US 5,475,007 AGranted

1,2,3,4-tetrahydroquinoline-2,3,4-trione-3 or 4-oximes and the use thereof

AssigneesThe Regents of the University of California, State of Oregon, acting by and through the Oregon State Board of Higher Education, acting for and on behalf of the Oregon Health Sciences University and the University of Oregon

InventorsSui X. Cai, John F. W. Keana, Eckard Weber

Life of this patent

Estimating the term…

Abstract

Methods of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, as well as treating anxiety, chronic pain, convulsions and inducing anesthesia are disclosed by administering to an animal in need of such treatment a substituted or unsubstituted 1,2,3,4-tetrahydroquinoline-2,3,4-trione-3 or 4-oxime or pharmaceutically acceptable salts thereof which have high binding to the glycine receptor.

Claims10

Dependent claims

A method of treating or preventing convulsions, comprising administering to a mammal in need of such treatment or prevention a therapeutically effective amount of an excitatory amino acid antagonizing compound of the formula ##STR13## or a pharmaceutically acceptable salt thereof;

wherein one of X or Y is oxygen and the other of X or Y is N--OR, where R is
A.sup.1) hydrogen,
B.sup.1) alkyl of from 1 to 4 carbon atoms,
C.sup.1) aryl selected from the group consisting of phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl,
D.sup.1) heteroaryl selected from the group consisting of thienyl, benzo(b)thienyl, naphtho(2,3-b)thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, isoquinolyl, quinolyl, carbazolyl, isothiazolyl, isoxazolyl, and furazanyl groups,
E.sup.1) alkanoyl of from 2 to 6 carbon atoms,
F.sup.1) alkanoyl as in E.sup.1 substituted with at least one halogen or
G.sup.1) aryloyl which is the aryl of C.sup.1 substituted with a carbonyl group;
and
R.sub.1 -R.sub.3 are pharmaceutically acceptable moieties independently selected from the group consisting of
A) hydrogen,
B) nitro,
C) amino,
D) fluoro, chloro, or bromo,
E) haloalkyl of from 1 to 4 carbon atoms wherein the halo substituents are individually fluoro, chloro, or bromo,
F) alkyl of from 1 to 4 carbon atoms,
G) alkenyl of from 2 to 4 carbon atoms,
H) alkynyl of from 2 to 4 carbon atoms,
I) alkanoylamino of from 2 to 6 carbon atoms,
J) alkoxy which is an alkyl group as in F linked to the quinoline ring via an oxygen,
and K) haloalkoxy which is an alkoxy group listed in J above substituted with a halogen selected from the group consisting of fluoro, chloro, and bromo,
and R.sub.4 is hydrogen or fluoro.

19 more elements

A method of treating or preventing convulsions, comprising administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound selected from the group consisting of:

1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
5. 7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
5,7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
5-chloro-7-trifluoromethyl 1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
5-chloro-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime
5-bromo-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
5-bromo-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
5,6,7-trichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
5,6,7-trichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
6,7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
6,7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
6,7-dibromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
6,7-dibromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
6,7-dichloro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
6,7-dichloro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
6,7-dibromo-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
6,7-dibromo-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
6,7-difluoro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
6,7-difluoro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
5,7-bis(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
5,7-bis(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
5-(trifluoromethyl)-6-chloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxi me,
5-(trifluoromethyl)-6-chloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxi me,
5-(trifluoromethyl)-6-bromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxim e,
5-(trifluoromethyl)-6-bromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxim e,
5-(trifluoromethyl)-6- fluoro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
5-(trifluoromethyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxi me,
6-chloro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxi me,
6-chloro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxi me,
6-bromo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxim e,
6-bromo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxim e,
6-fluoro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxi me,
6- fluoro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxim e,
6-chloro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-3-oxime,
6-chloro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-4-oxime,
6-bromo-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trion e-3-oxime,
6-bromo-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trion e-4-oxime,
6-fluoro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-3-oxime,
6-fluoro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-4-oxime,
5,7-dichloro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
5,7-dichloro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
5,7-dibromo-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
5,7-dibromo-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
5,7-difluoro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-oxime,
5,7-difluoro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-oxime,
5,7-bis(trifluoromethyl)-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3 -oxime,
5,7-bis(trifluoromethyl)-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4 -oxime,
1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime,
1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime,
5. 7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime,
5,7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime,
5-chloro-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acety loxime,
5-chloro-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acety loxime,
5-bromo-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyl oxime,
5-bromo-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyl oxime,
5,6,7-trichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime,
5,6,7-trichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime,
6,7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime,
6,7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime,
6,7-dibromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime,
6,7-dibromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime,
6,7-dichloro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime
6,7-dichloro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime
6,7-dibromo-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime,
6,7-dibromo-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime,
6,7-difluoro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime
6,7-difluoro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime
5,7-bis(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetylo xime,
5,7-bis(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetylo xime,
5-(trifluoromethyl)-6-chloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-ace tyloxime,
5-(trifluoromethyl)-6-chloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-ace tyloxime,
5-(trifluoromethyl)-6-bromo-1,2,3,4-tetratrahydroquinoline-2,3,4-trione-3-a cetyloxime,
5-(trifluoromethyl)-6-bromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acet yloxime,
5-(trifluoromethyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-ace tyloxime,
5-(trifluoromethyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-ace tyloxime,
6chloro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acet yloxime,
6-chloro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-ace tyloxime,
6-bromo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acet yloxime,
6-bromo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acet yloxime,
6-fluoro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-ace tyloxime,
6-fluoro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-ace tyloxime,
6-chloro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-3-acetyloxime,
6-chloro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-4-acetyloxime,
6-bromo-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trion e-3-acetyloxime,
6-bromo-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trion e-4-acetyloxime,
6-fluoro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetratrahydroquinoline-2,3,4-t rione-3-acetyloxime,
6-fluoro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-4-acetyloxime,
5,7-dichloro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime
5,7-dichloro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime
5,7-dibromo-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime,
5,7-dibromo-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime,
5,7-difluoro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-acetyloxime
5,7-difluoro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-acetyloxime
5,7-b is(trifluoromethyl)-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-ace tyloxime,
5,7-bis(trifluoromethyl)-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4 -acetyloxime,
1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxime,
1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxime,
5. 7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxime,
5,7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxime,
5-chloro-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzo yloxime,
5-chloro-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzo yloxime,
5-bromo-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoy loxime,
5-bromo-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoy loxime,
5,6,7-trichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxime,
5,6,7-trichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxime,
6,7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxime,
6,7-dichloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxime,
6,7-dibromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxime,
6,7-dibromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxime,
6,7-dichloro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxim e,
6,7-dichloro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxim e,
6,7-dibromo-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxime
6,7-dibromo-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxime
6,7-difluoro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxim e,
6,7-difluoro-5-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxim e,
5,7-bis(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyl oxime,
5,7-bis(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyl oxime,
5-(trifluoromethyl)-6-chloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-ben zoyloxime,
5-(trifluoromethyl)-6-chloro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-ben zoyloxime,
5-(trifluoromethyl)-6-bromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benz oyloxime,
5-(trifluoromethyl)-6-bromo-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benz oyloxime,
5-(trifluoromethyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-ben zoyloxime,
5-(trifluoromethyl)-6-fluoro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-ben zoyloxime,
6-chloro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-ben zoyloxime,
6-chloro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-ben zoyloxime,
6-bromo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benz oyloxime,
6-bromo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benz oyloxime,
6-fluoro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-ben zoyloxime,
6-fluoro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-ben zoyloxime,
6-chloro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-3-benzoyloxime,
6-chloro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-4-benzoyloxime,
6-bromo-5nitro-7-(trifluoromethyl)-2,3,4-tetrahydroquinoline-1,2,3,4-trione -3-benzoyloxime,
6-bromo-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trion e-4-benzoyloxime,
6-fluoro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-3-benzoyloxime,
6-fluoro-5-nitro-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2,3,4-trio ne-4-benzoyloxime,
5,7-dichloro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxim e,
5,7-dichloro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxim e,
5,7-dibromo-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxime
5,7-dibromo-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxime
5,7-difluoro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3-benzoyloxim e,
5,7-difluoro-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4-benzoyloxim e,
5,7-bis(trifluoromethyl)-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-3 -benzoyloxime, and
5,7-bis(trifluoromethyl)-6-nitro-1,2,3,4-tetrahydroquinoline-2,3,4-trione-4 -benzoyloxime.

141 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/069,005Filed 28 May 1993
Granted: 12 Dec 1995
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 215/42
Nitrogen atoms: attached in position 4
A61K 31/47
Having six-membered rings with one nitrogen as the only ring hetero atom: quinolines; Isoquinolines
A61K 51/0455
Having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins: having six-membered rings with one nitrogen as the only ring hetero atom
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

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1,2,3,4-tetrahydroquinoline-2,3,4-trione-3 or 4-oximes and the use thereof

InventorsSui X. Cai, John F. W. Keana, Eckard Weber

Life of this patent

Estimating the term…

Abstract

Facts

Application

08/069,005Filed 28 May 1993

Granted

12 Dec 1995

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 215/42
Nitrogen atoms: attached in position 4
A61K 31/47
Having six-membered rings with one nitrogen as the only ring hetero atom: quinolines; Isoquinolines
A61K 51/0455
Having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins: having six-membered rings with one nitrogen as the only ring hetero atom
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…