Patent EA-004656-B1 (EA)
Title: Aminopyrimidines as sorbitol dehydrogenase inhibitors
Inventor: CHU-MOYER MARGARET YUHUA
IPC: C07D409/14
Filed: 2000-03-16
Abstract: 1. A compound of the formula I a prodrug thereof or a pharmaceutical acceptable salt of said compound or said prodrug, wherein: R<1> is (R)-1-hydroxy-ethyl; R<2> is hydrogen; R<3> is a radical of the formula R<9> is pyrimidyl or triazinyl; said pyrimidyl or triazinyl is optionally substituted with up to two hydroxy, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4) alkoxy-(C1-C4)alkeylenyl, phenyl, piperazinyl optionally substituted with (C1-C4) alkyl, or imidazolyl optionally substituted with up to two (C1-C4) alkyl. 2. A compound of claim 22, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R<9> is pyrimid-2-yl optionally substituted with up to two -(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or -(C1-C4)alkoxy-(C1-C4)alkyl. 3. The compound of claim 2, a prodrug thereof or a pharmaceutical acceptable salt of said compound or said prodrug, wherein R<9> is 4,6-dimethylpyrimid-2-yl; 4-methoxymethyl-6-methylpyrimid-2-yl or 4-hydroxymethyl-6-methylpyrimid-2-yl. 4. A compound of claim 1, a prodrug thereof or a pharmaceutical acceptable salt of said compound or said prodrug thereof is pyrimid-4-yl optionally substituted with up to two (C1-C4) alkylpiperazin; and said imidazolyl is optionally substituted with up to two (C1-C4) alkyl. 5. The compound of claim 1, a prodrug thereof or a pharmaceutical acceptable salt of said compound or said prodrug, wherein R<9> is 2-(4-methylpiperazin-1-yl)-pyrimid-4-yl; 2-(4-ethylpiperazin-1-yl)-pyrimid-4-yl; 2-(4-methylimidazol-1-yl)-methylimidazol-1-yl)-pyrimid-4-yl; 2-(2,4-pyrimid-4-yl; or 2-(4-isopropylpiperazin-1-yl)-pyrimid-4-yl-dimethylimidazol-1-yl)-pyrimid-4-yl. 6. A compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R<9> is triazinyl optionally substituted with up to two hydroxy, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4) alkoxy-(C1-C4)alkyl, phenyl, piperazinyl. Optionally substituted (C1-C4)alkyl, or imidazolyl optionally substituted with up to two(C1-C4) alkyl. 7. The compound of claim 6 a prodrug thereof or a pharmaceutical acceptable salt of said compound or said prodrug, wherein R<9> is [1,3,5]-triazin-2-yl, optionally substituted with up to two (C1-C4) alkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkylpiperazin-1-yl or phenyl. 8. The compound of claim 7 a prodrug thereof or a pharmaceutical acceptable salt of said compound or said prodrug, wherein R<9> is 4-methyl-6-(4-methylpiperazin-1-yl)-[1,3,5]-triazin-2-yl; 4-methoxy-6-methyl-[1,3, 5]-triazin-2-yl; 4,dimethyoxy-[1,3,5]-triazin-2-yl; 4-ethoxy-6-methyl-[1,3,5]-triazin-2-yl; 4-isopropoxy-6methyl-[1,3,5]-triazin-2-yl; 4-phenyl-[1,3,5]-triazin-2-yl; 4-hydroxymethyl-6-methoxy [1,3,5]-triazin-2-yl; 4-isopropoxy-6-methoxy-[1,3,5]-triazin-2-yl; 4-isopropyl-[1,3,5]-triazin-2-yl; 4-ethyl-6-methoxy-[1,3,5]-triazin-2-yl; 4-cyclopropyl-[1, 3, 5]-triazin-2-yi; 4,dimethyl-[1,3,5]-triazin-2-yl; or 4-methyl-6-phenyl-[1,3,5]-triazin-2-yl. 9. A compound of the formula I a prodrug thereof or a pharmaceutical acceptable salt of said compound or said prodrug, wherein: R<1> is (R)-1-hydroxy-ethyl; R<2> is hydrogen; R<3> is a radical of the formula R<9> is pyrimidyl or triazinyl; said pyrimidyl or triazinyl is optionally substituted with up to two hydroxy, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4) alkoxy-(C1-C4)alkyl, triazolyl, acetyl, morpholinyl, (C1-C4) alkylpiperazinyl, phenyl or imidazolyl optionally substituted with up to two(C1-C4) alkyl. 10. The compound of claim 9, a prodrug thereof or a pharmaceutical acceptable salt of said compound or said prodrug, wherein R<9> is pyrimid-4-yl, optionally substituted with up to two (C1-C4) alkyl or triazolyl. 11. The compound of claim 10, a prodrug thereof or a pharmaceutical acceptable salt of said compound or said prodrug, wherein R<9> is 4,6-dimethyl-pyrimid-2-yl; 4-hydroxymethyl-6-methylpyrimid-2-yl; or 4-[1,2,4]-triazol-1-yl-pyrimid-2-yl. 12. A compound of claim 9, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R<9> is pyrimid-4-yl optionally substituted with up to two (C1-C4)alkyl, hydroxy-(C1-C4)alkyl, acetyl, morpholinyl, (C1-C4)alkylpiperazinyl, triazolyl or imidazolyl optionally substituted with up to two(C1-C4) alkyl. 13. The compound of claim 12, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R<9> is 2,6-dimethyl-pyrimi4-yl; 2-hydroxymethyl-6-methyl-pyrimid-4-yl; 2-acetyl-pyrimid-4-yl; 2-morpholin-4-yl-pyrimid-4-yl; 2-(4-methylpiperazin-1-yl)-pyrimid-4-yl; 2-[1,2, 4]-triazol-1-yl-pyrimid-4-yl; 2-(1S-hydroxyethyl)-pyrimid-4-yl; 2-(1R-hydroxyethyl)-pyrimid-4-yl; 2-(4-ethylpiperazin-1-yl)-pyrimid-4-yl; 2-(4-methylimidazol-1-yl)-pyrimid-4-yl; or 2-(2,4dimethylimidazol-1-yl)-pyrimid-4-yl. 14. The compound of claim 9, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R<9> is triazinyl optionally substituted with up to two hydroxy, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4) alkoxy-(C1-C4)alkyl, triazolyl, acetyl, morpholinyl, (C1-C4) alkylpiperazinyl, phenyl or imidazolyl optionally substituted with up to two(C1-C4) alkyl. 15. The compound of claim 14, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R<9> is [1,3,5]-triazin-2-yl, optionally substituted with up to two hydroxy, (C1-C4) alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4) alkoxy-(C1-C4), alkyl, -(C1-C4)alkoxy, morpholinyl or phenyl. 16. The compound of claim 15, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R<9> is 4-morpholin-4-y[1,3,5]-triazin-2-yl; 4-methoxy-6-methyl-[1,3,5]-triazin-2-yl; 5]-triazin-2-yl; 4-phenyl-[1,3,5]-triazin-2-yl; 4-cyclopropyl-[1,3,5]-triazin-2-yl; 4,6-dimethy-[1,3,5]-triazin-2-yl; 4-hydroxymethyl-6-phenyl-[1,4-methoxy-6-methoxymethyl-[1,3,5]-triazin-2-yl; 4-methyl-[1,3,5]-triazin-2-yl; or 4-methoxymethyl-phenyl-[1,3,5] triazin-2-yl. 17. The compound of claim 16, wherein R<9> is 4,6-dimethyl-[1,3,5]-triazin-2-yl. 18. A compound selected from 1R-(4-{1'-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-[4, 4'jbipiperidinyl-1-yl}-pyrimidin-2-yl)-ethanol; furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethylpiperazin-1-yl}-methanone; (4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-(1R-hydroxy-ethyl)pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone; {4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-pyrrolidin-1-yl-furo [3,2-c]pyridin-2-yl)-methanone; {4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl(4-morpholin-4-yl-furo [3,2-c]pyridin-2-yl)-methanone; {4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-imidazo [1,2-a] pyridin-2-yl-methanone; furo [3,2-c] pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethylpiperazin-1-yl}-methanone; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-pyridin-3-yl-ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid-2R, 6S-dimethyl-piperazine-1-carboxylic acid 2-methyl-pyridin-3-yl ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 5-chloro-3-yl-ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid-2R, 6S-dimethyl-piperazine-1-carboxylic acid 6-methyl-pyridin-3-yl ester; (E)-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-1-carboxylicacid 4-yl]-2R,6S-dimethyl-piperazin-1-yl}-3-thiophen-2-yl-propenone; 1 R-{4-[4-(4, dimethyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}- ethanol; 1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3R, 5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-3R, 5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-imidazol-1-yl)pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(2,4-dimethy imidazol-1-yl)-pyrimidin-4-yl]-3R, 5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-isopropyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-iperazin-1-yl}pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1yl)-[1,3,5]triazin-2-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-3$,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethoxy-[1,3,5] triazin-2-yl)-3R, 5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}ethanol; 1R-{4-[4-(4-ethoxy-6-methyl-[1,3,5] triazin-2-yl)-3R, 5S-dimethyl-piperazin-1yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5 dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[3R, 5S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-methoxy-[1,3,5] triazin-2-yl)-3R, 5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropoxy-6-methoxy-[1,3,5] triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-y)}-ethanol; 1R-{4-[4-(4-isopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-ethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R, 5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R, 6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-[1,2,4] triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidi