Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-12-16
2001-04-03
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S009100, C514S016700, C530S317000, C530S323000, C530S329000
Reexamination Certificate
active
06211145
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a bicyclic depsipeptide and a pharmaceutical composition containing the same as an active ingredient. The bicyclic depsipeptides of the invention have a promoting activity on the production of apolipoprotein E which has a repairing action on neurologic damages so that the bicyclic depsipeptides of the invention are useful as the therapeutic agents for neurologic damages, especially as an antidementia agent, and also as a therapeutic agent for 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 display any improving effect on dysmnesia or acalculia which is said to be the main symptom of dementia. 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)), which suggests that apolipoprotein E will play an important role in repairing the nervous systems.
Moreover, it has recently been reported that a remarkable reduction in a plasma cholesterol level is 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, an increase in apolipoprotein E level in plasma 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 as a novel type of a therapeutic agent for senile dementia a drug which may promote the repair and growth of the nervous systems and inhibit the disintegration of the central nervous system, besides activators of cerebral circulation and metabolism.
Also, it has been desired to elucidate a drug which may increase apolipoprotein E level in plasma 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, a certain bicyclic depsipeptide may possess such an activity, upon which this invention has been completed.
The present invention relates to a bicyclic depsipeptide having the formula (1)
or a pharmacologically acceptable salt thereof.
In the above formula (1), R is a straight or branched alkyl group of 5-20 carbon atoms or a straight or branched alkoxymethyl group of 5-15 carbon atoms; A, D, E and J independently are a residue of an amino acid selected from the group of alanine, valine, leucine, isoleucine, serine, threonine, lysine, hydroxylysine, arginine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, histidine, proline, 4-hydroxyproline, aspartic acid, glutamic acid, 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 or 2-aminobutanoic acid which is optionally substituted with an N-(C
1
-C
4
) alkyl; B and F are the same or different and a residue of an amino acid selected from the group consisting of cysteine, aspartic acid, glutamic acid, lysine, hydroxylysine and serine; G is a disulfide bond, an amido bond or an ester bond; W is a residue of an amino acid selected from the group consisting of aspartic acid and glutamic acid; Z is a residue of an amino acid selected from the group consisting of aspartic acid, asparagine, glutamic acid and glutamine; l, m, n, p and q independently are 0 or 1; provided that G is formed by binding each other a thiol, carboxyl, hydroxyl or amino group contained in the amino acid residues B and F, a free amino, carboxyl, hydroxyl, mercapto or &ohgr;-carbamido group which possibly exists in said amino acid residue may be protected by a group commonly used in peptide chemistry as a protective group and when A, B, D, E, F, 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.
The invention specifically relates to a bicyclic depsipeptide having the formula (1) wherein A, J, D and E independently are a residue of an amino acid selected from the group of alanine, valine, leucine, isoleucine, serine, threonine, lysine, arginine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, histidine, proline, aspartic acid and glutamic acid or an N-(C
1
-C
4
) alkyl substituted amino acid residue thereof, or a pharmacologically acceptable salt thereof.
The compound of the present invention is preferably a bicyclic depsipeptide having the formula (1) wherein B is a cysteine residue; J is a residue of an amino acid selected from the group consisting of leucine, alanine, &bgr;-t-butylalanine, valine and phenylalanine; D is a residue of an amino acid selected from the group consisting of valine and alanine; E is a residue of an amino acid selected from the group consisting of leucine, isoleucine, alanine, &bgr;-t-butylalanine, valine and phenylalanine; F is a cysteine residue; W is a residue of an amino acid selected from the group consisting of aspartic acid and glutamic acid; Z is a residue of an amino acid selected from the group consisting of aspartic acid, glutamic acid, glutamine and asparagine; G is a disulfide linkage; l, m and n are 0 or 1; p is 0; q is 1; and R is a straight or branched alkyl or alkoxymethyl group of 6-12 carbon atoms, or a pharmacologically acceptable salt thereof.
Other type of the present compound is preferably a bicyclic depsipeptide having the formula (1) wherein A is a residue of an amino acid selected from the group consisting of isoleucine, leucine, alanine, &bgr;-t-butylalanine, valine and phenylalanine; B is a cysteine residue; D is a residue of an amino acid selected from the group consisting of valine and alanine; E is a residue of an amino acid selected from the group consisting of leucine, isoleucine, alanine, &bgr;-t-butylalanine, valine and phenylalanine; F is a cysteine residue; W is a residue of an amino acid selected from the group consisting of aspartic acid and glutamic acid; Z is a residue of an amino acid selected from the group consisting of aspartic acid, glutamic acid, glutamine and asparagine; G is a disulfide linkage; l, m and n are 0 or 1; p is 1; q is 0; and R is a straight or branched alkyl or alkoxymethyl group of 6-12 carbon atoms, or a pharmacologically acceptable salt thereof.
In the formula (1), preferably n=1 and p+q=1.
Further the present invention relates to a pharmaceutical composition which contains as an active ingredient a therapeutically effective amount of the bicyclic depsipeptide of the formula (1) and a pharmaceutically acceptable carrier therefor.
The invention especially relates to a pharmaceutical composition for promoting the production of apoprotein E which contains as an active ingredient a therapeutically effective amount of the bicyclic depsi
Hiramoto Shigeru
Kawamura Koji
Kinoshita Nobuhiro
Oshida Norio
Shingai Akiko
Low Christopher S. F.
Mohamed Abdel A.
Nisshin Flour Milling Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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