Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1991-04-11
1995-12-12
Robinson, Douglas W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
435 737, A61K 3170, C07H 304
Patent
active
054749867
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel synthetic analogues of galabiosides useful as i.a. synthetic biological receptors.
2. Description of the Prior Art
Adhesion to cell-surface carbohydrates is considered to be important for bacterial growth and possibly for the expression of pathogenicity and is mediated via proteinaceous appendages termed pill or fimbriae. Also, glycolipids, glycoproteins and simple glycosides have been shown to function as specific biological receptors towards lectins and antibodies. The specificity and strength of the binding depends on the presence of both hydrophilic (e.g. hydroxyl groups) and hydrophobic (e.g. CH-groups) areas in the sugar molecule.
In order to investigate possible affinity differences, applicants have prepared and investigated a number of glycosides of galabiose and investigated their properties as inhibitors. Thus, a series of galabioside analogues were prepared and used as inhibitors of the agglutination of human red blood cells by genetically well-defined bacteria, namely mutants (HB101/pPAP5) of uropathogenic E.coli which carries galabiose-specific adhesin but is void of other sugar-binding adhesins in the pill, the mutants therefore being used as a standardized model of the wild strain.
The investigations indicated that any alterations of most of the hydroxy groups (e.g. removal of the hydroxy group, replacement thereof with atoms such as fluorine, substitution thereof to form e.g. alkoxy groups) resulted in a drastic reduction or complete removal of the ability of the glycoside to inhibit agglutination of red blood cells by means of the above-mentioned uropathogenic E.coli mutants. It was concluded that the positions in which the alterations had these negative effects were in some way involved either in essential hydrogen bonding interactions (either H-donating or H-accepting) with the bacterial adhesin or were involved in intra-molecular hydrogen bonding.
However, the investigations revealed that alterations in the 3' position (meaning the 3-position of the non-reducing galacross unit) could result in increased inhibitor activity. Also, alterations in the nature of the aglycon moiety towards higher lipophilicity resulted in increased inhibitor activity.
SUMMARY OF THE INVENTION
Based on the above outlined observations, the present invention concerns compound of the general formula I ##STR1## wherein R.sub.1 is C.sub.1-24 alkyl; C.sub.2-24 alkenyl; C.sub.2-24 alkynyl; tri(C.sub.1-4 alkyl)silylethyl; aryl optionally substituted with hydroxy, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, nitro, halogen, or phenoxy; mono- or di-halogen-C.sub.1-4 alkyl; phenyl-C.sub.1-4 alkyl; --IIa a carrier, n is an integer from 1 to 24, and m is 0 or 2; monosubstituted with hydroxy, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, nitro, halogen, or phenoxy above; and C.sub.1-18 alkyl; C.sub.2-18 alkenyl; C.sub.2-18 alkynyl; C.sub.1-18 alkyloxymethyl; C.sub.1-18 alkanoyl; .alpha.-hydroxy-C.sub.1-18 alkanoyl; naphthyl-, heterocyclyl- or phenyl-C.sub.1-8 alkoxy where the naphthyl, heterocyclyl or phenyl group may be substituted with hydroxy, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, nitro, halogen, or phenoxy; tri(C.sub.1-4 -alkyl)silylethyl; tri(C.sub.1-4 -alkyl)silyl; tri(C.sub.1-4 -alkyl)silylethoxymethyl; halogen; .omega.-hydroxy-C.sub.1-4 alkyl; tetrahydropyranyl; benzyloxymethyl; C.sub.3-8 cycloalkyl, a monoterpenyl moiety; benzoyl optionally monosubstituted with hydroxy, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, nitro, halogen, or phenoxy; the acyl residue of a naturally occurring amino acid; or a group of the formula V with hydroxy, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, nitro halogen, or phenoxy, R.sub.3 is H or is one of the meanings for R.sub.2 above, and R.sub.3 and R.sub.1 optionally being connected to form a ring, and R.sub.2 optionally being connected to form a ring.
Since compounds of the formula I exhibit increased inhibiting activity towards the adhesion of bacteria to receptors on tissue surfaces, a further a
REFERENCES:
patent: 4657849 (1987-04-01), Kallenius et al.
patent: 4675392 (1987-06-01), Dahmen et al.
Carbohydrate Research, 152, 113-130, Kehlberg et al. (1986).
Kihlberg Jan O.
Magnusson Hans G.
Cooper Iver P.
Kunz Gary L.
Robinson Douglas W.
Symbicom Aktiebolag
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