WO2017184412A1 - Agoniste cannabinoïde de la purine pour traiter la stéatohépatite non alcoolique et la fibrose - Google Patents
Agoniste cannabinoïde de la purine pour traiter la stéatohépatite non alcoolique et la fibrose Download PDFInfo
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- WO2017184412A1 WO2017184412A1 PCT/US2017/027306 US2017027306W WO2017184412A1 WO 2017184412 A1 WO2017184412 A1 WO 2017184412A1 US 2017027306 W US2017027306 W US 2017027306W WO 2017184412 A1 WO2017184412 A1 WO 2017184412A1
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- Prior art keywords
- methyl
- purine
- piperazin
- pyran
- tetrahydro
- Prior art date
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Classifications
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
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.
- 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
- liver biopsy 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-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine to a patient.
- 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.
- CB2 receptor cannabinoid receptor 2
- 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-l-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-l-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-l-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-l-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-l-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-l-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-l-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-l-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-l-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-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or a pharmaceutically acceptable salt thereof, to a mammal.
- the compound, 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin- l-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-l-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 In a preferred embodiment, 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.
- 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4- yl)-9H-purine is preferably formulated as a pharmaceutical composition administered by any route which makes the compound bioavailable. Most preferably, such composition is for oral administration.
- Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (D.B. Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006).
- 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 (cytokeratin 18) are measured. After one week of acclimation, the mice are randomized into groups by their ALT, CK18 and body weight.
- D09100301 diet Research Diets, 40% fat, 2% cholesterol, 24% fructose, 3H diet
- CK18 cytokeratin 18
- Animals of each group are administrated either vehicle (0.5% methylcellulose (MC) + 0.25% Tween 80 in distilled water) or the compound of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine (at a 1, 3, 10, and 30 mg/kg dose) once daily in a volume of 5 ml/kg for 11 weeks.
- vehicle 0.5% methylcellulose (MC) + 0.25% Tween 80 in distilled water
- 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine at a 1, 3, 10, and 30 mg/kg dose
- mice treated with the compound of 8-(2-Chloro-phenyl)- 2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine for 76 days 2 hours after the last dose.
- Compound levels in the plasma are analyzed by mass spectroscopy. The results are listed below in Table 1. Treated mice exhibit a dose- dependent increase in plasma compound levels.
- the animals are sacrificed and their livers excised. Two sections of the left and right lobes are fixed in neutral buffered 10% formalin. Liver tissue slides are stained with hematoxylin and eosin (H&E), Sirius red, and Masson's Trichrome to prepare slides for pathological analysis. All specimens are examined microscopically and scored as a modified Brunt score system. Scores are based on the grading scheme and end-points as described in Brunt E. M, et al. , "Histopathology of nonalcoholic fatty liver disease," World J. of Gastroenterol, 2010, 16(42), 5286-5296. Group means are then calculated for each individual end-point.
- mice that received 8-(2- Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine exhibit a significant decrease in hepatic inflammation
- mice that received 3 mg/kg and higher doses of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine exhibit a significant decrease in macrovesicular vaculation and perisinusoidal fibrosis
- mice that received 10 and 30 mg/kg of 8-(2- Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine also exhibit a significant decrease in portal fibrosis.
- Plasma Levels of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine Dose Number of Plasma Compound (mg/kg) Animals Level (ng/ml)
- Nonparametric test is applied to compare scores between compound treatment groups and vehicle group. Scores for left and right laterals are compared separately.
- HFD high fat diet
- mice that received 30 mg/kg of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l- yl)-9-(tetrahydro-pyran-4-yl)-9H-purine exhibit a significant decrease in ALT and AST after 33 weeks of compound treatment.
- mice After 20 weeks of treatment, 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 ⁇ ) 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, "Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology," PLoS ONE, 9(12), 2014, 1- 17).
- fibrosis is assessed histochemically by Picro-Sirius Red staining (Chroma, WALDECK-Gmbh, Miinster, 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.
- mice treated with the compound of 8- (2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine is provided in Table 5.
- the results indicate that the mice that received 30 mg/kg of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine exhibit a significant decrease in hepatic inflammation, macrovesicular vacuolation and fibrosis.
- ANOVA test is applied to compare scores between compound treatment groups and vehicle group.
- IU refers to international units
- ANOVA test is applied to compare scores between compound treatment groups and vehicle group.
- the total collagen content is determined by quantitative analysis of
- results from this method can be useful to support that 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-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.
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- Medicinal Chemistry (AREA)
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Abstract
La présente invention concerne une méthode de traitement de la stéatohépatite non alcoolique comprenant l'administration d'une quantité efficace de 8-(2-chlorophényl)-2-méthyl-6-(4-méthylpipérazin-1-yl)-9-(tétrahydro-pyran-4-yl)-9H-purine, ou d'un sel pharmaceutiquement acceptable de celui-ci, à un patient.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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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 |
CNPCT/CN2016/079541 | 2016-04-18 | ||
PCT/CN2017/072622 WO2018137176A1 (fr) | 2017-01-25 | 2017-01-25 | Traitement de la fibrose et de la stéatohépatite non alcoolique |
CNPCT/CN2017/072622 | 2017-01-25 |
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WO2017184412A1 true WO2017184412A1 (fr) | 2017-10-26 |
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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 |
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WO (1) | WO2017184412A1 (fr) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1725223A2 (fr) * | 2004-03-09 | 2006-11-29 | Inserm | Utilisation d'antagonistes des récepteurs cb1 pour la fabrication d'un médicament destiné au traitement des maladies hépatiques |
WO2010080306A1 (fr) | 2008-12-18 | 2010-07-15 | Eli Lilly And Company | Composés purines |
WO2017039643A1 (fr) * | 2015-09-01 | 2017-03-09 | Arena Pharmaceuticals, Inc. | Internalisation de récepteur cb2 |
-
2017
- 2017-04-13 WO PCT/US2017/027306 patent/WO2017184412A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1725223A2 (fr) * | 2004-03-09 | 2006-11-29 | Inserm | Utilisation d'antagonistes des récepteurs cb1 pour la fabrication d'un médicament destiné au traitement des maladies hépatiques |
WO2010080306A1 (fr) | 2008-12-18 | 2010-07-15 | Eli Lilly And Company | Composés purines |
WO2017039643A1 (fr) * | 2015-09-01 | 2017-03-09 | Arena Pharmaceuticals, Inc. | Internalisation de récepteur cb2 |
Non-Patent Citations (6)
Title |
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BRUNT E. M ET AL.: "Histopathology of nonalcoholic fatty liver disease", WORLD J. OF GASTROENTEROL, vol. 16, no. 42, 2010, pages 5286 - 5296 |
BRUNT, E. M ET AL.: "Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions", AM J GASTROENTEROLOGY, vol. 94, no. 9, 1999, pages 2467 - 2474, XP055215446, DOI: doi:10.1111/j.1572-0241.1999.01377.x |
BRUNT, E. M.: "Histopathology of nonalcoholic fatty liver disease", CLIN LIVER DIS., vol. 13, 2009, pages 533 - 544 |
D.B. TROY: "Remington: The Science and Practice of Pharmacy, 21st ed", 2006, LIPPINCOTT, WILLIAMS & WILKINS |
LIANG ET AL.: "Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology", PLOS ONE, vol. 9, no. 12, 2014, pages 1 - 17 |
ROSSELLA GUIDETTI ET AL: "The SAR development of substituted purine derivatives as selective CB2 agonists for the treatment of chronic pain", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 24, no. 24, 1 December 2014 (2014-12-01), AMSTERDAM, NL, pages 5572 - 5575, XP055379448, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2014.11.006 * |
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