Brain-specific analogues of centrally acting amines
First Claim
1. A compound having the formula ##STR748## or a non-toxic pharmaceutically acceptable salt thereof, wherein Am is the residue of a centrally acting primary amine which is a non-heterocyclic natural amino acid neurotransmitter, said residue optionally containing, in place of at least one --COOH functional group in the amino acid neurotransmitter from which Am can be considered to be derived, at least one COOY'"'"' group wherein Y'"'"' is a hydrolytically or metabolically cleavable carboxyl protective group;
- and ##STR749## is a radical of the formula ##STR750## wherein 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 (b) indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring system;
m is zero or one;
n is zero, one or two;
p is zero, one or two, provided that when p is one or two, each R in formula (b) can be located on either of the two fused rings;
q is zero, one or two, provided that when q is one or two, each R in formula (c) can be located on either of the two fused rings; and
each R is independently selected from the group consisting of halo, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is H or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which can be the same or different, are each H or C1 -C7 alkyl.
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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 compounds of the formula ##STR1## and the non-toxic pharmaceutically acceptable salts thereof, wherein D is the residue of a centrally acting primary, secondary or tertiary amine and ##STR2## is an unsubstituted or substituted dihydropyridyl, dihydroquinolyl or dihydroisoquinolyl radical. The corresponding ionic pyridinium, quinolinium and isoquinolinium salts ##STR3## X-, wherein X- is the anion of a non-toxic pharmaceutically acceptable acid, are also disclosed.
12 Citations
31 Claims
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1. A compound having the formula ##STR748## or a non-toxic pharmaceutically acceptable salt thereof, wherein Am is the residue of a centrally acting primary amine which is a non-heterocyclic natural amino acid neurotransmitter, said residue optionally containing, in place of at least one --COOH functional group in the amino acid neurotransmitter from which Am can be considered to be derived, at least one COOY'"'"' group wherein Y'"'"' is a hydrolytically or metabolically cleavable carboxyl protective group;
- and ##STR749## is a radical of the formula ##STR750## wherein 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 (b) indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring system;
m is zero or one;
n is zero, one or two;
p is zero, one or two, provided that when p is one or two, each R in formula (b) can be located on either of the two fused rings;
q is zero, one or two, provided that when q is one or two, each R in formula (c) can be located on either of the two fused rings; and
each R is independently selected from the group consisting of halo, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is H or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which can be the same or different, are each H or C1 -C7 alkyl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)
- and ##STR749## is a radical of the formula ##STR750## wherein the dotted line in formula (a) indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring;
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24. A non-toxic pharmaceutically acceptable quaternary salt having the formula ##STR758## wherein Am'"'"' is the protected residue of a centrally acting primary amine which is a non-heterocyclic natural amino acid neurotransmitter, said residue containing, in place of at least one --COOH functional group in the amino acid neurotransmitter from which Am'"'"' can be considered to be derived, at least one --COOY" group wherein Y" is a hydrolytically or metabolically cleavable carboxyl protective function selected from the group consisting of ethyl, isopropyl, t-butyl, ##STR759## --CH2 OCH3 ;
- X- is the anion of a non-toxic pharmaceutically acceptable acid; and
##STR760## is a radical of the formula ##STR761## wherein n is zero, one or two;
p is zero, one or two, provided that when p is one or two, each R in formula (b) can be located on either of the two fused rings;
q is zero, one or two, provided that when q is one or two, each R in formula (c) can be located on either of the two fused rings; and
each R is independently selected from the group consisting of halo, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is H or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which can be the same or different, are each H or C1 -C7 alkyl. - View Dependent Claims (25, 26, 27, 28, 29, 30, 31)
- X- is the anion of a non-toxic pharmaceutically acceptable acid; and
Specification