Vasculostatic agents and methods of use thereof
First Claim
1. A method for treating a disorder associated with compromised vasculostasis, comprising administering to a subject in need thereof an effective amount of a compound having the general structure (III), or a pharmaceutically acceptable salt, hydrate, solvate, crystal form or individual diastereomers thereof:
- wherein;
each of Z1-Z6 is, independently, C, —
C═
O, N, or NRa, wherein Ra is —
H, alkyl, or substituted alkyl, wherein the substituents in the substituted alkyl are halogen, hydroxy, oxo, or amino;
each X is independently halogen, —
ORb, —
NRb2, or —
SRb, wherein Rb is —
H, lower alkyl, —
(CH2)2NH(CH2CH3), —
(CH2)3morpholyn-1-yl, —
(CH2)3(N-methylpiperazinyn-1-yl), aryl, heteroaryl, —
(NH—
NH—
Rc), —
(N═
N—
NH—
Rc), wherein Rc is H or lower alkyl;
each Y is independently —
ORd, —
NRd2, —
SRd, or —
OPO3H2, wherein Rd is H, lower alkyl, aryl, heteroaryl, —
(CH2)2NH(CH2CH3), —
(CH2)3morpholyn-1-yl, or —
(CH2)3(N-methyl piperazinyn-1-yl);
or each Y is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halogen, wherein said substituents are selected from halogen, —
ORe, —
NRe2, —
SRe, —
P(O)(OH)2, wherein Re is —
H, lower alkyl, aryl, or heteroaryl;
or each Y is independently CH2glycinyl, CH2NHethoxy, CH2NHCH2alkyl, CH2NHCH2t-Bu, CH2NHCH2aryl, CH2NHCH2substituted aryl, CH2NHCH2heteroaryl, CH2NHCH2substituted heteroaryl;
or when n is 2, each Y is taken together to form a fused aromatic or heteroaromatic ring system; and
each of m and n is, independently, an integer having the value between 1 and 4, wherein when Z1, Z3, Z5, and Z6 are each N, X is NH2, and m=n=2, Y is not phenyl or 4-hydroxyphenyl, or tautomers thereof, thereby treating the subject.
1 Assignment
0 Petitions
Accused Products
Abstract
Compositions and methods and are provided for treating disorders associated with compromised vasculostasis. Invention methods and compositions are useful for treating a variety of disorders including for example, stroke, myocardial infarction, cancer, ischemia/reperfusion injury, autoimmune diseases such as rheumatoid arthritis, eye diseases such as retinopathies or macular degeneration or other vitreoretinal diseases, inflammatory diseases, vascular leakage syndrome, edema, transplant rejection, adult/acute respiratory distress syndrome (ARDS), and the like.
89 Citations
63 Claims
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1. A method for treating a disorder associated with compromised vasculostasis, comprising administering to a subject in need thereof an effective amount of a compound having the general structure (III), or a pharmaceutically acceptable salt, hydrate, solvate, crystal form or individual diastereomers thereof:
-
wherein;
each of Z1-Z6 is, independently, C, —
C═
O, N, or NRa, wherein Ra is —
H, alkyl, or substituted alkyl, wherein the substituents in the substituted alkyl are halogen, hydroxy, oxo, or amino;
each X is independently halogen, —
ORb, —
NRb2, or —
SRb, wherein Rb is —
H, lower alkyl, —
(CH2)2NH(CH2CH3), —
(CH2)3morpholyn-1-yl, —
(CH2)3(N-methylpiperazinyn-1-yl), aryl, heteroaryl, —
(NH—
NH—
Rc), —
(N═
N—
NH—
Rc), wherein Rc is H or lower alkyl;
each Y is independently —
ORd, —
NRd2, —
SRd, or —
OPO3H2, wherein Rd is H, lower alkyl, aryl, heteroaryl, —
(CH2)2NH(CH2CH3), —
(CH2)3morpholyn-1-yl, or —
(CH2)3(N-methyl piperazinyn-1-yl);
or each Y is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halogen, wherein said substituents are selected from halogen, —
ORe, —
NRe2, —
SRe, —
P(O)(OH)2, wherein Re is —
H, lower alkyl, aryl, or heteroaryl;
or each Y is independently CH2glycinyl, CH2NHethoxy, CH2NHCH2alkyl, CH2NHCH2t-Bu, CH2NHCH2aryl, CH2NHCH2substituted aryl, CH2NHCH2heteroaryl, CH2NHCH2substituted heteroaryl;
or when n is 2, each Y is taken together to form a fused aromatic or heteroaromatic ring system; and
each of m and n is, independently, an integer having the value between 1 and 4, wherein when Z1, Z3, Z5, and Z6 are each N, X is NH2, and m=n=2, Y is not phenyl or 4-hydroxyphenyl, or tautomers thereof, thereby treating the subject. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
wherein;
each X is independently H, halogen, OR, NR2, or SR, wherein R is H, aryl, substituted aryl, or lower alkyl;
each Y is independently hydrogen, alkyl, substituted alkyl, alkenyl substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, or substituted acyl, with the proviso that at least one Y is not hydrogen, or when n is 2, each Y is taken together to form a fused aromatic ring system comprising at least one aromatic ring; and
each of m and n are is, independently, 1 or 2.
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3. The method of claim 1, wherein the compound of the general structure (III) has the formula (IIIb):
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4. The method of any one of claims 1-3, wherein the disorder is myocardial infarction, stroke, congestive heart failure, an ischemia or reperfusion injury, cancer, arthritis or other arthropathy, retinopathy or vitreoretinal disease, macular degeneration, autoimmune disease, vascular leakage syndrome, inflammatory disease, edema, transplant rejection, burn, or acute or adult respiratory distress syndrome (ARDS).
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5. The method of claim 4, wherein the disorder is vascular leakage syndrome (VLS).
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6. The method of claim 4, wherein the disorder is cancer.
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7. The method of claim 4, wherein the disorder is a vitreoretinal disease.
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8. The method of claim 4, wherein the disorder is ARDS.
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9. The method of claim 4, wherein the disorder is autoimmune disease.
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10. The method of claim 4, wherein the disorder is burn.
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11. The method of claim 4, wherein the disorder is stroke.
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12. The method of claim 4, wherein the disorder is myocardial infarction.
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13. The method of claim 4, wherein the disorder is ischemia or reperfusion injury.
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14. The method of claim 4, wherein the disorder is arthritis.
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15. The method of claim 4, wherein the disorder is edema.
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16. The method of claim 4, wherein the disorder is transplant rejection.
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17. The method of claim 4, wherein the disorder is inflammatory disease.
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18. The method of claim 4, wherein the disorder is congestive heart failure.
- 19. A method of treating a disorder associated with compromised vasculostasis comprising the administration of a therapeutically effective amount of at least one compound as set forth in Structures III, IIIa, or IIIb, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, in combination with an anti-inflammatory agent, a therapeutic agent, a chemotherapeutic agent, a PI3K inhibitor, an immunomodulatory agent, a therapeutic antibody or a protein kinase inhibitor, to a subject in need of such treatment, thereby treating the subject.
- 43. A method for inhibiting or reducing vascular leakage in a subject, comprising administering to a subject in need thereof an effective amount of IL-2 in combination with a a therapeutically effective amount of at least one compound as set forth in Structures III, IIIa, or IIIb, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, thereby reducing vascular leakage in the subject.
- 45. A method of treating acute myocardial infarction, comprising administering to a subject in need thereof a therapeutically effective amount of an inhibitor of phosphoinositide-3-kinase, thereby treating the subject.
- 53. A pharmaceutical composition, comprising 6,7-bis-(3-hydroxyphenyl)-pteridine-2,4-diamine, or a pharmceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.
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62. A pharmaceutical composition, comprising 6,7-bis-(3-hydroxyphenyl)-pteridine-2,4-diamine and sulfobutyl ether β
- -cyclodextrin, wherein the concentration of 6,7-bis-(3-hydroxyphenyl)-pteridine-2,4-diamine is 23 mg/ml and the concentration of sulfobutyl ether β
-cyclodextrin is 16% by mass.
- -cyclodextrin, wherein the concentration of 6,7-bis-(3-hydroxyphenyl)-pteridine-2,4-diamine is 23 mg/ml and the concentration of sulfobutyl ether β
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63. A pharmaceutical composition, comprising:
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(a) about 540.2 g 6,7-bis-(3-hydroxyphenyl)-pteridine-2,4-diamine;
(b) about 3,680 g a sulfobutyl ether derivative of β
-cyclodextrin;
(c) about 82.1 g citric acid; and
(d) about 21,595 g sterile water for injection.
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Specification