Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Utility Patent
1999-02-11
2001-01-02
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000, C514S061000, C514S062000, C514S536000, C536S017200, C536S018700, C536S053000, C536S055200
Utility Patent
active
06169077
ABSTRACT:
The invention relates to sialyl-Lewis
a
and sialyl-Lewis
x
epitope analogues, their preparation and use, and compositions comprising these compounds.
Carbohydrate domains and cell surfaces play a role in the treatment of many diseases, for example viral and bacterial infections, inflammatory diseases, rheumatic arthritis, allergies, post-infarction syndromes, septic shock, apoplexy, acute and chronic organ rejections, sepsis and cancer (formation of metastases) [Witczak, Z. J., Current Med. Commun. 1:392-405 (1995)]. Carbohydrate epitopes on eukaryotic cells are used by viruses, bacteria and toxins as specific adhesion points [Edwards, M., Curr. Op. in Therapeutic Patents 1617-1630 (1991)]. Carbohydrate domains also function as receptors of roaming malignant cells [Muramatsu, T., Glycobiology 3:294-296 (1993)]. However, they are also specific binding epitopes for certain transmembrane proteins, for example E-, P- and L-selectins. Selectins are found in the surface of both endothelial cells and circulating cells of the haemato-lymphoid system. They undergo specific interactions with carbohydrates [Lasky, L. A., Ann. Rev. Biochem. 64:113-139 (1995); Nelson, R. M., Dolich, S., Aruffo, A., Cecconi, O., Bevilacqua, M. P., J. Clin. Invest. 91:1157-1166 (1993)].
Sialylated and/or fucosylated carbohydrate epitopes are chiefly held responsible for such adhesion phenomena [Varki, A., Glycobiology 3:97-130 (1993)]. The two tetrasaccharide epitopes sialyl-Lewis
a
[&agr;sia(2→3)&bgr;gal(1→3)[&agr;fuc(1→4)]-&bgr;glcNAc-OR] and sialyl-Lewis
x
[&agr;sia(2→3)&bgr;gal(1→4)[&agr;fuc(1→3)]-&bgr;glcNAc-OR] (in which R must be an algycon having at least one carbon atom) are attributed particular importance in pathogenic inflammatory processes [Fukuda, M., Bioorg. Med. Chem. 3:207-215 (1995)].
Several routes have already been taken to isolate derivatives of these carbohydrate epitopes with better binding affinities than the naturally occurring ligand and an increased physiological stability. On the one hand, the natural epitope has been modified only slightly. Thus, N-acetylglucosamine has been replaced by sugars, such as glucosamine or glucose (WO 93/10,796), or by straight-chain or cyclic aliphatic radicals (EP 671,408). On the other hand, as many of the sugar monomers of the epitope as possible have been replaced by other functional units [Allanson, N. M., Davidson, A. H., Floyd, C. D., Martin, F. M., Tetra-hedron Assym. 5:2061-2076 (1994)]. However, none of these various approaches has so far led to epitope analogues having a significantly higher binding affinity. WO 94/26,760 discloses that compounds having higher binding affinities for selectins can be obtained if the N-acetyl group of N-acetylglucosamine, which is regarded as a group which is not relevant to binding (EP 671,408), is replaced by aromatic amides.
Surprisingly, the present invention provides sialyl-Lewis
x
and sialyl-Lewis
a
epitope analogues having an improved binding affinity for the corresponding selecting, in which the naturally occurring N-acetyl group of the N-acetylglucosamine monomer is replaced by various aliphatic and aromatic substituents and the L-fucose naturally present is replaced by various naturally occurring and non-naturally occurring sugars.
The present invention relates to compounds of the formula I or II
in which Z is an &agr;-bonded pyranose of the formula III
with the proviso that Z is not L-fucose,
R
1
is hydrogen, C
1
-C
20
alkyl, C
1
-C
20
alkenyl, C
3
-C
15
cycloalkyl or a mono- or bicyclic C
6
-C
10
aryl or C
2
-C
9
heteroaryl, where alkyl, alkenyl, cycloalkyl, aryl and heteroaryl are unsubstituted or mono- or polysubstituted by a substituent chosen from the group consisting of OH, halogen, halo-C
1
-C
18
alkyl, nitro, C
1
-C
18
alkyl, C
1
-C
18
alkoxy, amino, mono-C
1
-C
18
alkylamino, di-C
1
-C
18
alkylamino, benzylamino, sulfhydryl, thio-C
1
-C
18
alkyl and C
1
-C
18
alkylcarboxamide;
R
2
is C
1
-C
18
alkyl, mono- or polysubstituted C
1
-C
18
alkyl, C
3
-C
8
cycloalkyl or mono- or polysubstituted C
3
-C
8
cycloalkyl, where one or more CH
2
groups in the alkyl and in the cycloalkyl, where appropriate, independently of one another are replaced by oxygen, sulfur or an imino group and the substituents are chosen from the group consisting of OH, SH, NH
2
, carboxamide, C(O)O and C
1
-C
18
alkoxycarbonyl;
R
3
is a methyl or hydroxymethyl group;
the individual R
4
independently of one another are hydrogen, OH, C
1
-C
8
alkyl, O-C
1
-C
8
alkyl, halogen, NH
2
, SH or NHC(O)-C
1
-C
8
alkyl;
R
5
is hydrogen, C
1
-C
8
alkyl or (CH
2
)
m
R
4
, in which m is a number from 1 to 5; and
X is —C(O)—, —C(S)—, —S(O)
2
—, —C(O)Y— or —C(S)Y—, in which
Y is NH, O, S, S-C
1
-C
6
alkylene, NH-C
1
-C
6
alkylene or O-C
1
-C
6
alkylene.
In the context of the present invention, the pyranose is advantageously D-fucose, D,L-arabinose, D,L-ribose, D,L-xylose, D,L-lyxose, L-rhamnose, D,L-galactose, D,L-glucose, D,L-mannose, D,L-gulose, D,L-allose, D,L-altrose, D,L-idose or D,L-talose, in particular D-fucose, D-arabinose, L-galactose or L-glucose. Preferred compounds are those in which the pyranose is an &agr;-bonded D-fucose, D-arabinose, L-galactose or L-glucose, in which one or more R
4
independently of one another are hydrogen, halogen, sulfhydryl, a thioalkyl group, an amino group, an aminoalkyl group, a dialkylamino group or an aminoacyl group; and where the alkyl, where appropriate independently of one another, is a linear or branched C
1
-C
18
alkyl.
In the context of the present invention, the aryl or heteroaryl is a five- or six-membered ring or a bicyclic radical of two fused six- or five-membered rings or one six-membered and one five-membered ring, one or more heteroatoms chosen from the group consisting of the oxygen, nitrogen and sulfur atom being present in the heteroaryl. Examples are derived from benzene, pentalene, naphthalene, indene, furan, pyrrole, pyrazole, imidazole, isoxazole, oxazole, furazan, thiadiazole, thiophene, thiazole, oxadiazole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzothiazole, pyran, pyridine, pyridazine, triazine, pyrimidine, pyrazine, isoquinoline, cinnoline, phthalazine, quinoline, quinazoline, pteridine, benzotriazine or quinoxaline.
Halogen is preferably F, Cl or Br.
The abovementioned alkyl and alkylene can be linear or branched. Some examples of alkyl, alkoxy, thioalkyl and alkylamino, which preferably contain 1 to 12 C atoms, are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl, and corresponding alkoxy, thioalkyl and alkylamino radicals. Preferred alkyl, alkoxy, thioalkyl and alkylamino radicals are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, methoxy, ethoxy, isopropyloxy, methylthio, isopropylthio and ethylthio, aminomethyl, aminoisopropyl and aminoethyl.
Examples of alkenyl are allyl, but-1-en-3- or -4-yl, pent-3- or -4-en-1-, -2- or -3-yl, hex-3-, -4- or -5-en-1- or -2-yl and (C
1
-C
4
alkyl)CH═CH—CH
2
—. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the context of the present invention, preferred compounds of the formula I or II are those in which R
1
is hydrogen, C
1
-C
20
alkyl or C
1
-C
20
alkenyl, which are unsubstituted or mono- or polysubstituted by a substituent chosen from the group consisting of OH, halogen, halo-C
1
-C
18
alkyl, nitro, C
1
-C
18
alkyl, C
1
-C
18
alkoxy, amino, mono-C
1
-C
18
alkylamino, di-C
1
-C
18
alkyl-amino, benzylamino, sulfhydryl, thio-C
1
-C
18
alkyl and C
1
-C
18
alkylcarboxamide. Particularly preferred compounds are those in which R
1
is C
1
-C
10
alkyl or C
1
-C
10
alkenyl, which are unsubstituted or mono- or polysubstituted by a substituent chosen from the group consisting of OH, halogen, halo-C
1
-C
18
alkyl, nitro, C
1
-C
18
alkyl, C
1
-C
18
alkoxy, amino, mono-C
1
-C
18
alkylamino, di-C
1
-C
18
alkylamino, benzylamino, sulfhydryl, thi
Fonda Kathleen K.
GlycoTech Corp.
Seed Intellectual Property Law Group PLLC
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