CA2509981A1 - Hetero substitued sodium channel blockers - Google Patents
Hetero substitued sodium channel blockers Download PDFInfo
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- CA2509981A1 CA2509981A1 CA002509981A CA2509981A CA2509981A1 CA 2509981 A1 CA2509981 A1 CA 2509981A1 CA 002509981 A CA002509981 A CA 002509981A CA 2509981 A CA2509981 A CA 2509981A CA 2509981 A1 CA2509981 A1 CA 2509981A1
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Abstract
The present invention relates to novel pyrazinoylguanidine compounds and methods of using the same.
Claims (157)
1. A pyrazinoylguanidine compound represented by formula (I):
where X is hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl;
Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen, lower alkyl, unsubstituted or substituted mononuclear aryl, or -N(R2)2;
R1 is hydrogen or lower alkyl;
each R2 is, independently, -R7, -(CH2)m-OR8, -(CH2)m-NR7R10, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, -(CH2)n-Z g-R7,-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, or wherein when two -CH2OR8 groups are located 1,2- or 1,3- with respect to each other the R8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
R3 and R4 are each, independently, hydrogen, a group represented by formula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-lower alkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower (alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-lower alkyl, with the proviso that at least one of R3 and R4 is a group represented by formula (A):
wherein each R L is, independently, -R7, -(CH2)n-OR8, -O-(CH2)m-OR8, -(CH2)n-NR7R10, -O-(CH2)n-NR7R10, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)n,(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m-R8, -O-(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -O-(CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, -O-(CH2)m-C(=O)NR7R10, -(CH2)n-(Z)g-R7, -O-(CH2)m-(Z)g-R7, -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, -O-(CH2)m-CO2R7, -OSO3H, -O-glucuronide, -O-glucose, wherein when two -CH2OR8 groups are located 1,2- or 1,3- with respect to each other the R8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
each o is, independently, an integer from 0 to 10;
each p is an integer from 0 to 10;
with the proviso that the sum of o and p in each contiguous chain is from 1 to 10;
each x is, independently, O, NR10, C(=O), CHOH, C(=N-R10), CHNR7R10, or represents a single bond;
each R5 is, independently, -(CH2)n-NR12R12, -O-(CH2)m-NR12R12, -O-(CH2)m-(Z)g R12, -(CH2)n NR11R11, -O-(CH2)m NR11R11, -(CH2)n N~-(R11l)3, -O-(CH2)m-N~-(R11)3, -(CH2)n-(Z)g-(CH2)m-NR10R10, -O-(CH2)m-(Z)g-(CH2)m-NR10R10, -(CH2CH2O)m-CH2CH2NR12R12, -O-(CH2CH2O)m-CH2CH2NR12R12, -(CH2)n-(C=O)NR12R12, -O-(CH2)m-(C=O)NR12R12,-O-(CH2)m-(CHOR8)m CH2NR10-(Z)g-R10, -(CH2)n(CHOR8)m CH2-NR10-(Z)g-R10, -(CH2)n NR10-(CH2)m(CHOR8)n CH2NR10-(Z)g-R10, -O(CH2)m-NR10-(CH2)m-(CHOR8)n CH2NR10-(Z)g-R10, -(Het)-(CH2)m-OR8, -(Het)-(CH2)m-NR7R10, -(Het)-(CH2)2-7(CHOR8)(CHOR8)n-CH2OR8, -(Het)-(CH2CH2O)m-R8, -(Het)-(CH2CH2O)m-CH2CH2NR7R10, -(Het)-(CH2)m-C(=O)NR7R10, -(Het)-(CH2)m-(Z)g-R7, -(Het)-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(Het)-(CH2)m-CO2R7, -(Het)-(CH2)m-NR12R12, -(Het)-(CH2)n-NR12R12, -(Het)-(CH2)m-(Z)g R12, -(Het)-(CH2)m-NR12R12, -(Het)-(CH2)m-N~-(R11)3, -(Het)-(CH2)m-(Z)g-(CH2)m-NR10R10, -(Het)-(CH2CH2O)m-CH2CH2NR12R12, -(Het)-(CH2)m-(C=O)NR12R12, -(Het)-(CH2)m-(CHOR8)m CH2NR10-(Z)g-R10, -(Het)-(CH2)m-NR10-(CH2)m-(CHOR8)n CH2NR10-(Z)g-R10, -C(=O)NH-(CH2)m-NH-C(=NH)-N(R7)2, or NH-C(=O)-(CH2)m NH-C(=NH)-N(R10)2, wherein when two -CH2OR8 groups are located 1,2- or 1,3- with respect to each other the R8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono-or di-substituted 1,3-dioxane or 1,3-dioxolane, -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, or -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
each R6 is, independently, -R5, -R7, -OR8, -N(R7)2, -(CH2)m-OR8, -O-(CH2)m-OR8, -(CH2)n-NR7R10, -O-(CH2)m-NR7R10, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m-R8, -O-(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -O-(CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, -O-(CH2)m-C(=O)NR7R10,-(CH2)n-(Z)g-R7,-O-(CH2)m-(Z)g-R7, -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, -O-(CH2)m-CO2R7, -OSO3H, -O-glucuroriide, -O-glucose, wherein when two R6 are -OR11 and are located adjacent to each other on a phenyl ring, the alkyl moieties of the two R6 may be bonded together to form a methylenedioxy group, and wherein when two -CH2OR8 groups are located 1,2- or 1,3- with respect to each other the R8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
each R7 is, independently, hydrogen or lower alkyl;
each R8 is, independently, hydrogen, lower alkyl, -C(=O)-R11, glucuronide, 2-tetrahydropyranyl, or each R9 is, independently, -CO2R7, -CON(R7)2, -SO2CH3, or -C(=O)R7;
each R10 is, independently, -H, -SO2CH3, -CO2R7, -C(=O)NR7R9, -C(=O)R7, or -CH2-(CHOH)n-CH2OH;
each Z is, independently, CHOH, C(=O), CHNR7R10, C=NR10, or NR10;
each R11 is, independently, lower alkyl;
each R12 is independently, -SO2CH3, -CO2R7, -C(=O)NR7R9, -C(=O)R7, or -CH2-(CHOH)n-CH2OH;
each Het is independently, -NR7,-NR10, -S-, -SO-, or -SO2-;
each g is, independently, an integer from 1 to 6;
each m is, independently, an integer from 1 to 7;
each n is, independently, an integer from 0 to 7;
each Q is, independently, C-R5, C-R6, or a nitrogen atom, wherein at most three Q in a ring are nitrogen atoms;
or a pharmaceutically acceptable salt thereof, and inclusive of all enantiomers, diastereomers, and racemic mixtures thereof.
where X is hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl;
Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen, lower alkyl, unsubstituted or substituted mononuclear aryl, or -N(R2)2;
R1 is hydrogen or lower alkyl;
each R2 is, independently, -R7, -(CH2)m-OR8, -(CH2)m-NR7R10, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, -(CH2)n-Z g-R7,-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, or wherein when two -CH2OR8 groups are located 1,2- or 1,3- with respect to each other the R8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
R3 and R4 are each, independently, hydrogen, a group represented by formula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-lower alkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower (alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-lower alkyl, with the proviso that at least one of R3 and R4 is a group represented by formula (A):
wherein each R L is, independently, -R7, -(CH2)n-OR8, -O-(CH2)m-OR8, -(CH2)n-NR7R10, -O-(CH2)n-NR7R10, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)n,(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m-R8, -O-(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -O-(CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, -O-(CH2)m-C(=O)NR7R10, -(CH2)n-(Z)g-R7, -O-(CH2)m-(Z)g-R7, -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, -O-(CH2)m-CO2R7, -OSO3H, -O-glucuronide, -O-glucose, wherein when two -CH2OR8 groups are located 1,2- or 1,3- with respect to each other the R8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
each o is, independently, an integer from 0 to 10;
each p is an integer from 0 to 10;
with the proviso that the sum of o and p in each contiguous chain is from 1 to 10;
each x is, independently, O, NR10, C(=O), CHOH, C(=N-R10), CHNR7R10, or represents a single bond;
each R5 is, independently, -(CH2)n-NR12R12, -O-(CH2)m-NR12R12, -O-(CH2)m-(Z)g R12, -(CH2)n NR11R11, -O-(CH2)m NR11R11, -(CH2)n N~-(R11l)3, -O-(CH2)m-N~-(R11)3, -(CH2)n-(Z)g-(CH2)m-NR10R10, -O-(CH2)m-(Z)g-(CH2)m-NR10R10, -(CH2CH2O)m-CH2CH2NR12R12, -O-(CH2CH2O)m-CH2CH2NR12R12, -(CH2)n-(C=O)NR12R12, -O-(CH2)m-(C=O)NR12R12,-O-(CH2)m-(CHOR8)m CH2NR10-(Z)g-R10, -(CH2)n(CHOR8)m CH2-NR10-(Z)g-R10, -(CH2)n NR10-(CH2)m(CHOR8)n CH2NR10-(Z)g-R10, -O(CH2)m-NR10-(CH2)m-(CHOR8)n CH2NR10-(Z)g-R10, -(Het)-(CH2)m-OR8, -(Het)-(CH2)m-NR7R10, -(Het)-(CH2)2-7(CHOR8)(CHOR8)n-CH2OR8, -(Het)-(CH2CH2O)m-R8, -(Het)-(CH2CH2O)m-CH2CH2NR7R10, -(Het)-(CH2)m-C(=O)NR7R10, -(Het)-(CH2)m-(Z)g-R7, -(Het)-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(Het)-(CH2)m-CO2R7, -(Het)-(CH2)m-NR12R12, -(Het)-(CH2)n-NR12R12, -(Het)-(CH2)m-(Z)g R12, -(Het)-(CH2)m-NR12R12, -(Het)-(CH2)m-N~-(R11)3, -(Het)-(CH2)m-(Z)g-(CH2)m-NR10R10, -(Het)-(CH2CH2O)m-CH2CH2NR12R12, -(Het)-(CH2)m-(C=O)NR12R12, -(Het)-(CH2)m-(CHOR8)m CH2NR10-(Z)g-R10, -(Het)-(CH2)m-NR10-(CH2)m-(CHOR8)n CH2NR10-(Z)g-R10, -C(=O)NH-(CH2)m-NH-C(=NH)-N(R7)2, or NH-C(=O)-(CH2)m NH-C(=NH)-N(R10)2, wherein when two -CH2OR8 groups are located 1,2- or 1,3- with respect to each other the R8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono-or di-substituted 1,3-dioxane or 1,3-dioxolane, -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, or -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
each R6 is, independently, -R5, -R7, -OR8, -N(R7)2, -(CH2)m-OR8, -O-(CH2)m-OR8, -(CH2)n-NR7R10, -O-(CH2)m-NR7R10, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m-R8, -O-(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -O-(CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, -O-(CH2)m-C(=O)NR7R10,-(CH2)n-(Z)g-R7,-O-(CH2)m-(Z)g-R7, -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, -O-(CH2)m-CO2R7, -OSO3H, -O-glucuroriide, -O-glucose, wherein when two R6 are -OR11 and are located adjacent to each other on a phenyl ring, the alkyl moieties of the two R6 may be bonded together to form a methylenedioxy group, and wherein when two -CH2OR8 groups are located 1,2- or 1,3- with respect to each other the R8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
each R7 is, independently, hydrogen or lower alkyl;
each R8 is, independently, hydrogen, lower alkyl, -C(=O)-R11, glucuronide, 2-tetrahydropyranyl, or each R9 is, independently, -CO2R7, -CON(R7)2, -SO2CH3, or -C(=O)R7;
each R10 is, independently, -H, -SO2CH3, -CO2R7, -C(=O)NR7R9, -C(=O)R7, or -CH2-(CHOH)n-CH2OH;
each Z is, independently, CHOH, C(=O), CHNR7R10, C=NR10, or NR10;
each R11 is, independently, lower alkyl;
each R12 is independently, -SO2CH3, -CO2R7, -C(=O)NR7R9, -C(=O)R7, or -CH2-(CHOH)n-CH2OH;
each Het is independently, -NR7,-NR10, -S-, -SO-, or -SO2-;
each g is, independently, an integer from 1 to 6;
each m is, independently, an integer from 1 to 7;
each n is, independently, an integer from 0 to 7;
each Q is, independently, C-R5, C-R6, or a nitrogen atom, wherein at most three Q in a ring are nitrogen atoms;
or a pharmaceutically acceptable salt thereof, and inclusive of all enantiomers, diastereomers, and racemic mixtures thereof.
2. The compound of Claim 1, wherein R5 is -(CH2)n-N(SO2R7)2.
3. The compound of Claim 1, wherein R5 is -O-(CH2)m-N(SO2R7)2.
4. The compound of Claim 1, wherein R5 is -(CH2)n-CHNHBocCO2R7 (.alpha.).
5. The compound of Claim 1, wherein R5 is -O-(CH2)m-CHNHBocCO2R7 (.alpha.).
6. The compound of Claim 1, wherein R5 is -(CH2)n-N(R11)2.
7. The compound of Claim 1, wherein R5 is -O-(CH2)m-N(R11)2.
8. The compound of Claim 1, wherein R5 is -(CH2)n-CHNH2CO2CH3 (.alpha.).
9. The compound of Claim 1, wherein R5 is -O-(CH2)m-CHNH2CO2R7 (.alpha.).
10. The compound of Claim 1, wherein R5 is -O-(CH2)m-N+(R11)3.
11. The compound of Claim 1, wherein R5 is -(Z)g-(CH2)m-N(R10)2 [-(Z)g-(CH2)m-N(R11)2].
12. The compound of Claim 1, wherein R5 is -C(=O)NH-(CH2)m-N(R7)2.
13. The compound of Claim 1, wherein R5 is -NHC(=O)(CH2)m-N(R7)2.
14. The compound of Claim 1, wherein R5 is -C(=O)NH-(CH2)m-NH-C(=NH)-N(R7)2.
15. The compound of Claim 1, wherein R5 is NH-C(=O)-(CH2)m NH-C(=NH)-N(R7)2.
16. The compound of Claim 1, wherein R5 is -(CH2)n-NH-C(=NBoc)-NHBoc.
17. The compound of Claim 1, wherein R5 is -O-CH2-CHOH-CH2-NH-C(=NBoc)-NBoc.
18. The compound of Claim 1, wherein R5 is -(CH2)n-NR10CH2(CHOR8)n-(Z g)-R7.
19. The compound of Claim 1, wherein R5 is -O(CH2)m NR10CH2(CHOR8)n-(Z)g-R7.
20. The compound of Claim 19, represented by the formula:
21. The compound of Claim 1, wherein Y is -NH2.
22. The compound of Claim 21, wherein R2 is hydrogen.
23. The compound of Claim 22, wherein R1 is hydrogen.
24. The compound of Claim 23, wherein X is chlorine.
25. The compound of Claim 24, wherein R3 is hydrogen.
26. The compound of Claim 25, wherein each R L is hydrogen.
27. The compound of Claim 26, wherein o is 4.
28. The compound of Claim 27, wherein p is 0.
29. The compound of Claim 28, wherein x represents a single bond.
30. The compound of Claim 29, wherein each R6 is hydrogen.
31. The compound of Claim 30, wherein at most one Q is a nitrogen atom.
32. The compound of Claim 31, wherein R5 is -(CH2)n-NR12R12.
33. The compound of Claim 32, wherein R5 is -(CH2)n-N(SO2R7)2.
34. The compound of Claim 33, which is represented by the formula:
35. The compound Claim of 31, wherein R5 is -O-(CH2)m-NR12R12.
36. The compound of Claim 31, wherein R5 is -O-(CH2)m-N(SO2R7)2.
37. The compound of Claim 31, wherein R5 is -O-(CH2)m-(Z)g R12.
38. The compound of Claim 37, which is represented by the formula:
39. The compounds of Claim 37, which is represented by the formula:
40. The compound of Claim 31, wherein R5 is -(CH2)n-CHNHBocCO2R7 (.alpha.).
41. The compound of Claim 40, wherein R5 is -O-(CH2)m-CHNHBocCO2R7 (.alpha.).
42. The compound of Claim 41, which is represented by the formula:
43. The compound of Claim 31, wherein R5 is -(CH2)n-N(R11)2.
44. The compound of Claim 31, wherein R5 is -O-(CH2)m-N(R11)2.
45. The compound of Claim 44, which is represented by the formula:
46. The compound of Claim 31, wherein R5 is -(CH2)n-CHNH2CO2R7 (.alpha.).
47. The compound of Claim 46, which is represented by the formula:
48. The compound of Claim 46, which is represented by the formula:
49. The compound of Claim 31, wherein R5 is -O-(CH2)m-CHNH2CO2R7 (.alpha.).
50. The compound of Claim 49, which is represented by the formula:
51. The compound of Claim 49, which is represented by the formula:
52. The compound of Claim 31, wherein R5 is -O-(CH2)m-N+(R11)3.
53. The compound of Claim 52, which is represented by the formula:
54. The compound of Claim 31, wherein R5 is -(CH2)n -(Z)g-(CH2)m-NR10R10.
55. The compound of Claim 54, wherein R5 is -C(=O)NH-(CH2)m-N(R10)2.
56. The compound of Claim 55, which is represented by the formula:
57. The compound of Claim 54, wherein R5 is -NHC(=O)(CH2)m-N(R10)2.
58. The compound of Claim 57, which is represented by the formula:
59. The compound of Claim 1, wherein R5 is -C(=O)NH-(CH2)m-NH-C(=NH)-N(R7)2.
60. The compound of Claim 59, which is represented by the formula:
61. The compound of Claim 54, wherein R5 is NH-C(=O)-(CH2)m NH-C(=NH)-N(R10)2.
62. The compound of Claim 61, which is represented by the formula:
63. The compound of Claim 31, wherein R5 is -O-(CH2)m-(CHOR8)m CH2NR10-(Z)g-R10.
64. The compound of Claim 63, which is represented by the formula:
65. The compound of Claim 31, wherein R5 is -(CH2)n-(CHOR8)m CH2-NR10-(Z)g-R10.
66. The compound of Claim 31, wherein R5 is -(CH2)n NR10-(CH2)m(CHOR8)n CH2NR10-(Z)g-R10.
67. The compound of Claim 31, wherein R5 is -O(CH2)m-NR10-(CH2)m-(CHOH8)n CH2NR10-(Z)g-R10.
68. The compound of Claim 31, wherein R5 is -(CH2CH2O)m-CH2CH2NR12R12.
69. The compound of Claim 31, wherein R5 is -O-(CH2CH2O)m-CH2CH2NR12R12.
70. The compound of Claim 31, wherein R5 is -(CH2)n-(C=O)NR12R12.
71. The compound of Claim 31, wherein R5 is -O-(CH2)m-(C=O)NR12R12.
72. The compound of Claim 71, which is represented by the formula:
73. The compound of Claim 31, wherein R5 is -(Het)-(CH2)m-OR8.
74. The compound of Claim 31, wherein R5 is -(Het)-(CH2)m-NR7R10.
75. The compound of Claim 74, which is represented by the formula:
76. The compound of Claim 31, wherein R5 is -(Het)-(CH2)2-7(CHOR8)(CHOR8)n-CH2OR8.
77. The compound of Claim 31, wherein R5 is -(Het)-(CH2CH2O)m-R8.
78. The compound of Claim 31, wherein R5 is -(Het)-(CH2CH2O)m-CH2CH2NR7R10.
79. The compound of Claim 31, wherein R5 is -(Het)-(CH2)m-C(=O)NR7R10.
80. The compound of Claim 79, which is represented by the formula:
81. The compound of Claim 79, which is represented by the formula:
82. The compound of Claim 79, which is represented by the formula:
83. The compound of Claim 79, which is represented by the formula:
84. The compound of Claim 79, which is represented by the formula:
85. The compound of Claim 79, which is represented by the formula:
86. The compound of Claim 31, wherein R5 is -(Het)-(CH2)m-(Z)g-R7.
87. The compound of Claim 86, which is represented by the formula:
88. The compound of Claim 31, wherein R5 is -(Het)-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8.
89. The compound of Claim 88, which is represented by the formula:
90. The compound of Claim 88, which is represented by the formula:
91. The compound of Claim 88, which is represented by the formula:
92. The compound of Claim 88, which is represented by the formula:
93. The compound of Claim 31, wherein R5 is -(Het)-(CH2)m-CO2R7.
94. The compound of Claim 93, which is represented by the formula:
95. The compound of Claim-31, wherein R5 is -(Het)-(CH2)m-NR12R12.
96. The compound of Claim-31, wherein R5 is -(Het)-(CH2)n-NR12R12.
97. The compound of Claim-31, wherein R5 is -(Het)-(CH2)m-(Z)g-R12.
98. The compound of Claim-31, wherein R5 is -(Het)-(CH2)m NR11R11.
99. The compound of Claim-31, wherein R5 is -(Het)-(CH2)m-N~-(R11)3 [or -(Het)-(CH2)m-(Z)g-(CH2)m-NR10R10].
100. The compound of Claim-31, wherein R5 is -(Het)-(CH2CH2O)m-CH2CH2NR12R12.
101. The compound of Claim-31, wherein R5 is -(Het)-(CH2)m-(C=O)NR12R12.
102. The compound of Claim-31, wherein R5 is -(Het)-(CH2)m-(CHOR8)m-CH2NR10-(Z)g-R10.
103. The compound of Claim-31, wherein R5 is -(Het)-(CH2)m-NR10-(CH2)m-(CHOR8)n CH2NR10-(Z)g-R10.
104. The compound of Claim-31, wherein R5 is -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane.
105. The compound of Claim-31, wherein R5 is -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane.
106. The compound of Claim 31, wherein R5 is -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane.
107. The compound of Claim 31, wherein R5 is -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane.
108. The compound of Claim 1, which is represented by the formula:
109. The compound of Claim 1, which is represented by the formula:
110. The compound of Claim 1, which is represented by the formula:
111. The compound of Claim 1, which is represented by the formula:
112. The compound of Claim 1, which is represented by the formula:
113. The compound of claim 1, which is represented by the formula:
114. The compound of Claim 1, wherein X is halogen;
Y is -N(R7)2;
R1 is hydrogen or C1-C3 alkyl;
R2 is -R7, -(CH2)m-OR8, or -(CH2)n-CO2R7;
R3 is a group represented by formula (A); and R4 is hydrogen, a group represented by formula (A), or lower alkyl.
Y is -N(R7)2;
R1 is hydrogen or C1-C3 alkyl;
R2 is -R7, -(CH2)m-OR8, or -(CH2)n-CO2R7;
R3 is a group represented by formula (A); and R4 is hydrogen, a group represented by formula (A), or lower alkyl.
115. The compound of Claim 94, wherein X is chloro or bromo;
Y is -N(R7)2;
R2 is hydrogen or C1-C3 alkyl;
at most three R6 are other than hydrogen as defined above;
at most three R L are other than hydrogen as defined above; and at most 2 Q are nitrogen atoms.
Y is -N(R7)2;
R2 is hydrogen or C1-C3 alkyl;
at most three R6 are other than hydrogen as defined above;
at most three R L are other than hydrogen as defined above; and at most 2 Q are nitrogen atoms.
116. The compound of Claim 95, wherein Y is -NH2.
117. The compound of Claim 96, wherein R4 is hydrogen;
at most one R L is other than hydrogen as defined above;
at most two R6 are other than hydrogen as defined above; and at most 1 Q is a nitrogen atom.
at most one R L is other than hydrogen as defined above;
at most two R6 are other than hydrogen as defined above; and at most 1 Q is a nitrogen atom.
118. A pharmaceutical composition, comprising the compound of Claim 1 and a pharmaceutically acceptable carrier.
119. A composition, comprising:
the compound of Claim 1; and a P2Y2 inhibitor.
the compound of Claim 1; and a P2Y2 inhibitor.
120. A composition, comprising:
the compound of Claim 1; and a bronchodilator.
the compound of Claim 1; and a bronchodilator.
121. A method of promoting hydration of mucosal surfaces, comprising:
administering an effective amount of the compound of Claim 1 to a mucosal surface of a subject.
administering an effective amount of the compound of Claim 1 to a mucosal surface of a subject.
122. A method of restoring mucosal defense, comprising:
topically administering an effective amount of the compound of Claim 1 to a mucosal surface of a subject in need thereof.
topically administering an effective amount of the compound of Claim 1 to a mucosal surface of a subject in need thereof.
123. A method of blocking sodium channels, comprising:
contacting sodium channels with an effective amount of the compound of Claim 1.
contacting sodium channels with an effective amount of the compound of Claim 1.
124. A method of treating chronic bronchitis, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
125. A method of treating cystic fibrosis, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
126. A method of treating sinusitis, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
127. A method of treating vaginal dryness, comprising:
administering an effective amount of the compound of Claim 1 to the vaginal tract of a subject in need thereof.
administering an effective amount of the compound of Claim 1 to the vaginal tract of a subject in need thereof.
128. A method of treating dry eye, comprising:
administering an effective amount of the compound of Claim 1 to the eye of a subject in need thereof.
administering an effective amount of the compound of Claim 1 to the eye of a subject in need thereof.
129. A method of promoting ocular hydration, comprising:
administering an effective amount of the compound of Claim 1 to the eye of a subject.
administering an effective amount of the compound of Claim 1 to the eye of a subject.
130. A method of promoting corneal hydration, comprising:
administering an effective amount of the compound of Claim 1 to the eye of a subject.
administering an effective amount of the compound of Claim 1 to the eye of a subject.
131. A method of promoting mucus clearance in mucosal surfaces, comprising:
administering an effective amount of the compound of Claim 1 to a mucosal surface of a subject.
administering an effective amount of the compound of Claim 1 to a mucosal surface of a subject.
132. A method of treating Sjogren's disease, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
133. A method of treating distal intestinal obstruction syndrome, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
134. A method of treating dry skin, comprising:
administering an effective amount of the compound of Claim 1 to the skin of a subject in need thereof.
administering an effective amount of the compound of Claim 1 to the skin of a subject in need thereof.
135. A method of treating esophagitis, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
136. A method of treating dry mouth (xerostomia), comprising:
administering an effective amount of the compound of Claim 1 to the mouth of a subject in need thereof.
administering an effective amount of the compound of Claim 1 to the mouth of a subject in need thereof.
137. A method of treating nasal dehydration, comprising:
administering an effective amount of the compound of Claim 1 to the nasal passages of a subject in need thereof.
administering an effective amount of the compound of Claim 1 to the nasal passages of a subject in need thereof.
138. The method of Claim 137, wherein the nasal dehydration is brought on by administering dry oxygen to the subject.
139. A method of preventing ventilator-induced pneumonia, comprising:
administering an effective amount of the compound of Claim 1 to a subject on a ventilator.
administering an effective amount of the compound of Claim 1 to a subject on a ventilator.
140. A method of treating asthma, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
141. A method of treating primary ciliary dyskinesia, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
142. A method of treating otitis media, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
143. A method of inducing sputum for diagnostic purposes, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
144. A method of treating chronic obstructive pulmonary disease, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
145. A method of treating emphysema, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
146. A method of treating pneumonia, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
147. A method of treating constipation, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
148. The method of Claim 147, wherein the compound is administered orally or via a suppository or enema.
149. A method of treating chronic diverticulitis, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
150. A method of treating rhinosinusitis, comprising:
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
administering an effective amount of the compound of Claim 1 to a subject in need thereof.
151. A method of treating hypertension, comprising administering the compound of Claim 1 to a subject in need thereof.
152. A method of reducing blood pressure, comprising administering the compound of Claim 1 to a subject in need thereof.
153. A method of treating edema, comprising administering the compound of Claim 1 to a subject in need thereof.
154. A method of promoting diuresis, comprising administering the compound of Claim 1 to a subject in need thereof.
155. A method of promoting natriuresis, comprising administering the compound of Claim 1 to a subject in need thereof.
156. A method of promoting saluresis, comprising administering the compound of Claim 1 to a subject in need thereof.
157. The compound of Claim 31, wherein R5 is -(Het)-(CH2)m-(Z)g-(CH2)m-NR10R10.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US10/367,947 US6903105B2 (en) | 2003-02-19 | 2003-02-19 | Sodium channel blockers |
US10/367,947 | 2003-02-19 | ||
PCT/US2004/004451 WO2004073629A2 (en) | 2003-02-19 | 2004-02-18 | Hetero substitued sodium channel blockers |
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EP (1) | EP1599096B1 (en) |
JP (1) | JP4679505B2 (en) |
KR (1) | KR100984374B1 (en) |
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