WO2017181317A1 - Traitement de la stéatohépatite non alcoolique et de la fibrose - Google Patents

Traitement de la stéatohépatite non alcoolique et de la fibrose Download PDF

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Publication number
WO2017181317A1
WO2017181317A1 PCT/CN2016/079541 CN2016079541W WO2017181317A1 WO 2017181317 A1 WO2017181317 A1 WO 2017181317A1 CN 2016079541 W CN2016079541 W CN 2016079541W WO 2017181317 A1 WO2017181317 A1 WO 2017181317A1
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WIPO (PCT)
Prior art keywords
methyl
piperazin
pyran
tetrahydro
chloro
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PCT/CN2016/079541
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English (en)
Inventor
Zhiming Ding
Bei Betty ZHANG
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Eli Lilly And Company
Lilly China Research And Development Co., Ltd.
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Priority to PCT/CN2016/079541 priority Critical patent/WO2017181317A1/fr
Priority to PCT/US2017/027306 priority patent/WO2017184412A1/fr
Publication of WO2017181317A1 publication Critical patent/WO2017181317A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • Nonalcoholic steatohepatitis is a liver disease with an etiological constellation characterized by macrovesicular hepatic steatosis, inflammation hepatocyte ballooning and fibrosis.
  • Nonalcoholic steatohepatitis occurs in people who drink little or no alcohol and is often comorbid with obesity, type II diabetes, elevated levels of cholesterol, and triglycerides.
  • Nonalcoholic steatohepatitis may lead to cirrhosis and liver failure. It has been established that patients with nonalcoholic steatohepatitis are more likely to develop cirrhosis, and have a higher risk of cardiovascular mortality, and hepatocyte carcinoma. This non-alcoholic, non-viral cirrhosis is, in fact, among the top causes of liver transplantation.
  • Nonalcoholic steatohepatitis is a progressive disease characterized by the development of liver fibrosis.
  • the stage of disease can be defined, for example, by the nonalcoholic steatohepatitis CRN (Clinical Research Network) fibrosis staging which measures the amount and pattern of nonalcoholic steatohepatitis fibrosis, as well as parenchymal architectural remodeling in a patient.
  • Nonalcoholic steatohepatitis is typically diagnosed in a human patient using liver biopsy.
  • the present invention provides a pharmaceutical treatment for nonalcoholic steatohepatitis comprising administering an effective amount of the compound, 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine to a patient.
  • the compound, 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine is disclosed in WO 2010/080306 as Example 189.
  • Compounds of WO 2010/080306 are stated to be agonists of the cannabinoid receptor 2 (CB2 receptor) in vitro and useful for treatment or prevention of pain.
  • the present invention provides a method for treating nonalcoholic steatohepatitis, comprising administering an effective amount of 8- (2-Chloro-phenyl) -2-methyl-6- (4- methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or a pharmaceutically acceptable salt thereof, to a patient.
  • the present invention provides a method for treating nonalcoholic steatohepatitis and fibrosis, comprising administering an effective amount of 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or a pharmaceutically acceptable salt thereof, to a patient.
  • the present invention provides a method for treating nonalcoholic steatohepatitis, comprising administering an effective amount of 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine to a patient.
  • the present invention provides the compound 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or pharmaceutically acceptable salt thereof, for use in treating nonalcoholic steatohepatitis in a patient.
  • the present invention provides the compound 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or pharmaceutically acceptable salt thereof, for use in treating nonalcoholic steatohepatitis and fibrosis in a patient.
  • the present invention provides the compound 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, for use in treating nonalcoholic steatohepatitis in a patient.
  • the present invention provides the compound 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or pharmaceutically acceptable salt thereof, for use in treating hepatic fibrosis in a mammal.
  • the present invention provides a pharmaceutical composition for use in the treatment of nonalcoholic steatohepatitis comprising 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the present invention provides a pharmaceutical composition for use in the treatment of nonalcoholic steatohepatitis and fibrosis comprising 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the present invention provides the use of 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of nonalcoholic steatohepatitis.
  • the present invention provides the use of 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of nonalcoholic steatohepatitis and fibrosis.
  • the present invention provides the use of 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hepatic fibrosis.
  • the present invention provides a method for treating hepatic fibrosis, comprising administering an effective amount of 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or a pharmaceutically acceptable salt thereof, to a mammal.
  • Figure 1 illustrates the liver excision used in the pathological analysis for the 3H-Z mouse model for nonalcoholic steatohepatitis and fibrosis.
  • the compound, 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, has the following structural formula:
  • treating refers to restraining, slowing, or stopping the progression or alleviating the severity of the stated condition to be treated.
  • the term “effective amount” refers to the amount or dose of 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, or a pharmaceutically acceptable salt thereof which upon single or multiple dose administration to the patient, provides the desired effect in the patient. It will be understood that the amount of active agent actually administered will be determined by a physician, in light of the relevant circumstances.
  • patient refers to a mammal in need of treatment for nonalcoholic steatohepatitis .
  • the patient is a mammal.
  • mammal is a human. In a preferred embodiment the mammal is a human in need of treatment for nonalcoholic steatohepatitis and fibrosis .
  • mice Male C57BL/6N mice are fed with D09100301 diet (Research Diets, 40%fat, 2%cholesterol, 24%fructose, 3H diet) for 150 days. Each mouse is then singly housed after 5 days of acclimation period. Plasma alanine aminotransferase (ALT) and CK18 are measured. After one week of acclimation, the mice are randomized into groupsby their ALT, CK18 and body weight.
  • D09100301 diet Research Diets, 40%fat, 2%cholesterol, 24%fructose, 3H diet
  • Inflammation Number of inflammatory foci per 10 fields on 20x magnification. Most often neutrophils but macrophages, lymphocytes, and eosinophils may also be present. Lipogranulomas reported as ‘present’ with no grade given.
  • Steatosis (macrovesicular vacuolation /steatosis) : Large, discrete vacuoles that can be somewhat variable in size and distort hepatocytes. Zonal distribution or pattern is noted if a predominating pattern is present. Microvesicular vacuolation /steatosis is also graded similarly, but is not included in the overall sum NASH score.
  • Ballooning Degeneration Hepatocytes that have lost normal integrity and should have lost cellular or nuclear detail. May have clearing within cytoplasm (but is not a vacuole) or even be apoptosis /single cell necrosis. Disarray or disorganized hepatic cords may be observed as a result of this ‘drop out’ of cells.
  • Fibrosis Accounting for zone location (specifically zone 3/perisinusoidal) , and patterns of fibrosis, increase of connective tissue deposition, and architectural remodeling (progression) .
  • Pathological evaluation is useful to support that 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, can be useful for treating nonalcoholic steatohepatitis.
  • Obeticholic acid (OCA) is used as a positive control for this nonalcoholic steatohepatitis and fibrosis development model in high fat diet fed LDLr-/-Leiden Mice.
  • OCA is a semi-synthetic bile acid analogue currently in clinical trials for use in the treatment of nonalcoholic steatohepatitis and used in these studies as a control.
  • OCA has the chemical name 6 ⁇ -ethyl-chenodeoxycholic acid and is known to be a highly potent farnesoid X receptor (FXR) agonist.
  • the animals are then fed with high fed diet (HFD, control) , 10 mg/kg/day of obeticholic acid (OCA, positive control) mixed in HFD, or 30 mg/kg/day 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine, mixed in HFD.
  • HFD high fed diet
  • OCA obeticholic acid
  • mice are sacrificed (un-fasted) .
  • the liver is isolated and total liver weight is determined.
  • the medial lobe is isolated, fixed in formalin and embedded in paraffin for histological evaluation.
  • Formalin-fixed and paraffin-embedded cross-sections (3 ⁇ m) are stained with haematoxylin and eosin and are scored blindly by a board-certified pathologist using an adapted grading method for human nonalcoholic steatohepatitis (Liang et al, PLoS ONE 2014) . Briefly, two cross-sections/mouse are examined and the level of microvesicular and macrovesicular steatosis are determined relative to the liver area analyzed (expressed as a percentage) .
  • Hepatic inflammation is assessed by counting the number of inflammatory foci per field at a 100 ⁇ magnification (view size 3.1 mm2) in five non-overlapping fields per specimen, expressed as total number of foci.
  • Fibrosis is assessed histochemically by Picro-Sirius Red staining (Chroma, WALDECK-Gmbh, Weg, Germany) .
  • the development of fibrosis is assessed by a pathologist to gain insight into the distribution pattern of the collagen and to quantify the percentage of pericellular fibrosis specifically.
  • the total collagen content is determined by quantitative analysis of hydroxyproline in liver homogenate using a commercial colorimetric assay (QZBtotcol; Quickzyme Biosciences, Leiden, the Netherlands) .
  • Results from this method can be useful to support that 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine significantly reduces liver fibrosis and total collagen in the nonalcoholic steatohepatitis model at a 30 mg/kg /day food mixture dosing.
  • mice Female, 7-8 week old, BALB/c mice are acclimated for no less than 7 days. After the acclimation period, 15 untreated mice are allocated as sham or control group. Other mice are administered CCl 4 for a total period of 6 weeks to establish liver fibrosis. The CCl 4 is injected intraperitoneally (i.p. ) at 1 mL/kg (4 mL/kg of 25%CCl 4 in olive oil) , twice per week for a total period of 6 weeks except the sham control group.
  • vehicle 0.5%HEC (hydroxy ethyl cellulose) /0.25%tween80
  • Liver tissue is flushed with ice-cold PBS (phosphate buffered saline) , blotted briefly on paper towel, and weighed. Liver tissue is dissected into pieces and is fixed with 10%buffered neutral formalin for histopathology and immunohistochemistry (IHC) analysis, and then they are embedded in paraffin. Thin sections (4 ⁇ m) are deparaffinized and stains prepared using picro-Sirius red for 15 min at room temperature. Sections on the slides are dehydrated in 95%and 100%ethanol and in xylene, and are mounted with mounting medium. The liver fibrosis tissue and the total liver tissue are measured using Picrosirius Red stained sections.
  • PBS phosphate buffered saline
  • Histomorphometry are performed using an OsteoMeasure image analysis software program (OsteoMetrics, Inc., Atlanta, GA) interfaced with an Olympus light/epifluorescent microscope and video subsystem.
  • the histomorphometrist is blinded as to specimen identity when performing measurements.
  • Liver tissue is flushed with ice-cold PBS (phosphate buffered saline) , blotted briefly on paper towel, and weighed. Liver tissue is dissected into pieces and is fixed with 10%buffered neutral formalin for histopathology and immunohistochemistry (IHC) analysis, and then they are embedded in paraffin.
  • IHC immunohistochemistry
  • Thin sections (4 ⁇ m) are deparaffinized and stains prepared using picro-Sirius red for 15 min at room temperature. Sections on the slides are dehydrated in 95%and 100%ethanol and in xylene, and are mounted with mounting medium. The liver fibrosis tissue and the total liver tissue are measured using Picrosirius Red stained sections. Histomorphometry are performed using an OsteoMeasure image analysis software program (OsteoMetrics, Inc., Atlanta, GA) interfaced with an Olympus light/epifluorescent microscope and video subsystem. The histomorphometrist is blinded as to specimen identity when performing measurements.
  • Results from this method demonstrate 8- (2-Chloro-phenyl) -2-methyl-6- (4-methyl-piperazin-1-yl) -9- (tetrahydro-pyran-4-yl) -9H-purine %liver fibrosis reduction in the CCl 4 mouse model at a dose of 30 mg/kg.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne une méthode de traitement de la stéatohépatite non alcoolique comprenant l'administration à un patient d'une quantité efficace de 8-(2-chloro-phényl)-2-méthyl-6-(4-méthyl-pipérazin-1-yl)-9-(tétrahydro-pyran-4-yl)-9H-purine, ou d'un sel pharmaceutiquement acceptable de celle-ci.
PCT/CN2016/079541 2016-04-18 2016-04-18 Traitement de la stéatohépatite non alcoolique et de la fibrose WO2017181317A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2016/079541 WO2017181317A1 (fr) 2016-04-18 2016-04-18 Traitement de la stéatohépatite non alcoolique et de la fibrose
PCT/US2017/027306 WO2017184412A1 (fr) 2016-04-18 2017-04-13 Agoniste cannabinoïde de la purine pour traiter la stéatohépatite non alcoolique et la fibrose

Applications Claiming Priority (1)

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PCT/CN2016/079541 WO2017181317A1 (fr) 2016-04-18 2016-04-18 Traitement de la stéatohépatite non alcoolique et de la fibrose

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WO2017181317A1 true WO2017181317A1 (fr) 2017-10-26

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997046235A1 (fr) * 1996-06-06 1997-12-11 Eli Lilly And Company Composes antiviraux
WO2010080306A1 (fr) * 2008-12-18 2010-07-15 Eli Lilly And Company Composés purines
WO2011133611A1 (fr) * 2010-04-21 2011-10-27 Metabolic Solutions Development Company Analogues de thiazolidinedione
EP2604607A1 (fr) * 2010-08-12 2013-06-19 Kyorin Pharmaceutical Co., Ltd. Agent de prévention et de traitement d'une stéatohépatite d'origine non alcoolique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997046235A1 (fr) * 1996-06-06 1997-12-11 Eli Lilly And Company Composes antiviraux
WO2010080306A1 (fr) * 2008-12-18 2010-07-15 Eli Lilly And Company Composés purines
WO2011133611A1 (fr) * 2010-04-21 2011-10-27 Metabolic Solutions Development Company Analogues de thiazolidinedione
EP2604607A1 (fr) * 2010-08-12 2013-06-19 Kyorin Pharmaceutical Co., Ltd. Agent de prévention et de traitement d'une stéatohépatite d'origine non alcoolique

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