MIF modulators

Patent metadata

Field	Value
Publication number	US-9540322-B2
Application number	US-201113100922-A
Country	US
Kind code	B2
Filing date	May 4, 2011
Priority date	Aug 18, 2008
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

Abstract

The invention provides novel heterocyclic compounds, pharmaceutical compositions and methods of treatment that modulate levels of MIF expression and treat disorders associated with high or low levels of MIF expression.

First claim

The invention claimed is:

1. A compound according to formula III H:

wherein
each X 1 is selected from —H, R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
each X 2 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
each X 3 is —OH or —O(C 1 -C 6 alkyl);
each X 4 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
each X 5 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
each Y 1 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
each Y 2 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
each Y 3 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
each Y 4 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ; and
each Y 5 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
provided that X 3 is OH or Y 3 is —O(C 1 -C 6 )alkyl or —OH;
each R a is independently unsubstituted (C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl substituted with up to five halogen atoms and up to two substituents selected from the group consisting of —C≡N; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR 4 2 ; —OR b ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)NR c 2 ; —S(C 1 -C 6 )alkyl; —S(O)(C 1 -C 6 )alkyl; and —SO 2 (C 1 -C 6 )alkyl;
each R b is independently hydrogen or (C 1 -C 6 )alkyl;
each R c is independently hydrogen;

(C 1 -C 6 )alkyl; —(C 2 -C 6 )alkylene-OR b ; —(C 1 -C 6 )alkylene-C(═O)OR b ; —(C 1 -C 6 )alkylene-OC(═O)R b ; —(C 2 -C 6 )alkylene-NR b 2 ; —(C 1 -C 6 )alkylene-C(═O)NR b 2 ; —(C 1 -C 6 )alkylene-NR b C(═O)R b ; —(C 1 -C 6 )alkylene-NR b C(═O)NR b 2 ; or, optionally, within any occurrence of NR c 2 , independently of any other occurrence of NR c 2 , the two R c groups in combination are —(CH 2 ) α — or —(CH 2 ) β Q(CH 2 ) 2 —;
each α is independently selected from the group consisting of 4, 5, and 6;
each β is independently selected from the group consisting of 2 and 3;
each Q is independently selected from the group consisting of O, S, NR b ; NC(═O)R b ; NSO 2 R b ; N(C 2 -C 6 )alkylene-OR b ; N(C 1 -C 6 )alkylene-C(═O)OR b ; N(C 1 -C 6 )alkylene-OC(═O)R b ; N(C 2 -C 6 )alkylene-NR b 2 ; N(C 1 -C 6 )alkylene-C(═O)NR b 2 ; N(C 1 -C 6 )alkylene-NR b C(═O)R b ; and N(C 1 -C 6 )alkylene-NR b C(═O)NR b 2 ,
or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.

2. A compound according to formula III-B:

wherein
B is selected from the group consisting of —Ar 2 and —CH 2 Ar 2 ;
Ar 2 is an unsubstituted or substituted aromatic ring which is a 5, 6, 8, 9, or 10-membered monocyclic or bicyclic heteroaryl group containing 0, 1, 2, 3 or 4 nitrogen atoms, 0, 1 or 2 oxygen atoms, and 0, 1 or 2 sulfur atoms as heteroatoms;
wherein the optional substituents of Ar 2 are each independently selected from —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl;

and —SO 2 NR c 2 ;
each X 1 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
each X 2 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;
each X 3 is —OH or —O(C 1 -C 6 alkyl);
each X 4 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR

Assignees

• Jorgensen William L
• Bucala Richard J
• Univ Yale

Inventors

• Jorgensen William L
• Bucala Richard J

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P29/00

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