SK175699A3 - Treatment of insulin resistance with growth hormone secretagogues - Google Patents

Info

Publication number

SK175699A3

SK175699A3 SK1756-99A SK175699A SK175699A3 SK 175699 A3 SK175699 A3 SK 175699A3 SK 175699 A SK175699 A SK 175699A SK 175699 A3 SK175699 A3 SK 175699A3

Authority

SK

Slovakia

Prior art keywords

alkyl

carbon atoms

group

optionally substituted

oxo

Prior art date

1997-06-25

Links

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• Global Dossier
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• 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims abstract description 28
• 206010022489 Insulin Resistance Diseases 0.000 title claims abstract description 25
• 239000003324 growth hormone secretagogue Substances 0.000 title claims abstract description 17
• 239000000203 mixture Substances 0.000 claims abstract description 247
• 150000001875 compounds Chemical class 0.000 claims abstract description 212
• 150000003839 salts Chemical class 0.000 claims abstract description 33
• 239000000651 prodrug Substances 0.000 claims abstract description 26
• 229940002612 prodrug Drugs 0.000 claims abstract description 26
• 241000124008 Mammalia Species 0.000 claims abstract description 18
• 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 claims abstract description 7
• 125000004432 carbon atom Chemical group C* 0.000 claims description 217
• 125000000217 alkyl group Chemical group 0.000 claims description 128
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 125
• -1 1H-tetrazol-5-yl Chemical group 0.000 claims description 111
• 229910052757 nitrogen Chemical group 0.000 claims description 81
• 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 66
• 239000000460 chlorine Substances 0.000 claims description 62
• 229910052801 chlorine Inorganic materials 0.000 claims description 61
• 229920006395 saturated elastomer Polymers 0.000 claims description 61
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 58
• 229910052739 hydrogen Inorganic materials 0.000 claims description 55
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 54
• 239000001257 hydrogen Substances 0.000 claims description 53
• 229940047889 isobutyramide Drugs 0.000 claims description 48
• 229910052760 oxygen Inorganic materials 0.000 claims description 44
• 229910052717 sulfur Inorganic materials 0.000 claims description 44
• 239000001301 oxygen Substances 0.000 claims description 41
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 37
• 239000011593 sulfur Chemical group 0.000 claims description 37
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 36
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 35
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 35
• 125000005842 heteroatom Chemical group 0.000 claims description 35
• 239000002253 acid Substances 0.000 claims description 31
• 229910052799 carbon Inorganic materials 0.000 claims description 31
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
• 125000001424 substituent group Chemical group 0.000 claims description 31
• WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 28
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 27
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 25
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 25
• 125000005843 halogen group Chemical group 0.000 claims description 24
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 102100033367 Appetite-regulating hormone Human genes 0.000 claims description 20
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 19
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
• 125000002619 bicyclic group Chemical group 0.000 claims description 17
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 17
• 125000003545 alkoxy group Chemical group 0.000 claims description 15
• 125000004429 atom Chemical group 0.000 claims description 14
• 101710111255 Appetite-regulating hormone Proteins 0.000 claims description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
• 238000004519 manufacturing process Methods 0.000 claims description 13
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 13
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
• 125000000980 1H-indol-3-ylmethyl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[*])C2=C1[H] 0.000 claims description 10
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 10
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 10
• 125000001153 fluoro group Chemical group F* 0.000 claims description 10
• 125000000335 thiazolyl group Chemical group 0.000 claims description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 229910052731 fluorine Inorganic materials 0.000 claims description 9
• 208000008589 Obesity Diseases 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 125000002883 imidazolyl group Chemical group 0.000 claims description 8
• 235000020824 obesity Nutrition 0.000 claims description 8
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
• 238000002360 preparation method Methods 0.000 claims description 8
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 7
• 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 7
• 125000005907 alkyl ester group Chemical group 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
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
• 239000011737 fluorine Chemical group 0.000 claims description 7
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 6
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
• 101710142969 Somatoliberin Proteins 0.000 claims description 6
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
• 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 5
• 239000003814 drug Substances 0.000 claims description 5
• 108010077689 gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide Proteins 0.000 claims description 5
• 150000003254 radicals Chemical class 0.000 claims description 5
• 125000001544 thienyl group Chemical group 0.000 claims description 5
• 208000002705 Glucose Intolerance Diseases 0.000 claims description 4
• 125000004423 acyloxy group Chemical group 0.000 claims description 4
• 150000001345 alkine derivatives Chemical class 0.000 claims description 4
• 125000002947 alkylene group Chemical group 0.000 claims description 4
• 229910052794 bromium Inorganic materials 0.000 claims description 4
• 125000002541 furyl group Chemical group 0.000 claims description 4
• 125000001188 haloalkyl group Chemical group 0.000 claims description 4
• 125000005347 halocycloalkyl group Chemical group 0.000 claims description 4
• 201000001421 hyperglycemia Diseases 0.000 claims description 4
• 229910052740 iodine Inorganic materials 0.000 claims description 4
• 125000004434 sulfur atom Chemical group 0.000 claims description 4
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
• 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 claims description 3
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
• 125000005059 halophenyl group Chemical group 0.000 claims description 3
• 201000009104 prediabetes syndrome Diseases 0.000 claims description 3
• 208000011580 syndromic disease Diseases 0.000 claims description 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 2
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 150000003892 tartrate salts Chemical class 0.000 claims description 2
• 229910006080 SO2X Inorganic materials 0.000 claims 5
• 125000001309 chloro group Chemical group Cl* 0.000 claims 3
• 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims 3
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
• 102000038461 Growth Hormone-Releasing Hormone Human genes 0.000 claims 1
• 125000002355 alkine group Chemical group 0.000 claims 1
• 125000001246 bromo group Chemical group Br* 0.000 claims 1
• 150000007942 carboxylates Chemical class 0.000 claims 1
• 125000002346 iodo group Chemical group I* 0.000 claims 1
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
• 102000018997 Growth Hormone Human genes 0.000 abstract description 67
• 108010051696 Growth Hormone Proteins 0.000 abstract description 67
• 239000000122 growth hormone Substances 0.000 abstract description 67
• 238000000034 method Methods 0.000 abstract description 56
• 239000000543 intermediate Substances 0.000 abstract description 20
• 241001465754 Metazoa Species 0.000 abstract description 8
• 230000001965 increasing effect Effects 0.000 abstract description 8
• 230000008569 process Effects 0.000 abstract description 7
• 239000005557 antagonist Substances 0.000 abstract description 6
• 230000015572 biosynthetic process Effects 0.000 abstract description 5
• 238000003786 synthesis reaction Methods 0.000 abstract description 5
• 102000005157 Somatostatin Human genes 0.000 abstract description 4
• 108010056088 Somatostatin Proteins 0.000 abstract description 4
• 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 abstract description 4
• 229960000553 somatostatin Drugs 0.000 abstract description 4
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 354
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 186
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 169
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 147
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 127
• 235000019439 ethyl acetate Nutrition 0.000 description 117
• 239000000243 solution Substances 0.000 description 115
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 102
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 79
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
• 239000007787 solid Substances 0.000 description 56
• 239000011541 reaction mixture Substances 0.000 description 53
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 47
• 239000000047 product Substances 0.000 description 39
• 238000010898 silica gel chromatography Methods 0.000 description 37
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 35
• 239000012267 brine Substances 0.000 description 34
• 125000006239 protecting group Chemical group 0.000 description 34
• 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 description 32
• 238000010992 reflux Methods 0.000 description 31
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• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 30
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 30
• 235000019341 magnesium sulphate Nutrition 0.000 description 30
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
• 239000002904 solvent Substances 0.000 description 27
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
• 238000005481 NMR spectroscopy Methods 0.000 description 25
• 239000002585 base Substances 0.000 description 23
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• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
• 239000003921 oil Substances 0.000 description 22
• 235000019198 oils Nutrition 0.000 description 22
• 230000036961 partial effect Effects 0.000 description 22
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 21
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
• 241000700159 Rattus Species 0.000 description 19
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• 238000012360 testing method Methods 0.000 description 18
• 150000001412 amines Chemical class 0.000 description 17
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
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• KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 16
• 229940125396 insulin Drugs 0.000 description 16
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• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
• 239000003960 organic solvent Substances 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
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• 210000002966 serum Anatomy 0.000 description 12
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• HRNLPPBUBKMZMT-SSSXJSFTSA-N (2s)-6-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-aminopropanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]hexanamide Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](C)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(=O)[C@H](N)C)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 HRNLPPBUBKMZMT-SSSXJSFTSA-N 0.000 description 10
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• 101710202385 Growth hormone secretagogue receptor type 1 Proteins 0.000 description 10
• HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 10
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 10
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• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
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