Small molecule activators of Tie-2
Disclosed herein are compounds effective for activation of Tie-2 and inhibition of HPTP-beta. The compounds can provide effective therapy for vascular disorders that can include, for example, retinopathies, ocular edema, and ocular neovascularization.
1. A method of increasing cell survival, comprising administering to a patient in need thereof a therapeutically-effective amount of a compound of the formula:
wherein:
A is alkylene that is unsubstituted or substituted, or a bond;
B is thiazole, which is unsubstituted or substituted;
C is thiophene, which is unsubstituted or substituted;
D is alkylene that is unsubstituted or substituted, or a bond;
E is phenyl, which is unsubstituted or substituted;
R 1 is hydrogen, an acyl group, an alkoxycarbonyl group, an amidine group, or an amide group;
R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl, any of which is unsubstituted or substituted, or hydrogen;
R 3a is alkylene that is unsubstituted or substituted, or a bond;
R 3b is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, any of which is unsubstituted or substituted, or hydrogen; and
R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl, any of which is unsubstituted or substituted,
or a pharmaceutically-acceptable salt or zwitterion thereof.
2. The method of claim 1 , wherein:
A is a bond;
B is thiazole, which is unsubstituted or substituted;
C is thiophene;
D is alkylene that is unsubstituted or substituted;
E is phenyl, which is unsubstituted or substituted;
R 1 is an acyl group or an alkoxycarbonyl group;
R 2 is alkyl that is substituted or unsubstituted, or hydrogen;
R 3a is alkylene that is unsubstituted or substituted;
R 3b is aryl or heteroaryl, any of which is unsubstituted or substituted; and
R 4 is alkyl that is substituted or unsubstituted.
3. The method of claim 2 , wherein:
C is thiophene;
E is phenyl that is unsubstituted or substituted; and
R 1 is an alkoxycarbonyl group.
4. The method of claim 3 , wherein:
B is a thiazole;
D is methylene;
R 3a is methylene; and
R 3b is aryl that is unsubstituted or substituted.
5. The method of claim 4 , wherein:
B is a thiazole;
E is 4-substituted phenyl; and
R 3b is phenyl.
6. The method of claim 5 , wherein R 1 is a methoxycarbonyl group.
7. The method of claim 6 , wherein:
R 2 is methyl or hydrogen; and
R 4 is methyl.
8. The method of claim 7 , wherein R 2 and R 4 are methyl.
9. The method of claim 7 , wherein R 2 is hydrogen and R 4 is methyl.
10. The method of claim 7 , wherein E is
wherein:
X is methyl or hydrogen;
m is 0 or 1;
n is 0, 1, or 2; and
R 5 is hydrogen, hydroxyl, methyl, ethyl, phenyl, para-toluyl, N-piperidinyl, N-piperazinyl, N-pyrrolidinyl, OR 6 , or N(R 6 ) 2 , wherein each R 6 is independently hydrogen, methyl, ethyl, n-propyl, i-propyl, or n-butyl.
11. The method of claim 10 , wherein:
X is hydrogen;
m is 1;
n is 2; and
R 5 is hydroxyl.
12. The method of claim 8 , wherein the compound is:
13. The method of claim 9 , wherein the compound is:
14. The method of claim 1 , wherein administering the compound increases production of pAkt in the patient relative to the absence of administering the compound.
15. The method of claim 1 , wherein the compound is administered by intravenous, intravitreal, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, or topical administration.
16. The method of claim 1 , wherein the compound is administered in an amount of from about 1 mg to about 300 mg.
17. The method of claim 1 , wherein the increase in cell survival is measured according to protein electrophoresis and blotting quantified by a percentage of density of signal of a sample blot band compared to a control blot band in a Phospho-Akt Activation Assay.
18. The method of claim 17 , wherein the administration results in a signal of about 300% above the control.
19. A pharmaceutical composition comprising a compound of the formula:
wherein:
A is alkylene that is unsubstituted or substituted, or a bond;
B is thiazole, which is unsubstituted or substituted;
C is thiophene, which is unsubstituted or substituted;
D is alkylene that is unsubstituted or substituted, or a bond;
E is phenyl, which is unsubstituted or substituted;
R 1 is hydrogen, an acyl group, an alkoxycarbonyl group, an amidine group, or an amide group;
R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl, any of which is unsubstituted or substituted, or hydrogen;
R 3a is alkylene that is unsubstituted or substituted, or a bond;
R 3b is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, any of which is unsubstituted or substituted, or hydrogen; and
R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl, any of which is unsubstituted or substituted,
or a pharmaceutically-acceptable salt or zwitterion thereof, and a pharmaceutically acceptable excipient.
20. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition further comprises a carrier, stabilizer, diluent, dispersing agent, suspending agent, thickening agent, or one or more additional active ingredients.
21. The pharmaceutical composition of claim 20 , wherein the additional active ingredients are selected from the group consisting of antimicrobial agents, anti-inflammatory agents, and anesthetics.
22. The pharmaceutical composition of claim 19 , wherein the compound is selected from: