Brain-specific drug delivery
First Claim
1. A compound of the formula
or a nontoxic pharmaceutically acceptable salt thereof, wherein D is the residue of a centrally acting drug having anticonvulsant, sedative and/or hypnotic properties, said drug being a hydantoin or barbiturate or an analog of a hydantoin or barbiturate, said drug containing at least one reactive amide or imide functional group, said residue being characterized by the absence of a hydrogen atom from at least one of said amide or imide 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 penetrating, lipoidal form of a dihydropyridine⃡
pyridinium salt redox carrier, [DHC] being attached directly to an amide or imide nitrogen in the drug residue, [DHC] being a radical of the formula ##STR1678## wherein R is hydrogen, C1 -C7 alkyl, C3 -C8 cycloalkyl, C1 -C7 haloalkyl, furyl, phenyl, or phenyl substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl;
the dotted line in formulas (k'"'"'), (l'"'"') and (m'"'"') indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring;
the dotted line in formulas (n'"'"'), (o'"'"') and (p'"'"') indicates the presence of a double bond in either the 2 or 3 position of the dihyroquinoline ring;
R1 is C1 -C7 alkyl, C1 -C7 haloalkyl 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 carbonyl-containing groupings in formulas (k'"'"') and (m'"'"') and the X substituent in formula (l'"'"') can each be attached at the 2, 3 or 4 position of the dihydropyridine ring;
the carbonyl-containing groupings in formulas (n'"'"') and (p'"'"') and the X substituent in formula (o'"'"') can each be attached at the 2, 3 or 4 position of the dihydroquinoline ring; and
the carbonyl-containing groupings in formulas (q'"'"') and (s'"'"') and the X substituent in formula (r'"'"') can each be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring.
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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 dihydropyridine⃡pyridinium 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 function 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 dihydropyridine⃡pyridinium salt redox carrier. The corresponding ionic pyridinium salt type drug/carrier entitles [D--QC]+ X- are also disclosed.
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Citations
24 Claims
- 1. A compound of the formula
- space="preserve" listing-type="equation">D--DHC].sub.n (Ia)
or a nontoxic pharmaceutically acceptable salt thereof, wherein D is the residue of a centrally acting drug having anticonvulsant, sedative and/or hypnotic properties, said drug being a hydantoin or barbiturate or an analog of a hydantoin or barbiturate, said drug containing at least one reactive amide or imide functional group, said residue being characterized by the absence of a hydrogen atom from at least one of said amide or imide 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 penetrating, lipoidal form of a dihydropyridine⃡
pyridinium salt redox carrier, [DHC] being attached directly to an amide or imide nitrogen in the drug residue, [DHC] being a radical of the formula ##STR1678## wherein R is hydrogen, C1 -C7 alkyl, C3 -C8 cycloalkyl, C1 -C7 haloalkyl, furyl, phenyl, or phenyl substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl;
the dotted line in formulas (k'"'"'), (l'"'"') and (m'"'"') indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring;
the dotted line in formulas (n'"'"'), (o'"'"') and (p'"'"') indicates the presence of a double bond in either the 2 or 3 position of the dihyroquinoline ring;
R1 is C1 -C7 alkyl, C1 -C7 haloalkyl 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 carbonyl-containing groupings in formulas (k'"'"') and (m'"'"') and the X substituent in formula (l'"'"') can each be attached at the 2, 3 or 4 position of the dihydropyridine ring;
the carbonyl-containing groupings in formulas (n'"'"') and (p'"'"') and the X substituent in formula (o'"'"') can each be attached at the 2, 3 or 4 position of the dihydroquinoline ring; and
the carbonyl-containing groupings in formulas (q'"'"') and (s'"'"') and the X substituent in formula (r'"'"') can each be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
- 15. A quaternary salt of the formula
- space="preserve" listing-type="equation">D--QC.sup.+ ].sub.n qX.sup.-t (IIa)
wherein D is the residue of a centrally acting drug having anticonvulsant, sedative and/or hypnotic properties, said drug being a hydantoin or barbiturate or an analog of a hydantoin or barbiturate, said drug containing at least one reactive amide or imide functional group, said residue being characterized by the absence of a hydrogen atom from at least one of said amide or imide 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;
X- is the anion of a pharmaceutically acceptable organic or inorganic acid;
t is the valence of the acid anion;
q is the number which when multiplied by t is equal to n; and
[QC+ ] is the hydrophilic, ionic pyridinium salt form of a dihydropyridine⃡
pyridinium salt redox carrier, [QC+ ] being attached directly to an amide or imide nitrogen in the drug residue, [QC+ ] being a radical of the formula ##STR1682## wherein R is hydrogen, C1 -C7 alkyl, C3 -C8 cycloalkyl, C1 -C7 haloalkyl, furyl, phenyl, or phenyl substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl;
R1 is C1 -C7 alkyl, C1 -C7 haloalkyl 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 carbonyl-containing groupings in formulas (k) and (m) and the X substituent in formula (l) can each be attached at the 2, 3 or 4 position of the pyridinium ring;
the carbonyl-containing groupings in formulas (n) and (p) and the X substituent in formula (o) can each be attached at the 2, 3 or 4 position of the quinolinium rings; and
the carbonyl-containing groupings in formulas (q) and (s) and the X substituent in formula (r) can each be attached at the 1 3 or 4 position of the isoquinolinium ring.- View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24)
Specification
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- Resources
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Current AssigneeUniversity of Florida (State University System of Florida)
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Original AssigneeUniversity of Florida (State University System of Florida)
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InventorsBodor, Nicholas S.
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Primary Examiner(s)Gron, Teddy S.
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Assistant Examiner(s)Thomas, J. E.
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Application NumberUS06/665,940Time in Patent Office1,639 DaysField of Search514/341, 514/270, 514/307, 514/314, 514/318, 546/278, 546/145, 546/147, 546/169, 546/170, 546/165, 546/193, 424/1.1, 544/300, 544/310US Class Current514/270CPC Class CodesA61K 38/00 Medicinal preparations cont...A61K 47/559 Redox delivery systems, e.g...C07D 209/32 Oxygen atomsC07D 211/90 Carbon atoms having three b...C07D 213/80 in position 3C07D 213/82 in position 3C07D 401/12 linked by a chain containin...C07J 43/003 not condensedC07K 14/70 Enkephalins
