Bicyclic cyclohexylamines and their use as NMDA receptor...

Details Bicyclic cyclohexylamines and their use as NMDA receptor... Bicyclic cyclohexylamines and their use as NMDA receptor...

2002-11-12

2004-09-21

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S221000

Reexamination Certificate

active

06794402

ABSTRACT:

FIELD OF THE INVENTION
The invention pertains to bicycle-substituted cyclohexylamine derivatives as N-Methyl-D-Aspartate Antagonists (NMDA).
BACKGROUND OF THE INVENTION
Over excitation of NMDA receptor channel complexes on postsynaptic neurons following excessive release of glutamic acid from synaptosomes and glutamic acid from synaptosomes and glial cells results in excessive calcium ion influx into the neuronal cells, which leads to their death. This is believed to occur under ischemic or hypoxic conditions such as stroke, hypoglycemic, cardiac arrest and physical trauma. An NMDA receptor antagonist might be therapeutically useful because it may minimize damage of the central nervous system induced by ischemic or hypoxic conditions. The NMDA receptor channel complex consists of at least three binding domains including a glutamic acid (or NMDA) recognition site, a channel blocking binding site, and a strychnine-insensitive glycine binding type. Physiologically, a blockade of at least one of these sites terminates the channel opening of the NMDA receptor to prevent a calcium ion influx. (Nagata R., et al.,
J. Med. Chem
., 1994;37:3956-3968)
Excessive excitation of NMDA receptor channel complexes by neurotransmitters may be responsible for the loss of neurons in cerebral vascular disorders such as cerebral ischemia or cerebral infarction resulting in a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia, such as from near drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's disease, and Huntington's disease. Such conditions likewise suggest the use of agents that may act as antagonists in the receptors identified above may lead to treatment of amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain, and drug addiction. (PCT/EPO 94/01492 having publication number WO 94/26747 published Nov. 24, 1994, Watjen et al.)
L-glutamic acid, L-aspartic acid, and a number of other closely related amino acids have the ability to activate neurons in the nervous system, and therefore the vast majority of excitatory neurons in the mammalian CNS. Interaction with glutamic acid mediated neurotransmission is considered a useful approach in the treatment of neurological and psychiatric diseases. (WO 94/26746, published Nov. 24, 1994, Jacobsen et al.)
Excitatory amino acid receptor antagonists that block NMDA receptors are recognized for usefulness in the treatment of a variety 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 (Klockgether T., Turski L.,
Ann. Neurol
., 1993;34:585-59), human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (Francis P. T., Sims N. R, Procter A. W., Bowen D. M.,
J. Neurochem
., 1993;60(5);1589-1604), and Huntington's disease (see Lipton S.,
TINS
, 1993;16(12):527-532; Lipton S. A., Rosenberg P. A.,
New Eng. J. Med
., 1994;330(9):613-622; and Bigge C. F.,
Biochem. Pharmacol
., 1993;45: 1547-1561 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 (European Patent Application 488,959A).
Many of the properties of native NMDA receptors are seen in recombinant homomeric NR1 receptors. These properties are altered by the NR2 subunits. Recombinant NMDA receptors expressed in Xenopus Oocytes have been studied by voltage-clamp recording, and have been found to exhibit developmental and regional expression of the mRNAs encoding NMDA receptor subunits. Electrophysiological assays were utilized to characterize the actions of compounds at NMDA receptors expressed in Xenopus Oocytes. The compounds were assayed at four subunit combinations at cloned rat NMDA receptors, corresponding to three putative NMDA receptor subtypes (Moriyoshi et al.,
Nature
, 1991;354:31-37; Monyer et al.,
Science
, 1992;256:1217-1221; Kutsuwada et al.,
Nature
, 1992:358;36-41; Sugihara et al.,
Biochem. Biophys Res. Commun
., 1992;185:826-832).
Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) in Nakanishi's lab in 1991 provided an initial view of the molecular structure of the NMDA receptor (Moriyoshi et al., supra, 1991). There are several other structurally related subunits (NMDAR2A through NMDAR2D) that join NR1 in heteromeric assemblies to form the functional ion channel complex of the receptor (
Annu. Rev. Neurosci
., 1994;17:31-108). The molecular heterogeneity of NMDA receptors implies a future potential for agents with subtype selective pharmacology.
SUMMARY OF THE INVENTION
Described are bicycle-substituted cyclohexyl amines of Formula I and their pharmaceutically acceptable salts thereof
wherein:
Ar is substituted 1 to 3 times or unsubstituted aryl or substituted 1 to 3 times or unsubstituted heteroaryl, which heteroaryl is from 5 to 14 atoms having from 1 to 2 heteroatoms selected from N, O, and S wherein the substituents are selected from the groups F, Cl, Br, I, OH, NH
2
, SH, CN, NO
2
, OCH
3
, OC(O)CH
3
, CF
3
, OCH
2
CH
2
OH, NHC(O)CH
3
, NHCH
3
, or N(CH
3
)
2
;
wherein V is —(CH
2
)
n
—,
—S(O)—, or —S(O)
2
—,
W is —(CH
2
)
n
—,
—S(O)—, —S(O)
2
—, —O—, —S—,—C≡C—, or entgegen or zusammen —CH(R
1
)═CH(R
2
)—,
d is an integer from 0 to 2;
n is an integer from 1 to 6;
q is an integer from 0 to 6;
R
1
and R
2
are independently selected from the group consisting of hydrogen, alkyl, OH, hydroxyalkyl, aminoalkyl, aralkyl, or N(R
4
)(R
5
) wherein R
4
and R
5
are independently selected from hydrogen, alkyl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, hydroxyalkyl, and thioalkyl;
R is hydrogen, alkyl, C(O)R
6
, C(O)OR
6
, C(O)NHR
6
, -alkyl-C(O)NH
2
, aralkyl, (C
3
-C
7
cycloalkyl)-alkyl, hydroxyalkyl, aminoalkyl, amino(hydroxy)alkyl, carboxyalkyl, heteroaralkyl, alkenylalkyl, or OH wherein R
6
is alkyl or aralkyl;
X is independently selected from hydrogen or an electron withdrawing group; and
E—Y— is
—CH═CH—N(H)—,
—(CH
2
)
2
—N(H)—,
—CH═N—N(H)—,
—C(O)—CH
2
—N(H)—,
—CH
2
—C(O)—N(H)—,
—CH
2
—S(O)—N(H)—,
—CH
2
—S(O)
2
—N(H)—,
—CH═CH—CH(OH)—,
—(CH
2
)
2
—CH(OH)—,
—C(O)—CH
2
—C(O)—,
—C(O)—NH—C(O)—,
—N=CH—N(H)—,
—N(H)—C(O)—N(H)—,
—O—C(O)—NH—,
—S—C(O)—NH—,
—O—N═CH(OH)—,
—S—N═CH(OH)—,
—N═N—N(H)—,
—CH═CH—CH═C(OH)—,
—(CH
2
)
3
—CH(OH)—,
—(CH
2
)
2
—S(O)—N(H)—,
—(CH
2
)
2
—S(O)
2
—N(H)—,
—CH═CH—C(O)—N(H)—,
—C(O)—NH—N═C(OH)—,
—CH═N—NH—C(O),
—CH═N(O)—N═C(OH)—,
—N(H)—C(O)—N(H)—C(O)—,
—N═CH—C(O)—NH—,
—O—CH
2
—C(O)—NH—,
—S—CH
2
—C(O)—NH—, or
—N(H)—C(O)—C(O)—N(H)—;
- - - denotes a single or double bond; and
* denotes cis or trans or a mixture thereof.
The invention also relates to compounds of Formula II
or a pharmaceutically acceptable salt thereof wherein:
Ar, R, X, d, and —E—Y— are as defined above;
wherein U is —CH
2
—,
—S(O)—, or —S(O)
2
—,
A is —CH
2
,
—S(O)—, or —S(O)
2
—,
t is an integer from 1 to 3,
R
1
and R
2
are independently selected from hydrogen, alkyl, OH, hydroxyalkyl, aminoalkyl, thioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, guanidinyl, (aminocarbonyl)alkyl-, carboxyalkyl-, (methylthio)-alkyl-, or N(R
4
)(R
5
), wherein R
4
and R
5
are independently selected from hydrogen, alkyl, aralkyl, heteroaryl, heteroaralkyl, ureidoalkyl, aminoalkyl, hydroxyalkyl, or thioalkyl;
R
3
is hydrogen, alkyl, OH, or aralkyl;
R is hydrogen, alkyl, C(O)R
6
, C(O)OR
6
, C(O)NHR
6
, alkyl —CO
2
NH
2
, aralkyl, hydroxyalkyl, (C
3
-C
7
cycloalkyl) alkyl, aminoalkyl,

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