Sphingosine derivatives and medicinal composition

Details Sphingosine derivatives and medicinal composition Sphingosine derivatives and medicinal composition

2000-04-28

2001-05-29

Carr, Deborah D. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S056000, C554S103000, C554S108000, C514S613000, C514S625000, C514S626000

Reexamination Certificate

active

06239297

ABSTRACT:

TECHNICAL FIELD
The present invention relates to derivatives of sphingosine analogues and their pharmaceutical compositions, which are useful as drugs for the treatment of fungal infections, allergic diseases, immune disorders, etc.
PRIOR ART
Sphingosine is a compound having the chemical structure shown in the general formula described below, in which Y
1
is hydrogen. It is known that various sphingolipids having sphingosine as a constituent are widely distributed in the living body including on the surface of cell membranes of cells in the nervous system. Also we know glycosphingolipids, which have one or several kinds of sugars as Y
1
via a glycoside bond linked to a ceramide having a fatty acid bound to the amino group of sphingosine via a peptide bond, and sphingophospholipids, including sphingomyelin, which have a phosphoric acid and a base such as choline or ethanolamine as Y
1
linked to the above-mentioned ceramide.
A sphingolipid is one of the lipids having important roles in the living body. We know a disease called lipidosis which is caused by accumulation of a specified sphingolipid in the body concomitant with the abnormalities in the metabolic pathways due to defect of an enzyme and others. Attractive effects of sphingolipids present on the cell membranes include functions in the regulation of cell growth and discrimination of each cell; functions in the developments and differentiation; functions in nerves; involvement in the infections and malignancy of cells; and others. Lots of physiological roles of such effects remain to be solved. Recently a possibility that ceramide, a derivative of sphingosine, has an important role in the mechanism of cell signal transduction was indicated, and studies about its effects and so forth on apoptosis and cell cycle have been actively performed.
Fungi and plants have sphingolipids and the major sphingosine contained in these organisms has the formula described below. It is known that these lipids have important roles in the cell growth of fungi and plants, but details of the roles remain to be solved.
Recently it has been known that derivatives of sphingolipids and their related compounds exhibit a variety of biological activities through inhibition or stimulation of the metabolism pathways. These compounds include inhibitors of protein kinase C, inducers of apoptosis, immuno-suppressive compounds, antifungal compounds, and the like. Substances having these biological activities are expected to be useful compounds for various diseases.
SUMMARY OF THE INVENTION
In view of the above present states, the present invention intends to provide a derivative of sphingosine analogue that is able to regulate the functions of sphigolipid, and its pharmaceutical compositions.
In the course of a search for novel biologically active compounds, the inventors discovered novel biologically active compounds TKR1785's, which showed antifungal activity and immunosuppressive activity, in the culture broth of TKR1785 strain belonging to Penicillium sp.
In this specification, TKR1785's are compounds shown in the following general formula (II). TKR1785's described above include TKR1785-I shown as the following formula (IIa) and TKR1785-II (IIb).
The inventors succeeded in preparation of novel sphingosine analogues represented by the following formula (III) by hydrolysis of TKR1785's described above.
Furthermore they succeeded in synthesis of peptide derivatives described in the following general formula (Ia) using, as the starting material, the compound described by the above formula (III) or the compound described by the following formula (IIIa) that was prepared from the compound described by the above formula (III) used as the starting material. They found that these compounds showed biological activities such as antifungal activity and immunosuppressive activity.
In the formula, R
3
and R
4
, which are the same or different each other, are hydroxyl groups or hydrogen; or R
3
and R
4
make up a covalent bond. Y
2
is —COOH or —CH
2
OH.
In the formula, R
1
is hydrogen, an alkyl group having 1-4 carbon atoms, or an acyl group having 2-5 carbon atoms. R
3
and R
4
, which are the same or different each other, are hydrogen or hydroxyl groups; or R
3
and R
4
make up a covalent bond. X
2
is —CO—NH—CH(R
5
)—R
6
or —CH
2
—O—CO—CH(R
7
)—R
8
. R
5
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
6
is —CH
2
OH, —COOH, —CONH
2
, or —CO—NH—CH(R
9
)—R
10
. R
9
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
10
is —CH
2
OH, —COOH, —CONH
2
, or —CO—NH—CH(R
11
)—R
12
. R
11
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
12
is —CH
2
OH, —COOH, or —CONH
2
. R
7
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
8
is —CH
2
OH, —NH
2
, or —NH—CO—CH(R
13
)—R
14
.
R
13
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
14
is —CH
2
OH, —NH
2
, or —NH—CO—CH(R
15
)—R
16
. R
15
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
16
is —NH
2
or —CH
2
OH.
However, the compound which has hydrogen as R
1
and R
3
, a hydroxyl group as R
4
, and —CH
2
—CO—NH—CH(R
5
)—R
6 as X
2
, in which R
5
is —CH(CH
3
)
2
or —CH—(CH
3
)C
2
H
5
, and R
6
is —CO—NH—CH(R
9
)—R
10
in which R
9
and R
10
are —CH
2
OH, is excluded.
Also, the inventors succeeded in preparation of peptide derivatives described by the following general formula (Ib) from various sphingosine analogues which have the chemical structures similar to the above formula (III), including above sphingosine and phytosphingosine, and found that these showed biological activities similar to those of the compounds described by the above general formula (Ia), resulting in completion of the present invention.
In the formula, R
1
, R
3
, and R
4
are the same as described above. X
3
is the same as X
2
of the above formula (Ia).
DETAILED DESCRIPTION OF THE INVENTION
Following is the present invention now described in detail.
Derivatives of sphingosine analogues of the present invention are represented by the general formula (I) described below.
In the formula, R
1
and R
2
, which are the same or different each other, are hydrogen, alkyl groups having 1-4 carbon atoms, or acyl groups having 2-5 carbon atoms. R
3
and R
4
, which are the same or different each other, are hydrogen or hydroxyl groups; or R
3
and R
4
make up a covalent bond. X
1
is —(CH
2
)
n
—CO—NH—CH(R
5
)—R
6
or —(CH
2
)
m
—O—CO—CH(R
7
)—R
8
. The n means an integral number ranging from 0 to 3. R
5
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
6
is —CH
2
OH, —COOH, —CONH
2
, or —CO—NH—CH(R
9
)R
10
. R
9
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
10
is —CH
2
OH, —COOH, —CONH
2
, or —CO—NH—CH(R
11
)—R
12
. R
11
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
12
is —CH
2
OH, —COOH, or —CONH
2
. The m means an integral number ranging from 1 to 3. R
7
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
8
is —CH
2
OH, —NH
2
, or —NH—CO—CH(R
13
)—R
14
. R
13
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
14
is —CH
2
OH, —NH
2
, or —NH—CO—CH(R
15
)—R
16
. R
15
is hydrogen, a hydroxyl group, or an alkyl group having 1-4 carbon atoms which may have a hydroxyl group. R
16
is —NH
2
or —CH
2
OH.
However, the compound which has hydrogen as R
1
, R
2
, and R
3
, a hydroxyl group as R
4
, and —CH
2
CO—NH—CH(R
5
)—R
6
as X
1
, in which R
5
is —CH(CH
3
)
2
or —CH(CH
3
)C
2
H
5
, and R
6
is —CO—NH—CH(R
9
)—R
10
in which R
9
and R
10
are —CH
2
OH, is excluded.
The alk

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