1-benzofuran Chemical group C1=CC=C2C(C)=COC2=C1 ZRXHLJNBNWVNIM-UHFFFAOYSA-N 0.000 claims description 2
• VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 claims description 2
• 125000003342 alkenyl group Chemical group 0.000 claims description 2
• 239000000969 carrier Substances 0.000 claims description 2
• 238000000605 extraction Methods 0.000 claims description 2
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
• 125000005945 imidazopyridyl group Chemical group 0.000 claims description 2
• 125000004536 indazol-1-yl group Chemical group N1(N=CC2=CC=CC=C12)* 0.000 claims description 2
• PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
• 125000004043 oxo group Chemical group O=* 0.000 claims description 2
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 2
• 230000002079 cooperative effect Effects 0.000 claims 5
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 3
• LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims 2
• RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims 2
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• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 2
• 125000001041 indolyl group Chemical group 0.000 claims 2
• 210000003296 saliva Anatomy 0.000 claims 2
• 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 claims 2
• ZKXGQPQAMRSBOL-UHFFFAOYSA-N 1,2,3-trifluoro-9h-fluorene Chemical compound C12=CC=CC=C2CC2=C1C=C(F)C(F)=C2F ZKXGQPQAMRSBOL-UHFFFAOYSA-N 0.000 claims 1
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• HBODQAPNDVOAIZ-UHFFFAOYSA-N 5-chloro-3-propan-2-yl-1-benzofuran Chemical compound C1=C(Cl)C=C2C(C(C)C)=COC2=C1 HBODQAPNDVOAIZ-UHFFFAOYSA-N 0.000 claims 1
• JJXPTUWJVQUHKN-UHFFFAOYSA-N 5-methoxy-1-benzofuran Chemical compound COC1=CC=C2OC=CC2=C1 JJXPTUWJVQUHKN-UHFFFAOYSA-N 0.000 claims 1
• PCVZAQJNRVZDSN-UHFFFAOYSA-N 5-methyl-1-benzothiophene-2-sulfonic acid Chemical compound CC1=CC=C2SC(S(O)(=O)=O)=CC2=C1 PCVZAQJNRVZDSN-UHFFFAOYSA-N 0.000 claims 1
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• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 1
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• 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 claims 1
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