Tricyclic diterpene derivatives
View Patent ↗Disclosed herein are novel tricyclic diterpene compounds. These compounds, including their prodrug esters and acid-addition salts, are useful as Interleukin-1 and Tumor Necrosis Factor-α modulators, and thus are useful in the treatment of various diseases. Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of the novel compounds that are useful 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 the compounds and their analogs are also disclosed, as are methods of using these synthetic and semi-synthetic compounds in the treatment of the above-listed disease states.
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 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 2 -C 12 aryls; with the proviso that 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 not COOH, C 1 ester, C 1 secondary amide, C 1 alcohol, C 1 alkyl, or methyl-acetyl ether;
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, with the proviso that R 14 and R 15 are not both hydrogen;
wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof.
2. The compound of claim 1 , wherein:
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.
3. The compound of claim 1 , 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 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 compound 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 compound of claim 1 , wherein R 1 is selected from the group consisting of C 2 -C 6 esters.
6. 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.
7. The compound of claim 1 , wherein R 3 -R 5 , R 7 , R 8 , R 11 -R 15 is each hydrogen.
8. The compound 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 compound of claim 1 , wherein R 15 is hydrogen, and R 14 is selected from 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. 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 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 2 -C 12 aryls; with the proviso that 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 not COOH, C 1 ester, C 1 secondary amide, C 1 alcohol, C 1 alkyl, or methyl-acetyl ether;
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 hydrogen;
wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof.
11. The compound of claim 1 , wherein:
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.
12. The compound of claim 1 , 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 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.
13. The compound 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.
14. The compound of claim 1 , wherein R 1 is selected from the group consisting of C 2 -C 6 esters.
15. 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.
16. The compound of claim 1 , wherein R 3 -R 5 , R 7 , R 8 , R 11 -R 15 is each hydrogen.
17. The compound 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 .