摘要 |
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-alpha modulators, and thus are useful in the treatment of various diseases. wherein the R groups are defined as follows: if any R<SUB>3</SUB>-R<SUB>5</SUB>, R<SUB>7</SUB>, R<SUB>8</SUB>, R<SUB>11</SUB>-R<SUB>13 </SUB>is not hydrogen, R<SUB>2 </SUB>or R<SUB>6 </SUB>or R<SUB>9 </SUB>is not methyl, or R<SUB>10 </SUB>is not CH<SUB>2</SUB>, then R<SUB>1 </SUB>is selected from the group consisting of hydrogen, a halogen, COOH, C<SUB>1</SUB>-C<SUB>12 </SUB>carboxylic acids, C<SUB>1</SUB>-C<SUB>12 </SUB>acyl halides, C<SUB>1</SUB>-C<SUB>12 </SUB>acyl residues, C<SUB>1</SUB>-C<SUB>12 </SUB>esters, C<SUB>1</SUB>-C<SUB>12 </SUB>secondary amides, (C<SUB>1</SUB>-C<SUB>12</SUB>)(C<SUB>1</SUB>-C<SUB>12</SUB>) tertiary amides, (C<SUB>1</SUB>-C<SUB>12</SUB>)(C<SUB>1</SUB>-C<SUB>12</SUB>) cyclic amides, (C<SUB>1</SUB>-C<SUB>12</SUB>) amines, C<SUB>1</SUB>-C<SUB>12 </SUB>alcohols, (C<SUB>1</SUB>-C<SUB>12</SUB>)(C<SUB>1</SUB>-C<SUB>12</SUB>) ethers, C<SUB>1</SUB>-C<SUB>12 </SUB>alkyls, C<SUB>1</SUB>-C<SUB>12 </SUB>substituted alkyls, C<SUB>2</SUB>-C<SUB>12 </SUB>alkenyls, C<SUB>2</SUB>-C<SUB>12 </SUB>substituted alkenyls, and C<SUB>5</SUB>-C<SUB>12 </SUB>aryls. If all R<SUB>3</SUB>-R<SUB>5</SUB>, R<SUB>7</SUB>, R<SUB>8</SUB>, R<SUB>11</SUB>-R<SUB>13 </SUB>are hydrogen, R<SUB>2</SUB>, R<SUB>6</SUB>, and R<SUB>9 </SUB>are each methyl, and R<SUB>10 </SUB>is CH<SUB>2</SUB>, then R<SUB>1 </SUB>is selected from hydrogen, a halogen, C<SUB>1</SUB>-C<SUB>12 </SUB>carboxylic acids, C<SUB>1</SUB>-C<SUB>12 </SUB>acyl halides, C<SUB>1</SUB>-C<SUB>12 </SUB>acyl residues, C<SUB>2</SUB>-C<SUB>12 </SUB>esters, C<SUB>2</SUB>-C<SUB>12 </SUB>secondary amides, (C<SUB>1</SUB>-C<SUB>12</SUB>)(C<SUB>1</SUB>-C<SUB>12</SUB>) tertiary amides, C<SUB>2</SUB>-C<SUB>12 </SUB>alcohols, (C<SUB>1</SUB>-C<SUB>12</SUB>)(C<SUB>1</SUB>-C<SUB>12</SUB>) ethers other than methyl-acetyl ether, C<SUB>2</SUB>-C<SUB>12 </SUB>alkyls, C<SUB>1</SUB>-C<SUB>12 </SUB>substituted alkyls, C<SUB>2</SUB>-C<SUB>12 </SUB>alkenyls, C<SUB>2</SUB>-C<SUB>12 </SUB>substituted alkenyls, and C<SUB>2</SUB>-C<SUB>12 </SUB>aryls. R<SUB>2 </SUB>and R<SUB>9 </SUB>are each separately selected from hydrogen, a halogen, C<SUB>1</SUB>-C<SUB>12 </SUB>alkyl, C<SUB>1</SUB>-C<SUB>12 </SUB>substituted alkyls, C<SUB>2</SUB>-C<SUB>12 </SUB>alkenyl, C<SUB>2</SUB>-C<SUB>12 </SUB>substituted alkenyl, C<SUB>2</SUB>-C<SUB>12 </SUB>alkynyl, C<SUB>1</SUB>-C<SUB>12 </SUB>acyl, C<SUB>1</SUB>-C<SUB>12 </SUB>alcohol, and C<SUB>5</SUB>-C<SUB>12 </SUB>aryl. R<SUB>3</SUB>-R<SUB>5</SUB>, R<SUB>7</SUB>, R<SUB>8</SUB>, and R<SUB>11</SUB>-R<SUB>13 </SUB>are each separately selected from hydrogen, a halogen, C<SUB>1</SUB>-C<SUB>12 </SUB>alkyl, C<SUB>1</SUB>-C<SUB>12 </SUB>substituted alkyls, C<SUB>2</SUB>-C<SUB>12 </SUB>alkenyl, C<SUB>2</SUB>-C<SUB>12 </SUB>substituted alkenyl, C<SUB>2</SUB>-C<SUB>12 </SUB>alkynyl, and C<SUB>5</SUB>-C<SUB>12 </SUB>aryl. R<SUB>6 </SUB>is selected from hydrogen, a halogen, C<SUB>1</SUB>-C<SUB>12 </SUB>alkyl, C<SUB>1</SUB>-C<SUB>12 </SUB>substituted alkyls, C<SUB>2</SUB>-C<SUB>12 </SUB>alkenyl, C<SUB>2</SUB>-C<SUB>12 </SUB>substituted alkenyl, and C<SUB>2</SUB>-C<SUB>12 </SUB>alkynyl. R<SUB>10 </SUB>is selected from hydrogen, a halogen, CH<SUB>2</SUB>, C<SUB>1</SUB>-C<SUB>6 </SUB>alkyl, C<SUB>1</SUB>-C<SUB>6 </SUB>substituted alkyl, C<SUB>2</SUB>-C<SUB>6 </SUB>alkenyl, C<SUB>2</SUB>-C<SUB>6 </SUB>substituted alkenyl, C<SUB>1</SUB>-C<SUB>12 </SUB>alcohol, and C<SUB>5</SUB>-C<SUB>12 </SUB>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.
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