Patent US3552349A successfully refreshed from Google Patents.
Patent US4727079A successfully refreshed from Google Patents.
US4727079A
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US
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Brain-specific dopaminergic activity involving dihydropyridine carboxamides, dihydroquinoline and isoquinoline carboxamides
Assignee: University of Florida
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Filing: 1985-05-13
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Granted: 1988-02-23
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Expires: 2005-05-13
Abstract
Abstract A brain-specific dopaminergic response is elicited in a patient in need of such treatment, e.g., a patient afflicted with Parkinson's disease of hyperprolactinemia, by administering thereto a therapeutically effective amount of preferably catechol protected dopamine tethered to a reduced, blood-brain barrier penetrating lipoidal form [D-DHC] of a dihydropyridine⃡pyridinium salt type redox carrier, e.g., 1,4-dihydrotrigonelline. Oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt type dopamine/carrier entity [D-QC] + prevents elimination thereof from the brain, while elimination from the general circulation is accelerated, resulting in significant and prolongedly sustained brain-specific dopaminergic activity.
Inventors
- 👤 Nicholas S. Bodor
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-26 12:18
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: 42
Claim 1
Independent Claim
241 words
A compound having the formula ##STR42## or a non-toxic pharmaceutically acceptable salt thereof, wherein each R is independently hydrogen or an acyl radical selected from the group consisting of alkanoyl having 2 to 8 carbon atoms; ##STR43## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; and ##STR44## 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 ##STR45## 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 (d') indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring system; R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; the ##STR46## substituent in formula (a') can be in the 2, 3 or 4 position on the dihydropyridine ring; the ##STR47## substituent in formula (d') can be in the 2, 3 or 4 position on the dihydroquinoline ring system; and the ##STR48## substituent in formula (g') can be in the 1, 3 or 4 position of the dihydroisoquinoline ring system.
Claim 2
Dependent Claim
241 words
A compound having the formula ##STR42## or a non-toxic pharmaceutically acceptable salt thereof, wherein each R is independently hydrogen or an acyl radical selected from the group consisting of alkanoyl having 2 to 8 carbon atoms; ##STR43## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; and ##STR44## 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 ##STR45## 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 (d') indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring system; R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; the ##STR46## substituent in formula (a') can be in the 2, 3 or 4 position on the dihydropyridine ring; the ##STR47## substituent in formula (d') can be in the 2, 3 or 4 position on the dihydroquinoline ring system; and the ##STR48## substituent in formula (g') can be in the 1, 3 or 4 position of the dihydroisoquinoline ring system.
Claim 3
Dependent Claim
45 words
A compound as defined by claim 1, wherein [DHC] is ##STR49## wherein the ##STR50## substituent in formula (i) can be in the 2, 3 or 4 position on the ring; and R 1 is C 1 -C 7 alkyl or C 7 -C 10 aralkyl.
Claim 4
Dependent Claim
14 words
A compound as defined by claim 1, wherein at least one R is hydrogen.
Claim 5
Dependent Claim
12 words
A compound as defined by claim 1, wherein both R's are hydrogen.
Claim 6
Dependent Claim
16 words
A compound as defined by claim 1, wherein at least one R is an acyl group.
Claim 7
Dependent Claim
13 words
A compound as defined by claim 1, wherein both R's are acyl groups.
Claim 8
Dependent Claim
20 words
A compound as defined by claim 1, wherein at least one R is alkanoyl having 2 to 8 carbon atoms.
Claim 9
Dependent Claim
25 words
A compound as defined by claim 1, wherein at least one R is acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl, 3-methylpentanoyl, 3,3-dimethylbutanoyl or 2,2-dimethylpentanoyl.
Claim 10
Dependent Claim
20 words
A compound as defined by claim 1, wherein one R is pivalyl and the other R is hydrogen or pivalyl.
Claim 11
Dependent Claim
20 words
A compound as defined by claim 1, wherein one R is isobutyryl and the other R is hydrogen or isobutyryl.
Claim 12
Dependent Claim
32 words
A compound as defined by claim 1, wherein at least one R is ##STR51## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three.
Claim 13
Dependent Claim
31 words
A compound as defined by claim 1, wherein at least one R is cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl, cyclopropaneacetyl, α-methylcyclopropaneacetyl, 1-methylcyclopropaneacetyl, cyclopropanepropionyl, α-methylcyclopropanepropionyl, 2-isobutylcyclopropanepropionyl, cyclobutanecarbonyl, 3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl, 2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclopentanecarbonyl, cyclohexaneacetyl, cyclohexanecarbonyl, cycloheptanecarbonyl or cycloheptanepropionyl.
Claim 14
Dependent Claim
65 words
A compound as defined by claim 1, wherein at least one R is ##STR52## 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 15
Dependent Claim
64 words
A compound as defined by claim 1, wherein at least one R is benzoyl, phenylacetyl, α-phenylpropionyl, β-phenylpropionyl, p-toluyl, m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl, 3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl, m-methylphenylacetyl, p-isobutylphenylacetyl, β-(p-ethylphenyl)propionyl, p-anisoyl, m-anisoyl, o-anisoyl, m-isopropoxybenzoyl, p-methoxyphenylacetyl, m-isobutoxyphenylacetyl, m-diethylaminobenzoyl, 3-methoxy-4-ethoxybenzoyl, 3,4,5-trimethoxybenzoyl, p-dibutylaminobenzoyl, p-n-butoxybenzoyl, 2,4,6-triethoxybenzoyl, 3,4-diethoxyphenylacetyl, β-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl, m-bromobenzoyl, p-chlorobenzoyl, p-fluorobenzoyl, 2-bromo-4-chlorobenzoyl, 2,4,6-trichlorobenzoyl, p-chlorophenylacetyl, α-(m-bromophenyl)propionyl, p-trifluoromethylbenzoyl, 2,4-di(trifluoromethyl)benzoyl, m-trifluoromethylphenylacetyl, β-(p-trifluoromethylphenyl)propionyl, 2-methyl-4-methoxybenzoyl, 3-chloro-4-ethoxybenzoyl, β-(3-methyl-4-chlorophenyl)propionyl, p-dimethylaminobenzoyl, p-(N-methyl-N-ethylamino)benzoyl, o-acetamidobenzoyl, m-propionamidobenzoyl, 3-chloro-4-acetamidophenylacetyl or p-acetamidophenylpropionyl.
Claim 16
Dependent Claim
11 words
A compound as defined by claim 1, wherein [DHC] is ##STR53##
Claim 17
Dependent Claim
12 words
The compound as defined by claim 1, having the structural formula: ##STR54##
Claim 18
Dependent Claim
12 words
The compound as defined by claim 1, having the structural formula: ##STR55##
Claim 19
Dependent Claim
12 words
The compound as defined by claim 1, having the structural formula: ##STR56##
Claim 20
Dependent Claim
12 words
The compound as defined by claim 1, having the structural formula: ##STR57##
Claim 21
Dependent Claim
24 words
A pharmaceutical composition of matter comprising an effective amount of a compound as defined by claim 1 and a nontoxic pharmaceutically acceptable carrier therefor.
Claim 22
Dependent Claim
54 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 effective amount 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 23
Dependent Claim
17 words
A pharmaceutical composition as defined by claim 21, said composition being a pharmaceutically acceptable sustained release composition.
Claim 24
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 25
Dependent Claim
42 words
A method as defined by claim 23, 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 capably of slowly releasing the compound into the body.
Claim 26
Dependent Claim
33 words
A method for the treatment of Parkinsonism, comprising administering to a patent afflicted with Parkinson's disease a quantity of a compound as defined by claim 1 sufficient to elicit an effective antiParkinsonism response.
Claim 27
Dependent Claim
46 words
A method for the treatment of hyperprolactinemia or an associate disorder in a patient afflicted with same, comprising administering to said patient a quantity of a compound as defined by claim 1 sufficient to elicit a pharmacologically effective lowering of the prolactin level in said patient.
Claim 28
Dependent Claim
19 words
A compound as defined by claim 1, wherein [DHC] comprises the reduced form of an N-substituted nicotinic acid derivative.
Claim 29
Dependent Claim
17 words
A compound as defined by claim 1, wherein [DHC] comprises the reduced form of an N-substituted isoquinoline.
Claim 30
Dependent Claim
197 words
A compound having the formula ##STR58## wherein each R is independently hydrogen or an acyl radical selected from the group consisting of alkanoyl having 2 to 8 carbon atoms; ##STR59## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; and ##STR60## 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; X - is an anion derived from a non-toxic, pharmaceutically acceptable acid; and [QC] + is ##STR61## wherein R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; the ##STR62## substituent in formula (a) can be in the 2, 3 or 4 position of the pyridinium ring; the ##STR63## substituent in formula (d) can be in 2, 3 or 4 position of the quinolinium ring system; and the ##STR64## substituent in formula (g) can be in the 1, 3 or 4 position of the isoquinolinium ring system.
Claim 31
Dependent Claim
197 words
A compound having the formula ##STR58## wherein each R is independently hydrogen or an acyl radical selected from the group consisting of alkanoyl having 2 to 8 carbon atoms; ##STR59## wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; and ##STR60## 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; X - is an anion derived from a non-toxic, pharmaceutically acceptable acid; and [QC] + is ##STR61## wherein R 1 is C 1 -C 7 alkyl, C 1 -C 7 haloalkyl or C 7 -C 10 aralkyl; the ##STR62## substituent in formula (a) can be in the 2, 3 or 4 position of the pyridinium ring; the ##STR63## substituent in formula (d) can be in 2, 3 or 4 position of the quinolinium ring system; and the ##STR64## substituent in formula (g) can be in the 1, 3 or 4 position of the isoquinolinium ring system.
Claim 32
Dependent Claim
46 words
A compound as defined by claim 29, wherein [QC] + is ##STR65## wherein the ##STR66## substituent in formula (i) can be in the 2, 3 or 4 position on the ring; and R 1 is C 1 -C 7 alkyl or C 7 -C 10 aralkyl.
Claim 33
Dependent Claim
14 words
A compound as defined by claim 29, wherein at least one R is hydrogen.
Claim 34
Dependent Claim
16 words
A compound as defined by claim 29, wherein at least one R is an acyl group.
Claim 35
Dependent Claim
13 words
A compound as defined by claim 29, wherein both R's are acyl groups.
Claim 36
Dependent Claim
20 words
A compound as defined by claim 29, wherein at least one R is alkanoyl having 2 to 8 carbon atoms.
Claim 37
Dependent Claim
25 words
A compound as defined by claim 29, wherein at least one R is acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl, 3-methylpentanoyl, 3,3-dimethylbutanoyl or 2,2-dimethylpentanoyl.
Claim 38
Dependent Claim
20 words
A compound as defined in claim 29, wherein one R is pivalyl and the other R is hydrogen or pivalyl.
Claim 39
Dependent Claim
20 words
A compound as defined by claim 29, wherein one R is isobutyryl and the other R is hydrogen or isobutyryl.
Claim 40
Dependent Claim
12 words
A compound as defined by claim 29, wherein [QC] + is ##STR67##
Claim 41
Dependent Claim
35 words
A compound as defined by claim 29, having the structural formula ##STR68## wherein each R is H or wherein each R is --COCH 3 , and wherein X - is as defined in claim 29.
Claim 42
Dependent Claim
40 words
A compound as defined by claim 29, having the structural formula ##STR69## wherein each R is --COC(CH 3 ) 3 or wherein each R is --COCH(CH 3 ) 2 , and wherein X - is as defined in claim 29.
References Cited (Backward Citations)
US4479932A
Cited
US4540564A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1991-02-22 | 1991-08-24 | 1992-02-23 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1995-02-22 | 1995-08-24 | 1996-02-23 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1999-02-22 | 1999-08-24 | 2000-02-23 | $7700.00 | Window Closed / Lapsed |