Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-13
2002-09-10
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S221000, C514S255030, C514S258100, C514S311000, C514S312000, C514S321000, C540S500000, C540S506000, C540S578000, C544S283000, C544S285000, C544S349000, C546S153000, C546S196000, C546S199000, C546S201000, C546S217000, C546S223000
Reexamination Certificate
active
06448270
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is related to 4-substituted piperidine analogs, including hydroxypiperidine and tetrahydropyridine analogs, as well as novel intermediates of the 4-substituted 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 4-substituted piperidine analogs as neuroprotective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headache, 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.
Various classes of substituted piperidine analogs are known. For example, U.S. Pat. No. 5,273,977 generically discloses tetrahydropyridine and hydroxy piperidine derivatives described by the formula:
wherein n is an integer of 2, 3, or 4; Z is
Ar
1
and Ar
2
are each independently substituted or unsubstituted aryl, a heteroaromatic ring, or a heteroaromatic bicylic ring. The tetrahydropyridines and hydroxypiperidines of this reference are indicated to be useful as central nervous system agents, particularly as dopaminergic, antipsychotic and antihypertensive agents, and for treating central nervous system disorders such as Parkinson Disease, Huntington Disease and depression. The particular 4-substituted piperidines, including the 4-hydroxypiperdines and tetrahydropyridines of this invention are not exemplified. In addition, there is no disclosure or suggestion of treating disorders with selective NMDA receptor subtype antagonists and the advantages of such treatment.
GB 1055548 discloses 1-aryl-3-aminopropynes having the generic formula:
wherein R represents unsubstituted phenyl or phenyl substituted by methyl, halogen, nitro, amino, (lower alkanoyl)amino, or lower alkoxyl; and either A is alkyl of 1 to 4 carbon atoms and A′ is alkyl of 1 to 4 carbon atoms, benzyl, chlorobenzyl, or dimethoxybenzyl; or A and A′, together with the adjacent nitrogen atom, from one of the following heterocyclic rings: pyrrolidino, morpholino, thiomorpholino, 4-phenylpiperidino, 4-phenyl-4-hydroxypiperidino, N′-methylpiperazino, N′-benzylpiperazino, N′-phenylpiperazino, N′-chlorophenylpiperazino, N′-tolylpiperazino, N′-methoxyphenylpiperamino, N′-(&bgr;-hydroxyethyl)-piperazino, N′-(&bgr;-acetoxyethyl)piperazino, N′-(&bgr;-propionyloxyethyl)-piperazino, N′-carbethoxypiperazino, hexamethyleneimino, and heptamethylene-imino; provided that when R is phenyl, p-methoxyphenyl, o- or p-nitrophenyl, or o-aminophenyl,
does not represent dimethylamino or diethylamino; and their acid addition salts, especially those containing physiologically innocuous anions. The compounds of this reference are said to have antiulcer activity. This reference does not disclose or suggest the 4-substituted piperidine analogs of this invention or their use as selective NMDA receptor subtype antagonists.
DE 3703435 discloses compounds having a piperidine ring substituted by an aminothiazole moiety. The compounds are said to be useful for treating Parkinson's Disease, schizophrenia and circulatory disorders with a particular effect on the dopaminergic system. This reference does not disclose or suggest the compositions of the present invention, let alone their use as selective NMDA receptor subtype antagonists.
PCT International Publication Number WO 92/02502 generically discloses N-hydrocarbyl 4-substituted piperidines described by the formula:
in which
R is C
1-8
alkyl (phenyl)p, C
2-8
alkenyl (phenyl)p, C
2-8
alkynyl (phenyl)p, C
3-8
cycloalkyl;
p is 0 to 2;
n is 0 to 6;
A is a bond, oxygen, sulphur or NR
1
;
R
1
is hydrogen, C
1-8
alkyl or phenylC
1-4
alkyl;
m is 0 to 3; and
Ar is aryl or heteroaryl, each of which may be optionally substituted; and salts thereof.
This reference exemplifies 4-aryloxyalkyl piperidines. The substituted piperidines are said to be calcium channel blockers expected to be useful in the treatment of anoxia, ischemia including stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative disorders and drug addiction. The reference does not disclose or suggest the particular 4-substituted piperidine analogs of this invention or their use as selective NMDA receptor subtype antagonists for the treatment of disorders responsive thereto.
PCT International Publication Number WO 93/15052 generically describes compounds that are said to be calcium channel antagonists broadly represented by the formula:
and the salts thereof, wherein
W is —CH
2
—, a bond, O or S; k is 0, or when W represents —CH
2
— k may also be 2, in which case the dotted lines represent single bonds;
R is C
1-8
alkyl (phenyl)p, C
2-8
alkenyl (phenyl)p, C
2-8
alkynyl (phenyl)p, C
3-8
cycloalkyl or C
1-8
alkylC
3-8
cycloalkyl, or R may also represent hydrogen when k is 2;
p is 0 to 2
n is 0 to 6;
m is 0 to 6; and
A is a bond, —CH═CH—, —C≡C—, oxygen, sulphur or NR
1
;
R
1
is hydrogen, C
1-8
alkyl or phenylC
1-4
alkyl; and
Ar is aryl or heteroaryl,
each of which may be optionally substituted; provided that: when W is a bond the side chain is a to the ring nitrogen atom; when W is CH
2
, k is zero, the side chain is at the 3- or 4-position of the piperidine ring and A is a bond, oxygen, sulphur or NR
1
then Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined; and when W is CH
2
and k is 2 the side chain —(CH
2
)
n
A(CH
2
)
m
Ar is not &agr; to the nitrogen atom. This reference exemplifies mostly 2 and 3 substituted piperidines. In addition, the particular group of 3 and 4 substituted piperidines described by the reference requires A to be —CH═CH— or —C≡C—. This reference does not disclose or suggest the 4-substituted piperidine analogs of this invention. Moreover, there is no suggestion of employing 4-substituted piperidine analogs as selective NMDA receptor subtype antagonists.
EP 0235463 discloses N-substituted-arylalkyl and arylalkylene aminoheterocyclics as coronary vasodilators, antihypertensives, antiarrhythmic, antiallergy, antihistamic and antisecretory agents. 4-substituted N-alkene and alkyne piperidine analogs of this invention, as well as their NMDA antagonistic activity, are not disclosed or suggested.
U.S. Pat. No. 5,169,855 generically discloses disubstituted piperidine ether derivatives for use as antipsychotic agents selective for sigma receptors. Similarly, PCT International Publication No. WO 92/18127 and PCT International Publication No. WO 91/06297 generically disclose N-phthalimidoalkyl piperidines which are useful as antipsychotic agents and which are selective for sigma receptors. However, the 4-substituted piperidine analogs of this invention are not disclosed by these references and there is no mention of NMDA receptor activity.
Numerous references have disclosed additional piperidine derivatives substituted at the 4 and 3 position for use in a variety of treatments. Such references
Bigge Christopher F.
Cai Sui Xiong
Keana John F.W.
Lan Nancy C.
Weber Eckard
Chang Ceila
Fitzpatrick ,Cella, Harper & Scinto
Warner-Lambert & Company
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