Novel treatments for nonalcoholic steatohepatitis and fibrosis

Abstract

Novel therapies for non-alcoholic steatohepatitis and fibrosis: Compounds of formula (I) Or use of their enantiomers, their diastereomers, and addition salts with pharmaceutically acceptable bases or acids for therapeutic purposes, preferably for the treatment of NASH.

Description

[Technical field]

[0001] The present invention relates to novel treatments for non-alcoholic steatohepatitis (NASH) and fibrosis.

[0002] Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by (1) steatosis (fat accumulation) in the liver, (2) lobular inflammation, and (3) destruction of hepatocytes (hypertrophy). It is part of the nonalcoholic fatty liver disease (NAFLD) family, which begins with benign hepatic steatosis but can progress to NASH, fibrosis, cirrhosis with permanent liver damage, hepatocellular carcinoma, and death.

[0003] NAFLD is often associated with obesity and type 2 diabetes, and its prevalence is significant and continues to increase worldwide.

[0004] In the United States, NASH is estimated to be present in 12% of the adult population and 22% of diabetic patients. It is also estimated that 15-25% of patients with NASH will develop cirrhosis of the liver (liver fibrosis, i.e., the excessive deposition of fibrous tissue within the organ). NASH also significantly increases the risk of cardiovascular events.

[0005] Currently, there are no effective drugs to treat NASH, and health regulatory agencies (FDA, EMA) consider managing the NASH epidemic a priority.

[0006] Therefore, there is a need to provide an effective treatment for NASH.

[0007] It is an object of the present invention to provide compounds which are suitable for use for the prevention and / or treatment of NASH.

[0008] It is also an object of the present invention to provide compounds which may be suitable for use for the prevention and / or treatment of fibrosis, preferably liver fibrosis.

[0009] Still other objects will become apparent from a reading of the following description of the invention.

[0010] The present invention relates to compounds of formula (I): [ka] During the ceremony, R 1 teeth, - -C(O)CR 4 R 5 CR 6 R 7 C(O)OH group; - -C(OH)(H)CR 4 R 5 CR 6 R 7 C(O)OH group; - [ka] - -(CH 2 ) 4 C(O)OH group; Represents: m represents an integer from 0 to 8; R 2 teeth, - optionally substituted, C 6 ~C 10 an aryl group; or an optionally substituted 5- to 10-membered heteroaryl group; Represents: R 3 are the same or different, C 1 ~C 5 , preferably C 1 ~C 4straight or branched chain alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, optionally substituted with a carbocyclic or heterocyclic ring; said carbocyclic ring being 5-10 membered, substituted or unsubstituted, saturated, partially unsaturated or aromatic, said heterocyclic ring being 5-10 membered, substituted or unsubstituted, saturated, partially unsaturated or aromatic, containing 1, 2 or 3 heteroatoms, which may be the same or different and are in particular selected from nitrogen, oxygen or sulfur; Represents: R 4 ,R 5 ,R 6 and R 7 are the same or different: - Hydrogen atom; - C 1 ~C 5 , preferably C 1 ~C 4 a straight or branched chain alkyl group; - represents a saturated, partially unsaturated or aromatic, substituted or unsubstituted, 5-, 6- or 7-membered carbocyclic group; or R 4 and R 5 together with the carbon atoms to which they are attached form a 5-, 6- or 7-membered carbocyclic ring, which may be substituted or unsubstituted, preferably saturated, e.g., cyclopentyl or cyclohexyl; or R 6 and R 7 together with the carbon atom to which they are attached form a 5-, 6- or 7-membered carbocyclic ring which may be substituted or unsubstituted, preferably saturated, e.g., cyclopentyl or cyclohexyl; or their enantiomers, their diastereomers and pharma- ceutically acceptable base or acid addition salts thereof, It relates to use for treatment, preferably for the treatment of NASH.

[0011] In the present invention, "compound X used for the treatment of Y" is equivalent to "compound X used in a method for the treatment of Y" or "compound X used in the treatment of Y".

[0012] The term heteroaryl relates to a 5-10 membered heteroaryl containing at least one heteroatom, which may be the same or different, selected among O, N, S, preferably N. Heteroaryl contains 1, 2, 3 or 4, preferably 1, 2 or 3, which may be the same or different, heteroatoms, which may be the same or different, selected among O, N, S, preferably N.

[0013] Said carbocycle, heterocycle, aryl, heteroaryl are unsubstituted or substituted by one or more substituents which are the same or different, in particular selected from the following: - linear or branched, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy groups, C 1 ~C 6 Alkoxy groups; - halogen atoms; - linear or branched, preferably alkyl, C 1 ~C 5 , preferably C 1 ~C 4 a hydrocarbon group, for example methyl, ethyl, propyl, butyl, isopropyl, tert-butyl; - linear or branched, preferably alkyl, C1-C5, preferably C1-C4, hydrocarbon radicals, in particular substituted by one or more halogen atoms; - a cyano (-CN) group; or - Sulfonylalkyl (-S(O) 2 -alkyl) radical, where alkyl is linear or branched, preferably alkyl, C 1 ~C 5 , preferably C 1 ~C 4 , for example methyl, ethyl, propyl, butyl, isopropyl, tert-butyl; - identically or differently, in particular a halogen atom, a linear or branched, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy radical, C 1 ~C 6 Alkoxy groups, or linear or branched, preferably alkyl, C1 ~C 5 , preferably C 1 ~C 4 a 5-, 6- or 7-membered, saturated or partially unsaturated or aromatic, preferably phenyl, substituted or unsubstituted by one or more substituents selected from hydrocarbon groups, e.g. methyl, ethyl, propyl, butyl, isopropyl, tert-butyl.

[0014] Preferably, in the compounds of the present invention, m is 0.

[0015] Preferably, in the compounds of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH or -(CH 2 ) 4 C(O)OH.

[0016] Preferably, in the compounds of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH.

[0017] Preferably, in the compounds of the present invention, R 2 teeth: - At least linear or branched C 1 -C 6 Alkyl group, or straight or branched chain O-(C 1 -C 6 )-alkyl groups, preferably linear or branched O—(C 1 -C 3 )-alkyl groups, C 6 ~C 10 Aryl Group; or - 5-10 membered heteroaryl group Represents.

[0018] Preferably, in the compounds of the present invention, R 2 teeth: - 5-10 membered heteroaryl group Represents.

[0019] Preferably, in the compounds of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH and m is 0.

[0020] Preferably, in the compound of the present invention, m is 0; and R 2 teeth: - At least linear or branched C 1 -C 6 Alkyl group, linear or branched Chain O-(C 1 -C 6 )-alkyl groups, preferably linear or branched O—(C 1 -C 3 )-alkyl groups, 6 ~C 10 Aryl Group; or - 5-10 membered heteroaryl group Represents.

[0021] Preferably, in the compound of the present invention, m is 0; and R 2 teeth - 5-10 membered heteroaryl group Represents.

[0022] Preferably, in the compound of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH, and R 2 teeth: - At least linear or branched C 1 -C 6 Alkyl group, linear or branched Chain O-(C 1-C 6 )-alkyl groups, preferably linear or branched O—(C 1 -C 3 )-alkyl groups, 6 ~C 10 an aryl group; or - 5-10 membered heteroaryl group Represents.

[0023] Preferably, in the compound of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH, and R 2 teeth: -5 to 10 membered heteroaryl group Represents.

[0024] Preferably, in the compound of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH, m is 0, and R 2 teeth: - At least linear or branched C 1 -C 6 Alkyl group, or straight or branched chain O-(C 1 -C 6 )-alkyl groups, preferably linear or branched O—(C 1 -C 3 )-alkyl groups, 6 ~C 10 Aryl Group ;or - 5-10 membered heteroaryl group Represents.

[0025] Preferably, in the compound of the present invention, R 1 -C(O)CH 2CH 2 C(O)OH, m is 0, and - 5-10 membered heteroaryl group Represents.

[0026] Preferably, in the compounds of the present invention, R 2 teeth: - At least one linear or branched C 1 -C 6 Alkyl groups, or straight or branched chain O-(C 1 -C 6 )-alkyl groups, preferably linear or branched O—(C 1 -C 3 ) -C optionally substituted with a substituent selected from alkyl groups 6 ~C 10 Aryl groups; or a 6-membered heteroaryl group, preferably containing one or more nitrogens, preferably pyridine Represents.

[0027] Preferably, in the compounds of the present invention, R 2 teeth: a 6-membered heteroaryl group, preferably containing one or more nitrogens, preferably pyridine Represents.

[0028] Preferably, in the compound of the present invention, m is 0 and R 2 teeth: -C 6 ~C 10 Aryl groups, at least one of linear or branched C 1 -C 6 Alkyl group, or a straight or branched chain O-(C 1 -C 6 )-alkyl groups, preferably straight-chain or or branched chain O-(C 1 -C 3)-alkyl groups. or a 6-membered heteroaryl group, preferably containing one or more nitrogens, preferably pyridine Represents.

[0029] Preferably, in the compound of the present invention, m is 0; and R 2 teeth: a 6-membered heteroaryl group, preferably containing one or more nitrogens, preferably pyridine Represents.

[0030] Preferably, in the compound of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH; and R 2 teeth: - At least linear or branched C 1 -C 6 Alkyl group, or straight or branched chain O-(C 1 -C 6 )-alkyl groups, preferably linear or branched O—(C 1 -C 3 )-alkyl groups, C 6 ~C 10 Aryl Group; or a 6-membered heteroaryl group, preferably containing one or more nitrogens, preferably pyridine Represents.

[0031] Preferably, in the compound of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH; and R 2 teeth: a 6-membered heteroaryl group, preferably containing one or more nitrogens, preferably pyridine Represents.

[0032] Preferably, in the compound of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH; m is 0, and R 2 teeth: - At least linear or branched C 1 -C 6 Alkyl group, or straight or branched chain O-(C 1 -C 6 )-alkyl groups, preferably linear or branched O—(C 1 -C 3 a phenyl group, optionally substituted by a substituent selected from the group consisting of phenyl, ... teeth a 6-membered heteroaryl group, preferably containing one or more nitrogens, preferably pyridine Represents.

[0033] Preferably, in the compound of the present invention, R 1 -C(O)CH 2 CH 2 C(O)OH; m is 0, and R 2 teeth: a 6-membered heteroaryl group, preferably containing one or more nitrogens, preferably pyridine Represents.

[0034] Compounds according to the invention can be synthesised as described in WO2012 / 17515 and WO2012 / 175707, which are incorporated herein by reference.

[0035] The compounds of formula (I) have a carboxylic acid group function and may be salified. They may then be in the form of addition salts with organic or inorganic bases. The addition salts with bases are, for example, pharmaceutically acceptable salts, such as sodium salts, potassium salts or calcium salts, obtained using the corresponding alkali metal and alkaline earth metal hydroxides as bases. Other types of pharmaceutically acceptable base addition salts include salts made with amines, in particular glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.

[0036] The compounds of formula (I) may also be salified with a pharma- ceutically acceptable acid such as a mineral or organic acid, preferably hydrochloric acid, phosphoric acid, fumaric acid, citric acid, oxalic acid, sulfuric acid, ascorbic acid, tartaric acid, maleic acid, mandelic acid, methanesulfonic acid, lactobionic acid, gluconic acid, glucaric acid, succinic acid, sulfonic acid or hydroxypropanesulfonic acid.

[0037] The compounds of the present invention are useful for the treatment or prevention, preferably the treatment, of NASH.

[0038] The present invention also relates to pharmaceutical compositions comprising at least one compound according to the present invention as an active ingredient for use in the prevention or treatment, preferably in the treatment, of NASH. These compositions may also comprise pharma- ceutically acceptable vehicles and / or excipients.

[0039] The pharmaceutical composition may be in any form known to those skilled in the art, in particular in a form intended to be administered by parenteral, oral, enteral, transmucosal or transdermal means, preferably oral means.

[0040] The compositions according to the invention are presented in the form of injectable solutions or suspensions or multiple dose vials, naked or coated tablets, pills, capsules, powders, suppositories or enteric coated capsules, solutions or suspensions in polar solvents, for transdermal use or for transmucosal use.

[0041] Suitable excipients for such administration are cellulose or derivatives of microcrystalline cellulose, alkaline earth carbonates, magnesium phosphates, starches, modified starches or lactose in solid form.

[0042] For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients.

[0043] For parenteral use, water, aqueous solutions, saline and isotonic solutions are the most conveniently used vehicles.

[0044] The dosage may vary widely according to the therapeutic indication and the method of administration, as well as the age and weight of the subject.

[0045] The present invention also relates to a method for preventing or treating, preferably treating, NASH comprising administering to a patient in need thereof a sufficient amount of at least one compound of the present invention together with a pharma- ceutically acceptable vehicle or excipient.

[0046] Identification of patients in need of the above treatments is defined by one of skill in the art. A veterinarian or physician may identify subjects in need of such treatments by clinical examination, physical examination, biological tests or diagnosis, and family and / or medical history.

[0047] By sufficient amount is meant an amount of the compound of the present invention that is effective in preventing or treating a disease state. A sufficient amount may be determined by one skilled in the art using conventional techniques and by observing results obtained under similar circumstances. To determine a sufficient amount, various factors must be considered by the skilled artisan, including, but not limited to; the subject, size, age, general health, associated diseases and their severity; the subject's response, type of compound, method of administration, bioavailability of the administered composition, dosage, co-administration of other pharmaceuticals, etc. Preferably, 5-500 mg / day of the compound of the present invention is administered to the patient in one or more doses, preferably in one dose.

[0048] The present invention also relates to a method for preventing or treating, preferably treating, NASH comprising administering to a patient in need thereof a sufficient amount of at least one composition of the present invention.

[0049] The present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for the prevention or treatment, preferably the treatment, of NASH.

[0050] The present invention also relates to the use of the composition of the present invention for the manufacture of a medicament for the prevention or treatment, preferably the treatment, of NASH.

[0051] In addition to treating NASH, the compound of the present invention is also useful for treating fibrosis, preferably liver fibrosis.Indeed, the present invention also relates to the compound according to the present invention for use in preventing or treating, preferably treating, fibrosis, preferably liver fibrosis.The present invention also relates to the composition of the present invention for use in preventing or treating, preferably treating, fibrosis, preferably liver fibrosis.

[0052] The present invention also relates to a method for preventing or treating, preferably treating, fibrosis, preferably liver fibrosis, comprising administering to a patient in need thereof a sufficient amount of at least one compound or composition of the present invention, together with a pharma- ceutically acceptable vehicle or excipient.

[0053] The present invention also relates to the use of a compound or composition of the invention for the manufacture of a medicament for the prevention or treatment, preferably the treatment, of fibrosis, preferably liver fibrosis.

[0054] The present invention also relates to the compounds of the present invention for use in the prevention or treatment, preferably treatment, of NASH and fibrosis, preferably liver fibrosis.The present invention also relates to the compositions of the present invention for use in the prevention or treatment, preferably treatment, of NASH and fibrosis, preferably liver fibrosis.

[0055] The present invention also relates to a method for preventing or treating, preferably treating, NASH and fibrosis, preferably liver fibrosis, comprising administering to a patient in need thereof a sufficient amount of at least one compound or composition of the present invention, together with a pharma- ceutically acceptable vehicle or excipient.

[0056] The present invention also relates to the use of a compound or composition of the invention for the manufacture of a medicament for the prevention or treatment, preferably the treatment, of NASH and fibrosis, preferably liver fibrosis.

[0057] The invention will now be illustrated by way of non-limiting examples.

[0058] The following compound (1) of formula (I) was tested: [ka] The compound is obtained as described in WO2012 / 175715. The study was performed in the STAM model. Pathogenic-free 14-day pregnant C57BL / 6 mice were obtained from Japan SLC Co., Ltd. (Japan). NASH was developed in male mice by a single subcutaneous injection of streptozotocin (Sigma, USA) after birth and feeding a high-fat diet (CLEA Japan, Japan) after 4 weeks of age (28 days ± 2 days). Days before the start of treatment, mice were randomly divided into three groups of 10 mice at 6 weeks of age (42 ± 2 days) and three groups of 10 mice at 9 weeks of age (63 ± 2 days). Individual body weights were measured daily during the treatment period. Food consumption was measured twice a week during the treatment period. Survival, clinical signs and behavior of mice were monitored daily.

[0059] In vivo study to evaluate the effect on NASH1 The in vivo study of NASH had three parts. Group 1 (vehicle): 10 NASH mice were orally administered vehicle (0.5% methylcellulose / water) similar to the mice treated with compound (1). Group 2 (telmisartan): Five mice received the same vehicle supplemented with telmisartan at a dose of 100 mg / kg (0.5% methylcellulose / water) once daily between 6 and 9 weeks of age. Telmisartan, an angiotensin receptor blocker, is a reference compound that has been shown to be active in treating NASH and fibrosis in the STAM animal model. Group 3 (Compound (1)): 10 NASH mice were administered vehicle supplemented with Compound (1) at a dose of 100 mg / kg (in 0.5% methylcellulose / water) once daily from 6 to 9 weeks of age. Parameters evaluated and histological outcome measures are described below.

[0060] In vivo study 2 to assess effects on fibrosis The in vivo study of fibrosis had three parts. Group 1 (vehicle): 10 NASH mice were orally administered vehicle (0.5% methylcellulose / water) similar to the mice treated with compound (1). Group 2 (telmisartan): Five mice received the same vehicle supplemented with telmisartan at a dose of 100 mg / kg (in 0.5% methylcellulose / water) once daily from 9 to 12 weeks of age. Group 3 (Compound (1)): 10 NASH mice were administered vehicle supplemented with Compound (1) at a dose of 100 mg / kg (in 0.5% methylcellulose / water) once daily from 9 to 12 weeks of age. Parameters evaluated and histological outcome measures are described below.

[0061] Study Measurements, Analytes, Results and Analysis The following measurements were performed for both in vivo studies: Liver weight in each individual Individual weight Plasma ALT (alanine aminotransferase), AST (aspartate aminotransferase), triglycerides, and total cholesterol were measured by FUJI DRI-CHEM (Fujifilm, Japan). Liver triglycerides were quantified using a Triglyceride E Test Kit (Wako, Japan). Histological analysis of liver sections (by conventional methods)

[0062] Definition and Calculation of NAS The NAFLD Activity Score (NAS), proposed by the NASH Clinical Research Network, is the most widely used scoring system in the field of NAFLD / NASH research (Kleiner, DE et al., (2005). Histological scoring for alcoholic fatty liver disease. Hepatology, 41, 1313-21). NAS is defined as the unweighted sum of histological scores for fatty liver (0–3), lobular inflammation (0–3) and hepatocellular hypertrophy (0–2), which represent active liver injury. NAS gives a total score of 0–8, allowing detailed analysis of histological changes for comparative and correlative studies in clinical and non-clinical trials.

[0063] The NAS was initially developed for the assessment, but not for the diagnosis of NAFLD / NASH. Nevertheless, the score is frequently used to diagnose NASH, with a threshold of NAS5. Although the NAS shows good correlation with the diagnosis, careful interpretation is essential. Non-NASH livers may have a score of total NAS ≤ 5, or conversely, livers with NAS ≤ 4 may receive a diagnosis of NASH (Brunt, E. M., et al., (2011). Non-alcoholic fatty liver disease (NAFLD) activity score and histopathological diagnosis in NAFLD: Differential clinicopathological significance. Hepatology, 53, 810-20, and Hjelkrem, M., et al., (2011). Validation of the Non-alcoholic Fatty Liver Disease Activity Score. Aliment. Pharmacol. Ther., 34, 214-8).

[0064] For efficacy evaluation, NAS is useful when applied strictly to patients with histologically proven NASH. From the perspective of nonclinical trials, NAS should be used with caution when applied to animal models in which the development of NASH pathology is heterogeneous.

[0065] Stelic's proprietary NASH-HCC model (STAM model) shows uniform and reproducible [100%] disease progression, making the STAM model suitable for comparative studies with NASH.

[0066] A network established in 2002 by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to conduct naturalistic studies and clinical trials of fatty liver disease in adults and children.

[0067] NAS Component Definitions Table 1. NAFLD activity score structure [Table 1]

[0068] The results are shown in the accompanying figures. [Brief description of the drawings]

[0069] [Figure 1] FIG. 1 represents the NAS scores in trials 1 and 2 for each of groups 1 (vehicle), 2 (telmisartan) and 3 (compound of the invention). [Diagram 2] FIG. 2 represents the amount of triglycerides in the liver in studies 1 and 2 for each of groups 1 (vehicle), 2 (telmisartan) and 3 (compound of the invention). [Diagram 3] FIG. 3 represents the plasma triglyceride levels in studies 1 and 2 for each of groups 1 (vehicle), 2 (telmisartan) and 3 (compound of the invention).

[0070] Compound (1) of the present invention shows a significant reduction in NAFLD activity score (NAS) in both studies 1 and 2, in comparison to both vehicle and telmisartan.

[0071] Compound (1) of the present invention exhibits a reduction in the amount of hepatic triglycerides (TG).

[0072] Compound (1) of the present invention, particularly in Study 2, shows a reduction in plasma triglyceride (TG) levels.

Claims

1. A pharmaceutical composition for the treatment or prevention of NASH, comprising a compound of formula (I): 【Chemistry 1】 (In the formula, R 1 teeth, - -C(O)CR 4 R 5 CR 6 R 7 C(O)OH group; or --C(OH)(H)CR 4 R 5 CR 6 R 7 a C(O)OH group; represents m represents 0; R 2 teeth, - a C6 aryl group optionally having a substituent selected from C1 to C5 linear or branched alkyl, C1 to C5 linear or branched alkoxy, or represents a 6-membered heteroaryl group, R 4 , R 5 , R 6 and R 7 teeth, - represents a hydrogen atom) or a pharma- ceutically acceptable base or acid addition salt thereof.

2. R 1 -C(O)CH 2 CH 2 2. The pharmaceutical composition of claim 1, wherein said compound is C(O)OH.

3. R 2 but - a C6 aryl group optionally having a substituent selected from C1 to C5 linear or branched alkyl, or C1 to C5 linear or branched alkoxy; or -6-membered heteroaryl group containing an N atom 3. The pharmaceutical composition according to claim 1, wherein

4. A pharmaceutical composition according to any one of claims 1 to 3 for the treatment of NASH.

5. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3 or an addition salt with a pharma- ceutically acceptable base or acid for the prevention or treatment of fibrosis.

6. The pharmaceutical composition according to claim 5 , wherein the fibrosis is liver fibrosis.

7. The pharmaceutical composition according to claim 6 for the treatment of fibrosis.

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