Compounds and compounds for use in methods for treating diseases or conditions mediated by protein disulfide isomerase

Patent metadata

Field	Value
Publication number	US-2016145209-A1
Application number	US-201414899180-A
Country	US
Kind code	A1
Filing date	Jun 20, 2014
Priority date	Jun 21, 2013
Publication date	May 26, 2016
Grant date	—

Abstract

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)

First claim

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.

Assignees

• Broad Inst Inc
• Beth Israel Hospital

Inventors

• Flaumenhaft Robert
• Nag Partha Pratim
• Pilyugina Tatiana
• Pu Jun
• Dandapani Sivaraman
• Munoz Benito

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/445 Primary

  Non condensed piperidines, e.g. piperocaine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title