Patent EA-001404-B1 (EA)
Title: Acyclic nucleoside derivatives
Inventor: ENGELHARDT PER
IPC: C07D473/18
Filed: 1997-02-14
Abstract: 1. A compound of the Formula I    where a) R1 is -C(O)CH(CH(CH3)2)NH2 or -C(O)CH(CH(CH3)CH2CH3)NH2 and R2 is -C(O)C3-C21 saturated or monounsaturated, optionally substituted by a hydroxygroup, C1-6 alkyl, C1-6 alkoxy-, C1-6 alkoxy C1-6 alkyl, C1-6 alkanoyl, amino-, halogen-, ciano-, azido-, mercapto- and alkyl nitrogroup; b) R1 is -C(O)C3-C21 saturated or monounsaturated, optionally substituted by a hydroxygroup, C1-6 alkyl, C1-6 alkoxy-, C1-6 alkoxy C1-6 alkyl, C1-6 alkanoyl, amino-, halogen-, ciano-, azido-, mercapto- and alkyl nitrogroup; and R2 is -C(O)CH(CH(CH3)2)NH2 or -C(O)CH(CH(CH3)CH2CH3)NH2; and R3 is OH or H; and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, wherein R1 is -C(O)CH(CH(CH3)2)NH2 or -C(O)CH(CH(CH3)CH2CH3)NH2 and R2 is -C(O)C3-C21 saturated or monounsaturated, optionally substituted by a hydroxygroup, C1-6 alkyl, C1-6 alkoxy-, C1-6 alkoxy C1-6 alkyl, C1-6 alkanoyl, amino-, halogen-, ciano-, azido-, mercapto- and alkyl nitrogroup. 3. A compound according to claim 1 wherein the -C(=O) alkyl comprises a C9 to C17, saturated or n:9 monounsaturated, alkyl. 4. A compound according to claim 1 wherein R3 is hydroxy. 5. A compound according to claim 1, selected from the group consisting of  (R)-9-[2-(Stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine,  (R)-9-[2-(Myristoyloxymethyl)-4-(L-valyloxy)butyl]guanine,  (R)-9-[2-(Oleoyloxymethyl)-4-(L-valyloxy)butyl]guanine,  (R)-9-[2-(Butyrloxymethyl)-4-(L-valyloxy)butyl]guanine,  (R)-9-[2-(Decanoyloxymethyl)-4-(L-valyloxy)butyl]guanine,  (R)-9-[2-(Docosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine,  (R)-9-[4-(L-Isoleucyloxy)-2-(stearoyloxymethyl)butyl]guanine,  (R)-9-[2-(Decanoyloxymethyl)-4-(L-isoleucyloxy)butyl]guanine,  (R)-9-[4-(L-Isoleucyloxy)-2-(myristoyloxymethyl)butyl] guanine,  (R)-9-[2-(4-Acetylbutyryloxymethyl-4-(L-valyloxy)butyl,  (R)-9-[2-Dodecanoyloxymethyl-4-(L-valyloxy)butyl]guanine,  (R)-9-[2-Palmitoyloxymethyl-4-(L-valyloxy)butyl]guanine,  (R)-2-amino-9-(2-Stearoyloxymethyl-4-(L-valyloxy)butyl)purine,  (R)-9-[2-(L-Valyloxymethyl)-4-(stearoyloxy)butyl]guanine or a pharmaceutically acceptable salt thereof. 6. (R)-9-[2-(Stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine. 7. (R)-9-[2-(stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine or a pharmaceutically acceptable salt thereof. 8. A pharmaceutical composition comprising a compound according to claim 1 in conjunction with a pharmaceutically acceptable carrier or diluent. 9. A pharmaceutical composition comprising a compound according to claim 5 in conjunction with a pharmaceutically acceptable carrier or diluent. 10. A pharmaceutical composition comprising a compound according to claim 6 in conjunction with a pharmaceutically acceptable carrier or diluent. 11. A method for the treatment or prophylaxis of viral infections comprising the administration of an effective amount of a compound according to claim 1 to a human or animal. 12. A method according to claim 11 for the treatment or prophylaxis of herpes infections including Varicella zoster virus, Herpes simplex virus types 1 & 2, Epstein-Barr virus or Herpes type 6 (HHV-6) and type 8 (HHV-8). 13 A method according to claim 11 for the treatment or prophylaxis of retroviral infections including SIV, HIV-1 and HIV-2. 14. A method for the preparation of a compound as defined in claim 1, the method comprising  a) optionally N-protecting the purine 2 and/or 6 positions of a compound of formula I wherein R1 and R2 are each hydrogen;  b) regioselectively acylating the compound of Formula 1 at the side chain 4-hydroxy group with either  i) an optionally N-protected valine or isoleucine group, ii) an optionally substituted, saturated or monounsaturated C3-C21COOH derivative, or iii) a regioselective protecting group; c) acylating at the side chain 2-hydroxymethyl group with  i) an optionally N-protected valine or isoleucine group, or ii) an optionally substituted, saturated or monounsaturated C3-C21COOH derivative; d) replacing the regioselective protecting group at R1, if present, with  i) an optionally N-protected valine or isoleucine group; or ii) an optionally substituted, saturated or monounsaturated C3-C21COOH derivative; and  e) deprotecting the resulting compound as necessary.