Method of treating inflammation with acanthoic acid derivatives
Novel compounds are disclosed that have the chemical structure of Formula (II), and its prodrug esters and acid-addition salts, and that are useful as Interleukin-1 and Tumor Necrosis Factor-α modulators, and thus are useful in the treatment of various listed diseases. wherein the R groups are defined as provided in the specification. These compounds are useful, for example, as 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 are disclosed, as are methods of using these synthetic and semi-synthetic compounds in the treatment of the above-listed disease states.
1. A method of treating inflammation comprising administering an effective amount of a compound to an animal suffering from inflammation, wherein the compound is:
wherein:
R 1 is selected from the group consisting of hydrogen, a halogen, COOH, C 2 -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 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 at least one of R 3 -R 5 , R 7 , R 8 , or R 11 -R 15 is not hydrogen, R 2 or R 6 or R 9 is not methyl, or R 10 is not CH 2 ;
wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof.
2. The method of claim 1 , wherein R 1 is selected from hydrogen, a halogen, C 2 -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.
3. The method of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, a halogen, C 2 -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 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.
4. The method of claim 1 , wherein R 1 is selected from the group consisting of C 2 -C 12 esters and C 1 -C 12 acyl residues.
5. The method of claim 1 , wherein R 1 is selected from the group consisting of C 2 -C 6 esters.
6. The method 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.
7. The method of claim 1 , wherein R 3 -R 5 , R 7 , R 8 , R 11 -R 15 is each hydrogen.
8. The method of claim 1 , 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 .
9. The method 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.
10. The method of claim 1 , wherein R 1 is a C 1 -C 12 secondary amide.
11. The method of claim 1 , wherein R 1 is a C 1 -C 12 acyl residue.
12. A method of treating inflammation comprising administering an effective amount of a compound to an animal suffering from inflammation, wherein the compound is:
wherein:
R 1 is selected from the group consisting of hydrogen, a halogen, C 2 -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 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 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 ;
wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof.