1,3-diphenylpropane derivatives, preparations and uses thereof

Patent metadata

Field	Value
Publication number	US-9115073-B2
Application number	US-201214368823-A
Country	US
Kind code	B2
Filing date	Dec 28, 2012
Priority date	Dec 28, 2011
Publication date	Aug 25, 2015
Grant date	Aug 25, 2015

Abstract

The present invention relates to novel 1,3-diphenylpropane derivatives, pharmaceutical compositions comprising the same and therapeutic uses thereof, in particular in the fields of human and animal health. The compounds according to the present invention have intrinsic PPAR agonist properties. They are therefore of particular interest in the treatment of metabolic and/or inflammatory diseases and particularly peripheral and central diseases associated with the metabolic syndrome, such as diverse forms of steatohepatitis, type 2 diabetes, diverse neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis.

First claim

The invention claimed is:

1. A compound, derived from 1,3-diphenylpropane, having the general formula (I):

in which:
X 1 represents a halogen atom, a hydrogen atom, an R1 group or G1-R1 group;
X 2 represents a halogen atom, a hydrogen atom, an R2 group or G2-R2 group;
X 3 represents a halogen atom, a hydrogen atom, an R3 group or G3-R3 group;
X 4 represents a halogen atom, a hydrogen atom, an R4 group or G4-R4 group;
X 5 represents a halogen atom, a hydrogen atom, an R5 group or G5-R5 group;
X 6 , X 7 , X 9 and X 10 , which can be identical or different, represent a halogen atom, a hydrogen atom, or an alkyl group; and
X 8 represents a G8-R8 group;
wherein R1, R2, R3, R4 and R5, which can be identical or different, represent an alkyl group or a halogenated alkyl group;
R8 represents an alkyl group substituted by at least one COOR12 group;
R12 represents a hydrogen atom or an alkyl group;
G1, G2, G3, G4, G5, and G8, which can be identical or different, represent an oxygen atom or a sulfur atom; and
X 11 represents an alkyl group, optionally substituted by an aryl or a cycloalkyl group.

2. The compound according to claim 1 , wherein when at least one of X 1 , X 2 , X 3 , X 4 and X 5 represents R1, R2, R3, R4 or R5, respectively, then said R1, R2, R3, R4 or R5 is optionally halogenated C1-C4, an alkyl group, a methyl group or a trifluoromethyl group.

3. The compound according to claim 1 , wherein when at least one of X 1 , X 2 , X 3 , X 4 and X 5 represents G1-R1, G2-R2, G3-R3, G4-R4 or G5-R5, respectively, then said R1, R2, R3, R4 or R5 is an optionally halogenated C1-C4, an alkyl group, a methyl group or a trifluoromethyl group.

4. The compound according to claim 1 , wherein at least three or four X5 out of the X 1 , X 2 , X 3 , X 4 and X 5 groups are hydrogen atoms, or X 2 , X 4 and X 5 are hydrogen atoms or X 1 , X 2 , X 4 and X 5 are hydrogen atoms.

5. The compound according to claim 1 , wherein the X 1 , X 2 , X 3 , X 4 and X 5 groups represent R1, R2, R3, R4 and R5, respectively, and said R1, R2, R3, R4 and R5 are optionally halogenated C1-C4, alkyl groups, methyl groups or trifluoromethyl groups.

6. The compound according to claim 1 , wherein X 3 represents a halogen atom, R3 or a G3-R3 group, X 1 represents a halogen atom or a hydrogen atom, and X 2 , X 4 and X 5 are hydrogen atoms.

7. The compound according to claim 1 , wherein X 1 represents a halogen atom, R1 or a G1-R1 group, X 3 represents a halogen atom or a hydrogen atom, and X 2 , X 4 and X 5 are hydrogen atoms.

8. The compound according to claim 1 , wherein X 6 , X 7 , X 9 and X 10 independently represent a hydrogen atom, a halogen atom or an alkyl group, with at least one of X 7 and X 9 not being a hydrogen atom.

9. The compound according to claim 1 , wherein R8 is a linear or branched (C1-C4)alkyl or R8 is —CH(CH 3 )-, or —C(CH 3 ) 2 -.

10. The compound according to claim 1 , wherein X 11 is a hydrogen atom or a linear or branched (C 1 -C 4 )alkyl, optionally substituted by an aryl group or a cycloalkyl group.

11. The compound according to claim 1 , wherein the compound is selected from:
2-(4-(2-(methoxy(4-bromophenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(4-methylphenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(4-(methylthio)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(4-(trifluoromethyl)phenyemethyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(butyloxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(cyclohexylethyloxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)-2-methylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(4-(propyloxy)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(4-(trifluoromethylthio)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(ethoxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(benzyloxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(2-fluoro-4-(trifluoromethyl)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(2-(trifluoromethyloxy)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(2-isopropyl-4-(2-(methoxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)phenoxy)-2-methylpropanoic acid;
2-(4-(2-((2,4-bis(trifluoromethyl)phenyl)(methoxy)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-(methoxy(2-methoxy-4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(4-(2-((2-(hexyloxy)phenyl)(methoxy)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid;
2-(2-bromo-4-(2-(methoxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)phenoxy)-2-methylpropanoic acid;
2-(2,6-difluoro-4-(2-(methoxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)phenoxy)-2-methylpropanoic acid; or
2-(2-cyclopropyl-4-(2-(methoxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)phenoxy)-2-methylpropanoic acid.

12. The compound according to claim 1 , wherein the compound is 2-(4-(2-(methoxy(4-(trifluoromethoxy)phenyl)methyl)cyclopropyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid.

13. A pharmaceutical composition comprising, in a pharmaceutically acceptable support, at least one of the compounds as defined in claim 1 .

14. A method for the treatment of a metabolic and/or inflammatory disease, the method comprising administering a compound according to claim 1 to a subject in need thereof.

15. The method according to claim 14 , wherein said disease is selected from overweight condition, bulimia, anorexia nervosa, hyperlipidemia, dyslipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, low HDL, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), diseases associated with hepatic fibrosis, such as primary biliary cirrhosis, viral hepatitis, or drug-induced hepatitis, alcoholic liver disease, type 2 diabetes, type 1 diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, a diabetic complication of neuropathy, nephropathy, retinopathy, diabetic foot ulcer or cataracts, hypertension, coronary heart disease, heart failure, congestive heart failure, atherosclerosis, arteriosclerosis, stroke, cerebrovascular disease, myocardial infarction, peripheral vascular disease, vitiligo, uveitis, pemphigus foliaceus, inclusion body myositis, polymyositis, dermatomyositis, scleroderma, Graves' disease, Hashimoto's disease, chronic graft versus host disease, rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic lupus erythematosis, Sjögren's syndrome, multiple sclerosis, asthma, chronic obstructive pulmonary disease, polycystic kidney disease, polycystic ovary syndrome, pancreatitis, nephritis, hepatitis, eczema, psoriasis, dermatitis, impaired wound healing, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, acute disseminated encephalomyelitis, Guillain-Barré syndrome, thrombosis, infarction of the large or small intesti

Assignees

• Genfit

Inventors

• Dubernet Mathieu
• Delhomel Jean-Francois
• Bertrand Karine

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P37/02

  Immunomodulators · 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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title