US5017566A
Expired / Lapsed
US
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Redox systems for brain-targeted drug delivery
Assignee: University of Florida
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Filing: 1989-11-03
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Granted: 1991-05-21
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Expires: 2009-11-03
Abstract
Abstract Inclusion complexes of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β- and γ-cyclodextrin with the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal forms of dihydropyridine⃡pyridinium salt redox systems for brain-targeted drug delivery provide a means for stabilizing the redox systems, particularly against oxidation. The redox inclusion complexes also provide a means for decreasing initial drug concentrations in the lungs after administration of the systems, leading to decreased toxicity. In selected instances, complexation results in substantially improved water solubility of the redox systems as well.
Inventors
- 👤 Nicholas S. Bodor
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-10 02:13
CPC Classifications
C; C07; C07D; C07D401/00; C07D401/14; A; A61; A61K; A61K31/00; A61K31/33; A61K31/395; A61K31/41; A61K31/425; A61K31/429; A61K31/43; A61K47/00; A61K47/50; A61K47/51; A61K47/54; A61K47/559; A61K47/69; A61K47/6949; A61K47/6951; B; B82; B82Y; B82Y5/00; C07C; C07C219/00; C07C219/26; C07C219/28; C07C229/00; C07C229/02; C07C229/04; C07C229/06; C07C229/08; C07C233/00; C07C233/01; C07C233/16; C07C233/17; C07C233/18; C07C271/00; C07C271/06; C07C271/08; C07C271/10; C07C271/16; C07D211/00; C07D211/04; C07D211/80; C07D211/84; C07D211/90; C07D213/00; C07D213/02; C07D213/04; C07D213/60; C07D213/78; C07D213/79; C07D213/80; C07D213/81; C07D213/82; C07D223/00; C07D223/14; C07D223/18; C07D223/22; C07D223/24; C07D223/28; C07D233/00; C07D233/54; C07D233/66; C07D233/72; C07D233/74; C07D233/76; C07D233/78; C07D243/00; C07D243/06; C07D243/10; C07D243/38; C07D401/02; C07D401/12; C07D473/00; C07D499/00; C07H; C07H19/00; C07H19/02; C07H19/04; C07H19/06; C07J; C07J43/00; C07J43/003; C08; C08B; C08B37/00; C08B37/0006; C08B37/0009; C08B37/0012; C08B37/0015; C07C2601/00; C07C2601/12; C07C2601/14
Claims Analysis
Total Claims: 75
Claim 1
Independent Claim
58 words
A method for stabilizing the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal dihydropyridine form of a dihydropyridine ⃡ pyridinium salt redox system for brain-targeted drug delivery, said method comprising complexing said dihydropyridine form with cyclodextrin selected from the group consisting of hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β-cyclodextrin and hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of τ-cyclodextrin.
Claim 2
Independent Claim
58 words
A method for stabilizing the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal dihydropyridine form of a dihydropyridine ⃡ pyridinium salt redox system for brain-targeted drug delivery, said method comprising complexing said dihydropyridine form with cyclodextrin selected from the group consisting of hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β-cyclodextrin and hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of τ-cyclodextrin.
Claim 3
Dependent Claim
44 words
A method according to claim 1, wherein said dihydropyridine form is a compound of the formula [D--DHC] 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.
Claim 4
Dependent Claim
49 words
A method according to claim 2 wherein the centrally acting drug species is a dopaminergic agent, an androgenic agent, an anticonvulsant, an anxiolytic agent, a neurotransmitter, an antibiotic or antibacterial agent, an antidepressant, an antiviral agent, an anticancer or antitumor agent, an antiinflammatory agent, an estrogen or a progestin.
Claim 5
Dependent Claim
54 words
A method according to claim 3, wherein the centrally acting drug species is dopamine, testosterone, phenytoin, GABA, valproic acid, tyrosine, methicillin, oxacillin, benzylpenicilli, cloxacillin, dicloxacillin, desipramine, acyclovir, trifluorothymidine, zidovuidine, hydroxy-CCNU, chlorambucil, tryptamine, dexamethasone, hydrocortisone, ethinyl estradiol, norethindrone, estradiol, ethisterone, norgestrel, estrone, estradiol 3-methyl ether, estradiol benzoate, norethynodrel, mestranol, indomethacin, naproxen, FENU, HENU or 5-FU.
Claim 6
Dependent Claim
21 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 1-methyl-3-{(N-{β-[3,4-bis(pivalyloxy)phenyl] ethyl}carbamoyl}}-1,4-dihydropyridine, 1-methyl-3-{N-[[β-[3,4-bis(isobutyryloxy)phenyl] ethyl]]}carbamoyl-1,4-dihydropyridine or N-{β-[3,4-bis(pivalyloxy)phenyl]ethyl}aminocarbonyloxymethyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate.
Claim 7
Dependent Claim
18 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 17β-[(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy] androst-4-en-3-one or 17β-{[(3"-carbamoyl-1',4'-dihydropyridinyl)acetyl]-oxy}androst-4-en-3-one.
Claim 8
Dependent Claim
21 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 5,5-diphenyl-3-[(1'-methyl-1',4'-dihydropyridin-3'-yl) carbonyloxymethyl]-2,4-imidazolidinedione, 3-[(3'-carbamoyl-1',4'-dihydropyridin-1'-yl)acetyloxymethyl] -5,5-diphenyl-2,4-imidazolidinedione or 3-[3'-(3"-carbamoyl-1",4"-dihydropyridin-1"-yl)propionyloxymethyl] -5,5-diphenyl-2,4-imidazolidinedione.
Claim 9
Dependent Claim
18 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 1-methyl-3-N-[3-(benzyloxycarbonyl)propyl] carbamoyl-1,4-dihydropyridine or 1-methyl-3-{N-[(3'-cyclohexylcarbonyl)propyl]}-carbamoyl-1,4-dihydropyridine.
Claim 10
Dependent Claim
19 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 1-methyl-3-[2'-(2"-propyl)pentanoyloxy] ethylcarbamoyl-1,4-dihydropyridine, 1-methyl-3-[2'-(2"-propyl)pentanoyloxy]ethoxycarbonyl1,4-dihydropyridine or 1-[2'-(2"-propyl)pentanoyloxy]-ethyl-3-carboxamide-1,4-dihydropyridine.
Claim 11
Dependent Claim
19 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 1-methyl-3-{N-[1'-ethoxycarbonyl)-2'-(4"-pivaloyloxyphenyl )ethyl] }-carbamoyl-1,4-dihydropyridine or 1-methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-isobutyryloxyphenyl)ethyl]}-carbamoyl-1,4-dihydropyridine.
Claim 12
Dependent Claim
37 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2α,5α,6β)]-3,3-dimethyl-7-oxo-6-[(2,6-dimethoxy)benzamido] -4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2α5α,6β)-3,3-dimethyl-6-(5-methyl-3-phenyl-4-isoxazolecarboxamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2α,5α6β)]-3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino] -4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, [[(1,4-dihydro1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S(2α,5α,6β)] -6-[3-(2-chlorophenyl)-5-methyl-4-isoxazolecarboxamidol-3,3-dimethyl-7-oxo-4-thia-1-aza bicyclo[3.2.0]heptane-2-carboxylate or [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2α,5α,6β)]6[ 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarboxamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylate.
Claim 13
Dependent Claim
23 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is [{N-[3-(10,11-dihydro-5h-dibenz[b,f] azepin-5-yl)]propyl-N-methlamino}carbonyloxy] methyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate or [1-{N-[3-(10,11-dihydro-5H-dibenz[b,f] azepin-5-yl)]propyl-N-methylamino}carbonyloxy] ethyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate.
Claim 14
Dependent Claim
16 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 1-methyl-3-{[2-(9-guanylmethoxy)ethoxy] carbonyl}-1,4-dihydropyridine.
Claim 15
Dependent Claim
15 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 3'-(1,4-dihydro-1methyl-3-pyridinylcarbonyl)-5'-pivaloyltrifluorothymidine.
Claim 16
Dependent Claim
16 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 3'-azido-3'-deoxy5'-(1-methyl-1,4-dihydro-3-pyridinyl)carbonyl] thymidine.
Claim 17
Dependent Claim
21 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is N-(2-chloroethyl)N'-[4-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy) cyclohexyl]-N-nitrosourea, N-(2-fluoroethyl)-N'-[2-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)ethyl] -N-nitrosourea or N-(2-chloroethyl)-N'-[2-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)ethyl] -N-nitrosourea.
Claim 18
Dependent Claim
30 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 1-methyl-3-[(N-{2-[4-({4-[bis(2-chloroethyl)] amino}phenyl)butanoyloxy]ethyl})carbamoyl] -1,4-dihydropyridine, 1-methyl-3-(N-{4-[4-(4-{[bis(2-chloroethyl)] amino}phenyl)butanoyloxy] cyclohexyl)}carbamoyl)-1,4-dihydropyridine, 1-methyl-3-[(N-{2-[4-({4-bis(2-chloroethyl)] amino}phenyl)butanoyloxy] propyl})carbamoyl]-1,4dihydropyridine, 1-methyl-3-[(N-{2-phenyl-2-({4-[bis(2-chloroethyl)] amino}phenyl)butanoyloxy]}ethyl)carbammoyl] -1,4-dihydropyridine or 1-methyl-3-[N-({1-[4-(4-{[bis(2-chloroethyl)] amino}phenyl)butanoyloxy]cyclohexyl}methyl)carbamoyl] -1,4-dihydropyridine.
Claim 19
Dependent Claim
16 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 1-methyl-3-N-[2-(3-indolyl)ethyl] carbamoyl-1,4-dihydropyridine.
Claim 20
Dependent Claim
19 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 9-fluoro-11β,17-dihydroxy-16α-methyl-21-{[(1-methyl-1,4-dihydropyridin3-yl)carbonyl] oxy}pregna-1,4-diene-3,20-dione or 11β,17-dihydroxy-21-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}pregn-4-ene-3,20-dione.
Claim 21
Dependent Claim
16 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 3-hydroxy-17β-[(1-methyl-1,4-dihydropyridin-3yl)carbonyl] oxyestra-1,3,5(10)-triene.
Claim 22
Dependent Claim
30 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 3-hydroxy-17β-{[1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}-19-nor-17α-pregna-1,3,5(10-triene-20-yne, 3-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy] estra-1,3,5(10)-trien17-one, 17β-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy] estra-1,3,5(10)-trien-3-ol 3-methyl ether, 3,17β-bis-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}estra-1,3,5(10)-triene, 3-(phenylcarbonyloxy)-17β-{[(1-methyl-1,4-dihydropyridin-3-yl) carbonyl] oxy}estra-1,3,5(10)-triene or 3-methoxy-17β-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}-19-nor-17α-pregna-1,3,5(10)-trien-20-yne.
Claim 23
Dependent Claim
24 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 17β-}[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}-19-norpregn-4-en-20-yn-3-one, 17β-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}pregn-4-en-20-yn-3-one, 13-ethyl-17β-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl ] oxy}-18,19-dinorpregn-4-en-20-yn-3-one or 17β-{[(1-methyl-1,4-dihydropyridin-3yl)carbonyl] oxy}-19-norpregn-5(10)-en-20-yn-3-one.
Claim 24
Dependent Claim
19 words
A method according to claim 4 wherein the compound of the formula [D-DHC] is 1-methyl-3-[N-(2-{1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoyl] -acetoxy}ethyl)carbamoyl]-1,4-dihydropyridine or 1-methyl-3-{N-[2-(6-methoxy-α-methyl-2-naphthalenylacetoxy)ethyl] carbamoyl-1,4-dihydropyridine.
Claim 25
Dependent Claim
17 words
A method according to claim 4, wherein the compound of the formula [D-DHC] is 3-(1,4-dihydro-1-methyl-3-pyridinylcarbonyloxymethyl)-5-fluorouracil or 1-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxymethyl-5-fluorouracil.
Claim 26
Independent Claim
71 words
A method for decreasing initial lung concentrations of drug resulting from administration of the reduced, booxidizable, blood-brain barrier penetrating, lipoidal dihydropyridine form of a dihydropyridine ⃡ pyridinium salt redox system for brain-targeted drug delivery, said method comprising administering said dihydropyridine form as its inclusion complex with cyclodextrin selected from the group consisting of hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β-cyclodextrin and hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of τ-cyclodextrin.
Claim 27
Independent Claim
71 words
A method for decreasing initial lung concentrations of drug resulting from administration of the reduced, booxidizable, blood-brain barrier penetrating, lipoidal dihydropyridine form of a dihydropyridine ⃡ pyridinium salt redox system for brain-targeted drug delivery, said method comprising administering said dihydropyridine form as its inclusion complex with cyclodextrin selected from the group consisting of hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β-cyclodextrin and hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of τ-cyclodextrin.
Claim 28
Dependent Claim
44 words
A method according to claim 25, wherein said dihydropyridine form is a compound of the formula [D--DHC] wherein [D] is a centrally acting drug species and [DHC] is the reduced, booxidizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine ⃡ pyridinium salt redox carrier.
Claim 29
Dependent Claim
49 words
A method according to claim 26, wherein the centrally acting drug species is a dopaminergic agent, an androgenic agent, an anticonvulsant, an anxiolytic agent, a neurotransmitter, an antibiotic or antibacterial agent, an antidepressant, an antiviral agent, an anticancer or antitumor agent, an antiinflammatory agent, an estrogen or a progestin.
Claim 30
Dependent Claim
54 words
A method according to claim 27, wherein the centrally acting drug species is dopamine, testosterone, phenytoin, GABA, valproic acid, tyrosine, methicillin, oxacillin, benzylpenicillin, cloxacillin, dicloxacillin, desipramine, acyclovir, trifluorothymidine, zidovudine, hydroxy-CCNU, chlorambucil, tryptamine, dexamethasone, hydrocortisone, ethinyl estradoiol, norethindrone, estradiol, ethisterone, norgestrel, entrone, estradiol 3-methyl ether, estradiol benzoate, norethynodrel, mestranol, indomethacin, naproxen, FENU, HENU or 5-FU.
Claim 31
Dependent Claim
21 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 1-methyl-3-{{N-{β-[3,4-bis(dipivalyloxy)phenyl] ethyl}carbamoyl}}-1,4-dihydropyridine, 1-methyl-3-{N-[[β-[3,4-bis(isobutyryloxy)phenyl] ethyl]]}carbamoyl-1,4-dihydropyridine or N-{β-[3,4-bis(pivalyloxy)phenyl]-ethyl}aminocarbonyloxymethyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate.
Claim 32
Dependent Claim
17 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 17β-[(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy]androst-4-en-3-one or 17β-}[(3"-carbamoyl-1',4"-dihydropyridinyl)acetyl]-oxy}androst-4-en-3-one.
Claim 33
Dependent Claim
21 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 5,5-diphenyl-3-[(1'-methyl-1',4'-dihydropyridin-3'-yl(carbonyloxymethyl] 2,4-imidazolidinedione, 3-[(3'-carbamoyl-1',4'-dihydropyridin-1'-yl)acetyloxymethyl] -5,5-diphenyl-2,4-imidazolidinedione or 3-[3'-(3"-carbamoyl-1",4"-dihydropyridin-1"-yl)propionyloxymethyl] -5,5-diphenyl-2,4-imidazolidinedione.
Claim 34
Dependent Claim
18 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 1-methyl-3-N-[3-(benzyloxycarbonyl)propyl] carbamoyl-1,4-dihydropyridine or 1-methyl-3-{N-[(3'-cyclohexylcarbonyl)propyl[}-carbamoyl-1,4-dihydropyridine.
Claim 35
Dependent Claim
20 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 1-methyl-3-[2'-(2"-propyl)pentanoyloxy] ethylcarbamoyl-1,4-dihydropyridine, 1-methyl-3[2'-(2"-propyl)pentanoyloxy]ethoxycarbonyl-1,4-dihydropyridine or 1-[2'-(2"-propyl)pentanoyloxy] -ethyl-3-carboxamide-1,4-dihydropyridine.
Claim 36
Dependent Claim
19 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 1-methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-pivaloyloxyphen yl)ethyl]}-carbamoyl-1,4-dihydropyridine or 1-methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-isobutyryloxyphenyl)ethyl] }-carbamoyl-1,4-dihydropyridine.
Claim 37
Dependent Claim
36 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2α,5α,6β)]-3,3-dimethyl-7-oxo-6-[(2,6-dimethoxy)benzamido] -4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2α,5α,6β)-3,3-dimethyl-6-(5-methyl-3-phenyl-4-isoxazolecarboximido)-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2α,5α,6β)]-3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino] -4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [[2S-(2α,5α,6β)]-6-[3-(2-chlorophenyl)-5-methyl-4-isoxazolecarboxamido ] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate or [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxo]methyl [2S-(2α,5α,6β)]-6-[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarboxamido ] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate.
Claim 38
Dependent Claim
23 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is [{N-[3-(10,11-dihydro-5H-dibez[b,f] azepin-5-yl)]propyl-N-methylamino}carbonyloxy] methyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate or [1-{N-[3-(10,11-dihydro-5H-dibenz[b,f] azepin-5yl)]propyl-N-methylamino}carbonyloxy] ethyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate.
Claim 39
Dependent Claim
16 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 1-methyl-3-{[2-(9-guanylmethoxy)ethoxy] carbonyl}-1,4-dihydropyridine.
Claim 40
Dependent Claim
16 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 3'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)-5'-pivaloyltrifluoro thymidine.
Claim 41
Dependent Claim
16 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 3'-azido-3'-deoxy-5'-(1-methyl-1,4-dihydro-3-pyridinyl)carbonyl] thymidine.
Claim 42
Dependent Claim
22 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is N-(2-chloroethyl)-N'-[4-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy )-cyclohexyl] -N-nitrosourea, N-(2-fluoroethyl)-N'-[2-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)ethyl] -N-nitrosourea or N-(2-chloroethyl)-N'-[2-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)ethyl] -N-nitrosourea.
Claim 43
Dependent Claim
23 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 1-methyl-3-[(N-{2-[4-({4[bis(2-chloroethyl)] amino}phenyl)butanoyloxy]-ethyl})carbamoyl] -1,4-dihydropyridine, 1-methyl-3-(N-{4-[4-(4-{[bis(2-chloroethyl)] amino}phenyl)butanoyl-oxy] cyclohexyl}carbamoyl)-1,4-dihydropyridine, 1-methyl-3-[(N-{2[4-({4-bis(2-chloroethyl)] amino}-phenyl)butanoyloxy]cyclohexyl}-methyl)carbamoyl] -1,4-dihydropyridine.
Claim 44
Dependent Claim
16 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 1-methyl-3-N-[2-(3-indolyl)ethyl] carbamoyl-1,4-dihydropyridine.
Claim 45
Dependent Claim
19 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 9-fluoro-11β,17-dihydroxy-16α-methyl-21-{[(1-methyl-1,4-dihydropyridin-3yl)carbonyl] oxy}pregna-1,4-diene-3,20-dione or 11β,17-dihydroxy-21-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}pregn-4-ene-3,20-dione.
Claim 46
Dependent Claim
16 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 3-hydroxy-17β-[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxyestra-1,3,5(10)-triene.
Claim 47
Dependent Claim
30 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 3-hydroxy-17β-}[1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}-19-nor-17α-pregna-1,3,5(10)-trien-20-yne, 3-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy] estra-1,3,5(10)-trien-17-one, 17β-[(1-methyl-1,4-dihydro-3-pyridinyl)-carbonyloxy] estra-1,3,5(10)-trien-3-ol 3-methyl ether, 3,17β-bis-{[(1-methyl-1,4-dihydropyridin3-yl)carbonyl] oxy}estra-1,3,5(10)-triene, 3-(phenylcarbonyloxy)-17β-{[(1-methyl-1,4-dihydropyridin-3-yl) -carbonyl]oxy}estra-1,3,5(10)-triene or 3-methoxy-17β-}[1-methyl-1,4-dihydropyridin-3-yl )carbonyl] oxy}-19-nor-17α-pregna-1,3,5(10)-trien-20-yne.
Claim 48
Dependent Claim
23 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 17β-}[(1-methyl-1,4-dihydropyridin-3yl)carbonyl] oxy}-19-norpregn-4-en-20-yn-3-one, 17β-{[(1-methyl-1,4-dihydropyridin-3yl)-carbonyl] oxy}pregn-4-en-20-yn-3-one, 13-ethyl-17β-{[(1-methyl-1,4-dihydropyridin-3yl)carbonyl] oxy}-18,19-dinorpregn-4-en-20-yn-3-one or 17β-{[(1-methyl-1,4-dihydropyridin-3yl)carbonyl]oxy}-19-norpregn-5(10)-en-20-yn -3-one.
Claim 49
Dependent Claim
20 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 1-methyl-3-[N-(2-{1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3 -indolyl] -acetoxy}ethyl)carbamoyl]-1,4-dihydropyridine or 1-methyl-3-{N-[2-(6-methoxy-α-methyl-2-naphthalenyl-acetoxy)ethyl] carbamoyl-1,4-dihydropyridine.
Claim 50
Dependent Claim
17 words
A method according to claim 28, wherein the compound of the formula [D-DHC] is 3-(1,4-dihydro-1-methyl-3-pyridinylcarbonyloxymethyl)-5-fluorouracil or 1-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxymethyl)-5-fluorouracil.
Claim 51
Independent Claim
76 words
A method for decreasing the tendency of the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal dihydropyridine form of a dihydropyridine ⃡ pyridinium salt redox system for brain-targeted drug delivery to provide high initial concentrations of drug in the lungs following administration, said method comprising complexing said dihydropyridine form with cyclodextrin selected from the group consisting of hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β-cyclodextrin and hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of τ-cyclodextrin prior to administration.
Claim 52
Independent Claim
76 words
A method for decreasing the tendency of the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal dihydropyridine form of a dihydropyridine ⃡ pyridinium salt redox system for brain-targeted drug delivery to provide high initial concentrations of drug in the lungs following administration, said method comprising complexing said dihydropyridine form with cyclodextrin selected from the group consisting of hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β-cyclodextrin and hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of τ-cyclodextrin prior to administration.
Claim 53
Dependent Claim
44 words
A method according to claim 49 wherein said dihydropyridine form is a compound of the formula [D--DHC] wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxodizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine ⃡ pyridinium salt redox carrier.
Claim 54
Dependent Claim
49 words
A method according to claim 30, wherein the centrally acting drug species is a dopaminergic agent, an androgenic agent, an anticonvulsant, an anxiolytic agent, a neurotransmitter, an antibiotic or antibacterial agent, an antidepressant, an antiviral agent, an anticancer or antitumor agent, an antiinflammatory agent, an estrogen or a progestin.
Claim 55
Dependent Claim
54 words
A method according to claim 51, wherein the centrally acting drug species is dopamine, testosterone, phenytoin, GABA, valproic acid, tyrosine, methicillin, oxacillin, benzylpenicillin, cloxacillin, dicloxacillin, desipramine, acyclovir, trifluorothymidine, zidovudine, hydroxy-CCNU, chlorambucil, tryptamine, dexamethasone, hydrocortisone, ethinyl estradiol, norethindrone, estradiol, ethisterone, norgestrel, estrone, estradiol 3-methyl ether, estradiol benzoate, norethynodrel, mestranol, indomethacin, naproxen, FENU, HENU or 5-FU.
Claim 56
Dependent Claim
21 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 1-methyl-3-}}N-}β-[3,4-bis(pivalyloxy)phenyl] ethyl}carbamoyl}}-1,4-dihydropyridine, 1-methyl-3-{N-[[β-[3,4-bis(isobutyryloxy)phenyl] ethyl]]}carbamoyl-1,4-dihydropyridine or N-{β-[3,4-bis(pivalyloxy)phenyl]ethyl}aminocarbonyloxymethyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate.
Claim 57
Dependent Claim
18 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 17β-[(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy] androst-4-en-3-one or 17β-{[(3"-carbamoyl-1',4"-dihydropyridinyl)acetyl]-oxy}androst-4-en-3-one.
Claim 58
Dependent Claim
21 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 5,5-diphenyl-3-[(1'-methyl-1',4'-dihydropyridin-3'-yl)carbonyloxymethyl] -2,4-imidazolidinedione, 3-[(3'-carbamoyl-1',4'-dihydropyridin-1'-yl)acetyloxymethyl] -5,5-diphenyl-2,4-imidazolidinedione or 3-[3'-(3"-carbamoyl-1",4"-dihydropyridin-1"-yl)propionyloxymethyl] -5,5-diphenyl-2,4imidazolidinedione.
Claim 59
Dependent Claim
18 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 1-methyl-3-N-[3-(benzyloxycarbonyl)propyl] carbamoyl-1,4-dihydropyridine or 1-methyl-3-N-[(3'-cyclohexylcarbonyl)propyl]}-carbamoyl-1,4-dihydrooyridine.
Claim 60
Dependent Claim
19 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 1-methyl-3-[2'-(2"-propyl)pentanoyloxy] ethylcarbamoyl-1,4-dihydropyridine, 1-methyl-3-[2'-(2"-propyl)pentanoyloxy]ethoxycarbonyl-1,4-dihydropyridine or 1-[2'-(2"-propyl)pentanoyloxy]-ethyl-3-carboxamide-1,4-dihydropyridine.
Claim 61
Dependent Claim
21 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 1-methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-pivaloyloxypheny l)ethyl] }-carbamoyl-1,4-dihydropyridine or 1-methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-isobutyryloxy phenyl)ethyl] }-carbamoyl-1,4-dihydropyridine.
Claim 62
Dependent Claim
38 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2-(2α,5α,6β)]-3,3-dimethyl-7-oxo-6-F-(2,6-dimethoxy)benzamido] -4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S(2α,5α,6β)-3,3-dimethyl-6-(5-methyl-3-phenyl-4-isoxazolecarboxamido)-7 oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2α,5α,6β)]-3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino] -4-thia-1azabicyclo[3.2.0]heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S(2α,5α,6β)] -6-[3-(2-chlorophenyl)-5-methyl-4-isoxazolecarboxamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo-3.2.0]heptane-2-carboxylate or [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl] oxy]methyl [2S-(2α,5α,6β)] -6-[-3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarboxamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate.
Claim 63
Dependent Claim
21 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is [{N-[3-(10,11-dihydro-5H-dibenz[b,f] azepin-5-yl)]propyl-N-methylamino}carbonyloxy] methyl 1,4-dihydro-1-methyl-3pyridinecarboxylate dibenz[b,f]-lazepin-5-yl)]propyl-N-methylamino}carbonyl-oxy] ethyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate.
Claim 64
Dependent Claim
16 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 1-methyl-3-{[2-(9-guanylmethoxy)ethoxy] carbonyl}-1,4-dihydropyridine.
Claim 65
Dependent Claim
16 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 3'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)-5'-pivaloyltrifluoro thymidine.
Claim 66
Dependent Claim
17 words
A method according to claim 52, wherein the compound of the formula [0-DHC] is 3'-azido-3'-deoxy-5'-(1-methyl-1,4-dihydro-3-pyridin yl)carbonyl] thymidine.
Claim 67
Dependent Claim
20 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is N-(2-chloroethyl)-N'-[4-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy )ethyl] -N-nitrosourea or N-(2-fluoroethyl)-N'-[2-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)ethyl] -N-nitrosourea.
Claim 68
Dependent Claim
23 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 1-methyl-3-[(N-{2[ 4-({4-[bis(2-chloroethyl)] amino}phenyl)butanoyloxy]-ethyl})carbamoyl]-1,4-dihydropyridine, 1-methyl-3-(N-4-[4-(4-[bis(2-chloroethyl)] amino}phenyl)butanoyloxy] cyclohexyl}carbamoyl)-1,4-dihydropyridine, 1-methyl-3-[(N-{2-[4-({4-bis(2-chloroethyl)] amino}phenyl)butanoyloxy] cyclohexyl}-methyl)carbamoyl]-1,4-dihydropyridine.
Claim 69
Dependent Claim
16 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 1-methyl-3-N-[2-(3-indolyl)ethyl] carbamoyl-1,4-dihydropyridine.
Claim 70
Dependent Claim
19 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 9-fluoro-11β,17-dihydroxy-16α-methyl-21-}[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxypregna-1,4-diene-3,20-dione or 11β,17-dihydroxy-21-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}pregn-4-ene-3,20-dione.
Claim 71
Dependent Claim
16 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 3-hydroxy-17β-[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxyestra-1,3,5(10)-triene.
Claim 72
Dependent Claim
27 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 3-hydroxy-17β-}[1-methyl-1,4-dihydrooyridin-3-yl)carbonyl] oxy}-19-nor-17α-pregna-1,3,5(10-trien-20-yne, 3-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy] estra-1,3,5(10)-trien17-one, 17β-[(1-methyl-1,4-dihydro-3-pyridinyl)-carbonyloxy] estra-1,3,5(10)-trien-3-ol 3-methyl ether, 3,17β-bis-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}estra-1,3,5(10)-triene or 3-methoxy-17β-{[1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}-19-nor-17α-pregna-1,3,5(10)-trien-20-yne.
Claim 73
Dependent Claim
23 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 17β-{[(1-methyl-1,4-dihydropyridin-3yl)carbonyl] oxy}-19-norpregn-4-en-20-yn-3-one, 17β-{[(1-methyl-1,4-dihydropyridin-3-yl)-carbonyl] oxy}pregn-4-en-20yn-3-one, 13ethyl-17β-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}-18,19-dinorpregn-4-en-20-yn-3-one or 17β-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl] oxy}-19-norpregn-5(10)-en-20-yn-3-one.
Claim 74
Dependent Claim
19 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 1-methyl-3-[N-(2-{1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoyl] -acetoxy}ethyl)carbamoyl]-1,4-dihydropyridine or 1-methyl-3-{N-[2-(6-methoxy-α-methyl-2-naphthalenylacetoxy)ethyl] carbamoyl-1,4-dihydropyridine.
Claim 75
Dependent Claim
17 words
A method according to claim 52, wherein the compound of the formula [D-DHC] is 3-(1,4-dihydro-1-methyl-3-pyridinylcarbonyloxymethyl)-5-fluorouracil or 1-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxymethyl)-5-fluorouracil.
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