Compounds, compositions and methods for treating insulin resistance

Patent metadata

Field	Value
Publication number	US-11020378-B2
Application number	US-201816496111-A
Country	US
Kind code	B2
Filing date	Mar 20, 2018
Priority date	Mar 20, 2017
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

The invention relates to a compound inhibiting the interaction between a Grb14 protein and an insulin receptor of Formula (I) or Formula (II),

their salts, solvates, and/or diastereoisomers, for use for therapeutic purposes, in particular for the treatment of insulin resistance, and to pharmaceutical compositions containing such compounds.

First claim

The invention claimed is:

1. A method for treatment of insulin resistance and/or prevention and/or treatment of a pathology associated with insulin resistance, comprising administering to a patient in need thereof a compound inhibiting interaction between a Grb14 protein and an insulin receptor, said compound being selected from the group consisting of compounds belonging to the family of sulfonamide isoxazoles of Formula (I), and salts, solvates, and/or diastereoisomers thereof:

wherein:
the group R 1 represents a linear, cyclic or branched-chain alkyl group containing up to 5 carbon atoms, and
the groups R 2 , R 3 , R 4 , and R 5 are identical or different and represent a hydrogen atom or a linear, cyclic or branched-chain alkyl group containing up to 5 carbon atoms.

2. The method according to claim 1 , said compound being of Formula (I) in a trans configuration.

3. The method according to claim 1 , said compound being of Formula (I) wherein the groups R 2 and R 3 represent a hydrogen atom.

4. The method according to claim 1 , said compound being of Formula (I) wherein the groups R 4 and R 5 represent a methyl group.

5. The method according to claim 1 , said compound being of Formula (I) wherein the group R 1 represents a saturated linear or branched-chain alkyl group containing up to 5 carbon atoms.

6. The method according to claim 1 , said compound being of Formula (I) wherein:
the group R 1 represents a linear or branched-chain alkyl group containing up to 5 carbon atoms,
the groups R 2 and R 3 represent a hydrogen atom, and
the groups R 4 and R 5 represent a methyl group.

7. The method according to claim 1 , wherein said compound is selected from the group consisting of compounds of Formula (Ia), Formula (Ib), and salts, solvates and/or diastereoisomers thereof:

8. The method according to claim 1 , said compound being effective as an insulin sensitizer upon administration to the patient in need thereof.

9. The method according to claim 1 , said compound being formulated in a pharmaceutical composition that is administered to the patient in need thereof.

10. A pharmaceutical composition, comprising at least one inhibitor compound selected from the group consisting of compounds belonging to the family of sulfonamide isoxazoles of Formula (I), and salts, solvates, and/or diastereoisomers thereof:

wherein:
the group R 1 represents a linear, cyclic or branched-chain alkyl group containing up to 5 carbon atoms, and
the groups R 2 , R 3 , R 4 , and R 5 are identical or different and represent a hydrogen atom or a linear, cyclic or branched-chain alkyl group containing up to 5 carbon atoms;
and at least one other active ingredient selected from: sulfonylureas, biguanides, thiazolidinediones, GLP1 analogues dipeptidyl peptidase-4 inhibitors alpha-glucosidase inhibitors, glinides, fibrates, and SGLT2 inhibitors.

11. The method according to claim 1 , wherein said pathology associated with insulin resistance is selected from: metabolic syndrome, obesity, polycystic ovary syndrome, pre-gestational diabetes, type 2 diabetes, hyperglycemia, lipodystrophy, diabetic nephropathy, and cardiovascular complications, including high blood pressure, diabetic microangiopathy, or diabetic macroangiopathy.

12. The method according to claim 10 , wherein said compound is administered at a dose between 50 mg and 250 mg per day.

13. A method for synthesizing a compound according to Formula (I) or its diastereoisomers:

wherein:
the group R 1 in Formula (I) represents a linear, cyclic or branched-chain alkyl group containing up to 5 carbon atoms, and the groups R 2 , R 3 , R 4 , and R 5 in Formula (I) are identical or different and represent a hydrogen atom or a linear, cyclic or branched-chain alkyl group containing up to 5 carbon atoms;

the method comprising a step of condensing a sulfonamide of Formula (V):

wherein:
the groups R 4 and R 5 are identical or different and represent a hydrogen atom or a linear, cyclic or branched-chain alkyl group containing up to 5 carbon atoms;

with an acrylic acid derivative of Formula (IV):

wherein:
the group R 1 represents a linear, cyclic or branched-chain alkyl group containing up to 5 carbon atoms, and
the groups R 2 and R 3 are identical or different and represent a hydrogen atom or a linear, cyclic or branched-chain alkyl group containing up to 5 carbon atoms.

14. The method according to claim 13 wherein said condensation step is carried out in the presence of a peptide coupling reagent.

15. The method according to claim 13 , wherein said condensation step is carried out in the presence of DIPEA (N-Ethyl-N-(propan-2-yl)propan-2-amine) and a peptide coupling reagent selected from HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium,3-oxide hexafluorophosphate) and Ghosez's reagent (1-Chloro-N,N,2-trimethylpropenylamine).

16. The method according to claim 12 , said dose being between 100 mg and 200 mg per day.

17. The method according to claim 10 , said pharmaceutical composition further comprising at least one other active ingredient selected from: sulfonylureas, biguanides, thiazolidinediones, GLP1 analogues, dipeptidyl peptidase-4 inhibitors alpha-glucosidase inhibitors, glinides, fibrates, and SGLT2 inhibitors.

18. The method according to claim 17 , wherein said at least one other active ingredient is selected from metformin, exenatide, liraglutide, sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, alogliptin, and canaglifozin.

19. The pharmaceutical composition according to claim 10 , wherein said at least one other active ingredient is selected from metformin, exenatide, liraglutide, sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, alogliptin, and canaglifozin.

Assignees

• Univ Paris Descartes
• Univ Paris Sud 11
• Inst Nat Sante Rech Med
• Univ Paris Diderot
• Centre Nat Rech Scient

Inventors

• Miteva Maria
• Villoutreix Bruno
• Aitken David J
• Burnol Anne-Françoise
• Gondoin Anais
• Issad Tarik

Classifications

• A61K31/422 Primary

  not condensed and containing further heterocyclic rings · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/341

  not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title