IP Library › Granted Patent US 7,091,353
Granted Patent B2
US 7,091,353 · App. 10/032,286 · Granted Aug 15, 2006

Isoindole-imide compounds, compositions, and uses thereof

Assignee: Celgene Corporation
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Quick Facts
Patent No.
US 7,091,353
App. No.
10/032,286
Granted
Aug 15, 2006
Kind
B2
Abstract

The invention relates to isoindole-imide compounds and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, or mixtures of stereoisomers thereof, pharmaceutical compositions comprising these isoindole-imide compounds, and methods for reducing the level of cytokines and their precursors in mammals. In particular, the invention pertains to isoindole-imide compounds that are potent inhibitors of the production of TNF-α in mammals. The isoindole-imides described herein are useful for treating or preventing diseases or disorders in mammals, for example, cancers, such as solid tumors and blood-born tumors; heart disease, such as congestive heart failure; osteoporosis; and genetic, inflammatory; allergic; and autoimmune diseases.

Claims (42)

1. The compound having the formula:

wherein:

R 1 is H, (C 1 –C 8 )alkyl, (C 3 –C 7 )cycloalkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C 1 –C 8 )alkyl-N(R 6 ) 2 , (C 1 –C 8 )alkyl-OR 5 , (C 1 –C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3′ , C(S)NR 3 R 3′ or (C 1 –C 8 )alkyl-O(CO)R 5 ;

R 2 is H or (C 1 –C 8 )alkyl;

R 3 and R 3′ are independently (C 1 –C 8 )alkyl, (C 3 –C 7 )cycloalkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl, (C 0 –C 8 )alkyl-N(R 6 ) 2 , (C 1 –C 8 )alkyl-OR 5 , (C 1 –C 8 )alkyl-C(O)OR 5 , (C 1 –C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ;

R 4 is (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 1 –C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, or (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl;

R 5 is (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, or (C 2 –C 5 )heteroaryl;

each occurrence of R 6 is independently H, (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, (C 2 –C 5 )heteroaryl, or (C 0 –C 8 )alkyl-C(O)O—R 5 or the R 6 groups can join to form a heterocycloalkyl group; and

the * represents a chiral-carbon center.

2. A compound of claim 1 , wherein R 1 is H, (C 1 –C 4 )alkyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or

wherein Q is O or S, and each occurrence of R 7 is independently H,(C 1 –C 8 )alkyl, (C 3 –C 7 )cycloalkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, halogen, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl, (C 0 –C 8 )alkyl-N(R 6 ) 2 , (C 1 –C 8 )alkyl-OR 5 , (C 1 –C 8 )alkyl-C(O)OR 5 , (C 1 –C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 , or adjacent occurrences of R 7 can be taken together to form a bicyclic alkyl or aryl ring.

3. A compound of claim 1 , wherein R 1 is C(O)R 3 .

4. A compound of claim 1 , wherein R 1 is C(O)OR 4 .

5. The compound having the formula:

wherein:

R 1 is H, (C 1 –C 8 )alkyl, (C 3 –C 7 )cycloalkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C 1 –C 8 )alkyl-N(R 6 ) 2 , (C 1 –C 8 )alkyl-OR 5 , (C 1 –C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3′ , C(S)NR 3 R 3′ or (C 1 –C 8 )alkyl-O(CO)R 5 ;

R 2 is H or (C 1 –C 8 )alkyl;

R 3 and R 3′ are independently (C 1 –C 8 )alkyl, (C 3 –C 7 )cycloalkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl, (C 0 –C 8 )alkyl-N(R 6 ) 2 , (C 1 –C 8 )alkyl-OR 5 , (C 1 –C 8 )alkyl-C(O)OR 5 , (C 1 –C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ;

R 4 is (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 1 –C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, or (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl;

R 5 is (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, or (C 2 –C 5 )heteroaryl;

each occurrence of R 6 is independently H, (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, (C 2 –C 5 )heteroaryl, or (C 0 –C 8 )alkyl-C(O)O—R 5 or the R 6 groups can join to form a heterocycloalkyl group; and

the * represents a chiral-carbon center.

6. A compound of claim 5 , wherein R 1 is H, (C 1 –C 4 )alkyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or

wherein Q is O or S, and each occurrence of R 7 is independently H,(C 1 –C 8 )alkyl, (C 3 –C 7 )cycloalkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, halogen, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl, (C 0 –C 8 )alkyl-N(R 6 ) 2 , (C 1 –C 8 )alkyl-OR 5 , (C 1 –C 8 )alkyl-C(O)OR 5 , (C 1 –C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 , or adjacent occurrences of R 7 can be taken together to form a bicyclic alkyl or aryl ring.

7. A compound of claim 5 , wherein R 1 is C(O)R 3 .

8. A compound of claim 5 , wherein R 1 is C(O)OR 4 .

9. A compound having the formula:

wherein:

R 1 is H, (C 1 –C 8 )alkyl, (C 3 –C 7 )cycloalkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C 1 –C 8 )alkyl-N(R 6 ) 2 , (C 1 –C 8 )alkyl-OR 5 , (C 1 –C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3′ , C(S)NR—R 3′ or (C 1 –C 8 )alkyl-O(CO)R 5 ;

R 2 is H or (C 1 –C 8 )alkyl;

R 3 and R 3′ are independently (C 1 –C 8 )alkyl, (C 3 –C 7 )cycloalkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl, (C 0 –C 8 )alkyl-N(R 6 ) 2 , (C 1 –C 8 )alkyl-OR 5 , (C 0 –C 8 )alkyl-C(O)OR 5 , (C 1 –C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ;

R 4 is (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 1 –C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, or (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl;

R 5 is (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, or (C 2 –C 5 )heteroaryl;

each occurrence of R 6 is independently H, (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, (C 2 –C 5 )heteroaryl, or (C 0 –C 8 )alkyl-C(O)O—R 5 or the R 6 groups can join to form a heterocycloalkyl group; and

the * represents a chiral-carbon center.

10. A compound of claim 9 , wherein R 1 is H, (C 1 –C 4 )alkyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 or

wherein Q is O or S, and each occurrence of R 7 is independently H,(C 1 –C 8 )alkyl, (C 3 –C 7 )cycloalkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, benzyl, aryl, halogen, (C 0 –C 4 )alkyl-(C 1 –C 6 )heterocycloalkyl, (C 0 –C 4 )alkyl-(C 2 –C 5 )heteroaryl, (C 0 –C 8 )alkyl-N(R 6 ) 2 , (C 1 –C 8 )alkyl-OR 5 , (C 1 –C 8 )alkyl-C(O)OR 5 , (C 1 –C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 , or adjacent occurrences of R 7 can be taken together to form a bicyclic alkyl or aryl ring.

11. A compound of claim 9 , wherein R 1 is C(O)R 3 .

12. A compound of claim 9 , wherein R 1 is C(O)OR 4 .

13. A compound of claim 1 , which is:

14. A compound of claim 1 , which is:

15. A compound of claim 1 , which is:

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 23, 2002
From: ROBARGE, MICHAEL J.; CHEN, ROGER SHEN-CHU; MULLER, GEORGE W.; MAN, HON-WAH
To: CELGENE CORPORATION
Reel/Frame 012848/0280 →
Continuity (3)
Continuation In Part 0997248700 · Oct 5, 2001
Provisional Application 6025837200 · Dec 27, 2000
Related Publication 20030096841A1 · May 22, 2003