MIF modulators

Patent metadata

Field	Value
Publication number	US-9643922-B2
Application number	US-77343010-A
Country	US
Kind code	B2
Filing date	May 4, 2010
Priority date	Aug 18, 2008
Publication date	May 9, 2017
Grant date	May 9, 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 the following formula B:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH; and R 2 is H; or
R 1 is H, and R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;
Z 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, C 1 alkoxy, F, Cl, or (CH 2 ) j —OH; Z 2 is H; and Z 3 is H; or
Z 1 is H; Z 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH; and Z 3 is H; or
Z 1 is H; Z 2 is H; and Z 3 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;
Z 4 is H;
Z 5 is H; and
each j is independently 0, 1, 2, 3, 4 or 5.

2. A pharmaceutical composition in dosage form comprising at least one compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.

3. A compound according to the following formula B:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from OH, OCH 3 , F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ; and R 2 is H; or
R 1 is H and R 2 is selected from OH, F, Cl, C 1 -C 4 alkyl which is optionally substituted with from one to three hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;
Z 1 is selected from OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ; Z 2 is H; and Z 3 is H; or
Z 1 is H; Z 2 is selected from OH, OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ; and Z 3 is H; or
Z 1 is H; Z 2 is H; and Z 3 is selected from OCH 3 , a C 1 -C 3 alkyl group which is optionally substituted with from one to three one hydroxyl groups or from one to three halogen groups, and —(CH 2 ) j OR a ;
Z 4 is H;
Z 5 is H;
each R a is independently H, or a methyl or ethyl group which is optionally substituted with a hydroxyl group or from one to three halogen groups; and
each j is independently 0, 1, 2, or 3.

4. A compound according to the following formula B:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is CH 3 , OCH 3 , F, or OH; R 2 is H, CH 3 or OH; Z 1 is H or OCH 3 ; Z 2 is H or OH; Z 3 is H or OCH 3 ; Z 4 is H; and Z 5 is H; or
R 1 is CH 3 , OCH 3 , F, or OH; R 2 is H, CH 3 or OH; Z 1 is H or OCH 3 ; Z 2 is H, OH or OCH 3; Z 3 is H; Z 4 is H; and Z 5 is H; and wherein Z 1 is OCH 3 ; or Z 2 is OH or OCH 3 ; or; Z 3 is OCH 3 .

5. A compound or pharmaceutically acceptable salt thereof according claim 4 , wherein:
R 1 is CH 3 , R 2 is H, Z 1 is OCH 3 , Z 2 is H, Z 3 is H, Z 4 is H and Z 5 is H;
R 1 is H, R 2 is OH, Z 1 is H, Z 2 is H, Z 3 is OCH 3 , Z 4 is H and Z 5 is H;
R 1 is OH, R 2 is H, Z 1 is OCH 3 , Z 2 is OCH 3 , Z 3 is H, Z 4 is H and Z 5 is H.

6. A compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein R 1 is CH 3 , R 2 is H, Z 1 is H, Z 2 is OH, Z 3 is H, Z 4 is H and Z 5 is H.

7. A compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein R 1 is CH 3 , R 2 is H, Z 1 is H, Z 2 is OCH 3 , Z 3 is H, Z 4 is H and Z 5 is H.

8. A compound selected from the following compounds and pharmaceutically acceptable salts thereof:
3-benzyl-5-fluorobenzoxazol-2-one;
3-(2-benzyloxybenzyl)-5-methylbenzoxazol-2-one;
3-(3-cyanobenzyl)-5-chlorobenzoxazol-2-one;
3-(2,3-dimethoxybenzyl)-5-hydroxybenzoxazol-2-one;
3-(2,3-dimethoxybenzyl)-5-methylbenzoxazol-2-one;
3-(2-ethoxybenzyl)-5-methylbenzoxazol-2-one;
3-(3,5-dimethoxybenzyl)-5-methylbenzoxazol-2-one;
3-(3-ethoxybenzyl)-5-methylbenzoxazol-2-one;
3-(3-ethoxy-5-hydroxybenzyl)-5-methylbenzoxazol-2-one;
5-ethyl-3-(3-hydroxybenzyl)benzoxazol-2-one;
5-ethyl-3-(3-methoxybenzyl)benzoxazol-2-one;
3-(3-fluorobenzyl)-5-methylbenzoxazol-2-one;
3-(4-fluorobenzyl)-5-methylbenzoxazol-2-one;
5-fluoro-3-(3-hydroxybenzyl)benzoxazol-2-one;
6-fluoro-3-(3-hydroxybenzyl)benzoxazol-2-one;
5-fluoro-3-(2-methoxybenzyl)benzoxazol-2-one;
5-fluoro-3-(3-methoxybenzyl)benzoxazol-2-one;
5-fluoro-3-(4-methoxybenzyl)benzoxazol-2-one;
6-fluoro-3-(3-methoxybenzyl)benzoxazol-2-one;
3-(3-hydroxybenzyl)-5-methoxybenzoxazol-2-one;
3-(3-hydroxybenzyl)-5-methylbenzoxazol-2-one;
3-(3-hydroxybenzyl)-6-methylbenzoxazol-2-one;
3-(4-hydroxybenzyl)-5-methylbenzoxazol-2-one;
5-hydroxy-3-(3-hydroxybenzyl)benzoxazol-2-one;
5-hydroxy-3-(2-methoxybenzyl)benzoxazol-2-one;
5-hydroxy-3-(3-methoxybenzyl)benzoxazol-2-one;
6-hydroxy-3-(2-methoxybenzyl)benzoxazol-2-one;
6-hydroxy-3-(4-methoxybenzyl)benzoxazol-2-one;
5-(hydroxymethyl)-3-(3-methoxybenzyl)benzoxazol-2-one;
3-(2-methoxybenzyl)-5-methylbenzoxazol-2-one;
3-(3-methoxybenzyl)-5-methylbenzoxazol-2-one;
3-(3-methoxybenzyl)-6-methylbenzoxazol-2-one;
3-(3-methoxybenzyl)-5,6-dimethylbenzoxazol-2-one; and
5-methoxy-3-(3-methoxybenzyl)benzoxazol-2-one.

9. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:
R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;
R 2 is H;
Z 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, C 1 alkoxy, F, Cl, or (CH 2 ) j —OH;
Z 2 is H;
Z 3 is H;
Z 4 is H; and
Z 5 is H.

10. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:
R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j OH;
R 2 is H;
Z 1 is H;
Z 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;
Z 3 is H;
Z 4 is H; and
Z 5 is H.

11. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:
R 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;
R 2 is H;
Z 1 is H;
Z 2 is H;
Z 3 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;
Z 4 is H; and
Z 5 is H.

12. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:
R 1 is H;
R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy, F, Cl, or (CH 2 ) j —OH;
Z 1 is hydroxyl, optionally substituted C 1 -C 8 alkyl, Cl alkoxy, F, Cl, or (CH 2 ) j —OH;
Z 2 is H;
Z 3 is H;
Z 4 is H; and
Z 5 is H.

13. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein:
R 1 is H;
R 2 is hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 10 alkoxy

Assignees

• Jorgensen William L
• Bucala Richard J
• Univ Yale

Inventors

• Jorgensen William L
• Bucala Richard J

Classifications

• A61P29/00

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

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D307/80

  Radicals substituted by oxygen atoms · CPC title

• C07D263/58

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2 · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title