Patent US4829070A successfully refreshed from Google Patents.
← Back to Patent Explorer
US4829070A Expired / Lapsed US ⏱️ 0.0 years remaining

Novel redox carriers for brain-specific drug delivery

Assignee: University of Florida
•
Filing: 1984-10-29
•
Granted: 1989-05-09
•
Expires: 2004-10-29
📄 Original PDF 🌐 Google Patents 🔄 Sync Now

Abstract

Abstract The invention provides compounds of the formula D--DHC].sub.n (I) and the nontoxic pharmaceutically acceptable salt thereof, wherein D is the residue of a centrally acting drug containing at least one reactive functional group selected from the group consisting of amino, hydroxyl, mercapto, carboxyl, amide and imide, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive 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 penetratring lipoidal form of a dihydropyridine⃡pyridinium salt redox carrier, said carrier comprising a bivalent radical of the formula ##STR1## wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R o is a radical identical to the corresponding portion of a natural amino acid; and p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R o radicals can be the same or different; said bivalent radical being so positioned that the terminal carbonyl function of the bivalent radical is linked to the drug residue while the terminal amino function of the bivalent radical is linked to the remaining portion of the carrier moiety. The subject compounds are adapted for the site-specific/sustained delivery of centrally acting drugs to the brain. The corresponding pyridinium salt type drug/carrier entities D--QC + ] n q y-t are also disclosed.

Inventors

  • 👤 Nicholas S. Bodor

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-10-26 20:03
CPC Classifications
C; C07; C07D; C07D213/00; C07D213/02; C07D213/04; C07D213/60; C07D213/78; C07D213/79; C07D213/80; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/54; A61K47/559; C07D209/00; C07D209/02; C07D209/04; C07D209/30; C07D209/32; C07D211/00; C07D211/04; C07D211/80; C07D211/84; C07D211/90; C07D213/81; C07D213/82; C07D401/00; C07D401/02; C07D401/12; C07J; C07J43/00; C07J43/003; C07K; C07K14/00; C07K14/435; C07K14/665; C07K14/70; A61K38/00

Claims Analysis

Total Claims: 56
Claim 1
Independent Claim 472 words
A compound having the structural formula ##STR1231## or a nontoxic pharmaceutically acceptable salt thereof, wherein: each R a is independently hydrogen or a hydroxyl protective group selected from the group consisting of alkanoyl having 2 to 8 carbon atoms, ##STR1232## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxyacetyl, and ##STR1233## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms; R b is hydrogen or --COOR c wherein R c is hydrogen or a carboxyl protective group selected from the group consisting of alkyl having 1 to 7 carbon atoms, alkenyl having one or two double bonds and 2 to 7 carbon atoms, cycloalkyl --C r H 2r -- wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxy, and phenyl --C r H 2r -- wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms; and [DHC] is ##STR1234## wherein: the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R o is hydrogen, methyl, --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR1235## --CH 2 OH, --CH(OH)--CH 3 , --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 , --CH 2 CH 2 --CONH 2 , ##STR1236## --CH 2 SH, --CH 2 COOH or --CH 2 CH 2 COOH; p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R o radicals can be the same or different; 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 (d') indicates a double bond in either the 2 or 3 position of the dihydroquinoline ring; R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; the carbonyl-containing grouping in formula (a') can be attached at the 2, 3 or 4 position of the dihydropyridine ring; the carbonyl-containing grouping in formula (d') can be attached at the 2, 3 or 4 position of the dihydroquinoline ring; and the carbonyl-containing grouping in formula (g') can be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring.
Claim 2
Dependent Claim 472 words
A compound having the structural formula ##STR1231## or a nontoxic pharmaceutically acceptable salt thereof, wherein: each R a is independently hydrogen or a hydroxyl protective group selected from the group consisting of alkanoyl having 2 to 8 carbon atoms, ##STR1232## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxyacetyl, and ##STR1233## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms; R b is hydrogen or --COOR c wherein R c is hydrogen or a carboxyl protective group selected from the group consisting of alkyl having 1 to 7 carbon atoms, alkenyl having one or two double bonds and 2 to 7 carbon atoms, cycloalkyl --C r H 2r -- wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxy, and phenyl --C r H 2r -- wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms; and [DHC] is ##STR1234## wherein: the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R o is hydrogen, methyl, --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR1235## --CH 2 OH, --CH(OH)--CH 3 , --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 , --CH 2 CH 2 --CONH 2 , ##STR1236## --CH 2 SH, --CH 2 COOH or --CH 2 CH 2 COOH; p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R o radicals can be the same or different; 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 (d') indicates a double bond in either the 2 or 3 position of the dihydroquinoline ring; R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; the carbonyl-containing grouping in formula (a') can be attached at the 2, 3 or 4 position of the dihydropyridine ring; the carbonyl-containing grouping in formula (d') can be attached at the 2, 3 or 4 position of the dihydroquinoline ring; and the carbonyl-containing grouping in formula (g') can be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring.
Claim 3
Dependent Claim 18 words
A compound according to claim 1, wherein [DHC] comprises the reduced form of an N-substituted nicotinic acid derivative.
Claim 4
Dependent Claim 15 words
A compound according to claim 1, wherein [DHC] comprises the reduced form of a trigonelline.
Claim 5
Dependent Claim 11 words
A compound according to claim 1, wherein R o is hydrogen.
Claim 6
Dependent Claim 10 words
A compound according to claim 1, wherein p is 1.
Claim 7
Dependent Claim 18 words
A compound according to claim 1, wherein each R a is hydrogen and wherein R b is hydrogen.
Claim 8
Dependent Claim 17 words
A compound according to claim 1, wherein at least one R a is a hydroxyl protective group.
Claim 9
Dependent Claim 11 words
A compound according to claim 7, wherein R b is hydrogen.
Claim 10
Dependent Claim 20 words
A compound according to claim 1, wherein R b is --COOR c wherein R c is a carboxylic protective group.
Claim 11
Dependent Claim 32 words
A compound according to claim 1, wherein at least one R a is a hydroxyl protective group and wherein R b is --COOR c wherein R c is a carboxyl protective group.
Claim 12
Dependent Claim 13 words
A compound according to claim 10, said compound having the structural formula: ##STR1237##
Claim 13
Dependent Claim 12 words
A compound according to claim 1, wherein alkylene is --CH 2 --.
Claim 14
Dependent Claim 46 words
A compound according to claim 1, wherein R o is H, --CH 3 , --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR1238## --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 or --CH 2 CH 2 --CONH 2 .
Claim 15
Dependent Claim 13 words
A compound according to claim 1, wherein R 1 is CH 3 .
Claim 16
Dependent Claim 24 words
A compound according to claim 1, wherein [DHC] has formula (a') wherein the carbonyl-containing grouping is attached at the 3-position of the dihydropyridine ring.
Claim 17
Dependent Claim 24 words
A compound according to claim 1, wherein [DHC] has formula (d') wherein the carbonyl-containing grouping is attached at the 3-position of the dihydroquinoline ring.
Claim 18
Dependent Claim 24 words
A compound according to claim 1, wherein [DHC] has formula (g') wherein the carbonyl-containing grouping is attached at the 4-position of the dihydroisoquinoline ring.
Claim 19
Dependent Claim 20 words
A compound according to claim 1, wherein at least one R a is alkanoyl having 2 to 8 carbon atoms.
Claim 20
Dependent Claim 25 words
A compound according to claim 18, wherein at least one R a is acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl, 3-methylpentanoyl, 3,3-dimethylbutanoyl, or 2,2-dimethylpentanoyl.
Claim 21
Dependent Claim 17 words
A compound according to claim 19, wherein at least one R a is pivalyl, isobutyryl or isovaleryl.
Claim 22
Dependent Claim 32 words
A compound according to claim 1, wherein at least one R a is ##STR1239## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three.
Claim 23
Dependent Claim 14 words
A compound according to claim 21, wherein at least one R a is cyclohexanecarbonyl.
Claim 24
Dependent Claim 65 words
A compound according to claim 1, wherein at least one R a is ##STR1240## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms.
Claim 25
Dependent Claim 23 words
A compound according to claim 1, wherein R b is --COOR c wherein R c is alkyl having 1 to 7 carbon atoms.
Claim 26
Dependent Claim 14 words
A compound according to claim 24, wherein R c is ethyl, isopropyl or t-butyl.
Claim 27
Dependent Claim 42 words
A method for site-specifically/sustainedly eliciting a dopaminergic response in the brain, comprising administering to an animal in need of such treatment a quantity of a compound as defined by claim 1 sufficient to elicit a pharmacologically effective dopaminergic response in the brain.
Claim 28
Dependent Claim 41 words
A method according to claim 26, 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.
Claim 29
Dependent Claim 52 words
A pharmaceutical composition of matter, in unit dosage form, for use in eliciting a dopaminergic response in the brain, said composition comprising: (i) an amount of a compound as defined by claim 1 sufficient to elicit a pharmacologically effective dopaminergic response in the brain; and (ii) a non-toxic pharmaceutically acceptable carrier therefor.
Claim 30
Dependent Claim 17 words
A pharmaceutical composition as claimed in claim 28, said composition being a pharmaceutically acceptable sustained release composition.
Claim 31
Dependent Claim 455 words
A quaternary salt having the structural formula ##STR1241## wherein: each R a is independently hydrogen or a hydroxyl protective group selected from the group consisting of alkanoyl having 2 to 8 carbon atoms, ##STR1242## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxyacetyl and ##STR1243## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms; R b is hydrogen or --COOR c wherein R c is hydrogen or a carboxyl protective group selected from the group consisting of alkyl having 1 to 7 carbon atoms, alkenyl having one or two double bonds and 2 to 7 carbon atoms, cycloalkyl --C r H 2r -- wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxy, and phenyl --C r H 2r -- wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms; [QC + ] is ##STR1244## wherein: the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R o is hydrogen, methyl, --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR1245## --CH 2 OH, --CH(OH)--CH 3 , --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 , --CH 2 CH 2 --CONH 2 , ##STR1246## --CH 2 SH, --CH 2 COOH or --CH 2 CH 2 COOH; p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R o radicals can be the same or different; R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; the carbonyl-containing grouping in formula (a) can be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl-containing grouping in formula (d) can be attached at the 2, 3 or 4 position of the quinolinium ring; the carbonyl-containing grouping in formula (g) can be attached at the 1, 3 or 4 position of the isoquinolinium ring; Y- is the anion of a pharmaceutically acceptable organic or inorganic acid; t is the valence of the acid anion; and q is the number which when multiplied by t is equal to one.
Claim 32
Dependent Claim 455 words
A quaternary salt having the structural formula ##STR1241## wherein: each R a is independently hydrogen or a hydroxyl protective group selected from the group consisting of alkanoyl having 2 to 8 carbon atoms, ##STR1242## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxyacetyl and ##STR1243## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms; R b is hydrogen or --COOR c wherein R c is hydrogen or a carboxyl protective group selected from the group consisting of alkyl having 1 to 7 carbon atoms, alkenyl having one or two double bonds and 2 to 7 carbon atoms, cycloalkyl --C r H 2r -- wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three, phenoxy, and phenyl --C r H 2r -- wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms; [QC + ] is ##STR1244## wherein: the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R o is hydrogen, methyl, --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR1245## --CH 2 OH, --CH(OH)--CH 3 , --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 , --CH 2 CH 2 --CONH 2 , ##STR1246## --CH 2 SH, --CH 2 COOH or --CH 2 CH 2 COOH; p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R o radicals can be the same or different; R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; the carbonyl-containing grouping in formula (a) can be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl-containing grouping in formula (d) can be attached at the 2, 3 or 4 position of the quinolinium ring; the carbonyl-containing grouping in formula (g) can be attached at the 1, 3 or 4 position of the isoquinolinium ring; Y- is the anion of a pharmaceutically acceptable organic or inorganic acid; t is the valence of the acid anion; and q is the number which when multiplied by t is equal to one.
Claim 33
Dependent Claim 21 words
A quaternary salt according to claim 30 wherein [QC + ] comprises the oxidized form of an N-substituted nicotinic acid derivative.
Claim 34
Dependent Claim 18 words
A quaternary salt according to claim 30, wherein [QC + ] comprises the oxidized form of a trigonelline.
Claim 35
Dependent Claim 12 words
A quaternary salt according to claim 30, wherein R 0 is hydrogen.
Claim 36
Dependent Claim 11 words
A quaternary salt according to claim 30, wherein p is 1.
Claim 37
Dependent Claim 19 words
A quaternary salt according to claim 30, wherein each R a is hydrogen and wherein R b is hydrogen.
Claim 38
Dependent Claim 18 words
A quaternary salt according to claim 30, wherein at least one R a is a hydroxyl protective group.
Claim 39
Dependent Claim 12 words
A quaternary salt according to claim 36, wherein R b is hydrogen.
Claim 40
Dependent Claim 21 words
A quaternary salt according to claim 30, wherein R b is --COOR c wherein R c is a carboxyl protective group.
Claim 41
Dependent Claim 33 words
A quaternary salt according to claim 30, wherein at least one R a is a hydroxyl protective group and wherein R b is --COOR c wherein R c is a carboxyl protective group.
Claim 42
Dependent Claim 13 words
A quaternary salt according to claim 30, wherein alkylene is --CH 2 --.
Claim 43
Dependent Claim 11 words
A quaternary salt according to claim 30, wherein p is 1.
Claim 44
Dependent Claim 47 words
A quaternary salt according to claim 30, wherein R 0 is H, --CH 3 , --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR1247## --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 or --CH 2 CH 2 --CONH 2 .
Claim 45
Dependent Claim 14 words
A quaternary salt according to claim 30, wherein R 1 is CH 3 .
Claim 46
Dependent Claim 27 words
A quaternary salt according to claim 30, wherein [QC + ] has formula (a) wherein the carbonyl-containing grouping is attached at the 3-position of the pyridinium ring.
Claim 47
Dependent Claim 27 words
A quaternary salt according to claim 30, wherein [QC + ] has formula (d) wherein the carbonyl-containing grouping is attached at the 3-position of the quinolinium ring.
Claim 48
Dependent Claim 27 words
A quaternary salt according to claim 30, wherein [QC + ] has formula (g) wherein the carbonyl-containing grouping is attached at the 4-position of the isoquinolinium ring.
Claim 49
Dependent Claim 21 words
A quaternary salt according to claim 30, wherein at least one R a is alkanoyl having 2 to 8 carbon atoms.
Claim 50
Dependent Claim 26 words
A quaternary salt according to claim 47, wherein at least one R a is acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl, 3-methylpentanoyl, 3,3-dimethylbutanoyl or 2,2-dimethylpentanoyl.
Claim 51
Dependent Claim 18 words
A quaternary salt according to claim 48, wherein at least one R a is pivalyl, isobutyryl or isovaleryl.
Claim 52
Dependent Claim 33 words
A quaternary salt according to claim 30, wherein at least one R a is ##STR1248## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three.
Claim 53
Dependent Claim 15 words
A quaternary salt according to claim 50, wherein at least one R a is cyclohexanecarbonyl.
Claim 54
Dependent Claim 66 words
A quaternary salt according to claim 30, wherein at least one R a is ##STR1249## wherein r is zero, one, two or three and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms, or alkanoylamino having 2 to 6 carbon atoms.
Claim 55
Dependent Claim 24 words
A quaternary salt according to claim 30, wherein R b is --COOR c wherein R c is alkyl having 1 to 7 carbon atoms.
Claim 56
Dependent Claim 15 words
A quaternary salt according to claim 53 wherein R c is ethyl, isopropyl or t-butyl.

References Cited (Backward Citations)

US3987175A Cited
US4065566A Cited
US4152521A Cited
US4083996A Cited
US4157396A Cited
US4143146A Cited
US4195984A Cited
US4479932A Cited
US4540564A Cited
US4532251A Cited
US4727079A Cited
US4558150A Cited
US4555520A Cited

USPTO Annuity & Maintenance Windows

Annuity Stage Window Opens Payment Deadline Surcharge Period Until Estimated Fee Status
3.5 Years (Year 4) 1992-05-08 1992-11-07 1993-05-09 $2000.00 Window Closed / Lapsed
7.5 Years (Year 8) 1996-05-08 1996-11-07 1997-05-09 $3760.00 Window Closed / Lapsed
11.5 Years (Year 12) 2000-05-08 2000-11-07 2001-05-09 $7700.00 Window Closed / Lapsed

Assigned Categories & Tags

No categories assigned to this patent yet.

Assign Category Tag