Details for Patent: 7,482,330
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Title: | Substituted fused heterocyclic C-glycosides |
Abstract: | This invention relates to substituted fused heterocyclic C-glycosides, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of diabetes and Syndrome X. |
Inventor(s): | Rybczynski; Philip (Branchburg, NJ), Urbanski; Maud (Flemington, NJ), Zhang; Xiaoyan (Belle Mead, NJ) |
Assignee: | Janssen Pharmaceutica N.V. (Beerse, BE) |
Filing Date: | Jun 15, 2006 |
Application Number: | 11/453,728 |
Claims: | 1. A method for treating diabetes in a mammal, said method comprising administering to a mammal in need of treatment an effective amount of a compound of formula (IV): ##STR00017## wherein: one of the dashed lines between NR.sub.1 and X or between X and Y is present, or both are absent; two of V, M, and W are H and the third is ##STR00018## R.sub.1 is H, or C.sub.1-4 alkyl; or, where the dashed line between NR.sup.1 and X is present, R.sub.1 is absent; X is N, C.dbd.O, CH, or C-Q-Z; Y is N-Q-Z or C-Q-Z, where X is N, C.dbd.O, or CH; Y is CH, where X is C-Q-Z; Q=--(CH.sub.2).sub.n-- where n=1 or 2; P=H, C.sub.1-7 acyl, or C.sub.1-6 alkoxycarbonyl; Z is substituted or unsubstituted, and is selected from C.sub.3-7 cycloalkyl, phenyl, a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, a biaryl, a 9- or 10-membered fused bicyclyl, and a fused heterobicyclyl, wherein said fused heterobicyclyl has between 1 and 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof. 2. A The method of claim 1, wherein said diabetes is type II diabetes. 3. A method for lowering serum glucose in a mammal, said method comprising administering to a mammal in need of treatment an effective amount of a compound of formula (IV): ##STR00019## wherein: one of the dashed lines between NR.sub.1 and X or between X and Y is present, or both are absent; two of V, M, and W are H and the third is ##STR00020## R.sub.1 is H, or C.sub.1-4 alkyl; or, where the dashed line between NR.sup.1 and X is present, R.sub.1 is absent; X is N, C.dbd.O, CH, or C-Q-Z; Y is N-Q-Z or C-Q-Z, where X is N, C.dbd.O, or CH; Y is CH, where X is C-Q-Z; Q=--(CH.sub.2).sub.n-- where n=1 or 2; P=H, C.sub.1-7 acyl, or C.sub.1-6 alkoxycarbonyl; Z is substituted or unsubstituted, and is selected from C.sub.3-7 cycloalkyl, phenyl, a 5- or 6- membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, a biaryl, a 9- or 10-membered fused bicyclyl, and a fused heterobicyclyl, wherein said fused heterobicyclyl has between 1 and 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof. 4. A method for treating diabetes or Syndrome X, or associated symptoms or complications thereof, said method comprising administering to a mammal in need of treatment an effective amount of a compound of formula (IV): ##STR00021## wherein: one of the dashed lines between NR.sub.1 and X or between X and Y is present. or both are absent; two of V, M, and W are H and the third is ##STR00022## R.sub.1 is H, or C.sub.1-4 alkyl; or, where the dashed line between NR.sup.1 and X is present, R.sub.1 is absent; X is N, C.dbd.O, CH, or C-Q-Z; Y is N-Q-Z or C-Q-Z, where X is N, C.dbd.O, or CH; Y is CH, where X is C-Q-Z; Q=--(CH.sub.2).sub.n-- where n=1 or 2; P=H, C.sub.1-7 acyl, or C.sub.1-6 alkoxycarbonyl; Z is substituted or unsubstituted, and is selected from C.sub.3-7 cycloalkyl, phenyl, a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, a biaryl, a 9-or 10-membered fused bicyclyl, and a fused heterobicyclyl, wherein said fused heterobicyclyl has between 1 and 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof. 5. The method of claim 4, wherein said diabetes or Syndrome X, or associated symptoms or complications thereof is selected from the group consisting of IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis, polycystic ovarian syndrome, hypertension, ischemia, stroke, heart disease, irritable bowel disorder, inflammation, and cataracts. 6. A method for reducing the body mass index, body weight, or percentage body fat in a mammal, said method comprising administering to a mammal in need of treatment an effective amount of a compound of formula (IV): ##STR00023## wherein: one of the dashed lines between NR.sub.1 and X or between X and Y is present, or both are absent; two of V, M, and W are H and the third is ##STR00024## R.sub.1 is H, or C.sub.1-4 alkyl; or, where the dashed line between NR.sup.1 and X is present, R.sub.1 is absent; X is N, C.dbd.O, CH, or C-Q-Z; Y is N-Q-Z or C-Q-Z, where X is N, C.dbd.O, or CH; Y is CH, where X is C-Q-Z; Q=--(CH.sub.2).sub.n-- where n=1 or 2; P=H, C.sub.1-7 acyl, or C.sub.1-6 alkoxycarbonyl; Z is substituted or unsubstituted. and is selected from C.sub.3-7 cycloalkyl, phenyl, a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, a biaryl, a 9- or 10-membered fused bicyclyl, and a fused heterobicyclyl, wherein said fused heterobicyclyl has between 1 and 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof. 7. The method of claim 6, wherein said reduction of body mass index is a method for treating obesity or an overweight condition. 8. A method for inhibiting the sodium glucose transporter in a cell, by exposing said cell to a compound of formula (IV): ##STR00025## wherein: one of the dashed lines between NR.sub.1 and X or between X and Y is present. or both are absent: two of V, M, and W are H and the third is ##STR00026## R.sub.1 is H, or C.sub.1-4 alkyl; or, where the dashed line between NR.sup.1 and X is present, R.sub.1 is absent; X is N, C.dbd.O, CH, or C-Q-Z; Y is N-Q-Z or C-Q-Z, where X is N, C.dbd.O, or CH; Y is CH, where X is C-Q-Z; Q=--(CH.sub.2).sub.n-- where n=1 or 2; P=H, C.sub.1-7 acyl, or C.sub.1-6 alkoxycarbonvl; Z is substituted or unsubstituted. and is selected from C.sub.3-7 cycloalkyl, phenyl, a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, a biaryl, a 9- or 10-membered fused bicyclyl, and a fused heterobicyclyl, wherein said fused heterobicyclyl has between 1 and 4 heteroatoms independently selected from N, O, and S; or a metabolite thereof. 9. A method for treating diabetes or Syndrome X, or associated symptoms or complications thereof in a subject in need thereof, comprising a) administering to said subject a jointly effective amount of a compound of formula (IV) ##STR00027## wherein: one of the dashed lines between NR.sub.1 and X or between X and Y is present, or both are absent; two of V, M, and W are H and the third is ##STR00028## R.sub.1 is H, or C.sub.1-4 alkyl; or, where the dashed line between NR.sup.1 and X is present, R.sub.1 is absent; X is N, C.dbd.O, CH, or C-Q-Z; Y is N-Q-Z or C-Q-Z, where X is N, C.dbd.O, or CH; Y is CH, where X is C-Q-Z; Q=--(CH.sub.2).sub.n-- where n=1 or 2; P=H, C.sub.1-7 acyl, or C.sub.1-6 alkoxycarbonyl; Z is substituted or unsubstituted, and is selected from C.sub.3-7 cycloalkyl, phenyl, a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, a biaryl, a 9- or 10-membered fused bicyclyl, and a fused heterobicyclyl, wherein said fused heterobicyclyl has between 1 and 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt, thereof; and b) administering to said subject a jointly effective amount of an RXR agonist, said co-administration being in any order and the combined jointly effective amounts providing the desired therapeutic effect. 10. The method of claim 9, wherein the diabetes or Syndrome X, or associated symptoms or complications thereof is selected from the group consisting of IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis, polycystic ovarian syndrome, hypertension, ischemia, stroke, heart disease, irritable bowel disorder, inflammation, and cataracts. 11. The method of claim 9 wherein the diabetes or Syndrome X, or associated symptoms or complication thereof is IDDM. 12. The method of claim 9, wherein the diabetes or Syndrome X, or associated symptoms or complications thereof is NIDDM. 13. The method of claim 9, wherein the diabetes or Syndrome X, or associated symptoms or complications thereof is IGT or IFG. 14. The method of claim 9, wherein the jointly effective amount of the compound of formula (IV) is from about 10 to 1000 mg. 15. The method of claim 9, wherein the jointly effective amount of the compound of formula (IV) is an amount sufficient to reduce the plasma glucose excretion following a meal. |