# US 5,705,489 A · Bisconjugates comprising two saccharides and a spacer

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- Number: US 5,705,489 A
- Document ID: US5705489A
- Status: Granted
- Kind: A
- Application number: 08/690,449
- Filed: 1996-08-05
- Granted: 1998-01-06
- Earliest claimed: 1993-09-01
- Assignees: Akzo Nobel N.V.; Elf Sanofi
- Inventors: Constant A. A. Van Boeckel; Peter D. J. Grootenhuis; Maurice Petitou; Pieter Westerduin
- Web page: https://patentgrep.com/patent/US5705489A

## CPC

- C07H 3/06: Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to a tuneable bisconjugate comprising two saccharides and a spacer, each saccharide being the same or different and comprising two to six monosaccharide units, at least one unit being uronic acid, characterized in that at least one of the saccharides per se has anti-thrombotic activity, and that the spacer connects at least one saccharide to the other through its non-reducing end, the chain length of the spacer being 20-120 atoms.

## Claims

### Claim 1

A bis/mixed conjugate consisting of two saccharides and a spacer, each saccharide being the same or different and comprising two to six monosaccharide units, at least one unit being uronic acid, wherein at least one of the saccharides per se has anti-thrombotic activity, and the spacer connects at least one saccharide to the other through its non-reducing end, the chain length of the spacer consisting of at least twenty atoms.

### Claim 2 (depends on 1)

The bis/mixed conjugate of claim 1, wherein at least one of the saccharides per se has affinity for at least one of AT-III and HC-II and/or has at least one activity selected from the group consisting of anti-factor IIa and anti-factor Xa activity.

### Claim 3 (depends on 2)

The bis/mixed conjugate of claim 2, wherein both saccharides per se have affinity for at least one of AT-III and HC-II and/or have at least one activity selected from the group consisting of anti-factor IIa and anti-factor Xa activity.

### Claim 4 (depends on 1)

The bis/mixed conjugate of claim 1, wherein at least one of the saccharides has the formula
wherein each
R is independently selected from H, OH, OSO.sub.3.sup.- and C1-C8 alkoxy;
R.sub.1 is independently selected from OSO.sub.3.sup.- and NSHO.sub.3.sup.3.sup.- ;
and the negative charges are compensated by hydrogen or an alkali metal cation.

### Claim 5 (depends on 1)

The bis/mixed conjugate of claim 1, wherein at least one of the saccharides has the formula ##STR30## wherein R.sub.2 is independently OSO.sub.3.sup.- or OCH.sub.3.

### Claim 6 (depends on 1)

The bis/mixed conjugate of claim 1, wherein the spacer has the formula ##STR31## wherein one of the two free valencies of the spacer is attached to the non-reducing end of one of the saccharides and the other free valency of the spacer is attached to the reducing or non-reducing end of the other saccharide, and T is independently H or C1-C8 alkyl; m is independently 1-8; r is independently 2-4; s is independently 1-12; w is 0-10; x is 0 or 1; y is 0 or 1; z is 0 or 1, and the total number of atoms in the spacer is 20-120.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising the bis/mixed conjugate of claim 1 and pharmaceutically acceptable auxiliaries.

### Claim 8 (depends on 7)

A method for the treatment or prevention of thrombotic disorders or smooth muscle cell proliferation comprising administering an effective amount of a composition according to claim 7.

### Claim 9 (depends on 1)

The bis/mixed conjugate of claim 1, wherein the length of the spacer is from 20 to 120.

### Claim 10 (depends on 1)

The bis/mixed conjugate of claim 1, wherein the spacer has the formula
--{Q--NT--CO--›(CH.sub.2).sub.n --NT--CO--(CH.sub.2).sub.m !.sub.p --S--}.sub.2
or
--{Q--O--›CH.sub.2).sub.n --O!.sub.p --(CH.sub.2).sub.m --S--}.sub.2
wherein
one of the two groups Q is attached to the non-reducing end of one of the saccharides and the other group Q is attached to the reducing or non-reducing end of the other saccharide, and each of the groups Q is a phenylene (C.sub.6 H.sub.4) group or --›(CH.sub.2 O).sub.q --(CH.sub.2).sub.r --O!.sub.s --›(CH.sub.2).sub.t --NT--CO!.sub.u --(CH.sub.2).sub.v, and T is independently hydrogen or C1-C8 alkyl; q is 0 or 1; r and t are independently 2-4; and s is 1-12; u and v are independently 1-6; n is 1-8; m is 1-8; p is 1-12; and the total number of atoms in the spacer is 20-120.

### Claim 11 (depends on 1)

The bis/mixed conjugate of claim 1, wherein the spacer has the formula ##STR32## wherein one of the two groups .phi. is attached to the non-reducing end of one of the saccharides and the other group .phi. is attached to the reducing or non-reducing end of the other saccharide, and .phi. denotes a phenylene (C.sub.6 H.sub.4) group; n, m and o are independently 1-8; and the total number of atoms in the spacer is 20-120.

### Claim 12 (depends on 1)

The bis/mixed conjugate of claim 1, which has the formula ##STR33##