1. A compound represented by formula (I):
53
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)mOR8, (CH2)mNR7R10, (CH2)n(CHOR8)(CHOR8)nCH2OR8, (CH2CH2O)mR8, (CH2CH2O)mCH2CH2NR7R10, (CH2)nC(O)NR7R10, (CH2)nZgR7, (CH2)mNR10CH2(CHOR8)(CHOR8)nCH2OR8, (CH2)nCO2R7, or
54
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):
55
wherein
each RL is, independently, R7, (CH2)nOR8, O(CH2)mOR8, (CH2)nNR7R10, O(CH2)mNR7R10, (CH2)n(CHOR8)(CHOR8)nCH2OR8, O(CH2)m(CHOR8)(CHOR8)nCH2OR8, (CH2CH2O)mR8, O(CH2CH2O)mR8, (CH2CH2O)mCH2CH2NR7R10, O(CH2CH2O)mCH2CH2NR7R10, (CH2)nC(O)NR7R10, O(CH2)mC(O)NR7R10, (CH2)n(Z)gR7, O(CH2)m(Z)gR7, (CH2)nNR10CH2(CHOR8)(CHOR8)nCH2OR8, O(CH2)mNR10CH2(CHOR8)(CHOR8)nCH2OR8, (CH2)nCO2R7, O(CH2)mCO2R7, OSO3H, O-glucuronde, O-glucose,
56
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(NR10), CHNR7R10, or represents a single bond;
each R5 is, independently, (CH2)mOR8, O(CH2)mOR8, (CH2)nNR7R10, O(CH2)mNR7R10, (CH2)n(CHOR8)(CHOR8)nCH2OR8, O(CH2)m(CHOR8)(CHOR8)nCH2OR8, (CH2CH2O)mR8, O(CH2CH2O)mR8, (CH2CH2O)mCH2CH2NR7R10, O(CH2CH2O)mCH2CH2NR7R10, (CH2)nC(O)NR7R10, O(CH2)mC(O)NR7R10, (CH2)n(Z)gR7, O(CH2)m(Z)gR7, (CH2)nNR10CH2(CHOR8)(CHOR8)nCH2OR8, O(CH2)mNR10CH2(CHOR8)(CHOR8)nCH2OR8, (CH2)nCO2R7, O(CH2)mCO2R7, OSO3H, O-glucuronide, O-glucose,
57
each R6 is, independently, R7, OR11, N(R7)2, (CH2)mOR8, O(CH2)mOR8, (CH2)nNR7R10, O(CH2)mNR7R10, (CH2)n(CHOR8)(CHOR8)nCH2OR8, O(CH2)m(CHOR8)(CHOR8)nCH2OR8,(CH2CH2O)mR8, O(CH2CH2O)mR8, (CH2CH2O)mCH2CH2NR7R10, O(CH2CH2O)mCH2CH2NR7R10, (CH2)nC(O)NR7R10, O(CH2)mC(O)NR7R10, (CH2)n(Z)gR7, O(CH2)m(Z)gR7, (CH2)nNR10CH2(CHOR8)(CHOR8)nCH2OR8, O(CH2)mNR10CH2(CHOR8)(CHOR8)nCH2OR8, (CH2)nCO2R7, O(CH2)mCO2R7, OSO3H, O-glucuronide, O-glucose,
58
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;
each R7 is, independently, hydrogen or lower alkyl;
each R8 is, independently, hydrogen, lower alkyl, C(O)R11, glucuronide, 2-tetrahydropyranyl, or
59
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)nCH2OH;
each Z is, independently, CHOH, C(O), CHNR7R10, CNR10, or NR10;
each R11 is, independently, lower alkyl;
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, CR5, CR6, 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 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 RL is hydrogen.
8. The compound of claim 7, wherein o is 4.
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 (CH2)mOR8.
15. The compound of claim 14, which is represented by the formula:
60
16. The compound of claim 14, which is represented by the formula:
61
17. The compound of claim 13, wherein R5 is O(CH2)mOR8.
18. The compound of claim 17, which is represented by the formula:
62
19. The compound of claim 17, which is represented by the formula:
63
20. The compound of claim 17, which is represented by the formula:
64
21. The compound of claim 13, wherein R5 is (CH2)nNR7R10.
22. The compound of claim 21, which is represented by the formula:
65
23. The compound of claim 13, wherein R5 is OO(CH2)mNR7R10.
24. The compound of claim 23, which is represented by the formula:
66
25. The compound of claim 23, which is represented by the formula:
67
26. The compound of claim 13, wherein R5 is (CH2)n(CHOR8)(CHOR8)nCH2OR8.
27. The compound of claim 13, wherein R5 is O(CH2)m(CHOR8)(CHOR8)nCH2OR8.
28. The compound of claim 27, which is represented by the formula:
68
29. The compound of claim 27, which is represented by the formula:
69
30. The compound of claim 27, which is represented by the formula:
70
31. The compound of claim 27, which is represented by the formula:
71
32. The compound of claim 27, which is represented by the formula:
72
33. The compound of claim 13, wherein R5 is (CH2CH2O)mR8.
34. The compound of claim 13, wherein R5 is O(CH2CH2O)mR8.
35. The compound of claim 34, which is represented by the formula:
73
36. The compound of claim 34, which is represented by the formula:
74
37. The compound of claim 34, which is represented by the formula:
75
38. The compound of claim 13, wherein R5 is (CH2CH2O))mCH2CH2NR7R10.
39. The compound of claim 13, wherein R5 is O(CH2CH2O)mCH2CH2NR7R10.
40. The compound of claim 13, wherein R5 is (CH2)nC(O)NR7R10.
41. The compound of claim 13, wherein R5 is O(CH2)mC(O)NR7R10.
42. The compound of claim 13, wherein R5 is (CH2)n(Z)gR7.
43. The compound of claim 13, wherein R5 is O(CH2)m(Z)gR7.
44. The compound of claim 43, which is represented by the formula:
76
45. The compound of claim 43, which is represented by the formula:
77
46. The compound of claim 13, wherein R5 is (CH2)nNR10CH2(CHOR8) (CHOR8)nCH2O)R8.
47. The compound of claim 13, wherein R5 is O(CH2)mNR10CH2(CHOR8) (CHOR8)nCH2O)R8.
48. The compound of claim 13, wherein R5 is O(CH2)mCO2R7.
49. The compound of claim 13, wherein R5 is OSO3H.
50. The compound of claim 13, wherein R5 is O-glucuronide.
51. The compound of claim 13, wherein R5 is O-glucose.
52. The compound of claim 13, wherein R5 is
78
53. The compound of claim 52, which is represented by the formula:
79
54. The compound of claim 13, wherein R5 is
80
55. The compound of claim 13, wherein R5 is
81
56. The compound of claim 55, which is represented by the formula:
82
57. 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)mOR8, or (CH2)mCO2R7;
R3 is a group represented by formula (A); and
R4 is hydrogen, a group represented by formula (A), or lower alkyl.
58. The compound of claim 57, 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 RL are other than hydrogen as defined above; and
at most 2 Q are nitrogen atoms.
59. The compound of claim 58, wherein Y is NH2.
60. The compound of claim 59, wherein R4 is hydrogen;
at most one RL 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.
61. The compound of claim 1, wherein R5 is (CH2)mOR8.
62. The compound of claim 1, wherein R5 is O(CH2)mOR8.
63. The compound of claim 1, wherein R5 is (CH2)nNR7R10.
64. The compound of claim 1, wherein R5 is O(CH2)mNR7R10.
65. The compound of claim 1, wherein R5 is (CH2)n(CHOR8)(CHOR8)nCH2OR8.
66. The compound of claim 1, wherein R5 is O(CH2)m(CHOR8) (CHOR8)nCH2OR8.
67. The compound of claim 1, wherein R5 is (CH2CH2O)mR8.
68. The compound of claim 1, wherein R5 is O(CH2CH2O)mR8.
69. The compound of claim 1, wherein R5 is (CH2CH2O)mCH2CH2NR7R10.
70. The compound of claim 1, wherein R5 is O(CH2CH2O)mCH2CH2NR7R10.
71. The compound of claim 1, wherein R5 is (CH2)nC(O)NR7R10.
72. The compound of claim 1, wherein R5 is O(CH2)mC(O)NR7R10.
73. The compound of claim 1, wherein R5 is (CH2)n(Z)gR.7
74. The compound of claim 1, wherein R5 is O(CH2)m(Z)gR7.
75. The compound of claim 1, wherein R5 is (CH2)nNR10CH2(CHOR8) (CHOR8)nCH2O)R8.
76. The compound of claim 1, wherein R5 is O(CH2)mNR10CH2(CHOR8) (CHOR8)nCH2OR8.
77. The compound of claim 1, wherein R5 is O(CH2)mCO2R7.
78. The compound of claim 1, wherein R5 is OSO3H.
79. The compound of claim 1, wherein R5 is O-glucuronide.
80. The compound of claim 1, wherein R5 is O-glucose.
81. The compound of claim 1, wherein R5 is
83
82. The compound of claim 1, wherein R5 is
84
83. The compound of claim 1, wherein R5 is
85
84. The compound of claim 1, wherein x is a single bond.
85. The compound of claim 1, which is in the form of a pharmaceutically acceptable salt.
86. A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
87. 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.
88. 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.
89. A method of blocking sodium channels, comprising:
contacting sodium channels with an effective amount of the compound of claim 1.
90. A method of treating chronic bronchitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
91. A method of treating cystic fibrosis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
92. A method of treating sinusitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
93. 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.
94. 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.
95. A method of promoting ocular hydration, comprising:
administering an effective amount of the compound of claim 1 to the eye of a subject.
96. A method of promoting corneal hydration, comprising:
administering an effective amount of the compound of claim 1 to the eye of a subject.
97. 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.
98. A method of treating Sjogren’s disease, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
99. 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.
100. 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.
101. A method of treating esophagitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
102. 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.
103. 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.
104. The method of claim 103, wherein the nasal dehydration is brought on by administering dry oxygen to the subject.
105. A method of preventing ventilator-induced pneumonia, comprising:
administering an effective amount of the compound of claim 1 to a subject on a ventilator.
106. A method of treating asthma, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
107. A method of treating primary ciliary dyskinesia, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
108. A method of treating otitis media, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
109. 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.
110. 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.
111. A method of treating emphysema, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
112. A method of treating pneumonia, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
113. A method of treating constipation, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
114. The method of claim 113, wherein the compound is administered orally or via a suppository or enema.
115. A method of treating chronic diverticulitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
116. A method of treating rhinosinusitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
117. A composition, comprising:
the compound of claim 1; and
a P2Y2 inhibitor.
118. A composition, comprising:
the compound of claim 1; and
a bronchodilator.
119. The compound of claim 1, wherein R5 is selected from the group consisting of
O(CH2)3OH, NH2, OCH2(CHOH)2CH2OHOCH2CHOHCH2OH, OCH2CH2O-tetrahydropyran-2-yl, OCH2CHOHCH2O-glucuronide, OCH2CH2OH, O(CH2CH2O))4CH3, OCH2CH2OCH3, OCH2(CHOC(O)CH3)CH2OC(O)CH3, O(CH2CH2O))2CH3, OCH2CHOHCHOHCH2OH, CH2OH, CO2CH3,
86
120. The compound of claim 1, wherein R5 is selected from the group consisting of
para O(CH2)3OH, para NH2, para OCH2(CHOH)2CH2OH, ortho OCH2CHOHCH2OH, meta OCH2CHOHCH2OH, para OCH2CH2O-tetrahydropyran-2-yl, para OCH2CHOHCH2O-glucuronide, para OCH2CH2OH, para O(CH2CH2O)4CH3, para OCH2CH2OCH3, para OCH2(CHOC(O)CH3) CH2OC(O)CH3, para O(CH2CH2O)2CH3, OCH2CHOHCHOHCH2OH, para CH2OH, para CO2CH3, para SO3H, para O-glucuronide, para
87
121. The compound of claim 119, wherein
X is chloro or bromo;
Y is N(R7)2;
R1 is hydrogen or C1-C3 alkyl;
R2 is hydrogen or C1-C3 alkyl;
R3 is a group represented by formula (A); and
R4 is hydrogen, a group represented by formula (A), or lower alkyl;
at most three R6 are other than hydrogen as defined above;
at most three RL are other than hydrogen as defined above; and
at most 2 Q are nitrogen atoms.
122. The compound of claim 121, wherein
R4 is hydrogen;
at most one RL 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.
123. The compound of claim 120, wherein
X is chloro or bromo;
Y is N(R7)2;
R1 is hydrogen or C1-C3 alkyl;
R2 is hydrogen or C1-C3 alkyl;
R3 is a group represented by formula (A); and
R4 is hydrogen, a group represented by formula (A), or lower alkyl;
at most three R6 are other than hydrogen as defined above;
at most three RL are other than hydrogen as defined above; and
at most 2 Q are nitrogen atoms.
124. The compound of claim 123, wherein
R4 is hydrogen;
at most one RL 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.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed is:
1. A spring-loaded piston for a spring-loaded brake cylinder of a commercial vehicle, wherein the spring-loaded piston is a plastic spring-loaded piston.
2. The spring-loaded piston according to claim 1, wherein the spring-loaded piston includes a ring-shaped shoulder adapted to receive a piston or piston rod.
3. The spring-loaded piston according to claim 2, wherein the shoulder has a defined longitudinal dimension in an axial direction of the spring-loaded brake cylinder.
4. The spring-loaded piston according to claim 1, wherein the spring-loaded piston includes a second ring-shaped shoulder adapted to engage in a corresponding recess of a piston or piston rod.
5. The spring-loaded piston according to claim 2, wherein the spring-loaded piston includes a second ring-shaped shoulder adapted to engage in a corresponding recess of the piston or the piston rod.
6. The spring-loaded piston according to claim 3, wherein the spring-loaded piston includes a second ring-shaped shoulder adapted to engage in a corresponding recess of the piston or the piston rod.
7. The spring-loaded piston according to claim 4, further comprising supporting elements extending substantially parallel to a longitudinal axis of the spring-loaded brake cylinder, the supporting elements being arranged in a ring and being molded to the second ring-shaped shoulder in one piece; and
wherein the supporting elements are adapted to engage in the piston or the piston rod.
8. The spring-loaded piston according to claim 5, further comprising supporting elements extending substantially parallel to a longitudinal axis of the spring-loaded brake cylinder, the supporting elements being arranged in a ring and being molded to the second ring-shaped shoulder in one piece; and
wherein the supporting elements are adapted to engage in the piston or the piston rod.
9. The spring-loaded piston according to claim 6, further comprising supporting elements extending substantially parallel to a longitudinal axis of the spring-loaded brake cylinder, the supporting elements being arranged in a ring and being molded to the second ring-shaped shoulder in one piece; and
wherein the supporting elements are adapted to engage in the piston or the piston rod.
10. The spring-loaded piston according to claim 2, further comprising an aluminum piston rod received by the spring-loaded piston.
11. The spring-loaded piston according to claim 3, further comprising an aluminum piston rod received by the spring-loaded piston.
12. The spring-loaded piston according to claim 4, further comprising an aluminum piston rod received by the spring-loaded piston.
13. The spring-loaded piston according to claim 7, further comprising an aluminum piston rod received by the spring-loaded piston.
14. A method of manufacturing a spring-loaded piston for a spring-loaded brake cylinder of a commercial vehicle, the method comprising the acts of:
forming an injection mold of the spring-loaded piston; and
injection molding with plastic the spring-loaded piston using the injection mold.
15. The method of making the spring-loaded piston according to claim 14, further comprising the act of extrusion molding a piston road; and
inserting the extrusion molded piston rod in the injection molded spring-loaded piston.