Fucosyltransferase specific inhibition using fucose mimetics

Patent metadata

Field	Value
Publication number	US-11517580-B2
Application number	US-202017136839-A
Country	US
Kind code	B2
Filing date	Dec 29, 2020
Priority date	Dec 29, 2020
Publication date	Dec 6, 2022
Grant date	Dec 6, 2022

Abstract

Provided are compositions and methods for specific fucosyltransferase inhibition for treatment of a variety of diseases. The compositions of the invention comprise a glycomimetic of L-Fucose that selectively inhibits the generation of sialyl Lewis X by FTVI and FTVII but has no effect on the generation of Lewis X by FTIX.

First claim

We claim:

1. A fucose mimetic compound having Structure A

and/or a therapeutically effective salt thereof, wherein the dotted line is an aliphatic, an aromatic, a heteroaliphatic, or a heteroaromatic ring and is substituted with at least one R 1 , wherein the ring can be substituted with any number of R 1 substituents up to the maximum number permitted by the structure of the ring, and n is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7 and 8;
wherein at each occurrence R is hydrogen or a group selected from hydroxyl, alkoxy, amino, thiol, sulfoxide, sulfone, sulfonamide, sulphate, sulfonate, keto, formyl, carboxylic, azido, (mono-, di, tri-) phosphate, (mono-, di-, tri-) phosphonate, ester, amide, and anhydride wherein said group further comprises a protecting group, wherein the protecting group can form an ester with the adjacent oxygen atom or is independently selected from (D/L)-cysteine, a mono-, di-, tri-thiol containing molecule, a fat acid with saturated and unsaturated alkyl chains, a natural ceramide, a sulphonamide, and a myristoyl-Gly-Cys molecule;
wherein at each occurrence R 1 is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, a substituted or unsubstituted polycyclic group, amino, thiol, sulfide, keto, formyl, carboxyl, azide, phosphyl, ester, amide, and anhydride; wherein the substituents are selected from keto, amino, phosphate, halogen, hydroxyl, nitro, alkyl, alkenyl, aryl, formyl, and acetyl;
wherein X and Y are independently CH 2 , S, S═O, SO 2 , O, or NH; R 2 is CH 2 R″, CH 2 OR″, CH 2 N(R″) 2 , or CH 2 SR″; R″ is selected from the group consisting of hydrogen, hydroxyl, amino, thiol, sulfide, keto, formyl, carboxyl, azide, (mono-, di-, tri-) phosphate, (mono-, di-, tri-) phosphonate, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and X′ is C, S, S═O, SO 2 , O, or N.

2. The fucose mimetic compound according to claim 1 having Structure B

wherein the five member cycle is substituted with up to four R 3 substituents; wherein each R 3 is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, amino, thiol, sulfide, keto, formyl, carboxyl, azide, ester, amide, and anhydride thereof; X′ is C, S, S═O, SO 2 , O, or N; and wherein X′ can be present in any position of the five member cycle.

3. The fucose mimetic compound according to claim 1 having Structure C

wherein the six member cycle is substituted with up to four R 4 substituents wherein each R 4 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, amino, thiol, sulfide, keto, formyl, carboxyl, azide, ester, amide, and anhydride, wherein the substituents are selected from keto, amino, phosphate, halogen, hydroxyl, nitro, alkyl, alkenyl, aryl, formyl, and acetyl; and X′ is C, S, S═O, SO 2 , O, or N.

4. The fucose mimetic compound according to claim 1 having Structure D

wherein the dotted line is an aliphatic or heteroaliphatic ring substituted with up to twelve R 5 substituents; n is an integer selected from the group consisting of 2, 3, 4, 5, and 6; X′ is C, S, S═O, SO 2 , O, or N; wherein each R 5 is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, amino, thiol, sulfide, keto, formyl, carboxyl, azide, ester, amide, and anhydride; and wherein X′ can be present in any position of the aliphatic or heteraliphatic ring.

5. A fucose mimetic compound having Structure E

and/or a therapeutically effective salt thereof, wherein:
X and Y each independently are selected from CH 2 , S, S═O, SO 2 , O, or NH;
R 2 is selected from CH 2 R″, CH 2 OR″, CH 2 N(R″) 2 , or CH 2 SR″; R″ is selected from hydrogen, hydroxyl, amino, thiol, sulfide, keto, formyl, carboxyl, (mono-, di-, tri-) phosphate, (mono-, di-, tri-) phosphonate group, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R 6 is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted polycyclic group, amino, thiol, sulfide, keto, formyl, carboxyl, azide, phosphyl, ester, amide, and anhydride; wherein the substituents are selected from halogen, hydroxyl, alkoxy, nitro, alkyl, alkenyl, aryl, formyl, acetyl;
R 7 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted polycyclic group, amino, thiol, sulfide, keto, formyl, carboxyl, azide, phosphyl, ester, amide, and anhydride; wherein the substituents are selected from halogen, hydroxyl, alkoxy, nitro, alkyl, alkenyl, aryl, formyl, acetyl; and
R is independently selected from hydrogen, (D/L)-cysteine, a mono-, di-, tri-thiol containing molecule, a fat acid with saturated and unsaturated alkyl chains, a natural ceramide, a sulphonamide, and a myristoyl-Gly-Cys molecule, or R can form an ester with the adjacent oxygen atom.

6. A composition comprising the fucose mimetic compound and/or a multivalent system containing the fucose mimetic compound according to claim 1 .

7. The composition according to claim 6 comprising a therapeutically effective amount of

and a pharmaceutically acceptable carrier.

8. The composition according to claim 6 comprising a therapeutically effective amount of

and a pharmaceutically acceptable carrier.

9. A composition comprising the fucose mimetic compound and/or a multivalent system containing the fucose mimetic compound according to claim 5 , wherein the compound is compound 9

and a pharmaceutically acceptable carrier.

10. A composition comprising the fucose mimetic compound and/or a multivalent system containing the fucose mimetic compound according to claim 5 , wherein the compound is compound 10

Assignees

• The Florida International Univ Board Of Trustees
• Univ Of Florence

Inventors

• Sackstein Robert
• Richichi Barbara
• Martin Kyle

Classifications

• A61K31/7042 Primary

  Compounds having saccharide radicals and heterocyclic rings · CPC title

• C07H9/00

  Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical · CPC title