Brain-specific drug delivery

• US 4,540,564 A
• Filed: 07/22/1983
• Issued: 09/10/1985
• Est. Priority Date: 05/18/1982
• Status: Expired due to Term

• Current Assignee: Nicholas S. Bodor
• Original Assignee: University of Florida (State University System of Florida)
• Inventors: Bodor, Nicholas S.
• Primary Examiner(s): Nucker, Christine M.
• Application Number:
  US06/516,382
• Time in Patent Office: 781 Days
• Field of Search: 424/9, 424/241, 260/239.5
• US Class Current: 514/176
• 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 subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are:

(a) compounds of the formula

[D-DHC]                                                    (I)

wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine ⃡ pyridinium salt redox carrier, with the proviso that when [DHC] is ##STR1## wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH₂ or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH₂ or OH functional group to the carbonyl function of [DHC], then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol; and

(b) non-toxic pharmaceutically acceptable salts of compounds of formula (I) wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine ⃡ pyridinium salt redox carrier. The corresponding ionic pyridinium salt type drug/carrier entities [D-QC]⁺ Y^- are also disclosed.

Claims

1. A compound adapted for the site-specific/sustained delivery of a centrally acting drug species to the brain, said compound being:

(a) a compound of the formula

space="preserve" listing-type="equation">[D-DHC] (I)

wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine ⃡

pyridinium salt redox carrier, with the proviso that when [DHC] is ##STR799## wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH₂ or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH₂ or OH functional group to the carbonyl function of [DHC], then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol;

or

(b) a non-toxic pharmaceutically acceptable salt of a compound of formula (I) wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine ⃡

pyridinium salt redox carrier.

2. A compound according to claim 1, wherein [DHC] comprises the reduced form of a 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 [DHC] comprises the reduced form of an isoquinoline or of a pyridinium alcohol.

5. A compound according to claim 1, wherein [DHC] is ##STR800## wherein the ##STR801## substituents in formulae (i), (ii) and (iii) each can be in the 2-, 3- or 4-position on the ring, R₁ is C₁ -C₇ alkyl or C₇ -C₁₀ aralkyl and R₃ is (CH₂)_n wherein n is 1, 2 or 3.

6. A compound according to claim 5, wherein [DHC] is ##STR802##

12. A compound according to claim 1, wherein [D] is a steroid residue.

13. A compound according to claim 12, wherein the steroid is a steroid sex hormone.

14. A compound according to claim 13, wherein the steroid sex hormone is an androgen.

15. A compound according to claim 13, wherein the steroid sex hormone is an estrogen.

16. A compound according to claim 13, wherein the steroid sex hormone is a progestin.

17. A compound according to claim 13, wherein the steroid sex hormone is testosterone.

18. A compound according to claim 13, wherein the steroid sex hormone is methyl testosterone.

19. A compound according to claim 13, wherein the steroid sex hormone is ethinyl estradiol.

20. A compound according to claim 13, wherein the steroid sex hormone is norgestrel.

21. A compound according to claim 13, wherein the steroid sex hormone is mestranol.

22. A compound according to claim 13, wherein the steroid sex hormone is norethindrone.

23. A compound according to claim 13, wherein the steroid sex hormone is norethynodrel.

24. A compound according to claim 13, wherein the steroid sex hormone is ethisterone.

25. A compound according to claim 13, wherein the steroid sex hormone is estradiol.

26. A compound according to claim 13, wherein the steroid sex hormone is estriol.

27. A compound according to claim 13, wherein the steroid sex hormone is estrone.

28. A compound according to claim 13, wherein the steroid sex homone is dimethisterone.

29. A compound according to claim 13, wherein the steroid sex hormone is allylestrenol.

30. A compound according to claim 13, wherein the steroid sex hormone is cingestol.

31. A compound according to claim 13, wherein the steroid sex hormone is ethynerone.

32. A compound according to claim 13, wherein the steroid sex hormone is lynestrenol.

33. A compound according to claim 13, wherein the steroid sex hormone is norgesterone.

34. A compound according to claim 13, wherein the steroid sex hormone is norvinisterone.

35. A compound according to claim 13, wherein the steroid sex hormone is ethynodiol.

36. A compound according to claim 13, wherein the steroid sex hormone is oxogestone.

37. A compound according to claim 13, wherein the steroid sex hormone is tigestol.

38. A compound according to claim 13, wherein the steroid sex hormone is quinestrol.

39. A compound according to claim 12, wherein the steroid is an antiinflammatory steroid.

40. A compound according to claim 39, wherein the antiinflammatory steroid is hydrocortisone.

41. A compound according to claim 39, wherein the antiinflammatory steroid is betamethasone.

42. A compound according to claim 39, wherein the antiinflammatory steroid is cortisone.

43. A compound according to claim 39, wherein the antiinflammatory steroid is dexamethasone.

44. A compound according to claim 39, wherein the antiinflammatory steroid is flumethasone.

45. A compound according to claim 39, wherein the antiinflammatory steroid is fluprednisolone.

46. A compound according to claim 39, wherein the antiinflammatory steroid is meprednisone.

47. A compound according to claim 39, wherein the antiinflammatory steroid is methyl prednisolone.

48. A compound according to claim 39, wherein the antiinflammatory steroid is prednisolone.

49. A compound according to claim 39, wherein the antiinflammatory steroid is prednisone.

50. A compound according to claim 39, wherein the antiinflammatory steroid is triamcinolone.

51. A compound according to claim 39, wherein the antiinflammatory steroid is cortodoxone.

52. A compound according to claim 39, wherein the antiinflammatory steroid is fludrocortisone.

53. A compound according to claim 39, wherein the antiinflammatory steroid is flurandrenolone acetonide.

54. A compound according to claim 39, wherein the antiinflammatory steroid is paramethasone.

79. A compound according to claim 27, wherein D'"'"'" is a residue of cortisone or hydrocortisone.

80. A compound according to claim 27, wherein D'"'"'" is a residue of betamethasone, dexamethasone, flumethasone, fluprednisolone, methyl, prednisolone, meprednisone, prednisolone, prednisone, cortodoxone, fludrocortisone, paramethasone or triamcinolone.

82. A method for site-specifically/sustainedly delivering a centrally acting drug species to the brain, comprising administering to an animal in need of such treatment a quantity of a compound as claimed in claim 1 sufficient to release a pharmacologically effective amount of said centrally acting drug species to the brain.

83. A method according to claim 82, 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.

84. A pharmaceutical composition of matter comprising a compound as claimed in claim 1 and a non-toxic pharmaceutically acceptable carrier thereof.

85. A pharmaceutical composition of matter, in unit dosage form, for use in delivering a pharmacologically effective amount of a centrally acting drug species to the brain, said composition comprising:

(i) an amount of a compound as claimed in claim 1 sufficient to release a pharmacologically effective amount of a centrally acting drug species to the brain; and

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

86. A pharmaceutical composition as claimed in claim 85, said composition being a pharmaceutically acceptable sustained release composition.

7. A compound of the formula

View Dependent Claims (8, 9, 10, 11)

8. A compound according to claim 7, wherein [QC[⁺ comprises the ionic pyridinium salt form of a nicotinic acid derivative;

of an isoquinoline;

or of a pyridinium alcohol.

9. A compound according to claim 8, wherein [QC]⁺ compises the ionic pyridinium salt form of a trigonelline.

10. A compound according to claim 7, wherein [QC]⁺ is ##STR804## wherein the ##STR805## substituents in formulae (i), (ii) and (iii) each can be in the 2-, 3- or 4-position on the ring, R₁ is C₁ -C₇ alkyl or C₇ -C₁₀ aralkyl and R₃ is (CH₂)_n where n is 1, 2 or 3.

11. A compound as defined by claim 10, wherein [QC]⁺ is ##STR806##

55. A compound adapted for the site-specific/sustained delivery of a centrally acting drug species to the brain, said compound being:

(i) a compound of the formula

space="preserve" listing-type="equation">D'"'"'"(--Q").sub.n (I'"'"'")

wherein D'"'"'" is the residue of a centrally acting drug containing at least one --OH or --SH functional group, said residue being formed by removal of a hydrogen atom from at least one of the --OH or --SH functional groups in said drug;

n" is a positive integer equal to the number of said --OH or --SH functional groups from which a hydrogen atom has been removed; and

--Q" is a radical of the formula ##STR807## wherein the dotted line in formulae (a), (b), (c), (d) or (e) indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring;

the dotted line in formulae (g), (i), (k), (l) and (n) indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring;

R₁ is C₁ -C₇ alkyl or C₇ -C₁₀ aralkyl;

R₃ is C₁ to C₃ alkylene;

X is --CONR'"'"'R" wherein R'"'"' and R", which can be the same or different, are each H or C₁ -C₇ alkyl, or X is --CH═

NOR'"'"'" wherein R'"'"'" is H or C₁ -C₇ alkyl, the ##STR808## groupings in formulae (a), (b), (c) and (e) and the X substituent in formula (d) can each be attached at the 2, 3 or 4 position of the dihydropyridine ring;

the ##STR809## groupings in formulae (g), (i), (k) and (n) and the X substituent in formula (1) can each be attached at the 2, 3 or 4 position of the dihydroquinoline ring; and

the ##STR810## groupings in the formulae (f), (h), (j) and (o) and the X substituent in formula (m) can each be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring;

or

(ii) a non-toxic pharmaceutically acceptable salt of a compound of formula (I'"'"'");

with the proviso that when the compound is other than a salt as claimed in (ii) above, when n is 1, when --Q" is ##STR811## wherein R₁ is defined as above, and when the centrally acting drum from which D'"'"'" is derived contains only one primary or secondary --OH functional group, no other --OH functional groups and no --NH₂, --NH--, --SH or --COOH functional groups, then D'"'"'" must be the residue of a centrally acting drug other than a steroid sex hormone or long chain alkanol.

56. A compound according to claim 55, wherein D'"'"'" is the residue of a steroid sex hormone.

57. A compound according to claim 56, wherein D'"'"'" is the residue of an androgen.

58. A compound according to claim 56, wherein D'"'"'" is the residue of an estrogen.

59. A compound according to claim 56, wherein D'"'"'" is the residue of a progestin.

60. A compound according to claim 56, wherein D'"'"'" is the residue of testosterone.

61. A compound according to claim 56, wherein D'"'"'" is the residue of methyl testosterone.

62. A compound according to claim 56, wherein D'"'"'" is a residue of estradiol.

63. A compound according to claim 56, wherein D'"'"'" is a residue of estriol or estrone.

64. A compound according to claim 56, wherein D'"'"'" is a residue of ethinyl estradiol.

65. A compound according to claim 56, wherein D'"'"'" is the residue of mestranol.

66. A compound according to claim 56, wherein D'"'"'" is the residue of quinestrol.

67. A compound according to claim 56, wherein D'"'"'" is the residue of norethindrone.

68. A compound according to claim 56, wherein D'"'"'" is the residue of norgestrel.

69. A compound according to claim 56, wherein D'"'"'" is the residue of ethisterone.

70. A compound according to claim 56, wherein D'"'"'" is the residue of dimethisterone.

71. A compound according to claim 56, wherein D'"'"'" is the residue of allylestrenol.

72. A compound according to claim 56, wherein D'"'"'" is the residue of cingestol or ethynerone.

73. A compound according to claim 56, wherein D'"'"'" is the residue of lynestrenol.

74. A compound according to claim 56, wherein D'"'"'" is the residue of norgesterone or norvinisterone.

75. A compound according to claim 56, wherein D'"'"'" is a residue of ethynodiol.

76. A compound according to claim 56, wherein D'"'"'" is the residue of oxogestone or tigestol.

77. A compound according to claim 56, wherein D'"'"'" is the residue of of norethynodrel.

78. A compound according to claim 56, wherein D'"'"'" is the residue of an anti-inflammatory steroid.

81. A non-toxic pharmaceutically acceptable quaternary salt having the formula