Title of Invention	SULFONAMIDE SUBSTITUTED XANTHINE COMPOUNDS FOR USE AS PEPCK INHIBITORS
Abstract	The present invention is concerned with sulfonamide substituted xanthine compounds of formula I or a phannaceutically acceptable salts thereof, wherein R1 , R2 and R3 are as defined in the specification. Compounds of formula I and phannaceutically acceptable salts or prodrugs thereof show activity as modulators of gluconeogenesis.

Full Text

The present invention is directed to sulfonamide substituted xanthine compounds for use as PEPCK inhibitors of formula I (Formula Removed) Compounds of formula I and pharmaceutically acceptable salts and prodrugs thereof are modulators of gluconeogenesis and are useful in the treatment of type 2 diabetes. The control of glucose production is one of the key aspects of anti-diabetic therapy. Type 2 diabetics have elevated levels of postprandial and fasting blood glucose (Consoli, A., Nurjhan, N., Capani, F. and Gerich, J. Diabetes 38, 550-7, 1989; Shulman, GI Am.J. Card. 84 (Suppl.lA):3J-10J, 1999). Excessive hepatic glucose production (HGP) contributes to the fasting hyperglycemia observed in patients with Type 2 diabetes (T2D) (Gastadelli, A., Baldi S., Pettiti M, Toschi, E., Camastra, S., Natali, A., Landau, B.R. & Ferranini, E., Diabetes 49:1367-1373, 2000). Gluconeogenesis is believed to be the major pathway for this increased glucose production (Defronzo, R.A., Bonadonna, R.C. and Ferrannini, E., Diabetes Care 15:318-367, 1992). Phosphoenolpyruvate carboxykinase (PEPCK) is a key regulatory enzyme in the gluconeogenic pathway. PEPCK is believed to be the flux controlling, rate limiting enzyme for this pathway (Cimbala, A.N., Lamers, W.H., Nelson, J.E., Monahan, J.E., Yoo-Warren, H., and Hanson R.W., J.Biol.Chem. 257:7629-7636, 1982), hence inhibition of this enzyme represents a novel way to improve glucose homeostasis. Previous attempts to control hepatic glucose production through inhibition of gluconeogeneis were limited to biguanides such as metformin, which inhibits HGP (Defronzo, R.A., Diabetes Reviews 6:89-131, 1998). Metformin has side effects such as gastrointestinal (GI) disturbances and lactic acidosis. Inhibition of PEPCK provides superior efficacy and, coupled with reduced side effects, represents a novel treatment for type 2 diabetes. The present invention is directed to a compound of formula (Formula Removed) wherein R1 is selected from the group consisting of lower alkyl, lower alkyl substituted by phenyl and lower alkyl substituted by halogen substituted phenyl; R2 is selected from the group consisting of lower alkyl and lower alkyl substituted by lower cycloalkyl; R3 is selected from the group consisting of (Formula Removed) R4 is selected from the group consisting of H and lower alkyl; R5 is selected from the group consisting of lower alkyl, amino lower alkyl, WE CLAIM: 1. Sulfonamide substituted xanthine compounds for use as PEPCK inhibitors of general formula I (Formula Removed) wherein R1 is selected from the group consisting of C1-7 alkyl, C1-7 alkyl substituted by phenyl and C1-7alkyl substituted by halogen substituted phenyl; R2 is selected from the group consisting of C1-7 alkyl and C1-7alkyl substituted by C3-7 cycloalkyl; R is selected from the group consisting of (Formula Removed) R4 is selected from the group consisting of H and C1-7 alkyl; R5 is selected from the group consisting of C1-7alkyl, aminoC1-7alkyl, C1-7alkyl substituted by phenyl, C2-7 alkenyl substituted by phenyl, phenyl, phenyl substituted by at least one substituent selected from the group consisting of C1-7 alkyl, C1-7 alkyl substituted by halogen, halogen,C1-7alkoxy, C1-7alkoxy substituted by halogen, nitro and acetamido, a 5-membered heteroaromatic ring having one heteroatom independently selected from the group consisting of N, O and S, the 5-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7alkyl, amino, alkyl amino and acetamido, a 5-membered heteroaromatic ring having two heteroatoms wherein a first heteroatom is N and a second heteroatom is independently selected from the group consisting of N, O and S, the 5-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido, a 6-membered heteroaromatic ring having one N, the 6-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7alkyl, halogen,carboxy C1-7alkyl, amino, alkyl amino and acetamido, (Formula Removed)wherein Ar is selected from the group consisting of a 5-membered heteroaromatic ring fused to the 6-membered ring, having one, two, or three heteroatoms, and wherein a first heteroatom is N, a second heteroatom is N and a third heteroatom is selected from the group consisting of O and S, a 6-membered aromatic ring fused to the 6-membered ring, having no or one N heteroatoms, the fused 6-membered aromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido; and R6 is selected from the group consisting of H, a 5-membered aromatic heterocyclic ring with one or two heteroatoms wherein a first heteroatom is N and a second heteroatom is selected from the group consisting of N and S, the 5-membered heterocyclic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido, and a 6-membered aromatic heterocyclic ring with one or two N heteroatoms, the 6-membered heterocyclic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido, or a pharmaceutically acceptable salts thereof. 2. A compound as claimed in claim 1 having general formula I (Formula Removed) wherein R1 is selected from the group consisting of C1-7 alkyl, C1-7 alkyl substituted by phenyl and C1-7 alkyl substituted by halogen substituted phenyl; R is selected from the group consisting of C1-7alkyl and C1-7 alkyl substituted by C3-7 cycloalkyl; R3 is selected from the group consisting of (Formula Removed) R4 is selected from the group consisting of H and C1-7 alkyl; R5 is selected from the group consisting of C1-7 alkyl, amino C1-7aalkyl, C1-7alkyl substituted by phenyl, C1-7 alkenyl substituted by phenyl, phenyl, phenyl substituted by at least one substituent selected from the group consisting of C1-7 alkyl, C1-7 alkyl substituted by halogen, halogen, C1-7 alkoxy, lower alkoxy substituted by halogen, nitro and acetamido, a 5-membered heteroaromatic ring having one heteroatom independently selected from the group consisting of N, O and S, the 5-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7, amino, alkyl amino and acetamido, a 5-membered heteroaromatic ring having two heteroatoms wherein a first heteroatom is N and a second heteroatom is independently selected from the group consisting of N, O and S, the 5-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxyC1-7 alkyl, amino, alkyl amino and acetamido, a 6-membered heteroaromatic ring having one N, the 6-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen,carboxy C1-7 alkyl, amino, alkyl amino and acetamido, (Formula Removed)wherein Ar is selected from the group consisting of a 5-membered heteroaromatic ring fused to the 6-membered ring, having one, two, or three heteroatoms, and wherein a first heteroatom is N, a second heteroatom is N and a third heteroatom is selected from the group consisting of O and S, a 6-membered aromatic ring fused to the 6-membered ring, having no or one N heteroatoms, the fused 6-membered aromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of lower alkyl, halogen, carboxy C1-7alkyl, amino, alkyl amino and acetamido; and R6 is selected from the group consisting of H, a 5-membered aromatic heterocyclic ring with one or two heteroatoms wherein a first heteroatom is N and a second heteroatom is selected from the group consisting of N and S, the 5-membered heterocyclic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7alkyl, amino, alkyl amino and acetamido, and a 6-membered aromatic heterocyclic ring with one or two N heteroatoms, the 6-membered heterocyclic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of lower alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido, or a pharmaceutically acceptable salts thereof. 3. A compound as claimed in claim 1 or 2 wherein R1 is C1-7 alkyl. 4. A compound as claimed in claim 1 or 2 wherein R1 is C1-7 alkyl substituted by phenyl. 5. A compound as claimed in any one of claims 1 to 4 wherein R is C1-7alkyl. 6. A compound as claimed in claim 1 having the formula (Formula Removed) 7. A compound as claimed in claim 6 wherein R is C1-7 alkyl. 8. A compound as claimed in claim 7 wherein R is n-butyl. 9. A compound as claimed in claim 6 wherein R is (Formula Removed) 10. A compound as claimed in claim 9 wherein R4 is H. 11 A compound as claimed in claim 9 wherein R5 is a 5-membered heteroaromatic ring having one heteroatom independently selected from the group consisting of N, O and S, the 5-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido. 12. A compound as claimed in claim 9 wherein R5 is a 5-membered heteroaromatic ring having two heteroatoms wherein a first heteroatom is N and a second heteroatom is independently selected from the group consisting of N, O and S, the 5-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido. 13. A compound as claimed in claim 9 wherein R5 is a 6-membered heteroaromatic ring having one N, the 6-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of lower alkyl, halogen, carboxy lower alkyl, amino, alkyl amino and acetamido. 14. A compound as claimed in claim 9 wherein R5 is where Ar is selected from the group consisting of a 5-membered heteroaromatic ring fused to the 6-membered ring, having one, two, or three heteroatoms, and wherein a first heteroatom is N, a second heteroatom is N and a third heteroatom is selected from the group consisting of O and S, and a 6-membered aromatic ring fused to the 6-membered ring, having no or one N heteroatoms, the fused 6-membered aromatic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7alkyl, amino, alkyl amino and acetamido. 15. A compound as claimed in claim 9 wherein R5 is C1-7 alkyl or C1-7 alkyl substituted by phenyl. 16. A compound as claimed in claim 9 wherein R5 is C1-7 alkenyl substituted by phenyl. 17. A compound as claimed in claim 9 wherein R5 is phenyl. 18. A compound as claimed in claim 9 wherein R5 is phenyl substituted by at least one substituent selected from the group consisting of C1-7 alkyl, C1-7alkyl substituted by halogen, halogen,C1-7 alkoxy, C1-7 alkoxy substituted by halogen, nitro and acetamido. 19. A compound as claimed in claim 18 wherein R5 is phenyl substituted by halogen. 20. A compound as claimed in claim 18 wherein R5 is phenyl substituted by C1-7 alkyl or C1-7 alkyl substituted by halogen. 21. A compound as claimed in claim 18 wherein the phenyl group has two or three substituents selected from the group consisting of lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy, lower alkoxy substituted by halogen, nitro and acetamido. 22. A compound as claimed in claim 6 wherein R is (Formula Removed) A compound as claimed in claim 22 wherein R6 is a 5-membered aromatic heterocyclic ring with one or two heteroatoms wherein a first heteroatom is N and a second heteroatom is selected from the group consisting of N and S, the 5-membered heterocyclic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido. 24. A compound as claimed in claim 22 wherein R6 is a 6-membered aromatic heterocyclic ring with one or two N heteroatoms, the 6-membered heterocyclic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido. 25. A compound as claimed in claim 6 wherein R is (Formula Removed) 26. A compound as claimed in claim 25 wherein R4 is H, and R5 is a 5-membered aromatic heterocyclic ring with one or two heteroatoms wherein a first heteroatom is N and a second heteroatom is selected from the group consisting of N and S, the 5-membered heterocyclic ring being unsubstituted or substituted by at least one substituent selected from the group consisting of C1-7 alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido. A compound as claimed in claim 6 wherein R2 is C1-7 alkyl substituted by cycloalkyl. 28. A compound as claimed in claim 8 has formula (Formula Removed) 29. A compound as claimed in claim 28 wherein R is (Formula Removed) 30. A compound as claimed in claim 29 wherein R4 is H. 31. A compound as claimed in claim 29 wherein R5 is a 5-membered heteroaromatic ring having two heteroatoms wherein a first heteroatom is N and a second heteroatom is independently selected fiom the group consisting of N, O and S, the 5-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected fiom the group consisting of C1-7alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido. 32. A compound as claimed in claim 29 wherein R5 is phenyl substituted by at least one substituent selected fiom the group consisting of C1-7 alkyl, C1-7 alkyl substituted by halogen, halogen, C1-7 alkoxy, C1-7 alkoxy substituted by halogen, nitro and acetamido. 33. A compound as claimed in claim 29 wherein R5 is a 6-membered heteroaromatic ring having one N, the 6-membered heteroaromatic ring being unsubstituted or substituted by at least one substituent selected fiom the group consisting of C1-7 alkyl, halogen, carboxy C1-7 alkyl, amino, alkyl amino and acetamido. 34. A compound as claimed in claim 29 wherein R5 is C1-7 alkyl. 35. A compound as claimed in claim 29 wherein R4 is C1-7 alkyl. 36. A compound as claimed in claim 1 or 2 wherein the compound is selected from the group consisting of 5-chloro-1,3-dimethyl-1 H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1 -(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-ylmethyl]-phenyl} -amide, 1-methyl-lH-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)-2,6-dioxo-23,6,7-tetrahydro-lH-purin-8-ylmemyl]-phenyl}-amide N- {4-[3-cyclopropylmethyl-1 -(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-ylmethyl]-phenyl}-3-methoxy-benzenesulfonamide, N- {4-[3-cyclopropylmethyl-1 -(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-ylmethyl]-phenyl}-3-fluoro-benzenesulfonamide, 5-bromo-6-chloro-pyridine-3-sulfonic acid {4-[3-cyclopropylmethyl-l-(2-fluoro-ben2yl)-2,6-dioxo-2,3,6,7-teti^ydro-lH-purin-8-ylmethyl]-phenyl}-amide, 5-chloro-l,3-dimethyl-lH-pyrazole-4-sulfonic acid {3-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)-2,6-dioxo-23)6,7-tetrahydro-lH-puim-8-ylmethyl]-phenyl}-amide, l,3-dimethyl-lH-pyrazole-4-sulfonic acid (4-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-ylmethyl]-phenyl}-amide, N-(5-{4-[3-cyclopropymiemyl-l-(2-fluoro-benzyl)-2,6-dioxo-2,3,6J-tetrahydro-lH-purm-8-ylmemyl]-phenylsulfamoyl}-4-memyl-thiazol-2-yl)-acetaniide, 2-amino-4-methyl-thiazole-5-sulfonic acid {4-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)-2,6^oxo-23,6,7-tetrahydro-lH-purm-8-ylmethyl]-phenyl}-amide trifluoro-acetic acid salt, 3,5-dimethyl-isoxazole-4-sulfonic acid {4-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)-2,6-dioxc-2,3,6,7-tetrahydro-lH-purm-8-ylmethyl]-phenyl}-amide, l,2-dimemyl-lH-imidazole-4-sulfonic acid {4-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)-2,6^oxo-2^,6,7-tetrahydro-lH-purm-8-ylmethyl]-phenyl}-amide, 1 -methyl- lH-imidazole-4-sulfonic acid {4-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)-2,6^oxo-2^,6,7-tetrahydro-lH-purm-8-ylmethyl]-phenyl}-amide, N- {4-[3-cyclopropylmethyl-1 -(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-ylmemyl]-phenyl}-N,N-dimethylsulfamide, 5-chloro-l1,3-dimethyl-lH-pyrazole-4-sulfonic acid {4-[3-cyclopropymethyl-l-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purm-8-ylmethyl]-phenyl-amide quinoline-8-sulfonic acid {4-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)o-dioxo-23,6,7-tetrahydro-1 H-purin-8-ylmethyl]-phenyl}-amide, N-(4-{4-[3-cyclopropymethyl-l-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenylsulfamoyl}-phenyl)-acetamide, N-[4-(l-benzyl-3-butyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl)-phenyl]-4- methyl-benzenesulfonamide, pyridine-3-sulfonic acid {4-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7- tetrahydro-lH-purin-8-ylmethyl]-phenyl}-amide trifluoro-acetic acid salt, N- {4-[3-cyclopropylmethyl-1 -(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin- 8-ylmethyl]-phenyl}-methanesulfonamide, N-[4-( 1 -benzyl-3-butyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-ylrnethyl)-phenyl]- methanesulfonamide, 5-chloro-l,3-dimethyl-lH-pyrazole-4-sulfonic acid {6-[3-butyi-l-(2-fluoro-benzyl)-2,6- dioxo-2,3,6,7-tetrahydro-1 H-purm-8-ylmethyl]-pyridin-3-yl}-amide, 5-chloro-l,3-dimemyl-lH-pyrazole-4-sulfonic acid {6-[3-cyclobutylmethyl-l-(2-fluoro- benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-ylmethyl]-pyridm-3-yl} -amide, l,3-dimethyl-lH-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-l-(2-fluoro-benzyl)- 2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-ylmethyl]-phenyl}-methyl-ainide, 4-[3-butyl-l-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purm-8-ylmem pyridin-2-yl-benzenesulfonamide, 4-[3-butyl-1 -(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-ylmethyl]-N- pyridin-4-yl-benzenesulfonamide, 4-[3-butyl-l-(2-fluoro-benzyl)-2,6^oxo-2,3,6,7-tetrahydro-lH-purm-8-ylmem pyridin-3-yl-benzenesulfonamide, 4-[3-butyl-1 -(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydn)-1 H-purm-8-ylmethyl]-N- pyrimidin-2-yl-benzenesulfonamide, and 4-[3-butyl-1 -(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-l H-purin-8-ylmethyl]-N- (1,3,5-trimethyl-1 H-pyrazol-4-yl)-benzenesulfonaniide. 37. A process for the preparation of sulfonamide substituted xanthine compound as claimed in any one of claims 1 to 36, which process comprises cyclising a compound of formula II (Formula Removed) wherein R , R and R are as defined in any one of claims 1 to 36 in alkaline lower aliphatic alcohol or refluxing in lower aliphatic alcohol, wherein lower aliphatic alcohol is having carbon atoms up to 7 to yield the compound of formula I. 38. Pharmaceutical compositions comprising a compound as claimed in any preceding claims 1 to 36 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 39. A compound as claimed in claim 1, including a pharmaceutically salt thereof is useful as therapeutic active substances for preparation of medicaments for treating the subjects suffering from diseases associated with phosphoenolpyruvate carboxykinase preferably type 2 diabetes. 40. Sulfonamide substituted xanthine compound for use as PEPCK inhibitors of general formula I, substantially as described hereinbefore.

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3686-DELNP-2005-Description (Complete)-(16-04-2009).pdf

3686-delnp-2005-description (complete).pdf

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