Sphingosine analogues

Details Sphingosine analogues Sphingosine analogues

1999-10-15

2001-05-22

Richter, Johann (Department: 1609)

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

Organic compounds

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

C554S056000, C554S058000, C554S059000

Reexamination Certificate

active

06235912

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel sphingosine analogue, which is useful as an intermediate for syntheses of TKR1785's and their derivatives useful as drugs for the treatment of fungal infections, allergic diseases, etc., and also as an intermediate for syntheses of novel sphingolipid derivatives. The present invention also relates to a process for production of a novel sphingolipid.
PRIOR ART
Sphingosine is a compound having the chemical formula 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 binding one or several kinds of sugars as Y
1
via a glycoside bond to a ceramide having a fatty acid bound to the amino group of sphingosine via a peptide bond, and sphingophospholipids, including sphingomyelin, binding a phosphoric acid and a base such as choline or ethanolamine as Y
1
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 respiration deficiency and others. Attractive effects of sphingolipids present on the cell membranes include functions in the regulation of cell growth and discrimination of each cells; 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 is indicated, and studies about its effects 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 activation 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.
ABSTRACT OF THE INVENTION
The present invention intends to give a novel sphingosine analogue that is useful as an intermediate for synthesis of a novel lipid derivative, such as sphingolipid derivatives and the like, capable of controlling the function of sphingolipid.
In the course of a search for novel biologically active compounds, the inventors isolated lots of microorganisms, obtained biologically active compounds produced by the microorganisms, and studied on the biological properties. We discovered novel biologically active compounds TKR1785's, which were active against pathogenic fungi including Candida, Aspergillus, Cryptococcus and Malassezia in the culture broth of a strain belonging to Penicillium sp. The inventors also found that the TKR1785's inhibit enzymes involved in allergic reactions.
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 revealed that the compounds are useful intermediates for synthesis of TKR1785's.
Also, the inventors found that the group of compounds described in the following general formula (I), which includes the compound described in the above formula (III) as the representative, is useful to synthesize a novel biologically active compound including novel sphingolipid analogues or others, and then accomplished the present invention.
In the formula, as for Q
1
, Q
2
and Q
3
, Q
1
and Q
2
, which are the same or different each other, are hydrogen, alkyl groups having 1-4 of carbon atoms, acyl groups having 2-5 of carbon atoms, or protecting groups of the amino group, and Q
3
is a hydrogen or a protecting group of the hydroxyl group; or Q
2
and Q
3
make up an isopropylidene group and Q
1
is a hydrogen or a protecting group of the amino group. Q
4
and Q
5
, which are the same or different each other, are hydroxyl groups, acyl groups having 2-5 of carbon atoms, —O—Q
6
, or hydrogen; or Q
4
and Q
5
make up a covalent bond. Q
6
is a protecting group of the hydroxyl group. X
1
is —COOH, —CONH
2
, —CO—Q
7
, —CH
2
OH, or —CH
2
O—Q
8
. Q
7
is a protecting group of the carboxyl group, and Q
8
is a protecting group of the hydroxyl group.


REFERENCES:
patent: 0 897 988 A1 (1999-02-01), None
patent: 62-138497 (1987-06-01), None
Efficient synthesis of sphingosine-1-phosphonate and homo-sphingosine-1 phosphonate, vol. 7, Iss 5, p. 573-576, Mar. 1997.*
Tarnowski et al, Efficient Synthesis of Sphingosine-1-Phosphonate and Homo-Sphingosine-1-Phosphonate,Bioorganic&Medicinal Chemistry Letters 7(5): 573-576, Mar. 4, 1997.

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