Inositol derivatives for use in pathological crystallization

Patent metadata

Field	Value
Publication number	US-11028112-B2
Application number	US-202016852587-A
Country	US
Kind code	B2
Filing date	Apr 20, 2020
Priority date	Dec 11, 2015
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

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.

First claim

We 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 R 1 and the remaining X independently from each other are selected from OPO 3 2− , OPSO 2 2− , and OSO 3 − ; and
each R 1 independently of any other R 1 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.

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

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

4. 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 R 1 have the meaning outlined above.

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

6. 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 R 1 have the meaning outlined above.

7. The method of claim 1 , wherein one or two or three X are R 1 and the remaining X are
all OPO 3 2− or
all OPSO2 2− or
all OSO 3 − .

8. The method of claim 1 , wherein
one or two or three X are R 1 and the remaining X are OPO 3 2− ; and
R 1 is a polyethylene glycol and has a molar mass between 100 g/mol and 3000 g/mol.

9. The method of claim 1 , wherein
one or two or three X are R 1 and the remaining X are OPSO 2 2− ; and
R 1 is a polyethylene glycol and has a molar mass between 100 g/mol and 3000 g/mol.

10. The method of claim 1 , wherein two X are R 1 .

11. The method of claim 1 , wherein:
one X is R 1 and of the remaining X:
three X are OSO 3 − and two X are OPSO 2 2− , or three X are OSO 3 − and two X are OPO 3 2− , and
R 1 is a polyethylene glycol and has a molar mass between 100 g/mol and 3000 g/mol.

12. The method of claim 1 , wherein R 1 is a polyethylene glycol characterized by a formula R 3 —(O—CH 2 —CH 2 ) n — or R 3 —(O—CH 2 —CH 2 ) n —O—, and R 3 is hydrogen, methyl or ethyl.

13. 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 R 3 is selected from H, methyl and ethyl.

14. 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)

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

16. 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)

17. A compound of general formula (II)

wherein
three X are R 1 and the remaining X independently from each other X are selected from OPO 3 2− , OPSO 2 2− , and OSO 3 − ; and
each R 1 independently of any other R 1 is a polyethylene glycol or a polyglycerol.

18. The compound of claim 17 , wherein the compound is any one of:

wherein each X (independently) and R 1 have the meaning outlined above.

19. The compound of claim 17 , wherein R 1 is a polyethylene glycol and has a molar mass between 100 g/mol and 3000 g/mol.

20. The compound of claim 17 described by the formula (V c),

wherein n has a value from 2 to 200 and R 3 is selected from H, methyl and ethyl.

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

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

Assignees

• Eth Zuerich
• Univ Bern

Inventors

• Ivarsson Mattias
• Castagner Bastien
• Leroux Jean-Christophe
• Pasch Andreas

Classifications

• C07H15/08 Primary

  Polyoxyalkylene derivatives · CPC title

• A61P9/10 Primary

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K9/0019

  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) · CPC title

• A61K47/34

  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) · CPC title

• A61K31/663

  Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid · CPC title