Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-06-27
2004-02-10
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06689904
ABSTRACT:
This invention relates to novel bridged trycyclic analogs of 2-(carboxycyclopropyl)glycine which are selective inhibitors of human type 2 excitatory amino acid transporters (EMT-2). More particularly, this invention provides a process for preparing these compounds.
BACKGROUND OF THE INVENTION
Conformationally restricted glutamate analogs, that are selective inhibitors of human type 2 excitatory amino acid transporters (EAAT2) may thus serve to increase synaptic glutamate levels by inhibiting glutamate re-uptake and are useful for treatment of diseases characterized by glutamate hypofunction, such as schizophrenia, schizoaffective disorder and schizophreniform disorder (Int. Acad. Biomed. Drug Res. Basel, Karger, 1993, vol. 4, p. 118-129; Pharmacol., Biochem. Behav. (1997), 56(4), 797-802), with particular effectiveness against the negative symptoms of schizophrenia, and for the treatment of conditions which, though not necessarily caused by glutamate hypofunction, are nonetheless responsive to treatment by increased glutamate, such as the cognitive deficits due to aging, stroke, Alzheimer's disease or other neurodegenerative diseases, or schizophrenia (Behav. Pharmacol. (1995), Date 1995, Volume 6(5 & 6), 455-74). The compounds of this class are also useful as selective tools for the investigation of excitatory amino acid transport, especially for the identification of agents which selectively stimulate glutamate re-uptake and thus provide a neuroprotective effect for patients who have suffered stroke or head trauma.
WO 9947490, for example, claims a series of compounds described by the formula below in which n is 0-6, X is CH
2
, CH
2
CH or O, Z is CHR
2
or NR
2
and R
1
and R
2
are hydrogen, alkyl, aryl or heteroaryl as metabotropic glutamate receptor ligands useful for the treatment of a variety of neurological and psychiatric disorders.
The 2-(carboxycyclopropyl)glycines (CCG's) are conformationally restricted glutamate analogs and consist of eight isomers including L- and D-enantiomers. L-CCG-I, [(2S,3S,4S-CCG] isolated by Fowden et al. (Phytochemistry 1969, 8, 437) from immature fruits of
Aesculus parviflora
and
Blighia sapida
has been shown (Br. J. Pharmacol. 1992, 107, 539) to be a potent agonist for type 2 metabotropic glutamate receptors (mGluR2). L-CCG-III [(2S,3S,4R)-CCG], on the other hand, is a potent and competitive inhibitor of both glial and neuronal uptake of glutamate (Neuropharmacology 32, 833). EP0363994 claims the preparation of (2R,3S,4S)-alpha-(carboxycyclopropyl)glycine
as an N-methyl-D-aspartic acid (NMDA) agonist useful as a tool to investigate various neuronal functions related to the excitatory amino acid receptors.
WO 9947490 claims a series of compounds described by the formula below in which n is 0-6, X is CH
2
, CH
2
CH or O, Z is CHR
2
or NR and R
1
and R
2
are hydrogen, alkyl, aryl or heteroaryl as metabotropic glutamate receptor ligands useful for the treatment of a variety of neurological and psychiatric disorders.
U.S. Pat. No. 6,124,361 (Chenard) teaches substituted bicyclo[3.1.0]hexane compounds of the formula:
wherein n is an integer from 0 to 6; Z is (C
1
-C
4
) alkylene, oxygen, sulfur, NH or N(C
1
-C
6
)alkyl; and R
1
is H or optionally substituted aryl or heteroaryl; which are metabotropic glutamate receptor ligands useful in the treatment of a variety of neurological and psychiatric disorders.
The process described in the invention can be used for preparation of the novel restricted glutamate analogs. Known syntheses (prior art) of restricted glutamate analogs usually entail preparation of diastereomers, followed by their separation, removal of chiral auxiliary and, sometimes anion-exchange chromatography. The later processes are known to be time consuming, expensive and labor intensive. The present invention represents an alternative, more efficient process. It replaces precious chiral auxiliary with inexpensive non-chiral reagents. The reagents provide reliable protection in one simple step. Moreover, the process simultaneously introduces a chromophore, nitrogen protection and lipophilic load to simplify monitoring, hydrolysis and isolation/separation procedures. The process also allows for amplification of stereochemical bias of the corresponding derivatives that facilitates their chiral separation.
Disclosed herein process utilizes chiral chromatography, where chiral phase can be reused, rather than chiral auxiliary, where the latter is subsequently discarded or, sometimes, impractical to recover.
DESCRIPTION OF THE INVENTION
This invention provides a process for preparing a group of novel bridged tricyclic compounds having the formula:
wherein
X is (CH
2
)
n
, O, S, SO, SO
2
or CR
1
R
2
;
n is 1 or 2;
R
1
and R
2
are, independently, hydrogen, halogen, hydroxy, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, or R
1
and R
2
, taken together with the carbon to which they are attached, form cycloalkyl of three to six carbon atoms, an alkylidene of up to six carbon atoms or a carbonyl;
the process comprising the steps of:
a) treating keto-acid of formula (1):
in the presence of ammonium carbonate and an alkali metal cyanide, such as potassium cyanide, in a volume of organic solvent/water to give a spiro-fused hydantoin as a mixture of diastereomers having the formula (2);
b) treating the spiro-fused hydantoin mixture of diastereomers (2) with an appropriate benzylic halogenide or sulfonate and alkali metal carbonate in an aprotic solvent to provide tri-substituted diastereomeric mixture of hydantoins (3);
wherein R represents the benzyl residue of the corresponding benzylic halogenide or sulfonate;
c) Separating the exo- and endo-racemic pairs of tri-substituted diastereomeric mixture of hydantoins (3) to yield the racemic mixture of (4) and (4′);
d) Resolving the racemic mixture of (4) and (4′) on a chiral column to produce both enantiomers (4) and (4′) in an enantiomerically pure form;
e) treating intermediates (4), (4′), or a mixture thereof, with base to provide enantiomers of the formulae (5) and (5′):
f) treating the compounds (5) and (5′) with a palladium on carbon catalyst to provide the dextro-(+) and levorotatory (−) forms of the compounds (6′) and (6).
An additional and optional step of this process comprises the formation of a pharmaceutically acceptable salt form of a compound of formulae (6) or (6′). This salt formation may be completed by methods known in the art.
The process of this invention may be conducted in a solvent mixture of an organic solvent and water, preferably at an organic solvent/water ratio of from about 1:1 to about 4:1, more preferably at a ratio of from about 2.5/1 to about 1.5/1, most preferably about 2:1. Acceptable organic solvents are those known in the art to be miscible in water including, but not limited to, acetonitrile, acetone, tetrahydrofuran (THF), dimethylformamide (DMF), N-methylpyridine, N-methylpyrrolidone, dimethyl-sulfoxide (DMSO), sulfalane, C
1
-C
8
alkanols (including methanol and ethanol), glymes, such as monoglyme (1,2-Dimethoxyethane), or C
2
-C
8
glycols.
Treating of the keto acid of formula (1) in step a), above, may be conducted at room temperature or with heating. Preferably, heating of the solvent mixture during this step may be from room temperature up to the boiling point of the water in the solvent mixture, though higher temperatures may be utilized under pressure.
In step b) of the process, the benzylic halogenide or sulfonate may be any synthetically useful substituted or unsubstituted benzylic halogenide or sulfonate. Among the most preferred of these groups are benzyl halogenide or benzyl sulfonate groups, either unsubstituted or substituted by from 1 to 3 groups the same or different selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
thioalkyl, —CF
3
, —CN, —OH, —NH
2
, —CH
2
—(C
3
-C
6
cycloalkyl), etc. The halogen portion of the benzylic halogenides is preferably 1, Br or Cl. Among t
Butera John Anthony
Greenfield Alexander Alexei
Hild Kimberly R.
Killos Paul J.
Wyeth
LandOfFree
Bridged tricyclic analogs of 2-(carboxycyclopropyl)glycine does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Bridged tricyclic analogs of 2-(carboxycyclopropyl)glycine, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bridged tricyclic analogs of 2-(carboxycyclopropyl)glycine will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3354188