Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
1999-01-22
2001-06-26
Low, Christopher S. F. (Department: 1654)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C530S330000, C530S332000, C514S017400, C514S018700, C514S019300
Reexamination Certificate
active
06252041
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel depsipeptide 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 could 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 as a new type of the therapeutic agent for senile dementia a drug which may promote 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)), which 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 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 for 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
Under these circumstances, the present inventors have made earnest studies to provide a drug for promoting the production of apolipoprotein E, and as a result, the depsipeptide derivatives having a specific structure may possess such activities, upon which the invention has been completed.
The present invention relates to a depsipeptide having the formula (1):
wherein
R
1
represents a straight or branched C
5
-C
20
alkyl group or a straight or branched C
5
-C
15
alkoxymethyl group,
R
2
represents
—O—CO—CH(R
5
)—X—CH(R
6
)—NH—
(wherein X represents N(R
7
)—CO, N(R
8
)—CH
2
, CH
2
—CO, CH
2
—CH
2
, CH═CH, CH
2
—CH(OH) or CH(OH)—CH(OH), R
5
, R
6
, R
7
and R
8
represent a hydrogen atom or a straight or branched C
1
-C
6
alkyl group),
R
3
represents
(wherein Y represents N(R
12
)—CO, N(R
13
)—CH
2
, CH
2
—CO, CH
2
—CH
2
, CH═CH, CH
2
—CH(OH) or CH(OH)—CH(OH), n represents an integer of 1-3, R
9
, R
10
, R
12
and R
13
represent a hydrogen atom or a straight or branched C
1
-C
6
alkyl group and R
11
represents a protecting group for an amine commonly used in peptide chemistry),
R
4
represents a hydroxyl group, a straight or branched C
1
-C
6
alkoxy group, a benzyloxy group, A, A-B or
—NH—CH(R
14
)—Z—CH( R
15
)—COR
16
(wherein Z represents CH
2
—N(R
17
), CO—CH
2
, CO—N(R
18
), CH
2
—CH
2
, CH═CH, CH(OH)—CH
2
or CH(OH)—CH(OH), R
14
represents a hydrogen atom, a straight or branched C
1
-C
6
alkyl group or —(CH
2
)
m
—COR
19
, R
15
, R
17
and R
18
represent a hydrogen atom or a straight or branched C
1
-C
6
alkyl group, R
16
represents a hydroxyl group, a straight or branched C
1
-C
6
alkoxy group or a benzyloxy group, R
19
represents a hydroxyl group, an amino group or a C
1
-C
6
alkoxy group, and m represents an integer of 1-3),
A represents a residue of an amino acid selected from the group of alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, proline, aspartic acid, asparagine, glutamic acid, glutamine, serine, lysine and &bgr;-t-butylalanine or an N-methyl derivative of said amino acid residue,
B represents 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, asparagine, glutamic acid, glutamine, 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 and 2-aminobutanoic acid or an N-methyl derivative of said amino acid residue, when the amino acid for A or B contains a free amino group, free carboxyl group, free &ohgr;-carbamido group, free hydroxyl group, free mercapto group and/or an N-terminal amino group, said free group may be protected by a group commonly used in peptide chemistry, respectively, and when A and B are 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;
except that X is N(R
7
)—CO, Y is N(R
12
)—CO and R
4
is hydroxyl, straight or branched alkoxy having 1-6 carbon atoms, benzyloxy, A, A—B or —NH—CH(R
14
)—Z—CH(R
15
)—COR
16
(wherein Z is CO—N(R
18
));
or a pharmacologically acceptable salt thereof.
The invention also relates to a pharmaceutical composition which comprises as an active ingredient a depsipeptide containing non-natural amino acids as described above or a pharmacologically acceptable salt thereof.
Specifically, the invention relates to a pharmaceutical composition for promoting the production of apolipoprotein E which comprises as an active ingredient a depsipeptide containing non-natural amino acids as described above or a pharmacologically acceptable salt thereof.
Further, the invention relates to a pharmaceutical composition for treating neurologic damages, dementia or hyperlipemia which comprises as an active ingredient a depsipeptide containing non-natural amino acids as described above or a pharmacologically acceptable salt thereof.
Further, the invention relates to a method for treating neurologic damages, dementia or hyperlipemia which comprises administering a therapeutically effective amount of a depsipeptide containing non-natural amino acids as described above or a pharmacologically acceptable salt thereof to a host affected with neurologic damages, dementia or hyperlipemia.
Furthermore, the invention also relates to use of the depsipeptide containing non-natural amino acids as described above or a pharmacologically acceptable salt thereof for treating neurologic damages, dementia or hyperlipemia.
In the formula (1), there may be preferably mentioned that X is CH═CH or CH
2
—CH
2
, Y is N(R
12
)—CO or N(R
13
)—CH
2
and R
4
is a hydroxyl group, A, A—B or —NH—CH(R
14
)—Z—COR
15
)—COR
16
(wherein Z is CH═CH).
Preferable compounds of the formula (1) include the compounds wherein X is CH═CH, Y is N(R
12
)—CO or N(R
13
)—CH
2
and R
4
is a hydroxyl group, A, A—B or —NH—CH(R
14
)—Z—CH(R
15
)—COR
16
(wherein Z is CH═CH).
There may be preferably mentioned the depsipeptides containing non-natural amino acids of the above formula (1) wherein R
4
is a hydroxyl group or A is aspartic acid, asparagine, glutamic acid or glutamine, B is alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, proline, aspartic acid, asparagine, glutamic acid, glutamine or &bgr;-t-butylalanine, or a pharmacologically acceptable salt t
Hiramoto Shigeru
Kawamura Koji
Kinoshita Nobuhiro
Oshida Norio
Shingai Akiko
Low Christopher S. F.
Lukton David
Nisshin Flour Milling Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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