IP Library › Granted Patent US 8,188,125
Granted Patent B2
US 8,188,125 · App. 12/467,430 · Granted May 29, 2012

Human protein tyrosine phosphatase inhibitors and methods of use

View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 8,188,125
App. No.
12/467,430
Filed
May 18, 2009
Granted
May 29, 2012
Kind
B2
Art Unit
1626
USPC
514/363
Abstract

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 one or more human protein tyrosine phosphatase beta (HPTP-β) inhibitors, and to methods for regulating angiogenesis.

Claims (145)

1. A method for treating a disease or disorder chosen from skeletal muscle and myocardial ischemia, stroke, coronary artery disease, peripheral vascular disease, and coronary artery disease, comprising administering to a human in need thereof a compound of the formula:

wherein R is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted phenyl; and

iii) substituted or unsubstituted heteroaryl ring;

Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl unit having the formula:

R 1 is chosen from:

i) hydrogen;

ii) substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl;

iii) substituted or unsubstituted C 6 or C 10 aryl;

iv) —OR 4 ;

v) —C(O)OR 5 ;

yl) —COR 6 ;

vii) —NR 7 C(O)OR 8 ; and

viii) substituted or unsubstituted heteroaryl;

R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl; R 5 is C 1 -C 6 linear or branched alkyl, or benzyl; R 6 is C 1 -C 6 linear, branched, or cyclic alkyl, or phenyl; R 7 is hydrogen or methyl; R 8 is C 1 -C 6 linear or branched alkyl, or benzyl;

L is a unit having the formula —[C(R 9a R 9b )] y —;

R 9a and R 9b are each independently hydrogen, C 1 -C 6 linear or branched alkyl, or phenyl; and

the index x is 0 or 1; the index y is from 1 to 4;

or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1 , wherein the compound is a salt comprising anions chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, and citrate.

3. A method according to claim 1 , wherein the compound is a salt comprising cations chosen from ammonium, sodium, lithium, potassium, calcium, magnesium, and bismuth.

4. A method according to claim 1 , wherein the compound is chosen from:

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamic acid;

4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid; and

4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid.

5. A method for regulating angiogenesis in a human comprising administering to a human in need thereof a compound of the formula:

wherein R is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted phenyl; and

iii) substituted or unsubstituted heteroaryl ring;

Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl unit having the formula:

R 1 is chosen from:

i) hydrogen;

ii) substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl;

iii) substituted or unsubstituted C 6 or C 10 aryl;

iv) —OR 4 ;

v) —C(O)OR 5 ;

yl) —COR 6 ;

viii) —NR 7 C(O)OR 8 ; and

viii) substituted or unsubstituted heteroaryl;

R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl; R 5 is C 1 -C 6 linear or branched alkyl, or benzyl; R 6 is C 1 -C 6 linear, branched, or cyclic alkyl, or phenyl; R 7 is hydrogen or methyl; R 8 is C 1 -C 6 linear or branched alkyl, or benzyl;

L is a unit having the formula —[C(R 9a R 9b )] y —;

R 9a and R 9b are each independently hydrogen, C 1 -C 6 linear or branched alkyl, or phenyl;

and the index x is 0 or 1; the index y is from 1 to 4;

or a pharmaceutically acceptable salt thereof.

6. A method according to claim 5 , wherein the compound a salt comprising anions chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, and citrate.

7. A method according to claim 5 , wherein the compound is a salt comprising cations chosen from ammonium, sodium, lithium, potassium, calcium, magnesium, and bismuth.

8. A method according to claim 5 , wherein the compound is chosen from:

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamic acid;

4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid; and

4-*(S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid.

9. A method for vascularizing ischemic tissue in a human comprising administering to a human in need thereof a compound of the formula:

wherein R is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted phenyl; and

iii) substituted or unsubstituted heteroaryl ring;

Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl unit having the formula:

R 1 is chosen from:

i) hydrogen;

ii) substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl;

iii) substituted or unsubstituted C 6 or C 10 aryl;

iv) —OR 4 ;

v) —C(O)OR 5 ;

vi) —COR 6 ;

ix) —NR 7 C(O)OR 8 ; and

viii) substituted or unsubstituted heteroaryl;

R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl; R 5 is C 1 -C 6 linear or branched alkyl, or benzyl; R 6 is C 1 -C 6 linear, branched, or cyclic alkyl, or phenyl; R 7 is hydrogen or methyl; R 8 is C 1 -C 6 linear or branched alkyl, or benzyl;

L is a unit having the formula —[C(R 9a R 9b )] y —;

R 9a and R 9b are each independently hydrogen, C 1 -C 6 linear or branched alkyl, or phenyl;

and the index x is 0 or 1; the index y is from 1 to 4;

or a pharmaceutically acceptable salt thereof.

10. A method according to claim 9 , wherein the compound a salt comprising anions chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, and citrate.

11. A method according to claim 9 , wherein the compound is a salt comprising cations chosen from ammonium, sodium, lithium, potassium, calcium, magnesium, and bismuth.

12. A method according to claim 9 , wherein the compound is chosen from:

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamic acid;

4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid; and

4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid.

13. A method for promoting the growth of skin graft replacements comprising administering to a human in need thereof a compound of the formula:

wherein R is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted phenyl; and

iii) substituted or unsubstituted heteroaryl ring;

Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl unit having the formula:

R 1 is chosen from:

i) hydrogen;

ii) substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl;

iii) substituted or unsubstituted C 6 or C 10 aryl;

iv) —OR 4 ;

v) —C(O)OR 5 ;

vi) —COR 6 ;

x) —NR 7 C(O)OR 8 ; and

viii) substituted or unsubstituted heteroaryl;

R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl; R 5 is C 1 -C 6 linear or branched alkyl, or benzyl; R 6 is C 1 -C 6 linear, branched, or cyclic alkyl, or phenyl; R 7 is hydrogen or methyl; R 8 is C 1 -C 6 linear or branched alkyl, or benzyl;

L is a unit having the formula —[C(R 9a R 9b )] y —;

R 9a and R 9b are each independently hydrogen, C 1 -C 6 linear or branched alkyl, or phenyl;

and the index x is 0 or 1; the index y is from 1 to 4;

or a pharmaceutically acceptable salt thereof.

14. A method according to claim 13 , wherein the compound is a salt comprising anions chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, and citrate.

15. A method according to claim 13 , wherein the compound is a salt comprising cations chosen from ammonium, sodium, lithium, potassium, calcium, magnesium, and bismuth.

16. A method according to claim 13 , wherein the compound is chosen from:

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamic acid;

4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid; and

4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid.

17. A method for promoting tissue repair in the context of guided tissue regeneration (GTR) procedures comprising administering to a human in need thereof a compound of the formula:

wherein R is a unit chosen from:

i) hydrogen;

ii) substituted or unsubstituted phenyl; and

iii) substituted or unsubstituted heteroaryl ring;

Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl unit having the formula:

R 1 is chosen from:

i) hydrogen;

ii) substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl;

iii) substituted or unsubstituted C 6 or C 10 aryl;

iv) —OR 4 ;

v) —C(O)OR 5 ;

vi) —COR 6 ;

xi) —NR 7 C(O)OR 8 ; and

viii) substituted or unsubstituted heteroaryl;

R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl; R 5 is C 1 -C 6 linear or branched alkyl, or benzyl; R 6 is C 1 -C 6 linear, branched, or cyclic alkyl, or phenyl; R 7 is hydrogen or methyl; R 8 is C 1 -C 6 linear or branched alkyl, or benzyl;

L is a unit having the formula —[C(R 9a R 9b )] y —;

R 9a and R 9b are each independently hydrogen, C 1 -C 6 linear or branched alkyl, or phenyl;

and the index x is 0 or 1; the index y is from 1 to 4;

or a pharmaceutically acceptable salt thereof.

18. A method according to claim 17 , wherein the compound a salt comprising anions chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, and citrate.

19. A method according to claim 17 , wherein the compound is a salt comprising cations chosen from ammonium, sodium, lithium, potassium, calcium, magnesium, and bismuth.

20. A method according to claim 17 , wherein the compound is chosen from:

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamic acid;

4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid;

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid; and

4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 9, 2021
From: AERPIO PHARMACEUTICALS, INC.
To: EYEPOINT PHARMACEUTICALS, INC.
Reel/Frame 057448/0033 →