Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-06-27
2004-06-15
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C549S386000, C562S499000, C514S454000, C514S530000, C514S531000
Reexamination Certificate
active
06750364
ABSTRACT:
This invention relates to bridged tricyclic analogs of 2-(carboxycyclopropyl)glycine as inhibitors of glutamate transport, to processes for preparing them and to pharmaceutical compositions containing them. The novel compounds of the invention are useful in the treatment of disorders associated with brain glutamate hypofunction in a mammal. The invention particularly provides compounds which are useful in the treatment, prevention, alleviation or inhibition of maladies including schizophrenia, schizoaffective disorder and schizophreniform disorder, and for the treatment of cognitive deficits due to aging, stroke, Alzheimer's disease or other neurodegenerative diseases.
BACKGROUND OF THE INVENTION
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.
Bioorganic and Medicinal Chemistry 6 (1998) 195 describes the synthesis and pharmacological activity of a series of aminobicyclo[2.2.1]heptane dicarboxylic acids (ABHD's) as rigid analogs of 1-amino-cyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD). 2-endo-Aminobicyclo[2.2.1]heptane-2-exo-7-anti-dicarboxylic acid (ABHD-I) is described as a competitive antagonist at the 1
a
subtype of the metabotropic glutamate receptor with a K
b
of 300 &mgr;M. Both ABHD-I and ABHD-II (2-exo-aminobicyclo[2.2.1]-heptane-2-endo-7-anti-dicarboxylic acid):
are characterized as agonists at type 2 mGluR's. Neither compound has significant activity at glutamate transporters.
Literature from Tocris Cookson lists two isomers of aminotricyclo-[2.2.1.0
2,6
]heptane-dicarboxylic acid. 3-Exo-aminotricyclo[2.2.1.0
2,6
]heptane-3-endo-7-anti-dicarboxylic acid (designated below as ATHD-I) is described as a weak agonist at type 2 metabotropic glutamate receptors. The activity of 3-endo-aminotricyclo-[2.2.1.0
2,6
]heptane-3-exo-7-anti-dicarboxylic acid (designated ATHD-II) is said to
have not yet been established. No information on these compounds is available in the chemical or pharmacological literature. It should be noted that these compounds, while conformationally restricted analogs of trans-ACPD, are not analogs of 2-(carboxycyclopropyl)glycine. Furthermore, these compounds have no significant effect on glutamate transport.
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
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.
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.
DESCRIPTION OF THE INVENTION
This invention provides a group of novel bridged tricyclic analogs of 2-(carboxy-cyclopropyl)glycine of 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;
R
3
, R
4
and R
5
are, independently, hydrogen or alkyl of one to six carbon atoms;
Z is hydrogen, alkyl of one to six carbon atoms, alkanoyl of one to six carbon atoms or alkoxycarbonyl of two to seven carbon atoms;
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the invention, X is (CH
2
)
n
, O or CR
1
R
2
. More preferably, X is (CH
2
)
n
. Most preferably, n is 1.
In a further preferred embodiment of the invention, R
1
and R
2
are independently selected from hydrogen, methyl, chloro, bromo, hydroxy and methoxy.
In a still further preferred embodiment of the invention, R
3
, R
4
and R
5
are hydrogen.
In a still further preferred embodiment of the invention, Z is hydrogen or alkyl of 1 to 6 carbon atoms. More preferably, Z is hydrogen.
A preferred group of compounds of this invention are those in which R
1
, R
2
and n are defined as above, X is (CH
2
)
n
, O or CR
1
R
2
, R
3
, R
4
and R
5
are hydrogen and Z is hydrogen or alkyl of one to six carbon atoms. Most preferred are those examples in which n is defined as above, X is (CH
2
)
n
, O or CR
1
R
2
, wherein R
1
and R
2
are, independently, hydrogen, halogen, hydroxy, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms and R
3
, R
4
, R
5
and Z are hydrogen.
One group of this invention includes compounds of the formulae:
wherein:
R
1
and R
2
are independently selected from 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;
R
3
, R
4
and R
5
are, independently, hydrogen or alkyl of one to six carbon atoms;
Z is hydrogen, alkyl of one to six carbon atoms, alkanoyl of one to six carbon atoms or alkoxycarbonyl of two to seven carbon atoms;
or a pharmaceutically acceptable salt thereof.
A subgroup of compounds of those above have the formulae:
wherein:
Z is H or alkyl of from 1 to 6 carbon atoms; and
R
1
and R
2
are independently selected from H, halogen, hydroxy, alkyl of from 1 to 6 carbon atoms or alkoxy of from 1 to 6 carbon atoms;
or a pharmaceutically acceptable salt thereof.
Representative compounds of this invention wherein X is (CH
2
)
n
or CR
1
R
2
include, but are not limited to:
3-Amino-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
3-Methylamino-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
3-Ethylamino-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
3-Amino-5-methyl-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
3-Amino-5-chloro-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
3-Amino-5-bromo-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
3-Amino-5,5-dichloro-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
3-Amino-5,5-dimethyl-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
5,5-Dimethyl-3-methylamino-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
5-Hydroxy-3-methylamino-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
3-Amino-5-methoxy-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
5-Methoxy-3-methylamino-tricyclo[2.2.1.0
2,6
]heptane-1,3-dicarboxylic acid;
or a pharmaceutically acceptable salt thereof.
Another group of compounds of this invention comprises those of the formula:
wherein:
R
3
, R
4
and R
5
are independently selected from hydrogen or alkyl of one to six carbon atoms; and
Z is hydrogen, alkyl of one to six carbon atoms, alkanoyl of one to six carbon atoms or alkoxycarbonyl of two to seven carbon atoms;
or a pharmaceutically acceptable salt thereof.
A further group of these compounds are those of the formula:
w
Dunlop John
Greenfield Alexander Alexei
Gross Jonathan Laird
Stack Gary Paul
Barrett Rebecca R.
Hild Kimberly R.
Killos Paul J.
Wyeth
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