Ether type lipid A 1-carboxylic acid analogs

Details Ether type lipid A 1-carboxylic acid analogs Ether type lipid A 1-carboxylic acid analogs

2001-08-09

2003-01-28

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S053000, C536S004100, C536S117000, C536S119000, C536S115000, C536S055000, C514S023000, C514S053000, C514S042000

Reexamination Certificate

active

06511965

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel lipid A analogs having excellent macrophage activity inhibitory action and useful as an anti-inflammatory agent or a medicament against autoimmune diseases or septicemia.
BACKGROUND ART
The outermost layer of the cell wall of gram negative bacteria obtained from enterobacteria contains a toxic component (endotoxin) which is not secreted out of the cell. This endotoxin exhibits, in addition to its endotoxic activity, various biological activities such as immunoadjuvant activating action which is related to biophylaxis, macrophage activating action, mitogen activating action, fever producing action, tumor necrosis action, antibody production enhancing action and TNF inducing action.
It has been confirmed that this endotoxin is composed of a lipopolysaccharide and a portion called “lipid A” which is an active center of endotoxic activity (Imoto et al., Tetrahedron Letters, 26, 1545 (1985)).
It has also been revealed that lipid X and lipid Y, each of which is a monosaccharide separated from a variant of
E. coli
as a precursor for biosynthesis of lipid A, exhibit similar activities to lipid A.
Based on these results, attempts to synthesize derivatives of lipid A, X or Y having useful activity, among the above-described various activities, have been made frequently For example, known is a derivative as described in Japanese Patent Application Laid-Open No. Hei 10-324694.
DISCLOSURE OF THE INVENTION
An object of the present invention is to find a novel lipid A derivative having excellent macrophage activity inhibitory action and useful as an anti-inflammatory agent or a medicament against autoimmune diseases or septicemia.
The present inventors have made a great effort toward fulfilling the above-described object. As a result, it has been found that some series of ether type lipid A 1-carboxylic acid analogs exhibit excellent macrophage activity inhibitory action, leading to the completion of the present invention.
The compounds of the present invention have the general formula (I):
wherein:
R
1
and R
3
may be the same or different and each represents a C
1
-C
20
alkanoyl group which may optionally be substituted with one or more substituent groups selected from substituent group A, a C
3
-C
20
alkenoyl group which may optionally be substituted with one or more substituent groups selected from substituent group A or a C
3
-C
20
alkynoyl group which may optionally be substituted with one or more substituent groups selected from substituent group A;
R
2
and R
4
may be the same or different and each represents a C
1
-C
20
alkyl group which may optionally be substituted with one or more substituent groups selected from substituent group A, a C
2
-C
20
alkenyl group which may optionally be substituted with one or more substituent groups selected from substituent group A or a C
2
-C
20
alkynyl group which may optionally be substituted with one or more substituent groups selected from substituent group A;
R
5
is a hydrogen atom, a halogen atom, a hydroxy group, a C
1
-C
6
alkoxy group which may optionally be substituted with an oxo group, a C
2
-C
6
alkenyloxy group which may optionally be substituted with an oxo group, or a C
2
-C
6
alkynyloxy group which may optionally be substituted with an oxo group;
Substituent group A is a group consisting of a halogen atom, a hydroxy group, an oxo group, a C
1
-C
20
alkoxy group which may optionally be substituted with an oxo group, a C
2
-C
20
alkenyloxy group which may optionally be substituted with an oxo group, a C
2
-C
20
alkynyloxy group which may optionally be substituted with an oxo group, a C
1
-C
20
alkanoyloxy group which may optionally be substituted with an oxo group, a C
3
-C
20
alkenoyloxy group which may optionally be substituted with an oxo group, or a C
3
-C
20
alkynoyloxy group which may optionally be substituted with an oxo group;
or a pharmaceutically acceptable salt or ester thereof.
Preferred compounds of the present invention are:
2) a compound wherein R
1
is a C
4
-C
18
alkanoyl group optionally substituted with one or more substituent groups selected from substituent group A;
3) a compound wherein R
1
is a C
8
-C
16
alkanoyl group optionally substituted with one or more substituent groups selected from substituent group A;
4) a compound wherein R
1
is an unsubstituted C
12
-C
14
alkanoyl group or a C
12
-C
14
alkanoyl group substituted with a hydroxy group;
5) a compound wherein R
1
is an unsubstituted lauroyl or myristoyl group or a lauroyl or myristoyl group substituted with a hydroxy group;
6) a compound wherein R
2
is a C
4
-C
18
alkyl group optionally substituted with one or more substituent groups selected from substituent group A;
7) a compound wherein R
2
is a C
8
-C
16
alkyl group optionally substituted with one or more substituent groups selected from substituent group A;
8) a compound wherein R
2
is an unsubstituted C
12
-C
14
alkyl group or a C
12
-C
14
alkyl group substituted with a hydroxy group;
9) a compound wherein R
2
is an unsubstituted dodecyl or tetradecyl group or a dodecyl or tetradecyl group substituted with a hydroxy group;
10) a compound wherein R
3
is an unsubstituted C
1
-C
16
alkanoyl group;
11) a compound wherein R
3
is an unsubstituted C
1
-C
8
alkanoyl group;
12) a compound wherein R
3
is an unsubstituted C
1
-C
4
alkanoyl group;
13) a compound wherein R
3
is an acetyl group or a propionyl group;
14) a compound wherein R
3
is an acetyl group;
15) a compound wherein R
4
is a C
4
-C
18
alkyl group optionally substituted with one or more substituent groups selected from substituent group A;
16) a compound wherein R
4
is a C
8
-C
16
alkyl group optionally substituted with one or more substituent groups selected from substituent group A;
17) a compound wherein R
4
is a C
12
-C
14
alkyl group substituted with a fluorine atom, a hydroxy group, an unsubstituted C
12
-C
14
alkoxy group or an unsubstituted C
12
-C
14
alkanoyloxy group;
18) a compound wherein R
4
is a dodecyl group or a tetradecyl group substituted with a dodecyloxy group or a tetradecyloxy group;
19) a compound wherein R
4
is a dodecyl group or a tetradecyl group substituted with a lauroyloxy group or a myristoyloxy group;
20) a compound wherein R
5
is a halogen atom, a hydroxy group or an unsubstituted C
1
-C
6
alkoxy group; or
21) a compound wherein R
5
is a fluorine atom, a hydroxy group or a methoxy group.
More preferred compounds are selected from:
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-6-O-methyl-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-&bgr;-D-glucopyranosyl]-3- {(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-&bgr;-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
2,6-anhydro-7-O-[2-acetylamino-2,6-dideoxy-6-fluoro-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-&bgr;-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-3-O-{(R)-3-dodecyloxytetradecyl}-6-O-methyl-4-O-phosphono-&bgr;-D-glucopyranosyl]-3-{(R)-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-3-O-{(R)-3-dodecyloxytetradecyl}-4-phosphono-&bgr;-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid; or
2,6-anhydro-7-O-[2-acetylamino-2,6-dideoxy-3-O-{(R)-3-dodecyloxytetradecyl}-6-fluoro-4-O-phosphono-&bgr;-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid.
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