Novel cholesterol metabolite, 5-cholesten, 3beta-25-diol, disulfate (25hcds) for therapy of metabolic disorders, hyperlipidemia, diabetes, fatty livers diseases and atherosclerosis

Patent metadata

Field	Value
Publication number	US-2016355544-A1
Application number	US-201615241171-A
Country	US
Kind code	A1
Filing date	Aug 19, 2016
Priority date	Apr 12, 2012
Publication date	Dec 8, 2016
Grant date	—

Abstract

5-cholesten, 3β, 25-diol, disulfate (25HCDS) has been found to be an authentic PPAR γ agonist and LXR antagonist, and is used for the therapy of lipid disorders and inflammatory diseases, including without limitation fatty liver, inflammatory bowel, and atherosclerotic diseases.

First claim

We claim:

1 . A compound which is: (i) 5-cholesten, 3b, 25-diol, disulfate (25HCDS) of the formula

or (ii) a pharmaceutically acceptable salt thereof;
for use as a medicament.

2 . The compound for use according to claim 1 , wherein the compound is

3 . A compound as defined in claim 1 or 2 for use in a method of: reducing lipids in a subject in need thereof; reducing cholesterol and lipid biosynthesis in a subject in need thereof; reducing inflammation in a subject in need thereof; treating diabetes in a subject in need thereof; treating hyperlipidemia in a subject in need thereof; treating atherosclerosis in a subject in need thereof; treating fatty liver disease in a subject in need thereof; or treating inflammatory disease in a subject in need thereof.

4 . Use of a compound as defined in claim 1 or 2 for the manufacture of a medicament for: reducing lipids in a subject in need thereof; reducing cholesterol and lipid biosynthesis in a subject in need thereof; reducing inflammation in a subject in need thereof; treating diabetes in a subject in need thereof; treating hyperlipidemia in a subject in need thereof; treating atherosclerosis in a subject in need thereof; treating fatty liver disease in a subject in need thereof; or treating inflammatory disease in a subject in need thereof.

5 . A method of treating a subject, which method comprises administration to the said subject of an effective amount of a compound as defined in claim 1 or 2 , wherein said method is selected from: a method for reducing lipids in a subject in need thereof; a method of reducing cholesterol and lipid biosynthesis in a subject in need thereof; a method of reducing inflammation in a subject in need thereof; a method of treating diabetes in a subject in need thereof; a method of treating hyperlipidemia in a subject in need thereof; a method of treating atherosclerosis in a subject in need thereof; a method of treating fatty liver disease in a subject in need thereof; and a method of treating inflammatory disease in a subject in need thereof.

6 . The method of claim 5 wherein:
said compound is administered in an amount ranging from 0.1 mg/kg to 100 mg/kg based on body mass of said subject, or said compound is administered in an amount ranging from 1 mg/kg to 10 mg/kg, based on body mass of said subject; and/or
the administration comprises at least one of oral administration, enteric administration, sublingual administration, transdermal administration, intravenous administration, peritoneal administration, parenteral administration, administration by injection, subcutaneous injection and intramuscular injection.

7 . A compound as defined in claim 1 or 2 .

8 . The compound according to claim 7 , which is an isolated compound.

9 . The compound according to claim 7 or 8 , which is substantially pure.

10 . The compound according to any one of claims 7 to 9 , which is in solid form.

11 . The compound according to claim 10 , which is:
in powder form; and/or in freeze-dried form.

12 . A pharmaceutical composition comprising: (i) a compound as defined in claim 1 or 2 ; and (ii) a physiologically acceptable excipient, diluent or carrier.

13 . The pharmaceutical composition according to claim 12 , wherein the composition is formulated in unit dosage form.

14 . The pharmaceutical composition according to claim 12 or 13 , wherein the composition is in solid form.

15 . The pharmaceutical composition according to claim 14 , wherein:
the composition is in the form of a powder, a tablet, a capsule or a lozenge; or the composition comprises the compound in freeze-dried form together with a bulking agent, the composition optionally being in a sealed vial, ampoule, syringe or bag.

16 . A pharmaceutical composition according to claim 12 or 13 , which comprises a carrier that is a liquid.

17 . A pharmaceutical composition according to claim 16 , wherein:
the compound is solubilized in said liquid or dispersed in said liquid; and/or said liquid is aqueous; and/or said liquid is sterile water for injections or phosphate-buffered saline; and/or said composition is in a sealed vial, ampoule, syringe or bag.

18 . A process of producing a compound as defined in claim 1 or 2 , which process comprises reacting 25-hydroxycholesterol with a source of sulfur trioxide and, optionally, forming a pharmaceutically acceptable salt from the resulting 5-cholesten, 3b, 25-diol, disulfate (25HCDS).

19 . A process according to claim 18 , wherein the source of sulfur trioxide is a sulfur trioxide amine complex.

20 . A process of producing a pharmaceutical composition as defined in any one of claims 12 to 17 , which process comprises combining said compound with said physiologically acceptable excipient, diluent or carrier.

Assignees

• Univ Virginia Commonwealth

Inventors

• Ren Shunlin

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

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

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title