HRP20000327A2 - Combination of an aldose reductase inhibitor and a glycogen phosphorylase inhibitor - Google Patents

Info

Publication number

HRP20000327A2

HRP20000327A2 HR20000327A HRP20000327A HRP20000327A2 HR P20000327 A2 HRP20000327 A2 HR P20000327A2 HR 20000327 A HR20000327 A HR 20000327A HR P20000327 A HRP20000327 A HR P20000327A HR P20000327 A2 HRP20000327 A2 HR P20000327A2

Authority

HR

Croatia

Prior art keywords

chloro

indole

amide

carboxylic acid

oxo

Prior art date

1997-11-21

Links

• Espacenet
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• 239000003288 aldose reductase inhibitor Substances 0.000 title claims description 54
• 229940118148 Aldose reductase inhibitor Drugs 0.000 title claims description 39
• ROJNYKZWTOHRNU-UHFFFAOYSA-N 2-chloro-4,5-difluoro-n-[[2-methoxy-5-(methylcarbamoylamino)phenyl]carbamoyl]benzamide Chemical compound CNC(=O)NC1=CC=C(OC)C(NC(=O)NC(=O)C=2C(=CC(F)=C(F)C=2)Cl)=C1 ROJNYKZWTOHRNU-UHFFFAOYSA-N 0.000 title claims description 28
• MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 title claims description 16
• 150000001875 compounds Chemical class 0.000 claims description 361
• 238000000034 method Methods 0.000 claims description 184
• 108010046163 Glycogen Phosphorylase Proteins 0.000 claims description 87
• 102000007390 Glycogen Phosphorylase Human genes 0.000 claims description 87
• 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 87
• FUQOTYRCMBZFOL-UHFFFAOYSA-N 5-chloro-1H-indole-2-carboxylic acid Chemical compound ClC1=CC=C2NC(C(=O)O)=CC2=C1 FUQOTYRCMBZFOL-UHFFFAOYSA-N 0.000 claims description 81
• 230000000694 effects Effects 0.000 claims description 64
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 46
• 102000004877 Insulin Human genes 0.000 claims description 45
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• 229940125396 insulin Drugs 0.000 claims description 44
• 210000002216 heart Anatomy 0.000 claims description 29
• 241000124008 Mammalia Species 0.000 claims description 26
• 230000002829 reductive effect Effects 0.000 claims description 25
• 206010012601 diabetes mellitus Diseases 0.000 claims description 23
• 206010020772 Hypertension Diseases 0.000 claims description 22
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• 239000008194 pharmaceutical composition Substances 0.000 claims description 19
• 150000003839 salts Chemical class 0.000 claims description 19
• 239000003112 inhibitor Substances 0.000 claims description 16
• 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 claims description 15
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• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 9
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• YDCGVASFVACWKF-NRFANRHFSA-N 5-chloro-1h-indole-2-carboxylic acid [1-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1yl)-2-oxoethyl]amide Chemical compound C1CC(O)CCN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=C(F)C=C1 YDCGVASFVACWKF-NRFANRHFSA-N 0.000 claims description 8
• KLLOIWZUJAJGPU-IBGZPJMESA-N 5-chloro-n-[(2s)-1-(3-hydroxyazetidin-1-yl)-1-oxo-3-phenylpropan-2-yl]-1h-indole-2-carboxamide Chemical compound C1C(O)CN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=CC=C1 KLLOIWZUJAJGPU-IBGZPJMESA-N 0.000 claims description 8
• DJKMYENTBUQHNM-FQEVSTJZSA-N 5-chloro-n-[(2s)-1-(3-hydroxyiminopyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl]-1h-indole-2-carboxamide Chemical compound C1C(=NO)CCN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=CC=C1 DJKMYENTBUQHNM-FQEVSTJZSA-N 0.000 claims description 8
• FTMFRKISBMECSW-SLFFLAALSA-N 5-chloro-n-[(2s)-1-[(3r,4s)-3,4-dihydroxypyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-1h-indole-2-carboxamide Chemical compound C1[C@@H](O)[C@@H](O)CN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=CC=C1 FTMFRKISBMECSW-SLFFLAALSA-N 0.000 claims description 8
• JPXQQFCADYJMMN-UHFFFAOYSA-N 5-chloro-n-[2-(1,1-dioxo-1,3-thiazolidin-3-yl)-2-oxoethyl]-1h-indole-2-carboxamide Chemical compound C=1C2=CC(Cl)=CC=C2NC=1C(=O)NCC(=O)N1CCS(=O)(=O)C1 JPXQQFCADYJMMN-UHFFFAOYSA-N 0.000 claims description 8
• WAAVFJWSRFFSSW-BETUJISGSA-N 5-chloro-n-[2-[(3s,4r)-3,4-dihydroxypyrrolidin-1-yl]-2-oxoethyl]-1h-indole-2-carboxamide Chemical compound C1[C@@H](O)[C@@H](O)CN1C(=O)CNC(=O)C1=CC2=CC(Cl)=CC=C2N1 WAAVFJWSRFFSSW-BETUJISGSA-N 0.000 claims description 8
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• 210000000056 organ Anatomy 0.000 claims description 8
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• 208000031226 Hyperlipidaemia Diseases 0.000 claims description 7
• 206010022489 Insulin Resistance Diseases 0.000 claims description 6
• 208000011580 syndromic disease Diseases 0.000 claims description 6
• 210000005003 heart tissue Anatomy 0.000 claims description 5
• 229940088597 hormone Drugs 0.000 claims description 5
• 239000005556 hormone Substances 0.000 claims description 5
• 201000001421 hyperglycemia Diseases 0.000 claims description 5
• 210000003734 kidney Anatomy 0.000 claims description 5
• 210000003205 muscle Anatomy 0.000 claims description 5
• 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 5
• 208000015181 infectious disease Diseases 0.000 claims description 4
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• 230000035945 sensitivity Effects 0.000 claims description 4
• 206010000599 Acromegaly Diseases 0.000 claims description 3
• 208000037157 Azotemia Diseases 0.000 claims description 3
• 201000005255 adrenal gland hyperfunction Diseases 0.000 claims description 3
• 230000002458 infectious effect Effects 0.000 claims description 3
• 210000000936 intestine Anatomy 0.000 claims description 3
• 210000005228 liver tissue Anatomy 0.000 claims description 3
• 238000004806 packaging method and process Methods 0.000 claims description 3
• 210000000496 pancreas Anatomy 0.000 claims description 3
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• 210000000952 spleen Anatomy 0.000 claims description 3
• 208000009852 uremia Diseases 0.000 claims description 3
• 208000002705 Glucose Intolerance Diseases 0.000 claims description 2
• 102000018997 Growth Hormone Human genes 0.000 claims description 2
• 108010051696 Growth Hormone Proteins 0.000 claims description 2
• 239000000122 growth hormone Substances 0.000 claims description 2
• 230000000968 intestinal effect Effects 0.000 claims description 2
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• 230000003914 insulin secretion Effects 0.000 claims 9
• RIIVBOIBIOLLPO-UHFFFAOYSA-N 2-phthalazin-1-ylacetic acid Chemical group C1=CC=C2C(CC(=O)O)=NN=CC2=C1 RIIVBOIBIOLLPO-UHFFFAOYSA-N 0.000 claims 4
• 229940122294 Phosphorylase inhibitor Drugs 0.000 claims 2
• 210000000988 bone and bone Anatomy 0.000 claims 2
• 230000001780 adrenocortical effect Effects 0.000 claims 1
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• 235000012054 meals Nutrition 0.000 claims 1
• 210000000653 nervous system Anatomy 0.000 claims 1
• 210000004923 pancreatic tissue Anatomy 0.000 claims 1
• 210000005084 renal tissue Anatomy 0.000 claims 1
• -1 zopolrestat Chemical class 0.000 description 173
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• 125000006526 (C1-C2) alkyl group Chemical group 0.000 description 85
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 81
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• 150000001412 amines Chemical class 0.000 description 60
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 60
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 55
• 239000000543 intermediate Substances 0.000 description 55
• 239000002585 base Substances 0.000 description 50
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
• 229910052799 carbon Inorganic materials 0.000 description 47
• 125000005843 halogen group Chemical group 0.000 description 46
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
• 125000000217 alkyl group Chemical group 0.000 description 38
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 38
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 37
• 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 description 37
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 37
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 33
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