TH85583A - The compounds 3H-oxazolo and 3H-thiazolo[4,5-d]pyrimidine-2-one are replaced by two-3,5 and three-3,5,7 substitutes, and their products are replaced by - Google Patents

Abstract

DC60 (15/03/49) This invention is directed toward the compounds 3H-oxaxolo and 3H-thiazolo[4,5-d[pyrimidine-2-one substituted two-3,5 and substituted three-3,5,7] and their pro-drugs which possess immunomodulatory activity. The invention is also directed toward the therapeutic and preventive use of such compounds and pharmaceutical mixtures containing them, and toward the methods of treating the diseases and disorders described herein, by carrying out the effective dosage of such compounds and pro-drugs. This invention is directed toward the compounds 3H-oxaxolo and 3H-thiazolo[4,5-d[pyrimidine-2-one substituted two-3,5 and substituted three-3,5,7] and their pro-drugs which possess immunomodulatory activity. The invention is also directed toward the therapeutic and preventive use of such compounds and pharmaceutical mixtures containing them, and toward the methods of treating the diseases and disorders described herein, by delivering effective dosages of such compounds and pro-drugs.

Claims (20)

1. Compounds of formula I (chemical formula) I, where X is O or S, Y is O or S, R1 is H, alkyl, aryl, cycloalkyl, or heterocyclyl, R2 is NH2, -NHC(O)R4, -NHR5, -N=CHNR6R7, R3 is H, Cl, Br, or OR8, R4 is -C1-C7-alkyl or -O(C1-C7-alkyl), R5 is -C1-C7-alkyl, R6 and R7 independently are -C1-C7-alkyl or, coupled with a nitrogen atom, form a 5- or 6-membered heterocyclic ring, R8 is -CHR9R10, R9 is H, -C1-C7-alkyl, cycloalkyl, aryl, heterocyclyl, -NR11R12, or OR5. R10 is -C1-C7-alkyl, cycloalkyl, aryl, heterocyclyl, -NR11R12, or OR5, R11 and R12 independently are H, -C1-C7-alkyl, or -C(O)R4, where X is O, Y is S, and R3 is H, Cl, Br, or OR8, R1 is not H or beta-D-ribose or its ester, where the alkyl, aryl, cycloalkyl, or heterocyclyl moities above are substituted independently. An alternative of 1-4 representatives is selected from hydrogen, alkanoyl, alkylamine, amino, aryl, cycloalkyl, heterocyclyl, acido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkylamine, C1-C6 dialkylamine, C2-C6 alkynyl, or C2-C6 alkynyl, where each may be interpolated with one or more hetero atoms, carboxyl, cyano, halo, hydroxyl, mercapto, nitro, thioalkyl, -N=N-NH2, -C(O)2-(C1-C6 alkyl), -C(O)2-(aryl). -C(O)2-(cycloalkyl), -C(O)2-(heterocyclyl), -O-(C1-C6 haloalkyl), -O-(C1-C6 alkyl)eryl, -O-(C1-C6 alkyl)cycloalkyl, -O-(C1-C6 alkyl)heterocyclyl, -O-(C1-C6 alkyl)amino, -O- (C1-C6 alkyl)alkylamino, -O-(C1-C6 alkyl)dialkylamino, -O-(C1-C6 alkyl)-C(O)amino, -O-(C1-C6 alkyl)-C(O)-alkylamino, -O-(C1-C6 alkyl)-S(O)2-amino, -O-(C1-C6 Alkyl)-S(O)2-Alkylamino, -O-(C1-C6 alkyl)-S(O)2-Dialkylamino, -O-(C1-C6 alkyl)-C(O)-Dialkylamino, -O-Eryl, -O-Heterocyclyl, -NHC,(O)-(C1-C6 alkyl), -NHC(O)-(C1-C6 alkynyl), -NHC(O)-(Eryl), -NHC(O)-(Cycloalkyl), -NHC(O)-(Heterocyclyl), -NHC(O)-(C1-C6 alkyl)Eryl, -NHC(O)-(C1-C6 Alkyl)cycloalkyl, -NHC(O)- (C1-C6 alkyl)heterocyclyl, -NHC(O)-(C1-C6 alkyl)amino, -NHC(O)- (C1-C6 alkyl)alkylamine, -NHC(O)-(C1-C6 alkyl)dialkylamine, -NHC(O)- (C1-C6 alkyl)C(O)amino, -NHC(O)-(C1-C6 alkyl)C(O)alkylamine, -NHC(O) - (C1-C6 alkyl)C(O) dialkylamine, -NHC(O)-(C1-C6 alkyl)N(H)-(C1-C6 alkyl) C(O)2-(C1-C6 alkyl), -NHC(O)-(C1-C6 alkyl)-C(O)amino, -NH-(C1-C6 alkyl)-C(O)-alkylamino, -NH-(C1-C6 alkyl)-C(O)dialkylamino, -NHC(O)-(C1-C6 alkyl)S(O)2-(C1-C6 alkyl), -NHC(O)-(C1-C6 Alkyl)-S-(heterocyclyl), -NHS(O)2-(C1-C6 alkyl), -NHS(O)2-(aryl), -NH-(C1-C6 alkyl)-S(O)2-amino, -NH-(C1-C6 alkyl)-S(O)2-alkylamino, -NH-(C1-C6 alkyl)-S(O)2-dialkyl-amino, -NHS(O)2-(cycloalkyl), -NHS(O)2-(heterocyclyl), -NHS(O) (C1-C6 alkyl), -NHS(O)(aryl), -NHS(O)(cycloalkyl), -NHS(O)(heterocyclyl), -NHS(C1-C6 alkyl), -NHS(aryl), -NHS (cycloalkyl), and -NH-S- (heterocyclyl), where each of the above substitutes can be further alternatively replaced by 1-5 substitutes selected from amino, C1-C6 alkylamines, C1-C6 diallkylamines, C1-C6 alkyls, C1-C6 alkoxys, C1-C6 alkenyls, C1-C6 hydroxyls, and C1-C6 hydroxyalkyls, all of which can be alternatively replaced by cyano, halo, and nitro, or their pharmaceutically acceptable salts or hydrates. 2. A pharmaceutically acceptable compound, salt, or hydrate according to claim 1, where R2 is NH2. 3. A compound, salt, or hydrate that is pharmaceutically acceptable under claim 2, where R3 is H. 4. A compound, salt, or hydrate that is pharmaceutically acceptable under claim 3, where X is O and Y is S. 5. A pharmaceutically acceptable compound, salt, or hydrate according to Claim 1, where R1 is selected from (chemical formula), 6. A pharmaceutically acceptable compound, salt, or hydrate as per Claim 1, selected from (chemical formula). 7. A pharmaceutically acceptable compound, salt, or hydrate as per claim 6, selected from (chemical formula). 8. Compounds of formula II (chemical formula) II, where X is O or S, Y is O or S, Z is O or CH2, R2 is -NH2,-NHC(O)R4,-NHR5,-N=CHNR6R7, R4 is -C1-C7-alkyl or -O(C1-C7-alkyl), R5 is -C1-C7-alkyl, R6 and R7 independently are -C1-C7-alkyl or, coupled with a nitrogen atom, form a 5- or 6-membered heterocyclic ring, R13 is OH or SH, R14 is H,-CH2OH, or -CH2-O-C(O)C1-18 alkyl, R15 is OH, alkynyl, -O-C(O)C1-18 alkyl, -OC(O)aryl, or -OC(O)heterocyclyl. R16, R17, R18, and R19 independently are H, halo, N3, alkyl, -(CH2)mOR20, -(CH2)mO C(O)C1-18 alkyl, -OC(O)aryl, OS(O)2aryl, or R16 and R17 are alkyls, or R17 and R19 combine to form a dioxol ring, R20 is H or alkyl, m is O or 1, n is 1 or 2, where if R2 is NH2, then one of the following must exist: Z is CH2; either n is 2 or m is 1; At least one of R16, R17, R18, and R19 is halo, N3, alkyl, or -(CH2)mOR20, where m is 1, and where if R17 is N3, then R18 and R19 are not H, and where if R17 is OH and R16 and R19 are H, then R18 is not F; or R16 and R17 are alkynyl, where the alkyl, aryl, cycloalkyl, or heterocyclyl moity above are substituted. An alternative of 1-4 representatives is selected from hydrogen, alkanoyl, alkylamine, amino, aryl, cycloalkyl, heterocyclyl, acido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkylamine, C1-C6 dialkylamine, C2-C6 alkynyl, or C2-C6 alkynyl, where each may be interpolated with one or more hetero atoms, carboxyl, cyano, halo, hydroxyl, mercapto, nitro, thioalkyl, -N=N-NH2, -C(O)2-(C1-C6 alkyl), -C(O)2-(aryl). -C(O)-2 cycloylkyl, -C(O)2-(heterocyclyl), -O-(C1-C6 haloalkyl), -O-(C1-C6 alkyl)eryl, -O-(C1-C6 alkyl)cycloalkyl, -O-(C1-C6 alkyl)heterocyclyl, -O-(C1-C6 alkyl)amino, -O- (C1-C6 alkyl)alkylamino, -O-(C1-C6 alkyl)dialkylamino, -O-(C1-C6 alkyl)-C(O)amino, -O-(C1-C6 alkyl)-C(O)-alkylamino, -O-(C1-C6 alkyl)-S(O)2-amino, -O-(C1-C6 Alkyl)-S(O)2 alkylamino, -O-(C1-C6 alkyl)-S(O)2- dialkylamino, -O-(C1-C6 alkyl)-C(O)-dialkylamino, -O-aryl, -O-heterocyclyl, -NHC(O)-(C1-C6 alkyl), -NHC(O)-(C1-C6 alkynyl), -NHC(O)-(aryl), -NHC(O)-(cycloalkyl), -NHC(O)-(heterocyclyl), -NHC(O)-(C1-C6 alkyl)aryl, -NHC(O)-(C1-C6 Alkyl)cycloalkyl, -NHC(O)- (C1-C6 alkyl)heterocyclyl, -NHC(O)-(C1-C6 alkyl)amino, -NHC(O)- (C1-C6 alkyl)alkylamine, -NHC(O)-(C1-C6 alkyl)dialkylamine, - NHC(O)- (C1-C6 alkyl)C(O)amino, -NHC(O)-(C1-C6 alkyl )C(O)alkylamine, -NHC(O)- (C1-C6 alkyl)C(O)dialkylamine, -NHC(O)-(C1-C6 Alkyl)N(H)-(C1-C6 alkyl) C(O)2-(C1-C6 alkyl), -NHC(O)-(C1-C6 alkyl )-C(O) amino, -NH-(C1-C6 alkyl)- C(O)-alkylamino, -NH-(C1-C6 alkyl)-C(O)-dialkylamino, -NHC(O)-(C1-C6 alkyl)S(O)2-(C1-C6 alkyl, - NHC(O)-(C1-C6 Alkyl)-S-(heterocyclyl), -NHS(O)2-(C1-C6 alkyl), -NHS(O)2-(aryl), -NH-(C1-C6 alkyl)-S(O)2-amino, -NH-(C1-C6 alkyl)-S(O)2-alkylamino, -NH-(C1-C6 alkyl)-S(O)2-dialkyl-amino, -NHS(O)2-(cycloalkyl), -NHS(O)2-(heterocyclyl), NHS(O) (C1-C6 alkyl), -NHS(O)(aryl), -NHS(O)(cycloalkyl), -NHS(O)(heterocyclyl), -NHS(C1-C6 alkyl), -NHS(aryl), -NHS (cycloalkyl), and -NH-S- (heterocyclyl), where each of the above substitutes can be alternatively substituted with 1-5 substitutes selected from amino, C1-C6 alkylamines, C1-C6 diallkylamines, C1-C6 alkyls, C1-C6 alkoxys, C1-C6 alkenyls, C1-C6 hydroxyls, and C1-C6 hydroxyalkyls, all of which can be alternatively substituted with cyano, halo, and nitro, or their pharmaceutically acceptable salts, hydrates, and totomers. 9. A compound, salt, hydrate, or totomer that is pharmaceutically recognized under claim 8, where R2 is NH2. 10. A compound, salt, hydrate, or totomer that is pharmaceutically recognized under claim 9, where R13 is OH. 11. A compound, salt, hydrate, or totomer that is pharmaceutically recognized under claim 10, where X is O and Y is S. 12. A pharmaceutically recognized compound, salt, hydrate, or totomer as per claim 8, selected from (chemical formula). 13. Selected compounds derived from (chemical formula), or their salts, hydrates, or totomers that are pharmaceutically acceptable. 14. Selected compounds from (chemical formula), or their salts, hydrates, or totomers that are scientifically acceptable. 15. A pharmaceutical mixture comprising a pharmaceutically acceptable carrier and the compounds specified in Patent 1; or its pharmaceutically acceptable salts or solvates. 16. Pharmaceutical mixtures under claim 15 whereby the compounds are selected from (chemical formula), or their salts or solvates that are pharmaceutically acceptable. 17. Methods of optimizing immunological cytokine activity in patients include: administering patients therapeutic or preventive doses of the compound of claim 1, or its pharmacologically accepted salts or solves. 18. The method under claim 17, where the compound is selected from (chemical formula), 19. The use of the compounds of claim 1, or their salts or solvates that are pharmaceutically acceptable for the manufacture of drugs for the treatment of hepatitis C virus infection in patients. 20. Use pursuant to claim 19, where the compound is selected from (chemical formula),