# US 11,028,112 B2 · Inositol derivatives for use in pathological crystallization

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- Number: US 11,028,112 B2
- Document ID: US11028112B2
- Status: Granted
- Kind: B2
- Application number: 16/852,587
- Filed: 2020-04-20
- Published: 2020-08-06
- Granted: 2021-06-08
- Earliest claimed: 2015-12-11
- Assignees: ETH Zurich; UniversitäT Bern
- Applicants: ETH Zurich; UniversitäT Bern
- Inventors: Mattias Ivarsson; Bastien Castagner; Jean-Christophe Leroux; Andreas Pasch
- Web page: https://patentgrep.com/patent/US11028112B2

## CPC

- C07H 15/08: Polyoxyalkylene derivatives
- A61K 31/663: Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- 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)
- 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

## Abstract

The present invention relates to inositol derivatives covalently modified with one, two or three solubility functions, particularly polyethylene glycol moieties, for use in therapy or prevention of conditions related to pathological calcium crystallization, such as cardiovascular calcifications, nephrocalcinosis, calcinosis cutis, chondrocalcinosis and kidney stones.

## Claims

### Claim 1

A method for treatment of a condition associated with cardiovascular calcification, comprising administering to a subject in need thereof a compound described by a general formula (II)
wherein
one or two or three X are R1 and the remaining X independently from each other are selected from OPO32−, OPSO22−, and OSO3−; and
each R1 independently of any other R1 is a polyethylene glycol or a polyglycerol,
and wherein the condition is selected from the group consisting of coronary artery disease, vascular stiffening, valvular calcification, myocardial infarction, cardiovascular mortality, progression of chronic kidney disease, peripheral arterial disease, critical limb ischemia, calciphylaxis, general arterial calcification of infancy, aortic stenosis, atherosclerosis, pseudoxanthoma elasticum, cardiac hypertrophy, heart failure, arrhythmia, aneurysm, valvular stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, stroke, and cognitive function.

### Claim 2 (depends on 1)

The method of claim 1, wherein the condition is selected from aortic stenosis and valvular calcification.

### Claim 3 (depends on 1)

The method of claim 1, wherein R1 has a molar mass between 100 g/mol and 3000 g/mol.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound is characterized by a general formula III a, III b, III c or III d:
wherein each X (independently) and R1 have the meaning outlined above.

### Claim 5 (depends on 1)

The method of claim 1, wherein more than one R1 is present and each R1 is the same as any other R1.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is characterized by a general formula (IV a), (IV b), (IV c), (IV d), (V a) or (V b)
wherein each X (independently) and R1 have the meaning outlined above.

### Claim 7 (depends on 1)

The method of claim 1, wherein one or two or three X are R1 and the remaining X are
all OPO32− or
all OPSO22− or
all OSO3−.

### Claim 8 (depends on 1)

The method of claim 1, wherein
one or two or three X are R1 and the remaining X are OPO32−; and
R1 is a polyethylene glycol and has a molar mass between 100 g/mol and 3000 g/mol.

### Claim 9 (depends on 1)

The method of claim 1, wherein
one or two or three X are R1 and the remaining X are OPSO22−; and
R1 is a polyethylene glycol and has a molar mass between 100 g/mol and 3000 g/mol.

### Claim 10 (depends on 1)

The method of claim 1, wherein two X are R1.

### Claim 11 (depends on 1)

The method of claim 1, wherein:
one X is R1 and of the remaining X:
three X are OSO3− and two X are OPSO22−, or three X are OSO3− and two X are OPO32−, and
R1 is a polyethylene glycol and has a molar mass between 100 g/mol and 3000 g/mol.

### Claim 12 (depends on 1)

The method of claim 1, wherein R1 is a polyethylene glycol characterized by a formula R3—(O—CH2—CH2)n— or R3—(O—CH2—CH2)n—O—, and R3 is hydrogen, methyl or ethyl.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is described by a general formula (III k), (III I), (III m), (III n), (IV e) or (V c)
and wherein n has a value from 2 to 200 and R3 is selected from H, methyl and ethyl.

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound is described by any one of formulae (III o), (III p), (III q), (III r), (III s), (III t), (III u), (III v), (III w), (III x), (III y), (III z), (IV f), (IV g), (IV h), (IV i), (IV j), (IV k), (V d), (V e), (V f), (V g), (V h) or (V i)

### Claim 15 (depends on 1)

The method of claim 1, wherein said polyethylene glycol is a monodisperse polyethylene glycol.

### Claim 16 (depends on 1)

The method of claim 1, wherein the compound is described by any one of formulae (III o), (III p), (III q), (III u), (III v) or (III w)

### Claim 17

A compound of general formula (II)
wherein
three X are R1 and the remaining X independently from each other X are selected from OPO32−, OPSO22−, and OSO3−; and
each R1 independently of any other R1 is a polyethylene glycol or a polyglycerol.

### Claim 18 (depends on 17)

The compound of claim 17, wherein the compound is any one of:
wherein each X (independently) and R1 have the meaning outlined above.

### Claim 19 (depends on 17)

The compound of claim 17, wherein R1 is a polyethylene glycol and has a molar mass between 100 g/mol and 3000 g/mol.

### Claim 20 (depends on 17)

The compound of claim 17 described by the formula (V c),
wherein n has a value from 2 to 200 and R3 is selected from H, methyl and ethyl.

### Claim 21 (depends on 16)

A composition comprising the compound of claim 16, wherein the composition is formulated for intravenous, intraperitoneal, intramuscular, intra-arterial, or subcutaneous administration.

### Claim 22 (depends on 16)

A composition comprising the compound of claim 16, wherein the composition is formulated as a haemodialysis or peritoneal dialysis solution.