Novel redox carriers for brain-specific drug delivery

• US 4,829,070 A
• Filed: 10/29/1984
• Issued: 05/09/1989
• Est. Priority Date: 05/18/1982
• Status: Expired due to Fees

• Current Assignee: University of Florida (State University System of Florida)
• Original Assignee: University of Florida (State University System of Florida)
• Inventors: Bodor, Nicholas S.
• Primary Examiner(s): Terapane, John F.
• Assistant Examiner(s): Thomas, J. E.
• Application Number:
  US06/666,210
• Time in Patent Office: 1,653 Days
• Field of Search: 546/316, 546/318, 546/323, 546/328, 546/146, 546/165, 546/169, 546/316, 514/354, 514/307, 514/311, 514/355, 424/1.1, 424/9
• US Class Current: 514/307
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/559 Redox delivery systems, e.g. dihydropyridine pyridinium salt redox systems
• CPC Class Codes: C07D 209/32 Oxygen atoms
• CPC Class Codes: C07D 211/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07J 43/003 not condensed
• CPC Class Codes: C07K 14/70 Enkephalins

Abstract

The invention provides compounds of the formula

D--DHC].sub.n                                              (I)

and the nontoxic pharmaceutically acceptable salt thereof, wherein D is the residue of a centrally acting drug containing at least one reactive functional group selected from the group consisting of amino, hydroxyl, mercapto, carboxyl, amide and imide, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive 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 [DHC] is the reduced, biooxidizable, blood-brain barrier penetratring lipoidal form of a dihydropyridine⃡pyridinium salt redox carrier, said carrier comprising a bivalent radical of the formula ##STR1## wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R_o is a radical identical to the corresponding portion of a natural amino acid; and p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R_o radicals can be the same or different; said bivalent radical being so positioned that the terminal carbonyl function of the bivalent radical is linked to the drug residue while the terminal amino function of the bivalent radical is linked to the remaining portion of the carrier moiety. The subject compounds are adapted for the site-specific/sustained delivery of centrally acting drugs to the brain. The corresponding pyridinium salt type drug/carrier entities D--QC⁺ ]_n q^y-t are also disclosed.

Claims

1. A compound having the structural formula ##STR1231## or a nontoxic pharmaceutically acceptable salt thereof, wherein:

each R_a is independently hydrogen or a hydroxyl protective group selected from the group consisting of alkanoyl having 2 to 8 carbon atoms, ##STR1232## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxyacetyl, and ##STR1233## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms;

R_b is hydrogen or --COOR_c wherein R_c is hydrogen or a carboxyl protective group selected from the group consisting of alkyl having 1 to 7 carbon atoms, alkenyl having one or two double bonds and 2 to 7 carbon atoms, cycloalkyl --C_r H_2r -- wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxy, and phenyl --C_r H_2r -- wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms; and

[DHC] is ##STR1234## wherein;

the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms;

R_o is hydrogen, methyl, --CH(CH₃)₂, --CH₂ --CH(CH₃)₂, ##STR1235## --CH₂ OH, --CH(OH)--CH₃, --(CH₂)₂ --SCH₃, --CH₂ --CONH₂, --CH₂ CH₂ --CONH₂, ##STR1236## --CH₂ SH, --CH₂ COOH or --CH₂ CH₂ 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_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 a double bond in either the 2 or 3 position of the dihydroquinoline ring;

R₁ is C₁ -C₇ alkyl, C₁ -C₇ haloalkyl or C₇ -C₁₀ 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 [DHC] comprises the reduced form of an N-substituted nicotinic acid derivative.

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

4. A compound according to claim 1, wherein R_o is hydrogen.

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

6. A compound according to claim 1, wherein each R_a is hydrogen and wherein R_b is hydrogen.

7. A compound according to claim 1, wherein at least one R_a is a hydroxyl protective group.

8. A compound according to claim 7, wherein R_b is hydrogen.

9. A compound according to claim 1, wherein R_b is --COOR_c wherein R_c is a carboxylic protective group.

10. A compound according to claim 1, wherein at least one R_a is a hydroxyl protective group and wherein R_b is --COOR_c wherein R_c is a carboxyl protective group.

11. A compound according to claim 10, said compound having the structural formula:

##STR1237##

12. A compound according to claim 1, wherein alkylene is --CH₂ --.

13. A compound according to claim 1, wherein R_o is H, --CH₃, --CH(CH₃)₂, --CH₂ --CH(CH₃)₂, ##STR1238## --(CH₂)₂ --SCH₃, --CH₂ --CONH₂ or --CH₂ CH₂ --CONH₂.

14. A compound according to claim 1, wherein R₁ is CH₃.

15. A compound according to claim 1, wherein [DHC] has formula (a'"'"') wherein the carbonyl-containing grouping is attached at the 3-position of the dihydropyridine ring.

16. A compound according to claim 1, wherein [DHC] has formula (d'"'"') wherein the carbonyl-containing grouping is attached at the 3-position of the dihydroquinoline ring.

17. A compound according to claim 1, wherein [DHC] has formula (g'"'"') wherein the carbonyl-containing grouping is attached at the 4-position of the dihydroisoquinoline ring.

18. A compound according to claim 1, wherein at least one R_a is alkanoyl having 2 to 8 carbon atoms.

19. A compound according to claim 18, wherein at least one R_a is acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl, 3-methylpentanoyl, 3,3-dimethylbutanoyl, or 2,2-dimethylpentanoyl.

20. A compound according to claim 19, wherein at least one R_a is pivalyl, isobutyryl or isovaleryl.

21. A compound according to claim 1, wherein at least one R_a is ##STR1239## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three.

22. A compound according to claim 21, wherein at least one R_a is cyclohexanecarbonyl.

23. A compound according to claim 1, wherein at least one R_a is ##STR1240## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms.

24. A compound according to claim 1, wherein R_b is --COOR_c wherein R_c is alkyl having 1 to 7 carbon atoms.

25. A compound according to claim 24, wherein R_c is ethyl, isopropyl or t-butyl.

26. A method for site-specifically/sustainedly eliciting a dopaminergic response in the brain, comprising administering to an animal in need of such treatment a quantity of a compound as defined by claim 1 sufficient to elicit a pharmacologically effective dopaminergic response in the brain.

27. A method according to claim 26, wherein the compound is administered in the form of a pharmaceutically acceptable sustained release composition or wherein the compound is administered via a route of administration capable of slowly releasing the compound into the body.

28. A pharmaceutical composition of matter, in unit dosage form, for use in eliciting a dopaminergic response in the brain, said composition comprising:

(i) an amount of a compound as defined by claim 1 sufficient to elicit a pharmacologically effective dopaminergic response in the brain; and

(ii) a non-toxic pharmaceutically acceptable carrier therefor.

29. A pharmaceutical composition as claimed in claim 28, said composition being a pharmaceutically acceptable sustained release composition.

30. A quaternary salt having the structural formula ##STR1241## wherein:

each R_a is independently hydrogen or a hydroxyl protective group selected from the group consisting of alkanoyl having 2 to 8 carbon atoms, ##STR1242## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxyacetyl and ##STR1243## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms;

R_b is hydrogen or --COOR_c wherein R_c is hydrogen or a carboxyl protective group selected from the group consisting of alkyl having 1 to 7 carbon atoms, alkenyl having one or two double bonds and 2 to 7 carbon atoms, cycloalkyl --C_r H_2r -- wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxy, and phenyl --C_r H_2r -- wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms;

[QC⁺ ] is ##STR1244## wherein;

the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms;

R_o is hydrogen, methyl, --CH(CH₃)₂, --CH₂ --CH(CH₃)₂, ##STR1245## --CH₂ OH, --CH(OH)--CH₃, --(CH₂)₂ --SCH₃, --CH₂ --CONH₂, --CH₂ CH₂ --CONH₂, ##STR1246## --CH₂ SH, --CH₂ COOH or --CH₂ CH₂ 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_o radicals can be the same or different;

R₁ is C₁ -C₇ alkyl, C₁ -C₇ haloalkyl or C₇ -C₁₀ 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- 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 one.

31. A quaternary salt according to claim 30 wherein [QC⁺ ] comprises the oxidized form of an N-substituted nicotinic acid derivative.

32. A quaternary salt according to claim 30, wherein [QC⁺ ] comprises the oxidized form of a trigonelline.

33. A quaternary salt according to claim 30, wherein R₀ is hydrogen.

34. A quaternary salt according to claim 30, wherein p is 1.

35. A quaternary salt according to claim 30, wherein each R_a is hydrogen and wherein R_b is hydrogen.

36. A quaternary salt according to claim 30, wherein at least one R_a is a hydroxyl protective group.

37. A quaternary salt according to claim 36, wherein R_b is hydrogen.

38. A quaternary salt according to claim 30, wherein R_b is --COOR_c wherein R_c is a carboxyl protective group.

39. A quaternary salt according to claim 30, wherein at least one R_a is a hydroxyl protective group and wherein R_b is --COOR_c wherein R_c is a carboxyl protective group.

40. A quaternary salt according to claim 30, wherein alkylene is --CH₂ --.

41. A quaternary salt according to claim 30, wherein p is 1.

42. A quaternary salt according to claim 30, wherein R₀ is H, --CH₃, --CH(CH₃)₂, --CH₂ --CH(CH₃)₂, ##STR1247## --(CH₂)₂ --SCH₃, --CH₂ --CONH₂ or --CH₂ CH₂ --CONH₂.

43. A quaternary salt according to claim 30, wherein R₁ is CH₃.

44. A quaternary salt according to claim 30, wherein [QC⁺ ] has formula (a) wherein the carbonyl-containing grouping is attached at the 3-position of the pyridinium ring.

45. A quaternary salt according to claim 30, wherein [QC⁺ ] has formula (d) wherein the carbonyl-containing grouping is attached at the 3-position of the quinolinium ring.

46. A quaternary salt according to claim 30, wherein [QC⁺ ] has formula (g) wherein the carbonyl-containing grouping is attached at the 4-position of the isoquinolinium ring.

47. A quaternary salt according to claim 30, wherein at least one R_a is alkanoyl having 2 to 8 carbon atoms.

48. A quaternary salt according to claim 47, wherein at least one R_a is acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl, 3-methylpentanoyl, 3,3-dimethylbutanoyl or 2,2-dimethylpentanoyl.

49. A quaternary salt according to claim 48, wherein at least one R_a is pivalyl, isobutyryl or isovaleryl.

50. A quaternary salt according to claim 30, wherein at least one R_a is ##STR1248## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three.

51. A quaternary salt according to claim 50, wherein at least one R_a is cyclohexanecarbonyl.

52. A quaternary salt according to claim 30, wherein at least one R_a is ##STR1249## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms.

53. A quaternary salt according to claim 30, wherein R_b is --COOR_c wherein R_c is alkyl having 1 to 7 carbon atoms.

54. A quaternary salt according to claim 53 wherein R_c is ethyl, isopropyl or t-butyl.