US 4,540,564 A · Brain-specific drug delivery

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 .revreaction. 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 NH.sub.2 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 NH.sub.2 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 .revreaction. pyridinium salt redox carrier. The corresponding ionic pyridinium salt type drug/carrier entities [D-QC].sup.+ Y.sup.- are also disclosed.

Claims86

Dependent claims

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
[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 .revreaction. 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 NH.sub.2 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 NH.sub.2 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 .revreaction. pyridinium salt redox carrier.

2 more elements

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
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;
R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl;
R.sub.3 is C.sub.1 to C.sub.3 alkylene;
X is --CONR'R" wherein R' and R", which can be the same or different, are each H or C.sub.1 -C.sub.7 alkyl, or X is --CH.dbd.NOR'" wherein R'" is H or C.sub.1 -C.sub.7 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 R.sub.1 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 --NH.sub.2, --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.

11 more elements

Dependencies are inferred from the claim text.

Brain-specific drug delivery

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Brain-specific drug delivery

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Abstract

Claims86