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Disaccharides for drug discovery

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Title: Disaccharides for drug discovery.
Abstract: Methods are described for the preparation of combinatorial libraries of potentially biologically active disaccharide compounds. These compounds are variously functionalized, with a view to varying lipid solubility size, function an other properties, with the particular aim of discovering novel drug or drug-like compounds, or compounds with useful properties. The invention provides intermediates, processes and synthetic strategies for the solution or solid phase synthesis of disaccharides, variously functionalized about the sugar ring, including the addition of aromaticity and charge, and the placement of pharmaceutically useful groups and isosteres. ...


USPTO Applicaton #: #20110201794 - Class: 536 175 (USPTO) - 08/18/11 - Class 536 
Organic Compounds -- Part Of The Class 532-570 Series > Azo Compounds Containing Formaldehyde Reaction Product As The Coupling Component >Carbohydrates Or Derivatives >O- Or S- Glycosides >Nitrogen Containing >Sulfur Containing (e.g., Methylthiolincosaminide, Etc.)

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The Patent Description & Claims data below is from USPTO Patent Application 20110201794, Disaccharides for drug discovery.

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FIELD OF THE INVENTION

This invention relates to methods for the preparation of combinatorial libraries of potentially biologically active disaccharide compounds. These compounds are variously functionalized, with a view to varying lipid solubility, size, function and other properties, with the particular aim of discovering novel drug or drug-like compounds, or compounds with useful properties. The invention provides intermediates, processes and synthetic strategies for the solution or solid phase synthesis of disaccharides, variously functionalised about the sugar ring, including the addition of aromaticity and charge, and the placement of pharmaceutically useful groups and isosteres.

BACKGROUND OF THE INVENTION

From a drug discovery perspective, carbohydrate pyranose and furanose rings and their derivatives are well suited as templates. Each sugar represents a three-dimensional scaffold to which a variety of substituents can be attached, usually via a scaffold hydroxyl group, although occasionally a scaffold carboxyl or amino group may be present for substitution. By varying the substituents, their relative position on the sugar scaffold, and the type of sugar to which the substituents are coupled, numerous highly diverse structures are obtainable. An important feature to note with carbohydrates, is that molecular diversity is achieved not only in the type of substituents, but also in the three dimensional presentation. The different stereoisomers of saccharides that occur naturally (examples include glucose, galactose, mannose etc), offer the inherent structural advantage of providing alternative presentation of substituents.

Although there are a number of examples of monosaccharides being used as scaffolds for drug discovery purposesi,ii,iii, there are only a limited number of examples of disaccharides or higher saccharides being used as templates for the presentation of pharmaceutically useful functional groups.

Derivatised disaccharides and higher saccharides, represent a new class of compounds for drug discovery that are able to address a significant and different group of receptors from those addressed by monosaccharide scaffolds. This group or receptors can be broadly described as those receptors in which the critical binding groups are distal to each other. In principle, monosaccharide scaffolds can be used to address up to five binding groups (more usually 3 binding groups would be chosen), the connection points on the scaffold are each separated by between 1 and 5 angstroms in space. Disaccharide scaffolds on the other hand can accommodate up to eight binding groups although more usually 3-4 binding groups would be chosen, the connection points for each of these groups being separated by as much as 10 angstroms in space. Obviously the appended functional groups may be separated by even greater distances in 3-dimensional space. The replacement of the glycosidic bond linking the two monosaccharide components with a spacer group can further increase the separation between binding groups of interest.

The ability to address more distally placed binding groups is an important feature for a number of biological receptor molecules including the G-protein coupled receptors, where at the extra-cellular opening to many of these receptors, the width of the binding channel is up to 14 angstroms. Additionally, disaccharide scaffolds can be used as probes of interactions which involve large surface areas for example the protein-protein interaction of the CD4-GP120 system, an important interaction in the aetiology of the human immunodeficiency virus.

Through the development of a range of selectively protected and modified monosaccharide, cyclitols and tetrahydropyran building blocks, we have developed a system that allows the chemical synthesis of highly structurally and functionally diverse derivatised disaccharide and disaccharide analogue structures, of both natural and unnatural origin. The diversity accessible is particularly augmented by the juxtaposition of both structural and functional aspects of the molecules. In order to access a wide range of diverse structures, stereo-center inversion chemistry is required, so as to achieve non-naturally occurring and hard to get sugars and sugar analogues in a facile manner. Other chemistries are also required that provide unnatural deoxy or deoxy amino derivative which impart greater structural stability to the drug-like target molecules. With a suite of reagents to effect a suitable range of chemistries on a solid support, allowing such things as; wide functional diversity, highly conserved intermediates, a limited number of common building block to be required, and with suitable chemistry to allow access to unusual carbohydrate stereo-representations and including access to deoxy and deoxy amino analogues, a methodology is then established that can create focused libraries for a known target, or alternatively diversity libraries for unknown targets for random screening.

It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

Many of the traditional methods of carbohydrate synthesis have proved to be unsuitable to a combinatorial approach, particularly because modern high-throughput synthetic systems require procedures to be readily automatable. The compounds and processes described herein are particularly suited to the solid and solution phase combinatorial synthesis of carbohydrate-based libraries, and are amenable to automation. The methods of the invention yield common intermediates that are suitably functionalized to provide diversity in the structure of the compounds so generated. Using the method described, it is possible to introduce varied functionality in order to modulate both the biological activity and pharmacological properties of the compounds generated.

Thus the compounds and methods disclosed herein provide the ability to produce random or focused combinatorial-type libraries for the discovery of other novel drug or drug-like compounds, or compounds with other useful properties in an industrially practical manner.

SUMMARY

OF THE INVENTION

In a first aspect, the invention provides disaccharide compounds of formula I

A-d-L-e-B  formula I

In which the groups A and B are independently chosen from

in which the ring may be of any configuration and the anomeric center where present may be of either the α or β configuration;

Independently for each ring

T may be O or CH2;

R6 and R7 are hydrogen, or together form a carbonyl oxygen;

R1 may be hydrogen, —N(Z)Y, C(Z)Y, OZ or SZ wherein;

When R1 is N(Z)Y

Y is selected from hydrogen, or the following;

Z is selected from hydrogen or X1;

Q is selected from hydrogen or W;

The groups Z and Y may be combined to form a monocyclic or bicyclic ring structure of 4 to 10 atoms. This ring structure may be further substituted with X1 groups;

The groups W are independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO2, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid;

The groups X1 are independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO2, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid;

Where R1 is C(Z)Y;

Y, where present, is selected from hydrogen, double bond oxygen (═O) to form a carbonyl, or triple bond nitrogen to form a nitrile.

Z may be optionally absent, or is selected from hydrogen or X2

Wherein X2 is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, aminoalkyl, aminoaryl, aryloxy, alkoxy, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO2, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted;

The groups Z and Y may be combined to form a monocyclic or bicyclic ring structure of 4 to 10 atoms. This ring structure may be further substituted with X1 groups;

Where R1 is OZ or SZ,

Z is selected from hydrogen or X3,

Wherein X3 is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroaryialkyl of 1 to 20 atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO2, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted;

The groups R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, N3, OH, OX4, N(Z)Y, wherein N(Z)Y is as defined above or additionally Y is

where Q and W are as defined above, and X4 is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, aminoalkyl, aminoaryl, aryloxy, alkoxy, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, aryalkyl or heteroarylalkyl of 1 to 20 atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO2, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid;

The groups Z and Y may be combined to form a monocyclic or bicyclic ring structure of 4 to 10 atoms. This ring structure may be further substituted with X1 groups;

The groups A and B are linked together with a linking structure d-L-e, in which the groups d and e represent the connection points for A and B and replace one of the groups R1, R2, R3, R4, or R5 in each of the groups A and B and form the connection point for the linker L.

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stats Patent Info
Application #
US 20110201794 A1
Publish Date
08/18/2011
Document #
12926913
File Date
12/17/2010
USPTO Class
536 175
Other USPTO Classes
536 53, 536 172, 536 291, 536 55
International Class
/
Drawings
0


Disaccharide
Groups
Libraries
Lipid
Processes
Solubility


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