Aminoalcohol derivative and medicament comprising the same

Details Aminoalcohol derivative and medicament comprising the same Aminoalcohol derivative and medicament comprising the same

2000-12-05

2002-06-18

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S019300, C514S025000, C514S035000, C514S043000, C514S237800, C530S331000, C536S017400, C536S029110, C544S168000, C544S169000

Reexamination Certificate

active

06407064

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an aminoalcohol derivative which is a ceramide analogue and a medicament, particularly an agent for treating neuronal diseases and an agent for protecting brain, comprising the same.
2. Brief Description of the Background Art
Glycosphingolipids (hereinafter referred to as “GSL”) are present as a constitutional component of cell surface membranes of mammalian cells and play important roles in cellular functions, such as development, growth, differentiation, malignant transformation, immunoreaction and the like, through a receptor function of a physiologically active substance, an intercellular mutual recognizing function, an intercellular interaction, and the like.
Among them, a ganglioside is a GSL containing sialic acid and is said to be active in the recovery from neuronal diseases, such as peripheral nervous injury, central nervous disorder and the like, i.e., an acceleration of nervous regeneration and a process of neurotransmission. Heretofore, the effectiveness of exogenous gangliosides has been investigated toward various pathological models of nervous system. As a medicament utilizing the same, a medicament named “Cronassial™” has already been commercialized in Italy and a related patent is also known (JP-B-62-50450).
Currently, the addition of a ganglioside to an experimental system from outside is the most popular type of a procedure for searching a function of the ganglioside. In that case, however, a relation to endogenous gangliosides becomes a problem. That is, it is considered that the result obtained from the further addition of the ganglioside to the system where endogenous gangliosides present in cell membranes have already formed complexes with various cell surface receptors etc. does not always reflect the actual cytophysiological significance of endogenous gangliosides. Therefore, a method of specifically changing biosynthesis of endogenous GSLs is necessary to identify an intrinsic role of a ganglioside in cell cytophysiology.
Incidentally, it is reported that a ceramide analogue, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) specifically inhibits an enzyme for glucosylceramide biosynthesis and remarkably reduces intracellular content of all GSLs which are produced starting with glucosylceramide (
J. Lipid Res.,
28: 565-571 (1987)). Furthermore, it is also reported that D-threo-PDMP suppresses the extension of neurite (
J. Biochem.,
110: 96-103 (1991)). In addition, it has been found that D-threo-PDMP suppresses synaptic function and the suppression is specifically released by GQ1b among various gangliosides (
Biochem. Biophys. Res. Commun.,
222: 494-498 (1996)). Based on these results, it is suggested that the ganglioside GQ1b is an active molecule necessary for synaptic function and the importance of endogangliosides on nervous functions is recognized.
On the other hand, there is suggested a possibility that L-threo-PDMP (hereinafter often referred to as “L-PDMP”) which is an optical enantiomer of D-threo-PDMP accelerates the biosynthesis of GSL (
J. Cell. Physiol.,
141: 573-583 (1989)).
In addition, it is also shown that 2-acylaminopropanol compounds, such as L-threo-PDMP and the like, accelerate ganglioside biosynthesis of neurocytes and exhibit an effect of accelerating neurite extension (
J. Neurochem.,
67: 1821-1830, 1996) and an effect of accelerating synapse formation, and therefore, is promising as an agent for treating neuronal diseases (WO 95/05177).
Furthermore, as a result of the examination of the effects of L-threo-PDMP on MAPkinase (mitogen-activated protein kinase) activated when synaptic transmission is continuously accelerated by N-methyl-D-aspartate (NMDA) or a brain derived neurotropic factor (BDNF) in order to elucidate an action mechanism of the neurotropic factor-like activity of L-threo-PDMP, it was found that L-threo-PDMP activates MAPkinase for a long period of time in proportion to the effect of accelerating synapse formation and further, L-threo-PDMP increases the activity of an enzyme for GQ1b synthesis (
Biochem. Biophys. Res. Commun.,
237: 595-600 (1997)).
However, in order to exhibit the pharmaceutical effect of L-threo-PDMP in vivo, it is judged that there is room for the improvement in an pharmaceutical effect-toxicity ratio and a distribution ability of the compound into tissues.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an aminoalcohol derivative or pharmaceutically acceptable salt thereof which has an activity of accelerating synapse formation and/or an activity of accelerating glycolipid biosynthesis, a low toxicity, and an improved distribution ability into tissues.
Another object of the present invention is to provide a medicament, particularly an agent for treating neuronal diseases or an agent for protecting brain comprising the aminoalcohol derivative.
The present invention have been achieved by an aminoalcohol derivative which is a ceramide analogue, and a medicament, especially an agent for treating neuronal diseases and an agent for protecting brain, comprising the same.
A first embodiment of the present invention is as follows:
(1) An aminoalcohol derivative represented by formula (I):
wherein * represents an asymmetric carbon; and
R represents a residue of a monocarboxylic acid derivative represented by the following (i) or (ii), or a residue of a dicarboxylic acid or a derivative thereof represented by the following (iii):
(i) a residue of glycine or polyglycine represented by (COCH
2
NH)
m
Z,
wherein m represents an integer of from 1 to 3; and
Z represents an amino-protecting group or an alkanoyl group;
(ii) a residue of a carboxylic acid derivative represented by CO—W—Y,
wherein W represents an alkylene group or a cycloalkylene group; and
Y represents a hydroxyl group, a monosaccharide residue, an aryl group which is optionally substituted, or an alkoxyl group optionally having an oxygen atom in the alkyl chain;
(iii) a residue of a dicarboxylic acid or a derivative thereof represented by CO—W—CO—X,
wherein W represents an alkylene group or a cycloalkylene group; and
X represents a hydroxyl group, a chain or cyclic alkoxyl group, an alkyl group, an &agr;-amino acid residue, or NR
1
R
2
, in which R
1
and R
2
are the same or different and each independently represents a hydrogen atom, a chain or cyclic alkyl group optionally having an oxygen atom in the alkyl chain, or a chain or cyclic hydroxyalkyl group optionally having an oxygen atom in the alkyl chain, or
a pharmaceutically acceptable salt thereof.
A second embodiment of the present invention is as follows:
(2) A medicament comprising, as an active ingredient, the aminoalcohol derivative represented by formula (I) or a pharmaceutically acceptable salt thereof.
Also, the compound of formula (I) has 4 configurations, (1S,2S), (1S,2R), (1R,2S), and (1R,2R). As the active ingredient of an agent for treating neuronal diseases and an agent for protecting brain, L-threo compound having a configuration of (1S,2S) is preferred.
Specific embodiments of the present invention include the following aminoalcohol derivatives and pharmaceutically acceptable salts thereof:
(a) The aminoalcohol derivative according to the above (1), wherein R is represented by any one of the following (i) to (iii) in formula (I):
(i) (COCH
2
NH)
m
Z,
wherein Z represents an amino-protecting group selected from an aralkyloxycarbonyl group having from 8 to 15 carbon atoms and an alkoxycarbonyl group having from 5 to 7 carbon atoms, or an alkanoyl group having from 4 to 8 carbon atoms;
(ii) CO—W—Y,
wherein W represents an alkylene group having from 1 to 12 carbon atoms or a cycloalkylene group having from 4 to 8 carbon atoms; and
Y represents a hydroxyl group, a glucose residue, a galactose residue, an N-acetylglucosamine residue, an N-acetylgalactosamine residue, a mannose residue, a fucose residue, a sialic acid residue, a phenyl group which is optionally substituted, an alkoxyl group having from 1 to 6 carbon atoms, or an alkoxyl g

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