US4837218A
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US
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Alkylated bicycloalkaneamines for treatment of neurotoxic injury
Assignee: Washington University in St. Louis
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Filing: 1987-10-23
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Granted: 1989-06-06
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Expires: 2007-10-23
Abstract
Abstract Compounds, compositions and methods of treatment are described to control brain damage associated with anoxia or ischemia which typically follows such conditions as stroke, cardiac arrest or perinatal asphyxia. The treatment includes administration of an alkylated bicycloalkaneamine compound as an antagonist to inhibit excitotoxic actions at major neuronal exzcitatory amino acid receptor sites.
Inventors
- 👤 John W. Olney
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 18:03
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/13
Claims Analysis
Total Claims: 11
Claim 1
Independent Claim
155 words
A method to inhibit neuronal degeneration in mammals induced by anoxia, hypoxia or ischemia, which method comprises treating a susceptible mammal with a therapeutically-effective amount of a compound of the formula ##STR25## wherein R 1 is one or more groups independently selected from hydrido, alkyl, amino, alkoxy, hydroxyl and oxo; wherein R 2 is selected from hydrido, alkyl, alkoxy and hydroxyl; and wherein each of R 3 and R 4 is independently selected hydrido, alkyl, acyl, aldehyde, hydroxyalkyl, haloalkyl, hydroxycarbonylalkyl, alkylaminoalkyl, aminoalkyl, alkenyl, bicycloalkyliminoalkyl, phenylalkyl, phenyloxyalkylcarbonylalkyl, amino, aminocarbonylamino, guanido, aminocarbonyl, alkylcarbonyl, alkylaminocarbonyl, N-alkoxy-N-alkylamido, alkynylcarbonyl, alkyliminooxocarbonyl, carboxyalkylaminocarbonylaminoalkylcarbonyl, cycloalkylcarbonyl, phenylalkylcarbonyl, phenylalkyliminooxycarbonyl, alkylcarbonylaminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, aminophenylcarbonyl, alkylaminoalkylcarbonyl, haloalkylcarbonyl, bicycloalkylamidoalkylcarbonyl, tricycloalkyliminooxycarbonyl and cycloalkyliminooxycarbonyl; wherein any of one of the aforementioned R 3 and R 4 groups having one or more substitutable positions may be substituted with one or more groups selected from aldehyde, alkyl, alkoxy, acyl, hydroxyl, amino, nitro, halo, carboxyl, haloalkyl, haloalkylcarbonyl and phenyl; or a pharmaceutically-acceptable salt thereof.
Claim 2
Independent Claim
155 words
A method to inhibit neuronal degeneration in mammals induced by anoxia, hypoxia or ischemia, which method comprises treating a susceptible mammal with a therapeutically-effective amount of a compound of the formula ##STR25## wherein R 1 is one or more groups independently selected from hydrido, alkyl, amino, alkoxy, hydroxyl and oxo; wherein R 2 is selected from hydrido, alkyl, alkoxy and hydroxyl; and wherein each of R 3 and R 4 is independently selected hydrido, alkyl, acyl, aldehyde, hydroxyalkyl, haloalkyl, hydroxycarbonylalkyl, alkylaminoalkyl, aminoalkyl, alkenyl, bicycloalkyliminoalkyl, phenylalkyl, phenyloxyalkylcarbonylalkyl, amino, aminocarbonylamino, guanido, aminocarbonyl, alkylcarbonyl, alkylaminocarbonyl, N-alkoxy-N-alkylamido, alkynylcarbonyl, alkyliminooxocarbonyl, carboxyalkylaminocarbonylaminoalkylcarbonyl, cycloalkylcarbonyl, phenylalkylcarbonyl, phenylalkyliminooxycarbonyl, alkylcarbonylaminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, aminophenylcarbonyl, alkylaminoalkylcarbonyl, haloalkylcarbonyl, bicycloalkylamidoalkylcarbonyl, tricycloalkyliminooxycarbonyl and cycloalkyliminooxycarbonyl; wherein any of one of the aforementioned R 3 and R 4 groups having one or more substitutable positions may be substituted with one or more groups selected from aldehyde, alkyl, alkoxy, acyl, hydroxyl, amino, nitro, halo, carboxyl, haloalkyl, haloalkylcarbonyl and phenyl; or a pharmaceutically-acceptable salt thereof.
Claim 3
Dependent Claim
104 words
The method of claim 1 wherein R 1 is one or more groups independently selected from hydrido, alkyl, alkoxy, hydroxyl and oxo; wherein R 2 is selected from hydrido, alkyl, alkoxy and hydroxyl; and wherein each of R 3 and R 4 is independently selected from hydrido, alkyl, acyl, hydroxylalkyl, haloalkyl, amino, aminoalkyl, alkenyl, phenylalkyl, aminocarbonylamino, bicycloalkylamidoalkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl, phenylalkylcarbonyl, aminophenylcarbonyl, haloalkylcarbonyl and bicycloalkylamidoalkylcarbonyl; wherein any one of the aforementioned R 3 and R 4 groups having one or more substitutable positions may be substituted with one or more groups selected from alkyl, alkoxy, acyl, hydroxyl, amino, fluoro, chloro, bromo, haloalkyl and phenyl.
Claim 4
Dependent Claim
57 words
The method of claim 2 wherein R 1 is one or more groups selected from hydrido, lower alkyl and oxo; wherein R 2 is selected from hydrido, lower alkyl, and alkoxy; and wherein each of R 3 and R 4 is independently selected from hydrido, lower alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, phenylalkyl, alkoxyalkyl, chloroalkyl, chlorophenylalkyl, nitrophenylalkyl and hydroxyphenylalkyl.
Claim 5
Dependent Claim
73 words
The method of claim 3 wherein R 1 is one or more groups selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl and tert-butyl; wherein R 2 is selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl and tert-butyl; wherein each of R 3 and R 4 is indepedently selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, hydroxyethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluorethyl, aminomethyl, aminoethyl, benzyl, nitrobenzyl, hydroxybenzyl and chlorobenzyl.
Claim 6
Dependent Claim
65 words
The method of claim 4 wherein R 1 is hydrido or a single substituent selected from methyl and ethyl attached at the 5- or 6-position of the cyclohexyl ring of Formula I; wherein R 2 is selected from hydrido, methyl and ethyl; and wherein each of R 3 and R 4 is independently selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
Claim 7
Dependent Claim
45 words
The method of claim 1 wherein said compound is selected from 3-(methylamino)-2,2,3-trimethylbicyclo[2.2.1]heptane; N-2,3,3-tetramethyl-2-norbornanamine hydrochloride; N,N-2,3,3-pentamethylbicyclo[2.2.1]heptan-2-amine; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; N,N-2,3,3-pentamethylbicyclo[2.2.1]heptan-2-amine hydrobromide; and N-2,3,3-tetramethylbicyclo[2.2.1]heptan-2-amine hydrobromide; N-(1,3,3-trimethyl-2-norbornyl)formamide; 1,1-dimethyl-3-(1,3,3-trimethyl-2-norbornyl)urea; 1-ethoxy-1-ethyl-3-(2,3,3-trimethyl-2-norbornyl)-urea; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; N-(2,3,3-trimethyl-2-norbornyl)propiolamide; N-(2,3,3-trimethyl-2-norbornyl)glycine hydrochloride; 1-[(1,3,3-trimethyl-2-norbornyl)amino]guanidine monohydrochloride; (1,3,3-trimethyl-2-norbornyl)hydrazine monohydrochloride; 6-methoxy-N-2,3,3-tetramethyl-bicyclo[2.2.1]heptan-2-amine hydrochloride; 5,5,6-trimethyl-6-(methylamino)bicyclo[2.2.1]heptan-2-ol hydrochloride; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime-7-ethyl-2-methyl-4-nonanone; 3-(2-chloroethylamino)-2,2,3-trimethylnorcamphane hydrochloride; N-(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)cyclopropanecarboxamide; N-methyl-N-(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)-1,2-ethanediamine; 2,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; 3,3-dimethylbicyclo[2.2.1]heptan-2-amine; N,N'-methanetetraylbis[1,3,3-trimthylbicyclo[2.2.1]heptan-2-amine; αaspartyl-N-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)alaninamide;
Claim 8
Dependent Claim
48 words
3-dimethyl-N-(2,3,3-trimethyl-2-norbornyl)butyramide; N-ethyl-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; 1,3,3-trimethyl-N-propylbicyclo[2.2.1]heptan-2-amine; N-butyl-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; N-butyl-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; N-(2,3,3-trimethyl-2-norbornyl)phenethylamine; N-(2,3,3-trimethyl-2-norbornyl)acetamide; N-(2-ethyl-3,3-dimethyl-2-norbornyl)formamide; N-3,3-trimethyl-2-propyl-2-norbornanamine hydrochloride; N-(2,3,3-trimethyl-2-norbornyl)butyramide; N,N-dimethyl-N'-(2,3,3-trimethyl-2-norbornyl)-1,3-propanediamine; N-hexyl-2,3,3-trimethyl-2-norbornanamine hydrochloride; 2,2-dichloro-4'-[(2,3,3-trimethyl-2-norbornyl)carbamoyl]acetanilide; N,N'-dimethyl-N,N'-bis(2,3,3-trimethyl-2-norbornyl)glutaramide; 2,3,3-trimethyl-N-(3-phenylpropyl)-2-norbornanamine; 2-phenyl-N-(2,3,3-trimethyl-2-norbornyl)acetamide; p-nitro-N-(2,3,3-trimethyl-2-norbornyl)brenzamide; N-phenyl-N'-(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)urea; 2-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)imino]methyl]phenol; N-(6-methoxy-2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)-N-methylbenzamide; 5,5,6-trimethyl-6-[methyl(phenylmethyl)amino]-bicyclo[2.2.1]heptan-2-one hydrochloride; N,N'-bis(3,3-dimethylbicyclo[2.2.1]hept-2-yl)urea; 2,4-dibromo-6-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]methyl]phenol hydrochloride; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime tricyclo[2.2.1.0 2 , 6 ]heptanone; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime-5-methyl-2-(1-methylethyl)cyclohexanone; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime cycloheptanone; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime 4-phenyl-2-butanone; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime cyclododecanone; 2-(diethylamino)-N-(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)acetamide monohydrochloride; 2-chloro-N-methyl-N-(2,3,3-trimethyl-2-norbornyl)acetamide; N-allyl-2,3,3-trimethyl-2-norbornanamine hydrochloride; α-aspartyl-O-methyl-3-oxo-N-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)-serinamide; 2-[methyl(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]ethanol.
Claim 9
Dependent Claim
48 words
3-dimethyl-N-(2,3,3-trimethyl-2-norbornyl)butyramide; N-ethyl-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; 1,3,3-trimethyl-N-propylbicyclo[2.2.1]heptan-2-amine; N-butyl-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; N-butyl-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; N-(2,3,3-trimethyl-2-norbornyl)phenethylamine; N-(2,3,3-trimethyl-2-norbornyl)acetamide; N-(2-ethyl-3,3-dimethyl-2-norbornyl)formamide; N-3,3-trimethyl-2-propyl-2-norbornanamine hydrochloride; N-(2,3,3-trimethyl-2-norbornyl)butyramide; N,N-dimethyl-N'-(2,3,3-trimethyl-2-norbornyl)-1,3-propanediamine; N-hexyl-2,3,3-trimethyl-2-norbornanamine hydrochloride; 2,2-dichloro-4'-[(2,3,3-trimethyl-2-norbornyl)carbamoyl]acetanilide; N,N'-dimethyl-N,N'-bis(2,3,3-trimethyl-2-norbornyl)glutaramide; 2,3,3-trimethyl-N-(3-phenylpropyl)-2-norbornanamine; 2-phenyl-N-(2,3,3-trimethyl-2-norbornyl)acetamide; p-nitro-N-(2,3,3-trimethyl-2-norbornyl)brenzamide; N-phenyl-N'-(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)urea; 2-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)imino]methyl]phenol; N-(6-methoxy-2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)-N-methylbenzamide; 5,5,6-trimethyl-6-[methyl(phenylmethyl)amino]-bicyclo[2.2.1]heptan-2-one hydrochloride; N,N'-bis(3,3-dimethylbicyclo[2.2.1]hept-2-yl)urea; 2,4-dibromo-6-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]methyl]phenol hydrochloride; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime tricyclo[2.2.1.0 2 , 6 ]heptanone; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime-5-methyl-2-(1-methylethyl)cyclohexanone; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime cycloheptanone; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime 4-phenyl-2-butanone; O-[[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]oxime cyclododecanone; 2-(diethylamino)-N-(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)acetamide monohydrochloride; 2-chloro-N-methyl-N-(2,3,3-trimethyl-2-norbornyl)acetamide; N-allyl-2,3,3-trimethyl-2-norbornanamine hydrochloride; α-aspartyl-O-methyl-3-oxo-N-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)-serinamide; 2-[methyl(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]ethanol.
Claim 10
Dependent Claim
21 words
The method of claim 1 wherein said compound is selected from 3-(methylamino)-2,2,3-trimethylbicyclo[2.2.1]heptane; N-2,3,3-tetramethyl-2-norbornanamine hydrochloride; N,N-2,3,3-pentamethylbicyclo[2.2.1]heptan-2-amine; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine; N,N-2,3,3-pentamethylbicyclo[2.2.1]heptan-2-amine hydrobromide; and N-2,3,3-tetramethylbicyclo[2.2.1]heptan-2-amine hydrobromide.
Claim 11
Dependent Claim
14 words
The method of claim 7 wherein said compound is 3-(methylamino)-2,2,3-trimethylbicyclo[2.2.1]heptane or its hydrochloride salt.
References Cited (Backward Citations)
No citation records indexed.
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