Patent US5262568A successfully refreshed from Google Patents.
US5262568A
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Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists
Assignee: Oregon State Board of Higher Education
•
Filing: 1991-03-04
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Granted: 1993-11-16
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Expires: 2011-03-04
Abstract
Abstract Tri- and tetra-substituted guanidines which exhibit a high binding affinity to phencyclidine (PCP) receptors and, more preferably, low affinity to the brain sigma receptors. These guanidine derivatives act as non-competitive inhibitors of glutamate induced responses of the NMDA receptor by acting as blockers for the ion channel of the NMDA receptor-ion channel complex. These compounds thus exert neuroprotective activity and are useful in the therapeutic treatment of neuronal loss in hypoxia, hypoglycemia, brain or spinal cord ischemia, and brain or spinal chord trauma as well as being useful for the treatment of epilepsy, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington's disease, Down's Syndrome, Korsakoff's disease and other neurodegenerative disorders.
Inventors
- 👤 Eckard Weber
- 👤 John F. W. Keana
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-08 01:01
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/13; A61K31/155; C; C07; C07C; C07C279/00; C07C279/18; C07D; C07D311/00; C07D311/02; C07D311/04; C07D311/06; C07D311/08; C07D311/18
Claims Analysis
Total Claims: 58
Claim 1
Independent Claim
42 words
A neuroprotecting N,N,N'-trisubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in mammalian nerve cells, wherein said guanidine is N,N'-di-(1-naphthyl)-N-methylguanidine, N,N'-di-(m-ethylphenyl)-N-methylguanidine, N-(o-isopropylphenyl)-N'-methyl-N'-(1-naphthyl)guanidine, N-(m-ethylphenyl)-N-methyl-N'-(1-naphthyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)-N'-ethylguanidine, N,N'-di-(1-naphthyl)-N-ethylguanidine, N-methyl-N'-(m-ethylphenyl)-N-(1-naphthyl)guanidine, N,N'-di-(1-naphthyl)-N-phenylguanidine, N-(1-naphthyl)-N'-(3-methylphenyl)-N'-methylguanidine, N-(1-naphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine, N-(7-fluoro-1-naphthyl)-N'-(3-ethylphenyl)-N-methylguanidine, N-(4-fluoro-1-naphthyl)-N'-(3-ethylphenyl)-N-methylguanidine, N-(1-naphthyl)-N'-(4fluoro-3-ethylphenyl)-N'-methylguanidine; or physiologically acceptable salts thereof.
Claim 2
Dependent Claim
42 words
A neuroprotecting N,N,N'-trisubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in mammalian nerve cells, wherein said guanidine is N,N'-di-(1-naphthyl)-N-methylguanidine, N,N'-di-(m-ethylphenyl)-N-methylguanidine, N-(o-isopropylphenyl)-N'-methyl-N'-(1-naphthyl)guanidine, N-(m-ethylphenyl)-N-methyl-N'-(1-naphthyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)-N'-ethylguanidine, N,N'-di-(1-naphthyl)-N-ethylguanidine, N-methyl-N'-(m-ethylphenyl)-N-(1-naphthyl)guanidine, N,N'-di-(1-naphthyl)-N-phenylguanidine, N-(1-naphthyl)-N'-(3-methylphenyl)-N'-methylguanidine, N-(1-naphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine, N-(7-fluoro-1-naphthyl)-N'-(3-ethylphenyl)-N-methylguanidine, N-(4-fluoro-1-naphthyl)-N'-(3-ethylphenyl)-N-methylguanidine, N-(1-naphthyl)-N'-(4fluoro-3-ethylphenyl)-N'-methylguanidine; or physiologically acceptable salts thereof.
Claim 3
Dependent Claim
1 words
N,N'-Di-(1-naphthyl)-N-methylguanidine.
Claim 4
Dependent Claim
1 words
N,N'-Di-(1-naphthyl)-N-methylguanidine.
Claim 5
Dependent Claim
1 words
N,N'-Di-(m-ethylphenyl)-N-methylguanidine.
Claim 6
Dependent Claim
1 words
N,N'-Di-(m-ethylphenyl)-N-methylguanidine.
Claim 7
Dependent Claim
1 words
N-(o-Isopropylphenyl)-N'-methyl-N'-(1-naphthyl)guanidine.
Claim 8
Dependent Claim
1 words
N-(o-Isopropylphenyl)-N'-methyl-N'-(1-naphthyl)guanidine.
Claim 9
Dependent Claim
1 words
N-(m-Ethylphenyl)-N-methyl-N'-(1-naphthyl)guanidine.
Claim 10
Dependent Claim
1 words
N-(m-Ethylphenyl)-N-methyl-N'-(1-naphthyl)guanidine.
Claim 11
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(m-ethylphenyl)-N'-ethylguanidine.
Claim 12
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(m-ethylphenyl)-N'-ethylguanidine.
Claim 13
Dependent Claim
1 words
N,N'-Di-(1-naphthyl)-N-ethylguanidine.
Claim 14
Dependent Claim
1 words
N,N'-Di-(1-naphthyl)-N-ethylguanidine.
Claim 15
Dependent Claim
1 words
N-Methyl-N'-(m-ethylphenyl)-N-(1-naphthyl)guanidine.
Claim 16
Dependent Claim
1 words
N-Methyl-N'-(m-ethylphenyl)-N-(1-naphthyl)guanidine.
Claim 17
Dependent Claim
1 words
N,N'-Di-(1-naphthyl)-N-phenylguanidine.
Claim 18
Dependent Claim
1 words
N,N'-Di-(1-naphthyl)-N-phenylguanidine.
Claim 19
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine.
Claim 20
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine.
Claim 21
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine.
Claim 22
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(3-nitrophenyl)-N'-methylguanidine.
Claim 23
Dependent Claim
1 words
N-(7Fluoro-1-naphthyl)-N'-(3-ethylphenyl-N'-methylguanidine.
Claim 24
Dependent Claim
1 words
N-(7Fluoro-1-naphthyl)-N'-(3-ethylphenyl-N'-methylguanidine.
Claim 25
Dependent Claim
1 words
N-(4Fluoro-1-naphthyl)-N'-(3-ethylphenyl-N'-methylguanidine.
Claim 26
Dependent Claim
1 words
N-(4Fluoro-1-naphthyl)-N'-(3-ethylphenyl-N'-methylguanidine.
Claim 27
Dependent Claim
310 words
A neuroprotecting guanidine of the formula: ##STR4## wherein R and R"' are independently indanyl, indenyl, a carbocyclic aryl group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl, or said carbocyclic aryl group substituted by one or more substituents, R' and R" are independently indanyl, indenyl, a C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 3 -C 12 cycloalkyl group, C 3 -C 12 cycloalkyl group substituted by one or more substituents, C 5 -C 12 cycloalkenyl group, C 5 -C 12 cycloalkenyl group substituted with one or more substituents, carbocyclic aryl group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl, said carbocyclic aryl group substituted by one or more substituents, C 1 -C 18 aralkyl group, or a C 1 -C 18 aralkyl group substituted with one or more substituents, and wherein R" can, in addition, be hydrogen; or a physiologically acceptable salt thereof; wherein said substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 15 dialkylaminoalkyl, C 1 -C 8 alkylthio, allyl, C 1 -C 18 aralkyl, C 1 -C 18 alkaryl, C 3 -C 6 cycloalkyl, aroyl selected from the group consisting of benzoyl, 1-naphthoyl, 2-naphthoyl, biphenoyl, phenanthroyl, and anthroyl, aralkoxy selected from the group consisting of C 1 -C 6 alkoxy groups substituted by an aryl group selected from the group consisting of phenyl, 1-napththyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl, C 2 -C 8 acyl, carbocyclic aryl selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl, C 1 -C 8 alkylsulfonyl, amino, C 1 -C 8 alkylamino, C 2 -C 15 dialkylamino, hydroxy, and nitro; and wherein said guanidine exhibits high binding to the PCP receptor.
Claim 28
Dependent Claim
310 words
A neuroprotecting guanidine of the formula: ##STR4## wherein R and R"' are independently indanyl, indenyl, a carbocyclic aryl group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl, or said carbocyclic aryl group substituted by one or more substituents, R' and R" are independently indanyl, indenyl, a C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 3 -C 12 cycloalkyl group, C 3 -C 12 cycloalkyl group substituted by one or more substituents, C 5 -C 12 cycloalkenyl group, C 5 -C 12 cycloalkenyl group substituted with one or more substituents, carbocyclic aryl group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl, said carbocyclic aryl group substituted by one or more substituents, C 1 -C 18 aralkyl group, or a C 1 -C 18 aralkyl group substituted with one or more substituents, and wherein R" can, in addition, be hydrogen; or a physiologically acceptable salt thereof; wherein said substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 15 dialkylaminoalkyl, C 1 -C 8 alkylthio, allyl, C 1 -C 18 aralkyl, C 1 -C 18 alkaryl, C 3 -C 6 cycloalkyl, aroyl selected from the group consisting of benzoyl, 1-naphthoyl, 2-naphthoyl, biphenoyl, phenanthroyl, and anthroyl, aralkoxy selected from the group consisting of C 1 -C 6 alkoxy groups substituted by an aryl group selected from the group consisting of phenyl, 1-napththyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl, C 2 -C 8 acyl, carbocyclic aryl selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl, C 1 -C 8 alkylsulfonyl, amino, C 1 -C 8 alkylamino, C 2 -C 15 dialkylamino, hydroxy, and nitro; and wherein said guanidine exhibits high binding to the PCP receptor.
Claim 29
Dependent Claim
30 words
A neuroprotecting N,N,N',N'-tetrasubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in mammalian nerve cells, wheren sid guanidine is N-methyl-N-'-phenyl-N,N'-di-(1-naphthyl)guanidine, N-methyl-N'-ethyl-N,N'-di-(1-naphthyl)guanidine, N,N'-di(1-naphthyl)-N,N'-dimethylguanidine, N-(1-naphthyl)-N'-(3-ethylphenyl)-N,N'-dimethylguanidine, or N-(1-naphthyl)-N'-(3-ethylphenyl)-N-ethyl-N'-methylguanidine.
Claim 30
Dependent Claim
30 words
A neuroprotecting N,N,N',N'-tetrasubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in mammalian nerve cells, wheren sid guanidine is N-methyl-N-'-phenyl-N,N'-di-(1-naphthyl)guanidine, N-methyl-N'-ethyl-N,N'-di-(1-naphthyl)guanidine, N,N'-di(1-naphthyl)-N,N'-dimethylguanidine, N-(1-naphthyl)-N'-(3-ethylphenyl)-N,N'-dimethylguanidine, or N-(1-naphthyl)-N'-(3-ethylphenyl)-N-ethyl-N'-methylguanidine.
Claim 31
Dependent Claim
1 words
N-Methyl-N'-phenyl-N,N'-di-(1-naphthyl)guanidine.
Claim 32
Dependent Claim
1 words
N-Methyl-N'-phenyl-N,N'-di-(1-naphthyl)guanidine.
Claim 33
Dependent Claim
1 words
N-Methyl-N'-ethyl-N,N'-di-(1-naphthyl)guanidine.
Claim 34
Dependent Claim
1 words
N-Methyl-N'-ethyl-N,N'-di-(1-naphthyl)guanidine.
Claim 35
Dependent Claim
1 words
N,N'-Di(1-naphthyl)-N,N'-dimethylguanidine.
Claim 36
Dependent Claim
1 words
N,N'-Di(1-naphthyl)-N,N'-dimethylguanidine.
Claim 37
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(3-ethylphenyl)-N,N'-dimethylguanidine.
Claim 38
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(3-ethylphenyl)-N,N'-dimethylguanidine.
Claim 39
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(3-ethylphenyl)-N-ethyl-N'-methylguanidine.
Claim 40
Dependent Claim
1 words
N-(1-Naphthyl)-N'-(3-ethylphenyl)-N-ethyl-N'-methylguanidine.
Claim 41
Dependent Claim
115 words
A guanidine having the formula: ##STR5## wherein: R and R"' are independently selected from the group consisting of: A) carbocyclic aryl groups selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl; and B) carbocyclic aryl groups as defined in A) substituted with one or more substituents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, and nitro; R' is selected from the group consisting of alkyl of 1-6 carbon atoms and carbocyclic aryl groups as in A) and B); and R" is selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, and carbocyclic aryl groups as in A) and B); or physiologically acceptable salts thereof.
Claim 42
Dependent Claim
115 words
A guanidine having the formula: ##STR5## wherein: R and R"' are independently selected from the group consisting of: A) carbocyclic aryl groups selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, biphenyl, phenanthryl, and anthracyl; and B) carbocyclic aryl groups as defined in A) substituted with one or more substituents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, and nitro; R' is selected from the group consisting of alkyl of 1-6 carbon atoms and carbocyclic aryl groups as in A) and B); and R" is selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, and carbocyclic aryl groups as in A) and B); or physiologically acceptable salts thereof.
Claim 43
Dependent Claim
9 words
The guanidine of claim 21 wherein R" is hydrogen.
Claim 44
Dependent Claim
36 words
The guanidine of claim 22 wherein R is a carbocyclic aryl group as defined in A) substituted with one or more substituents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, and nitro.
Claim 45
Dependent Claim
13 words
The guanidine of claim 22 wherein R' is alkyl of 1-6 carbon atoms.
Claim 46
Dependent Claim
34 words
The guanidine of claim 22 wherein R is a carbocyclic group as defined in A) substituted with one or more substituents selected from the group consisting of alkyl having 1-4 carbon atoms and halogen.
Claim 47
Dependent Claim
35 words
The guanidine of claim 22 wherein R is a carbocyclic group as defined in A) substituted with one or more substituents selected from the group consisting of alkyl having from 1-4 carbon atoms and chloride.
Claim 48
Dependent Claim
95 words
A guanidine having the formula: ##STR6## wherein: R and R"' are independently selected from the group consisting of: A) carbocyclic aryl groups selected from the group consisting of phenyl, 1-naphthyl; and B) carbocyclic aryl groups as defined in A) substituted with one or more substituents selected from the group consisting of halogen, alkyl of 1-3 carbon atoms, and nitro; R' is selected from the group consisting of alkyl of 1-3 carbon atoms and phenyl; R" is selected from the group consisting of hydrogen, alkyl of 1-3 carbon atoms, and phenyl; or physiologically acceptable salts thereof.
Claim 49
Dependent Claim
95 words
A guanidine having the formula: ##STR6## wherein: R and R"' are independently selected from the group consisting of: A) carbocyclic aryl groups selected from the group consisting of phenyl, 1-naphthyl; and B) carbocyclic aryl groups as defined in A) substituted with one or more substituents selected from the group consisting of halogen, alkyl of 1-3 carbon atoms, and nitro; R' is selected from the group consisting of alkyl of 1-3 carbon atoms and phenyl; R" is selected from the group consisting of hydrogen, alkyl of 1-3 carbon atoms, and phenyl; or physiologically acceptable salts thereof.
Claim 50
Dependent Claim
9 words
The guanidine of claim 27 wherein R" is hydrogen.
Claim 51
Dependent Claim
13 words
The guanidine of claim 28 wherein R' is alkyl of 1-3 carbon atoms.
Claim 52
Dependent Claim
65 words
A guanidine having the formula: ##STR7## wherein: R is selected from the group consisting of 1-naphthyl, 3-methylphenyl, 3-ethylphenyl, and 3-nitrophenyl; R' is selected from the group consisting of methyl, ethyl and phenyl; R"' is selected from the group consisting of hydrogen, methyl, ethyl, and phenyl; and R"' is selected from the group consisting of 3-ethylphenyl, 2-isopropylphenyl, 1-naphthyl, 4-fluoro-1-naphthyl, and 7-fluoro-1-naphthyl; or physiologically acceptable salts thereof.
Claim 53
Dependent Claim
65 words
A guanidine having the formula: ##STR7## wherein: R is selected from the group consisting of 1-naphthyl, 3-methylphenyl, 3-ethylphenyl, and 3-nitrophenyl; R' is selected from the group consisting of methyl, ethyl and phenyl; R"' is selected from the group consisting of hydrogen, methyl, ethyl, and phenyl; and R"' is selected from the group consisting of 3-ethylphenyl, 2-isopropylphenyl, 1-naphthyl, 4-fluoro-1-naphthyl, and 7-fluoro-1-naphthyl; or physiologically acceptable salts thereof.
Claim 54
Dependent Claim
9 words
The guanidine of claim 30 wherein R" is hydrogen.
Claim 55
Dependent Claim
11 words
The guanidine of claim 31 wherein R' is methyl or ethyl.
Claim 56
Dependent Claim
34 words
The guanidine of any one of claims 14, 21, 22, 23, or 24 where said alkyl groups are independently selected from the group of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl and hexyl.
Claim 57
Dependent Claim
33 words
The guanidine of any one of claims 14, 21, 22, 23, 24, 25, 26, 27, 28 or 29 where said alkyl groups are independently selected from the group of methyl, ethyl and isopropyl.
Claim 58
Dependent Claim
32 words
The guanidine of any one of claims 14, 21, 22, 23, 24, 25, 26, 27, 28 or 29 where said alkyl groups are independently selected from the group of methyl and ethyl.
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