HRI ACTIVATORS USEFUL FOR THE TREATMENT OF CARDIOMETABOLIC DISEASES

• US 20190322632A1
• Filed: 03/29/2017
• Published: 10/24/2019
• Est. Priority Date: 07/13/2016
• Status: Abandoned Application

• Current Assignee: Universitat de Barcelona (University of Barcelona)
• Original Assignee: Universitat de Barcelona (University of Barcelona)
• Inventors: ZAREI, Mohammad, VAZQUEZ CARRERA, Manuel, VAZQUEZ CRUZ, Santiago, LEIVA MARTINEZ, Rosana, PUJOL BECH, Eugenia
• Application Number:
  US16/317,485
• Publication Number:
  US 20190322632A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 381/00 Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
• CPC Class Codes: C07D 271/12 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 285/14 condensed with carbocyclic rings or ring systems

Abstract

Compounds of formula (I) include: X is CH or N, preferably CH; n is 1-5, preferably 1-2; m is 0-5, preferably 1-2; and, when m is 2-5, two of the R² radicals taken together with two adjacent carbons of the benzene ring can form a 5- or 6-membered heterocyclic ring fused with the benzene ring. Compounds of formula (I) are heme-regulated inhibitor (HRI) activators and useful for prevention or treatment of cardiometabolic diseases such as metabolic syndrome, obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease, steatosis, non-alcoholic steatohepatitis, hypertension, dyslipidemia, atherosclerosis, and heart disease.

Claims

1. A compound of formula (I)

2. The compound according to claim 1, wherein X is CH.

3. The compound according to claim 1, wherein n is 1 or 2, and m is 1 or 2.

4. The compound according to claim 1, wherein:

m is an integer from 2 to 5, and two R² radicals taken together with two adjacent carbons of the benzene ring to which they are joined form a 5- or 6-membered heterocyclic ring having from 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S, the heterocyclic ring being fused with the benzene ring, and the benzene ring being optionally substituted with one or more radicals independently selected from the group consisting of SF₅, halogen, CF₃, NO₂, CN, and OCF₃.

5. The compound according to claim 4, wherein two R² radicals are forming a heterocyclic ring which has one of the following formulas:

6. The compound according to claim 1, wherein R² is independently selected from the group consisting of SF₅, halogen, CF₃, NO₂, CN, OCF₃, hydroxyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, di-(C₁-C₄)alkylaminoethoxy, 2-(piperidin-1-yl)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, 2-(azepan-1-yl)ethoxy, 2-morpholinoethoxy, and 2-(piperazin-1-yl)ethoxy.

7. The compound according to claim 1, which has an SF₅ radical attached to the 3 position of the phenyl ring that has the R¹ radicals.

8. The compound according to claim 1, wherein halogen is F or Cl.

9. The compound according to claim 5, which has one of the following formulas:

10. The compound according to claim 6, which has one of the following formulas:

11. A compound according to claim 1, for use as active pharmaceutical ingredient.

12. A compound according to claim 1, for use in the prevention or treatment of a cardiometabolic disease selected from the group consisting of metabolic syndrome, obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease, steatosis, non-alcoholic steatohepatitis, hypertension, dyslipidemia, atherosclerosis, and heart disease.

13. The compound for use according to claim 12, wherein the cardiometabolic disease is metabolic syndrome.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, together with appropriate amounts of pharmaceutically acceptable excipients or carriers.

15. A pharmaceutical composition according to claim 14, for use in the prevention or treatment of a cardiometabolic disease selected from the group consisting of metabolic syndrome, obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease, steatosis, non-alcoholic steatohepatitis, hypertension, dyslipidemia, atherosclerosis, and heart disease.