CA2509981A1 - Hetero substitued sodium channel blockers - Google Patents

Hetero substitued sodium channel blockers Download PDF

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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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Michael R. Johnson
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Parion Sciences Inc
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    • C07D241/14Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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.
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.
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.
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.
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.
120. A composition, comprising:
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.
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.
123. A method of blocking sodium channels, comprising:

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.
125. A method of treating cystic fibrosis, comprising:
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.
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.
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.
129. A method of promoting ocular hydration, comprising:
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.
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.
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.
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.
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.
135. A method of treating esophagitis, comprising:
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.
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.
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.
140. A method of treating asthma, comprising:

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.
142. A method of treating otitis media, comprising:
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.
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.
145. A method of treating emphysema, comprising:
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.
147. A method of treating constipation, comprising:
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.
150. A method of treating rhinosinusitis, comprising:
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.
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