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    1,3-DIPHENYL-PROP-2-EN-1-ONA DERIVED COMPOUND, USE OF THAT COMPOUND, AND, PHARMACEUTICAL COMPOSITION The invention relates to 1,3-diphenyl-prop-2-en-1-one derivatives and pharmaceutical compositions comprising such derivatives for the treatment of liver disorders, in particular those requiring a reduction in the plasma level of biochemical markers, such as aminotransferases. The 1,3-diphenyl-prop-2-en-1-one derivatives of General Formula (I) have hepatoprotective properties and can be used in methods to treat liver disorders involving pathological disorder, inflammation, degeneration, and / or proliferation of liver cells, such as liver fibrosis or fatty liver disease.
    公开号:BR112012012815B1
    申请号:R112012012815-9
    申请日:2010-11-26
    公开日:2021-02-02
    发明作者:Raphaël Darteil；Rémy Hanf；Dean Hum；Ingrid Dufour
    申请人:Genfit；
    IPC主号:
    专利说明:

    TECHNICAL FIELD
    [0001] The invention relates to the use of compounds having hepatoprotective effects in the preparation of pharmaceutical compositions and to methods for treating liver disorders. BACKGROUND OF THE INVENTION
    [0002] According to the publication “Washington Manual of Medical Therapeutics” (31st ed .; 2004; Lippincott Williams & Wilkins), liver disorders can be classified into different groups of disease, and, in particular, viral diseases, liver diseases related to drug and alcohol, immune-mediated liver diseases, metabolic liver diseases, heterogeneous diseases, such as non-alcoholic fatty liver disease, and complications of liver failure (such as fulminant liver failure or hepatocellular carcinoma) and liver transplantation.
    [0003] In particular, non-alcoholic fatty liver disease (NAFLD) is a common liver disorder with histological features of alcohol-induced fatty liver disease in individuals who consume little or no alcohol (Yeh M. et al., 2007; Marchesini G. and others, 2003). NAFLD is due to the abnormal retention of lipids in cells (usually defined as steatosis), a more frequent event in the liver since this organ is mainly responsible for lipid metabolism. NAFLD has a spectrum of histological forms including hepatic steatosis, and non-alcoholic steatohepatitis (NASH), which is characterized by inflammation of the liver, steatosis, necrosis and fibrosis due to the rupture of liver cells. Conditions associated with NAFLD are varied, and include type 2 diabetes, obesity, dyslipidemia, metabolic syndrome, treatment with hepatotoxic drugs, toxins, infectious agents, or other exogenous causes.
    [0004] Although NAFLD typically follows a benign, non-progressive clinical course, NASH is a potentially serious condition; almost 25% of patients can progress to advanced fibrosis, cirrhosis and experience complications of portal hypertension, liver failure and hepatocellular carcinoma, which makes an early and correct assessment mandatory (Yeh M et al., 2007).
    [0005] Liver imaging systems are useful for assessing liver structure and the presence of steatosis as well. However, liver biopsy remains the essential standard for the assessment of liver fibrosis, however this method of analysis may not be done for each single study due to its invasiveness. Noninvasive assessment of liver metabolism and biochemistry is generally used to define liver disease, such as in NAFLD and NASH (Gressner A. et al., 2009; Vuppalanchi R. and Chalasani N., 2009). Using plasma, elevated levels of enzymes such as Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), Alkaline phosphatase (AP), and / or Gamma Glutamyl Transpeptidase (GGT), as well as the presence of other proteins of origin of the liver (including haptoglobin, total bilirubin, alpha-2-microglobulin, resistin, cleaved or intact cytokeratin-18) are generally measured, in addition to serum insulin and glucose resistance parameters. Since the level of ALAT activity is often higher in patients with NASH (Angulo P et al., 2002), this criterion is considered as a substitute marker for assessing liver injury. In reality, reliable non-invasive methods are not available to correctly diagnose NAFLD or NASH and yet the histological characteristics are not always sufficient to properly distinguish NAFLD or NASH from other conditions, such as alcoholic liver disease (Yeh M and others, 2007, Vuppalanchi R and Chalasani N, 2009).
    [0006] The means for an effective treatment for fibrotic liver diseases, and NAFLD and NASH in particular, are still insufficient. No treatment is established for the patient with NASH, and several therapeutic options are tested in clinical experience (Vuppalanchi R. and Chalasani N, 2009, Dowman J.K. and others, 2009). These studies involve the use of many different families of chemical compounds (fibrates, thiazolidinediones, biguanides, statins, cannabinoids) and therapeutic targets (nuclear receptors, angiotensin receptors, cannabinoid receptors, HMG-CoA reductase). Recently, studies involving thiazolidinediones (Rosiglitazone and Pioglitazone) have shown that these drugs can improve the condition of the liver, however, treatment with these drugs does not occur without unwanted effects, such as higher risks of osteoporosis and congestive heart failure, as well as weight gain with psychological effects on the patient (Dowman JK et al., 2009; Shiri-Sverdlov R et al., 2006; Neuschwander-Tetri et al., 2003). Clinical experiences involving the administration of cannabinoids have led to concern about neuropsychiatric disorder (Vuppanchi R. and Chalasani N, 2009). Other therapies currently underway are focused on evaluating drugs for NASH as antioxidants, however, none of these treatments has so far shown convincing results (Nelson A. et al., 2009).
    [0007] The need for new therapeutic options for the control of liver disorders, and, in particular, those involving steatosis and / or liver fibrosis, is still clear and urgent. SUMMARY OF THE INVENTION
    [0008] A clinical study surprisingly showed that treating patients with a 1,3-diphenyl-prop-2-en-1-one derivative provides a statistically relevant reduction in liver specific biochemical markers in plasma, demonstrating hepatoprotective properties of a family of compounds that is defined by means of a General Formula (I).
    [0009] The present invention provides new 1,3-diphenyl-prop-2-en-1-one derivatives of General Formula (I) (said derivatives cited herein being also referred to as the "compounds") or pharmaceutical compositions comprising the same for use in a method to treat liver disorders, and, in particular, those that lead to increased plasma levels of biochemical markers, such as aminotransferases. The 1,3-diphenyl-prop-2-en-1-one derivatives of General Formula (I) and pharmaceutical compositions comprising them have hepatoprotective properties and can be used in methods to treat liver disorders involving pathological disorder, inflammation, degeneration, and / or proliferation of liver cells, such as liver fibrosis, fatty liver disease and non-alcoholic steatohepatitis.
    [0010] Other objectives of the present invention, including the General Formulas specific to the compounds of interest, are provided in the Detailed Description. DESCRIPTION OF THE FIGURES
    [0011] Abbreviations in figures and text: - ALAT = alanine aminotransferase - CCL5 = chemokine ligand 5 (CC portion) - Col1 a1 = collagen, type I, alpha 1 - Cpd 1 = compound 1 of patent application WO2007 / 147879 - Cpd 29 = compound 29 of patent application WO2004 / 005233 - Ctrl = control or vehicle - Hay = Fenofibrate - HDL = High Density Lipoprotein - LDL = Low Density Lipoprotein - NAFLD = Non-Alcoholic Fatty Liver Disease - NASH = Steato- Non-Alcoholic Hepatitis - PPAR = Peroxisome Proliferate Activated Receptor - Rosi = Rosiglitazone - RT-PCR = Reverse Transcription Polymerase Chain Reaction - TGFp = Transforming Growth Beta Factor - TNFa = Tumor Necrosis Alpha Factor
    [0012] Figure 1: Structure of exemplary compounds of General Formula (I)
    [0013] Exemplary compounds of General Formula (I) are grouped according to the more specific definitions of General Formula (II) (Panel A), General Formula (IV) (Panel B), and General Formula (V) (Panel C).
    [0014] Figure 2: In vivo evaluation, in ob / ob mice, of the anti-inflammatory properties of the compounds of the General Formula (I)
    [0015] The compounds of General Formula (I) were tested in a murine model of type II diabetes, the ob / ob mice. The mice were treated daily orally with Compound 29 of patent application WO2004 / 005233 in two different doses (10 and 30 mg / kg / day) and with the specific reference compounds of prototype PPARalpha and PPARgama (Fenofibrate at a dose of 100mg / kg / day and Rosiglitazone at a dose of 10mg / kg / day, respectively). After 26 days of treatment, the animals were sacrificed and the plasma and liver samples were collected. The liver expression of genes that are known to be involved in the liver inflammation process has been assessed and plasma ALAT levels have been measured (Panels A-C). Statistical analysis was performed using unpaired t-test with three p-values that define statistical relevance (* mean p <0.05; ** means p <0.01; *** means p <0.001).
    [0016] Figure 3: In vivo evaluation, in KI hApoE2 mice, of the anti-inflammatory and anti-fibrotic properties of the compounds of General Formula (I)
    [0017] The compounds of General Formula (I) were tested in vivo in a high-fat diet mouse model. Dyslipidemic "humanized" ApoE2 knockout mice (KI hApoE2) were fed a western diet and treated for 12 weeks. The compounds of interest, including Compound 29 of patent application WO2004 / 005233 at 0.3 mg / kg / day and Fenofibrate at 100 mg / kg / day (used as a reference compound) were incorporated into the diet. At the end of the protocol, the animals were sacrificed, the livers were collected and the liver expression of the genes that are known to be involved in liver inflammation and fibrosis processes, were evaluated by quantitative RT-PCR (Panels A-D). The statistical analysis was performed as shown in Figure 1.
    [0018] Figure 4: In vivo evaluation, in the KI hApoE2 and KI hApoE2 / KO PPARalfa mice, of the anti-inflammatory and anti-steatotic properties of the compounds of the General Formula (I)
    [0019] The compounds of the General Formula (I) were tested in vivo in a high-fat diet mouse model. The dyslipidemic "humanized" KI hApoE2 mice deficient in PPARalpha were fed a western diet and treated for 6 weeks. The compounds of interest, including Compound 29 of patent application WO2004 / 005233 at a dose of 30 mg / kg / day and Compound 1 of patent application WO2007 / 147879 at a dose of 30 mg / kg / day were administered orally by a feeding tube (“gavage”). At the end of the protocol, the animals were sacrificed, the livers were collected and the liver expression of relevant genes involved in liver inflammation and fibrosis processes were evaluated by quantitative RT-PCR. In parallel, the levels of triglycerides in the liver were assessed (Panels A-D). The statistical analysis was performed as shown in Figure 1. DETAILED DESCRIPTION OF THE INVENTION
    [0020] The present invention provides new therapeutic uses and methods of administering 1,3-diphenyl-prop-2-en-1-one derivatives of General Formula (I) and pharmaceutical compositions comprising them to treat liver disorders. The specific 1,3-diphenyl-prop-2-en-1-one derivatives that are substituted in both phenyl groups can be defined according to the Examples as being useful for treating liver disorders, since such compounds decrease surprisingly, specific markers of liver inflammation as well as liver cell disruption, degeneration, and / or proliferation in human subjects and animal models, and thus, they can provide a hepatoprotective effect.
    [0021] The compounds to be used and administered according to the invention and comprised in the compositions according to the invention have the following General Formula (I):

    [0022] where:
    [0023] X1 represents a halogen, an R1 or G1-R1 group;
    [0024] A represents a CH = CH group or a CH2-CH2 group;
    [0025] X2 represents a G2-R2 group;
    [0026] G1 and G2, identical or different, represent an oxygen or sulfur atom;
    [0027] R1 represents a hydrogen atom, an unsubstituted alkyl group, an aryl group or an alkyl group that is substituted with one or more halogen atoms, an alkoxy group or an alkyl-thio group, cycloalkyl groups, cycloalkyl groups uncle or heterocyclic groups;
    [0028] R2 represents an alkyl group substituted with at least one group - COOR3, where R3 represents a hydrogen atom, or an alkyl group that is substituted or not with one or more halogen atoms, cycloalkyl groups, or heterocyclic groups.
    [0029] R4 and R5, identical or different, represent an alkyl group that is or is not substituted with one or more halogen atoms, cycloalkyl groups, heterocyclic groups.
    [0030] In a particular embodiment, the compounds of the General Formula (I) are substituted with at least one alkyloxy group or an alkylthio group at positions X1 and X2. In addition, the derivatives can be in the form of substituted 1,3-diphenyl-propanes which are obtained by reducing the corresponding 1,3-diphenyl-prop-2-en-1-one derivatives.
    [0031] In a particular embodiment, X1 is a G1 -R1 group, and more preferably G1 is a sulfur atom and R1 is a linear or branched alkyl group that is substituted or not with one or more halogen atoms, cycloalkyl groups, heterocyclic groups. Even more preferably, X1 is an alkylthio group comprising an alkyl group that is linear or branched, having from one to seven carbon atoms which is or is not substituted with one or more halogen atoms. In a preferred embodiment, X1 is a methylthio group.
    [0032] In a particular embodiment, X2 is a G2-R2 group, where G2 is an oxygen atom and R2 is an alkyl group substituted with a -COOR3 group, where R3 represents a hydrogen atom or a linear alkyl group or unsubstituted branched having one to seven carbon atoms, and more preferably one to four carbon atoms. In a preferred embodiment, both R4 and R5 represent methyl groups.
    [0033] Furthermore, R4 and R5, identical or different, are preferably unsubstituted linear branched alkyl groups of one to seven carbon atoms, and more preferably one to four carbon atoms.
    [0034] In the context of the present invention, the term "alkyl" refers to a saturated hydrocarbon radical that is linear or branched, preferably having one to twenty-four, and even more preferably one to seven carbon atoms, such as such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ter-butyl, sec-butyl, pentyl, neopentyl, or n-hexyl.
    [0035] The term "alkyloxy" refers to an alkyl group that is attached to the rest of the compound by an oxygen atom.
    [0036] The term "alkylthio" refers to an alkyl group that is attached to the rest of the compound by a sulfur atom (thioether bond).
    [0037] The term "cycloalkyl" means an alkyl group that forms a cycle having preferably three to fourteen carbon atoms, and more preferably three to eight carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycle -heptila, and cyclooctyl.
    [0038] The term "cycloalkyl-thio" refers to a cycloalkyl group that is attached to the rest of the compound by a sulfur atom (thioether bond).
    [0039] The term "aryl" means an aromatic group, substituted or not having preferably six to fourteen carbon atoms, such as phenyl, D-naphthyl, □ □ - naphthyl, biphenyl, or anthracenyl.
    [0040] The term "heterocyclic" refers to a heterocycloalkyl group or a heteroaryl group.
    [0041] The term "heterocycloalkyl" group refers to a cycloalkyl as indicated above which also comprises one or more heteroatoms selected from nitrogen, oxygen, or sulfur. They generally comprise four to fourteen carbon atoms, such as morpholinyl, piperidinyl, tetrahydropyranyl, dithiolanyl.
    [0042] The term "heteroaryl" refers to an aryl group as indicated above that also comprises one or more heteroatoms selected from nitrogen, oxygen, or sulfur. They generally comprise four to fourteen carbon atoms, such as furanyl, thiophenyl, pyridinyl, pyrimidinyl, quinoline, isoquinoleinyl.
    [0043] By halogen atom, a bromine, chlorine, fluorine, or iodine atom must be understood.
    [0044] The different families of 1,3-diphenyl-prop-2-en-1-one and 1,3-diphenyl-propanes derivatives that are substituted in both phenyl groups can be found in the prior art (WO2003 / 037315 , WO2001 / 0461 10, JP2006-303800, JP04-202129). However, none of these documents shows that specific hepatoprotective effects are associated with compounds as defined in General Formula (I).
    [0045] The structure, synthesis, and some activities of the compounds that are covered by General Formula (I) have been described in a series of patent applications (WO2004 / 005243, WO2004 / 005233, WO2005 / 005369, US20070032543, WO2005 / 073184, WO2007 / 147879, and WO2007 / 147880), which do not describe the use of such compounds in methods to treat liver disorders.
    The specific derivatives of 1,3-diphenyl-prop-2-en-1-one of the General Formula (I) which can be used in the present invention and which can be comprised in the compositions according to the invention can be selected among the compounds described in patent applications WO2004 / 005243 and WO2004 / 005233, being in particular the following:
    [0047] 1- [4-chlorophenyl] -3- [3,5-dimethyl-4-isopropyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 15;
    [0048] 1- [4-chlorophenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 16;
    [0049] 1- [4-chlorophenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 17;
    [0050] 1- [4-methyl-thio-phenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 27;
    [0051] 1- [4-methyl-thio-phenyl] -3- [3,5-dimethyl-4-isopropyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 28 ;
    [0052] 1- [4-methyl-thio-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 29;
    [0053] 1- [4-hexyloxy-phenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 32 ;
    [0054] 1- [4-hexyloxy-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 33;
    [0055] 1- [4-heptyl-phenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 38 ;
    [0056] 1- [4-heptyl-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 39;
    [0057] 1- [4-bromophenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one, described as compound 40; and
    [0058] 1- [4-bromophenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy described as compound 41.
    [0059] In another embodiment of the invention, compounds as described in patent applications WO2004 / 005243 and WO2004 / 005233 (referred to herein as compounds of General Formula (II)) that can be used and administered and that can be comprised in compositions according to the invention have the following General Formula (I):

    [0060] where:
    [0061] X1 represents a halogen, an R1 group, or a G1-R1 group;
    [0062] A represents a CH = CH group;
    [0063] X2 represents a G2-R2 group;
    [0064] G1 and G2, identical or different, represent an oxygen or sulfur atom;
    [0065] R1 represents an alkyl or cycloalkyl group having from one to seven carbon atoms, in particular, the alkyl or cycloalkyl group being substituted or not with one or more halogen atoms;
    [0066] R2 represents an alkyl group substituted with a -COOR3 group, where R3 represents a hydrogen atom or an alkyl group having from one to four carbon atoms; and
    [0067] R4 and R5 represent an alkyl group having one to four carbon atoms.
    [0068] Patent applications WO2005 / 005369 and US20070032543 also describe the structure and an alternative process for the synthesis of compounds according to General Formula (I), as well as according to General Formula (II), and, in particular, the following compounds:
    [0069] 1- [4-trifluoro-methyl-phenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 57 of patent application US20070032543)
    [0070] 1- [4-trifluoro-methyl-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 58 of the patent application US20070032543)
    [0071] 1- [4-trifluoro-methyloxy-phenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 61 of patent application US20070032543)
    [0072] 1- [4-trifluoro-methyloxy-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 62 of the patent application US20070032543).
    [0073] Additional examples of the compounds to be used and administered and which can be comprised in compositions according to the invention can be selected from among the compounds described in patent application WO2005 / 073184, and, in particular, the following compounds:
    [0074] 1- (4- (pentyl-thio-ethyloxy) phenyl) -3- (4-ter-butyloxy-carbonyl-dimethyl-methyloxy-3,5-dimethyl-phenyl) prop-2-en-1-one , described as compound 1;
    [0075] 1- (4- (pentyl-thio-ethyloxy) phenyl) -3- (4-carboxy-dimethyl-methyloxy-3,5-dimethyl-phenyl) prop-2-en-1-one, described as a compound two;
    [0076] 1- (4 - ((R, S) -5- [1,2] dithiolan-3-yl-pentyloxy) phenyl) -3- (4-ter-butyloxy-carbonyl-dimethyl-methyloxy-3, 5-dimethyl-phenyl) prop-2-en-1-one, described as compound 5;
    [0077] 1- (4 - ((R, S) -5- [1,2] dithiolan-3-yl-pentyloxy) phenyl) -3- (4-carboxy-dimethyl-methyloxy-3,5-dimethyl- phenyl) prop-2-en-1-one, described as compound 6;
    [0078] 1- (4-cyclohexyl-ethyloxy-phenyl) -3- (4-ter-butyloxy-carbonyl-dimethyl-methyloxy-3,5-dimethyl-phenyl) prop-2-en-1-one, described as compound 10;
    [0079] 1- (4-cyclohexyl-ethyloxy-phenyl) -3- (4-carboxy-dimethyl-methyloxy-3,5-dimethyl-phenyl) prop-2-en-1-one, described as compound 11 ;
    [0080] 1- (4-cyclohexyl-thio-ethyloxy-phenyl) -3- (4-ter-butyloxy-carbonyl-dimethyl-methyloxy-3,5-dimethyl-phenyl) prop-2-en-1- one, described as compound 22;
    [0081] 1- (4-cyclohexyl-thioethyloxy-phenyl) -3- (4-carboxy-dimethyl-methyloxy-3,5-dimethyl-phenyl) prop-2-en-1-one, described as compound 23 ;
    [0082] 1- (4-phenyloxy-phenyl) -3- (4-ter-butyloxy-carbonyl-dimethyl-methyloxy-3,5-dimethyl-phenyl) prop-2-en-1-one, described as compound 32 ;
    [0083] 1- (4-phenyloxy-phenyl) -3- (4-carboxy-dimethyl-methyloxy-3,5-dimethyl-phenyl) prop-2-en-1-one described as compound 33.
    [0084] In another embodiment of the invention, compounds as described in patent application WO2005 / 073184 (hereinafter referred to as compounds of General Formula (III)) that can be used and administered, and that can be comprised in the compositions according to the invention has the following General Formula (I):

    [0085] where:
    [0086] X1 represents a G1-R1 group;
    [0087] A represents a CH = CH group;
    [0088] X2 represents a G2-R2 group;
    [0089] G1 and G2 represent an oxygen atom;
    [0090] R1 represents a cycloalkyl, an aryl group or an alkyl group that is substituted or not with one or more alkylthio, cycloalkyl, cycloalkylthio groups or heterocycloalkyl groups or an alkylthio group;
    [0091] R2 represents an alkyl group substituted with at least one group - COOR3, where R3 represents a hydrogen atom or an alkyl group having from one to four carbon atoms; and
    [0092] R4 and R5 represent an alkyl group having one to four carbon atoms.
    [0093] Additional examples of compounds used and administered according to the invention and which can be comprised in the compositions according to the invention can be selected from the compounds described in patent applications WO2004 / 005243, WO2004 / 005233, WO2005 / 005369 , US20070032543 or WO2005 / 073184, and reduced in the form of the corresponding substituted 1,3-diphenyl-propanes.
    Consequently, compounds that can be used and administered according to the invention and that can be comprised in the compositions according to the invention can be selected from among the compounds described in patent application WO2007 / 147879, and in particular, among the following compounds:
    [0095] 2- [2,6-dimethyl-4- [3- [4- (methyl-thio) phenyl] -3-oxo-propyl] phenoxy] -2-methylpropanoic acid, described as compound 1;
    [0096] 2- [2,6-dimethyl-4- [3- [4- (methoxy) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid, described as compound 6;
    [0097] 2- [2,6-dimethyl-4- [3- [4- (methyl-thio) phenyl] -3-oxo-propyl] phenoxy] etanoic acid, described as compound 7;
    [0098] 2- [2,6-dimethyl-4- [3- [4- (propyloxy) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid, described as compound 8;
    [0099] 2- [2,6-dimethyl-4- [3- [4- (methyl-thio) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid isopropyl ester, described as compound 13.
    [0100] In another embodiment of the invention, compounds as described in patent application WO2007 / 147879 (hereinafter referred to as compounds of General Formula (IV)) that can be used and administered and that can be comprised in compositions according to invention have the following General Formula (I):

    [0101] where:
    [0102] X1 represents a group R1 or a group G1-R1;
    [0103] A represents a CH2-CH2 group;
    [0104] X2 represents a G2-R2 group;
    [0105] G1 represents an oxygen or sulfur atom and G2 represents an oxygen atom;
    [0106] R1 represents an alkyl or cycloalkyl group having from one to seven carbon atoms;
    [0107] R2 represents an alkyl group substituted with at least one group - COOR3, where R3 represents a hydrogen atom or an alkyl group having from one to four carbon atoms; and
    [0108] R4 and R5 represent an alkyl group having one to four carbon atoms.
    [0109] Similarly, patent applications WO2007 / 147879 and WO2007 / 147880 describe compounds which can be comprised in compositions according to the invention and which correspond to the substituted reduced 1,3-diphenyl-propane derivatives of compounds which have been described in patent applications WO2004 / 005243, WO2004 / 005233, WO2005 / 005369, US20070032543, or WO2005 / 073184, and in particular, the compounds:
    [0110] 2- [2,6-dimethyl-4- [3- [4- (trifluoromethyloxy) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid, described as compound 1;
    [0111] 2- [2,6-dimethyl-4- [3- [4- (trifluoromethyl-thio) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid, described as compound 2 ;
    [0112] 2- [2,6-dimethyl-4- [3- [4-bromophenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid, described as compound 3;
    [0113] 2- [2,6-dimethyl-4- [3- [4- (trifluoromethyl) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid, described as compound 4;
    [0114] 2- [2,6-dimethyl-4- [3- [4- (3,3,3-trifluor-propyloxy) phenyl] -3-oxo-propyl] phenoxy] -2-methyl propanoic acid, described as compound 11;
    [0115] 2- (2,6-dimethyl-4- (3-oxo-3- (4- (2,2,2-trifluor-ethoxy) phenyl) propyl) phenoxy) -2-methyl-propanoic acid, described as compound 12;
    [0116] 2- (2,6-Dimethyl-4- (3-oxo-3- (4- (2,2,2-trifluor-ethyl-thio) phenyl) propyl) phenoxy) - 2-methyl-propanoic acid , described as compound 13
    [0117] 2- (2,6-dimethyl-4- (3-oxo-3- (4- (trifluoromethoxy) phenyl) propyl) phenoxy) propanoic acid, described as compound 29;
    [0118] 4- (2,6-Dimethyl-4- (3-oxo-3- (4- (trifluoro-methoxy) phenyl) propyl) phenoxy) -2,2-dimethyl-butanoic acid, described as compound 34;
    [0119] 2- (2,6-Dimethyl-4- (3-oxo-3- (4- (trifluoromethoxy) phenyl) propyl) phenoxy) -2-methyl-propanoic acid tert-butyl ester, described as compound 35;
    [0120] 2- (2,6-dimethyl-4- (3-oxo-3- (4- (trifluoro-methoxy) phenyl) propyl) phenoxy) -2-methyl-propanoic isopropyl ester, described as compound 36;
    [0121] 2,2-Difluoro-2- (2,6-dimethyl-4- (3-oxo-3- (4-trifluoro-methoxy) phenyl) propyl) phenoxy) acetic acid, described as compound 37.
    [0122] In another embodiment of the invention, compounds as described in patent application WO2007 / 147880 (referred to herein as compounds according to General Formula (V)) that can be used and administered and that can be comprised in the compositions of according to the invention have the following General Formula (I):

    [0123] where:
    [0124] X1 represents a halogen atom or an R1 or G1-R1 group;
    [0125] A represents a CH2-CH2 group;
    [0126] X2 represents a G2-R2 group;
    [0127] G1 represents an oxygen or sulfur atom, and G2 represents an oxygen atom;
    [0128] R1 represents an alkyl or cycloalkyl group that is substituted with one or more halogen atoms;
    [0129] R2 represents an alkyl group substituted or not substituted with one or more halogen atoms and substituted with at least one -COOR3 group, where R3 represents a hydrogen atom or an alkyl group having from one to four carbon atoms.
    [0130] R4 and R5 represent an alkyl group having one to four carbon atoms.
    [0131] The compounds that can most preferably be used and administered according to the invention and comprised in compositions according to the invention are those compounds defined according to General Formula (II), General Formula (IV) or Formula General (V), and in particular are the following compounds:
    [0132] 1- [4-methyl-thio-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 29 of the patent application WO2004 / 005233);
    [0133] 1- [4-methyl-thio-phenyl] -3- [3,5-dimethyl-4-isopropyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 28 of the application patent WO2004 / 005233);
    [0134] 1- [4-methyl-thio-phenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 27 patent application WO2004 / 005233);
    [0135] 1- [4-trifluoro-methyl-phenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 57 of patent application US20070032543)
    [0136] 1- [4-trifluoro-methyl-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 58 of the patent application US20070032543)
    [0137] 1- [4-trifluoro-methyloxy-phenyl] -3- [3,5-dimethyl-4-ter-butyloxy-carbonyl-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 61 of patent application US20070032543)
    [0138] 1- [4-trifluoro-methyloxy-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one (compound 62 of the patent application US20070032543)
    [0139] 2- [2,6-dimethyl-4- [3- [4- (methyl-thio) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid (compound 1 of the patent application WO2007 / 147879);
    [0140] 2- [2,6-dimethyl-4- [3- [4- (methyl-thio) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid isopropyl ester (compound 13 of patent application WO2007 / 147879);
    [0141] 2- [2,6-dimethyl-4- [3- [4- (trifluoromethyloxy) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid (compound 1 of the patent application WO 2007147880);
    [0142] 2- [2,6-dimethyl-4- [3- [4- (trifluoromethyl-thio) phenyl] -3-oxo-propyl] phenoxy] -2-methyl-propanoic acid (compound 2 of the application patent WO 2007147880);
    [0143] 2- (2,6-Dimethyl-4- (3-oxo-3- (4- (trifluoromethyloxy) phenyl) propyl) phenoxy) -2-methyl-propanoic acid tert-butyl ester (compound 35 of patent application WO 2007147880).
    [0144] The present invention also addresses the specific uses of compounds of General Formula (I) and related pharmaceutical compositions comprising them. The compound may or may not be in the form of a pharmaceutically acceptable salt and is used in a therapeutically effective amount to treat liver disorders. Any compound that is defined according to General Formula (II), General Formula (III), General Formula (IV), or General Formula (V), these formulas being covered by General Formula (I), can be used in the present invention to treat liver disorders, and, in particular, in the form of a pharmaceutical composition comprising said compound.
    [0145] The invention also provides a method for treating liver disorders comprising administering to an individual in need of treatment of a compound of General Formula (I) wherein:
    [0146] X1 represents a halogen, an R1 or G1-R1 group;
    [0147] A represents a CH = CH group or a CH2-CH2 group;
    [0148] X2 represents a G2-R2 group;
    [0149] G1 and G2, identical or different, represent an oxygen or sulfur atom;
    [0150] R1 represents a hydrogen atom, an unsubstituted alkyl group, an aryl group, or an alkyl group that is substituted with one or more halogen atoms, an alkoxy or alkylthio group, cycloalkyl groups, cycloalkyl-thio groups or heterocyclic groups;
    [0151] R2 represents an alkyl group substituted with at least one group - COOR3, where R3 represents a hydrogen atom, or an alkyl group that is substituted or not with one or more halogen atoms, cycloalkyl groups, or heterocyclic groups.
    [0152] R4 and R5, identical or different, represent an alkyl group that is or is not substituted with one or more halogen atoms, cycloalkyl groups, and heterocyclic groups.
    [0153] Compositions comprising compounds, wherein X1, X2, A, G1, G2, R1, R2, R3, R4, and R5 are as defined according to General Formula (II), General Formula (III), General Formula (IV), or General Formula (V), can also be used to perform the method for treating liver disorders.
    [0154] The term "liver disorder" includes any disorder affecting the liver, and in particular, any acute or chronic liver disease involving pathological disorder, inflammation, degeneration and / or proliferation of liver cells. In particular, the liver disorder is liver fibrosis, liver cirrhosis, or any other liver disease in which the plasma level of some markers of hepatocellular damage, alteration or necrosis, is high when compared to normal plasma levels. These biochemical markers associated with liver status and activity can be selected from those described in the literature and, in particular, Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), Alkaline phosphatase (AP), Gama Glutamila transpeptidase ( GGT), Cytokeratin-18 (CK-18) or Resistin. In a particular embodiment, the liver disorder is a fatty liver disease in which the elevation of one or more of these markers is associated with more or less significant steatosis in the liver, as can be confirmed by a liver biopsy. A non-exhaustive list of fatty liver diseases includes NAFLD, NASH, and the fatty liver disease associated with disorders, such as hepatitis or metabolic syndrome (obesity, insulin resistance, hyperglyceridemia, and the like).
    [0155] The term "Hepatoprotection" or "Hepatoprotection" refers to the ability of a compound to reduce, reverse or prevent damage to the liver, in particular by reducing, reversing or preventing pathological disturbance, inflammation, degeneration, and / or proliferation of liver cells, such as hepatocytes.
    [0156] The term "treatment" or "treating" refers to the therapy, prevention and prophylaxis of a disorder, and in particular, a liver disorder. Treatment involves administering a compound or pharmaceutical composition to the patient having a disorder declared to be cured, to be slowed or to slow it down in its progress, thereby improving the condition of the patients. Treatment can also be given to healthy individuals who are at risk of developing a liver disorder.
    [0157] In the context of the invention, the term "individual" means a mammal and more particularly a human. Individuals to be treated according to the invention can be appropriately selected based on various criteria associated with liver disorders, such as treatment with previous drugs, associated pathologies, genotype, exposure to risk factors, viral infection , as well as any other relevant biomarker that can be evaluated using an immunological, biochemical, enzymatic, chemical or nucleic acid detection method. In a particular embodiment, the individual is an overweight patient (in particular a pre-diabetic or diabetic overweight patient) or an obese patient suffering from atherogenic dyslipidemia.
    [0158] In reality, these patients are at risk of developing a liver disorder, in particular NAFLD or NASH. The inventors have shown that the compounds as defined above have a beneficial effect on the liver functions of such patients.
    [0159] The compounds of General Formula (I) can contain one or more asymmetric centers. When an enanciomerically pure (or enriched) compound is desired, it can be obtained by purifying the end products or chiral intermediates, or by asymmetric synthesis following typical methods known to a person skilled in the art (for example, using reactive and chiral catalysts). Some of these compounds can have different stable tautomeric forms. This invention includes the use of stereoisomers (diastereoisomers, enanciomers), pure or mixed, as well as racemic mixtures and geometric isomers of the compounds of General Formula (I).
    [0160] The compounds of General Formula (I) can be formulated as "pharmaceutically acceptable" salts, with slightly or non-toxic salts obtained from organic or inorganic acids or bases of the compounds of General Formula (I). These salts can be obtained during the final purification step of the compound or by incorporating the salt into the previously purified compound.
    [0161] Pharmaceutical compositions comprising a compound of General Formula (I) for the treatment of liver disorders may comprise one or more excipients or vehicles, acceptable in a pharmaceutical context (for example, saline solutions, physiological solutions, isotonic solutions, etc.). , compatible with pharmaceutical use and which are well known to those of skill in the art These compositions may comprise one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, preservatives, etc. The agents or vehicles useful for these formulations (liquid and / or injectable and / or solid) are particularly methyl-cellulose, hydroxy-methyl-cellulose, carboxy-methyl-cellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, liposomes, etc. These compositions can be formulated in the form of injectable suspensions, gels, oils, pills, suppositories, powders, gel capsules, capsules, aerosols etc., possibly by means of galley forms devices or devices ensuring a prolonged and / or slow release. For this type of formulation, agents, such as cellulose, carbonates or amides, can advantageously be used.
    [0162] The compounds of General Formula (I) should be administered in an effective amount of a compound using a pharmaceutical composition as well defined above. In the context of the invention, the term "an effective amount" refers to an amount of the compound sufficient to produce the desired therapeutic result.
    [0163] The compounds of the General Formula (I) can be administered in different ways and in different forms that allow the administration of said compounds in a therapeutically effective amount. Thus, for example, they can be administered systematically, orally, parenterally, by inhalation, or by injection, such as, for example, intravenously, intramuscularly, subcutaneously, transdermally, or by intra-arterial route, etc. Oral administration is the preferred route of administration for pharmaceutical compositions comprising a compound of General Formula (I) for the treatment of liver disorders.
    [0164] The frequency and / or dose related to the administration can be adapted by a person skilled in the art, depending on the patient, the pathology, the form of administration, etc. Typically, the compounds of General Formula (I) can be administered for the treatment of liver disorders in doses ranging from 0.01 mg to 1 g per administration, and preferably from 1 mg to 100 mg per administration. Administration can be carried out daily or even several times a day, if necessary.
    [0165] The compounds and compositions of the invention can advantageously be administered in combination with other therapeutic agents, currently available on the market or under development for the treatment of metabolic and / or liver disorders, such as metformin, insulin, thiazolidinediones, glitazones, statins , cholesterol inhibitors and / or other lipid-lowering drugs.
    [0166] In another embodiment, the present invention provides methods for the treatment of liver disorders comprising administering a compound of General Formula (I), and, in particular, in the form of pharmaceutical compositions containing those compounds. Such methods can comprise an administration of any compound that is defined according to General Formula (II), General Formula (III), General Formula (IV), or General Formula (V).
    [0167] The compounds and compositions of the invention provide advantageous therapeutic tools for the treatment of liver disorders, and, in particular, fatty liver diseases, including NAFLD and NASH, due to the hepatoprotective effects of the compounds of General Formula (I) . In particular, these compounds can be selected from those in which X1, X2, A, G1, G2, R1, R2, R3, R4, and R5 are defined according to General Formula (II), General Formula (III) , the General Formula (IV), or the General Formula (V). Another object of the present invention relates to a compound of General Formula (I) as described above, and, in particular, a compound of General Formulas (II), (III), (IV) and (V), for use in a method to treat liver disorders. In a particular embodiment, the specific liver disorders intended to be treated are those described above, such as liver fibrosis or a fatty liver disease. In another embodiment of the invention, the compounds for use in said methods are those specifically described above.
    [0168] In general, the specific liver-related properties of the compounds of General Formula (I) can be evaluated in specific patient populations showing liver disorders, such as NAFLD and / or NASH in inclusion. For example, a double-blind, placebo-controlled, randomized study can assess the effectiveness of oral administration of the compound (at a dose of 80mg / day or more) for 3-12 months in subjects who have been diagnosed for NAFLD (steatosis only ) and / or NASH (steatosis and fibrosis) and high levels of aminotransferases present. Any statistically relevant improvement in major biochemical parameters (such as a reduction in the levels of aminotransferases, GGT, and / or Cytokeratin-18 and / or a reduction in Resistin levels), in the volume of hepatic steatosis measured by imaging technique or histological features of liver biopsy (measurement of steatosis, liver inflammation and fibrosis) can be regularly assessed in these patients during the study (on a monthly or more frequent basis). Additional parameters, such as hemodynamic parameters of total cholesterol / LDL- / HDL, Body Mass Index, insulin resistance, markers of inflammatory or oxidative stress, glucose and plasma insulin, markers of urine renal function, hepatic image formation by MRI, and / or histomorphology in liver biopsy can also be measured during the study and / or at the end of the study to complete the efficacy profile of the compounds for treating liver disorders.
    [0169] All references cited here are fully incorporated as a reference in their entirety. Having now fully described the invention, it should be understood by those skilled in the art that the invention can be practiced in a wide and equivalent range of conditions, parameters and the like, without affecting the spirit or scope of the invention or any modality thereof. Several other advantages of the invention will emerge from reading the following examples; which should be considered as illustrative data and not as limiting. EXAMPLES Example 1: Effects of compounds of General Formula (I) on specific biochemical indices of the liver Materials and methods
    [0170] 1- [4-methyl-thio-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2- en-1-one (Compound 29 of the application for patent WO2004 / 005233) was formulated as hard shell capsules containing 5, 10 or 20 mg of the compound. The compound (80mg) was administered orally once a day for 28 days. The study was carried out in two parallel groups in double-blind conditions: placebo or Compound 29 of patent application WO2004 / 005233.
    [0171] The tolerance and safety of once-a-day administrations, as well as the effectiveness in improving plasma lipids and glucose homeostasis, compared with placebo, were evaluated in two pilot experiments using relevant biochemical parameters. The data were used to calculate the percentage of change due to the compound when compared to placebo after 28 days of treatment. Results and Conclusions:
    [0172] A first, double-blind, placebo-controlled, randomized study was conducted in patients suffering from atherogenic dyslipidemia and abdominal obesity to assess the tolerability and safety of once daily dosing of Compound 29 oral doses of the application. patent WO2004 / 005233 (at a dose of 80mg / day), as well as the efficacy in plasma triglycerides and HDL cholesterol (primary objectives).
    [0173] In relation to the group that received a placebo, the therapeutic efficacy of this compound was demonstrated with a statistically significant reduction of 21% (p <0.01) in plasma triglycerides and an increase of 9% (p <0.01) in good cholesterol level (HDL-C). These metabolic effects were comparable to those published for fibrates in the same patient population. In addition, the compound showed a remarkable need for an effect on homocysteine (a known cardiovascular risk factor). The compound showed significant effects on multiple secondary evaluation criteria including the reduction of acute liver inflammation markers, such as fibrinogen and haptoglobin (p <0.01). The effects on the biochemical parameters of liver function were also measured and the administration of oral doses of Compound 29 of patent application WO2004 / 005233 unexpectedly leads to a statistically significant 23% reduction in the level of Gamma Glutamyl transpeptidase (p <0.001) and a 13% reduction in the level of Alanine aminotransferase (p <0.01).
    [0174] A second pilot, double-blind, placebo-controlled, randomized study was carried out in patients suffering from impaired fasting glucose, impaired glucose tolerance and abdominal obesity, to assess the tolerance and safety of health administrations. once a day of oral doses of Compound 29 of patent application WO2004 / 005233 (at a dose of 80 mg / day), as well as the effectiveness in the metabolism of glucose and lipids.
    [0175] Regarding the placebo group, the therapeutic efficacy of this compound was demonstrated with a statistically significant reduction in fasting plasma glucose (-5%, p <0.05), of fasting insulinemia (-25%, p < 0.01) and insulin resistance index, HOMA-IR (-31%, p <0.01). In parallel, Compound 29 of patent application WO2004 / 005233 reduced plasma triglycerides (-25%, p <0.001) and LDL-C, while enhancing HDL-C (+ 9%, p <0, 01). The compound showed significant effects on multiple secondary evaluation criteria, including the reduction of markers of acute liver inflammation, such as haptoglobin (p <0.01). Biochemical parameters in liver function were also calculated and administrations of oral doses of Compound 29 from patent application WO2004 / 005233 led to a statistically 15% reduction in the level of Gamma Glutamyl transpeptidase (p <0.01).
    [0176] These results demonstrated that an oral formulation of a compound of General Formula (I) is not only well tolerated by patients, but also has positive effects on multiple biochemical parameters associated with NAFLD and NASH, including liver enzymes, sensitivity insulin, lipid metabolism, and markers of liver inflammation. In particular, Compound 29 of patent application WO2004 / 005233 significantly decreased plasma levels of ALAT and GGT, two common specific biomarkers of liver dysfunction that are elevated in patients suffering from NAFLD and NASH. Example 2: Animal models to test the liver-specific properties of compounds of General Formula (I) Materials and methods Animal model and treatment: ob / ob mice
    [0177] Male ob / ob mice (8 weeks old) were purchased from Charles River (L'Arbresle, France) and maintained on a 12-hour light / dark cycle at a constant temperature of 20 ± 3 ° C . After acclimatizing for 1 week, the mice were separated into groups of 8 animals selected in such a way that the distribution of their body weights and their glycemic levels fasted for 6 hours determined before the experiment, were uniform. The animals were fed a standard diet (R03, SAFE) and treated for 26 days with the compounds of interest. The compounds, including Compound 29 of patent application WO2004005233 (Compound 29, in doses of 10 or 30 mg / kg / day), Fenofibrate (100 mg / kg / day) and Rosiglitazone (10 mg / kg / day) were administered daily by feeding through a tube (“gavage”). Control animals were treated with vehicle only (Carboxy-methylcellulose 1% + Tween-80 0.1%). The animals had access to food and water at will.
    [0178] Animal model and treatment: Study in hApoE2 knockout mice.
    [0179] Transgenic female mice hApoE2 (Kl) (Sullivan et al., 1998) (4 weeks old).
    [0180] The mice were kept on a 12-hour light / dark cycle, at a constant temperature of 20 ± 3 ° C. After a 1-week acclimation, the mice were separated into groups of 7-10 animals selected in such a way that the distribution of their body weight and plasma lipid levels determined before the experiment were uniform. The animals were fed a western diet (20% saturated fat and 0.2% cholesterol, Harlan Teklad TD88137) at weaning and for 12 weeks. The compounds of interest (Compound 29 at a dose of 0.3 mg / kg / day and Fenofibrate at a dose of 100 mg / kg / day) were incorporated into the western diet (SAFE, Augy, France) and administered to the mice for 12 weeks . Control animals received a western diet only. The animals had access to food and water at will.
    [0181] Animal model and treatment: Studies in KI hApoE2 and KI hApoE2 KO PPARalfa mice
    [0182] Transgenic knockout aged mice (KO) KI hApoE2 / PPARalfa and female knockout (Kl) hApoE2 female (8 to 25 weeks old for the first experiment 10 to 14 weeks old for the second experiment).
    [0183] KO KI hApoE2 / PPARalfa mice were generated by crossing homozygous KI hApoE2 mice (Sullivan P et al., 1998) and homozygous PPARalpha deficient mice (Lee et al., 1995). The mice were kept on a 12-hour light / dark cycle, at a constant temperature of 20 ± 3 ° C. After acclimatizing for 1 week, the mice were separated into groups of 4-6 animals, selected in such a way that the distribution of their ages, body weight, and plasma lipid levels determined before the experiment, were uniform. The animals were fed a western diet (20% saturated fat and 0.2% cholesterol, Harlan Teklad TD88137) for 2 weeks in the first study, which involved daily administration of Compound 29 (at a dose of 30 mg / kg / day by tube feeding (“gavage”) orally), and for 6 weeks in the second study, which involved the daily administration of Compound 1 of patent application WO2007147879 (Compound 1, at a dose of 30 mg / kg / day per tube feeding (“gavage”) orally). Control animals were treated with vehicle only (Carboxy-methylcellulose 1% + Tween-80 0.1%). The animals had access to food and water at will. Preparation of biological samples obtained from animal models
    [0184] At the end of the studies, the animals were weighed and sacrificed under anesthesia. Blood was collected from the retro-orbital bell; the plasma was obtained by centrifugation (4,000 rpm, at 4 ° C, for 15 minutes) and subsequently frozen and stored at -20 ° C. The tissues and livers were isolated and frozen instantly in liquid nitrogen and stored at -80 ° C for subsequent analysis (biochemistry and gene expression) or fixed in 4% paraformaldehyde for histology. Plasma Analysis
    [0185] The levels of alanine aminotransferase were determined in plasma using the RX Daytona ™ automatic analyzer (Randox) and the appropriate dosing kit (Randox, Catalog No. AL 3801). Gene expression analysis
    [0186] Total RNA was isolated from frozen livers using the NucleoSpin® 96 RNA kit (Macherey Nagel), according to the manufacturer's instructions. Reverse transcription was performed in 1μg of total RNA per action of 1 μl of MMLV-RT enzyme (Invitrogen) for 1 hour, at 37 ° C, in a total volume of 30 μl. The reaction conditions were 1 X buffer (Invitrogen), 1.5 mM DTT (Invitrogen), 0.18 mM dNTPs (Promega), 200ng pdN6 (Amersham), 30U RNase inhibitor (Promega). Quantitative PCR was then performed using the MyiQ Single Color Real-Time PCR Detection system (Biorad). Briefly, PCR reactions were performed in 96-well plates in 5 μl of diluted reverse transcription mix using the iQ SYBR Green Supermix kit. The reaction conditions were: 25 μl of reaction volume, 3 mM MgCl2, and 0.5 μl of each forward and reverse initiator solution (10 pMol), and Tm of 60 ° C. The primer pairs that have been designated for the specific amplification of each target gene are summarized in Table 1.Table 1

    [0187] The amount of fluorescence emitted is directly proportional to the amount of complementary DNA present at the beginning of the reaction and amplified during the PCR. The relative levels of expression were determined using the standard curve for each transcript. The results were then normalized with respect to the signals obtained with the 36B4 control (a reference transcript for liver gene expression). The induction factor, that is, the relationship between the relative signal induced by the compound according to the invention and the average of the values related to the control group, was then calculated for each sample. The higher this factor was, the more the compound would promote target gene expression. The final result is described as the average of the induction values in each experimental group. Histological analysis of the liver
    [0188] The liver tissue fixed with formalin was processed, and sections of paraffin 5 μm thick were stained with Hematoxylin and Eosin. Histological analysis of stained liver sections was performed in a blind condition to quantify hepatic steatosis and intralobular inflammation of the liver. Liver steatosis was classified from 0 to 3 as follows: 0 (very slightly affected), 1 (slightly affected), 2 (moderately affected), 3 (highly affected). The intralobular inflammation of the liver was also classified depending on the number of inflammatory foci counted per field of observation as follows: 0 (<1 focus / field), 1 (1 to 2 foci / field), 2 (2 to 4 foci / field) , 3 (more than 4 foci / field). Analysis of hepatic lipids
    [0189] Approximately 100 mg of frozen liver tissue was homogenized with a tissue homogenizer (Precellys®24, Bertin Technologies, France) in 150 mM NaCl buffer solution, containing 15.4 mM NaN3. The lipid fractions in homogenates were extracted with chloroform-methanol (2: 1, v / v) followed by measurement of total cholesterol (using the Cholesterol RTUMR 61218 kit, Biomerieux, France) and the true triglycerides (TR0100 kit, Sigma- Aldrich ). Results and Conclusions
    [0190] Various animal models are described in the literature as reflecting the etiology, disease progression, and pathology of human liver diseases. However, these models do not always have a range of histopathological and pathophysiological characteristics associated with specific liver diseases. As recently reviewed (Fan J. and Qiao L., 2009), this is particularly evident in the case of NAFLD or NASH, with genetic models (in transgenic mice), nutritional models (in rats or mice), or mixed models have been established.
    [0191] NASH is characterized by pathological changes in the liver ranging from steatosis and inflammation of the liver to degeneration, fibrosis and liver cirrhosis. The pathogenesis of NASH remains poorly understood. It is a component of the metabolic syndrome and is therefore often associated with hyperlipidemia. Different models of transgenic animals were used to characterize the effects of exemplary compounds of General Formula (I), and more specifically of General Formula (I) and General Formula (IV): insulin-resistant mice deficient in ob / ob leptin and the dyslipidemic hApoE2 knockout mice (the last of these, with or without an additional genomic modification consisting of the activation of the PPARalpha gene).
    [0192] Leptin deficient ob / ob mice are obese, dyslipidemic, insulin resistant and develop liver damage and steatosis. Liver steatosis is relatively asymptomatic, however, individuals with this disorder have a high risk of developing NASH. This first protocol was programmed to analyze the effects of Compound 29 and the reference Fenofibrate Rosiglitazone compounds in the early stages of NASH, that is, inflammation in the fatty liver of ob / ob mice. In ob / ob mice, a 26-day course of treatment with Rosiglitazone induced increased hepatic expression of TNFalpha in ob / ob mice, while no major change in the expression of this cytokine was observed in animals treated with Fenofibrate . Otherwise, an administration of Compound 29 inhibited the expression of this cytokine in a dose-response manner (Figure 2A). Following the same treatment, the level of hepatic expression of TGFbeta was equivalent in all control and reference groups (Control, Fenofibrate and Rosiglitazone). Again, administration of Compound 29 inhibited the expression of this growth factor in a dose-response manner, an effect that is more statistically relevant when Compound 29 was administered at a dose of 30 mg / kg / day (Figure 2B).
    [0193] The plasma ALAT was measured as a surrogate marker to assess liver damage in these ob / ob mice after the 26-day treatment period for the different compounds. When the plasma ALAT level is compared with any of the control group or the Fenofibrate-treated group, the group of mice that was treated with Rosiglitazone showed a significant increase in their plasma ALAT levels. In contrast, administration of Compound 29 at a dose of 30 mg / kg / day induced a statistically significant decrease in plasma ALAT levels (Figure 2C).
    [0194] Another in vivo model was used to study the effects of Compound 29 and Reference Compound Fenofibrate on physiological parameters that are normally considered to be relevant for assessing NASH. In "humanized" ApoE2 knockout mice (referred to as KI hApoE2), the human ApoE2 allele replaces the murine apoe genes, so that these mice express human ApoE2 (hApoE2) under the control of endogenous promoter sequences at physiological levels. However, hApoE2 has a markedly reduced affinity for the LDL receptor, leading to a plasma lipoprotein profile similar to human type III hyperlipoproteinemia (Sullivan et al., 1998). Similar to humans, KI hApoE2 mice are responsive to lipid-lowering drugs, such as fibrates (ligands for PPARa). This class of drugs has been shown to reverse steatohepatitis in mice (Shiri- Sverdlov R et al., 2006) and, thus, this model can allow the evaluation of specific anti-inflammatory and anti-fibrotic effects in the liver of compounds of the General Formula (I). In particular, elevated levels of TNFα are related to liver inflammation, necrosis and fibrosis typical of NASH (Larter et al., 2008). TGF3 is a peptide found in many types of cells that regulate wound healing and apoptosis. The isoform found in liver cells, TGF31, has been found in many models of liver fibrosis and the levels increase in fibrotic alcoholic liver diseases and in chronic active hepatitis (Nan et al., 2009).
    [0195] The different KI hApoE2 mice were treated for 12 weeks at the same time that they were fed a western diet. In this model, Compound 29 inhibited liver gene expression that are relevant to liver inflammation (TNFa, CCL5, TGF3; Figure 3A, 3B, 3C, respectively) with an efficacy similar (if not superior) to the Fenofibrate that was administered at a higher dose.
    [0196] However, the group of mice treated with Compound 29 showed a statistically significant inhibition of expression of genes such as those for the specific collagen chains that are involved in liver fibrosis (Basaranoglu et al., 2010), and in particular Col1a1 (Figure 3D). Such an effect on the collagen genes was not observed in the group of mice treated with Fenofibrate. These results demonstrate that Compound 29 has anti-inflammatory and anti-fibrotic properties in an in vivo model of NASH.
    [0197] Exemplary compounds of General Formula (I) were tested in vivo on a high-fat diet mouse model. KI hApoE2 and KI hApoE2 / KO PPARalfa ("humanized" ApoE2 knockout mice deficient for the mPPARalpha gene) were fed a western diet and daily treated with Compound 29 at doses of 30 mg / kg / day for 2 weeks. At the end of the protocol, hepatic steatosis and intralobular inflammation were evaluated in the control mice and treated by means of histological analysis and specific classifications.
    [0198] This study demonstrated that treatment with Compound 29 inhibits the development of both hepatic steatosis and liver inflammation that is induced by diet in KI hApoE2 mice and, even more quickly in KI hApoE2 / KO PPARalfa mice, being that it is an acceleration of the liver disorder is evident due to the need for PPARalpha (Table 2 and Table 3).
    Table 3

    [0199] In another study, the effects of specific anti-fibrotic and anti-inflammatory properties on the liver of Compound 29 and Compound 1 of patent application WO2007 / 147879 (Compound 1) were evaluated in the KI hApoE2 / KO PPARalfa mice, which were fed a western diet and daily treated with the selected compounds for 6 weeks.
    [0200] Both Compound 29 and Compound 1 inhibited liver expression of TNFa, TGF3 and collagen in KI hApoE2 / KO PPARalfa mice (Figures 4A, 4B, and 4C, respectively), confirming the specific properties (mainly independent of PPARalpha ) anti-inflammatory and anti-fibrotic, in the liver, of these compounds in a relevant model in vivo for NASH. Analysis of liver lipids also showed that both Compound 29 and Compound 1 prevented the accumulation of triglycerides in the liver of KI hApoE2 / KO PPARalfa mice (Figure 4D).
    [0201] Taken together, these results highlighted the specific anti-inflammatory, anti-fatty and anti-fibrotic properties, in the liver, of Compound 29 of patent application WO2004 / 005233 (included in General Formulas I and II) and Compound 1 of patent application WO2007 / 147879 (comprised in General Formula (I) and (IV)) in vivo.
    [0202] The additional model for testing the compounds of General Formula (I) are NASH nutritional animal models, such as the methionine and choline (MCD) deficient model which is based on a diet containing high sucrose and fat content however, they require two components, methionine and choline, which are essential factors for the metabolism of the liver. Mice or mice fed this diet quickly developed liver inflammation, which also progressed to steatosis, necrotic inflammation, fibrosis, and oxidative stress. This methodology was used to show the potential therapeutic effects on liver steatosis, fibrosis, oxidative stress, and / or inflammation that are associated with the administration of compounds such as Rosiglitazone (Tahan V., et al. 2007), the pan-caspase inhibitor VX-166 (Witek R et al, 2009), Zeaxanthin (Chamberlain S et al, 2009), Telmisartan (Kudo H et al, 2009) or Wy-14,643 (Ip E et al, 2004).
    [0203] The compounds of the General Formula (I) can be tested in an MCD model established in Sprague Dawley rats (8 weeks of age) or C57BI6 mice that are fed the deficient diet of methionine and choline for 4 to 12 weeks. The treatment with the compounds of interest, including the compounds that are chosen as a negative or positive control, is then administered daily in different doses to groups of ten or more animals by feeding through a tube (“gavage”), during the following 4 to 12 weeks. Various types of measurements can be performed before, during, or at the end of treatment, with or without animal sacrifice. Biochemical measurements (aspartate aminotransferase and alanine aminotransferase activities, total bilirubin, alkaline phosphatase, LDL / HDL-cholesterol, serum hyaluronate, hepatic triglyceride and plasma triglyceride) and histomorphometric analysis (to determine the liver area showing fibrosis and steatosis / fibrosis and / ) are the most relevant measurements. The dosage of inflammatory markers (such as interleukins -1 a, -1 b, -2, -4, -6, -10, Interferon gamma, or TNFalpha) and / or the expression of relevant genes (such as type I collagen or liver-specific chemokine receptors) can also be evaluated.
    [0204] Alternatively, animal models based on chemically induced liver fibrosis can be used to study the antifibrotic effect of the compounds of the General Formula (I). For example, an administration of thioacetamide (TAA) or carbon tetrachloride (CCL4) induces an increase in reactive oxygen species (ROS) promoting lipid peroxidation, proliferation of hepatic stellate cells and collagen overproduction, leading to injury chronic liver disease and fibrosis in rats. This methodology was used to show the positive effect on liver fibrosis, oxidative stress, and / or inflammation with compounds, such as Curcumin (Fu Y. et al., 2008) or Pioglitazone (Yuan G. et al., 2004).
    [0205] The compounds of the General Formula (I) can be tested in a CCL4 model that is established in Sprague Dawley rats (8 weeks of age) that receive increased doses of CCL4 intraperitoneally diluted in liquid paraffin (50%) each five days for 4 to 12 weeks. Phenobarbital can also be administered starting 10 days before the first dose of CCL4 to enhance the model. The treatment with the compounds of interest, including the compounds that are chosen as a negative or positive control, is then administered daily in different doses (between 0.01 and 100 mg / kg / day) to groups of ten or more rats per feeding through a tube (“gavage”) for the next 4 to 12 weeks. As in the MCD model, several types of measurements can be performed before, during, or at the end of the treatment, with or without sacrifice of the rats, to evaluate the effectiveness of the treatment based on biochemical dosages and histomorphometric analysis, in association with hemodynamic indexes dosage of inflammatory markers and / or expression of relevant genes.
    [0206] The animal models described above allow to compare liver-specific activities of compounds of the General Formula (I) with each other and with compounds already known to have specific therapeutic properties in the liver (and in particular, NAFLD- / NASH) . In particular, the data shown in this example suggest the superiority of the compounds of the General Formula (I) when compared to the reference compounds. Example 3: In vitro / ex vivo models to test the specific liver properties of the compounds of the General Formula (I)
    [0207] Some in vitro / ex vivo models have been established to evaluate compounds that may have a positive effect on liver fibrosis, oxidative stress, and / or inflammation of the liver. In reality, a major event in liver fibrosis is the activation of hepatic stellate cells (HSC). After damage to the hepatocyte, this type of cell becomes activated and begins to proliferate (Sato M. et al., 2003). Activated HSCs (for example, rat or human HSC isolated from liver HSC or rat HSC-T6 cell line) can be activated and produce excessive amounts of extracellular matrix compounds and matrix degradation inhibitors. This methodology was used to show the positive effect of compounds, such as curcumin (Xu and others, 2003), thiazolidinediones (Miyahara T. and others, 2000), or 17beta-estradiol (Liu Q. and others, 2004).
    [0208] The in vitro / ex vivo models described above allow to compare the specific liver activities of the compounds of the General Formula (I) with each other and with the compounds known to have specific therapeutic properties in the liver (and, in particular, specific to NAFLD / NASH). REFERENCES Angulo P. et al., 2002. Best Pract. Res. Clin. Gastroenterol .; 16: 797810. Basasaranoglu, M. et al., 2010. World J Gastroenterol; 16: 2223-6. Chamberlain S et al., 2009. Dig. Dis. Sci.; 54: 1460-4. Dowman J.K. et al., 2010, Q. J. Med .; 103: 71 -83 Fan J. and Qiao L., 2009. Hepatobil. Pancrat. Dis. Int .; 8: 233-240. Fu Y. et al., 2008. Mol. Pharmacol .; 73: 399-409. Gressner A. et al., 2009. World J. Gastroenterol .; 15: 2433-2440. Ip E et al., 2004. Hepatology; 39: 1286-96. Kudo H et al., 2009. Liver Int .; 29: 988-96. Larter C. et al., 2008. J. Gastroenterol. Hepatol .; 23: 1635-48. Lee S. et al., 1995. Mol. Cell Biol .; 15: 3012-22. Liu Q. et al., 2004. World J. Gastroenterol .; 10: 1315-20. Marchesini G. et al., 2003. Hepatology; 37: 917-923. Miyahara T. et al., 2000. J. Biol. Chem .; 275: 35715-22. Nan Y. et al., 2009. Scand. J. Gastroenterol., 44, 1 121-31. Nelson A. et al., 2009. J. Clin. Gastroenterol .; 43: 990-994 Neuschwander-Tetri et al., 2003. Hepatology; 38: 1008-1017. Sato M. et al., 2003. Cell Struct. Funct .; 28: 105-12. Shiri-Sverdlov R. et al., 2006. J Hepatol; 44: 732-41. Sullivan P. et al., J Clin Invest .; 102: 130-5. Tahan V. et al., 2007 Dig. Dis. Sci .; 52: 3465-3472. Vuppalanchi R. and Chalasani N., 2009. Hepatology; 49: 306-317. Witek R. et al., 2009. Hepatology; 50: 1421-30. Xu et al., 2003. Am. J. Physiol. Gastrointest. Liver Physiol .; 285: G20- G30. Yeh M. et al., 2007. Am. J. Clin. Pathol .; 128: 837-847. Yuan G. et al., 2004. World J. Gastroenterol .; 10: 1047-51.
    权利要求:
    Claims (5)
    [0001]
    1. Use of a compound selected from 1- [4-methyl-thio-phenyl] -3- [3,5-dimethyl-4-carboxy-dimethyl-methyloxy-phenyl] prop-2-en-1-one and Acid 2- [2,6-dimethyl-4- [3- [4- (methyl-thio) phenyl] -3-oxo-propyl] phenoxy] -2-methylpropanoic or a pharmaceutically acceptable salt thereof characterized by the fact that said compound be for the treatment of liver fibrosis or a non-alcoholic fatty liver disease.
    [0002]
    2. Use of a compound according to claim 1, characterized by the fact that liver fibrosis is liver cirrhosis.
    [0003]
    Use of a compound according to any one of claims 1 to 2, characterized by the fact that non-alcoholic liver fat disease is non-alcoholic hepatitis.
    [0004]
    Use of a compound according to any one of claims 1 to 3, characterized in that said treatment delays the progression of said liver fibrosis.
    [0005]
    Use of a compound according to any one of claims 1 to 3, characterized in that said treatment delays the progression of said fatty disease in the non-alcoholic liver.
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    法律状态:
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-04-17| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2019-08-20| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-09-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-05-05| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2020-08-04| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-01-12| B09Y| Publication of grant cancelled [chapter 9.1.2 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 9.1 NA RPI NO 2603 DE 24/11/2020 POR TER SIDO INDEVIDA. O PARECER EMQUESTAO POSSUI INCORRECOES POIS NO QUADRO 1 DEIXOU DE MENCIONAR A VIA RELATIVA A SEQUENCIAGENETICA. |
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    优先权:
    申请号 | 申请日 | 专利标题
    EP09306146|2009-11-26|
    EP09306146.3|2009-11-26|
    PCT/EP2010/068346|WO2011064350A1|2009-11-26|2010-11-26|Use of 1,3-diphenylprop-2-en-1-one derivatives for treating liver disorders|
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