# US 2021/0330693 A1 · Heparanase inhibitors and their use as anti-cancer compounds

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- Number: US 2021/0330693 A1
- Document ID: US20210330693A1
- Status: Published application
- Kind: A1
- Application number: 17/311,088
- Filed: 2019-12-05
- Published: 2021-10-28
- Earliest claimed: 2018-12-05
- Assignees: Wayne State University; Technion, Israel Institute of Technology; University of Iowa Research Foundation
- Applicants: Wayne State University; Technion, Israel Institute of Technology; University of Iowa Research Foundation
- Inventors: Hien M. Nguyen; Ravi Sankar Loka; Eric Sletten; Israel Vlodavsky
- Web page: https://patentgrep.com/patent/US20210330693A1

## CPC

- A61K 31/727: Heparin; Heparan
- A61K 31/795: Polymers containing sulfur
- A61P 35/00: Antineoplastic agents
- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- C12N 9/2402: {hydrolysing O- and S- glycosyl compounds (3.2.1)}
- C12N 9/99: Enzyme inactivation by chemical treatment
- C12Y 302/01166: Heparanase (3.2.1.166)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

Anti-heparanase compounds for the treatment of cancer are described. The anti-heparanase compounds are high affinity, synthetic glycopolymers that result in minimal anticoagulant activity. Stereoselective fluorinated forms of these compounds are also provided.

## Claims

### Claim 1

A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a salt form of an anti-heparanase compound having the structure:
wherein n=2-100 repeating units of the structure; the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 2 (depends on 1)

A method of claim 1 wherein the salt form is sodium salt.

### Claim 3

A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a salt form of an anti-heparanase compound to the subject wherein the anti-heparanase compound comprises a glycopolymer linked to a disaccharide.

### Claim 4 (depends on 3)

The method of claim 3 wherein the salt form of the anti-heparanase compound has 5-12 repeating units of the glycopolymer linked to the disaccharide.

### Claim 5 (depends on 3)

The method of claim 3 wherein the glycopolymer is linked to the disaccharide through nitrogen bonding.

### Claim 6 (depends on 3)

The method of claim 3 wherein the disaccharide comprises a glucosamine unit sulfated at the carbon 2 and carbon 6 nitrogen positions of the disaccharide.

### Claim 7 (depends on 3)

The method of claim 3 wherein the disaccharide comprises a glucosamine unit fluorinated at the carbon 2 or carbon 3 positions of the disaccharide.

### Claim 8 (depends on 3)

The method of claim 3 wherein the salt form of the anti-heparanase compound is a heparan sulfate mimicking glycopolymer having the structure:
wherein:
X is —O— or
Y is —O— or —CH2—; R1 is OH or —N(H)-L-Ra; L is a linking group; Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises a —SO3Na group; Q is —NSO3Na or —F; Z is either —OH or —F; the positioning of the carboxylic acid, or salt thereof, can either be axial or equatorial; and the dash bond --- is a single bond or a double bond.

### Claim 9 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 10 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 11 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 12 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 13 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 14 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 15 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 16 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 17 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 18 (depends on 8)

The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:
wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

### Claim 19 (depends on 3)

The method of claim 3 wherein the salt form of the anti-heparanase compound has the structure:
wherein:
X is —O— or
Y is —O— or —CH2—; R1 is OH or —N(H)-L-Ra; L is a linking group; Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises a —SO3Na group; and the dash bond --- is a single bond or a double bond.

### Claim 20 (depends on 19)

The method of claim 19 wherein X is —O— and Y is —O—; or X is
and Y is —CH2—.

### Claim 21 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:
wherein R1 is OH or —N(H)-L-Ra; L is a linking group; and Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises a —SO3Na group; and the carboxylic acid group is a salt thereof.

### Claim 22 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

### Claim 23 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

### Claim 24 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

### Claim 25 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

### Claim 26 (depends on 19)

The method of claim 19 wherein the salt for of the anti-heparanase compound has the structure:

### Claim 27 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:
wherein L is a linking group; Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises a —SO3Na group.

### Claim 28 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

### Claim 29 (depends on 19)

The method of claim 19 wherein Ra is selected from:

### Claim 30 (depends on 19)

The method of claim 19 wherein Ra is selected from:

### Claim 31 (depends on 19)

The method of claim 19 wherein Ra is:

### Claim 32 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

### Claim 33 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

### Claim 34 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

### Claim 35 (depends on 19)

The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:
wherein n is 8.

### Claim 36 (depends on 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The method of any one of claim 8-35 wherein n is an integer from 2-100.

### Claim 37 (depends on 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The method of any one of claim 8-35 wherein n is an integer from 5-55.

### Claim 38 (depends on 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The method of any one of claim 8-35 wherein n is 5, 8, 9, 12, 27, or 51.

### Claim 39

A compound having the structure:
wherein:
X is —O— or
Y is —O— or —CH2—; n=2-100 repeating units; R1 is OH or —N(H)-L-Ra; L is a linking group; Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises one or more —SO3H groups; the carboxylic acid group is a salt thereof; and the dash bond --- is a single bond or a double bond.

### Claim 40 (depends on 39)

The compound of claim 39, having the structure:
wherein: n=2-100 repeating units; and the saccharide or disaccharide further comprises one or more F− groups.

### Claim 41 (depends on 39)

The compound of claim 39, having the structure:

### Claim 42 (depends on 39)

The compound of claim 39, having the structure:

### Claim 43 (depends on 39)

The compound of claim 39, having the structure:

### Claim 44

The compound of 40 wherein the one or more F− groups comprise axial 2-fluoro-glycoside.

### Claim 45

The compound of 41 wherein the one or more F− groups comprise axial 2-fluoro-glycoside.

### Claim 46

The compound of 42 wherein the one or more F− groups comprise axial 2-fluoro-glycoside.

### Claim 47

The compound of 43 wherein the one or more F− groups comprise axial 2-fluoro-glycoside.

### Claim 48 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

An anti-cancer composition comprising: (i) an anti-heparanase compound of any one of claims 1-35 and (ii) a pharmaceutically acceptable carrier.

### Claim 49 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to FGF-1 is more than the binding affinity of heparin to FGF-1.

### Claim 50 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to FGF-1 is at least 2000 nM more than the binding affinity of heparin to FGF-1.

### Claim 51 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to FGF-2 is more than the binding affinity of heparin to FGF-2.

### Claim 52 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to FGF-2 is at least 530 nM more than the binding affinity of heparin to FGF-2.

### Claim 53 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to VEGF is more than the binding affinity of heparin to VEGF.

### Claim 54 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to VEGF is at least 115 nM more than the binding affinity of heparin to VEGF.

### Claim 55 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to PF4 is more than the binding affinity of heparin to PF4

### Claim 56 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to PF4 is at least 35 nM more than the binding affinity of heparin to PF4.

### Claim 57 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to P-Selectin is more than or equal to the binding affinity of heparin to P-Selectin

### Claim 58 (depends on 48)

The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to P-Selectin is at least −570 nM more than or equal to the binding affinity of heparin to P-Selectin.

### Claim 59 (depends on 48)

The anti-cancer composition of claim 48 wherein the anti-heparanase compound has lower binding affinity to antithrombin III than heparin's binding affinity to antithrombin III.

### Claim 60 (depends on 48)

The anti-cancer composition of claim 48 wherein the pharmaceutically acceptable carrier is aqueous or alcoholic and comprises a viscous base.