WO2021037702A1 - Combinaison pharmaceutique d'un dérivé de thiénopyridone spécifique avec un agoniste de fxr pour le traitement de maladies du foie - Google Patents

Combinaison pharmaceutique d'un dérivé de thiénopyridone spécifique avec un agoniste de fxr pour le traitement de maladies du foie Download PDF

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WO2021037702A1
WO2021037702A1 PCT/EP2020/073461 EP2020073461W WO2021037702A1 WO 2021037702 A1 WO2021037702 A1 WO 2021037702A1 EP 2020073461 W EP2020073461 W EP 2020073461W WO 2021037702 A1 WO2021037702 A1 WO 2021037702A1
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nash
compound
combination
liver
cirrhotic
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Sébastien BOLZE
Pascale Fouqueray
Sophie Hallakou-Bozec
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Poxel
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the invention relates to a pharmaceutical combination
  • a pharmaceutical combination comprising a specific thienopyridone derivative, namely 2-chloro-4-hydroxy-3-(5-hydroxytetralin-6-yl)-5-phenyl-7H-thieno[2,3- b]pyridin-6-one or one of its pharmaceutically acceptable salts and/or solvates, and at least one farnesoid-X receptor (FXR) agonist.
  • This combination may be used for treating a liver disease such as NASH, including cirrhotic and non-cirrhotic NASH.
  • Non-alcoholic fatty liver disease consists of a spectrum of conditions ranging from relatively benign steatosis to more severe non-alcoholic steatohepatitis (NASH).
  • NASH is characterized by hepatic lipid accumulation coming mainly from adipose tissue (AT) lipolysis (60%) and hepatic de novo lipogenesis (25%), causing liver inflammation, hepatocyte ballooning and fibrosis.
  • AT adipose tissue
  • hepatic de novo lipogenesis 25%
  • steatosis notably results in an excess storage of lipids in the form of particular vesicles called lipid droplets (LD).
  • LD lipid droplets
  • a-smooth muscle actin a-smooth muscle actin
  • galectin-3 which is expressed by immune and inflammatory cell types, in NASH inflammation process (Lacobini et al., Journal of Hepatology , 54(5), 2011), thus making galectin-3 a valuable marker in the context of NASH (Jeftic et al., Molecular Medicine , 21, 2015).
  • the disease can be silent for a long period of time, but once it accelerates, severe damage and usually also liver cirrhosis can occur, which can significantly impact liver function or can even result in liver failure or liver cancer.
  • Typical risk factors for NASH include obesity, elevated levels of blood lipids (such as cholesterol and triglycerides) and diabetes. The frequency of this disease has become increasingly common due to consumption of carbohydrate-rich and high- fat diets.
  • no efficient and safe curative or specific therapies are currently available (G. C. Farrell and C. Z. Larter, Hepatology , 2006, 43, 99-112).
  • the current treatment for NASH patients with end-stage disease is liver transplant.
  • NASH has become the second indication for liver transplantation in the US and should become the first one in the short term (Wong et al., Gastro 2015).
  • cirrhosis due to NASH increases the risk of hepatocellular carcinoma and hepatocellular cancer, although these have also been observed among patients having non cirrhotic NASH.
  • Cardiovascular mortality is also a major cause of death in NASH patients.
  • the NAS is a score that was developed as a tool to measure changes in NASH during therapeutic trials. This score is calculated as the underweighted sum of the score of steatosis (0- 3), lobular inflammation (0-3) and ballooning (0-2). In particular, steatosis score can be evaluated to monitor the progression of NASH.
  • FXR agonists famesoid X receptor agonists
  • liver disease such as improved efficacy and/or better tolerance of the treatment.
  • Such drug combination allows reducing the effective amount of at least one of said compounds while obtaining a satisfactory therapeutic effect and/or obtaining a higher therapeutic effect of the liver disease.
  • the invention relates to a pharmaceutical combination comprising:
  • liver disease such as diabetes, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH) and liver fibrosis, preferably non-alcoholic steatohepatitis (NASH), including cirrhotic and non-cirrhotic NASH.
  • a liver disease such as diabetes, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH) and liver fibrosis, preferably non-alcoholic steatohepatitis (NASH), including cirrhotic and non-cirrhotic NASH.
  • This invention further pertains to the use of this combination in the manufacture of a pharmaceutical composition intended for the treatment of a liver disease.
  • Figure 2 Steatosis score improvement in DIO-NASH mice treated with different compounds.
  • Figure 3 Lipid droplets-containing hepatocytes in DIO-NASH mice treated with different compounds.
  • FIG. 4 Steatosis quantification in DIO-NASH mice treated with different compounds.
  • Figure 5 Triglyceride levels of DIO-NASH mice treated with different compounds.
  • Figure 6 a-SMA liver content of DIO-NASH mice treated with different compounds.
  • FIG. 7 Galectin-3 liver content of DIO-NASH mice treated with different compounds. DETAILED DESCRIPTION OF THE INVENTION
  • the combination of this invention comprises as a first ingredient a thienopyridone derivative which is the compound of formula (I): or one of its pharmaceutically acceptable salts and/or solvates.
  • Examples of pharmaceutically acceptable salts of the compound of formula (I) can be obtained by reacting the compound of formula (I) with various organic and inorganic bases by procedures usually known in the art to give the corresponding base-addition salt.
  • bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkali metal carbonates, including potassium carbonate and sodium carbonate; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkaline earth metal carbonates; alkali metal alkoxides, for example potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methylglutamine.
  • the aluminium salts of the compounds of formula (1) are likewise included.
  • the salts of the compound of formula (I) thus include aluminium, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(III), manganese(II), potassium, sodium and zinc salts, but this is not intended to represent a restriction.
  • any of the pharmaceutically acceptable salts of the compound of formula (I), or this compound itself, may be used in this invention in the form of one of its solvates.
  • “Solvates” of the compounds are taken in the present invention to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. The nature of the solvate thus depends on the solvent used during the reaction of the base with the compound of formula (I). Examples of solvates include alcohol solvates, for instance methanol or ethanol solvates, and hydrates, including mono-, di-, tri- or tetrahydrates, but this is not intended to represent a restriction.
  • the compound used in this invention is the monohydrate monopotassium salt of the compound of formula (I), corresponding to the following structure (la):
  • This compound also referred to as PXL770, may be prepared according to a process comprising the steps of: (A) reacting a compound of formula (I) with potassium carbonate in a solution comprising water and a solvent selected from «-butyl acetate and isopropanol:
  • step (C) recovering the precipitate obtained in step (B), preferably by filtration.
  • said compound of formula (I) may be obtained by an improved process comprising the steps of:
  • step (b) reacting the compound obtained in step (a) with ethyl cyanoacetate in the presence of hexamethyldisilazane and acetic acid;
  • step (c) reacting the compound obtained in step (b) with sulfur in the presence of a base;
  • step (d) optionally forming a salt of the compound obtained in step (c), preferably a hydrochloride salt;
  • step (e) reacting the compound obtained in step (c) or (d) with an electrophilic chlorine source, preferably N-chlorosuccinimide;
  • step (f) reacting the compound obtained in step (e) with phenylacetyl chloride
  • step (g) reacting the compound obtained in step (f) with a base
  • step (h) reacting the compound obtained in step (g) with boron tribromide or trichloride, preferably boron trichloride;
  • step (B) can comprise a substep (bl) of heating the mixture obtained in step (A), preferably at a temperature close to reflux of the mixture, followed by a sub step (b2) of cooling the resulting mixture, for instance at a temperature comprised between -15 °C and 35 °C.
  • close to reflux of the mixture refers typically to a temperature comprised between 90% and 100 % of the boiling point of the solvent system in step (A) (for instance, water/isopropanol or water///-butyl acetate).
  • a distillation step preferably under reduced pressure, can be carried out between the heating substep and substep (b2).
  • Step (B) allows a crystalline precipitate to form, which formation may be favored or triggered by adding seeds to steps (b2).
  • said precipitate is recovered by filtration in step (C). It may then be washed successively with one or more solvents, preferably water, «-butyl acetate and/or tert- butyl methyl ether.
  • the compound of formula (la) is thus obtained in the form of a solid, such as a powder, having the following XRPD (X-Ray Powder Diffraction) peaks, as measured by means of a diffractometer, using Cu K(alpha) radiation:
  • the wording "the thienopyridone derivative” refers to the compound of formula (I) or to one of its pharmaceutically acceptable salts and/or solvates such as the compound of formula (la).
  • the thienopyridone derivative is combined with at least one farnesoid X receptor agonist (referred to hereafter as FXR agonist).
  • FXR agonist refers to any agent that is capable of binding and activating farnesoid X receptor (FXR) which may be referred to as a bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4) receptor.
  • FXR agonists specifically stimulate ligand-dependent FXR transcriptional activity, as differentiated from the baseline level determined in the absence of any ligand. This action is also referred to as an FXR- stimulating or activating action.
  • FXR agonists may be full or partial FXR agonists. The activity of a FXR agonist may be measured by several different methods, e.g.
  • chenodeoxycholic acid having the following formula:
  • 6-alpha-ethyl-chenodeoxycholic acid (6-ECDCA), having the following formula: LY-2562175, or 6-(4- ⁇ [5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy ⁇ - piperidin-l-yl)-l -methyl- liI-indole-3 -carboxylic Acid, which has the following formula :
  • Tropifexor (LIN-452) or 2-(3-((5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4- yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]- thiazole-6-carboxylic acid, which has the following formula :
  • Other useful FXR agonists include Tern-101, AGN-242266, AGN-242256, LMB763, EYP- 001, EDP-305, nidufexor, MET-409, EP-024297, M-480, IOT-022 and INV-33, inter alia.
  • Preferred FXR agonists for use in this invention include tropifexor, cilofexor, obeticholic acid, Tern-101 and AGN-242266 and more particularly obeticholic acid.
  • the pharmaceutical combination comprising the FXR agonist and the thienopyridone derivative may be used as a medicament and more specifically in the treatment of a liver disease, such as diabetes, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and liver fibrosis, preferably non-alcoholic steatohepatitis (NASH), including cirrhotic and non-cirrhotic NASH.
  • a liver disease such as diabetes, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and liver fibrosis, preferably non-alcoholic steatohepatitis (NASH), including cirrhotic and non-cirrhotic NASH.
  • treatment refers to therapy, prevention and prophylaxis of a liver disease.
  • the treatment involves the administration of the pharmaceutical combination to a subject having a declared liver disorder to cure the disease or to delay its outcome or slow down its progress, thus improving the condition of patient.
  • the term treatment includes preventing or reducing the risk of developing liver disease, such NAFLD or NASH, i.e., causing the clinical symptoms of NAFLD or NASH not to develop in a subject who may be predisposed to NAFLD or NASH but who does not yet experience or display symptoms of the NAFLD or NASH (i.e. prophylaxis).
  • the term treatment includes inhibiting liver disease, such as NAFLD or NASH, i.e., arresting or reducing the development of NAFLD or NASH or its clinical symptoms.
  • the term treatment includes relieving liver disease, such as NAFLD or NASH, i.e., causing regression, reversal, or amelioration of the NAFLD or NASH or reducing the number, frequency, duration or severity of its clinical symptoms. This term thus broadly includes “preventing, delaying or treating.”
  • the term “subject” or “patient” means a mammal and more particularly a human.
  • the FXR agonist and (ii) the thienopyridone derivative are administered simultaneously or sequentially, in the form of separate pharmaceutical compositions, one comprising the FXR agonist in a pharmaceutically acceptable vehicle, the other comprising the thienopyridone derivative in a pharmaceutically acceptable vehicle.
  • the FXR agonist and the thienopyridone derivative are combined and administered in the same pharmaceutical composition.
  • pharmaceutical combination and “combined administration” refers to one or the other of these aspects.
  • pharmaceutically acceptable support refers to carrier, adjuvant, or excipient acceptable to the subject from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding to composition, formulation, stability, subject acceptance and bioavailability.
  • carrier refers to any substance, not itself a therapeutic agent, that is added to a pharmaceutical composition to be used as a carrier, adjuvant, and/or diluent for the delivery of a therapeutic agent to a subject in order to improve its handling or storage properties or to enable or facilitate formation of a dosage unit of the composition into a discrete article.
  • the pharmaceutical compositions used in this invention can comprise one or several agents or vehicles chosen among dispersants, solubilizers, stabilisers, preservatives, etc.
  • “combined administration” means, for the purpose of the present invention, fixed and, in particular, free combinations, i.e. either the FXR agonist and the thienopyridone derivative are present together in one dosage unit, or the FXR agonist and said compound, which are present in separate dosage units, are administered successively, either immediately or at a relatively large time interval; a relatively large time interval means a time span up to a maximum of 24 hours.
  • a “dosage unit” means, in particular, a medicinal dosage form in which the release of the active ingredient(s) is achieved with as few problems as possible, such that the two active-ingredient components (the FXR agonist on the one hand and said thienopyridone derivative on the other hand) are released, or made available effectively for the body, in such a way that an optimal active ingredient profile, and thus action profile, is achieved.
  • the separate dosage units are preferably made available together in one pack and either mixed prior to administration or sequentially administered.
  • the two dosage units may be packed together in blister packs that are designed with regard to the relative arrangement of the two dosage units with respect to one another, the inscription and/or coloring in a manner known per se so that the times for taking the individual components (dosage regimen) of the two dosage units are evident to a patient.
  • This free combination is of benefit by individually allotting an effective amount of both compounds to the patient.
  • Another possibility is the provision of single preparations of both compounds, i.e. being independent medicaments.
  • the single preparations are converted to contain the required amounts of ingredient for the inventive combination.
  • Corresponding instructions are given at the package insert concerning the combined administration of the respective medicament.
  • the invention may be practiced as a pharmaceutical package comprising as active ingredients an effective amount of the FXR agonist, together with one or more pharmaceutically acceptable adjuvants, in a first dosage unit, and an effective amount of the thienopyridone derivative as defined above, together with one or more pharmaceutically acceptable adjuvants, in a second dosage unit.
  • This package may include an article that comprises written instructions or directs the user to written instructions for how to practice the method of the invention.
  • the prior teaching of the present specification concerning the composition and its administration is considered as valid and applicable without restrictions to the pharmaceutical package if expedient.
  • the dosage units mentioned above can comprise, for example, 0.5 mg to 1000 mg, preferably 20 mg to 1000 mg, more preferably 60 mg to 500 mg, of the thienopyridone derivative, and 0.01 mg to 1000 mg, preferably 0.05 mg to 1000 mg, more preferably 0.3 mg to 500 mg, of the FXR agonist, depending on the disease condition treated, the method of administration and the age, weight and condition of the patient.
  • Preferred dosage unit formulations are those which comprise a daily dose or a corresponding fraction thereof of an active ingredient.
  • pharmaceutical compositions of this type can be prepared using a process which is generally known in the pharmaceutical art.
  • a single pharmaceutical formulation may also be prepared which includes both ingredients.
  • This invention is thus also directed to the use of (i) the FXR agonist, and (ii) the thienopyridone derivative as defined above in the manufacture of a pharmaceutical composition intended for the treatment of a liver disease.
  • the ratio between each of the thienopyridone derivative, the FXR agonist and the pharmaceutically acceptable support may be comprised in a wide range. In particular, this ratio may be comprised between 1/99 (w/w) and 99/1 (w/w), preferably between 10/90 (w/w) and 90/10 (w/w).
  • This invention is further directed to a method for treating a liver disease, comprising administering to a patient an effective amount of a combination of (i) a FXR agonist, and (ii) the thienopyridone derivative as defined above.
  • the pharmaceutical combination of this invention may be suitable for administration via any desired appropriate route, for example by oral (including buccal or sublingual), topical (including buccal, sublingual or transdermal), or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods.
  • oral including buccal or sublingual
  • topical including buccal, sublingual or transdermal
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • the pharmaceutical combination according to the invention is suited for oral administration.
  • compositions and dosage units suitable for oral administration of the pharmaceutical combination include capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or emulsions, such as oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the therapeutically effective amount of the compounds included in the pharmaceutical combination of this invention depends on a number of factors, including, for example, the age and weight of the human or animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor.
  • an effective amount of each of the active compounds of the combination is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day.
  • the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. It can be assumed that similar doses are suitable for the treatment of other conditions mentioned above.
  • Abbreviations a/a ratio of the peak area of a given compound to the total of the peak areas on a spectrum or a chromatogram.
  • X-Ray Powder Diffraction (XRPD) analyses were performed using a Panalytical Xpert Pro diffractometer equipped with a Cu (K alpha radiation) X-ray tube and a Pixcel detector system. The samples were analysed in transmission mode and held between low density polyethylene films. XRPD patterns were sorted, manipulated and indexed using HighScore Plus 2.2c software.
  • Thermogravimetric (TG) analyses were carried out on a Perkin Elmer Diamond Thermogravimetric/Differential Temperature Analyser (TG/DTA).
  • the calibration standards were indium and tin. Samples were placed in an aluminium sample pan, inserted into the TG furnace and accurately weighed. The samples were heated from 30-300°C in a stream of nitrogen at a rate of 10°C/minute. The temperature of the furnace was equilibrated at 30°C prior to the analysis of the samples.
  • Crystallization of potassium salt monohydrate may occur here. 4.2 parts of water were added and the mixture was seeded with compound (I) (1 to 2% of seeds). The suspension was then cooled down from 40°C to 5°C in 7 hours (5°C/hour) and kept at 5°C for several hours. The suspension was filtered. The cake was washed twice by 1.42 parts of water. The collected solid was dried at 40°C under vacuum given minimum 80% yield of Compound (la), at required chemical purity (i.e. 98%+).
  • Example 2 Characterization of compound (la) a) X-ray powder diffraction (XRPD) data of compound (la) indicated that it was composed of a crystalline material. The XRPD description of compound (la) is shown in Table 1.
  • Example 3 Biological effects of compound (la) on DIO-NASH mice The effects of the compound of formula (la) as prepared in Example 1 (also called PXL770) on liver and adipose tissue (AT) metabolism in a diet-induced obesity non-alcoholic steatohepatitis (DIO-NASH) mouse model are reported here.
  • NASH steatohepatitis
  • TG triglycerides
  • TG liver triglycerides
  • TG elevated liver triglycerides
  • x26 elevated liver triglycerides
  • compound (I) at both doses increased AMPK activity in the liver and improved liver health.
  • compound (la) at both doses decreased liver weight.
  • Compound (la) reduced NAS decreasing steatosis, also confirmed by the reduction of liver TG content, inflammation and hepatocellular ballooning.
  • the benefit of the compound (la) on fibrosis was measured by a strong down- regulation in the expression of
  • compound (la) improved adipose tissue metabolism.
  • Compound (la) activated AMPK in AT and reduced fat pad mass.
  • Compound (la) decreased the activity of hormone-sensitive lipase, consistent with the decrease in plasma free fatty acid level.
  • Compound (la) reduced AT inflammation, decreasing MCP-1 gene expression and increased AT mitochondrial biogenesis, increasing PGCl-a protein expression.
  • Compound (la) evidenced beneficial effects on both liver and adipose tissue in DIO-NASH mice model through direct activation of AMPK.
  • Example 4 Biological effects of compound (la) in combination with an incretin agonist on DIO-NASH mice
  • mice C57BL/6J, male were feed with a High Fat High Fructose diet (40% fat, 20% fructose and 2% cholesterol - D09100301, Research diets, New Jersey) for 34 weeks to induce a NASH phenotype. They were then treated for 8 weeks while kept on high fat diet.
  • a High Fat High Fructose diet (40% fat, 20% fructose and 2% cholesterol - D09100301, Research diets, New Jersey) for 34 weeks to induce a NASH phenotype. They were then treated for 8 weeks while kept on high fat diet.
  • mice were anesthetized by inhalation anesthesia using isoflurane (2-3%). A small abdominal incision was made in the midline and the left lateral lobe of the liver was exposed. A cone shaped wedge of liver tissue (approximately 50 mg) was excised from the distal portion of the lobe and fixated in 10% neutral buffered formalin (10% NBF) for histology. The cut surface of the liver was instantly electrocoagulated using bipolar coagulation (ERBE VIO 100 electrosurgical unit). The liver was returned to the abdominal cavity, the abdominal wall is sutured, and the skin was closed with staplers. For post-operative recovery mice received carprofen (5mg/kg) administered subcutaneously on OP day and post-OP day 1 and 2.
  • carprofen 5mg/kg administered subcutaneously on OP day and post-OP day 1 and 2.
  • mice with fibrosis stage >1 and steatosis score >2 were selected for randomization.
  • a stratified randomization into treatment groups was performed according to liver Collagen lal quantification of pre-biopsies taken at week -4, i.e. 4 weeks before the beginning of compounds administration. Mice were then divided into four groups to receive different administration of compounds (as detailed in Table 2), each diluted in the same vehicle solution (Carboxy methylcellulose 0.5% / Tween 80 (98/2 in volume).
  • liver was collected and weighed. Specific liver samples were dissected and processed as specified in table 3 and further described below. The left lateral lobe was used for the pre-biopsy (not applicable at termination) and a termination biopsy. The liver termination biopsy (-200 mg, less than 0.7 x 0.5 cm) was cut 4 mm from the prebiopsy site and with an edge. The tissue was collected in paraformaldehyde (4%).
  • slides with paraffin embedded sections are de-paraffmated in xylene and rehydrated in series of graded ethanol.
  • the slides are incubated in Mayer’s Hematoxylin (Dako), washed in tap water, stained in Eosin Y solution (Sigma-Aldrich), hydrated, mounted with Pertex and then allowed to dry before scanning.
  • Hematoxylin Dako
  • Eosin Y solution Sigma-Aldrich
  • Galectin-3 (Biolegend, Cat. # 125402) Immuno Histo Chemistry was performed using standard procedures. Briefly, after antigen retrieval and blocking of endogenous peroxidase activity, slides are incubated with primary antibody. The primary antibody is detected using a linker secondary antibody followed by amplification using a polymeric HRP-linker antibody conjugate. Next, the primary antibody is visualized with DAB as chromogen. Finally, sections are counterstained in hematoxylin and cover-slipped.
  • a-SMA IHC staining Alpha-smooth muscle actin (Abeam, Cat. Ab 124964) Immuno Histo Chemistry was performed using standard procedures. Briefly, after antigen retrieval and blocking of endogenous peroxidase activity, slides are incubated with primary antibody. The primary antibody is detected using a polymeric HRP-linker antibody conjugate. Next, the primary antibody is visualized with DAB as chromogen. Finally, sections are counterstained in hematoxylin and cover-slipped. NAFLD Activity Score (NAS) and fibrosis stage
  • NAS steatosis stage
  • Steatosis was quantified on H&E stained slides by image analysis using the VIS software (Visiopharm, Denmark). VIS protocols are designed to analyze the virtual slides in two steps: Firstly, crude tissue is detected at low magnification (1 x objective). Then, steatosis (blue) and tissue (black) are detected at high magnification (20 x objective). The quantitative estimates of steatosis were calculated as an area fraction in the following way:
  • Area fractionsteatosis Areasteatosts / Area sue + Areasteatosis
  • Deep learning-based image analysis was used to quantify the percent of hepatocytes containing lipid droplets, at termination.
  • Liver samples were homogenized, and TG were extracted in 5% NP-40 by heating twice at 90°C. The samples were centrifuged and the TG content was measured in the supernatant, using commercial kits (Roche Diagnostics) on the Cobas c 501 Autoanalyzer according to the manufacturer's instructions.
  • mice with biopsy-confirmed steatosis (score >2) and fibrosis (stage >1) were selected.
  • NAS and steatosis score were quantified (Fig. 1-2) and LDs detected in hepatocytes (Fig. 3), using histological methods for each group of mice. Liver samples from the four mice groups were fixed in formalin, paraffin embedded, and sections were stained with H&E. The improvement in the measured NAS and steatosis score was determined by comparing samples taken before (pre-biopsy) and after (termination dissection) administration of the different compounds. For each group of treated mice, percentage of animals with improved score was assessed and represented on a bar plot ( Figures 1 and 2). Compared to control mice treated with vehicle, percentage of animals with improved score was significantly higher for mice treated with PXL770 or OCA. Interestingly, NAS and steatosis score improvement was even higher in mice treated with PXL770 and OCA, as more than 80% of these mice exhibited such an improvement.
  • the percentage of hepatocytes containing LDs was determined for each group of treated mice, from termination samples (Fig. 3). Compared to Vehicle group, the percentage of LD-containing hepatocytes was slightly but significantly reduced in the PXL770 group of mice. Importantly, the LD-containing hepatocytes percentage decrease was significantly higher when PXL770 and OCA were administered in combination than with the drugs administered alone.
  • OCA decreased relative liver Galectin-3 content by 30% (p ⁇ 0.001) when compared to vehicle treated DIO-NASH mice and its combination with PXL770 significantly reduced Galectin-3 content compared to OCA alone (-36%, p ⁇ 0.05) and to the vehicle (-55%, p ⁇ 0.001).

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Abstract

L'invention concerne une combinaison pharmaceutique comprenant un dérivé de thiénopyridone spécifique, à savoir le 2-chloro-4-hydroxy-3-(5-hydroxytétraline-6-yl)-5-phényl-7H-thiéno[2,3-b]pyridin-6-one ou l'un de ses sels et/ou solvates pharmaceutiquement acceptables, et au moins un agoniste du récepteur farnésoïde-X (FXR). Cette combinaison peut être utilisée pour traiter une maladie du foie telle que la NASH, y compris la NASH cirrhotique et non-cirrhotique.
PCT/EP2020/073461 2019-08-28 2020-08-21 Combinaison pharmaceutique d'un dérivé de thiénopyridone spécifique avec un agoniste de fxr pour le traitement de maladies du foie WO2021037702A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014001554A1 (fr) 2012-06-29 2014-01-03 Poxel Dérivés de thiénopyridone utiles en tant qu'activateurs de la protéine kinase activée par l'amp
WO2018126016A1 (fr) * 2016-12-28 2018-07-05 Modunex Bio Corp. Polythérapie pour la stéatohépatite non alcoolique (shna) et la fibrose hépatique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014001554A1 (fr) 2012-06-29 2014-01-03 Poxel Dérivés de thiénopyridone utiles en tant qu'activateurs de la protéine kinase activée par l'amp
WO2018126016A1 (fr) * 2016-12-28 2018-07-05 Modunex Bio Corp. Polythérapie pour la stéatohépatite non alcoolique (shna) et la fibrose hépatique

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BOLAND ET AL., NATURE METABOLISM, vol. 2, no. 5, 2020
CHERNG ET AL., THE JOURNAL OF AMERICAN SCIENCE, vol. 4, no. 4, 2008
G. C. FARRELLC. Z. LARTER, HEPATOLOGY, vol. 43, 2006, pages 99 - 112
GLUCHOWSKI ET AL., NAT REV GASTROENTEROL HEPATOL., 2017
JEFTIC ET AL., MOLECULAR MEDICINE, vol. 21, 2015
LACOBINI ET AL., JOURNAL OF HEPATOLOGY, vol. 54, no. 5, 2011
OBEN ET AL., GUT, vol. 53, no. 3, 2004
PELLICCIARI ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 15, no. 45, 2002, pages 3569 - 72
WONG ET AL., GASTRO, 2015

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