WO2005018644B1 - Capped pyrazinoylguanidine sodium channel blockers - Google Patents

Capped pyrazinoylguanidine sodium channel blockers

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Publication number
WO2005018644B1
WO2005018644B1 PCT/US2004/026885 US2004026885W WO2005018644B1 WO 2005018644 B1 WO2005018644 B1 WO 2005018644B1 US 2004026885 W US2004026885 W US 2004026885W WO 2005018644 B1 WO2005018644 B1 WO 2005018644B1
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Prior art keywords
compound
link
cap
chor
administering
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PCT/US2004/026885
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French (fr)
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WO2005018644A1 (en
Inventor
Michael R Johnson
Bruce F Molino
Jianzhong Zhang
Bruce J Sargent
Original Assignee
Parion Sciences Inc
Michael R Johnson
Bruce F Molino
Jianzhong Zhang
Bruce J Sargent
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Application filed by Parion Sciences Inc, Michael R Johnson, Bruce F Molino, Jianzhong Zhang, Bruce J Sargent filed Critical Parion Sciences Inc
Priority to PL04781545T priority Critical patent/PL1663235T3/en
Priority to AU2004266704A priority patent/AU2004266704B2/en
Priority to DK04781545.1T priority patent/DK1663235T3/en
Priority to EP04781545.1A priority patent/EP1663235B1/en
Priority to CA2534682A priority patent/CA2534682C/en
Priority to SI200432100T priority patent/SI1663235T1/en
Priority to JP2006524028A priority patent/JP4805824B2/en
Priority to ES04781545T priority patent/ES2432529T3/en
Publication of WO2005018644A1 publication Critical patent/WO2005018644A1/en
Publication of WO2005018644B1 publication Critical patent/WO2005018644B1/en

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    • C07D241/10—Heterocyclic 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
    • C07D241/14—Heterocyclic 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
    • C07D241/30—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms in which said hetero-bound carbon atoms are part of a substructure —C(=X)—X—C(=X)—X— in which X is an oxygen or sulphur atom or an imino radical, e.g. imidoylguanidines
    • C07D241/32—(Amino-pyrazinoyl) guanidines
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms

Abstract

The present invention relates to sodium channel blockers. The present invention also includes a variety of methods of treatment using these inventive sodium channel blockers.

Claims

Claims PCT / U S 0 4 / 2 6 8 8 5 1 7 MAR 2005 1. A compound represented by formula (I):
Figure imgf000002_0001
wherein 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-CH2CH2NR7R' °, -(CH2)n-C(=O)NR7R' °, -(CH2)n-Zg-R7,-(CH2)m-NR' °- CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, or
Figure imgf000002_0002
R and R 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 R and R is a group represented by formula
(A): (A)
Figure imgf000002_0003
99 wherein each RL is, independently, -R7, -(CH2)n-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)„- (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,
Figure imgf000003_0001
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; wherein each R5 is, independently, Link-(CH )n-CAP, Link- (CH2)n(CHOR8)(CHOR8)n-CAP, Link-(CH2CH2θ)m-CH2-CAP, Link-(CH2CH2O)m-CH2CH2- CAP, Link-(CH2)n-(Z)g-CAP, Link-(CH2)n(Z)g-(CH2)m-CAP, Link-(CH2)n-NR13- CH2(CHOR8)(CHOR8)n-CAP, Link-(CH2)n-(CHOR8)mCH2-NR13-(Z)g-CAP, Link- (CH2)nNR' 3-(CH2)m(CHOR8)nCH2NR13-(Z)g-C AP, Link-(CH2)m-(Z)g-(CH2)m-C AP, Link-NH- C(=O)-NH-(CH2)m-CAP, Link-(CH2)m-C(=O)NR,3-(CH2)m-C(=O)NR10R10, Link-(CH2)m- C(=O)NRl 3-(CH2)m-CAP, Link-(CH2)m-C(=O)NRl lR1 1, Link-(CH2)m-C(=0)NR'2R12, Link- (CH2) n-(Z)g-(CH2)m-(Z)g-CAP, Link-Zg-(CH2)m-Het-(CH2)m-CAP; each Link is, independently, -O-, -(CH2)n-, -O(CH2)m-, -NRl 3-C(=O)- R13, -NR13- C(=O)-(CH2)m-, -C(=O)NR13-(CH2)m, -(CH2)n-Zg-(CH2)n, -S-, -SO-, -SO2-, -SO2NR7-, -SO2NR10-, or -Het-; each CAP is, independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(=O)N R13R13, heteroaryl-W, -CN, -O-C(=S)NR13 R13, -C(=O)OAr,
100 -C(=O)N R13Ar, imidazoline, tetrazole, tetrazole amide, -SO2NHR13, -SO2NH-C(Rl 3R13)- (Z)g-R13, a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
CONRl3R13
Figure imgf000004_0001
each Ar is, independently, phenyl, substituted phenyl, wherein the substituents of the substituted phenyl are 1-3 substituents independently selected from the group consisting of OH, OCH3, NR13R13, Cl, F, and CH3, or heteroaryl; each W is independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(=O)N R13R13, -CN, -O-C(=S)NR13 R13, -ZgR13, -CR10(ZgR13)(ZgR13), -C(=O)OAr, -C(=O)N R13Ar, imidazoline, tetrazole, tetrazole amide, -SO2NHR13, -SO2NH-C(R13Rl3)-(Z)g-R13, a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
Figure imgf000004_0002
each R6 is, independently, -R7, -OR7, -OR11, -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-glucuronide, -O-glucose,
Figure imgf000004_0003
101 wherein when two R6 are -OR1 ' 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; each R7 is, independently, hydrogen lower alkyl, phenyl, substituted phenyl or - CH2(CHOR)8 m-R10; each R8 is, independently, hydrogen, lower alkyl, -C(=O)-Rπ, glucuronide, 2- tetrahydropyranyl, or
Figure imgf000005_0001
each R9 is, independently, -CO2R13, -CON(R13)2, -SO2CH2R13, or -C(=O)R13; each R10 is, independently, -H, -SO2CH3, -CO2R13, -C(=O)NR13R13,
-C(=O)R13, or -(CH2) m-(CHOH)n-CH2OH; each Z is, independently, CHOH, C(=O), -(CH2)n-,CHNR 13rR> 13,
Figure imgf000005_0002
NτRπ l 3. each R1 1 is, independently, lower alkyl; each R12 is independently, -SO2CH3, -CO2R13, -C(=O)NR13R13, -C(=O)R13, or -CH2- (CHOH)n-CH2OH; each R13 is, independently, hydrogen, R7, R10, -(CH2)m-NR13R13, + -(CH2)m- NR13R13R13, -(CH2)m-(CHOR8)m-(CH2)mNR13R13, -(CH2)m-NR10R10, + -(CH2)m-(CHOR8)m-(CH2)mNR13R13R13,
102
Figure imgf000006_0001
-(CH2)n- N— V -(CH2 ; ■N ΓΛ NR 13 v_v , _(CH2)- N NR13 , or
Figure imgf000006_0002
-(CH2)n N N— Y
with the proviso that NR R can be joined on itself to form a ring comprising one of the following:
CH2)m(CHOR)B m-(CH2)nR1 J ,
(CH2)m(CHOR)8 m-(CH2)nR11 ,
CH2)m(CHOR)8 m-(CH2)nR11R11 ;
Figure imgf000006_0003
103 each Het is independently, -NR13, -S-, -SO-, or -SO2-; -O-, -SO2NR13-, -NHSO2-, -NR13CO-, or -CONR13-; 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; each V is, independently, -(CH2)m-NR7R10, -(CH2)m-NR7R7, -(CH2)m- + NR1 'R1 'R1 ', -(CH2)n-(CHOR8)m-(CH2)mNR7R10, -(CH2)n-NR10R10, + -(CH2)n-(CHOR8)m-(CH2)mNR7R7, -(CH2)n-(CHOR8)m-(CH2)mNR1 1R, 1R11, with the proviso that when V is attached directly to a nitrogen atom, then V can also be, independently, R7, R10, or (Rπ)2; with the proviso that, when any two -CH2OR groups are located 1,2 or 1,3- with respect to each other, the R groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane; or a pharmaceutically acceptable salt thereof; and inclusive of all enantiomers, diastereomers, and racemic mixtures thereof.
2. The compound of Claim 1, wherein Y is -NH2.
3. The compound of Claim 2, wherein R2 is hydrogen.
4. The compound of Claim 3, wherein R1 is hydrogen.
5. The compound of Claim 4, wherein X is chlorine.
6. The compound of Claim 5, wherein R3 is hydrogen.
7. The compound of Claim 6, wherein each R is hydrogen.
8. The compound of Claim 7, wherein o is 4.
104
9. The compound of Claim 8, wherein p is 0.
10. The compound of Claim 9, wherein x represents a single bond.
11. The compound of Claim 10, wherein each R6 is hydrogen.
12. The compound of Claim 11, wherein at most one Q is a nitrogen atom.
13. The compound of Claim 12, wherein no Q is a nitrogen atom.
14. The compound of Claim 13, wherein R5 is Link-(CH2)n-CAP.
15. The compound of Claim 14, wherein Link is -O- and CAP is thiazolidinedione.
16. The compound of Claim 15, which is represented by the formula:
Figure imgf000008_0001
17. The compound of Claim 14, wherein Link is -O- and CAP is tetrazole.
18. The compound of Claim 17, which is represented by the formula:
Figure imgf000008_0002
19. The compound of Claim 14, wherein Link is -O- and CAP is N,N-dimethyl sulfonamide.
105
20. The compound of Claim 19, which is represented by the formula:
Figure imgf000009_0001
21. The compound of Claim 19, which is represented by the formula:
Figure imgf000009_0002
22. The compound of Claim 14, wherein Link is -O- and CAP is sulfonamide.
23. The compound of Claim 22, which is represented by the formula:
Figure imgf000009_0003
24. The compound of Claim 14, wherein Link is -O- and CAP is oxazolidinedione.
25. The compound of Claim 24, which is represented by the formula:
Figure imgf000009_0004
26. The compound of Claim 14, wherein Link is -O- and CAP is -C(=O)N-RιυAr
106
27. The compound of Claim 26, which is represented by the formula:
Figure imgf000010_0001
28. The compound of Claim 26, which is represented by the formula:
Figure imgf000010_0002
29. The compound of Claim 26, which is represented by the formula:
Figure imgf000010_0003
30. The compound of Claim 26, which is represented by the formula:
Figure imgf000010_0004
31. The compound of Claim 26, which is represented by the formula:
Figure imgf000010_0005
107
32. The compound of Claim 26, which is represented by the formula:
Figure imgf000011_0001
33. The compound of Claim 26, which is represented by the formula:
Figure imgf000011_0002
34. The compound of claim 14, wherein Link is -O- and CAP is imidazole.
35. The compound of Claim 34, which is represented by the formula:
Figure imgf000011_0003
36. The compound of Claim 14, wherein Link is -O- and CAP is cyano.
37. The compound of Claim 36, which is represented by the formula:
Figure imgf000011_0004
38. The compound of Claim 14, wherein the CAP
Figure imgf000011_0005
39. The compound of Claim 38 which is represented by the formula:
Figure imgf000012_0001
40. The compound of Claim 13, wherein R5 is Link-(CH2)n(CHOR8)(CHOR8)n-CAP.
41. The compound of Claim 13, wherein R5 is Link-(CH2CH2O)m-CH2-CAP.
42. The compound of Claim 13, wherein R5 is Link-(CH2CH2O)m-CH2CH2-CAP,
43. The compound of Claim 13, wherein R5 is Link-(CH2)n-(Z)g-CAP.
44. The compound of Claim 13, wherein R5 is Link- (CH2)n(Z)g-(CH2)m-CAP.
Claim 45: Cancelled.
Claim 46: Cancelled.
47. The compound of Claim 13, wherein R5 is Link-(CH2)n-NR10- CH2(CHOR8)(CHOR8)n-CAP.
48. The compound of Claim 13, wherein R5 is Link-(CH2)n-(CHOR8)mCH2-NR' (Z)g-CAP,
49. The compound of Claim 13, wherein R5 is Link-(CH2)nNR10- (CH2)m(CHOR8)nCH2NR10-(Z)g-CAP.
50. The compound of Claim 13, wherein R5 is Link-(CH2)m-(Z)g-(CH2)m-CAP.
51. The compound of Claim 13, wherein R5 is Link-NH-C(=O)-NH-(CH2)m-CAP.
109
52. The compound of Claim 13, wherein R5 is Link-(CH2)m-C(=O)NR10-(CH2)n
Figure imgf000013_0001
53. The compound of Claim 13, wherein R3 is Link-(CH2)m-C(=O)NR' υ-(CH2) CAP.
54. The compound of Claim 13, wherein R5 is Link-(CH2)m-C(=O)NR' 'R' '.
55. The compound of Claim 13, wherein R5 is Link-(CH2)m-C(=O)NR12R12.
56. The compound of Claim 13, wherein R5 is Link-(CH2) n-(Z)g-(CH2)m-(Z)g-CAP.
57. The compound of Claim 1 , wherein R5 is Link-(CH2)n-CAP.
58. The compound of Claim 1, wherein R5 is Link-(CH2)n(CHOR8)(CHOR8)n-CAP.
59. The compound of Claim 1, wherein R5 is Link-(CH2CH2O)m-CH2-CAP.
60. The compound of Claim 1, wherein R5 is Link-(CH2CH2O)m-CH2CH2-CAP.
61. The compound of Claim 1, wherein R5 is Link-(CH2)n-(Z)g-CAP.
62. The compound of Claim 1, wherein R5 is Link-(CH2)n(Z)g-(CH2)m-CAP.
63. The compound of Claim 1, wherein R5 is Link-(CH2)n-NR10- CH2(CHOR8)(CHOR8)n-CAP.
64. The compound of Claim 1, wherein R5 is Link-(CH2)n-(CHOR8)mCH2-NR10-(Z)g- CAP.
65. The compound of Claim 1, wherein R5 is Link-(CH2)nNR10- (CH2)m(CHOR8)nCH2NR10-(Z)g-CAP.
110
66. The compound of Claim 1, wherein R5 is Link-(CH2)m-(Z)g-(CH2)m-CAP.
67. The compound of Claim 1, wherein R5 is Link-NH-C(=O)-NH-(CH2)m-CAP.
68. The compound of Claim 1 , wherein R5 is Link-(CH2)m-C(=O)NR10-(CH2)m-
C(=O)NR10R10.
69. The compound of Claim 1, wherein R5 is Link-(CH2)m-C(=O)NR10-(CH2)m-CAP.
70. The compound of Claim 1 , wherein R5 is Link-(CH2)m-C(=O)NR1 'R1 ' .
71. The compound of Claim 1, wherein R5 is Link-(CH2)m-C(=O)NR12R12.
72. The compound of Claim 1, wherein R5 is Link-(CH2) n-(Z)g-(CH2)m-(Z)g-CAP.
73. The compound of Claim 1, wherein x is a single bond.
74. The compound of Claim 1, wherein the heteroaryl is a pyridyl, pyrazyl, tinazyl, furyl, furfuryl, thienyl, tetrazyl, thiazolidinedionyl and imidazoyl, pyrrolyl, furanyl, thiophenyl, quinolyl, indolyl, adenyl, pyrazolyl, thiazolyl, isoxazolyl, indolyl, benzimidazolyl, purinyl, quinolinyl, isoquinolinyl, pyridazyl, pyrimidyl, pyrazyl, 1,2,3-triazyl, 1,2,4-triazyl, 1,3,5-triazyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl or pterdyl.
75. The compound of Claim 1 , which is in the form of a pharmaceutically acceptable salt.
76. A composition, comprising: the compound of Claim 1; and a P2Y2 receptor agonist.
ill
77. A composition, comprising: the compound of Claim 1 ; and a bronchodilator.
78. A pharmaceutical composition, comprising the compound of Claim 1 and a pharmaceutically acceptable carrier.
79. 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.
80. 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.
81. A method of blocking sodium channels, comprising: contacting sodium channels with an effective amount of the compound of Claim 1.
82. A method of treating chronic bronchitis, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
83. A method of treating cystic fibrosis, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
84. A method of treating sinusitis, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
85. 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. 112
86. 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.
87. A method of promoting ocular hydration, comprising: administering an effective amount of the compound of Claim 1 to the eye of a subject.
88. A method of promoting corneal hydration, comprising: administering an effective amount of the compound of Claim 1 to the eye of a subject.
89. 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.
90. A method of treating Sjogren's disease, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
91. 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.
92. 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.
93. A method of treating esophagitis, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
113
94. 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.
95. 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.
96. The method of Claim 95, wherein the nasal dehydration is brought on by administering dry oxygen to the subject.
97. A method of preventing ventilator-induced pneumonia , comprising: administering an effective amount of the compound of Claim 1 to a subject on a ventilator.
98. A method of treating asthma, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
99. A method of treating primary ciliary dyskinesia, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
100. A method of treating otitis media, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
101. 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.
114
102. 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
103. A method of treating emphysema, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
104. A method of treating pneumonia, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
105. A method of treating constipation, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
106. The method of Claim 105, wherein the compound is administered orally or via a suppository or enema.
107. A method of treating chronic diverticulitis, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
108. A method of treating rhinosinusitis, comprising: administering an effective amount of the compound of Claim 1 to a subject in need thereof.
109. A method of treating hypertension, comprising administering the compound of Claim 1 to a subject in need thereof.
110. A method of reducing blood pressure, comprising administering the compound of Claim 1 to a subject in need thereof.
115
111. A method of treating edema, comprising administering the compound of Claim 1 to a subject in need thereof.
112. A method of promoting diuresis, comprising administering the compound of Claim 1 to a subject in need thereof.
113. A method of promoting natriuresis, comprising administering the compound of Claim 1 to a subject in need thereof.
114. A method of promoting saluresis, comprising administering the compound of Claim 1 to a subject in need thereof.
115. The compound of Claim 1, wherein the sum of o and p is 4 to 10.
116. The compound of Claim 1, wherein each Link is, independently, -O-, -O(CH2)m-, -NR13-C(=O)-NR13, -NR13-C(=O)-(CH2)m-, -C(=O)NR13-(CH2)m, -S-, -SO-, - SO2-, -SO2NR7-, -SO2NR10-, or -Het-.
116
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