WO2009109525A1 - Use of a specific pde4 inhibitor for the treatment and/or prophylaxis of non-alcoholic fatty liver disease - Google Patents
Use of a specific pde4 inhibitor for the treatment and/or prophylaxis of non-alcoholic fatty liver disease Download PDFInfo
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- WO2009109525A1 WO2009109525A1 PCT/EP2009/052349 EP2009052349W WO2009109525A1 WO 2009109525 A1 WO2009109525 A1 WO 2009109525A1 EP 2009052349 W EP2009052349 W EP 2009052349W WO 2009109525 A1 WO2009109525 A1 WO 2009109525A1
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- fatty liver
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- 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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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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
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
Abstract
The invention relates to the use of (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of non-alcoholic fatty liver disease (NAFLD).
Description
Description
Use of a specific PDE4 inhibitor for the treatment and/or prophylaxis of Non-alcoholic fatty liver disease
Field of application of the invention
The invention relates to the use of (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8- methoxy-1 ,2,3,4,4a,10b-hexahydrophenanthridin-2-ol or a pharmaceutically acceptable salt thereof in the manufacture of pharmaceutical compositions for the treatment and/or prophylaxis of nonalcoholic fatty liver disease (NAFLD).
Known technical background
Under the term "Non-alcoholic fatty liver disease" (NAFLD) a whole spectrum of different forms and severity grades of pathologic liver fatty degeneration with varied prognosis is summarized. The spectrum includes on the one hand side the benign, non-progressive form of non-alcoholic fatty liver (NAFL) and on the other hand side the non-alcoholic fat-liver hepatitis or steatohepatitis (NASH), which is accompanied by liver inflammation and therefore can lead to liver fibrosis und liver cirrhosis.
Non-alcoholic fatty liver disease is emerging as a common, clinically important type of chronic liver disease in industrialized countries. Due to the strong correlation to type 2 diabetes mellitus and insulin resistance, prevalence is dramatically increasing. Available data indicates that the pre- valence rates are now in the range of 17-33% for NAFLD and 5.7-17% for NASH. Currently, no established treatment exists for these potentially serious disorders. The management of NAFLD/NASH is largely conservative and includes diet and exercise, weight reduction drugs as well as insulin sensitizers, lipid-lowering agents and several antioxidant approaches (e.g. vitamins, glutathione). Among them, the more promising agents are peroxisomal proliferation-activated receptors gamma (PPARγ) agonists and Metformin. The mechanism of the latter compound remains uncertain in spite of its therapeutic benefits. Metformin reduces hepatic glucose output and also possesses insulin sensitization action improving whole body glucose homeostasis. The members of the PPARγ agonists comprise the chemical class of thiazolinediones (e.g. Rosiglita- zone or Pioglitazone), which facilitate insulin-signaling pathway and promote glucose utilization at muscular levels. Unfortunately, these drugs are associated with a massive increase of body weight due to fat redistribution. In addition, new long-term clinical studies provide evidence for an increased cardio-vascular risk and bone fractures in subjects treated with thiazolinediones, and therefore questions the further intensive use of this class of compounds.
In Hepatology 2006, Vol. 44, No. 4 Supplement 1 , Abstract 1281 Kenichi Ikejima et al describe the effect of FR216117, a PDE4 inhibitor, on dietary steatohepatitis in rodents. In the international patent applications WO2006004188 and WO2006004191 pyrazolopyridine and pyrrolopyridazine derivatives, which inhibit PDE4 and TNFα are described; hepatic steatosis (alcoholic and non- alcoholic steatohepatitis) is mentioned as one of diseases, which potentially can be treated by the administration of these PDE4 and/or TNFα inhibitors.
In summary, therapeutic approaches of NAFLD and NASH are mainly restricted to life style modification. Some exploratory treatments with vitamins or other anti-oxidative acting compounds as well as with established anti-diabetic medicaments are ongoing, but the question of whether these medications are beneficial in NAFLD and NASH is still unanswered. Thus, there is still a high demand of novel and effective medicaments for the treatment of NAFLD and NASH.
Description of the invention
It has now been found that the PDE4 inhibitor (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-eth- oxy-8-methoxy-1 ,2,3,4,4a,10b-hexahydrophenanthridin-2-ol (hereinafter referred to as "Compound A") or a pharmaceutical acceptable salt thereof show surprising and advantageous properties in the treatment of non-alcoholic fatty liver disease (NAFLD).
The invention thus relates in a first aspect to the use of Compound A or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment and/or prophylaxis of non-alcoholic fatty liver disease (NAFLD), in particular for the treatment and/or prophylaxis of the benign, non-progressive form of non-alcoholic fatty liver (NAFL) or non- alcoholic steatohepatitis (NASH).
The invention further relates to Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of non-alcoholic fatty liver disease (NAFLD), in particular for the treatment and/or prophylaxis of the benign, non-progressive form of non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
The invention further relates to a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of non-alcoholic fatty liver disease (NAFLD), in particular for the treatment and/or prophylaxis of the benign, nonprogressive form of non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
In a further aspect the invention relates to a method for the treatment and/or prophylaxis of nonalcoholic fatty liver disease (NAFLD), in particular the benign, non-progressive form of nonalcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH), in a patient, comprising administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
As pharmaceutically acceptable salts of Compound A may be mentioned water-insoluble and, particularly, water-soluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid, 3-hydroxy-2-naphthoic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, caprylic acid (octanoic acid), dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, ga- lactaric acid, gentisic acid, D-glucoheptonic acid, D-glucuronic acid, glutamic acid, 2-oxo- glutaric acid, hippuric acid, lactic acid, malonic acid, mandelic acid, naphthalene-1 ,5-di- sulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, palmitic acid or pyroglutamic acid, it being possible to employ the acids in salt preparation - depending on whether a mono- or poly- basic acid is concerned and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom. On the other hand, pharmaceutically acceptable salts with bases are also suitable. Examples of pharmaceutically acceptable salts with bases, which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammo- nium, meglumine or guanidinium salts.
In one embodiment of the present invention a preferred pharmaceutically acceptable salt of Compound A is selected from the tosylate, esylate, hydrobromide and hydrochloride salt of Compound A.
In another embodiment of the present invention a preferred pharmaceutically acceptable salt of Compound A is the hydrochloride salt of Compound A.
Compound A or its pharmaceutically acceptable salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention is therefore also the use of Compound A or the pharmaceutically acceptable salts thereof in form of its solvates. Hydrates are a preferred example of said solvates.
- A -
The preparation of Compound A and its pharmaceutically acceptable salts is described in the international patent applications WO2005085225 and WO2006092422.
The pharmaceutical compositions used according to the invention in the treatment and/or prophylaxis of NAFLD comprise the Compound A or a pharmaceutically acceptable salt thereof and at least one auxiliary. The pharmaceutical compositions can be manufactured in a manner known to a person skilled in the art, e.g. by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
The selected formulation depends inter alia on the route of administering the pharmaceutical composition. The pharmaceutical compositions of the invention can be administered by any suitable route, for example, by the oral, sublingual, buccal, intravenous, intramuscular, subcutaneous, transdermal, intranasal, intraperitoneal or rectal route, by inhalation or by insufflation. Oral administration is preferred.
The pharmaceutical compositions can contain Compound A or a pharmaceutically acceptable salt thereof in a total amount of from 0.1 to 99.9 wt%, preferably 5 to 95 wt%, more preferably 20 to 80 wt%.
As pharmaceutically acceptable auxiliaries, any auxiliaries known to be suitable for preparing pharmaceutical compositions can be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrating agents, buffers, permeation promoters, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes. In particular, auxiliaries of a type appropriate to the desired formulation and the desired mode of administration are used.
The pharmaceutical compositions can be formulated, for example, into tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g. sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays and patches (e.g. transdermal therapeutic systems).
Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration. In particular, said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form.
Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under different conditions (e.g. pH conditions) or by coupling the active compound to a biodegradable polymer.
Administration by inhalation is preferably made by using an aerosol. The aerosol is a liquid- gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion.
The aerosol may be generated by means of aerosol-producing devices such as dry powder inhalers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers. Depending on the kind of the active compound to be administered, the aerosol-producing device can contain the active compound in form of a powder, a solution or a dispersion. The powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers. The solution may contain in addition to the solvent, for example, one or more of the following auxiliaries: propellants, solubili- zers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings. The dispersion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: propellants, surfactants, stabilizers, buffers, preservatives and flavorings. Examples of carriers include, but are not limited to, saccharides, e.g. lactose and glucose. Examples of propellants include, but are not limited to, fluorohydrocarbons, e.g. 1 , 1 , 1 ,2-tetra- fluoroethane and 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
The particle size of the aerosol particles (solid, liquid or solid/liquid particles) is preferably less than 100 μm, more preferably it is in the range of from 0.5 to 10 μm, in particular in the range of from 2 to 6 μm (D50 value, measured by laser diffraction).
Specific aerosol-producing devices which may be used for inhaled administration include, but are not limited to, Cyclohaler®, Diskhaler®, Rotadisk®, Turbohaler®, Autohaler®, Novolizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus®, Ultrahaler® and Mystic® inhalers. The aerosol- producing devices may be combined with spacers or expanders, e.g. Aerochamber®, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency.
In case of topical administration, suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (e.g. transdermal therapeutic systems).
For parenteral modes of administration such as, for example, intravenous, intramuscular, subcutaneous and intraperitoneal administration, preferably solutions (e.g. sterile solutions, isotonic solutions) are used. They are preferably administered by injection or infusion techniques.
In case of intranasal administration, for example, sprays and solutions to be applied in drop form are preferred formulations.
It is known to the person skilled in the art that the optimum dose of an active compound can vary as a function of age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the disease to be treated, etc.
In the case of oral administration of Compound A the daily dose for an adult patient (70 kg) is in the range from 0.2 to 30 mg per day, preferably in the range of 0.2 to 10 mg per day, more preferably in the range of 0.5 to 5 mg per day.
The pharmaceutical compositions can be administered in a single dose per day or in multiple sub- doses, for example, 2 to 4 doses per day. Preferred is a once or twice daily oral administration of Compound A or a pharmaceutically acceptable salt thereof. Particularly preferred is a once daily oral administration of Compound A or a pharmaceutically acceptable salt thereof.
Biological investigations
1) Investigation of the effect of Compound A, Rosiglitazone maleate and Rimonabant hydrochloride on liver lipidosis and hepatic triglyceride content in female db/db mice
Animals and compounds
Female db/db mice [C57BLKS/Bom-db/db; breeder M+B Taconic, DK-8680 RY, Denmark] were used. These mice display a defective leptin receptor resulting in hyperphagia, obesity, and insulin resistance. In young mice, insulin resistance is compensated by hyperinsulinemia resulting in only a slight increase in fasted blood glucose and a weakly impaired glucose tolerance. During life span, however, pancreatic β-cells get exhausted and the animals are no longer able to cope with the insulin resistant state. The animals get overt diabetic showing hyperglycemia due to insulin resistance as well as NAFLD due to hyperphagia and obesity. This model is widely used as an animal model for human type 2 diabetes mellitus. The animals are 11-12 weeks of age at start of treatment and were treated for 8 weeks with Compound A. Animals were kept in groups of 10 mice in Makro- lon® cages type III with free access to food and tap water. The room was maintained as follows: dark light rhythm [6 a.m. to 6 p.m. light], room temperature 22 ± 2 0C, relative humidity 50 ± 10 %.
Compound A was suspended in 4 % [w/v] aqueous methylcellulose solution, pH 6.0. Single daily oral administrations of 3, 10 and 30 mg/kg/d of Compound A in a volume of 10 ml/kg by gavage were performed. Control animals received 4 % [w/v] aqueous methylcellulose solution, pH 6.0, also in a volume of 10 ml/kg. In addition, the PPARγ agonist Rosiglitazone maleate and the anorectic anti obesity drug Rimonabant hydrochloride [purchased from Sequoia, Oxford, UK] were used as reference compounds in a single daily oral dose of 1 and 10 mg/kg/d, respectively (volume of 10 ml/kg by gavage). At the end of the treatment period (8 weeks), animals were dissected and liver biopsies taken.
Detection of liver triglyceride content
Samples for hepatic triglyceride content measurement were generated by homogenizing a liver probe previously heated 10 min to 95 0C in lysis buffer (0,5 % polyoxyethylen 10 tridecylether (Sigma P 2393), 0.01 M NaPi (NaPi = 0.01 M NaH2PO4 + 0.01 M Na2HPO4 in the ratio of 1 :1 ), 1 mM EDTA, pH 7.4). Following the initial homogenization, samples were processed using the MP Biotech (FastPrep-24) equipment. Samples were then centrifuged 2 min at 3000 rpm. The supernatant was collected for further analysis. Triglyceride content was measured using the Sigma serum triglyceride kit (TR-0100).
Necropsy and histology
Necropsy was performed in ad libitum fed animals. Mice were anesthetized with 3 % isoflurane / oxygen [Isoba®, batch J10417, Essex Pharma GmbH, 81737, Germany]. The liver was removed and fixed in 8 % formaldehyde solution for later microscopic evaluation. Liver lipidosis was evalu- ated blinded by light microscopy and semi-quantitatively scored (= severity index) by the following scheme:
Score 1 = no changes
Score 2 = minimal changes (< 5 % of pancreatic islets/liver tissues affected) Score 3 = mild changes (5 -15 % of pancreatic islets/liver tissue affected)
Score 4 = moderate changes (15 - 25 % of pancreatic islets/liver tissue affected) Score 5 = severe changes (> 25 % of pancreatic islets/liver tissue affected)
The results were presented as mean scores (= severity index) for each group (compare Fig. 1 ).
Statistics
Mean ± SEM values were shown; a total number of 20 animals per group were used.
Results
Histological analysis of liver lipidosis showed highly condensed lipid droplets in liver biopsies of control animals and a dose-dependent reduction of lipid accumulation in Compound A treated ani- mals. In addition, the livers of Compound A treated groups had a brown colour appearance, indicating low hepatic lipid content, whereas control livers appeared white and marmorized. Livers of the animals treated with Rosiglitazone maleate were yellowish in appearance, while livers of animals treated with Rimonabant hydrochloride were comparable to control.
Blinded and semi-quantitatively analysis of the liver lipidosis severity index confirmed the dose- dependent reduction of lipid accumulation in Compound A treated animals (compare Fig. 1 ). Animals treated with Rosiglitazone maleate showed increased lipid accumulation, while animals treated with Rimonabant hydrochloride showed no differences compared to control.
In line with this observation, the biochemical analysis of the hepatic triglyceride content revealed an increased hepatic triglyceride content in the Rosiglitazone (4-5 fold) and in the Rimonabant treated animals group (1.5 fold). In contrast, all Compound A treated animal groups demonstrated in comparison to vehicle, reduced hepatic triglyceride levels, mostly pronounced in the animal group that received the 30 mg/kg/d dose of Compound A (Tab. 1 ).
Tab. 1 : Hepatic triglyceride content of db/db mice [mg triglycerides / g liver tissue; mean ± SEM] after 8 weeks of treatment with Rosiglitazone maleate, Rimonabant hydrochloride and different doses of Compound A.
In conclusion, Compound A is effective in reducing hepatic lipid accumulation in livers of a representative animal model of NAFLD (db/db mice). Together with its anti-inflammatory characteristics, Compound A is a promising approach for the treatment of NAFLD, respectively NASH.
2) Investigation of the influence of Compound A on liver lipidosis in male C57BL/6 mice with diet induced obesity
The aim of this study was to investigate the influence of Compound A on liver lipidosis in male C57BL/6 mice with diet induced obesity. These animals are insulin resistant and develop NAFLD due to obesity.
Animals
Male C57BL/6-mice [C57BL/6NCrl] supplied by CharlesRiver [Sulzfeld, Germany] were fed with a high fat diet [D12492, 60% kcal of fat, 5.24 kcal/g, ResearchDiets, New Brunswick, USA] starting at the age of 9 weeks. Animals received chow and water ad libitum. They were kept under controlled conditions [220C, 12h light / 12h dark cycle].
Experimental Protocol
Animals received the high fat diet for 7 weeks before treatment start. Thereafter, animals were treated with Compound A [3, 10 or 30mg/kg orally, suspended in methocel (hypromellose, 4% aequous solution)] or vehicle for 6 weeks once daily orally.
After the treatment period animals were sacrificed after an overnight fast. Liver was removed, fixed with 8% neutral buffered formaldehyde, embedded in paraffin wax, cut at 4 μm thickness and stained with hematoxylin and eosin. A semiquantitative analysis was performed according to the following scheme: 1 = no change [compared to healthy tissue], 2 = minimum changes [<5% of tis- sue affected], 3 = mild changes [5 - 15% of tissue affected], 4 = moderate changes [15 - 25% of tissue affected], 5 = severe changes [>25% of tissue affected].
Results Animals treated with Compound A showed a dose-dependent decrease in liver lipidosis compared to vehicle-treated controls [Fig. 1].
Conclusion
Treatment with Compound A results in an improvement in liver lipidosis.
Description of the figures
Figure 1 : Severity index of liver lipidosis after treatment with different concentrations of Compound A, Rosiglitazone maleate, Rimonabant hydrochloride and controls.
Mean ± SEM.
Figure 2: Effect Compound A on liver lipidosis in male C57BL/6-mice with diet-induced obesity (**p<0.01 , One-Way ANOVA with Dunnet's correction).
Claims
1. Use of (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a,10b- hexahydrophenanthridin-2-ol or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment of non-alcoholic fatty liver disease (NAFLD).
2. Use according to claim 1 , wherein non-alcoholic fatty liver disease (NAFLD) stands for the benign, non-progressive form of the non-alcoholic fatty liver (NAFL).
3. Use according to claim 1 , wherein non-alcoholic fatty liver disease (NAFLD) stands for nonalcoholic steatohepatitis (NASH).
4. Use according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a,10b-hexahy- drophenanthridin-2-ol is (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy- 1 ,2,3,4,4a,10b-hexahydrophenanthridin-2-ol hydrochloride.
5. Pharmaceutical composition comprising (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9- ethoxy-8-methoxy-1 ,2,3,4,4a,10b-hexahydrophenanthridin-2-ol or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of non-alcoholic fatty liver disease (NAFLD).
6. Pharmaceutical composition according to claim 5, wherein non-alcoholic fatty liver disease (NAFLD) stands for the benign, non-progressive form of the non-alcoholic fatty liver (NAFL).
7. Pharmaceutical composition according to claim 5, wherein wherein non-alcoholic fatty liver disease (NAFLD) stands for non-alcoholic steatohepatitis (NASH).
8. Pharmaceutical composition according to any one of claims 5 to 7, wherein the pharmaceutically acceptable salt of (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8- methoxy-1 , 2,3,4,4a, 10b-hexahydrophenanthridin-2-ol is (2R,4aR,10bR)-6-(2,6-Dimethoxy- pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a,10b-hexahydrophenanthridin-2-ol hydrochloride.
9. A method for the treatment and/or prophylaxis of non-alcoholic fatty liver disease (NAFLD) in a patient, comprising administering a therapeutically effective amount of (2R,4aR,10bR)-6- (2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a,10b-hexahydrophenanthridin-2- ol or a pharmaceutically acceptable salt thereof.
10. The method according to claim 9, wherein non-alcoholic fatty liver disease (NAFLD) stands for the benign, non-progressive form of the non-alcoholic fatty liver (NAFL).
11. The method according to claim 9, wherein non-alcoholic fatty liver disease (NAFLD) stands for non-alcoholic steatohepatitis (NASH).
12. The method according to any one of claims 9 to 11 , wherein the pharmaceutically acceptable salt of (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 , 2,3,4,4a, 10b- hexahydrophenanthridin-2-ol is (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8- methoxy-1 ,2,3,4,4a,10b-hexahydrophenanthridin-2-ol hydrochloride.
13. (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a,10b- hexahydrophenanthridin-2-ol or a pharmaceutically acceptable salt thereof for use in the treatment and/or prophylaxis of non-alcoholic fatty liver disease (NAFLD), in particular for the treatment and/or prophylaxis of the benign, non-progressive form of non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).
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JP2013119550A (en) * | 2011-12-08 | 2013-06-17 | Medicinova Inc | Method for treating nonalcoholic fatty liver disease and nonalcoholic steatohepatitis |
EP2604607A1 (en) * | 2010-08-12 | 2013-06-19 | Kyorin Pharmaceutical Co., Ltd. | Prophylactic or therapeutic agent for non-alcoholic steatohepatitis |
JP2017518967A (en) * | 2014-05-08 | 2017-07-13 | メディシノバ・インコーポレイテッドMediciNova, Inc. | Method for treating advanced non-alcoholic steatohepatitis |
WO2018037109A1 (en) * | 2016-08-26 | 2018-03-01 | Takeda Gmbh | Treatment of nonalcoholic fatty liver disease |
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