1. A harmonica comprising a pair of a blow reed and a draw reed in each of an upper part and a lower part of a hole and having four tone rows of a tone row for the upper blow reeds, a tone row for the upper draw reeds, a tone row for the lower blow reeds, and a tone row for the lower draw reeds, wherein one of the four tone rows is a pattern in which \u201cDo Mi Sol Ti-flat\u201d is repeated, one of the remaining three tone rows is a pattern in which \u201cRe Fa Sol Ti\u201d is repeated, one of the remaining two tone rows is a pattern in which \u201cRe-flat Sol-flat La-flat Ti-flat\u201d is repeated, and the remaining one tone row is a pattern in which \u201cMi-flat Fa La Do\u201d is repeated.
2. A harmonica comprising a pair of a blow reed and a draw reed in each of an upper part and a lower part of a hole and having four tone rows of a tone row for the upper blow reeds, a tone row for the upper draw reeds, a tone row for the lower blow reeds, and a tone row for the lower draw reeds, wherein one of the four tone rows is a pattern in which \u201cDo Mi Sol La\u201d is repeated, one of the remaining three tone rows is a pattern in which \u201cRe Fa Sol Ti\u201d is repeated, one of the remaining two tone rows is a pattern in which \u201cRe-flat Sol-flat La-flat Ti-flat\u201d is repeated, and the remaining one tone row is a pattern in which \u201cMi-flat Fa La Do\u201d is repeated.
3. A harmonica comprising a pair of a blow reed and a draw reed in each of an upper part and a lower part of a hole and having four tone rows of a tone row for the upper blow reeds, a tone row for the upper draw reeds, a tone row for the lower blow reeds, and a tone row for the lower draw reeds, wherein one of the four tone rows is a pattern in which \u201cLa Do Mi Fa-sharp\u201d is repeated, one of the remaining three tone rows is a pattern in which \u201cTi Re Mi Sol\u201d is repeated, one of the remaining two tone rows is a pattern in which \u201cDo-sharp Re-sharp Sol-sharp La-sharp\u201d is repeated, and the remaining one tone row is a pattern in which \u201cDo Re Fa La\u201d is repeated.
4. A harmonica comprising a pair of a blow reed and a draw reed in each of an upper part and a lower part of a hole and having four tone rows of a tone row for the upper blow reeds, a tone row for the upper draw reeds, a tone row for the lower blow reeds, and a tone row for the lower draw reeds, wherein one of the four tone rows is a pattern in which \u201cLa Do Mi Sol\u201d is repeated, one of the remaining three tone rows is a pattern in which \u201cTi Re Mi Sol-sharp\u201d is repeated, one of the remaining two tone rows is a pattern in which \u201cDo-sharp Re-sharp Fa-sharp La-sharp\u201d is repeated, and the remaining one tone row is a pattern in which \u201cDo Re Fa La\u201d is repeated.
5. A harmonica comprising a pair of a blow reed and a draw reed in each of an upper part and a lower part of a hole and having four tone rows of a tone row for the upper blow reeds, a tone row for the upper draw reeds, a tone row for the lower blow reeds, and a tone row for the lower draw reeds, wherein one of the four tone rows is a pattern in which \u201cLa Do Mi Sol\u201d is repeated, one of the remaining three tone rows is a pattern in which \u201cTi Re Mi Sol\u201d is repeated, one of the remaining two tone rows is a pattern in which \u201cDo-sharp Re-sharp Fa-sharp La-sharp\u201d is repeated, and the remaining one tone row is a pattern in which \u201cDo Re Fa La\u201d is repeated.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of treating inflammation that is associated with a metabolic disorder, wherein the metabolic disease is selected from the group consisting of Type II diabetes, insulin resistance, atherosclerosis, dyslipidemia, retinopathy associated with diabetic complications, nephropathy associated with diabetic complications, neuropathy associated with diabetic complications, and macular edema associated with diabetic complications, comprising administering to a patient in need thereof an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof,
wherein:
R1, R2, R3, and R4 are each independently selected from the group consisting of H, Cl, F, CN, \u2014NH(C1-C3 alkyl), \u2014N(C1-C3 alkyl)2, \u2014NH(C(O)C1-C3 alkyl), \u2014N(C(O)C1-C3 alkyl)2, \u2014C(O)H, \u2014C(O)C1-C3 alkyl, \u2014C(O)OC1-C3 alkyl, \u2014C(O)NH2, \u2014C(O)NH(C1-C3 alkyl), \u2014C(O)N(C1-C3 alkyl)2, \u2014O\u2014C1-C3 alkyl;
W1 is NH and W2 is selected from null or NH;
– – – – – represents an optional bond that when present requires that Q is null;
a and c are each independently H, CH3, \u2014OCH3, \u2014OCH2CH3, or C(O)OH;
b is H, CH3, C(O)OH, or O\u2014Z;
d is H or C(O)OH;
each n, o, p, and q is independently 0 or 1;
each Z is H or
with the proviso that there is at least one
in the compound;
each r is independently 2 or 3;
each s is independently 5 or 6;
each t is independently 0 or 1;
Q is null, C(O)CH3, Z,
e is H or any one of the side chains of the naturally occurring amino acids;
W3 is null or N(R)\u2014;
R is H or C1-C3 alkyl; and
T is H, C(O)CH3, or Z.
2. The method of claim 1, wherein the compound is a compound wherein W2 is NH.
3. The method of claim 2, wherein the compound is a compound wherein r is 2, s is 6, t is 1, and Z is
4. The method of claim 3, wherein the compound is
5. The method of claim 1, wherein the compound is a compound wherein Q is Z.
6. The method of claim 1, wherein the compound is a compound wherein Q is
7. The method of claim 1, wherein the compound is a compound wherein Q is Z and Z is H.
8. The method of claim 1, wherein the compound is a compound wherein two of n, o, p, and q are each 1.
9. The method of claim 1, wherein the compound is a compound wherein r is 3, s is 5, t is 1, and Z is
10. The method of claim 1, wherein the compound is
11. A method of treating inflammation that is associated with an inflammatory bowel disease selected from the group consisting of ileitis, ulcerative colitis, Barrett’s syndrome, and Crohn’s disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof,
wherein:
R1, R2, R3 and R4 are each independently selected from the group consisting of H, Cl, F, CN, \u2014NH(C1-C3 alkyl), \u2014N(C1-C3 alkyl)2, \u2014NH(C(O)C1-C3 alkyl), \u2014N(C(O)C1-C3 alkyl)2, \u2014C(O)H, \u2014C(O)C1-C3 alkyl, \u2014C(O)OC1-C3 alkyl, \u2014C(O)NH2, \u2014C(O)NH(C1-C3 alkyl), \u2014C(O)N(C1-C3 alkyl)2, \u2014O\u2014C1-C3 alkyl;
W1 is NH and W2 is selected from null or NH;
– – – – – represents an optional bond that when present requires that Q is null;
a and c are each independently H, CH3, \u2014OCH3, \u2014OCH2CH3, or C(O)OH;
b is H, CH3, C(O)OH, or O\u2014Z;
d is H or C(O)OH;
each n, o, p, and q is independently 0 or 1;
each Z is H or
with the proviso that there is at least one
in the compound;
each r is independently 2 or 3;
each s is independently 5 or 6;
each t is independently 0 or 1;
Q is null, C(O)CH3, Z,
e is H or any one of the side chains of the naturally occurring amino acids;
W3 is null or \u2014N(R)\u2014;
R is H or C1-C3 alkyl; and
T is H, C(O)CH3, or Z.
12. The method of claim 11, wherein the compound is a compound wherein W2 is NH.
13. The method of claim 11, wherein the compound is a compound wherein r is 2, s is 6, t is 1, and Z is
14. The method of claim 11, wherein the compound is
15. The method of claim 11, wherein the compound is a compound wherein Q is Z.
16. The method of claim 11, wherein the compound is a compound wherein Q is
17. The method of claim 11, wherein the compound is a compound wherein Q is Z and Z is H.
18. The method of claim 11, wherein the compound is a compound wherein two of n, o, p, and q are each 1.
19. The method of claim 11, wherein the compound is a compound wherein r is 3, s is 5, t is 1, and Z is
20. The method of claim 11, wherein the compound is
21. A method of treating inflammation that is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, comprising administering to a patient in need thereof an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof,
wherein:
R1, R2, R3 and R4 are each independently selected from the group consisting of H, Cl, F, CN, \u2014NH(C1-C3 alkyl), \u2014N(C1-C3 alkyl)2, \u2014NH(C(O)C1-C3 alkyl), \u2014N(C(O)C1-C3 alkyl)2, \u2014C(O)H, \u2014C(O)C1-C3 alkyl, \u2014C(O)OC1-C3 alkyl, \u2014C(O)NH2, \u2014C(O)NH(C1-C3 alkyl), \u2014C(O)N(C1-C3 alkyl)2, \u2014O\u2014C1-C3 alkyl;
W1 is NH and W2 is selected from null or NH;
– – – – – represents an optional bond that when present requires that Q is null;
a and c are each independently H, CH3, \u2014OCH3, \u2014OCH2CH3, or C(O)OH;
b is H, CH3, C(O)OH, or O\u2014Z;
d is H or C(O)OH;
each n, o, p, and q is independently 0 or 1;
each Z is H or
with the proviso that there is at least one
in the compound;
each r is independently 2 or 3;
each s is independently 5 or 6;
each t is independently 0 or 1;
Q is null, C(O)CH3, Z
e is H or any one of the side chains of the naturally occurring amino acids;
W3 is null or \u2014N(R)\u2014;
R is H or C1-C3 alkyl; and
T is H, C(O)CH3, or Z.
22. The method of claim 21, wherein the compound is a compound wherein W2 is NH.
23. The method of claim 21, wherein the compound is a compound wherein r is 2, s is 6, t is 1, and Z is
24. The method of claim 21, wherein the compound is
25. The method of claim 21, wherein the compound is a compound wherein Q is Z.
26. The method of claim 21, wherein the compound is a compound wherein Q is
27. The method of claim 21, wherein the compound is a compound wherein Q is Z and Z is H.
28. The method of claim 21, wherein the compound is a compound wherein two of n, o, p, and q are each 1.
29. The method of claim 21, wherein the compound is a compound wherein r is 3, s is 5, t is 1, and Z is
30. The method of claim 21, wherein the compound is
31. A method of treating inflammation that is associated with Duchenne’s muscular dystrophy comprising administering to a patient in need thereof an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof,
wherein:
R1, R2, R3 and R4 are each independently selected from the group consisting of H, Cl, F, CN, \u2014NH(C1-C3 alkyl), \u2014N(C1-C3 alkyl)2, \u2014NH(C(O)C1-C3 alkyl), \u2014N(C(O)C1-C3 alkyl)2, \u2014C(O)H, \u2014C(O)C1-C3 alkyl, \u2014C(O)OC1-C3 alkyl, \u2014C(O)NH2, \u2014C(O)NH(C1-C3 alkyl), \u2014C(O)N(C1-C3 alkyl)2, \u2014O\u2014C1-C3 alkyl;
W1 is NH and W2 is selected from null or NH;
– – – – – represents an optional bond that when present requires that Q is null;
a and c are each independently H, CH3, \u2014OCH3, \u2014OCH2CH3, or C(O)OH;
b is H, CH3, C(O)OH, or O\u2014Z;
d is H or C(O)OH;
each n, o, p, and q is independently 0 or 1;
each Z is H or
with the proviso that there is at least one
in the compound;
each r is independently 2 or 3;
each s is independently 5 or 6;
each t is independently 0 or 1;
Q is null, C(O)CH3, Z,
e is H or any one of the side chains of the naturally occurring amino acids;
W3 is null or \u2014N(R)\u2014;
R is H or C1-C3 alkyl; and
T is H, C(O)CH3, or Z.
32. The method of claim 31, wherein the compound is a compound wherein W2 is NH.
33. The method of claim 31, wherein the compound is a compound wherein r is 2, s is 6, t is 1, and Z is
34. The method of claim 31, wherein the compound is
35. The method of claim 31, wherein the compound is a compound wherein Q is Z.
36. The method of claim 31, wherein the compound is a compound wherein Q is
37. The method of claim 31, wherein the compound is a compound wherein Q is Z and Z is H.
38. The method of claim 31, wherein the compound is a compound wherein two of n, o, p, and q are each 1.
39. The method of claim 31, wherein the compound is a compound wherein r is 3, s is 5, t is 1, and Z is
40. The method of claim 31, wherein the compound is