Excitatory amino acid receptor modulators

Details Excitatory amino acid receptor modulators Excitatory amino acid receptor modulators

2001-11-16

2002-12-24

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S531000, C548S253000, C560S124000

Reexamination Certificate

active

06498180

ABSTRACT:

In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans,
Ann. Rev. Pharmacol. Toxicol.,
21, 165 (1981); Monaghan, Bridges, and Comas,
Ann. Rev. Pharmacol. Toxicol.,
29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore,
Trans. Pharm. Sci.,
11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed “ionotropic”. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked “metabotropic” excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D or C, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn,
Trends in Pharmacol. Sci.,
14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek,
Trends in Pharmacol. Sci.,
11, 508 (1990); McDonald and Johnson,
Brain Research Reviews,
15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
The metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation. Compounds which modulate the function of these receptors, in particular agonists and antagonists of glutamate, are useful for the treatment of acute and chronic neurodegenerative conditions, and as antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant, and anti-emetic agents.
Pellicciari et al.,
J. Med. Chem.,
1996, 39, 2259-2269 refers to compounds known as metabotropic glutamate receptor agonists, in particular (2S,1′S,2′S)-2-(2-carboxycyclopropyl)glycine, also known as L-CCG-I; (2S, 1′S,2′R,3′R)-2-(2′-carboxy-3′-(methoxymethyl)cyclopropyl-glycine, also known as cis-MCG-I; (2S,1′S,2′R,3′S)-2-(2′-carboxy-3′-(methoxymethyl)cyclopropylglycine, also known as trans-MCG-I; and (2S,1′R,2′R,3′R)-2-(2′,3′-dicarboxy-cyclopropyl)glycine, also known as DCG-IV. The paper also describes the synthesis of the sixteen possible stereoisomers of 2-(2′-carboxy-3′-phenylcyclopropyl)glycine and their evaluation as excitatory amino acid receptor ligands. The compound (2S,1′S,2′S,3′R)-2-(2′-carboxy-3′-phenylcyclopropyl)glycine, also known as PCCG 4 is reported to be a metabotropic glutamate receptor antagonist.
Japanese patent application publication number JP 06179643 discloses MCG and generically discloses (2S,1′S,2′R)-2-(2-carboxy-3-alkoxymethyl- and 3-aralkoxymethyl-cyclopropyl)glycines as glutamate receptor agonists.
International patent application publication number WO 97/19049 discloses PCCG 4 and also generically discloses various 2-carboxy-3-arylcyclopropylglycines having affinity for metabotropic glutamate receptors.
International patent application publication number WO 98/00391 discloses 2-carboxy-3,3-dihalocyclopropylglycines, including (2S,1′S,2′S)-2-(2-carboxy-3,3-difluoro)-cyclopropylglycine as metabotropic glutamate receptor agonists.
European patent application, publication number EP-A1-0870760 discloses that certain 3-substituted 2-carboxycyclopropyl glycine derivatives are modulators of metabotropic glutamate receptor function. The preferred compounds are said to be those in which the substituents at the 1 and 2 positions are in a trans relationship. The examples illustrate such compounds in which the substituents at the 1 and 3 positions are also in a trans relationship. One such compound is (2S,1′S,2′S,3′S)-2′-carboxy-3′-methylcyclopropylglycine.
Surprisingly, novel 3-substituted 2-carboxycyclopropyl glycine derivatives have now been found which are potent agonists of glutamate at metabotropic glutamate receptors.
Accordingly, the present invention provides a compound of the formula:
in which:
R
1
is halo-C
1-10
alkyl; halo-C
2-10
alkenyl; or (CH
2
)
n
Y in which n is 1 or 2 and Y is OH, CN, N
3
, SH, S(O)
p
R
4
, S(O)
3
H, NH
2
, NHR
5
, NR
6
R
7
, NHCOR
8
, NO
2
, CO
2
H, CONHR
9
, 1H-tetrazol-5-yl, 5-phenyltetrazol-2-yl, or PO
3
H
2
; R
3
, R
5
, R
6
, R
7
, R
8
and R
9
are each selected independently from C
1-4
alkyl, aryl and aryl-C
1-4
alkyl; R
4
is selected from C
1-4
alkyl, aryl, aryl-C
1-4
alkyl, 1H-tetrazol-5-yl, carboxy-C
1-4
alkyl and 1H-tetrazol-5-yl-C
1-4
alkyl; and p is 0, 1, 2 or 3;
or a salt or ester thereof.
Compounds of the invention have been found to be agonists of glutamate at metabotropic glutamate receptors and are therefore useful in the treatment of diseases of the central nervous system such as neurological diseases, for example neurodegenerative diseases, and as antipsychotic, anxiolytic, drug-withdrawal, antidepressant, anticonvulsant, analgesic and anti-emetic agents.
It will be appreciated that the compounds of formula (I) contain at least four asymmetric carbon atoms, three being in the cyclopropane ring and one being at the &agr;-carbon of the amino acid group. Accordingly, the compounds of the invention may exist in and be isolated in enantiomerically pure form, in racemic form, or in a diastereoisomeric mixture.
Preferred compounds of the invention are those of the formula
The amino acid moiety preferably has the natural amino configuration. Accordingly, preferred compounds according to the invention are those of the formula:
As used herein, the term halogen atom, as such or as halo, for example as in haloalkyl, includes a fluorine or chlorine atom; a C
1-10
alkyl group includes a C
1-4
alkyl group and can be straight or branched chain, such as, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl, and is preferably methyl or ethyl. A C
2-10
alkenyl group includes, for example, vinyl, prop-2-enyl, but-3-enyl, pent-4-enyl and isopropenyl, and an alkenyl group can contain more than one double bond and, in addition, one or more triple bonds. A preferred alkenyl group is of the formula R′—CH═CH—(CH
2
)
r
— where R′ is hydrogen or C
1-4
alkyl and r is 0, 1 or 2. An aryl group, as such or in an aryl-C
1-4
alkyl may be, for example, a phenyl group or a substituted phenyl group, for example with one or two substituents selected i

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