Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-12-24
2001-07-03
Moezie, F. T. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S018700, C530S330000, C530S331000, C530S333000, C530S323000
Reexamination Certificate
active
06255286
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel depsipeptide and a pharmaceutical preparation containing the same as an active ingredient. The depsipeptides of the invention have a promoting activity on the production of apolipoprotein E, and they are useful as a therapeutic agent for neurologic damages, especially for dementia, and also as a therapeutic agent for hyperlipemia.
BACKGROUND 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 possess no improving effect on dysmnesia and acalculia which are said to be central symptoms of dementia. In view of the above, there has been desired a new therapeutic agent for senile dementia which promotes the repair and growth of nervous systems while inhibiting the disintegration of the central nervous system.
On the other hand, it was reported that apolipoprotein E may be generated at a high level at the sites of nervous systems which were damaged and are being repaired (For example, refer to M. J. Igunatius et al., Proc. Natl. Acad. Sci. U.S.A., 83, 1125 (1986)), which suggests that apolipoprotein E will play an important role in repairing nervous systems. Moreover, it has recently been reported that a remarkable reduction in a plasma cholesterol level can be observed by intravenous administration of apolipoprotein E 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 for the treatment of hyperlipemia, especially, familial hypercholesterolemia homozygote which has been hitherto considered as difficult to be treated with the prior art drugs.
DISCLOSURE OF THE INVENTION
The present invention relates to a depsipeptide represented by the formula (1):
(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—B, —A—B—W, —A—B—W—D or —A—B—W—D—E, R
3
is a hydroxyl group, a lower alkoxy group, a benzyloxy group, —Z, —Z—G or —Z—G—J, said A, B, D, E, G and J independently each other are a residue of an amino acid selected from alanine, valine, leucine, isoleucine, serine, threonine, lysine, hydroxylysine, arginine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, histidine, proline, 4-hydroxyproline, piperizine-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)piperizylalanine, 3-(2-naphthyl)alanine, &bgr;-cyclohexylalanine, &bgr;-t-butylalanine, 9-anthracenylalanine, &agr;-methylalanine, 2-aminobutanoic acid, aspartic acid, asparagine, glutamic acid and glutamine or an N—(C
1
-C
4
) alkyl derivative of said amino acid residue; W and Z independently each other are a residue of an amino acid selected from aspartic acid, asparagine, glutamic acid, glutamine, alanine, serine or lysine; and wherein a free amino group, a free carboxyl group or a free &ohgr;-carbamido group of said amino acid residue and/or an N-terminal amino group may be protected by a protecting group commonly used in peptide chemistry, and when said amino acid residue in the above A, B, D, E, G, J, W and Z is a residue of lysine, hydroxylysine, glutamic acid or aspartic acid, the amino group or carboxyl group capable of being bound to an adjacent amino acid by peptide linkage may be located at either the &agr;-position or the &ohgr;-position) or a pharmacologically acceptable salt thereof.
The present invention also relates to pharmaceutical preparations, an agent for promoting the production of apolipoprotein E, therapeutic agents for neurologic damages, dementia and hyperlipemia, which contains as an active ingredient a depsipeptide represented by the above formula (1) or a pharmacologically acceptable salt thereof.
The invention also relates to a method for the promotion of the production of apolipoprotein E, a method for the treatment of neurologic damages or a method for the treatment of dementia, which comprises administering a depsipeptide represented by the above formula (1) or a pharmacologically acceptable salt thereof.
The invention also relates to a method for the treatment of hyperlipemia, which comprises administering a depsipeptide represented by the above formula (1) or a pharmacologically acceptable salt thereof.
In the above formula (1), it is preferable that A, B, D, E, G and J independently each other are alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, proline, &bgr;-t-butylalanine or aspartic acid, and W and Z independently each other are aspartic acid, asparagine, glutamic acid, glutamine, alanine, serine or lysine.
It is more preferable that A is isoleucine, alanine or aspartic acid, B is leucine, phenylalanine, &bgr;-t-butylalanine or aspartic acid, D is valine, phenylalanine, alanine or aspartic acid, E is leucine or alanine, G is leucine or alanine, J is leucine or alanine, W is aspartic acid, glutamic acid, asparagine, glutamine or serine and Z is aspartic acid, glutamic acid, asparagine, glutamine or lysine.
It is still more preferable that A is isoleucine or alanine, B is leucine or alanine, D is valine or alanine, E is leucine, alanine or glutamic acid, G is leucine or alanine, J is leucine or alanine, W is asparagine or glutamic acid and Z is glutamine, asparagine, glutamic acid, aspartic acid or lysine.
It is particularly preferable that A is isoleucine, B is leucine, D is valine, E is leucine, G is leucine, J is leucine, W is aspartic acid or glutamic acid and Z is glutamine, asparagine, glutamic acid, aspartic acid or lysine.
In the above formula (1), R
1
is preferably a straight alkyl or alkoxymethyl group of 6-12 carbon atoms.
The above-recited amino acids which compose the depsipeptides having the formula (1) of the invention may be either L-isomers or D-isomers, while the amino acids represented by A, D, G, J, W and Z are preferably L-isomers and the amino acid represented by B and E are preferably D-isomers. A protecting group for the free amino groups in said amino acid residues includes, for example, a t-butoxycarbonyl (hereinafter referred to as “Boc”) group, a benzyloxycarbonyl group (hereinafter referred to as “Cbz”), a p-methoxy-benzyloxycarbonyl group or a 9-fluorenylmethoxycarbonyl group (hereinafter referred to as “Fmoc”) or the like, a protecting group for the free carboxyl groups in said amino acid residues includes a benzyloxy group (hereinafter referred to as “Obzl”) or a t-butoxy group (hereinafter referred to as “OtBu”) or the like, and a protecting group for &ohgr;-carbamido groups in Gln or Asn includes 4,4′-dimethoxybenzhydryl (hereinafter referred to as “Mbh”) group or the like.
As a protecting group for the N-terminal amino group in said depsipeptide, there may be used those conventionally employed in peptide chemistry, such as a Boc group, a Cbz group, a p-methoxybenzyloxycarbonyl group, a Fmoc group and the like.
As a protecting group for the C-terminal carboxy group in said depsipeptide, there may be used an OBzl group, an OtBu group and the like.
The depsipeptides of the above formula (1) have an action of promoting the production of apolipoprotein E in Hep G2 cells, which possess various functions of the liver. Apolipoprotein E has an action of repairing neurologic damages and also an action of lowering blood cholesterol and triglyceride levels. Therefore, the depsipeptides
Hiramoto Shigeru
Kawamura Koji
Kinoshita Nobuhiro
Oshida Norio
Shingai Akiko
Moezie F. T.
Nisshin Flour Milling Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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