COMPOUNDS AND COMPOUNDS FOR USE IN METHODS FOR TREATING DISEASES OR CONDITIONS MEDIATED BY PROTEIN DISULFIDE ISOMERASE
The invention provides compounds of formula (I) that inhibit PDI, for use in methods to treat or prevent a disease or condition in a subject that would benefit by inhibition of PDI. Formula (I)
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein:
R 1 is selected from OH, acyloxy or a moiety capable of being hydrolyzed or otherwise metabolized under physiological conditions to a hydroxyl substituent;
R 2 is selected from H, lower alkyl, or halogen;
R 3 and R 4 are independently selected from H, F, and alkyl, or taken together with the carbon atom to which they are attached form a carbonyl group or a substituted or unsubstituted 3-7 membered cycloalkyl ring;
R 5 is selected from OR 7 , NHR 7 , and NR 7 R 8 , wherein R 7 and R 8 are each independently selected from H and substituted or unsubstituted alkyl, aryl, aralkyl, cycloalkyl, and cycloalkylalkyl, or taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-7 membered heterocyclyl ring (e.g., a pyrrolidine, piperidine, morpholine, or piperazine ring);
W represents a C 1 -C 3 alkylene group;
X is selected from O, S, and NR 9 , wherein R 9 is selected from H or lower alkyl; and
R 6 is selected from substituted or unsubstituted aryl or heteroaryl;
with the proviso that the following compounds are excluded:
2 . The compound according to claim 1 , wherein R 1 is OH.
3 . The compound according to claim 1 , wherein R 2 is H or Cl.
4 . The compound according to claim 3 , wherein R 3 and R 4 are both H or, taken together with the carbon atom to which they are attached, form a carbonyl group.
5 . The compound according to claim 4 , wherein R 5 is OR 7 , wherein R 7 is substituted or unsubstituted alkyl.
6 . The compound according to claim 5 , wherein W is ethylene.
7 . The compound according to claim 6 , wherein X is O.
8 . The compound according to claim 7 , wherein R 6 is substituted or unsubstituted aryl.
9 . The compound according to claim 1 , having a structure selected from:
or a pharmaceutically acceptable salt and/or prodrug thereof.
10 . The compound according to claim 1 , wherein the compound is selected from:
, or a pharmaceutically acceptable salt and/or prodrug thereof.
11 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient or solvent.
12 . A method for inhibiting protein disulfide isomerase in a patient, comprising administering to the patient a compound of Formula (I):
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein:
R 1 is selected from OH, acyloxy or a moiety capable of being hydrolyzed or otherwise metabolized under physiological conditions to a hydroxyl substituent;
R 2 is selected from H, lower alkyl, or halogen;
R 3 and R 4 are independently selected from H, F, and alkyl, or taken together with the carbon atom to which they are attached form a carbonyl group or a substituted or unsubstituted 3-7 membered cycloalkyl ring;
R 5 is selected from OR 7 , NHR 7 , and NR 7 R 8 , wherein R 7 and R 8 are each independently selected from H and substituted or unsubstituted alkyl, aryl, aralkyl, cycloalkyl, and cycloalkylalkyl, or taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-7 membered heterocyclyl ring (e.g., a pyrrolidine, piperidine, morpholine, or piperazine ring);
W represents a C 1 -C 3 alkylene group;
X is selected from O, S, and NR 9 , wherein R 9 is selected from H or lower alkyl; and
R 6 is selected from substituted or unsubstituted aryl or heteroaryl.
13 . The method according to claim 12 , wherein the method is for treating thrombosis, thrombotic diseases, infectious diseases, cancer, inflammation, platelet aggregation and/or fibrin generation.
14 . A method for inhibiting protein disulfide isomerase in a cell, comprising contacting the cell with a compound of Formula (I):
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein:
R 1 is selected from OH, acyloxy or a moiety capable of being hydrolyzed or otherwise metabolized under physiological conditions to a hydroxyl substituent;
R 2 is selected from H, lower alkyl, or halogen;
R 3 and R 4 are independently selected from H, F, and alkyl, or taken together with the carbon atom to which they are attached form a carbonyl group or a substituted or unsubstituted 3-7 membered cycloalkyl ring;
R 5 is selected from OR 7 , NHR 7 , and NR 7 R 8 , wherein R 7 and R 8 are each independently selected from H and substituted or unsubstituted alkyl, aryl, aralkyl, cycloalkyl, and cycloalkylalkyl, or taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-7 membered heterocyclyl ring (e.g., a pyrrolidine, piperidine, morpholine, or piperazine ring);
W represents a C 1 -C 3 alkylene group;
X is selected from O, S, and NR 9 , wherein R 9 is selected from H or lower alkyl; and
R 6 is selected from substituted or unsubstituted aryl or heteroaryl.
15 . The method according to claim 12 , wherein R 1 is OH.
16 . The method according to claim 15 , wherein R 2 is H or Cl.
17 . The method according to claim 16 , wherein R 3 and R 4 are H, or taken together with the carbon atom to which they are attached form a carbonyl group.
18 . The method according to claim 17 , wherein R 5 is OR 7 , wherein R 7 is substituted or unsubstituted alkyl.
19 . The method according to claim 18 , wherein W is ethylene.
20 . The method according to claim 19 , wherein X is O.
21 . The method according to claim 20 , wherein R 6 is substituted or unsubstituted aryl.
22 . The method according to claim 12 , wherein the compound is a compound selected from:
or a pharmaceutically acceptable salt and/or prodrug thereof.
23 . The method according to claim 12 , wherein the compound is selected from:
or a pharmaceutically acceptable salt and/or prodrug thereof.