Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-11
2001-07-31
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S119000, C514S385000
Reexamination Certificate
active
06268507
ABSTRACT:
BACKGROUND OF THE INVENTION
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 Cotman,
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), &agr;-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 heterogenous 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.
International Patent Application Publication No. WO 96/05175 discloses the compound 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid and its salts and esters as metabotropic glutamate receptor agonists.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula
in which:
(a) R
1
represents fluoro, XOR
3
, XNR
4
R
5
, SO
3
H, tetrazol-5-yl, CN or PO
3
R
2
6
and R
2
represents hydrogen; or
(b) R
1
and R
2
each represents fluoro; or
(c) R
1
and R
2
together represent ═O, ═NOR
7
or ═CR
8
R
9
; or
(d) one of R
1
and R
2
represents amino and the other represents carboxyl; or
(e) R
1
represents N
3
, (CH
2
)
m
COOR
3a
, (CH
2
)
m
PO
3
R
6a
2
, NHCONHR
3b
or NHSO
2
R
3c
and R
2
represents hydrogen; or
(f) R
1
and R
2
together represent ═CHCOOR
3b
, ═CHPO
3
R
2
6a
or ═CHCN; and
R
3
represents a hydrogen atom; a (1-6C) alkyl group; a (3-6C)alkenyl group; a (3-6C)alkynyl group; an optionally substituted aromatic group; an optionally substituted heteroaromatic group; a non-aromatic carbocyclic group; a non-aromatic heterocyclic group; a non-aromatic monocyclic carbocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups; a non-aromatic monocyclic heterocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups; or a (1-6C) alkyl, (3-6C)alkenyl or (3-6C)alkynyl group which is substituted by one, two or three groups selected independently from an optionally substituted aromatic group, an optionally substituted heteroaromatic group, a non-aromatic carbocyclic group, a non-aromatic heterocyclic group, a non-aromatic monocyclic carbocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups and a non-aromatic monocyclic heterocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups;
R
3a
, R
3b
and R
3c
are as defined for R
3
;
X represents a bond, CH
2
or CO;
m represents an integer of from 1 to 3;
R
4
represents COR
10
or is as defined for R
3
;
R
5
, R
7
, R
8
, R
9
and R
10
are as defined for R
3
;
R
6
represents hydrogen or a (1-6C)alkyl group; and
R
6a
is defined for R
6
;
or a non-toxic metabolically labile ester or amide thereof; or a pharmaceutically acceptable salt thereof.
The compounds of formula I are modulators of metabotropic glutamate receptor function, in particular agonists or antagonists of glutamate at metabotropic glutamate receptors.
According to another aspect, therefore, the present invention provides a method of modulating metabotropic glutamate receptor function in a mammal including a human, which comprises administering an effective amount of a compound of formula I, or a non-toxic metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof.
According to yet another aspect, the present invention provides the use of a compound of formula I as defined hereinabove for the manufacture of a medicament for use in modulating metabotropic glutamate receptor function.
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 or two being in the cyclopentane ring. It will also be appreciated that compounds of formula I in which R
1
and R
2
together represent ═NOR
7
may be in the syn or anti form, and that compounds of formula I in which R
1
and R
2
together represent ═CR
8
R
9
, ═CHCOOR
3b
, ═CHPO
3
R
2
6a
or ═CHCN may be in the (E) or (Z) form. The present invention includes all stereoisomeric forms of the compounds of formula I, including each of the individual enantiomers and mixtures thereof.
The present invention also includes all physical forms of the compounds of formula I, including crystalline solvates.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
Preferably the compounds of formula I have the configuration Ia or Ib shown below
Unless specified otherwise, the term “alkyl” as used herein means a straight chain or branched alkyl group. Examples of values for a (1-6C)alkyl group include (1-4C)alkyl such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl.
The term (3-6C)alkenyl includes (3-4C)alkenyl such as allyl.
The term (3-6C)alkynyl includes (3-4C)alkynyl such as propynyl.
The term heteroaromatic group includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen. Examples of heteroaromatic groups are furyl, thiophenyl, oxazolyl, isoxazolyl,
Massey Steven Marc
Monn James Allen
Valli Matthew John
Anderson Arvie J.
Eli Lilly and Company
Higel Floyd D.
Sackey Ebenezer
LandOfFree
Hydantoin derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Hydantoin derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hydantoin derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2495077