Brain-specific drug delivery
First Claim
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 Assignments
0 Petitions
Accused Products
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.
-
Citations
86 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. - View Dependent Claims (2, 3, 4, 5, 6, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 79, 80, 82, 83, 84, 85, 86)
-
- 7. A compound of the formula
- space="preserve" listing-type="equation">[D-QC].sup.+ Y.sup.- (II)
wherein Y- is the anion of a non-toxic pharmaceutically acceptable acid, [D] is a centrally acting drug species and [QC]+ is the hydrophilic, ionic pyridinium salt form of a dihydropyridine ⃡
pyridinium salt redox carrier, with the proviso that when [QC]+ is ##STR803## 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 [QC]+, then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol.- View Dependent Claims (8, 9, 10, 11)
-
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. - View Dependent Claims (56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 81)
-
Specification