Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-31
2001-09-04
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S322000, C546S197000, C546S198000, C546S199000
Reexamination Certificate
active
06284774
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
This invention is related to 4-benzyl piperidine alkylsulfoxide heterocycles. The compounds of this invention are selectively active as antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is also directed to the use of 4-benzyl piperidine alkyl sulfoxide heterocycles as neuroprotective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, macular and other retinal degenerative diseases, hypoglycemia, anxiety, psychosis, asthma, glaucoma, CMV retinitis, urinary incontinence, tinnitus, aminoglycoside antibiotics-induced hearing loss, convulsions, migraine headache, chronic pain, depression, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington's Disease. A particularly preferred use of the compositions of this invention is in the treatment of Parkinson's Disease.
4-Benzyl piperidine analogs that are useful as subtype-selective NMDA receptor antagonists are described in PCT International Publication No. WO 97/23216. However, piperidine analogs having sulfoxide functionality are not described.
Benzylpiperidine derivatives are also disclosed in U.S. Pat. No. 5,698,553, as having the formula:
in which
R
1
is H, Hal or nitro,
R
2
is a benzyl group, which is unsubstituted or substituted by Hal on the aromatic portion, in the 2-, 3- or 4-position of the piperidine ring, with the proviso that R
2
≠4-benzyl, i.e., R
2
is not in the 4-position of the piperidine ring, if X is —CO—, Y and Z are —CH
2
and R
1
is H,
R
3
is H or A,
X is —O—, —S—, —NH—, —CO— or —SO
2
—,
Y is —CH
2
—, —O—, —S—, —NH— or alternatively —CO— if X is —CO— and Z is —NH— or —NA—,
Z is —CH
2
—, —C(A)
2
—, —CH
2
CH
2
—, —CH═CH—, —CO—, —NH—, —NA—, —O—, —S— or a bond, wherein X-Y or Y-Z is not —O—O—, —S—S—, —NH—O—, —O—NH—, —NH—NH—, —O—S— or —S—O—,
A is alkyl having 1-6 C atoms,
B is O or both H and OH, i.e,
together with the
carbon atom to which B
is bonded,
Hal is F, Cl, Br or I and
n is 0, 1 or 2 and their salts.
The compounds are said to be useful for the treatment of cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's, Parkinson's, or Huntington's disease, cerebral ischaemias or infarctions. However, subtype selectivity is not indicated and, again, piperidine analogs having sulfoxide functionality are not suggested or described.
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).
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 [Nature 354, 31-37 (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. 17, 31-108 (1994)]. The molecular heterogeneity of NMDA receptors implies a future potential for agents with subtype selective pharmacology.
Many of the properties of native NMDA receptors are seen in recombinant homomeric NR1 receptors expressed in Xenopus oocytes. These properties are altered by the NR2 subunits. Recombinant NMDA receptors expressed in Xenopus oocytes have been studied by voltage-clamp recording, as has 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 of 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].
Novel 4-benzyl piperidines that have enhanced subtype selectivity would be highly desirable, particularly for the treatment of Parkinson's disease.
SUMMARY OF THE INVENTION
The invention relates to novel 4-benzyl piperidine alkylsulfoxide heterocycles represented by the formula
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R and R′ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, nitro, cyano, carboxaldehyde, aldehyde amine, lower alkoxy carbonylmethyl, hydroxy lower alkyl, amino carbonylmethyl, hydrazinocarbonylmethyl, acetamido, aryl, aralkyl, amino, a halogenated alkyl group, a lower alkyl amino group or a lower alkoxy group;
R″ and R′″ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, amino, a halogenated alkyl group, a lower alkyl amino group or a lower alkoxy group;
X is hydrogen or hydroxy;
Z is —CH
2
— or
n is 2 to 4; and
Y is O, NH or S.
The compounds of this invention include stereoisomers such as enantiomers as well as the racemic mixtures thereof. A particularly preferred enantiomer of the present invention is (+)-6-{2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanesulfinyl}-3H-benzooxazol-2-one.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, oxalate, and the acetate.
Halogen is fluorine, chlorine, bromine, or iodine; fluorine, chlorine, and bromine are preferred groups.
Alkyl means a straight or branched chain of from one to six carbon atoms or cyclic alkyl of from three to seven carbon atoms including, but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Aryl means a monocyclic or bicyclic carbocyclic aromatic ring system which can be substituted or unsubstituted, for example, but not limited to phenyl, naphthyl or the like.
Aralkyl means any of the alkyl groups defined herein substituted by any of the aryl groups as defined herein.
Halogenated alkyl means any of the alkyl groups defined herein substituted by one or more halogens as defined herein.
Lower alkyl amino means any of the alkyl groups defined herein substituted by an amino group.
Lower alkoxy means an alkoxy group containing an alkyl group as defined herein.
The instant invention is also related to a pharmaceutical composition containing the compound of this invention in an amount effective to treat chronic neurodegenerative disorders or cerebrovascular disorders responsive to the selective blockade of NMDA receptor subtypes and a pharmaceutically acceptable carrier. Exemplary disorders responsive to such treatment include cerebral ischemia caused b
Kesten Suzanne Ross
Lan Nancy C.
Upasani Ravindra B.
Wright Jonathan L.
Davis Zinna Northington
Fitzpatrick ,Cella, Harper & Scinto
Warner-Lambert & Company
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