US4906779A
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N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists
Assignee: Oregon Health & Science University
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Filing: 1988-08-29
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Granted: 1990-03-06
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Expires: 2008-08-29
Abstract
Abstract Disubstituted guanidines, e.g., N,N'-di-m-tolyl guanidine, N,N'-di-o-ethylphenyl guanidine, N,N'-di-m-ethylphenyl guanidine, and N,N'-di-o-iodophenyl-guanidine, exhibit a high binding affinity to phenylcyclidine (PCP) receptors. These guanidine derivatives act as non-competitive blockers to 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 a neuroprotective property and are useful in the therapeautic treatment of neuronal loss in ischemia, hypoxia, hypoglycemia, and brain and spinal cord trauma as well as being useful for the treatment of epilepsy, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Down's Syndrome and other neurodegenerative disorders.
Inventors
- 👤 Eckard Weber
- 👤 John F. Keana
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 11:56
CPC Classifications
C; C07; C07C; C07C279/00; C07C279/18
Claims Analysis
Total Claims: 36
Claim 1
Independent Claim
37 words
A neuroprotecting N,N'-disubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in mammalian nerve cells selected from the group consisting of N,N'-di-o-iodo-phenyl-guanidine; N,N'-di-m-tolyl-guanidine; N,N'-di-o-ethylphenyl guanidine; N,N'-di-m-ethylphenyl guanidine; and physiologically acceptable salts thereof.
Claim 2
Dependent Claim
37 words
A neuroprotecting N,N'-disubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in mammalian nerve cells selected from the group consisting of N,N'-di-o-iodo-phenyl-guanidine; N,N'-di-m-tolyl-guanidine; N,N'-di-o-ethylphenyl guanidine; N,N'-di-m-ethylphenyl guanidine; and physiologically acceptable salts thereof.
Claim 3
Dependent Claim
7 words
N,N-di-o-ethylphenyl guanidine, a compound of claim 1.
Claim 4
Dependent Claim
7 words
N,N'-di-m-ethylphenyl guanidine, a compound of claim 1.
Claim 5
Dependent Claim
7 words
N,N-di-m-tolyl guanidine, a compound of claim 1.
Claim 6
Dependent Claim
6 words
N,N'-di-o-iodo-phenyl-guanidine, a compound of claim 1.
Claim 7
Independent Claim
73 words
A method for treating a disease of the nervous system in which the pathophysiology of the disorder involves excessive excitation of nerve cells by agonists of NMDA receptors comprising the administration to a mammal exhibiting symptoms of such disorders or susceptible to such disorders, a N,N'-disubstituted guanidine having a high affinity for the PCP receptor of the nerve cell in an amount effective to block the ion channel of the NMDA-receptor ion-channel complex.
Claim 8
Independent Claim
73 words
A method for treating a disease of the nervous system in which the pathophysiology of the disorder involves excessive excitation of nerve cells by agonists of NMDA receptors comprising the administration to a mammal exhibiting symptoms of such disorders or susceptible to such disorders, a N,N'-disubstituted guanidine having a high affinity for the PCP receptor of the nerve cell in an amount effective to block the ion channel of the NMDA-receptor ion-channel complex.
Claim 9
Dependent Claim
67 words
A method according to claim 6, said N,N'-disubstituted guanidine having the formula ##STR3## wherein R and R, each are an alkyl group of 4-12 carbon atoms, a cycloalkyl group of 3-12 carbon atoms, carbocyclic aryl, alkaryl, or aralkyl of 6-18 carbon atoms and containing 1-3 separate or fused rings, or a heterocyclic compound, and further wherein each of R and R' may be substituted in 1-3 positions.
Claim 10
Dependent Claim
27 words
A method according to claim 7, wherein the N,N'-disubstituted guanidine is selected from the group consisting of N,N'-di-m-tolyl-guanidine; N,N'-di-o-iodophenyl-guanidine; N,N'-di-o-ethylphenyl-guanidine; and N,N'-di-m-ethylphenyl-guanidine and physiologically acceptable salts thereof.
Claim 11
Dependent Claim
12 words
A method according to claim 7, wherein said N,N'-disubstituted guanidine is N,N'-di-m-tolylguanidine.
Claim 12
Dependent Claim
12 words
A method according to claim 7, wherein said N,N'-disubstituted guanidine is N,N'-di-o-iodo-phenylguanidine.
Claim 13
Dependent Claim
13 words
A method according to claim 7, wherein said N,N'-disubstituted guanidine is N,N'-di-o-ethylphenyl guanidine.
Claim 14
Dependent Claim
13 words
A method according to claim 7, Wherein said N,N'-disubstituted guanidine is N,N'-di-m-ethylphenyl guanidine.
Claim 15
Dependent Claim
22 words
A method according to claim 6, wherein said neurotoxicity is associated with Alzheimer's disease, Huntington's chorea, Amyotrophic Lateral Sclerosis, or Down's Syndrome.
Claim 16
Dependent Claim
27 words
A method according to claim 13, wherein N,N' disubstituted guanidine is selected from the group consisting of N,N'-di-m-tolyl-guanidine; N,N'-di-o-iodophenyl-guanidine; N,N'-di-o-ethylphenyl-guanidine; and N,N'-di-m-ethylphenyl-guanidine and physiologically acceptable salts thereof.
Claim 17
Dependent Claim
12 words
A method according to claim 14, wherein the N,N'-disubstituted guanidine is N,N'-di-m-tolylguanidine.
Claim 18
Dependent Claim
12 words
A method according to claim 14, wherein the N,N'-disubstituted guanidine is N,N'-di-o-iodo-phenylguanidine.
Claim 19
Dependent Claim
13 words
A method according to claim 14, wherein said N,N'-disubstituted guanidine is N,N'-di-o-ethylphenyl guanidine.
Claim 20
Dependent Claim
13 words
A method according to claim 14, wherein said N,N'-disubstituted guanidine is N,N'-di-m-ethylphenyl guanidine.
Claim 21
Dependent Claim
19 words
A method according to claim 6, wherein the mammal is a human being suffering from epilepsy or memory disorder.
Claim 22
Dependent Claim
27 words
A method according to claim 19, Wherein the N,N'-disubstituted guanidine is selected from the group consisting of N,N'-di-m-tolyl-guanidine; N,N'-di-o-iodophenyl-guanidine; N,N'-di-o-ethylphenyl-guanidine; and N,N'-di-m-ethylphenyl-guanidine and physiologically acceptable salts thereof.
Claim 23
Dependent Claim
12 words
A method according to claim 19, wherein the N,N'-disubstituted guanidine is N,N'-di-m-tolylguanidine.
Claim 24
Dependent Claim
12 words
A method according to claim 19, wherein the N,N'-disubstituted guanidine is N,N'-di-o-iodo-phenylguanidine.
Claim 25
Dependent Claim
13 words
The method according to claim 19, wherein the N,N'-disubstituted guanidine is N,N'-di-o-ethylphenyl guanidine.
Claim 26
Dependent Claim
13 words
The method according to claim 19, wherein the N,N'-disubstituted guanidine is N,N'-di-m-ethylphenyl guanidine.
Claim 27
Independent Claim
37 words
A method of inhibiting NMDA receptor-ion channel related neurotoxicity comprising administering to a mammal a N,N'-disubstituted guanidine possessing a high affinity for the PCP receptor of a nerve cell, in an amount effective to inhibit the neurotoxicity.
Claim 28
Independent Claim
37 words
A method of inhibiting NMDA receptor-ion channel related neurotoxicity comprising administering to a mammal a N,N'-disubstituted guanidine possessing a high affinity for the PCP receptor of a nerve cell, in an amount effective to inhibit the neurotoxicity.
Claim 29
Dependent Claim
24 words
A method according to claim 25, wherein said neurotoxicity is caused by excessive release of endogenous glutamate following the occurrence of ischemic brain insults.
Claim 30
Dependent Claim
27 words
A method according to claim 25, wherein the N,N'-disubstituted guanidine is selected from the group consisting of N,N'-di-m-tolyl-guanidine; N,N'-di-o-iodophenyl-guanidine; N,N'-di-o-ethylphenyl-guanidine; and N,N'-di-m-ethylphenyl-guanidine and physiologically acceptable salts thereof.
Claim 31
Dependent Claim
12 words
A method according to claim 25, wherein the N,N'-disubstituted guanidine is N,N'-di-m-tolylguanidine.
Claim 32
Dependent Claim
12 words
A method according to claim 25, wherein the N,N'-disubstituted guanidine is N,N'-di-o-iodo-phenylguanidine.
Claim 33
Dependent Claim
13 words
The method according to claim 25, wherein the N,N'-disubstituted guanidine is N,N'-di-o-ethylphenyl guanidine.
Claim 34
Dependent Claim
13 words
The method according to claim 25, wherein the N,N'-disubstituted guanidine is N,N'-di-m-ethylphenyl guanidine.
Claim 35
Dependent Claim
22 words
A method according to claim 6, wherein said N,N'-disubstituted guanidine is administered at a dosage of about 10-100 um/kg of body weight.
Claim 36
Dependent Claim
22 words
A method according to claim 25, wherein said N,N'-disubstituted guanidine is administered at a dosage of about 10-100 um/kg of body weight.
References Cited (Backward Citations)
No citation records indexed.
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