Human protein tyrosine phosphatase inhibitors and methods of use
View Patent ↗The present disclosure relates to compounds effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors thereby regulating angiogenesis. The present disclosure further relates to compositions comprising said human protein tyrosine phosphatase beta (HPTP-β) inhibitors, and to methods for regulating angiogenesis.
1. A method for controlling an angiogenesis regulated disease or disorder comprising, contacting a subject with an effective amount of a compound having the formula:
wherein R is a substituted or unsubstituted thiazolyl unit having the formula:
R 4 and R 5 are each independently chosen from:
i) hydrogen;
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
iii) substituted or unsubstituted phenyl;
iv) substituted or unsubstituted heteroaryl; or
R 4 and R 5 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms;
said substitutions are independently chosen from one or more C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl, halogen, hydroxyl, or cyano units;
R 6 is a unit chosen from:
i) hydrogen;
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
iii) substituted or unsubstituted phenyl; and
iv) substituted or unsubstituted heteroaryl;
R 1 is chosen from:
i) hydrogen;
ii) C 1 -C 6 linear or C 3 -C 6 branched alkyl;
iii) substituted or unsubstituted phenyl; or
iv) substituted or unsubstituted benzyl;
R 2 is chosen from:
i) C 1 -C 6 linear or C 3 -C 6 branched alkyl; or
ii) C 1 -C 6 linear or C 3 -C 6 branched alkoxy;
R 3 is hydrogen or C 1 -C 4 linear or C 3 -C4 branched alkyl; or
a pharmaceutically acceptable salt thereof;
wherein the angiogenesis regulated disease or disorder is chosen from skeletal muscle and myocardial ischemia, stroke, coronary artery disease, or peripheral vascular disease.
2. The method according to claim 1 , wherein R has the formula:
3. The method according to claim 2 , wherein R 5 is hydrogen and R 4 is substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl.
4. The method according to claim 3 , wherein R 4 is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tent-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, cyclopropyl, n-hexyl, and cyclohexyl.
5. The method according to claim 3 , wherein R 4 is chosen from units having the formulae —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 Cl, —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , and —CH 2 NH(CH 2 CH 3 ).
6. The method according to claim 2 , wherein R 5 is hydrogen and R 4 is substituted or unsubstituted phenyl.
7. The method according to claim 6 , wherein R 4 is chosen from phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-methoxyphenyl, 4-(difluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 3-chlorophenyl, 4-chlorophenyl, and 3,4-dichlorophenyl.
8. The method according to claim 2 , wherein R 5 is hydrogen and R 4 is substituted or unsubstituted heteroaryl.
9. The method according to claim 8 , wherein R 4 is a substituted or unsubstituted heteroaryl unit, said heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl ,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl, [1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3 -yl, isoxazol-4-yl, isoxazol-5 -yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and [1,3 ,4]thiadiazol-2-yl.
10. The method according to claim 1 , wherein R is a unit wherein R 4 and R 5 are taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
11. The method according to claim 10 , wherein R is 5,6-dihydro-4H-cyclopenta[c/]thiazol-2-yl or 4,5,6,7-tetrahydrobenzo[c/]thiazol-2-yl.
12. The method according to claim 1 , wherein R units have the formula
13. The method according to claim 12 , wherein R 6 is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tent-butyl.
14. The method according to claim 13 , wherein R 6 is substituted or unsubstituted phenyl.
15. The method according to claim 14 , wherein R 6 is chosen from include phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, and 4-methoxyphenyl.
16. The method according to claim 12 , wherein R 6 is a substituted or unsubstituted heteroaryl unit, said heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl ,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl, [1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and [1,3,4]thiadiazol-2-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and 3-methyl-1,2,4-oxadiazol-5-yl.
17. The method according to claim 12 , wherein R 6 has the formula:
R 7 is C 1 -C 4 substituted or unsubstituted alkyl and substituted or unsubstituted phenyl.
18. The method according to claim 1 , wherein R l is hydrogen.
19. The method according to claim 1 , wherein R l is benzyl.
20. The method according to claim 1 , wherein R 1 is C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 alkyl.
21. The method according to claim 20 , wherein R 1 is iso-propyl.
22. The method according to claim 1 , wherein R 2 is a unit having the formula:
—OR 8
wherein R 8 is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, or n-hexyl.
23. The method according to claim 22 , wherein R 8 is methyl, ethyl, or tert-butyl.
24. The method according to claim 1 , wherein R 2 is chosen from methyl or tert-butyl.
25. The method according to claim 1 , wherein R 3 is hydrogen.
26. The method according to claim 1 , wherein the compound is chosen from:
wherein R 2 is chosen from:
i) C 1 -C 6 linear or C 3 -C 6 branched alkyl; or
ii) C 1 -C 6 linear or C 3 -C 6 branched alkoxy;
R 4 and R 5 are each independently chosen from:
i) hydrogen;
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
iii) substituted or unsubstituted phenyl;
iv) substituted or unsubstituted heteroaryl; or
R 4 and R 5 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms;
R 6 is a unit chosen from:
i) hydrogen;
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
iii) substituted or unsubstituted phenyl; and
iv) substituted or unsubstituted heteroaryl.
27. The method according to claim 1 , wherein the compound is chosen from;
4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3 -phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-[(R)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
{1-[1-(5 -Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methyl carbamic acid tert-butyl ester;
{(S)-2-Phenyl-1-[1-(2-phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethyl -carbamoyl]ethyl}carbamic acid tert-butyl ester
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(thiazol-2-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-methylthiazol-2-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-propylthiazol-2-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-(4-Cyclopropylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-(4-Cyclohexylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl -propanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl -propanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-(4-Ethyl-5-methylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl -propanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(2,2,2-trifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido)-2-[4-(3,3,3-trifluoropropyl)thiazol-2-yl]ethyl}phenylsulfamic acid;
4-{(S)-2-[4-(2,2-Difluorocyclopropyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(methoxy -methyl)thiazol-2-yl]ethyl}phenylsulfamic acid;
4-{(S)-2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(5-phenylthiazol-2-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl -propanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[4-(3,4-Dimethylphenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[4-(4-Chlorophenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-2-yl)thiazol-2-yllethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-3-yl)thiazol-2-yllethyl}phenylsulfamic acid;
4-{(S)-2-(5,6-Dihydro-4H-cyclopenta[c/]thiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino) -3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-[4-(5-Chlorothiophen-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Ethoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl) ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-methylthiazol-4-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan -amido]ethyl}phenylsulfamic acid;
4-{(S)-2-(2-Isopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan -amido]ethyl}phenylsulfamic acid;
4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxy -carbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamido]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-242-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid;
4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid;
4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(2-methylthiazole -4-yl)thiazole-4yl]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-pyrazine-2-yl)thiazole-4-yl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(6-methylpyridin -3-yl)thiazol-4-yl]ethyl}phenylsulfamic acid;
4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid;
4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-yl)ethyl]phenylsulfamic acid;
4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yflethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
(S)-4-{2-[2-(tert-Butoxycarbonylamino)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}phenyl -sulfamic acid;
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonylamino)acetamido]ethyl}phenyl -sulfamic acid;
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-methylbutanamido]-ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-4-methylpentan -amido]ethyl}phenylsulfamic acid;
4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; and
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid.