WO1997046556A1 - OXADIAZOLE BENZENESULFONAMIDES AS SELECTIVE β3 AGONISTS FOR THE TREATMENT OF DIABETES AND OBESITY - Google Patents
OXADIAZOLE BENZENESULFONAMIDES AS SELECTIVE β3 AGONISTS FOR THE TREATMENT OF DIABETES AND OBESITY Download PDFInfo
- Publication number
- WO1997046556A1 WO1997046556A1 PCT/US1997/009536 US9709536W WO9746556A1 WO 1997046556 A1 WO1997046556 A1 WO 1997046556A1 US 9709536 W US9709536 W US 9709536W WO 9746556 A1 WO9746556 A1 WO 9746556A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ethyl
- hydroxy
- oxadiazol
- phenyl
- amino
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 29
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 17
- 208000008589 Obesity Diseases 0.000 title claims abstract description 11
- 235000020824 obesity Nutrition 0.000 title claims abstract description 11
- -1 OXADIAZOLE BENZENESULFONAMIDES Chemical class 0.000 title claims description 56
- 239000000556 agonist Substances 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 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 claims abstract description 18
- 102000015779 HDL Lipoproteins Human genes 0.000 claims abstract description 9
- 108010010234 HDL Lipoproteins Proteins 0.000 claims abstract description 9
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 208000007920 Neurogenic Inflammation Diseases 0.000 claims abstract description 5
- 230000010243 gut motility Effects 0.000 claims abstract 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 411
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 210
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 206
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 166
- 150000002367 halogens Chemical class 0.000 claims description 88
- 229910052736 halogen Inorganic materials 0.000 claims description 80
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 78
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 229910052757 nitrogen Chemical group 0.000 claims description 39
- 229910052760 oxygen Inorganic materials 0.000 claims description 39
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 38
- 239000001301 oxygen Substances 0.000 claims description 38
- 229910052717 sulfur Inorganic materials 0.000 claims description 37
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 36
- 239000011593 sulfur Chemical group 0.000 claims description 36
- 125000005842 heteroatom Chemical group 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 31
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 18
- 125000002947 alkylene group Chemical group 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 235000019256 formaldehyde Nutrition 0.000 claims description 4
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- GWAKLMBIGDXTOM-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1C1=CC=C(F)C=C1 GWAKLMBIGDXTOM-UHFFFAOYSA-N 0.000 claims description 2
- BIUDHHGROGJSHN-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzaldehyde Chemical group FC1=CC=C(C=O)C=C1C(F)(F)F BIUDHHGROGJSHN-UHFFFAOYSA-N 0.000 claims description 2
- 125000006356 alkylene carbonyl group Chemical group 0.000 claims description 2
- NCTSAWXMVCCIFP-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound CC1=CC=CC=C1C1=NC(C=2C=CC(=CC=2)S(=O)(=O)NC=2C=CC(CCNCC(O)C=3C=NC=CC=3)=CC=2)=NO1 NCTSAWXMVCCIFP-UHFFFAOYSA-N 0.000 claims description 2
- GYWICHDKAKGABO-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-(3-nitrophenyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1C1=CC=CC([N+]([O-])=O)=C1 GYWICHDKAKGABO-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 10
- 230000003247 decreasing effect Effects 0.000 claims 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- ZZQJOPOKZTXCKB-UHFFFAOYSA-N 4-[5-(1,3-benzodioxol-5-ylmethyl)-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=C(NS(=O)(=O)C=2C=CC(=CC=2)C=2N=C(CC=3C=C4OCOC4=CC=3)ON=2)C=CC=1CCNCC(O)C1=CC=CN=C1 ZZQJOPOKZTXCKB-UHFFFAOYSA-N 0.000 claims 1
- AKVOHMWXKCTPRR-UHFFFAOYSA-N 4-[5-(1-benzofuran-2-yl)-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=C(NS(=O)(=O)C=2C=CC(=CC=2)C=2N=C(ON=2)C=2OC3=CC=CC=C3C=2)C=CC=1CCNCC(O)C1=CC=CN=C1 AKVOHMWXKCTPRR-UHFFFAOYSA-N 0.000 claims 1
- WOLUYNYAJCOOPT-UHFFFAOYSA-N 4-[5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1C1=CC=CC(F)=C1 WOLUYNYAJCOOPT-UHFFFAOYSA-N 0.000 claims 1
- ZBALLCANCTYRPS-UHFFFAOYSA-N 4-[5-(4-fluorobenzoyl)-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1C(=O)C1=CC=C(F)C=C1 ZBALLCANCTYRPS-UHFFFAOYSA-N 0.000 claims 1
- LJGZBXGXTXKHNC-UHFFFAOYSA-N 4-[5-[(3,4-difluorophenoxy)methyl]-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1COC1=CC=C(F)C(F)=C1 LJGZBXGXTXKHNC-UHFFFAOYSA-N 0.000 claims 1
- VVPOZWCWABYDFK-UHFFFAOYSA-N 4-[5-[(3-chlorophenyl)methyl]-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1CC1=CC=CC(Cl)=C1 VVPOZWCWABYDFK-UHFFFAOYSA-N 0.000 claims 1
- SBACQNMIKWVEKA-UHFFFAOYSA-N 4-[5-[(3-fluorophenyl)methyl]-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1CC1=CC=CC(F)=C1 SBACQNMIKWVEKA-UHFFFAOYSA-N 0.000 claims 1
- MLCHPVHJKNLRMJ-UHFFFAOYSA-N 4-[5-[(4-fluorophenyl)methyl]-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1CC1=CC=C(F)C=C1 MLCHPVHJKNLRMJ-UHFFFAOYSA-N 0.000 claims 1
- YQJZLWNUAQMPKM-UHFFFAOYSA-N 4-[5-[3-(4-fluorophenyl)-3-oxopropyl]-1,2,4-oxadiazol-3-yl]-n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1CCC(=O)C1=CC=C(F)C=C1 YQJZLWNUAQMPKM-UHFFFAOYSA-N 0.000 claims 1
- ORMYPXNHFOAYRQ-UHFFFAOYSA-N [4-[[3-[4-[[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]sulfamoyl]phenyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl] acetate Chemical compound C1=CC(OC(=O)C)=CC=C1OCC1=NC(C=2C=CC(=CC=2)S(=O)(=O)NC=2C=CC(CCNCC(O)C=3C=NC=CC=3)=CC=2)=NO1 ORMYPXNHFOAYRQ-UHFFFAOYSA-N 0.000 claims 1
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims 1
- 230000000994 depressogenic effect Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- UCZVAVMAKKOYDR-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-(1h-indol-3-ylmethyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound C=1C=C(NS(=O)(=O)C=2C=CC(=CC=2)C=2N=C(CC=3C4=CC=CC=C4NC=3)ON=2)C=CC=1CCNCC(O)C1=CC=CN=C1 UCZVAVMAKKOYDR-UHFFFAOYSA-N 0.000 claims 1
- QJNXILTVKUHXOF-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-(2-phenoxyethyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1CCOC1=CC=CC=C1 QJNXILTVKUHXOF-UHFFFAOYSA-N 0.000 claims 1
- KMFAUKAYKGTSJZ-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-(3-methylsulfanylphenyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound CSC1=CC=CC(C=2ON=C(N=2)C=2C=CC(=CC=2)S(=O)(=O)NC=2C=CC(CCNCC(O)C=3C=NC=CC=3)=CC=2)=C1 KMFAUKAYKGTSJZ-UHFFFAOYSA-N 0.000 claims 1
- OIOGLWJERDKLQQ-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-(3-methylsulfonylphenyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound CS(=O)(=O)C1=CC=CC(C=2ON=C(N=2)C=2C=CC(=CC=2)S(=O)(=O)NC=2C=CC(CCNCC(O)C=3C=NC=CC=3)=CC=2)=C1 OIOGLWJERDKLQQ-UHFFFAOYSA-N 0.000 claims 1
- BSSRIZKLUOVTPO-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-[(4-pyridin-3-ylphenyl)methyl]-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1CC(C=C1)=CC=C1C1=CC=CN=C1 BSSRIZKLUOVTPO-UHFFFAOYSA-N 0.000 claims 1
- YFBKYRWCIPHZIS-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1C1=CC=C(C(F)(F)F)C=C1 YFBKYRWCIPHZIS-UHFFFAOYSA-N 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 24
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 abstract description 15
- 230000004130 lipolysis Effects 0.000 abstract description 6
- 229940124530 sulfonamide Drugs 0.000 abstract description 6
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 abstract description 4
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 abstract description 4
- 102000016959 beta-3 Adrenergic Receptors Human genes 0.000 abstract description 4
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 abstract description 4
- 230000008878 coupling Effects 0.000 abstract description 4
- 238000010168 coupling process Methods 0.000 abstract description 4
- 238000005859 coupling reaction Methods 0.000 abstract description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 3
- 239000000935 antidepressant agent Substances 0.000 abstract description 2
- 150000008331 benzenesulfonamides Chemical class 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract description 2
- 239000000048 adrenergic agonist Substances 0.000 abstract 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 abstract 1
- 102000016967 beta-1 Adrenergic Receptors Human genes 0.000 abstract 1
- 108010014494 beta-1 Adrenergic Receptors Proteins 0.000 abstract 1
- 150000002118 epoxides Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 37
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- SBBOPUCCCOEMDA-UHFFFAOYSA-N 5-[4-chloro-3-(trifluoromethyl)phenyl]-3H-1,3,4-oxadiazol-2-one Chemical compound ClC1=C(C=C(C=C1)C1=NN=C(O1)O)C(F)(F)F SBBOPUCCCOEMDA-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
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- 229920005989 resin Polymers 0.000 description 13
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
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- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 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 8
- 150000004866 oxadiazoles Chemical class 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 230000000638 stimulation Effects 0.000 description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
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- 229910052744 lithium Inorganic materials 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- 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 description 1
- 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 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 229950008446 melinamide Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- BLBFLHCCPUAXDL-UHFFFAOYSA-N methyl 2-(4-fluorophenyl)-2-hydroxyacetate Chemical compound COC(=O)C(O)C1=CC=C(F)C=C1 BLBFLHCCPUAXDL-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- IMIDGDYKUKZXST-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound COC1=CC=CC(C=2ON=C(N=2)C=2C=CC(=CC=2)S(=O)(=O)NC=2C=CC(CCNCC(O)C=3C=NC=CC=3)=CC=2)=C1 IMIDGDYKUKZXST-UHFFFAOYSA-N 0.000 description 1
- WLNKOLLTYHYJCC-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound CC1=CC=CC(C=2ON=C(N=2)C=2C=CC(=CC=2)S(=O)(=O)NC=2C=CC(CCNCC(O)C=3C=NC=CC=3)=CC=2)=C1 WLNKOLLTYHYJCC-UHFFFAOYSA-N 0.000 description 1
- SLIMEVKNMJKEMU-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-[(4-pyridin-2-ylphenyl)methyl]-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1CC(C=C1)=CC=C1C1=CC=CC=N1 SLIMEVKNMJKEMU-UHFFFAOYSA-N 0.000 description 1
- FYHUILYPFUNCMT-UHFFFAOYSA-N n-[4-[2-[(2-hydroxy-2-pyridin-3-ylethyl)amino]ethyl]phenyl]-4-[5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-oxadiazol-3-yl]benzenesulfonamide Chemical compound C=1C=CN=CC=1C(O)CNCCC(C=C1)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C(N=1)=NOC=1COC1=CC=CC(C(F)(F)F)=C1 FYHUILYPFUNCMT-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960004738 nicotinyl alcohol Drugs 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 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 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 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 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol 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)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007886 soft shell capsule Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 230000000929 thyromimetic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- WILBTFWIBAOWLN-UHFFFAOYSA-N triethyl(triethylsilyloxy)silane Chemical compound CC[Si](CC)(CC)O[Si](CC)(CC)CC WILBTFWIBAOWLN-UHFFFAOYSA-N 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 210000000636 white adipocyte Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- ⁇ -Adrenoceptors have been subclassified as ⁇ i and ⁇ 2 since 1967. Increased heart rate is the primary consequence of ⁇ l- receptor stimulation, while bronchodilation and smooth muscle relaxation typically result from ⁇ 2 stimulation.
- Adipocyte lipolysis was initially thought to be solely a ⁇ l -mediated process. However, more recent results indicate that the receptor-mediating lipolysis is atypical in nature. These atypical receptors, later called ⁇ 3- adrenoceptors, are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis (breakdown of fat) and energy expenditure.
- a major drawback in treatment of chronic diseases with ⁇ 3 agonists is the potential for stimulation of other ⁇ -receptors and subsequent side effects.
- the most likely of these include muscle tremor ( ⁇ 2) and increased heart rate ( ⁇ l).
- ⁇ 2 muscle tremor
- ⁇ l increased heart rate
- these phenylethanolamine derivatives do possess some ⁇ 3 selectivity, side effects of this type have been observed in human volunteers. It is reasonable to expect that these side effects resulted from partial ⁇ l and/or ⁇ 2 agonism.
- the instant invention is concerned with oxadiazole substituted benzenesulfonamides which are useful as antiobesity and antidiabetic compounds.
- a still further object is to describe processes for the preparation of such compounds.
- Another object is to describe methods and compositions which use the compounds as the active ingredient thereof. Further objects will become apparent from reading the following description.
- X is (1) a bond
- C1-C3 alkylene optionally substituted with 1 or 2 groups selected from methyl, C
- Rl is (1) Cl-ClO alkyl optionally substituted with up to 5 groups selected from
- R 3 is (1) R 2 or
- R 4 is (1) H, or (2) Cl-ClO alkyl
- the present compounds are potent and selective B3 agonists, and have improved oral bioavailability in animals.
- X is C1-C3 alkylene, optionally substituted with one or two groups selected from methyl, and halogen.
- X is -CH2-,
- X is C1-C3 alkylene-O, C1-C3 alkylene-carbonyl or N(R2), wherein the alkylene is optionally substituted with one or two groups selected from methyl, and halogen.
- X is -CH2O- or -C(CH3)2 ⁇ -, wherein the point of attachment to the oxadiazole ring is the carbon atom and the point of attachment to the A group is the oxygen atom; and a preferred embodiment is where X is CH2O.
- the oxadiazole ring may be attached to the benzenesulfonamide moiety via either the C3 carbon or the C5 carbon atom. The numbering of the oxadiazole ring is as shown below:
- A is (1) phenyl, (2) naphthyl, (3) a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (4) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
- Rl is (l) Cl-Cl ⁇ alkyl optionally substituted with up to 5 groups selected from hydroxy, halogen, cyano, QR 2 , C3-C8 cycloalkyl, A optionally substituted with up to 5 groups selected from halogen, Cl-C 10 alkyl and Cl-C 10 alkoxy, Q'COR 3 , S(0) n R 3 where n is 0 to 2, NR 2 S ⁇ 2R 3 , and NR 2 C ⁇ 2R 2 , (2) halogen, (3) QR 2 , (4) S(0) n R 3 where n is 0 to 2, (5) Q'COR 3 , (6) phenyl optionally substituted with up to 4 groups independently selected from R 2 , QR 2 and halogen, or (7) 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to 4 groups independently selected from oxo, R 2 , QR 2 and halogen
- X is CH2 or CH2O in which O is attached to A;
- A is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (4) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;
- Rl is (1) Cl-ClO alkyl optionally substituted with up to 5 groups selected from halogen, cyano, QR 2 , and A optionally substituted with up to 5 groups selected from halogen, Cl-C 10 alkyl and Cl- ClO alkoxy, (2) halogen, (3) phenyl optionally substituted with up to 5 groups independently selected from R 2 , QR 2 and halogen, (4) 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to 4 groups independently selected from
- X is CH2 or CH2O in which O is attached to A;
- A is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (4) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;
- R is (1) Cl-C 10 alkyl optionally substituted with up to 5 groups selected from halogen, and A optionally substituted with up to 5 groups selected from halogen, Cl-C 10 alkyl and Cl-C 10 alkoxy, (2) halogen, (3) 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to 4 groups selected from halogen, Cl-ClO alkyl and Cl-ClO alkoxy, or (4) QR 2 ;
- R 2 is Cl-ClO alkyl, optionally substitute
- Representative antiobesity and antidiabetic compounds of the present invention include the following: N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4- [5-(5-methylisoxazol-3-yl)-[l,2,4]-oxadiazol-3- yljbenzensulfonamide, N-[4-[2-[[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4- [5-(4-fluorophenyl)-[ 1 ,2,4]-oxadiazol-3-yl]benzensulfonamide, -[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4- [5-(3-fluorophenyl)-[ 1 ,2,4]-ox
- the compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural Formula I. Additional asymmetric centers may be present on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
- the asymmetric center represented by the asterisk in Formula I it has been found that the compound in which the hydroxy substituent is above the plane of the structure, as seen in Formula Ic, is more active and thus more preferred over the compound in which the hydroxy substituent is below the plane of the structure.
- Alkylene means -(CH2)p- where p is the designated carbon number.
- Optionally substituted alkylene may have one or two of the hydrogen atoms replaced with the same or different enumerated substituents.
- the Q, or carbonyl group may be at either end of the alkylene chain, or it may be embedded within the chain. Examples include OCH(CH3), OC(CH3)2, C(CH3)2 ⁇ , OCH2, CH20, C(0)CH2, CH2OCH2, OC(0)CH2, OCH2CH2C(0), OCH2CH2O, OCH2CH2C(0)CH2, CH2CH(OCH3)CH2, CH(OCH3)CH2, etc.
- alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration.
- exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
- alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
- halogen is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
- a benzene ring fused to a C5-C10 carbocyclic ring includes naphthyl, tetrahydronaphthyl, indanyl and indenyl.
- a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C5 -ClO carbocyclic ring includes benzene fused to a heterocyclic ring as well as a non- aromatic carbocyclic ring fused to a heterocyclic ring.
- the carbocyclic ring preferably is C5-C7.
- a 5 and 6-membered heterocyclic ring is intended to include aromatic and unsaturated non-aromatic heterocycles; and where the heterocycle is part of a fused ring, at least one of the rings is aromatic.
- Examples of a 5 or 6-membered ring include pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, oxazolyl, imidazolidinyl, pyrazolyl, isoxazolyl.
- Examples of a benzene ring fused to a 5 or 6-membered heterocyclic ring include benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, 2,3-dihydrobenzofuranyl, quinolinyl, benzotriazolyl, benzoxazolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl.
- Examples of a 5 or 6-membered heterocyclic ring fused to a non-aromatic carbocyclic ring include tetrahydrobenzothiazolyl, 5,6,7,8- tetrahydroquinolinyl, 2,3-cyclopentenopyridyl, 4,5,6,7- tetrahydroindolyl, 5,6,7, 8-tetrahydroisoquinolyl, 5,6,7,8- tetrahy droquinoxaliny 1.
- the preferred values of A are phenyl, naphthyl, benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or heterocycles with from 1 to 4 heteroatoms independently selected from one of oxygen or sulfur, and/or 1 to 4 nitrogen atoms.
- the more preferred values of A are phenyl, naphthyl, thienyl, pyridinyl, pyrrolyl, benzothienyl, and 2,3- dihydrobenzofuranyl.
- NR2R2 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
- the compounds (I) of the present invention can be prepared as described in the following schemes.
- oxadiazoles Ia where X is other than Q or Q-CI-C3 alkylene as illustrated in Scheme 1, the protected aniline derivative 1 (See Fisher, et. al., W09529159-A, Nov. 2, 1995, for the synthesis of this compound.) is treated with a 4-cyanobenzenesulfonyl halide, conveniently the sulfonyl chloride 2, and a base such as pyridine in an anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24 hours at temperatures of -20 to 50°C, preferably 0°C, to provide the sulfonamide 2.
- a 4-cyanobenzenesulfonyl halide conveniently the sulfonyl chloride 2
- a base such as pyridine
- an anhydrous solvent such as dichloromethane or chloroform
- hydroxylamine which may be formed in situ from hydroxylamine hydrochloride and a base such as potassium carbonate, in a solvent such as ethanol at temperatures from 0 °C to 100 °C, conveniently 70-80 °C, provides the corresponding amidoxime 4.
- a solvent such as ethanol
- the oxadiazole is then formed by methods known in the literature (See, for example, Borg, et. al., J. Org. Chem. 1995, 60, 3112-3120 and Diana, et. aL, J. Med. Chem. 1994, 37, 2421-2436, and references cited therein).
- the product Ia from the reaction described in Scheme 1 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on Rl .
- These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. SCHEME 1.
- the hydroxyl group is then protected, conveniently as its triethylsilyl ether using triethylsilyl chloride in the presence Of a base such as diisopropylethylamine.
- the resultant derivative 8 is treated with 4- cyanobenzenesulfonyl halide, conveniently the sulfonyl chloride 2, in the presence of a base such as pyridine, to provide the sulfonamide 2.
- Treatment of intermediate 2 with hydroxylamine as described above provides the corresponding amidoxime IQ.
- the oxadiazoles Ia are prepared from intermediate JO as illustrated in Scheme 3.
- Cleavage from the resin is effected, in the case of Novasyn TGA resin from Novabiochem, by treatment with acid such as trifluoroacetic acid as a 1 :1 mixture with dichloromethane.
- the oxadiazole may be prepared from the corresponding isocyanidedichloride (See for example, Japan Patent 05117255, 1993). As shown in Scheme 4, intermediate 4 is treated with isocyanidedichloride ⁇ and a base such as DBU. Removal of the Boc protecting group under acidic conditions, for example, with trifluoroacetic acid in dichloromethane, provides the desired oxadiazoles Ia.
- the requisite isocyanidedichlorides JT are known in the literature (for example, Kuhle, Angew. Chem. 1962, 74, 861-866) or readily prepared by methods known to those skilled in the art.
- compounds Ia may be prepared by reaction of the corresponding thiol or alcohol with an activated oxadiazole.
- the amidoxime 4 is treated with trichloroacetyl chloride in a base such as pyridine followed by heating to provide the corresponding oxadiazole 12.
- a base such as pyridine
- SCHEME 5 the amidoxime 4 is treated with trichloroacetyl chloride in a base such as pyridine followed by heating to provide the corresponding oxadiazole 12.
- the product Ia from the reactions described in Schemes 4 and 5 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on Rl .
- These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
- the isomeric oxadiazoles lb are readily available as illustrated in Scheme 6.
- Aniline derivative 1 is sulfonylated by treatment with 4-(chlorosulfonyl)benzoic acid (14) in the presence of a base such as pyridine to provide the corresponding sulfonamide 15_.
- the oxadiazole is then formed as described above by treatment of 15 with the appropriate amidoxime J_6 in the presence of a peptide coupling reagent such as dicyclohexylcarbodiimide or N-ethyl-N'- dimethylaminopropylcarbodiimide, followed by heating to effect cyclization in a solvent such as pyridine or diglyme. Removal of the protecting group with, in the case of a tert-butylcarbamate, acid such as trifluoroacetic acid or methariolic hydrogen chloride, provides the oxadiazole lb.
- the amidoximes 16 are commercially available, known in the literature, or readily prepared by methods commonly known to those skilled in the art. Conveniently, they are prepared from the corresponding nitrile by treatment with hydroxylamine.
- the product lb from the reaction described in Scheme 6 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on Rl .
- These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
- Compounds of the general Formula I may be present as pairs of enantiomers or, where there is more than one chiral centers, as mixtures of diastereomers.
- Enantiomeric pairs may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
- a mixture of diastereomers may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
- the pair of enantiomers may be separated as described above
- any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
- the instant compounds can be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids.
- acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like.
- certain compounds containing an acidic function such as a carboxy or tetrazole, can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
- the compounds of the present invention have valuable pharmacological properties.
- the present invention also provides a compound of the general Formula I or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
- the disease diabetes mellitus is characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia.
- Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral administration of drugs and dietary therapies.
- Two major forms of diabetes mellitus are now recognized.
- Type I diabetes, or insulin-dependent diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization.
- Type II diabetes, or insulin- independent diabetes often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese.
- the present invention provides a compound of the general Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of obesity or hyperglycemia (diabetes) in human or non-human animals.
- the present invention provides a method for the treatment of obesity which comprises administering to an obese patient a therapeutically effective amount of a compound of the general Formula I, or a pharmaceutically acceptable salt thereof.
- the present invention provides a method for the treatment of diabetes which comprises administering to a diabetic patient a therapeutically effective amount of a compound of formula I.
- the compounds of the present invention lower triglyceride levels and cholesterol levels and raise high density lipoprotein levels and are therefore of use in combatting medical conditions wherein such lowering (and raising) is thought to be beneficial.
- they may be used in the treatment of hyper- triglyceridaemia, hypercholesterolaemia and conditions of low HDL (high density lipoprotein) levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions.
- the present invention provides a method of lowering triglyceride and/or cholesterol levels and/or increasing high density lipoprotein levels which comprises administering, to a human or a non-human animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or pharmaceutically acceptable salt thereof.
- a method of treating atherosclerosis which comprises administering, to an animal in need thereof; a therapeutically effective amount of a compound of the formula (I) or pharmaceutically acceptable salt thereof.
- the compositions are formulated and administered in the same general manner as detailed below for treating diabetes and obesity.
- They may also contain other active ingredients known for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, simvastatin and pravastatin; inhibitors of cholesterol abso ⁇ tion for example beta-sitosterol and (acyl Co A: cholesterol acyltransferase) inhibitors for example melinamide; anion exchange resins for example cholestyramine, colestipol or a dialkylaminoalkyl derivatives of a cross-linked dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics.
- fibrates such as clofibrate, bezafibrate and gemfibrozil
- inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lov
- the compounds of the instant invention also have the effect of reducing intestinal motility and thus find utility as aiding in the treatment of various gastrointestinal disorders such as irritable bowel syndrome. It has been proposed that the motility of non-sphincteric smooth muscle contraction is mediated by activity at ⁇ 3 adrenoreceptors. The availability of a ⁇ 3 specific agonist, with little activity at ⁇ l and ⁇ 2 receptors will assist in the pharmacologic control of intestinal motility without concurrent cardiovascular effects.
- the instant compounds are administered generally as described below with dosages similar to those used for the treatment of diabetes and obesity.
- the compounds which act as agonists at ⁇ 3 adrenoreceptors may be useful in the treatment of gastrointestinal disorders, especially peptic ulcerations, esophagitis, gastritis and duodenitis, (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis) and gastrointestinal ulcerations.
- ⁇ 3 receptors have been indicated to have an effect on the inhibition of the release of neuropeptides in certain sensory fibers in the lung.
- ⁇ 3 adrenoreceptors are also able to produce selective antidepressant effects by stimulating the ⁇ 3 receptors in the brain and thus an additional contemplated utility of the compounds of this invention are as antidepressant agents.
- the active compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be inco ⁇ orated directly with the food of the diet.
- these active compounds may be inco ⁇ orated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like.
- Such compositions and preparations should contain at least 0.1 percent of active compound.
- the percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
- the amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
- the active compounds can also be administered intranasally as, for example, liquid drops or spray.
- the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.
- the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
- the total daily dose will generally be from about 0.07 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
- the compounds of the present invention are administered at a daily dosage of from 0.01 milligram to about 100 milligrams per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
- the total daily dose will generally be from about 0.7 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
- the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
- a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
- tablets may be coated with shellac, sugar or both.
- a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
- active compounds may also be administered parenterally.
- Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
- cAMP production in response to ligand is measured according to Barton et al (1991, Agonist-induced desensitization of D2 dopamine receptors in human Y-79 retinoblastoma cells. Mol. Pharmacol. v3229:650-658) modified as follows. CHO cells, stably transfected with the cloned ⁇ -adrenergic receptor ( ⁇ l , ⁇ 2 or ⁇ ) are harvested after 3 days of subculturing. Harvesting is done with Enzyme-free Dissociation Media (Specialty Media).
- Cells are counted and distributed in the assay tubes, after being resuspended in Tris buffer (ACC buffer: 75 mM Tris, pH 7.4, 250 mM Sucrose, 12.5 mM MgCl2, 1.5 mM EDTA, 0.2 mM Sodium Metabisulfite, 0.6mM IBMX) containing an antioxidant and a phosphodiesterase inhibitor.
- Tris buffer ACC buffer: 75 mM Tris, pH 7.4, 250 mM Sucrose, 12.5 mM MgCl2, 1.5 mM EDTA, 0.2 mM Sodium Metabisulfite, 0.6mM IBMX
- Reaction is initiated by mixing 200,000 cells in 100 ⁇ L with 20 ⁇ L of a 6x stock of ligand/unknown to be tested. Tubes shake at 275 ⁇ ra for 45 min at room temperature. The reaction is stopped by boiling the tubes for 3 min.
- the cell lysate is diluted 5-fold in 0.1 N HCI and then acetylated by the mixture of 150 ⁇ L of acid-diluted sample with 6 ⁇ L of acetylation mixture (acetic anhydride/triethylamine, 1 :2.5).
- the cAMP produced in response to the ligand is measured in the lysate by competing against 25l-cAMP for binding to a 25 ⁇ _ c AMP-directed antibody using an automated RIA machine (ATTOFLO, Atto Instruments, Baltimore, MD, Brooker et al 1979, Radioimmunoassay of Cyclic AMP and Cyclic GMP. Advances in Cyclic Nucleotide Research, vol 10: 1-32.).
- the unknown cAMP level is determined by comparing levels to a standard curve.
- cAMP is measured using the cAMP SPA kit (code number RPA 556) from Amersham according to the manufacturer's instructions. Samples tested with the latter method do not need to be acetylated.
- the non-selective, full agonist ⁇ -adrenergic ligand isoproterenol is used at all three receptors to determine maximal stimulation.
- the human ⁇ 3 AR-selective ligand (S)-N-[4-[2-[[2- hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-phenyl]-4- iodobenzenesulfonamide is used as a control in all assays.
- Isoproterenol is titrated at a final concentration in the assay of 10" 10 M to 10 ⁇ 5 M for the ⁇ 3 AR and 10" 1 M to 10" 6 M for the ⁇ l AR and ⁇ 2 AR assays.
- L- 742,791 is titrated at the ⁇ 3 receptor at concentration of 10"! 1 M to 10"6 M.
- concentrations used are 10" 8 M, 10" 7 M, 3X10" 7 M, 10-6 M, 3X10 "6 M and 10"5 M.
- B2 AR a single concentration of 10"5 M is used.
- Unknown ligands are initially tested at the ⁇ 3 AR at a final concentration in the assay of 10 ⁇ 7 M. Compounds that have an activation at this concentration equal to or greater than 35% of the isoproterenol stimulation are titrated at the ⁇ 3 AR at concentrations equal to those used to titrate the control (S)-N-[4-[2-[[2-hydroxy-3-(4- hydroxyphenoxy)propyl]amino]ethyl]-phenyl]-4- iodobenzenesulfonamide to determine the EC50.
- the EC50 is defined as the concentration of compound that gives 50% activation of its own maximum. Data are analyzed using the Prism program (GraphPan, San Diego, CA).
- a selective compound is defined as a compound with a (EC50 ⁇ 3 AR)/(IC50 ⁇ l AR, ⁇ 2 AR) greater than 100.
- IC50 is defined in the next section.
- Selective compounds are tested for agonist activity at the ⁇ l AR and the ⁇ 2 AR by assaying first at a single concentration, 10"5 M.
- Compounds with activations of less than 20% when compared to the isoproterenol control ( ⁇ l AR and ⁇ 2 AR) are retested at 10" 7 M and 10"5 M.
- Binding Assay Compounds are also assayed at the ⁇ l and B2 receptors to determine selectivity. This is done for all compounds using a 6 point binding assay as follows: CHO cells expressing the ⁇ l and the ⁇ 2 receptors are grown for 3-4 days after splitting. The attached cells are washed with PBS and lysed in ImM Tris, pH 7.2 for 10 minutes in ice. The flasks are scraped and the membranes centrifuged at 38,000 x g for 15 minutes at 4 °C. The membranes are resuspended in TME buffer (75 mM Tris, pH 7.4, 12.5 mM MgCl2, 1.5 mM EDTA) at a concentration of 1 mg protein/ml.
- TME buffer 75 mM Tris, pH 7.4, 12.5 mM MgCl2, 1.5 mM EDTA
- the binding assay is performed by incubating together membranes (20-50 ⁇ g of protein), the radiolabelled tracer 125 j_ cyanopindolol ( 25i_CYP, 45pM), and the test compounds at final concentrations ranging from 10" 0 M to 10-5 M in a final volume of 250 ⁇ L of TME buffer. The tubes are incubated for 1 hour with shaking at room temperature and the samples are filtered in an IMSCO 96-well cell harvester.
- the filters are counted in a Gamma counter and the data are analyzed using a 4 parameter fit routine in RS 1 (program developed in house using well documented statistical analysis programs) to determine the IC50.
- the IC50 is defined as the concentration of the compound capable of inhibiting 50% of the binding of the radiolabelled tracer (125j_c ⁇ p) Compounds having >100 fold selectivity are also tested for agonist activity at the ⁇ l and ⁇ 2 receptors following the protocols already described for the B3 AR above.
- Step A Preparation of the Resin-Bound Aniline.
- DIEA diisopropylethylamine
- the resin was thoroughly washed with THF/DCM until the eluate was colorless, treated with 2 mL of DIEA and 2 g of (R)-N-[2-[4- (aminophenyl)]ethyl]-2-hydroxy-2-(pyrid-3-yl)ethylamine (See Fisher, et. al., W09529159-A, Nov. 2, 1995, for the synthesis of this compound.) in 20 mL of DMF, and allowed to stir overnight. The resin was washed with DMF, treated with 2 mL of DIEA, 2 mL of triethylsilyl chloride and 10 mL of DMF, and allowed to stir overnight. The resin was then washed successively with 20% aqueous DMF, DMF, THF, iPrOH, ACOH and dichloromethane.
- Step B Preparation of the Resin-Bound Cyanobenzenesulfonamide .
- the above resin from Step A was treated with 3 mL of pyridine and 5 g of 4-cyanobenzenesulfonyl chloride in 30 mL dichloromethane and the reddish suspension was allowed to stir overnight.
- the resin was then washed successively with methanol, AcOH and dichloromethane and a small portion of the resin was cleaved with 1 : 1 dichloromethane/TFA and the purity was checked by HPLC.
- Step C Preparation of the Resin-Bound Amidoxime.
- the resultant cyano compound from Step B was suspended in 50 mL ethanol and treated with 3.6 g of powdered potassium carbonate and 1.8 g of hydroxylamine hydrochloride and stirred at 75 °C for 16 hrs. A small portion was cleaved as above and checked by HPLC, which indicated the presence of the desired amidoxime and the corresponding amide in a 9: 1 ratio. The resin was washed as above and used to prepare oxadiazoles as shown below.
- Step D Preparation of Resin-Bound Oxadiazoles.
- a 100-mg portion of the amidoxime resin (0.025 mmole) from Step C and 1 mL diglyme was allowed to swell for 15 min with stirring, and the excess diglyme was drained to the level of the top of resin.
- the tube was covered with a Teflon cover, vented to release excess pressure, and heated on a rack at 99 °C. After 5 minutes, it was vented again. Heating continued for 16 hrs.
- Step E Oxadiazole Final Products.
- the resin was treated with 1 : 1 TFA-DCM for 5 minutes.
- the solvent was drained, and the procedure was repeated.
- the combined eluants were concentrated to dryness to give the desired oxadiazole as its bistrifluoroacetic acid salt.
- the tBoc protecting group was then removed by stirring a dichloromethane solution (1 mL) of the compound with TFA (1 mL) at room temperature for 2 hr. Solvent and TFA were removed by a stream of nitrogen, and the residue was purified by flash column chromatography on silica gel, and eluted with 10% methanol (containing 1/10 aqueous ammonium hydroxide) in dichloromethane.
- Example 66 Following the procedure outlined in Example 66, the title compound was prepared: iH NMR (400 MHz, CDCI3) ⁇ 3.39 (s, 2H), 4.46 (broad, 2H), 7.0 (m, IH), 7.1 (m, 2H), 7.4 (very broad, IH).
- Step C (4-FluorophenyPmethoxyacetic acid.
- the above methyl ether methyl ester (1.01 g) and 3.67 mL of 2N aqueous sodium hydroxide in 14 mL of methanol at 0 °C was stirred at room temperature for 2 h.
- the mixture was evaporated, chilled in ice, acidified with 2N aqueous hydrochloric acid, extracted with ethyl acetate, washed with water and brine, and dried with magnesium sulfate. Evaporation yielded the corresponding carboxylic acid (1.0 g): Selected iH NMR (400 MHz, CDCI3) ⁇ 3.70 (s, 3H).
- Step E (R -N-r4-r2-rr2-hvdroxy-2-(pyridin-3- y ethvnamino1ethyl1phenyll-4-r5-r 1 -(4-fluorophenyl 1 - methoxymethyll-f 1.2.41-oxadiazol-3-yllbenzenesulfonamide.
- the above N-Boc compound from Step D was deprotected with 24 mL of trifluoroacetic acid in 36 mL of dichloromethane at 0 °C and at ambient temperature ovemight.
- Step A Methyl 4-trifluoromethylphenylacetate.
- a colorless solution of 4-trifluorophenylacetic acid (2.00 g, 9.8 mmol) in methanol (5 L) containing concentrated H2SO4 (0.5 mL) was heated at reflux for 3 h. After cooling to RT, the volume of methanol was reduced in vacuo. Ice was added and the mixture extracted with diethyl ether (3X).
- Step C (R)-N- 4-r2-ir2-Hvdroxy-2-(pyridin-3- yl)ethvnamino1ethvnphenvn-4-r5-ri-(4-trifluoromethylphenyl)-l- ethyl1- ⁇ .2.41-oxadiazol-3-yllbenzenesulfonamide.
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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AU33748/97A AU712057B2 (en) | 1996-06-07 | 1997-06-03 | Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity |
JP10500782A JP2000511903A (en) | 1996-06-07 | 1997-06-03 | Oxadiazole benzenesulfonamide as a selective beta 3 agonist for the treatment of diabetes and obesity |
EP97929769A EP0906310A4 (en) | 1996-06-07 | 1997-06-03 | OXADIAZOLE BENZENESULFONAMIDES AS SELECTIVE -g(b) 3? AGONISTS FOR THE TREATMENT OF DIABETES AND OBESITY |
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US1929596P | 1996-06-07 | 1996-06-07 | |
US60/019,295 | 1996-06-07 | ||
GB9614191.6 | 1996-07-05 | ||
GBGB9614191.6A GB9614191D0 (en) | 1996-07-05 | 1996-07-05 | Oxadiazole benzenesulfonamides as selectives B3 agonists for the treatment of diabetes and obesity |
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Also Published As
Publication number | Publication date |
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JP2000511903A (en) | 2000-09-12 |
EP0906310A4 (en) | 1999-09-01 |
EP0906310A1 (en) | 1999-04-07 |
AU3374897A (en) | 1998-01-05 |
CA2257206A1 (en) | 1997-12-11 |
AU712057B2 (en) | 1999-10-28 |
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