NZ520822A - O-aryl glucoside SGLT2 inhibitors and method - Google Patents

Info

Publication number

NZ520822A

NZ520822A NZ520822A NZ52082201A NZ520822A NZ 520822 A NZ520822 A NZ 520822A NZ 520822 A NZ520822 A NZ 520822A NZ 52082201 A NZ52082201 A NZ 52082201A NZ 520822 A NZ520822 A NZ 520822A

Authority

NZ

New Zealand

Prior art keywords

compound

hydrogen

inhibitor

alkyl

pct

Prior art date

2000-03-30

Links

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• Global Dossier
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• 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 title claims description 13
• 238000000034 method Methods 0.000 title abstract description 16
• 229930182478 glucoside Natural products 0.000 title description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 139
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 65
• 239000003472 antidiabetic agent Substances 0.000 claims abstract description 30
• 229940125708 antidiabetic agent Drugs 0.000 claims abstract description 25
• 239000003524 antilipemic agent Substances 0.000 claims abstract description 24
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 22
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 20
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 3
• 108091006269 SLC5A2 Proteins 0.000 claims abstract 2
• 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 claims abstract 2
• -1 -0CHF2 Chemical group 0.000 claims description 67
• 239000003112 inhibitor Substances 0.000 claims description 56
• 125000003118 aryl group Chemical group 0.000 claims description 35
• 229910052739 hydrogen Inorganic materials 0.000 claims description 31
• 239000001257 hydrogen Substances 0.000 claims description 29
• 230000000694 effects Effects 0.000 claims description 20
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
• 125000005842 heteroatom Chemical group 0.000 claims description 17
• 150000002431 hydrogen Chemical class 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 16
• 229910052736 halogen Inorganic materials 0.000 claims description 16
• 150000002367 halogens Chemical class 0.000 claims description 16
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 16
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 15
• 125000000623 heterocyclic group Chemical group 0.000 claims description 14
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 12
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 11
• 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 claims description 10
• 239000000460 chlorine Substances 0.000 claims description 10
• 150000002148 esters Chemical class 0.000 claims description 9
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 102000004877 Insulin Human genes 0.000 claims description 8
• 108090001061 Insulin Proteins 0.000 claims description 8
• 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 8
• 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
• 229940100389 Sulfonylurea Drugs 0.000 claims description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
• 229940125396 insulin Drugs 0.000 claims description 8
• 238000002360 preparation method Methods 0.000 claims description 8
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 7
• 206010022489 Insulin Resistance Diseases 0.000 claims description 7
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
• 229910052731 fluorine Inorganic materials 0.000 claims description 7
• XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 7
• 229940002612 prodrug Drugs 0.000 claims description 7
• 239000000651 prodrug Substances 0.000 claims description 7
• 239000004059 squalene synthase inhibitor Substances 0.000 claims description 7
• 208000011580 syndromic disease Diseases 0.000 claims description 7
• 201000001320 Atherosclerosis Diseases 0.000 claims description 6
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
• YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 6
• 239000000556 agonist Substances 0.000 claims description 6
• 239000000883 anti-obesity agent Substances 0.000 claims description 6
• 229940125710 antiobesity agent Drugs 0.000 claims description 6
• 229910052794 bromium Inorganic materials 0.000 claims description 6
• 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 6
• 201000001421 hyperglycemia Diseases 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 6
• 229960003105 metformin Drugs 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 6
• 150000003839 salts Chemical class 0.000 claims description 6
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 6
• ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 5
• XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 5
• XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 5
• 229940123208 Biguanide Drugs 0.000 claims description 5
• 208000002249 Diabetes Complications Diseases 0.000 claims description 5
• 206010012655 Diabetic complications Diseases 0.000 claims description 5
• 102000004366 Glucosidases Human genes 0.000 claims description 5
• 108010056771 Glucosidases Proteins 0.000 claims description 5
• TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 5
• RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 5
• 125000005018 aryl alkenyl group Chemical group 0.000 claims description 5
• 229960005370 atorvastatin Drugs 0.000 claims description 5
• 229960005110 cerivastatin Drugs 0.000 claims description 5
• SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 claims description 5
• 229910052801 chlorine Inorganic materials 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 229960003765 fluvastatin Drugs 0.000 claims description 5
• 229960004580 glibenclamide Drugs 0.000 claims description 5
• ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims description 5
• AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical group CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 5
• 229960001243 orlistat Drugs 0.000 claims description 5
• 229960002965 pravastatin Drugs 0.000 claims description 5
• TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 5
• 229960002855 simvastatin Drugs 0.000 claims description 5
• RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 5
• SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 claims description 4
• 102100028701 General vesicular transport factor p115 Human genes 0.000 claims description 4
• 101000767151 Homo sapiens General vesicular transport factor p115 Proteins 0.000 claims description 4
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
• 229940122355 Insulin sensitizer Drugs 0.000 claims description 4
• 241000124008 Mammalia Species 0.000 claims description 4
• PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 4
• VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 4
• ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 claims description 4
• 229960001381 glipizide Drugs 0.000 claims description 4
• 229960004844 lovastatin Drugs 0.000 claims description 4
• QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 4
• 229950004994 meglitinide Drugs 0.000 claims description 4
• DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims description 4
• YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 4
• 102000004217 thyroid hormone receptors Human genes 0.000 claims description 4
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• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
• XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 3
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• BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 3
• ILPUOPPYSQEBNJ-UHFFFAOYSA-N 2-methyl-2-phenoxypropanoic acid Chemical class OC(=O)C(C)(C)OC1=CC=CC=C1 ILPUOPPYSQEBNJ-UHFFFAOYSA-N 0.000 claims description 3
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• HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 claims description 3
• FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 claims description 3
• 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 3
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• 239000000867 Lipoxygenase Inhibitor Substances 0.000 claims description 3
• IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 claims description 3
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• 239000000048 adrenergic agonist Substances 0.000 claims description 3
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• 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 3
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• PKWDZWYVIHVNKS-UHFFFAOYSA-N netoglitazone Chemical compound FC1=CC=CC=C1COC1=CC=C(C=C(CC2C(NC(=O)S2)=O)C=C2)C2=C1 PKWDZWYVIHVNKS-UHFFFAOYSA-N 0.000 claims description 3
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