Redox Carriers for Brain-Specific Drug Delivery

1. A compound having the structural formula or a nontoxic pharmaceutically acceptable salt thereof, wherein D is the residue of a centrally acting drug containing at least one reactive hydroxyl functional group, said drug being a nucleaside-type antiviral, anticancer or antitumor agent, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive hydroxyl functional groups in said drug; n is a positive integer equal to the number of said functional groups from which a hydrogen atom is absent; and is a radical of the formula ##STR1196## wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R.sub.o is hydrogen, methyl, --CH(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3).sub.2, ##STR1197## --CH.sub.2 OH, --CH(OH)CH.sub.3, --(CH.sub.2).sub.2 --SCH.sub.3, --CH.sub.2 --CONH.sub.2, --CH.sub.2 CH.sub.2 --CONH.sub.2, ##STR1198## --CH.sub.2 COOH or --CH.sub.2 CH.sub.2 COOH; p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R.sub.o radicals can be the same or different; the dotted line in formula (a') indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formula (d') indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring; R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.10 aralkyl; the carbonyl-containing grouping in formula (a') can be attached at the 2, 3 or 4 position of the dihydropyridine ring; the carbonyl-containing grouping in formula (d') can be attached at the 2, 3 or 4 position of the dihydroquinoline ring; and the carbonyl-containing grouping in formula (g') can be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring.

2. A compound according to claim 1, wherein comprises the reduced form of an N-substituted nicotinic acid derivative.

3. A compound according to claim 1, wherein comprises the reduced form of a trigonelline.

4. A compound according to claim 1, wherein n is 1.

5. A compound according to claim 1, wherein R.sub.o is hydrogen.

6. A compound according to claim 1, wherein p is 1.

7. A compound according to claim 1, wherein alkylene is --CH.sub.2 --.

8. A compound according to claim 1, wherein R.sub.o is H, --CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3).sub.2, ##STR1199## --CH.sub.2 --CONH.sub.2 or --CH.sub.2 CH.sub.2 --CONH.sub.2.

9. A compound according to claim 1, wherein R.sub.1 is CH.sub.3.

10. A compound according to claim 1, wherein has formula (a') wherein the carbonyl-containing grouping is attached at the 3-position of the dihydropyridine ring, or wherein has formula (d') wherein the carbonyl-containing grouping is attached at the 3-position of the dihydroquinoline ring, or wherein has formula (g') wherein the carbonyl-containing grouping is attached at the 4-position of the dihydroisoquinoline ring.

11. A pharmaceutical composition of matter, in unit dosage form, for use in eliciting an antiviral, anticancer or antitumor response in the brain, said composition comprising: (i) an amount of a compound as defined by claim 1 sufficient to elicit a pharmacologically effective antiviral, anticancer or antitumor response in the brain; and (ii) a non-toxic pharmaceutically acceptable carrier therefor.

12. A pharmaceutical composition as claimed in claim 11, said composition being a pharmaceutically acceptable sustained release composition.

13. A quaternary salt having the structural formula wherein D is the residue of a centrally acting drug containing at least one reactive hydroxyl functional group, said drug being an antiviral, anticancer or antitumor agent, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive hydroxyl functional groups in said drug; n is a positive integer equal to the number of said functional groups from which a hydrogen atom is absent; is a radical of the formula ##STR1200## wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R.sub.o is hydrogen, methyl, --CH(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3).sub.2, ##STR1201## --CH.sub.2 OH, --CH(OH)CH.sub.3, --(CH.sub.2).sub.2 --SCH.sub.3, --CH.sub.2 --CONH.sub.2, --CH.sub.2 CH.sub.2 --CONH.sub.2, ##STR1202## --CH.sub.2 SH, --CH.sub.2 COOH or --CH.sub.2 CH.sub.2 COOH; p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R.sub.o radicals can be the same or different; R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.1 -C.sub.10 aralkyl; the carbonylcontaining grouping in formula (a) can be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl-containing grouping in formula (d) can be attached at the 2, 3 or 4 position of the quinolinium ring; the carbonylcontaining grouping in formula (g) can be attached at the 1, 3 or 4 position of the isoquinolinium ring; Y.sup.- is the anion of a pharmaceutically acceptable organic or inorganic acid; t is the valence of the acid anion; and q is the number which when multiplied by t is equal to n.

14. A quaternary salt according to claim 13, wherein comprises the oxidized form of an N-substituted nicotinic acid derivative.

15. A quaternary salt according to claim 13, wherein comprises the oxidized form of a trigonelline.

16. A quaternary salt according to claim 13, wherein n is 1.

17. A quaternary salt according to claim 13, wherein R.sub.o is hydrogen.

18. A quaternary salt according to claim 13, wherein p is 1.

19. A quaternary salt according to claim 13, wherein alkylene is --CH.sub.2 --.

20. A quaternary salt according to claim 13, wherein R.sub.o is H, --CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3).sub.2, ##STR1203## --(CH.sub.2).sub.2 --SCH.sub.3, --CH.sub.2 --CONH.sub.2 or --CH.sub.2 CH.sub.2 --CONH.sub.2.

21. A quaternary salt according to claim 13, wherein R.sub.1 is CH.sub.3.

22. A quaternary salt according to claim 13, wherein has formula (a) wherein the carbonyl-containing grouping is attached at the 3-position of the pyridinium ring, or wherein has formula (d) wherein the carbonyl-containing grouping is attached at the 3-position of the quinolinium ring, or wherein has formula (g) wherein the carbonyl-containing grouping is attached at the 4-position of the isoquinolinium ring.

23. A quaternary salt having the structural formula wherein D is the residue of a centrally acting drug containing at least one reactive hydroxyl functional group, said drug being a nucleoside-type antiviral, anticancer or antitumor agent and being selected from the group consisting of ribavirin, acyclovir, pentostatin, Ara-AC, Ara-C, dihydro-5-azacytidine, Ara-A 6-MMPR, 5-FUDR, 5-azacytidine, 5,7-dimethyl-6.beta.-D-ribofuranosyl-s-triazole(1,5-a)pyrimidine, (S)-9-(2,3-dihydroxypropyl)adenine, 6-azauridine, idoxuridine, trifluridine and 5,6-dichloro-1-.beta.-D-ribofuranoxylbenzimidazole, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive hydroxyl functional groups in said drug; n is a positive integer equal to the number of said functional groups from which a hydrogen atom is absent; is a radical of the formula ##STR1204## wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R.sub.o is hydrogen, methyl, --CH(CH.sub.3).sub.2, --CH.sub.2 -13 CH(CH.sub.3).sub.2, ##STR1205## --CH.sub.2 OH, --CH(OH)CH.sub.3, --(CH.sub.2).sub.2 --SCH.sub.3, --CH.sub.2 --CONH.sub.2, --CH.sub.2 CH.sub.2 --CONH.sub.2, ##STR1206## --CH.sub.2 SH, --CH.sub.2 COOH or --CH.sub.2 CH.sub.2 COOH; p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R.sub.o radicals can be same or different; R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.10 aralkyl; the carbonyl-containing grouping in formula (a) can be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl-containing grouping in formula (d) can be attached at the 2, 3 or 4 position of the quinolinium ring; the carbonyl-containing grouping in formula (g) can be attached at the 1, 3 or 4 position of the isoquinolinium ring; Y.sup.- is the anion of a pharmaceutically acceptable organic or inorganic acid; t is the valence of the acid anion; and q is the number which when multiplied by t is equal to n.

24. A quaternary salt according to claim 23, wherein D is a residue of ribavirin.

25. A quaternary salt according to claim 24, wherein comprises the oxidized form of a trigonelline.

26. A quaternary salt according to claim 25, the cation of which has the structural formula ##STR1207## wherein one R is ##STR1208## and each remaining R is H or ##STR1209## .

27. A compound having the structural formula or a nontoxic pharmaceutically acceptable salt thereof, wherein D is the residue of a centrally acting drug containing at least one reactive hydroxy functional group, said drug being a nucleoside-type antiviral, anticancer or antitumor agent and being selected from the group consisting of ribavirin, acyclovir, pentostatin, Ara-AC, Ara-C, dihydro-5-azacytidine, Ara-A, 6-MMPR, 5-FUDR, 5-azacytidine, 5,7-dimethyl-2-.beta.-D-ribofuranosyl-s-triazole(1,5-a)pyrimidine, (S)-9(2,3-dihydroxypropyl)adenine, 6-azauridine, idoxuridine, trifluridine and 5,6-dichloro-1-.beta.-D-ribofuranosylbenzimidazole, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive hydroxy functional groups in said drug; n is a positive integer equal to the number of said functional groups from which a hydrogen atom is absent; and is a radical of the formula ##STR1210## wherein the alkylene group can be straight or branched and can contain 1 or 3 carbon atoms; R.sub.o is hydrogen, methyl, --CH(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3).sub.2, ##STR1211## --CH.sub.2 OH, --CH(OH)CH.sub.3, --(CH.sub.2).sub.2 --SCH.sub.3, --CH.sub.2 --COHN.sub.2, --CH.sub.2 CH.sub.2 --CONH.sub.2, ##STR1212## --CH.sub.2 SH, --CH.sub.2 COOH or --CH.sub.2 CH.sub.2 COOH; p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R.sub.o radicals can be the same or different; the dotted line in formula (a') indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formula (d') indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring; R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.10 aralkyl; the carbonyl-containing grouping in formula (a') can be attached at the 2, 3 or 4 position of the dihydropyridine ring; the carbonyl-containing grouping in formula (d') can be attached at the 2, 3 or 4 position of the dihydroquinoline ring; and the carbonyl-containing grouping in formula (g') can be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring.

28. A compound according to claim 27, wherein D is a residue of ribavirin.

29. A compound according to claim 28, wherein comprises the reduced form of a trigonelline.

30. A compound according to claim 29, having the structural formula ##STR1213## wherein one R' is ##STR1214## and each remaining R' is H or ##STR1215## .

31. A compound according to claim 27, wherein comprises the reduced from of an N-substituted nicotinic acid derivative.

32. A compound according to claim 27, wherein comprises the reduced form of a trigonelline.

33. A compound according to claim 27, wherein n is 1.

34. A compound according to claim 27, wherein R.sub.o is hydrogen.

35. A compound according to claim 27, wherein p is 1.

36. A compound according to claim 27, wherein alkylene is --CH.sub.2 --.

37. A compound according to claim 27, wherein R.sub.o is H, --CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3).sub.2, ##STR1216## --(CH.sub.2).sub.2 --SCH.sub.3, --CH.sub.2 --CONH.sub.2 or --CH.sub.2 CH.sub.2 --CONH.sub.2.

38. A compound according to claim 27, wherein R.sub.1 is CH.sub.3.

39. A compound according to claim 27, wherein has formula (a') wherein the carbonyl-containing grouping is attached at the 3-position of the dihydropyridine ring, or wherein has formula (d') wherein the carbonyl-containing grouping is attached at the 3-position of the dihydroquinoline ring, or wherein has formula (g') wherein the carbonyl-containing grouping is attached at the 4-position of the dihydroisoquinoline ring.

40. A pharmaceutical composition of matter, in unit dosage form, for use in eliciting an antiviral, anticancer or antitumor response in the brain, said composition comprising: (i) an amount of a compound as defined by claim 27 sufficient to elicit a pharmacologically effective antiviral, anticancer or antitumor response in the brain; and (ii) a non-toxic pharmaceutically acceptable carrier thereof.

41. A pharmaceutical composition as claimed in claim 40, said composition being a pharmaceutically acceptable sustained release composition.

42. A quaternary salt according to claim 23, wherein comprises the oxidized form of an N-substituted nicotinic acid derivative.

43. A quaternary salt according to claim 23, wherein comprises the oxidized form of a trigonelline.

44. A quaternary salt according to claim 23, wherein n is 1.

45. A quaternary salt according to claim 23, wherein R.sub.o is hydrogen.

46. A quaternary salt according to claim 23, wherein p is 1.

47. A quaternary salt according to claim 23, wherein alkylene is --CH.sub.2 --.

48. A quaternary salt according to claim 23, wherein R.sub.o is H, --CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3).sub.2, ##STR1217## --(CH.sub.2).sub.2 --SCH.sub.3, --CH.sub.2 --CONH.sub.2 or --CH.sub.2 CH.sub.2 --CONH.sub.2.

49. A quaternary salt according to claim 23, wherein R.sub.1 is CH.sub.3.

50. A quaternary salt according to claim 23, wherein has formula (a) wherein the carbonyl-containing grouping is attached at the 3-position of the pyridinium ring, or wherein has formula (d) wherein the carbonyl-containing grouping is attached at the 3-position of the quinolinium ring, or wherein has formula (g) wherein the carbonyl-containing grouping is attached at the 4-position of the isoquinolinium ring.