IP Library › Granted Patent US 7,119,223
Granted Patent B2
US 7,119,223 · App. 10/112,681 · Granted Oct 10, 2006

Interleukin-1 and tumor necrosis factor-α modulators, synthesis of said modulators and their enantiomers and methods of using said modulators

Assignees: Nereus Pharmaceuticals, Inc.; The Regents of the University of California
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Quick Facts
Patent No.
US 7,119,223
App. No.
10/112,681
Granted
Oct 10, 2006
Kind
B2
Abstract

Novel compounds are disclosed that have the following chemical structures, and prodrug esters and acid-addition salts thereof, that are useful as Interleukin-1 and Tumor Necrosis Factor-α modulators, and thus are useful in the treatment of various diseases. wherein the R groups are defined as follows: if any R 3 –R 5 , R 7 , R 8 , R 11 –R 13 is not hydrogen, R 2 or R 6 or R 9 is not methyl, or R 10 is not CH 2 , then R 1 is selected from the group consisting of hydrogen, a halogen, COOH, C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 1 –C 12 esters, C 1 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, (C 1 –C 12 )(C 1 –C 12 ) cyclic amides, (C 1 –C 12 ) amines, C 1 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers, C 1 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 12 aryls. If all R 3 –R 5 , R 7 , R 8 , R 11 –R 13 are hydrogen, R 2 , R 6 , and R 9 are each methyl, and R 10 is CH 2 , then R 1 is selected from hydrogen, a halogen, C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 2 –C 12 esters, C 2 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, C 2 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers other than methyl-acetyl ether, C 2 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 2 –C 12 aryls. R 2 and R 9 are each separately selected from hydrogen, a halogen, C 1 –C 12 alkyl, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyl, C 2 –C 12 substituted alkenyl, C 2 –C 12 alkynyl, C 1 –C 12 acyl, C 1 –C 12 alcohol, and C 5 –C 12 aryl. R 3 –R 5 , R 7 , R 8 , and R 11 –R 13 are each separately selected from hydrogen, a halogen, C 1 –C 12 alkyl, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyl, C 2 –C 12 substituted alkenyl, C 2 –C 12 alkynyl, and C 5 –C 12 aryl. R 6 is selected from hydrogen, a halogen, C 1 –C 12 alkyl, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyl, C 2 –C 12 substituted alkenyl, and C 2 –C 12 alkynyl. R 10 is selected from hydrogen, a halogen, CH 2 , C 1 –C 6 alkyl, C 1 –C 6 substituted alkyl, C 2 –C 6 alkenyl, C 2 –C 6 substituted alkenyl, C 1 –C 12 alcohol, and C 5 –C 12 aryl. Pharmaceutical compositions comprising, and uses of, therapeutically effective amounts of the aove compounds and their prodrug esters, and a pharmaceutically acceptable carrier, are also disclosed, and are useful as, for example, anti-inflammatory analgesics, in treating immune disorders, as anti-cancer and anti-tumor agents, and in the treatment of cardiovascular disease, skin redness, and viral infection. Completely synthetic and semi-synthetic methods of making these compounds and their analogs, are also disclosed.

Claims (50)

1. A compound having the following chemical structure:

wherein:

R 1 is selected from the group consisting of hydrogen, a halogen, COOH, C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 1 –C 12 esters, C 1 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, (C 1 —C 12 ) cyclic amides, (C 1 –C 12 ) amines, C 1 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers, C 1 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 12 aryls;

R 2 and R 9 are each separately selected from hydrogen, a halogen, C 1 –C 12 alkyl, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyl, C 2 –C 12 substituted alkenyl, C 2 –C 12 alkynyl, C 1 –C 12 alcohol, C 1 –C 12 acyl, and C 5 –C 12 aryl;

R 3 –R 5 , R 7 , R 8 , and R 1 –R 13 are each separately selected from hydrogen, a halogen, C 1 –C 12 alkyl, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyl, C 2 –C 12 substituted alkenyl, C 2 –C 12 alkynyl, and C 5 –C 12 aryl;

R 6 is selected from hydrogen, a halogen, C 1 –C 12 alkyl, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyl, C 2 –C 12 substituted alkenyl, and C 2 –C 12 alkynyl;

R 10 is selected from a halogen, CH 2 , C 1 –C 6 alkyl, C 1 –C 6 substituted alkyl, C 2 –C 6 alkenyl, C 2 –C 6 substituted alkenyl, C 1 –C 12 alcohol, and C 5 –C 12 aryl; and

R 14 and R 15 are separately selected from hydrogen, a halogen, CH 2 , C 1 –C 6 alkyl, C 1 –C 6 substituted alkyl, C 2 –C 6 alkenyl, C 2 –C 6 substituted alkenyl, C 1 –C 6 alcohol, and C 5 –C 6 aryl;

wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof, and

wherein both R 1 and R 2 are not simultaneously methyl.

2. The compound of claim 1 , wherein:

R 1 is selected from hydrogen, a halogen, and C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 2 –C 12 esters, C 2 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, C 2 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers, C 2 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 12 aryls.

3. The compound of claim 1 , wherein:

R 1 is selected from the group consisting of hydrogen, a halogen, COOH, C 1 –C 6 carboxylic acids, C 1 –C 6 acyl halides, C 1 –C 6 acyl residues, C 1 –C 6 esters, C 1 –C 6 secondary amides, (C 1 –C 6 )(C 1 –C 6 ) tertiary amides, C 1 –C 12 cyclic amides, C 1 –C 12 amines, C 1 –C 6 alcohols, (C 1 –C 6 )(C 1 –C 6 ) ethers, C 1 –C 6 alkyls, C 1 –C 16 substituted alkyls, C 2 –C 6 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 6 aryls.

4. The compound of claim 1 , wherein R 10 is selected from the group consisting of C 2 –C 6 alkyl groups and C 2 –C 6 alkenyl groups.

5. The compound of claim 1 , wherein R 3 –R 5 , R 7 , R 8 , R 11 –R 15 is each hydrogen.

6. The compound of claim 5 , wherein R 3 –R 5 , R 7 , R 8 , R 11 –R 15 is each hydrogen; R 2 , R 6 , and R 9 are each methyl; and R 10 is CH 2 .

7. The compound of claim 1 , wherein R 15 is hydrogen, and R 14 is selected from hydrogen, a halogen, C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 2 –C 12 esters, C 2 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, C 2 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers, C 2 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 12 aryls.

8. The compound of claim 1 , wherein R 15 is hydrogen, and R 14 is selected from hydrogen, a halogen, C 2 –C 6 alcohols, C 2 –C 6 alkyls, C 1 –C 6 substituted alkyls, C 2 –C 6 alkenyls, C 2 –C 6 substituted alkenyls, and C 5 –C 6 aryls.

9. The compound of claim 1 , wherein R 1 is C 1 –C 12 secondary amide.

10. The compound of claim 9 , wherein R 10 is selected from the group consisting of C 2 –C 6 alkyl groups and C 2 –C 6 alkenyl groups.

11. The compound of claim 9 , wherein R 3 –R 5 , R 7 , R 8 , R 11 –R 15 is each hydrogen.

12. The compound of claim 11 , wherein R 3 –R 5 , R 7 , R 8 , R 11 –R 15 is each hydrogen; R 2 , R 6 , and R 9 are each methyl; and R 10 is CH 2 .

13. The compound of claim 9 , wherein R 15 is hydrogen, and R 14 is selected from hydrogen, a halogen, C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 2 –C 12 esters, C 2 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, C 2 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers, C 2 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 12 aryls.

14. The compound of claim 9 , wherein R 15 is hydrogen, and R 14 is selected from hydrogen, a halogen, C 2 –C 6 alcohols, C 2 –C 6 alkyls, C 1 –C 6 substituted alkyls, C 2 –C 6 alkenyls, C 2 –C 6 substituted alkenyls, and C 5 –C 6 aryls.

15. A compound having the following chemical structure:

wherein:

R 1 is selected from the group consisting of hydrogen, a halogen, COOH, C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 1 –C 12 esters, C 1 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, (C 1 –C 12 ) cyclic amides, (C 1 –C 12 ) amines, C 1 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers, C 1 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 12 aryls;

R 2 and R 9 are each separately selected from hydrogen, a halogen, C 1 –C 12 alkyl, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyl, C 2 –C 12 substituted alkenyl, C 2 –C 12 alkynyl, C 1 –C 12 alcohol, C 1 –C 12 acyl, and C 5 –C 12 aryl;

R 3 –R 5 , R 7 , R 8 , and R 11 –R 13 are each separately selected from hydrogen, a halogen, C 1 –C 12 alkyl, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyl, C 2 –C 12 substituted alkenyl, C 2 –C 12 alkynyl, and C 5 –C 12 aryl;

R 6 is selected from hydrogen, a halogen, C 1 –C 12 alkyl, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyl, C 2 –C 12 substituted alkenyl, and C 2 –C 12 alkynyl;

R 10 is selected from hydrogen, a halogen, CH 2 , C 1 –C 6 alkyl, C 1 –C 6 substituted alkyl, C 2 –C 6 alkenyl, C 2 –C 6 substituted alkenyl, C 1 –C 12 alcohol, and C 5 –C 12 aryl; and

R 14 and R 15 are separately selected from hydrogen, a halogen, CH 2 , C 1 –C 6 alkyl, C 1 –C 6 substituted alkyl, C 2 –C 6 alkenyl, C 2 –C 6 substituted alkenyl, C 1 –C 6 alcohol, and C 5 –C 6 aryl;

wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof, and

wherein both R 1 and R 2 are not simultaneously methyl.

16. The compound of claim 15 , wherein:

R 1 is selected from hydrogen, a halogen, and C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 2 –C 12 esters, C 2 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, C 2 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers, C 2 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 12 aryls.

17. The compound of claim 15 , wherein:

R 1 is selected from the group consisting of hydrogen, a halogen, COOH, C 1 –C 6 carboxylic acids, C 1 –C 6 acyl halides, C 1 –C 6 acyl residues, C 1 –C 6 esters, C 1 –C 6 secondary amides, (C 1 –C 6 )(C 1 –C 6 ) tertiary amides, C 1 –C 12 cyclic amides, C 1 –C 12 amines, C 1 –C 6 alcohols, (C 1 –C 6 )(C 1 –C 6 ) ethers, C 1 –C 6 alkyls, C 1 –C 16 substituted alkyls, C 2 –C 6 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 6 aryls.

18. The compound of claim 15 , wherein R 10 is selected from the group consisting of C 2 –C 6 alkyl groups and C 2 –C 6 alkenyl groups.

19. The compound of claim 15 , wherein R 3 –R 5 , R 7 , R 8 , R 11 –R 15 is each hydrogen.

20. The compound of claim 19 , wherein R 3 –R 5 , R 7 , R 8 , R 11 –R 15 is each hydrogen; R 2 , R 6 , and R 9 are each methyl; and R 10 is CH 2 .

21. The compound of claim 15 , wherein R 15 is hydrogen, and R 14 is selected from hydrogen, a halogen, and C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 2 –C 12 esters, C 2 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, C 2 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers, C 2 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 12 aryls.

22. The compound of claim 15 , wherein R 15 is hydrogen, and R 14 is selected from hydrogen, a halogen, C 2 –C 6 alcohols, C 2 –C 6 alkyls, C 1 –C 6 substituted alkyls, C 2 –C 6 alkenyls, C 2 –C 6 substituted alkenyls, and C 5 –C 6 aryls.

23. The compound of claim 15 , wherein R 1 is C 1 –C 12 secondary amide.

24. The compound of claim 23 , wherein R 10 is selected from the group consisting of C 2 –C 6 alkyl groups and C 2 –C 6 alkenyl groups.

25. The compound of claim 23 , wherein R 3 –R 5 , R 7 , R 8 , R 11 –R 15 is each hydrogen.

26. The compound of claim 25 , wherein R 3 –R 5 , R 7 , R 8 , R 11 –R 15 is each hydrogen; R 2 , R 6 , and R 9 are each methyl; and R 10 is CH 2 .

27. The compound of claim 15 , wherein R 15 is hydrogen, and R 14 is selected from hydrogen, a halogen, and C 1 –C 12 carboxylic acids, C 1 –C 12 acyl halides, C 1 –C 12 acyl residues, C 2 –C 12 esters, C 2 –C 12 secondary amides, (C 1 –C 12 )(C 1 –C 12 ) tertiary amides, C 2 –C 12 alcohols, (C 1 –C 12 )(C 1 –C 12 ) ethers, C 2 –C 12 alkyls, C 1 –C 12 substituted alkyls, C 2 –C 12 alkenyls, C 2 –C 12 substituted alkenyls, and C 5 –C 12 aryls.

28. The compound of claim 15 , wherein R 15 is hydrogen, and R 14 is selected from hydrogen, a halogen, C 2 –C 6 alcohols, C 2 –C 6 alkyls, C 1 –C 6 substituted alkyls, C 2 –C 6 alkenyls, C 2 –C 6 substituted alkenyls, and C 5 –C 6 aryls.

Assignments (3)
SECURITY AGREEMENT Recorded Aug 11, 2004
From: NEREUS PHARMACEUTICALS, INC.
To: ALTA CALIFORNIA PARTNERS II, L.P.; ALTA EMBARCADERO PARTNERS II, LLC; FORWARD VENTURES IV, L.P.; FORWARD VENTURES IV B, L.P.; FORWARD VENTURES III, L.P.; FORWARD VENTURES III INSTITUTIONAL PARTNERS, L.P.; GIMV N.V.; GIMV ADVIESBEHEEER LIFE SCIENCES N.V.; PACIFIC VENTURE GROUP II, L.P.; PVG ASSOCIATES II, L.P.
Reel/Frame 015017/0484 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 12, 2002
From: THEODORAKIS, EMMANUEL A.
To: REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE
Reel/Frame 013168/0140 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 12, 2002
From: PALLADINO, MICHAEL
To: NEREUS PHARMACEUTICALS, INC.
Reel/Frame 013168/0180 →
Continuity (9)
Continuation 1006833300 · Feb 4, 2002
Continuation In Part 0957020200 · May 12, 2000
Provisional Application 6033203100 · Nov 21, 2001
Provisional Application 6030285000 · Jul 2, 2001
Provisional Application 6027995200 · Mar 29, 2001
Provisional Application 6027938100 · Mar 28, 2001
Provisional Application 6018685300 · Mar 3, 2000
Provisional Application 6013429500 · May 14, 1999
Related Publication 20030050338A1 · Mar 13, 2003