Patent EA-004141-B1 (EA)
Title: Inhibitors of impdh enzyme
Inventor: STAMOS DEAN
IPC: A61K45/00
Filed: 2000-03-17
Abstract: 1. A compounds of formula (A): wherein: each of R1 and R2 is independently selected from hydrogen; -CF3; -(C1-C6)-straight or branched alkyl; -(C2-C6)-straight or branched alkenyl or alkynyl; -(C1-C6)-straight or branched alkyl-R7; -[(C2-C6)-straight or branched alkenyl or alkynyl]-R7 or -R7; and wherein at least one of R1 or R2 is -(C1-C6)-straight or branched alkyl-R7; -[(C2-C6)-straight or branched alkenyl or alkynyl]-R7 or -R7, wherein up to 4 hydrogen atoms in any of said alkyl, alkenyl or alkynyl are optionally and independently replaced by R3; and wherein one or both of R1 and R2 are optionally esterified to form a prodrug; or wherein R1 and R2 are alternatively taken together to form tetrahydrofuranyl, wherein when R9 is hydrogen, (R)-methyl, (R)-ethyl or (R)hydroxymethyl, one hydrogen atom in said tetrahydrofuran is replaced by -OR6 or -R7, and wherein when R9 is (S)methyl, (S)-ethyl or (S)-hydroxymethyl, one hydrogen atom in said tetrahydrofuran is optionally replaced by -OR6 or -R7; wherein when R9 is hydrogen, (R)methyl, (R)-ethyl or (R)-hydroxymethyl and each of R1 and R2 are independently hydrogen, unsubstituted -(C1-C6)-straight or branched alkyl, or unsubstituted -(C2-C6)-straight or branched alkenyl or alkynyl, then the portion of the compound represented by -CH(R1)R2 is a C5-C12 straight or branched alkyl, alkenyl or alkynyl; each R3 is independently selected from halo, CN, -OR4, or -N(R5)2; R4 is selected from hydrogen, -(C1-C6)-straight or branched alkyl, -(C2-C6)-straight or branched alkenyl or alkynyl, -[(C1-C6)-straight or branched alkyl]-R7, -[(C2-C6)-straight or branched alkenyl or alkynyl]-R7, -C(O)-[(C1-C6)-straight or branched alkyl], -C(O)-[(C2-C6)-straight or branched alkenyl or alkynyl], -C(O)-[(C1-C6)-straight or branched alkyl]-N(R8)2, -C(O)-[(C2-C6)-straight or branched alkenyl or alkynyl]-N(R8)2, -P(O)(O R8)2, -P(O)(OR8)(R8), -C(O)-R7, -S(O)2N(R5)2, -[(C1-C6)-straight or branched alkyl]-CN, or -[(C2-C6)-straight or branched alkenyl or alkynyl]-CN; each R5 is independently selected from hydrogen, -(C1-C6)-straight or branched alkyl, -(C2-C6)-straight or branched alkenyl or alkynyl, -[(C1-C6)-straight or branched alkyl] -R7, -[(C2-C6)-straight or branched alkenyl or alkynyl] -R7, -[(C1-C6)-straight alkyl]-CN, -[(C2-C6)-straight or branched alkenyl or alkynyl]-CN, -[(C1-C6)-straight or branched alkyl]-OR4, -[(C2-C6)-straight or branched alkenyl or alkynyl]-OR4, C(O)-(C1-C6)-straight or branched alkyl, -C(O)-[(C2-C6)-straight or branched alkenyl or alkynyl], -C(O)-R7, -C(O)O-R7, -C(O)O-(C1-C6)-straight or branched alkyl, -C(O)O-[(C2-C6)-straight or branched alkenyl or alkynyl], -S(O)2-(C1-C6)-straight or branched alkyl, or -S(O)2-R7; or two R5 moieties, when bound to the same nitrogen atom, are taken together with said nitrogen atom to form a 3 to 7 membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1 to 3 additional heteroatoms independently selected from N, O, S, S(O) or S(O)2; R6 is selected from -C(O)-CH3, -CH2-C(O)-OH, -CH2-C(O)-O-tBu, -CH2-CN, or -CH2-C=CH; each R7 is a monocyclic or bicyclic ring system wherein in said ring system: i. each ring comprises 3 to 7 ring atoms independently selected from C, N, O or S; ii. no more than 4 ring atoms are selected from N, O or S; iii. any CH2 is optionally replaced with C(O); iv. any S is optionally replaced with S(O) or S(O)2; each R8 is independently selected from hydrogen or -[C1-C4)-straight or branched alkyl; wherein in any ring system in said compound up to 3 hydrogen atoms bound to the ring atoms are optionally and independently replaced with halo, hydroxy, nitro, cyano, amino, (C1-C4)-straight or branched alkyl; O-(C1-C4)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl or alkynyl, or O-(C2-C4)-straight or branched alkenyl or alkynyl; and wherein any ring system is optionally benzofused; R9 is selected from hydrogen, (R)-methyl, (S)-methyl, (R)-ethyl, (S)-ethyl, (R)-hydroxymethyl or (S)-hydroxymethyl; R10 is selected from -C=N or 5-oxazolyl; and R11 is selected from halo, -O-(C1-C3) straight alkyl, or -O-(C2-C3) straight alkenyl or alkynyl. 2. The compound according to claim 1, wherein said compound has the formula (I): wherein R1 and R2 are as defined in claim 1. 3. The compound according to claim 1, wherein said compound has the formula (IA): wherein R9 is selected from (R)-methyl, (S)-methyl, (R)-ethyl, (S)-ethyl, (R)-hydroxymethyl or (S)hydroxymethyl; and R1 and R2 are as defined in claim 1. 4. The compound according to claim 3, wherein R9 is selected from (S)-methyl, (S)-ethyl, or (S)hydroxymethyl methyl. 5. The compound according to claim 4, wherein R9 is (S)-methyl. 6. The compound according to claim 3, wherein R11 is selected from O-methyl, O-ethyl or O-isopropyl. 7. The compound according to claim 1, wherein: at least one of R1 and R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, phenyl, pyridyl, -CH2OCH3, -CH2CN, -CH2OCH2CH2CN, -CH2C(CH3)2CH2CH2CN, -CH2C(CH2CH3)2CH2CH2CN, -CH2CH2CN, -CH2N(CH2CH2CN)2, -CH2N(CH3)CH2CH2CN, -CH(NH2)CH2CN, -CH2Cl, -CH2OH, -CH2CH2OH, -CH2CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OC(O)CH3, -CH2CH2OC(O)CH2NH2, -CH2CH2CHCH3, -CH2CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2CH2N(CH2CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2CH2N+(CH3)3, -CH2OCH2CH(CH3)2, -CH2CH2N(CH3)C(O)OC(CH3)3, -CH2N(CH2CH2CN)CH2CH(CH3)2, -CH(CH2CN)N(CH3)2, -CH2CH(CHCN)NHC(O)OC(CH3)3, wherein n is 0 or 1. 8. The compound according to claim 2, wherein R1 and R2 are taken together to form a 3-tetrahydrofuranyl moiety that is substituted at the 5 position by -OR6. 9. The compound according to claim 3, wherein one of R1 and R2 is selected from hydrogen, ethyl or phenyl; and the other of R1 and R2 is selected from -CH2OH, -CH2CN, -CH2CH2CN or CH2N(CH2CH3)2; or wherein R1 and R2 are taken together to form a 3-tetrahydrofuranyl moiety. 10. The compound according to claim 1, wherein said compound is selected from any one of compounds 1 to 187 11. The compound according to claim 10, wherein said compound is selected from any one of compounds 1, 23, 26, 27, 29, 32, 76, 80, 87, 89, 98, 101, 103, 104, 106, 108, 110, 157, 163, 169, 171, 181, 185, 186 or 187 12. A composition comprising a compound according to claim 1 in an amount effective to inhibit IMPDH and a pharmaceutically acceptable carrier, adjuvant or vehicle. 13. The composition according to claim 12, further comprising of this invention comprise a compound an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound. 14. A method of treating or preventing an IMPDH-mediated disease or condition in a mammal comprising the step of administrating to said mammal a composition according to claim 12 or 13. 15. The method according to claim 14, wherein said IMPDH-mediated disease or condition is selected from transplant rejection, graft versus host disease, an autoimmune disease. 16. The method according to claim 14, wherein said mammal is administered an additional immunosuppressant in a separate dosage form or as part of said composition. 17. A method for inhibiting viral replication in a mammal comprising the step of administering to said mammal a composition according to claim 12 or 13. 18. The method according to claim 17, wherein viral infection is caused by a virus selected from orthomyxovirus, paramyxovirus, herpesvirus, retrovirus, flavivirus, pestivirus, hepatotrophic virus, bunyavirus, Hantaan virus, Caraparu virus, human papilloma virus, encephalitis virus, arena virus, reovirus, vesicular stomatitis virus, rhinovirus, enterovirus, Lassa fever virus, togavirus, poxvirus, adenovirus, rubiola, or rubella is inhibited. 19. The method according to claim 17, wherein said mammal is administered an additional anti-viral agent in a separate dosage form or as part of said composition. 20. A method for inhibiting vascular cellular hyperproliferation in a mammal comprising the step of administrating to said mammal a composition according to claim 12 or 13. 21. The method according to claim 20, wherein said method is useful in treating or preventing restenosis, stenosis, artherosclerosis or other hyperproliferative vascular disease. 22. The method according to claim 20, wherein said mammal is administered an additional anti-vascular hyperproliferative agent in a separate dosage form or as part of said composition. 23. A method for inhibiting tumors and cancer in a mammal comprising the step of administrating to said mammal a composition according to claim 12 or 13. 24. The method according to claim 23, wherein said method is useful to treat or prevent lymphoma, leukemia and other forms of cancer. 25. The method according to claim 24, wherein said mammal is administered an additional anti-tumor or anti-cancer agent in a separate dosage form or as part of said composition. 26. A method for inhibiting inflammation or an inflammatory disease in a mammal comprising the step of administering to said mammal a composition according to claim 12 or 13. 27. The method according to claim 26, wherein said method is useful for treating or preventing osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma or adult respiratory distress syndrome. 28. The method according to claim 27, wherein said mammal is administered an additional antiinflammatory agent in a separate dosage form or as part of said composition.