Patent US5093525A successfully refreshed from Google Patents.
US5093525A
Expired / Lapsed
US
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N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists
Assignee: University of Oregon
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Filing: 1990-03-02
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Granted: 1992-03-03
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Expires: 2010-03-02
Abstract
Abstract Disubstituted guanidines, e.g., bis-1,3-(o-isopropylphenyl)guanidine, bis-1,3-(m-isopropylphenyl)guanidine, bis-1,3-(1-naphthyl)guanidine, bis-1,3-(m-methoxyphenyl)guanidine, N-(1-naphthyl)-N'-(o-iodophenyl)-guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine, and N-(1-napthyl)-N'-(o-isoproylphenyl) guanidine, exhibit a high binding affinity to phencyclidine (PCP) receptors. These N,N'-disubstituted guanidine derivatives act as non-competitive inhibitors of glutamate-induced responses generated via 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 therapeutic treatment of neuronal loss in hypoxia, hypoglycemia, brain or spinal chord ischemia, brain or spinal cord trauma, as well as being useful for the treatmnet of epilepsy, Alzheimer's disease, Amyotrophic Laterla Scherosis, 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
2026-11-06 14:17
CPC Classifications
C; C07; C07C; C07C279/00; C07C279/18; A; A61; A61P; A61P25/00
Claims Analysis
Total Claims: 63
Claim 1
Independent Claim
40 words
A neuroprotecting symmetrical N,N'-disubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in the NMDA receptor-channel complex and is selected from the group consisting of bis-1,3-(o-isopropylphenyl)guanidine, bis-1,3-(m-isopropylphenyl)guanidine, and bis-1,3-(m-methoxyphenyl)guanidine; or a physiologically acceptable salt thereof.
Claim 2
Dependent Claim
40 words
A neuroprotecting symmetrical N,N'-disubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in the NMDA receptor-channel complex and is selected from the group consisting of bis-1,3-(o-isopropylphenyl)guanidine, bis-1,3-(m-isopropylphenyl)guanidine, and bis-1,3-(m-methoxyphenyl)guanidine; or a physiologically acceptable salt thereof.
Claim 3
Dependent Claim
1 words
Bis-1,3-(o-isopropylphenyl)guanidine.
Claim 4
Dependent Claim
1 words
Bis-1,3-(o-isopropylphenyl)guanidine.
Claim 5
Dependent Claim
1 words
Bis-1,3-(m-isopropylphenyl)guanidine.
Claim 6
Dependent Claim
1 words
Bis-1,3-(m-isopropylphenyl)guanidine.
Claim 7
Dependent Claim
1 words
Bis-1,3-(m-methoxyphenyl)guanidine.
Claim 8
Dependent Claim
1 words
Bis-1,3-(m-methoxyphenyl)guanidine.
Claim 9
Dependent Claim
40 words
A neuroprotecting asymmetrical N,N'-disubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in the NMDA receptor-channel complex and is selected from the group consisting of N-(1-naphthyl)-N'-(o-iodophenyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine, and N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine; or a physiologically acceptable salt thereof.
Claim 10
Dependent Claim
40 words
A neuroprotecting asymmetrical N,N'-disubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in the NMDA receptor-channel complex and is selected from the group consisting of N-(1-naphthyl)-N'-(o-iodophenyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine, and N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine; or a physiologically acceptable salt thereof.
Claim 11
Dependent Claim
1 words
N-(1-naphthyl)-N'-(o-iodophenyl)guanidine.
Claim 12
Dependent Claim
1 words
N-(1-naphthyl)-N'-(o-iodophenyl)guanidine.
Claim 13
Dependent Claim
1 words
N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine.
Claim 14
Dependent Claim
1 words
N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine.
Claim 15
Dependent Claim
1 words
N-(1-naphthyl)-N'-(o-isopropylphenyl)-guanidine.
Claim 16
Dependent Claim
1 words
N-(1-naphthyl)-N'-(o-isopropylphenyl)-guanidine.
Claim 17
Independent Claim
75 words
A method of inhibiting NMDA receptor-ion channel related neurotoxicity in a mammal exhibiting such neurotoxicity or susceptible thereto, comprising administering to the mammal a symmetrical N,N'-disubstituted guanidine selected from the group consisting of bis-1,3-(o-isopropylphenyl)guanidine, bis-1,3-(m-isopropylphenyl)guanidine, bis-1,3-(1-naphthyl)guanidine and bis-1,3-(m-methoxyphenyl)guanidine; or a physiologically acceptable salt thereof; wherein said N,N'-disubstituted guanidine possesses a high affinity for the PCP receptor of a nerve cell, and wherein said N,N'-disubstituted guanidine is administered in an amount effective to inhibit the neurotoxicity.
Claim 18
Independent Claim
75 words
A method of inhibiting NMDA receptor-ion channel related neurotoxicity in a mammal exhibiting such neurotoxicity or susceptible thereto, comprising administering to the mammal a symmetrical N,N'-disubstituted guanidine selected from the group consisting of bis-1,3-(o-isopropylphenyl)guanidine, bis-1,3-(m-isopropylphenyl)guanidine, bis-1,3-(1-naphthyl)guanidine and bis-1,3-(m-methoxyphenyl)guanidine; or a physiologically acceptable salt thereof; wherein said N,N'-disubstituted guanidine possesses a high affinity for the PCP receptor of a nerve cell, and wherein said N,N'-disubstituted guanidine is administered in an amount effective to inhibit the neurotoxicity.
Claim 19
Dependent Claim
34 words
The method according to claim 10, wherein said neurotoxicity is caused by excessive release of endogenous glutamate following the occurrence of hypoxia, hypoglycemia, brain or spinal chord ischemia, or brain or spinal cord trauma.
Claim 20
Dependent Claim
12 words
The method according to claim 10, wherein said N,N'-disubstituted guanidine is bis-1,3-(o-isopropylphenyl)guanidine.
Claim 21
Dependent Claim
12 words
The method according to claim 10, wherein said N,N'-disubstituted guanidine is bis-1,3-(m-isopropylphenyl)guanidine.
Claim 22
Dependent Claim
12 words
The method according to claim 10, wherein said N,N'-disubstituted guanidine is bis-1,3-(1-naphthyl)guanidine.
Claim 23
Dependent Claim
12 words
The method according to claim 10, wherein said N,N'-disubstituted guanidine is bis-1,3-(m-methoxyphenyl)guanidine.
Claim 24
Independent Claim
53 words
A method of inhibiting NMDA receptor-ion channel related neurotoxicity in a mammal exhibiting such neurotoxicity or susceptible thereto, comprising administering to the mammal exhibiting such neurotoxicity or susceptible thereto an asymmetrical 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 25
Independent Claim
53 words
A method of inhibiting NMDA receptor-ion channel related neurotoxicity in a mammal exhibiting such neurotoxicity or susceptible thereto, comprising administering to the mammal exhibiting such neurotoxicity or susceptible thereto an asymmetrical 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 26
Dependent Claim
34 words
The method according to claim 15, wherein said neurotoxicity is caused by excessive release of endogenous glutamate following the occurrence of hypoxia, hypoglycemia, brain or spinal chord ischemia, or brain or spinal cord trauma.
Claim 27
Dependent Claim
28 words
The method according to claim 16, wherein the asymmetrical N,N'-disubstituted guanidine is selected from the group consisting of N-(1-naphthyl)-N'-(o-iodophenyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine, and N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine; or a physiologically acceptable salt thereof.
Claim 28
Dependent Claim
13 words
The method according to claim 18, wherein the asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(o-iodophenyl)-guanidine.
Claim 29
Dependent Claim
13 words
The method according to claim 18, wherein the asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine.
Claim 30
Dependent Claim
13 words
The method according to claim 18, wherein the asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine.
Claim 31
Independent Claim
96 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 symmetrical N,N'-disubstituted guanidine selected from the group consisting of bis-1,3-(o-isopropylphenyl)guanidine, bis-1,3-(m-isopropylphenyl)guanidine, bis-1,3-(1-naphthyl)guanidine and bis 1,3-(m-methoxyphenyl)guanidine; or a physiologically acceptable salt thereof; wherein said symmetrical N,N'-disubstituted guanidine has a high affinity for the PCP receptor of the nerve cell, and said guanidine is administered in an amount effective to treat said disease.
Claim 32
Independent Claim
96 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 symmetrical N,N'-disubstituted guanidine selected from the group consisting of bis-1,3-(o-isopropylphenyl)guanidine, bis-1,3-(m-isopropylphenyl)guanidine, bis-1,3-(1-naphthyl)guanidine and bis 1,3-(m-methoxyphenyl)guanidine; or a physiologically acceptable salt thereof; wherein said symmetrical N,N'-disubstituted guanidine has a high affinity for the PCP receptor of the nerve cell, and said guanidine is administered in an amount effective to treat said disease.
Claim 33
Dependent Claim
11 words
The method of claim 22, wherein said N,N'-disubstituted guanidine is bis-1,3-(o-isopropylphenyl)guanidine.
Claim 34
Dependent Claim
11 words
The method of claim 22, wherein said N,N'-disubstituted guanidine is bis-1,3-(m-isopropylphenyl)guanidine.
Claim 35
Dependent Claim
11 words
The method of claim 22, wherein said N,N'-disubstituted guanidine is bis-1,3-(1-naphthyl)guanidine.
Claim 36
Dependent Claim
11 words
The method of claim 22, wherein said N,N'-disubstituted guanidine is bis-1,3-(m-methoxyphenyl)guanidine.
Claim 37
Independent Claim
70 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 is susceptible to such disorders, an asymmetrical N,N'-disubstituted guanidine having a high affinity for the PCP receptor of the NMDA receptor-channel complex, in an amount effective to treat said disease.
Claim 38
Independent Claim
70 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 is susceptible to such disorders, an asymmetrical N,N'-disubstituted guanidine having a high affinity for the PCP receptor of the NMDA receptor-channel complex, in an amount effective to treat said disease.
Claim 39
Dependent Claim
54 words
The method according to claim 27, said asymmetrical N,N'-disubstituted guanidine having the formula ##STR3## wherein R and R' are different and are an alkyl group of 4-12 carbon atoms, a cycloalkyl group of 3-12 carbon atoms, carbocyclic aryl, alkaryl, aralkyl or heterocyclic groups of 6-18 carbon atoms and containing 1-3 separate or fused rings.
Claim 40
Dependent Claim
28 words
The method according to claim 28, wherein the asymmetrical N,N'-disubstituted guanidine is selected from the group consisting of N-(1-naphthyl)-N'-(o-iodophenyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine, and N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine; or a physiologically acceptable salt thereof.
Claim 41
Dependent Claim
13 words
The method according to claim 29, wherein said asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(o-iodophenyl)guanidine.
Claim 42
Dependent Claim
13 words
The method according to claim 29, wherein said asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine.
Claim 43
Dependent Claim
13 words
The method according to claim 29, wherein said asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine.
Claim 44
Dependent Claim
22 words
The method according to claim 22, wherein said disease is Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome or Korsakoff's disease.
Claim 45
Dependent Claim
12 words
The method according to claim 33, wherein said N,N'-disubstituted guanidine is bis-1,3-(o-isopropylphenyl)guanidine.
Claim 46
Dependent Claim
12 words
The method according to claim 33, wherein said N,N'-disubstituted guanidine is bis-1,3-(m-isopropylphenyl)guanidine.
Claim 47
Dependent Claim
12 words
The method according to claim 33, wherein said N,N'-disubstituted guanidine is bis-1,3-(1-naphthyl)guanidine.
Claim 48
Dependent Claim
12 words
The method according to claim 33, wherein said N,N'-disubstituted guanidine is bis-1,3-(m-methoxyphenyl)guanidine.
Claim 49
Dependent Claim
22 words
The method according to claim 27, wherein said disease is Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome or Korsakoff's disease.
Claim 50
Dependent Claim
28 words
The method according to claim 38, wherein the asymmetrical N,N'-disubstituted guanidine is selected from the group consisting of N-(1-naphthyl)-N'-(o-iodophenyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine, and N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine; or a physiologically acceptable salt thereof.
Claim 51
Dependent Claim
13 words
The method according to claim 39, wherein the asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(o-iodophenyl)-guanidine.
Claim 52
Dependent Claim
13 words
The method according to claim 39, wherein the asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine.
Claim 53
Dependent Claim
13 words
The method according to claim 39, wherein said asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine.
Claim 54
Dependent Claim
16 words
The method according to claim 22, wherein the mammal is a human being suffering from epilepsy.
Claim 55
Dependent Claim
11 words
The method of claim 43, wherein said N,N'-disubstituted guanidine is bis-1,3-(o-isopropylphenyl)guanidine.
Claim 56
Dependent Claim
11 words
The method of claim 43, wherein said N,N'-disubstituted guanidine is bis-1,3-(m-isopropylphenyl)guanidine.
Claim 57
Dependent Claim
11 words
The method of claim 43, wherein said N,N'-disubstituted guanidine is bis-1,3-(1-naphthyl)guanidine.
Claim 58
Dependent Claim
11 words
The method of claim 43, wherein said N,N'-disubstituted guanidine is bis-1,3-(m-methoxyphenyl)guanidine.
Claim 59
Dependent Claim
16 words
The method according to claim 27, wherein the mammal is a human being suffering from epilepsy.
Claim 60
Dependent Claim
28 words
The method according to claim 48, wherein the asymmetrical N,N'-disubstituted guanidine is selected from the group consisting of N-(1-naphthyl)-N'-(o-iodophenyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine, and N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine; or a physiologically acceptable salt thereof.
Claim 61
Dependent Claim
14 words
The method according to claim 49, wherein the asymmetrical N,N -disubstituted guanidine is N-(1-naphthyl)-N'-(o-iodophenyl)guanidine.
Claim 62
Dependent Claim
13 words
The method according to claim 49, wherein the asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine.
Claim 63
Dependent Claim
13 words
The method according to claim 49, wherein the asymmetrical N,N'-disubstituted guanidine is N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine.
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