GPBP inhibition using Q2 peptidomimetics

Patent metadata

Field	Value
Publication number	US-10544083-B2
Application number	US-201815892317-A
Country	US
Kind code	B2
Filing date	Feb 8, 2018
Priority date	Nov 5, 2009
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

Abstract

Disclosed are compounds of formula:

that inhibiting GPBP activity, making them useful as therapeutics in antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding and ER stress-mediated disorders, and aberrant apoptosis.

First claim

What is claimed is:

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
R is CR 5 ;
R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, amino(C 1 -C 6 alkyl), sulfanyl(C 1 -C 6 alkyl), (C 1 -C 6 alkyl)sulfanyl(C r C 6 alkyl), —(CH 2 ) 1-5 —C(O)(C 1 -C 6 alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , (aryl)C 2 -C 6 alkyl, and (heteroaryl)C 1 -C 6 alkyl;

R 1 is hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, amino(C 1 -C 6 alkyl), sulfanyl(C 1 -C 6 alkyl), or (C 1 -C 6 alkyl)sulfanyl(C 1 -C 6 alkyl);
R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, or formyl(C 0 -C 6 alkyl);
R 3 is —CH═CH—C(O)OH or —CH═CH—C(O)(C 1 -C 6 alkoxy); and
R 4 is hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), benzyloxy, —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6 alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6 alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6 alkyl) 2 , —CH═CH—C(O)OH, —CH═CH—C(O)(C 1 -C 6 alkoxy), —O(CH 2 ) 1-5 —C(O)OH, —O(CH 2 ) 1-5 —C(O)(C 1 -C 6 alkoxy), (aryl)C 1 -C 6 alkyl, or (heteroaryl)C 1 -C 6 alkyl.

2. A compound according to claim 1 having the formula:

wherein:
R is CR 5 ;
R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, amino(C 1 -C 6 alkyl), sulfanyl(C 1 -C 6 alkyl), (C 1 -C 6 alkyl)sulfanyl(C 1 -C 6 alkyl), —(CH 2 ) 1-5 —C(O)(C 1 -C 6 alkoxy), and —(CH 2 ) 1-5 —C(O)NH 2 ;

R 1 is hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, amino(C 1 -C 6 alkyl), sulfanyl(C 1 -C 6 alkyl), or (C 1 -C 6 alkyl)sulfanyl(C 1 -C 6 alkyl);
R 2 is C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, or formyl(C 0 -C 6 alkyl);
R 3 is —CH═CH—C(O)OH, or —CH═CH—C(O)(C 1 -C 6 alkoxy); and
R 4 is hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), benzyloxy, —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6 alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6 alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6 alkyl) 2 , —CH═CH—C(O)OH, —CH═CH—C(O)(C 1 -C 6 alkoxy), —O(CH 2 ) 1-5 —C(O)OH, or —O(CH 2 ) 1-5 —C(O)(C 1 -C 6 alkoxy).

3. A compound according to claim 1 , wherein
R is CR 5 ;
R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, and amino(C 1 -C 6 alkyl);

R 1 is hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, or halo(C 1 -C 6 alkoxy);
R 2 is C 1 -C 6 alkyl, hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, or formyl(C 0 -C 6 alkyl);
R 3 is CH═CH—C(O)OH, or —CH═CH—C(O)(C 1 -C 6 alkoxy); and
R 4 is hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), benzyloxy, —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6 alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6 alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6 alkyl) 2 , —CH═CH—C(O)OH, —CH═CH—C(O)(C 1 -C 6 alkoxy), —O(CH 2 ) 1-5 —C(O)OH, or —O(CH 2 ) 1-5 —C(O)(C 1 -C 6 alkoxy).

4. A compound according to claim 1 , having the formula:

5. A compound according to claim 1 , wherein
R 1 is hydrogen.

6. A compound according to claim 1 , wherein
R 2 is C 1 -C 6 alkyl, hydroxy(C 1 -C 6 alkyl), or formyl(C 0 -C 6 alkyl).

7. A compound according to claim 6 , wherein R 2 is hydroxy(C 1 -C 6 alkyl).

8. A compound according to claim 1 , wherein
R 3 is CH═CH—C(O)OH.

9. A compound according to claim 1 , wherein
R 4 is hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), or benzyloxy.

10. A compound according to claim 9 , wherein R 4 is hydroxy or C 1 -C 6 alkoxy.

11. A compound according to claim 1 , wherein
R 5 is C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, or halo(C 1 -C 6 alkoxy).

12. A compound according to claim 1 , wherein
R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, and amino(C 1 -C 6 alkyl);
R 1 is hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, or halo(C 1 -C 6 alkoxy);
R 2 is C 1 -C 6 alkyl or hydroxy(C 1 -C 6 alkyl);
R 3 is —CH═CH—C(O)OH, or —CH═CH—C(O)(C 1 -C 6 alkoxy); and
R 4 is hydroxy, C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), or benzyloxy.

13. A compound according to claim 1 , wherein
R 1 is hydrogen;
R 2 is C 1 -C 6 alkyl, hydroxy(C 1 -C 6 alkyl), or formyl(C 1 -C 6 alkyl);
R 3 is —CH═CH—C(O)OH, or —CH═CH—C(O)(C 1 -C 6 alkoxy);
R 4 is hydroxy or C 1 -C 6 alkoxy; and
R 5 is C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, or halo(C 1 -C 6 alkoxy).

14. A compound according to claim 1 , wherein
R is CR 5 ;
R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, and amino(C 1 -C 6 alkyl);

R 1 is hydrogen;
R 2 is C 1 -C 6 alkyl or hydroxy(C 1 -C 6 alkyl);
R 3 is —C(O)OH CH═CH—C(O)OH; and
R 4 is C 1 -C 6 alkoxy.

15. A compound according to claim 1 , wherein
R is CR 5 ;
R 5 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, halo(C 1 -C 6 alkoxy), amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, hydroxy(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, and amino(C 1 -C 6 alkyl);

R 1 is hydrogen;
R 2 is methyl or hydroxymethyl;
R 3 is —CH═CH—C(O)OH; and
R 4 is methoxy.

16. A compound according to claim 1 , which is:
ethyl (E)-3-[4″-(benzyloxy)-2′-formyl-3-methyl-(1,1′;4′,1″)terphenyl-2″-yl]acrylate;
ethyl (E)-3-[4″-(benzyloxy)-2′-formyl-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]acrylate;
ethyl (E)-3-[4″-(

Assignees

• Fibrostatin S L
• Univ Valencia

Inventors

• Saus Juan
• Fustero Santos
• Sanz-Cervera Juan F
• Pérez-Payá Enrique
• Blasco Raül
• Revert-Ros Francisco
• Revert Fernando

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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