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Generated: August 19, 2017

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Title:Substituted indole-O-glucosides
Abstract: Substituted indole-O-glucosides, compositions containing them, and methods of using them, for example for the treatment of diabetes and Syndrome X are disclosed.
Inventor(s): Beavers; Mary Pat (New Hope, PA), Patel; Mona (Belle Mead, NJ), Rybczynski; Philip (Branchburg, NJ), Urbanski; Maud (Flemington, NJ), Zhang; Xiaoyan (Belle Mead, NJ)
Assignee: Janssen Pharmaceutica N.V (BE)
Filing Date:Jul 30, 2004
Application Number:10/903,233
Claims:1. A compound of formula (I) ##STR00048## wherein R.sub.1 is H, C.sub.1-4 alkyl, or R.sub.4R.sub.5N--(CO)--; each of R.sub.4 and R.sub.5 is independently C.sub.1-5 alkyl; R.sub.2 is H, F, Cl or C.sub.1-4 alkyl; R.sub.3 is H or C.sub.1-4 alkyl, provided that where R.sub.3 is C.sub.1-4 alkyl, then R.sub.2 is H; Q is --C(O)--, or --(CH.sub.2).sub.n-- where n=0, 1, or 2; P.dbd.H, C.sub.1-7 acyl, or (C.sub.1-6 alkoxy)carbonyl; Z is substituted or unsubstituted, and is selected from C.sub.3-7 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, a biaryl, a 9- or 10-membered fused bicyclyl or 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 compound of claim 1, wherein R.sub.1 is H.

3. A compound of claim 1, wherein R.sub.2 is H, methyl, or ethyl.

4. A compound of claim 1, wherein Q is --(CH.sub.2).sub.n-- and n is 1 or 2.

5. A compound of claim 1, wherein Z is unsubstituted or independently substituted with between 1 and 3 substituents independently selected from C.sub.1-4 alkoxy, phenoxy, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, halo, hydroxy, cyano, amino, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylsulfinyl, C.sub.1-4 aminoalkyl, mono and di (C.sub.1-4 alkyl)amino, phenyl, C.sub.1-4 alkylaminosulfonyl (SO.sub.2NHR), amino (C.sub.1-4 alkylsulfonyl) (NHSO.sub.2R), di C.sub.1-4 alkylaminosulfinyl (SONHRR), C.sub.1-4 alkylamido (NHCOR), C.sub.1-4 alkylcarbamido (CONHR), and 5 6 membered heterocyclyl containing between 1 and 3 heteroatoms independently selected from N, S, and O; and wherein the substituent(s) on Z can be further independently substituted with between 1 and 3 substituents independently selected from C.sub.1-4 alkoxy, C.sub.1-4 alkyl, halo, hydroxy, cyano, amino, mono- or di C.sub.1-4 alkylamino and C.sub.1-4 alkylthio.

6. A compound of claim 1, wherein Z is selected from 4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substituted or unsubstituted thiophene, biaryl, benzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl, indanyl, and naphthyl.

7. A compound of claim 5, wherein Z is unsubstituted or substituted with between 1 and 2 substituents independently selected from methoxy, ethoxy, fluoro, chloro, methyl, ethyl, propyl, butyl and isopropyl.

8. A compound of claim 1, wherein Z is biphenyl, 4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl, 4-(1H-pyrazol-1-yl)phenyl, 2-(5-phenyl)thiophenyl, (4-ethyl)phenyl, (4-propyl)phenyl, (4-methoxy)phenyl, dihydrobenzofuran-5-yl, or dihydrobenzofuran-6-yl.

9. A compound of claim 1, wherein R.sub.1 is H; and R.sub.2 is H, methyl, ethyl, propyl, or isopropyl.

10. A compound of claim 1 wherein Q is --(CH.sub.2).sub.n--; n is 1 or 2; and R.sub.2 is H, methyl or ethyl.

11. A compound of claim 1, wherein P is H, C.sub.1-3 acyl, or (C.sub.1-3 alkoxy)carbonyl.

12. A compound of claim 2, wherein R.sub.1 is H; R.sub.2 is H, methyl, or ethyl; Q is --(CH.sub.2).sub.n-- and n is 1 or 2; and Z is 4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substituted or unsubstituted thiophene, biaryl, benzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl, indanyl, and naphthyl.

13. A compound of claim 1 wherein R.sub.1 is H; R.sub.2 is H, methyl, or ethyl; wherein Z is 4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substituted or unsubstituted thiophene, biaryl, benzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl, indanyl, and naphthyl; and Z is unsubstituted or substituted with between 1 and 2 substituents independently selected from methoxy, ethoxy, fluoro, chloro, methyl, ethyl, propyl, butyl and isopropyl.

14. A compound of claim 1, selected from 2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-.beta.-D-g- lucopyranoside; 2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1-methyl-1H-indol-4-yloxy}-.- beta.-D-glucopyranoside; 2-{3-[2-(4-Methoxy-phenyl)-ethyl]-1H-indol-4-yloxy}-.beta.-D-glucopyranos- ide; 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-methoxycarbonyl-.beta.-D-gluc- opyranoside; 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-.beta.-D-gluco- pyranoside; 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-hexanoyl-.beta.-D-glucopyrano- side; 2-[3-(4-Methyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-(3-Biphenyl-4-ylmethyl-1H-indol-4-yloxy)-.beta.-D-glucopyranoside; 2-[3-(4-Ethoxy-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(4-Methylsulfanyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside- ; 2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indol-4-yloxy]-.beta.-D-glucopyranosid- e; 2-[3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranosid- e; and 2-[3-(4-Pyridin-3-yl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyrano- side.

15. A compound of claim 1, selected from 2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-6-O-acetyl- -.beta.-D-glucopyranoside; 2-[3-(2-Benzo[1,3]dioxol-5-yl-ethyl)-1H-indol-4-yloxy]-.beta.-D-glucopyra- noside; 2-{3-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1H-indol-4-ylox- y}-.beta.-D-glucopyranoside; 2-[3-(2-Naphthalen-2-yl-ethyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside- ; 2-{3-[2-(4-Ethoxy-phenyl)-ethyl]-1H-indol-4-yloxy}-.beta.-D-glucopyranos- ide; 2-{3-[2-(4-Methoxy-phenyl)-ethyl]-6-methyl-1H-indol-4-yloxy}-.beta.-D- -glucopyranoside; 2-[3-(3-Fluoro-4-methyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranosid- e; 2-[3-(4-Propyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(4-Isopropyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(2-Fluoro-biphenyl-4-ylmethyl)-1H-indol-4-yloxy]-.beta.-D-glucopyran- oside; 2-[3-(4-Methoxy-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(3-Fluoro-4-methoxy-benzyl)-1H-indol-4-yloxy]-D-glucopyranoside; 2-[3-(4-Phenoxy-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(4-Chloro-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-(3-Naphthalen-2-ylmethyl-1H-indol-4-yloxy)-.beta.-D-glucopyranoside and 2-[3-(4-Ethyl-benzyl)-2-methyl-1H-indol-4-yloxy]-.beta.-D-glucopyranoside- .

16. A compound of claim 1, selected from 2-{3-[2-(4-Ethyl-phenyl)-ethyl]-1H-indol-4-yloxy}-.beta.-D-glucopyranosid- e; 2-[1-Diethylcarbamoyl-3-(4-methoxy-benzyl)-1H-indol-4-yloxy]-.beta.-D-g- lucopyranoside; 2-[3-(4-Methoxy-benzyl)-1-methyl-1H-indol-4-yloxy]-.beta.-D-glucopyranosi- de; 2-[3-(4-Ethyl-benzyl)-1-isopropyl-1H-indol-4-yloxy]-.beta.-D-glucopyra- noside; 2-[3-Methyl-2-thienyl(-1H-indol-4-yloxy)-.beta.-D-glucopyranoside; 2-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-1H-indol-4-yloxy]-.beta.-D-gluco- pyranoside and 2-[3-(4-Ethylbenzoyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside and 2-[3-(4-Methoxy-phenyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside.

17. A compound from claim 1, selected from 2-[3-(4-Cyclopropyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(4-Pyrazol-1-yl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[6-Chloro-3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside- ; 2-[3-(4-Ethyl-benzyl)-6-fluoro-1H-indol-4-yloxy]-.beta.-D-glucopyranosid- e; 2-[3-(5-Ethyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-.beta.-D-glucopyra- noside; 2-[3-(5-Propyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-.beta.-D-glu- copyranoside; and 2-[3-(5-Phenyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-.beta.-D-glucopyran- oside.

18. A compound from claim 1, selected from: 2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}-.beta.-D-g- lucopyranoside; 2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1-methyl-1H-indol-4-yloxy}-.- beta.-D-glucopyranoside; 2-[3-(3-Fluoro-4-methyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranosid- e; 2-[3-(4-Methylsulfanyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranosi- de; 2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indol-4-yloxy]-.beta.-D-glucopyranos- ide; 2-[3-(4-Methyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-methoxycarbonyl-.beta.-D-gluc- opyranoside; 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-.beta.-D-gluco- pyranoside; 2-[3-(4-Propyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-(3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy)-.beta.-D-glucopyranoside; 2-[3-(4-Cyclopropyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(4-Pyrazol-1-yl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside, 2-[6-Chloro-3-(4-ethyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside- ; 2-[3-(4-Ethyl-benzyl)-6-fluoro-1H-indol-4-yloxy]-.beta.-D-glucopyranosid- e; 2-[3-(5-Ethyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-.beta.-D-glucopyra- noside and 2-[3-(5-Phenyl-thiophen-2-ylmethyl)-1H-indol-4-yloxy]-.beta.-D-- glucopyranoside.

19. A compound in claim 1, selected from 2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1H-indol-4-yloxy}.beta.-D-gl- ucopyranoside; 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-.beta.-D-glucopyranoside; 2-[3-(4-Ethyl-benzyl)-1H-indol-4-yloxy]-6-O-ethoxycarbonyl-.beta.-D-gluco- pyranoside; and 2-(3-(4-Thiophen-3-yl-benzyl)-1H-indol-4-yloxy)-.beta.-D-glucopyranoside.

20. A pharmaceutical composition, comprising a compound of claim 1, 5, 6, 11, 12, 14, 15, 16, 17, 18 or 19.

21. A pharmaceutical composition, comprising a compound selected from claim 18 or 19.
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