Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-28
2001-06-12
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C560S124000, C562S506000
Reexamination Certificate
active
06245919
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel cyclopropylglycine derivatives and an agonist comprising the derivative as an active compound. The agonist acts on metabotropic L-glutamate receptors.
BACKGROUND OF THE INVENTION
Glutamate receptors are roughly categorized into two types, namely, ionotropic type (iGluR) and metabotropic type (mGluR). The receptors of ionotropic type (iGluR) are further categorized into NMDA (N-methyl-D-aspartic acid) type and non-NMDA type [Jpn. J. Neuropsychopharmacol., 18(5), 345-365 (1996)].
When NMDA receptors are activated with agonists, they introduce calcium ions (Ca
2+
) into cells to increase the intracellular Ca
2+
concentration. In the cells, accordingly, various Ca
2+
-dependent enzymes are activated to cause a chain of cellular changes. If the cellular changes proceed over a certain threshold value, the cell is presumed to lose irreversibly its life [Folia Pharmacol. Jpn., No. 104, 177-187 (1994)].
The metabotropic L-glutamate receptors (mGluR) are classified into three groups (Groups-I, -II and -III) based on their sequence homology, intracellular signal transduction pathway, and selectivity of agonists for receptor sub-types. A typical example of the agonist for Group-I is quisqualic acid, which promotes formation of inositol triphosphate (IP
3
) and variations of intracellular Ca
2+
dynamics.
The agonists for Group-II and Group-III inhibit intracellular CAMP formation induced by forskolin. In the agonist selectivity, the mGluR of Group-II differs from that of Group-III.
Examples of the agonists for mGluR of Group-II include DCG-IV [(2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine] and L-CCG-I [(2S,1′S,2′S)-2-(2-carboxycyclopropyl)glycine]. Examples of the agonists for mGlu R of Group-III include L-AP4 [L-2-amino-4-phosphonobutyric acid] [Japanese Patent Provisional Publications No. 6(1994)-256323 and No. 6(1994)-24970, and Jpn. J. Neuropsychopharmacol., 18(6), 419-425 (1996)].
The agonists for mGluR of Group-II are known to inhibit release of transmitter at synapses, and consequently to lower the efficiency of synaptic conduction. If the synaptic transmission efficiency is lowered in the central nervous system, the muscles in the kinetic system are presumed to be relaxed. Actually, it has been ascertained by experiments on animals that the agonists for mGluR of Group-II remarkably potentiate anesthesia. These agonists are also known to give sedation (or tranquilizer-like) effect and anti-epileptic effect. Further, since these agonists can protect the neurons cells from death in vivo and in vitro caused by excitatory amino acids, they are expected to be used as neuron protectors. Since the agonists for mGluR of Group-II are utterly new agonists for glutamate receptors and seem to be indispensable for pharmaceutical studies of the central nervous system, they are of great value as reagents for the laboratory study. [Folia Pharmacol. Jpn., No. 104, 177-187 (1994)].
DCG-IV (which is one of the known agonists for mGluR of Group-II) strongly activates the mGluR, and is hence expected to act as a neuron protector. However, since DCG-IV also activates NMDA receptors (which are presumed to be concerned with cell death caused by excitatory amino acids), it is desired to develop a new agonist for mGluR having no NMDA activating component.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel cyclopropylglycine derivative having better selectivity and characteristics than known agonists for glutamic acid receptors of metabolic regulation type.
It is another object of the invention to provide a new compound employable as an intermediate for preparing the novel cyclopropylglycine derivative.
This invention resides in a cyclopropylglycine derivative having the following formula (I).
In the formula (I), each of R
1
and R
2
independently represents a hydroxyl group or an alkoxy group having 1 to 6 carbon atoms, each of R
3
and R
4
independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and each of X
1
and X
2
independently represents a halogen atom.
The invention also resides in an agonist which acts on L-glutamic acid receptors of metabolic regulation type and which comprises the cyclopropylglycine derivative having the formula (I) as an active component.
Further, the invention resides in a pharmaceutical composition comprising the cyclopropylglycine derivative having the formula (I) as an active component.
The intermediate provided by the invention is a lactam derivative having the following formula (II).
In the formula (II), R
2
represents a hydroxyl group or an alkoxy group having 1 to 6 carbon atoms, R
3
represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and each of X
1
and X
2
independently represents a halogen atom.
PREFERRED EMBODIMENTS OF THE INVENTION
The cyclopropylglycine derivative of the invention has the following formula (I):
In the formula (I), each of R
1
and R
2
independently represents a hydroxyl group or an alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and isobutoxy), each of R
3
and R
4
independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl), and each of X
1
and X
2
independently represents a halogen atom (e.g., fluorine, chlorine, bromine, and iodine).
The cyclopropylglycine derivative of the invention can be used in the form of a free acid or its salt. Preferably, in the formula (I), each of R
1
and R
2
represents a hydroxyl group, each of R
3
and R
4
represents a hydrogen atom, and each of X
1
and X
2
represents a fluorine atom. In other words, a preferred embodiment of the derivative is 2-(2′-carboxy-3′,3′-difluoro)cyclopropylglycine. This compound has the following eight optical isomers.
L-I: (2S,1′S,2′S)-2-(2′-carboxy-3′,3′-difluoro)-cyclopropylglycine,
L-II: (2S,1′R,2′R)-2-(2′-carboxy-3′,3′-difluoro)-cyclopropylglycine,
L-III: (2S,1′S,2′R)-2-(2′-carboxy-3′,3′-difluoro)-cyclopropylglycine,
L-IV: (2S,1′R,2′S)-2-(2′-carboxy-3′,3′-difluoro)-cyclopropylglycine,
D-I: (2R,1′R,2′R)-2-(2′-carboxy-3′,3′-difluoro)-cyclopropylglycine,
D-II: (2R,1′S,2′S)-2-(2′-carboxy-3′,3′-difluoro)-cyclopropylglycine,
D-III: (2R,1′R,2′S)-2-(2′-carboxy-3′,3′-difluoro)-cyclopropylglycine,
D-IV: (2R,1′S,2′R)-2-(2′-carboxy-3′,3′-difluoro)-cyclopropylglycine,
Most preferred is (2S,1′S,2′S)-2-(2′-carboxy-3′,3′-difluoro)cyclopropylglycine [L-I].
The cyclopropylglycine derivative of the invention can be prepared in the manner shown in the following reaction scheme-1 and -2. In the reaction scheme-1, a known olefin compound [E-1 or Z-1; see J. Org. Chem., 59(1), 97-103(1994)] is caused to react with sodium chlorodifluoroacetate to prepare two optical isomers of 2-(2′-benzyloxymethyl-3′,3′-difluoro)cyclopropylethyleneglycol 1,2-O-acetonide [reaction from E-1 is described in Tetrahedron: Asymmetry, 5(8), 1423-1426(1994)]. From thus obtained compounds, the target cyclopropylglycine derivatives can be prepared in the manner shown in the reaction scheme-2. The reaction scheme-2 shows, for example, the reactions for preparing the derivatives of L-I and D-II.
REFERENCES:
patent: 06024970 (1994-02-01), None
Tetrahedron, vol. 52, No. 1, p271-278, 1996, Shibuya et al., ‘A highly diastereoselective synthesis of trans-3,4-(difluoromethano)glutamic acid.’
Ishida Michiko
Shinozaki Haruhiko
Taguchi Takeo
Davis Brian J.
Reed Smith LLP
Richter Johann
Shinozaki Haruhiko
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