Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-01-08
2001-02-13
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000, C514S061000, C514S062000, C536S017200, C536S018700, C536S053000, C536S055200
Reexamination Certificate
active
06187754
ABSTRACT:
The invention relates to sialyl-Lewis
a
and sialyl-Lewis
x
epitope analogues, in which the natural N-acetyl group of the N-acetylglucosamine monomer is replaced by various hydroxylated aromatic substituents, to their preparation and use and to compositions which comprise these compounds.
Carbohydrate domains on cell surfaces are of importance in the therapy of many diseases, for example of viral and bacterial infections, inflammatory diseases, rheumatic arthritis, allergies, post-infarction syndromes, septic shock, stroke, 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 attachment sites [Edwards, M., Curr. Op. in Therapeutic Patents 1617-1630 (1991)]. Carbohydrate domains also function as receptors for peripatetic malignant cells [Muramatsu, T., Glycobiology 3:294-296 (1993)]. However, they also constitute specific binding epitopes for certain transmembrane proteins, for example E, P and L selectins. Selectins are present in the surface of endothelial cells and of circulating cells of the hematolymphoid system. They enter into 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- (1993)].
Sialylated and/or fucosylated carbohydrate epitopes are in the main thought to be responsible for these adhesion phenomena [Varki, A., Glycobiology 3:97-130 (1993)]. A particular importance in pathogenic inflammatory processes is attributed to the two tetrasaccharide sialyl-Lewis
a
[&agr;sia(2→3)&bgr;gal(1→3)[&agr;fuc(1→4)]-&bgr;glcNAc-OR*] and sialyl-Lewis
x
[asia(2→3)&bgr;gal(1→4)[&agr;fuc(1→3)]-&bgr;glcNAc-OR*] epitopes (with R* having to be an aglycone having at least one carbon atom) [Fukuda, M., Bioorg. Med. Chem. 3:207-215 (1995)].
Several routes have already been pursued for obtaining derivatives of these carbohydrate epitopes which have both better binding affinities than that of the natural ligand and an increased physiological stability. On the one hand, the native epitope has been modified to only a trivial extent. Thus, N-acetylglucosamine has been replaced by sugars such as glucosamine or glucose (WO 93/10 796) or by straight-chain or cyclic aliphatic residues (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., Tetrahedron Assym. 5:2061-2076 (1994)]. However, none of these different approaches has so far resulted in epitope analogues having significantly higher binding affinities. WO 94/26 760 discloses that compounds having higher binding affinities for selectins can be obtained if the N-acetyl group of the N-acetylglucosamine, which group is not regarded as being relevant for binding (EP 671 408), is replaced by aromatic amides.
Surprisingly, the present invention makes available sialyl-Lewis
x
and sialyl-Lewis
a
epitope analogues having an improved binding affinity for the corresponding selectins, in which analogues the natural N-acetyl group of the N-acetylglucosamine monomer is replaced by various hydroxylated aromatic substituents.
Inter alia, the present invention provides compounds of the formula I or II
in which
Z is an &agr;-bonded L-fucose of the formula III
R
1
is a monocyclic or bicyclic C
6
-C
10
aryl or C
2
-C
9
heteroaryl which is substituted by at least one OH and can be substituted, once or more than once, by a substituent selected from the group comprising 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, monosubstituted or polysubstituted C
1
-C
18
alkyl, C
3
-C
8
cycloalkyl or monosubstituted or polysubstituted C
3
-C
8
cycloalkyl, where one or more CH
2
groups in the alkyl and in the cycloalkyl can be replaced, independently of each other, by oxygen, sulfur or an imino group and the substituents are selected from the group comprising OH, SH, NH
2
, carboxamide and C(O)OR, in which R is H or C
1
-C
18
alkyl;
R
3
is a methyl group or hydroxymethyl group; and
X is —C(O)—, —C(S)—, —S(O)
2
—, —C(O)Y— or —C(S)Y—, where Y is NH, O, S, S-C
1
-C
6
alkylene, NH—C
1
-C
6
alkylene or O—C
1
-C
6
alkylene.
Within the scope of the present invention, the aryl or heteroaryl is a five-membered or six-membered ring or a bicycle formed from two fused six-membered or five-membered rings or one six-membered ring and one five-membered ring, with one or more heteroatoms, selected from the group comprising oxygen, nitrogen and sulfur atoms, 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.
OH as a substituent of aryl and heteroaryl in the definition of R
1
is preferably present once or twice. Both the C atoms and the heteroatoms can be substituted in the heteroaryl. The position(s) of the OH substituent(s) can be variable. If two OH substituents are present, it has then been found to be advantageous if they are in the ortho or meta positions relative to each other.
Halogen is preferably F, Cl or Br.
The previously mentioned alkyl and alkylene can be linear or branched. Some examples of alkyl, alkoxy, thioalkyl and alkylamino, which preferably contain from 1 to 12 C atoms, are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl, and also 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, methylthio and ethylthio, aminomethyl and aminoethyl.
Within the scope of the present invention, those compounds of the formula I or II are preferred in which R
1
is (a) a monohydroxylated, dihydroxylated or trihydroxylated phenyl; (b) a monohydroxylated, dihydroxylated or trihydroxylated monocyclic heteroaryl, in which one or more CH units are replaced, independently of each other, by one or more nitrogen atoms, or (c) a hydroxylated heteroaryl consisting of two six-membered rings, in which one or more CH units is/are replaced, independently of each other, by one or more nitrogen atoms. Of these compounds, those are in particular preferred in which additionally a hydrogen atom on the aryl or heteroaryl nucleus is replaced by halogen, a nitro group, a trifluoromethyl group, an O—C
1
-C
8
alkyl group, a linear or branched C
1
-C
18
alkyl, an amino group, a sulfhydro group; NH—C
1
-C
18
alkyl, a dialkylamino group, an NH-phenyl or NH-benzyl residue, a thio-C
1
-C
18
alkyl or a carbamate group such as OC(O)NHalkyl or NHC(O)Oalkyl, with it being .possible for the alkyl, independently of each other, to be a linear or branched C
1
-C
18
alkyl.
Another group of preferred compounds comprises compounds of the formula I or II in which R
1
is a monocyclic aryl or heteroaryl which is substituted by at least one OH and can be substituted, once or more than once, by a substituent selected from the group comprising halogen, trifluoromethyl, 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. Those compounds are particularly preferred in which R
1
is a monocyclic aryl or heteroaryl which is substituted by
Fonda Kathleen K.
GlycoTech Corp.
Seed Intellectual Property Law Group PLLC
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