# US 5,703,059 A · Disaccharide ligands for selectins

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- Number: US 5,703,059 A
- Document ID: US5703059A
- Status: Granted
- Kind: A
- Application number: 08/492,002
- Filed: 1996-03-12
- Granted: 1997-12-30
- Earliest claimed: 1993-01-19
- Assignees: British Biotech Pharmaceuticals Limited
- Inventors: Nigel Mark Allanson; Alan Hornsby Davidson
- Web page: https://patentgrep.com/patent/US5703059A

## CPC

- C07H 15/10: containing unsaturated carbon-to-carbon bonds
- C07H 15/04: attached to an oxygen atom of the saccharide radical
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- 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)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

Compounds of formula (I), or a salt, solvate or hydrate thereof, wherein Z represents a divalent group selected from those of formulae I(a) to I(g) defined in the specification; Y represents a single bond or a divalent group selected from those of formulae I(h) to I(j) defined in the specification; each Z independently represents hydrogen or a hydroxyl protecting group; R.sup.1 represents hydrogen or a group --CH(OZ)CH.sub.2 (OZ) wherein Z has the meaning defined above; R.sup.2 represents hydrogen, a pharmaceutically acceptable cation, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or (optionally substituted)phenyl-(C.sub.1-4) alkyl; and R.sup.3 represents hydrogen, C.sub.1-6 alkyl, (C.sub.1-4) alkyl-substituted phenyl or benzoate; and n is 1, 2 or 3. The compounds are ligands of E-, P-, and L-selectins and are useful as anti-inflammatory agents and as agents for the control of tumour metastasis.

## Claims

### Claim 1

A compound of formula (I), or a salt, solvate or hydrate thereof: ##STR55## wherein: X represents a divalent group selected from those of formulae I(a) to I(g) below ##STR56## wherein R.sub.1 and R.sub.2 independently represent hydrogen, C.sub.1-3 alkyl or --COOR.sub.6 where R.sub.6 is C.sub.1-6 alkyl; and R.sub.3 and R.sub.4 independently represent hydrogen, hydroxyl or C.sub.1-3 alkyl; and bonds a and b may be single or double;
Y represents a single bond or a divalent group selected from those of formulae I(h) to I(j) below ##STR57## wherein R.sub.5 represents C.sub.1-3 alkyl or a glycosyl residue;
each Z independently represents hydrogen or a hydroxyl protecting group;
R.sup.1 represents hydrogen or a group --CH(OZ)CH.sub.2 (OZ) wherein Z has the meaning defined above;
R.sup.2 represents hydrogen, a pharmaceutically acceptable cation, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or (optionally substituted)phenyl-(C.sub.1-4) alkyl;
R.sup.3 represents hydrogen, C.sub.1-6 alkyl, (C.sub.1-4) alkyl-substituted phenyl or benzoate; and
n is 1, 2 or 3.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 wherein X is a group of formula I(a), I(b) or I(c).

### Claim 3 (depends on 1)

A compound as claimed in claim 1 wherein each Z independently represents hydrogen, acetyl or benzoyl.

### Claim 4 (depends on 1)

A compound as claimed in claim 1 wherein R.sup.1 is hydrogen or --CH(OH)CH.sub.2 OH.

### Claim 5 (depends on 1)

A compound as claimed in claim 1 wherein R.sup.2 is methyl, hydrogen, or a sodium, lithium or potassium cation.

### Claim 6 (depends on 1)

A compound as claimed in claim 1 wherein R.sup.3 is methyl.

### Claim 7 (depends on 1)

A compound as claimed in claim 1 wherein n is 1 or 3.

### Claim 8 (depends on 1)

A compound as claimed in claim 1, selected from the group consisting of:
O-methyl-4R-›5'-oxy-{N-acetyl-.alpha.2"-O-neuramidinyl methyl ester}-2'-oxo-pent-1'-yl!-L-fucopyranoside;
O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}5'oxy-2'-oxo-pent-1'-yl!-L-fucopyranoside;
O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}5'oxy-2',3',4'-trihydroxy-pent-1'-yl!-L-fucopyranoside;
O-methyl-4R-›7'-oxy-{N-acetyl-.alpha.2"-O-neuramidinyl methyl ester}-2'-hydroxy-hept-3'-en-1'-yl!-L-fucopyranoside; and
O-methyl-4R-›7'-oxy-{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}-2'-hydroxy-hept-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›5'-oxy-{tetra-O-acetyl-N-acetyl-.alph a.2"-O-neuramidinyl methyl ester}-2'-oxo-pent-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›{tetra-O-acetyl-N-acetyl-.alpha.2"-O- neuramidinyl methyl ester}5'oxy-2'-oxo-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›5'-oxy-{N-acetyl-.alpha.2"-O-neuramidinyl methyl ester}-2'-oxo-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}5'oxy-2'-oxo-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›{tetra-O-acetyl-N-acetyl-.alpha.2"-O- neuramidinyl methyl ester}5'-oxy-2'(R and S)-hydroxy-pent-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl methyl ester}5'-oxy-2'(R and S)-hydroxy-pent-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}5'-oxy-2'(R and S)-hydroxy-pent-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›{tetra-O-acetyl-N-acetyl-.alpha.2 "-O-neuramidinyl methyl ester}5'oxy-2'(R and S)-hydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl methyl ester}5'-oxy-2'(R and S)-hydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›{tetra-O-acetyl-N-acetyl-.alpha.2"-O- neuramidinyl methyl ester}5'oxy-2'R,3'R,4'S-trihydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›{tetra-O-acetyl-N-acetyl-.alpha.2"-O- neuramidinyl methyl ester}5'oxy-2'S,3'R,4'S-trihydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›{tetra-O-acetyl-N-acetyl-.alpha.2"-O- neuramidinyl methyl ester}5'oxy-2'R,3'S,4'R-trihydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›{tetra-O-acetyl-N-acetyl-.alpha.2"-O- neuramidinyl methyl ester}5'oxy-2'S,3'S,4'R-trihydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}5'oxy-2'R,3'R,4'S-trihydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}5'oxy-2'S,3'R,4'S-trihydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}5'oxy-2'R,3'S,4'R-trihydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}5'oxy-2'S,3'S,4'R-trihydroxy-pent-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›7'-oxy-{tetra-O-acetyl-N-acetyl-.alph a.2"-O-neuramidinyl methyl ester}-2'-oxo-hept-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4R-›7'-oxy-{tetra-O-acetyl-N-acetyl-.alph a.2"-O-neuramidinyl methyl ester}-2'(R and S)-hydroxy-hept-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›7'-oxy-{N-acetyl-.alpha.2"-O-neuramidinyl methyl ester}-2'(Rand S)-hydroxy-hept-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-4R-›7'-oxy-{N-acetyl-.alpha.2"-O-neuramidinyl sodium carboxylate}-2'(R and S)-hydroxy-hept-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4S-›5'-oxy-{tetra-O-acetyl-N-acetyl-.alph a.2"-O-neuramidinyl methyl ester}-2'-oxo-pent-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2,3-di-O-benzoyl-4S-›{tetra-O-acetyl-N-acetyl-.alpha.2"-O- neuramidinyl methyl ester}5'-oxy-2'(R and S)-hydroxy-pent-3'-en-1'-yl!-L-fucopyranoside;
.alpha.-O-methyl-2-O-benzoyl-4S-›{tetra-O-acetyl-N-acetyl-.alpha.2"-O-neura midinyl methyl ester}5'-oxy-2'(R and S)-hydroxy-pent-3'-en-1'-yl!-L-fucopyranoside; and
.alpha.-O-methyl-4S-›{N-acetyl-.alpha.2"-O-neuramidinyl carboxylic acid}5'-oxy-2'(R and S)-hydroxy-pent-3'-en-1'-yl!-L-fucopyranoside.

### Claim 9 (depends on 1)

A process for the preparation of compounds of claim 1 formula (I) wherein X is a divalent group of formula (Ia) and Y is a divalent group of formula (Ih), which process comprises
(a) reacting a compound of formula (II): ##STR58## wherein n, R.sup.1, R.sup.2, and Z are as defined in formula (I), and X.sup.1 is an aldehyde group --CHO or a group --CH.sub.2 L wherein L is a leaving group, with a compound of formula (III): ##STR59## wherein R.sup.3 and Z are as defined in formula (I) and Y.sup.1 represents an activating group for the methylene group to which it is attached, to form an intermediate of formula (IV) ##STR60## wherein n, R.sup.1, R.sup.2, R.sup.3, Z and Y.sup.1 are as defined in formulae (II) and (III) and Q is either (1) OH when X.sup.1 in formula (II) is --CHO, or (2) H when X.sup.1 in formula (II) is a group --CH.sub.2 L wherein L is a leaving group;
and then
(b) forming a double bond between the carbon atoms carrying the groups Q and Y.sup.1 by either (I) in cases where X.sup.1 in compound (II) is an aldehyde group --CHO allowing the said intermediate product to eliminate Q sponaneously and Y.sup.1, or treating the said intermediate product to eliminate Q and Y.sup.1, or (2) cases where X.sup.1 in compound (II) is a group --CH.sub.2 L wherein L is a leaving group treating the said intermediate product to eliminate Q and Y.sup.1 ;
and optionally
(c) in the resultant compound of formula (I), removing one or more hydroxyl protecting groups Z, and/or hydrolyzing any ester group --CO.sub.2 R.sup.2 to a carboxylic acid or pharmaceutically acceptable cationic carboxylate group.

### Claim 10 (depends on 9)

A process as claimed in claim 9 wherein the activating group Y.sup.1 is an alkyl or fluoroalkyl phosphonate, diphenyl phosphine oxide, triphenyl phosphine, phenyl sulfoxide, phenyl sulfonate, or alkyl carboxylate group.

### Claim 11 (depends on 9)

A process as claimed in claim 9 wherein X.sup.1 in compound (II) is a group --CH.sub.2 L, and the leaving group L is iodo, bromo, or chloro, or a tosylate or mesylate group.

### Claim 12 (depends on 9)

A process as claimed in claim 9 wherein the activating group Y.sup.1 is an alkyl or fluoroalkyl phosphonate, diphenyl phosphine oxide, phenyl sulfoxide, phenyl sulfonate, or alkyl carboxylate group, and the reaction of compounds (II) and (III) is carried out in the presence of a base to form an enolate of compound (III).

### Claim 13 (depends on 9)

A process as claimed in claim 9 wherein the activating group Y.sup.1 is an alkyl or fluoroalkyl phosphonate, and X.sup.1 in compound (II) is a group --CHO, and the reaction is carried out in the presence of cesium carbonate in t-butanol at a temperature in the range 25.degree.-35.degree. C.

### Claim 14 (depends on 1)

A process for the preparation of compounds of claim 1 formula (I) wherein X is a divalent group of formula (Ia) and Y is a bond which process comprises coupling a sialic acid derivative of formula (V); ##STR61## wherein R.sup.1, R.sup.2 and Z are as defined in formula (I) and X.sup.2 is a leaving group, with an alcohol of formula (VI): ##STR62## wherein n, R.sup.3 and Z are as defined in formula (I), X is a divalent group of formula (Ia) above and Y is bond, and if desired removing one or more hydroxyl protecting groups Z, and/or hydrolyzing any ester group --CO.sub.2 R.sup.2 to a carboxylic acid or pharmaceutically acceptable cationic carboxylate group.

### Claim 15 (depends on 14)

A process as claimed in claim 14 wherein the leaving group X.sup.2 in the sialic acid derivative of formula (V) is iodo, bromo, and chloro; a sulfonyl ester such as tosylate, mesylate, triflate or other sulfonyl ester; methylthio, substituted phenylthio or other sulfide group; trichloroacetimidate; or an alpha-S--(.dbd.S)--OEt or alpha-O--P(OEt).sub.2 group.

### Claim 16 (depends on 9, 14)

A process as claimed in claim 9 or claim 14 which comprises an additional step selected from the group consisting of the following steps (a)-(g):
(a) hydrogenation of a C.dbd.C double bond of a compound of formula (I) wherein X=(Ia) to form a compound of formula (I) wherein X=(Ib);
(b) dihydroxylation of a compound of formula (I) wherein X=(Ia) to form a compound of formula (I) wherein X=(Ic);
(c) epoxidation of a compound of formula (I) wherein X=(Ia) to form a compound of formula (I) wherein X=(Id);
(d) cyclopropanation of a compound of formula (I) wherein X=(Ia) to form a compound of formula (I) wherein X=(Ie);
(e) Diels-Alder reaction between a compound of formula (I), X=(Ia) and a diene to form a compound of formula (I) wherein X=(If) or (Ig);
(f) reduction of the ketone group (Ih) of a compound of formula (I), wherein X=(Ia) and Y=(Ih) followed by one of the preceding steps to form a compound of formula (I) wherein X=(Ia)-(Ig) and Y=(Ii); or
(g) reaction of a glycosyl donor, a promoter and a compound of formula (I) wherein Y=(Ii) to form a compound of formula (I) wherein X=(Ia) to (Ig) and Y=(Ij).

### Claim 17 (depends on 1)

A method of treatment of (a) a condition mediated by excess accumulation of neutrophils in tissue in a mammal, and/or (b) metastasis in which neutrophils or tumor cells leave the circulation and infiltrate tissue in a mammal, which method comprises administering to said mammal an effect amount of a compound as claimed in claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein either an inflammatory condition or tumor metastasis is treated.

### Claim 19 (depends on 17)

The method of claim 17, wherein the condition is Adult Respiratory Distress Syndrome (ARDS), asthma, reperfusion injury following myocardial infarction, stroke, transplant rejection, inflammatory bowel disease, rheumatoid arthritis, or endotoxic hemorrhagic shock.

### Claim 20 (depends on 17)

The method of claim 17, wherein the condition is chronic skin inflammation, psoriasis, lichen planus, or nonspecific contact dermatitis in which higher than normal levels of skin-homing memory T cells are implicated.

### Claim 21 (depends on 1)

A pharmaceutical or veterinary composition comprising a compound as claimed in claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, together with a pharmaceutically or veterinarily acceptable excipient or carrier.