Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-08-24
2001-11-13
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S323000
Reexamination Certificate
active
06316406
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel depsipeptide containing N-substituted glycine residue and a pharmaceutical composition containing the same as an active ingredient. The depsipeptides of the invention have a promoting activity on the production of apolipoprotein E and are useful as therapeutic agents for neurologic damages, especially dementia, and hyperlipemia.
2. Description of the Prior Art
As a therapeutic agent for senile dementia, there have been mainly applied activators of cerebral circulation and metabolism, but these drugs have no improving effect on disintegration of the central nervous system which is believed to cause senile dementia. Consequently, they do not show any improving effect on dysmnesia or acalculia which is said to be the main symptom of dementia. In view of this, there has been desired a drug as a new type of the therapeutic agent for senile dementia which may promote the repair and growth of nervous systems while inhibiting the disintegration of the central nervous system. On the other hand, it has been reported that apolipoprotein E may be generated at a high level at the damaged sites of nervous systems which are being repaired (For example, refer to M. J. Igunatius et al., Proc. Natl. Acad. Sci. U.S.A., 83, 1125 (1986)). This suggests that apolipoprotein E will play an important role in repairing the damaged nervous systems.
Moreover, it has recently been reported that a remarkable reduction in a plasma cholesterol level can be observed when apolipoprotein E is administered intravenously to WHHL rabbit, which is a model animal for human familial hypercholesterolemia homozygote (Yamada et al., Proceeding of National Academy Science USA, Vol. 86, pp. 665-669, 1989). Also, it has been reported that plasma cholesterol and plasma triglyceride can be noticeably decreased by transducing a gene for apolipoprotein E into the mouse liver and expressing apolipoprotein E in a large mass (Shimano, H. et al., Journal of Clinical Investigation, Vol. 90, pp. 2084-2091, 1992).
As is apparent from these reports, the increase in plasma apolipoprotein E concentration has been regarded as extremely effective in the treatment of hyperlipemia, especially familial hypercholesterolemia homozygote which has been hitherto considered as difficult to be treated with the prior art drugs.
DETAILED DESCRIPTION OF THE INVENTION
In view of the foregoing, there has been desired a novel type of an antidementia agent which may promote the repairing and growth of the nervous systems and inhibit the disintegration of the central nervous system. It may be inferred that such a desire would be accomplished by compounds promoting the production of apolipoprotein E.
Also, it has been desired to research and develop a drug which may increase a plasma apolipoprotein E concentration as a therapeutic method for hyperlipemia, especially familial hypercholesterolemia homozygote which has been hitherto considered as difficult to be treated with the prior art drugs.
Under these circumstances, we have made our earnest studies to provide a drug for promoting the production of apolipoprotein E, and as a result, the depsipeptides having a specific structure may possess such activities, upon which this invention has been completed.
The present invention relates to a depsipeptide containing N-substituted glycine residue having the formula (1) or (2):
wherein
R
1
is a straight or branched alkyl group of 5-20 carbon atoms or a straight or branched alkoxymethyl group of 5-15 carbon atoms;
R
2
is a group of the formula —A—B—W—(D)
m
—(E)
n
, —A—B—W—(D)
m
—(E)
n
—F or —A—B—W—(D)
m
—(E)
n
—F—Z;
R
3
is a hydroxyl group, a C
1
-C
6
alkoxy group, a benzyloxy group, or a group of the formula —Z, —Z—G or —Z—G—J;
A, B, D, E, F, G and J independently are a N-substituted glycine residue having the formula (3)
(in which R
4
is an alkylene group of 1-4 carbon atoms and R
5
is a hydrogen atom, a hydroxy group, a carboxy group or a carbamido group) or a residue of an amino acid selected from the group consisting of alanine, valine, leucine, isoleucine, serine, threonine, lysine, hydroxylysine, arginine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, histidine, proline, 4-hydroxyproline, piperidine-4-carboxylic acid, homoproline, octahydroindole-2-carboxylic acid, norvaline, norleucine, &agr;-t-butylglycine, cyclohexylglycine, azetidine-2-carboxylic acid, 3-(3-pyridyl)alanine, (3-N-methyl)piperidylalanine, 3-(2-naphthyl)alanine, &bgr;-cyclohexylalanine, &bgr;-t-butylalanine, 9-anthracenylalanine, &agr;-methylalanine, 2-aminobutanoic acid, aspartic acid, asparagine, glutamic acid and glutamine which is optionally substituted with an N-(C
1
-C
4
) alkyl;
W is a residue of an amino acid selected from the group consisting of aspartic acid, glutamic acid and an amino acid of the formula (4)
(wherein p is an integer of 1-4);
Z is a residue of an amino acid selected from the group consisting of aspartic acid, asparagine, glutamic acid, glutamine, alanine, serine and lysine or the N-substituted glycine residue of the formula (3); m and n are independently 0 or 1; provided that a free amino group, a free carboxy group, a free hydroxy group, a free mercapto group or a free &ohgr;-carbamido group and/or a N-terminal amino group possibly existing in said amino acid residues for the above A, B, D, E, F, G, J, W and Z may be protected by a group commonly used as a protecting group in peptide chemistry, and when A, B, D, E, F, G, J, W and Z are a residue of lysine, hydroxylysine, glutamic acid or aspartic acid, either &agr;- or &ohgr;-amino or carboxyl group existing in said residue may form a peptide linkage with its adjacent amino acid and at least one of A, B, D, E, F, G, J, W and Z is the N-substituted glycine residue of the formula (3), or a pharmacologically acceptable salt thereof.
Especially the present invention relates to a depsipeptide of the formula (1) or (2) wherein A, B, D, E, F, G and J independently are the N-substituted glycine residue of the formula (3) or a residue of an amino acid selected from the group of alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, proline, &bgr;-t-butylalanine and aspartic acid; W is a residue of an amino acid selected from the group consisting of aspartic acid, glutamic acid and the amino acid of the formula (4); Z is a residue of an amino acid selected from the group consisting of aspartic acid, asparagine, glutamic acid, glutamine, alanine, serine and lysine or the N-substituted glycine residue of the formula (3) and at least one of A, B, D, E, F, G, J and W is the N-substituted glycine residue of the formula (3); and m and n are 1, or a pharmacologically acceptable salt thereof.
Preferable compounds of the formula (1) are the depsipeptides wherein A is an N-(C
1
-C
4
) alkylglycine residue of the formula (3); B is a residue of an amino acid selected from the group consisting of leucine, isoleucine, phenylalanine, &bgr;-t-butylalanine and aspartic acid; D is a residue of an amino acid selected from the group consisting of valine, phenylalanine, alanine and aspartic acid; E, F, G and J are each independently residues of an amino acid selected from the group consisting of leucine, isoleucine and alanine; W is a residue of an amino acid selected from the group consisting of aspartic acid, glutamic acid and the amino acid of the formula (4); Z is a residue of an amino acid selected from the group consisting of aspartic acid, glutamic acid, glutamine, asparagine and lysine or the N-substituted glycine residue of the formula (3); and m and n are 1, or a pharmacologically acceptable salt thereof.
More preferable compounds of the invention are the depsipeptides of the formula (1) wherein A is an N-(C
1
-C
4
) alkylglycine residue of the formula (3); B is an N-(C
1
-C
4
) alkylglycine residue of the formula (3); D is a residue of an amino acid selected from the group consisting of valine, phenylalanine, alanine and aspartic acid; E, F, G and J are each independently residues of an amino acid selected fro
Hiramoto Shigeru
Kawamura Koji
Kinoshita Nobuhiro
Oshida Norio
Shingai Akiko
Nisshin Seifun Group Inc.
Oblon, Spivak, McClelland & Neustadt, P.C.
Russel Jeffrey E.
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