Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-05-08
2001-01-16
Lee, Howard C. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06174867
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel 1-galactose derivatives having a carbon- or nitrogen-containing aglycon linkage. The compounds of this invention inhibit binding of toxins, such as heat-labile enterotoxin (LT) or cholera toxin (CT), to their receptors either in vitro or in vivo. Additionally, the compounds of this invention inhibit binding enterovirulent organisms (e.g., bacteria, virus, fungi, and the like) such as
Vibrio cholerae
and enterotoxigenic strains of
Escherichia coli
, to their cell surface receptors.
References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1
Spangler, B. D., “Structure and Function of Cholera Toxin and
Related
Escherichia coli
Heat-Labile Enterotoxin”, Microbiological
Reviews, 56(4): 622-647 (1992).
2
Hol, W. G. J., et al., “Structure and Function of
E. coli
Heat-Labile
Enterotoxin and Cholera Toxin B Pentamer”, Bacterial Toxins and
Virulence Factors in Disease, Ed. by J. Moss et al., Marcel Dekker,
Inc. (1995).
3
Williams (ed.), Synthesis of Optically Active &agr;-Amino Acids,
Pergamon Press (1989).
4
Evans et al., J. Amer. Chem. Soc., 112: 4011-4030 (1990).
5
Pu et al., J. Amer. Chem. Soc., 56: 1280-1283 (1991).
6
Williams et al., J. Amer. Chem. Soc., 113: 9276-9286 (1991).
7
Maarten H. D. Postema, “Recent Developments in the Synthesis of
C- Glycosides” Tetrahedron, Vol. 48, No. 40, pp. 8545-8599
(1992).
8
O. R. Martin et al., J. Org. Chem. 1990, 55, 5188-5190.
9
L. Petrus et al., Chem zvesti 1982, 36, 103.
10
A. Förtsch et al., Carbohydr. Res. 1987, 164, 391.
11
Y. Araki et al., Tetrahedron Lett. 1987, 28, 5853.
12
B. Giese et al., Angew. Chem. Intl. Ed. Engl. 1986, 25, 450.
13
Norberg et al., Carbohydr. Res. 1988, 183, 71.
14
R. M. Williams et al., Tetrahedron Lett. 1983, 27, 2715.
15
A. O. Stewart et al., J. Am. Chem. Soc. 1985, 107, 4289.
16
D. S. Brown et al., Tetrahedron Lett. 1989, 45, 4293.
17
K. Narasaka et al., Chem. Lett. 1987, 2139.
18
S. Murata et al., Tetrahedron Lett. 1982, 25, 2601.
19
T. Mukaiyama et al., Carbohydr. Res. 1987, 171, 71.
20
M. Shimizu et al., Chem. Lett. 1984, 1531.
21
M. G. Hoffman et al., Liebigs Ann. Chem. 1985, 2403.
22
P. Allevi et al., J. Chem. Soc., Chem. Commun. 1987, 101.
23
Kagen et al., Synlett, 1990, 643-650.
24
U.S. Pat. No. 5,580,858, issued December 3, 1996, to R. M. Ippolito
et al.
25
M. Dubois et al., Anal. Chem., 28, (1979) 350-356.
26
U.S. Pat. No. 4,137,401, issued January 30, 1979, to R. Lemieux et
al.
27
H. H. Westal et al., “Methods of Enzymology,” 34(b), 64 (1974).
28
Svennerholm, A-M. et al., Current Microbiology, 1: 19-23 (1978).
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
2. State of the Art
Toxins produced by organisms, such as bacteria, viruses, protozoa, fungi and other organisms, are known to cause a number of animal and human diseases, including many diarrheal diseases. For example, heat-labile enterotoxin (“LT”), secreted by certain enterotoxigenic strains of
Escherichia coli
, has been identified as one of the causative agents of bacterial-induced traveller's diarrhea.
1
Additionally, cholera toxin (“CT”), produced by
Vibrio cholerae
, has been identified as the causative agent of the severe diarrheal disease, cholera.
1
Heat-labile enterotoxin and cholera toxin are known to bind to oligosaccharide receptors on host cells as an initial step in the pathological development of the associated disease condition.
2
Specifically, both LT and CT are known to bind to ganglioside G
M1
, a glycosphingolipid situated in the outer leaflet of the host cell membrane.
2
G
M1
has a characteristic pentasaccharide structure, i.e., Gal(&bgr;1→3)GalNAc(&bgr;1→4){NeuAc(&agr;2→3)}Gal(&bgr;1-→4)Glc, on its surface which serves as a receptor for LT and CT. LT is also known to bind to other gangliosides, such as ganglioside G
D1b
.
Additionally, many virulent organisms (e.g., bacteria, virus, fungi, and the like) including enterovirulent organisms bind to cell surface receptors as part of the disease process. For example, bacteria such as
Vibrio cholerae
and enterotoxigenic strains of
Escherichia coli
can directly bind to cell surface receptors forming a colony at the point of attachment. Such binding is detrimental because it permits expressed toxin to immediately interact with the cell surface.
In order to ameliorate or prevent the noxious or deleterious effects caused by toxins and organisms, it would be highly desirable to be able to inhibit the binding of the toxin or the organism to its corresponding cell surface receptor. The present invention provides novel 1-galactose derivatives which effectively inhibit such binding.
SUMMARY OF THE INVENTION
This invention is directed to the discovery of a novel class of 1-galactose derivatives which inhibit the binding of toxins, such as heat-labile enterotoxin (LT) or cholera toxin (CT), to their receptors. The compounds of this invention also inhibit binding of organisms, such as
Vibrio cholerae
and enterotoxigenic strains of
Escherichia coli
, to their cell surface receptors.
Accordingly, in one of its composition aspects, this invention provides compounds of formula I:
wherein
A is selected from the group consisting of arylene, cycloalkylene, cycloalkenylene, heteroarylene and divalent heterocyclic;
B is selected from the group consisting of cycloalkyl, cycloalkenyl and heterocyclic;
Y is selected from the group consisting of alkylene, substituted alkylene and —N(R
1
)—, wherein R
1
is selected from the group consisting of —C(O)R
2
and —SO
2
R
3
, wherein R
2
and R
3
are independently selected from the group consisting of alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl;
Y′ is selected from the group consisting of oxygen, sulfur, —S(O)—, —SO
2
—, alkylene, substituted alkylene, and —N(R
4
)—, wherein R
4
is selected from the group consisting of hydrogen, alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, thioalkoxyalkyl, —C(O)R
5
and —SO
2
R
6
, wherein R
5
and R
6
are independently selected from the group consisting of alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl; and
R
a
, R
b
, R
c
and R
d
are each independently selected from the group consisting of hydrogen; sulfate; —C(O)R
7
, wherein R
7
is selected from the group consisting of alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl; and —P(O)(OR
8
)
2
, wherein each R
8
is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl;
and pharmaceutically acceptable salts thereof.
In one preferred embodiment, the present invention is directed to the &agr;-anomers of compounds of formula I. In another preferred embodiment, this invention is directed to the &bgr;-anomers of compounds of formula I.
In formula I above, A is preferably a cycloalkylene group having from 5 to 7 carbon atoms. More preferably, A is a cycloalkylene group having from 5 to 7 carbon atom wherein the cycloalkylene group is substituted with 1 to 3 alkyl groups. Still more preferably, A is a cyclopentylene, methylcyclopentylene, dimethylcyclopentylene, cyclohexylene, methylhexylene, dimethylcyclohexylene or cycloheptylene group. Still more preferably, A is a dimethylcyclopentylene group.
Preferably, B is a cycloalkyl group having from 4 to 7 carbon atoms. More preferably, B is a cycloalkyl group having 4 to 7 carbon atoms wherein the cycloalkyl group is substituted with 1 to 3 alkyl groups. More preferably, B is a cyclobutyl, methylcyclobutyl, d
Burns Doane , Swecker, Mathis LLP
Lee Howard C.
Synsorb Biotech Inc.
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