HRP980361A2 - Treatment of insulin resistance - Google Patents

Info

Publication number

HRP980361A2

HRP980361A2 HR60/050,790A HRP980361A HRP980361A2 HR P980361 A2 HRP980361 A2 HR P980361A2 HR P980361 A HRP980361 A HR P980361A HR P980361 A2 HRP980361 A2 HR P980361A2

Authority

HR

Croatia

Prior art keywords

alkyl

optionally substituted

cycloalkyl

group

optionally

Prior art date

1997-06-25

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• 238000011282 treatment Methods 0.000 title claims description 42
• 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims description 19
• 206010022489 Insulin Resistance Diseases 0.000 title claims description 16
• 239000000203 mixture Substances 0.000 claims description 274
• 150000001875 compounds Chemical class 0.000 claims description 223
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 199
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 170
• 229920006395 saturated elastomer Polymers 0.000 claims description 157
• 238000000034 method Methods 0.000 claims description 135
• 229910052757 nitrogen Inorganic materials 0.000 claims description 113
• 239000001257 hydrogen Substances 0.000 claims description 110
• 229910052739 hydrogen Inorganic materials 0.000 claims description 110
• -1 1H-tetrazol-5-yl Chemical group 0.000 claims description 106
• 229910052760 oxygen Inorganic materials 0.000 claims description 95
• 239000000460 chlorine Substances 0.000 claims description 87
• 102000018997 Growth Hormone Human genes 0.000 claims description 75
• 239000000122 growth hormone Substances 0.000 claims description 75
• 108010051696 Growth Hormone Proteins 0.000 claims description 74
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 71
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 71
• 229910052717 sulfur Chemical group 0.000 claims description 71
• 239000011593 sulfur Chemical group 0.000 claims description 71
• 239000001301 oxygen Substances 0.000 claims description 70
• 229910052801 chlorine Inorganic materials 0.000 claims description 68
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 58
• 125000005842 heteroatom Chemical group 0.000 claims description 58
• 125000004432 carbon atom Chemical group C* 0.000 claims description 55
• 229910052799 carbon Inorganic materials 0.000 claims description 50
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 48
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 47
• 125000000217 alkyl group Chemical group 0.000 claims description 44
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 42
• 150000003839 salts Chemical class 0.000 claims description 37
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 36
• 229910052736 halogen Inorganic materials 0.000 claims description 36
• 150000002367 halogens Chemical class 0.000 claims description 36
• 238000006243 chemical reaction Methods 0.000 claims description 33
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
• 125000001424 substituent group Chemical group 0.000 claims description 31
• 239000002904 solvent Substances 0.000 claims description 30
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 28
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
• 230000008569 process Effects 0.000 claims description 26
• 239000000651 prodrug Substances 0.000 claims description 26
• 229940002612 prodrug Drugs 0.000 claims description 26
• 241000124008 Mammalia Species 0.000 claims description 24
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 21
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 18
• 102100033367 Appetite-regulating hormone Human genes 0.000 claims description 18
• 108010077689 gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide Proteins 0.000 claims description 17
• 239000012442 inert solvent Substances 0.000 claims description 17
• 229910052740 iodine Inorganic materials 0.000 claims description 16
• 229910052731 fluorine Inorganic materials 0.000 claims description 15
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
• 125000006709 (C5-C7) cycloalkenyl group Chemical group 0.000 claims description 14
• 125000004429 atom Chemical group 0.000 claims description 14
• 125000001153 fluoro group Chemical group F* 0.000 claims description 14
• 125000002883 imidazolyl group Chemical group 0.000 claims description 14
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 14
• 125000000335 thiazolyl group Chemical group 0.000 claims description 14
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 14
• 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 13
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 13
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
• 239000003960 organic solvent Substances 0.000 claims description 12
• 239000000048 adrenergic agonist Substances 0.000 claims description 10
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 9
• 241001465754 Metazoa Species 0.000 claims description 9
• 125000004423 acyloxy group Chemical group 0.000 claims description 9
• 150000007530 organic bases Chemical class 0.000 claims description 9
• 208000008589 Obesity Diseases 0.000 claims description 8
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
• 125000006242 amine protecting group Chemical group 0.000 claims description 8
• 229910052794 bromium Inorganic materials 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 235000020824 obesity Nutrition 0.000 claims description 8
• 125000001544 thienyl group Chemical group 0.000 claims description 8
• WKDBMZQECSVNDS-UHFFFAOYSA-N (2,6-difluorophenyl)-pyrrolidin-1-ylmethanone Chemical compound FC1=CC=CC(F)=C1C(=O)N1CCCC1 WKDBMZQECSVNDS-UHFFFAOYSA-N 0.000 claims description 7
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 7
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 7
• 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 7
• 102000005157 Somatostatin Human genes 0.000 claims description 7
• 108010056088 Somatostatin Proteins 0.000 claims description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000002541 furyl group Chemical group 0.000 claims description 7
• 125000005059 halophenyl group Chemical group 0.000 claims description 7
• 125000004043 oxo group Chemical group O=* 0.000 claims description 7
• NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 claims description 7
• 229960000553 somatostatin Drugs 0.000 claims description 7
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 6
• 239000005557 antagonist Substances 0.000 claims description 6
• AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 6
• 239000011230 binding agent Substances 0.000 claims description 6
• 239000003153 chemical reaction reagent Substances 0.000 claims description 6
• GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 5
• 229960002896 clonidine Drugs 0.000 claims description 5
• HRLIOXLXPOHXTA-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CN=C[N]1 HRLIOXLXPOHXTA-UHFFFAOYSA-N 0.000 claims description 5
• 229960002140 medetomidine Drugs 0.000 claims description 5
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
• BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 claims description 5
• 229960001600 xylazine Drugs 0.000 claims description 5
• 208000002705 Glucose Intolerance Diseases 0.000 claims description 4
• 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
• 150000007529 inorganic bases Chemical class 0.000 claims description 4
• 239000001294 propane Substances 0.000 claims description 4
• 208000036119 Frailty Diseases 0.000 claims description 3
• 206010003549 asthenia Diseases 0.000 claims description 3
• 201000001421 hyperglycemia Diseases 0.000 claims description 3
• 201000009104 prediabetes syndrome Diseases 0.000 claims description 3
• MPHQKNPPPRRISM-UHFFFAOYSA-N 2-amino-2-methyl-n-[1-[2-methyl-3-oxo-3a-(pyridin-2-ylmethyl)-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]-1-oxo-3-phenylmethoxypropan-2-yl]propanamide Chemical compound O=C1N(C)N=C2CCN(C(=O)C(COCC=3C=CC=CC=3)NC(=O)C(C)(C)N)CC21CC1=CC=CC=N1 MPHQKNPPPRRISM-UHFFFAOYSA-N 0.000 claims description 2
• DLOHLXUQFHABCV-UHFFFAOYSA-N 2-amino-n-[3-[(3-chlorophenyl)methoxy]-1-oxo-1-[3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propan-2-yl]-2-methylpropanamide Chemical compound C1CC2=NN(CC(F)(F)F)C(=O)C2(CC=2N=CC=CC=2)CN1C(=O)C(NC(=O)C(C)(N)C)COCC1=CC=CC(Cl)=C1 DLOHLXUQFHABCV-UHFFFAOYSA-N 0.000 claims description 2
• CQEJJNLXQCNLHP-UHFFFAOYSA-N 2-amino-n-[3-[(4-chlorophenyl)methoxy]-1-oxo-1-[3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propan-2-yl]-2-methylpropanamide Chemical compound C1CC2=NN(CC(F)(F)F)C(=O)C2(CC=2N=CC=CC=2)CN1C(=O)C(NC(=O)C(C)(N)C)COCC1=CC=C(Cl)C=C1 CQEJJNLXQCNLHP-UHFFFAOYSA-N 0.000 claims description 2
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
• 230000001476 alcoholic effect Effects 0.000 claims description 2
• 229940088597 hormone Drugs 0.000 claims description 2
• 239000005556 hormone Substances 0.000 claims description 2
• 150000001261 hydroxy acids Chemical group 0.000 claims description 2
• UBEBVVBBTDUZKB-UHFFFAOYSA-N n-[1-(3a-benzyl-2-ethyl-3-oxo-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl)-1-oxo-3-phenylmethoxypropan-2-yl]-2-amino-2-methylpropanamide Chemical compound O=C1N(CC)N=C2CCN(C(=O)C(COCC=3C=CC=CC=3)NC(=O)C(C)(C)N)CC21CC1=CC=CC=C1 UBEBVVBBTDUZKB-UHFFFAOYSA-N 0.000 claims description 2
• CMFDKVQQVCBZTI-UHFFFAOYSA-N n-[1-(3a-benzyl-2-ethyl-3-oxo-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl)-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-2-amino-2-methylpropanamide Chemical compound O=C1N(CC)N=C2CCN(C(=O)C(CC=3C4=CC=CC=C4NC=3)NC(=O)C(C)(C)N)CC21CC1=CC=CC=C1 CMFDKVQQVCBZTI-UHFFFAOYSA-N 0.000 claims description 2
• KVLLHLWBPNCVNR-UHFFFAOYSA-N n-[1-(3a-benzyl-2-methyl-3-oxo-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl)-1-oxo-3-phenylmethoxypropan-2-yl]-2-amino-2-methylpropanamide Chemical compound O=C1N(C)N=C2CCN(C(=O)C(COCC=3C=CC=CC=3)NC(=O)C(C)(C)N)CC21CC1=CC=CC=C1 KVLLHLWBPNCVNR-UHFFFAOYSA-N 0.000 claims description 2
• RHQTZSQNBZVDGW-UHFFFAOYSA-N n-[1-(3a-benzyl-2-methyl-3-oxo-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl)-1-oxo-5-phenylpentan-2-yl]-2-amino-2-methylpropanamide Chemical compound O=C1N(C)N=C2CCN(C(=O)C(CCCC=3C=CC=CC=3)NC(=O)C(C)(C)N)CC21CC1=CC=CC=C1 RHQTZSQNBZVDGW-UHFFFAOYSA-N 0.000 claims description 2
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• FKOGOYQRCDITFG-UHFFFAOYSA-N n-[1-(3a-benzyl-3-oxo-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-1-oxo-3-phenylmethoxypropan-2-yl]-2-amino-2-methylpropanamide Chemical compound C1CC2=NNC(=O)C2(CC=2C=CC=CC=2)CN1C(=O)C(NC(=O)C(C)(N)C)COCC1=CC=CC=C1 FKOGOYQRCDITFG-UHFFFAOYSA-N 0.000 claims description 2
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• GWDQWGUUUGDHLC-UHFFFAOYSA-N n-[1-[3a-[(4-fluorophenyl)methyl]-2-methyl-3-oxo-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-2-amino-2-methylpropanamide Chemical compound O=C1N(C)N=C2CCN(C(=O)C(CC=3C4=CC=CC=C4NC=3)NC(=O)C(C)(C)N)CC21CC1=CC=C(F)C=C1 GWDQWGUUUGDHLC-UHFFFAOYSA-N 0.000 claims description 2
• YTRLNTAGPWHUIC-UHFFFAOYSA-N n-[1-[3a-benzyl-3-oxo-2-(2,2,2-trifluoroethyl)-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]-1-oxo-3-phenylmethoxypropan-2-yl]-2-amino-2-methylpropanamide Chemical compound C1CC2=NN(CC(F)(F)F)C(=O)C2(CC=2C=CC=CC=2)CN1C(=O)C(NC(=O)C(C)(N)C)COCC1=CC=CC=C1 YTRLNTAGPWHUIC-UHFFFAOYSA-N 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 24
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• 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims 1
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• 238000005160 1H NMR spectroscopy Methods 0.000 description 48
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• 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
• 235000019341 magnesium sulphate Nutrition 0.000 description 26
• 230000036961 partial effect Effects 0.000 description 26
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