Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-07
2001-09-04
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06284776
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method for treating disease-related or drug-induced dyskinesias.
2. Related Background Art
Dyskinesias are debilitating motor movements that can be caused by a neurological disease, or can be drug-induced. See, for example, A. B. Joseph and R. R. Young, Movement Disorders in Neurology and Neuropsychiatry (Blackwell Scientific Publications, 1992), the disclosure of which is incorporated by reference herein. Disease-related dyskinesias can result from a wide range of conditions, including Wilson's disease, Huntington's disease and Sydenham's chores Drug-induced dyskinesias have been attributed to administration of many drugs, including drugs used in treatment of Parkinson's disease, e.g., L-DOPA, nonselective dopamine-agonists (DA-agonists), as well as DA-agonists selective for the D1, D2, D3, D4 and D5 subtypes of the dopamine receptor; and DA antagonists, especially in the case of prolonged administration of antipsychotic agents, which leads to tardive dyskinesias.
Drugs which act as non-selective antagonists of the N-methyl-D-aspartate (NMDA) receptor have been shown to decrease dyskinesias induced by administration of L-DOPA to primates suffering from 1,2,3,6-tetrahydro-1-methyl4-phenylpyridine (MPTP)-induced Parkinson's disease. The NMDA receptor comprises a NR1 subunit in combination with one or more of the NR2 subunits, NR2B, NR2C or NR2D, as disclosed in Monyer et al., Science, Vol. 256, pages 1217-1221 (1992). K. W. Muir and K. R. Lees, Stroke, Vol. 26, pages 503-513 (1995), discloses that administration of NMDA receptor antagonists that are NR1A/2B-site-selective leads to reduced psychotomimetic side-effects than administration of non-selective antagonists. S. M. Papa and T. N. Chase, Annals of Neurology, Vol. 39, pages 574-578 (1996), discloses that administration of the drug LY235959, available from Eli Lilly, Inc., reduced the severity of dyskinesia in monkeys being treated with L-DOPA. However, LY235959 is a non-selective NMDA receptor antagonist. It is not obvious from this work which subtype of the NMDA receptor is responsible for the antidyskinetic effect.
PCT International Publication No. WO 96/37226 discloses treatment of Parkinsons disease with a combination of site-selective NMDA receptor antagonist compounds and L-DOPA. Administration of the antagonist compounds allowed use of lower amounts of L-DOPA. However, there is no suggestion that NR1A/2B site-selective NMDA receptor antagonist compounds could be administered to reduce the side effects accompanying normal doses of L-DOPA.
Methods of treatment of dyskinesias with compounds which are NR1A/2B-site-selective NMDA receptor antagonists would be desirable.
SUMMARY OF THE INVENTION
This invention is directed to a method for treating dyskinesias, said method comprising administering to a human suffering therefrom a therapeutically effective amount of a NR1A/2B-site-selective NMDA receptor antagonist compound.
In a preferred embodiment of this invention, the compound is
or a pharmaceutically acceptable salt thereof wherein
Ar
1
and Ar
2
are independently aryl or a heteroaryl group, either of which may be independently substituted by one to three of hydroxy, alkyl, halogen, nitro, cyano, carboxaldehyde, aldehyde oxime, lower alkoxy carbonylmethyl, hydroxy lower alkyl, aminocarbonylmethyl, hydrazinocarbonylmethyl, acetamido, aryl, aralkyl, amino, a halogenated alkyl group, a lower alkyl amino group or a lower alkoxy group;
X is —(CHR
3
)
m
—, wherein each R
3
is independently hydrogen, hydroxy, or a lower alkyl group having 1 to 6 carbon atoms; and m is 0 or 1;
each R
2
is independently hydrogen, hydroxy or a lower alkyl group having 1 to 6 carbon atoms;
n is 1,2,3 or 4;
Y is C≡C, O, SO
p
wherein p is 0, 1 or 2, NR
4
wherein R
4
is hydrogen or a lower alkyl group having 1 to 6 carbon atoms, or a single bond; and
R
5
is hydrogen or hydroxy.
In another preferred embodiment, the compound has a structure selected from those listed below, their stereoisomers, and their pharmaceutically acceptable salts:
&agr;-(4-chlorophenyl)-4-[(4-fluorophenyl)methyl]-1-piperidineethanol;
&agr;-(4-hydroxyphenyl)-&bgr;-methyl-4-(phenylmethyl)-1-piperidineethanol;
4-hydroxy-&agr;-(4-hydroxyphenyl)-&bgr;-methyl-4-phenyl-1-piperidineethanol;
3-[4-(4-phenyl)-4-hydroxypiperidin-1-yl]chroman4,7-diol; and
&agr;-(4-hydroxyphenyl)-&bgr;-methyl(phenylmethyl)-1-piperidinepropanol.
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patent: 91/06297 (1991-05-01), None
patent: 93/00313 (1993-01-01), None
patent: 93/22310 (1993-11-01), None
patent: 96/37226 (1996-11-01), None
patent: 9723214 (1997-07-01), None
Costall et al, J. Pharm., Pharmac., vol. 30, pp. 693-696, 1978.*
Merck Index, p. 785, 1996.*
A.B. Joseph and R.R. Young, editors, “Movement Disorders in Neurology and Neuropsychiatry”, Blackwell Scientific Publications, 1992.
Monyer et al., “Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes”,Science, vol. 256, 1992, pp. 1217-1221.
Muir and Lees, “Clinical Experience With Excitatory Amino Acid Antagonist Drugs”,Stroke, vol. 26, No. 3, 1995, pp. 503-513.
Anderson Elizabeth M.
Ashbrook Charles W.
Reamer James H.
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