Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-16
2001-04-17
Davis, Zinna Norhington (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S192000
Reexamination Certificate
active
06218404
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is related to 2-substituted piperidine analogs. The analogs are selectively active as antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is also directed to the use of 2-substituted piperidine analogs as neuro-protective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headaches, chronic pain, glaucoma, CMV retinitis, psychosis, urinary incontinence, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease.
2. Related Background Art
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-Aspartate (NMDA) receptor. This excitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.
Excitatory amino acid receptor antagonists that block NMDA receptors are recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's disease [T. Klockgether, L. Turski, Ann. Neurol. 34, 585-593 (1993)], human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease [P. T. Francis, N. R. Sims, A. W. Procter, D. M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington's disease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S. A. Lipton, P. A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994); and C. F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and references cited therein.]. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A).
U.S. Pat. No. 5,352,683, discloses the treatment of chronic pain with a compound with is an antagonist of the NMDA receptor.
U.S. Pat. No. 4,902,695, discloses certain competitive NMDA antagonists that are useful for the treatment of neurological disorders, including epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.
U.S. Pat. No. 5,192,751 discloses a method of treating urinary incontinence in a mammal which comprises administering an effective amount of a competitive NMDA antagonist.
Evidence indicates that the NMDA receptor comprises a class of such receptors with different subunits. Molecular cloning has revealed the existence of at least five subunits of the NMDA receptors designated NR1 & NR2A through 2D. It has been demonstrated that the co-expression of NR1 with one of the NR2 subunits forms a receptor with a functional ion channel. (
Ann. Rev. Neurosci
. 17:31-108(1994)). It is thought that NMDA receptors with different subunit composition generate the different NMDA receptor subtypes found in the mammalian brain.
An object of this invention is to provide novel—subtype-selective NMDA receptor ligands.
SUMMARY OF THE INVENTION
The invention relates to a subtype-selective NMDA receptor ligand having the Formula (I):
wherein
R
1
-R
4
are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN)
2
, guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
E is (CR
a
R
b
)
r
—G
s
—(CR
c
R
d
)
t
, wherein R
a
, R
b
, R
c
and R
d
are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO
2
or O
2
C), carbonyl (CO), or NR
e
, wherein R
e
is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;
R
5
is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
p is 0, 1, 2, or 3;
Y is hydrogen, hydroxy, CH
3
, CN, CO
2
R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y
1
, ═—Y
1
(which may be cis or trans, throughout) carbonylamido, hydrazino, oximo, amidino, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and
Y
1
is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.
The invention also relates to a subtype-selective NMDA receptor ligand having the Formula (II):
wherein
R
1
-R
4
, E, Y and Y
1
are the same as described in formula I;
R
5
is hydrogen, lower alkyl, acyl or aryl;
p is 0, 1, 2 or 3; and
R
6
is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group; and
The invention also relates to a subtype-selective NMDA receptor ligand having the Formula (IIa):
wherein
R
1
-R
4
, E, Y and Y
1
are the same as described in formula I;
R
5
is hydrogen, lower alkyl, acyl or aryl;
p is 0, 1, 2 or 3; and
R
6
is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group.
The invention also relates to a subtype-selective NMDA receptor ligand having the Formula (III):
wherein
W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
X is a bond, (CH
2
)
m
, carbonyl, oxygen, or NR;
E is the same as described in formula I;
Y is hydrogen, hydroxy, CH
3
, CN, CO
2
R; an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
R is hydrogen, alkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;
R
1
is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
m is 0, 1, 2, or 3; and
p is 0, 1, 2, 3 or 4.
with the proviso, that when W is adamantyl or when p is greater than zero, or when the piperidine is substituted in the 3-position by W-X, then Y may also be optionally substituted aryl
Araldi Gian Luca
Bigge Christopher F.
Cai Sui Xiong
Guzikowski Anthony P.
Keana John F. W.
Davis Zinna Norhington
Fitzpatrick ,Cella, Harper & Scinto
Warner-Lambert Co.
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