Use of (4-hydroxy-2-methyl-1,1-dioxido-2h-benzo[e][1,2]thiazine-3-yl)(naphthalene-2-yl) methanone in the prevention and/or treatment of non-alcoholic steatohepatitis

A technique for fatty liver, methyl, applied in the field of ketone or its pharmaceutically acceptable salt, which can solve the problem of impossible to predict tissue distribution, etc.

Inactive Publication Date: 2018-01-02
PIERRE FABRE MEDICAMENT SAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, an increase in insulin sensitivity was clearly shown with other compounds (Rosenstock et al., Diabetes Care 33, 1516–1522, 2010), emphasizing major differences in activity profiles within the same treatment type, thus making it impossible to predict Tissue distribution of one compound or another

Method used

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  • Use of (4-hydroxy-2-methyl-1,1-dioxido-2h-benzo[e][1,2]thiazine-3-yl)(naphthalene-2-yl) methanone in the prevention and/or treatment of non-alcoholic steatohepatitis
  • Use of (4-hydroxy-2-methyl-1,1-dioxido-2h-benzo[e][1,2]thiazine-3-yl)(naphthalene-2-yl) methanone in the prevention and/or treatment of non-alcoholic steatohepatitis
  • Use of (4-hydroxy-2-methyl-1,1-dioxido-2h-benzo[e][1,2]thiazine-3-yl)(naphthalene-2-yl) methanone in the prevention and/or treatment of non-alcoholic steatohepatitis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: Human type 1 11β-hydroxysteroid dehydrogenase (11β-HSD 1) Inhibition; primary human distribution in culture In Vitro Tests on Humanized Adipocytes

[0044] Inhibition of human 11β-HSD 1 enzyme was evaluated on primary human adipocytes in culture (ZenBio).

[0045] plan:

[0046] Preadipocytes were thawed and their viability was confirmed. Then, put the preadipocytes in the specific preadipocyte medium (PM-1) provided by ZenBio in 96-well microplate; place the plate at 37°C and 5% CO 2 Incubation. One or more days after cell fusion, PM-1 was replaced with a more specific differentiation medium (DM), also provided by ZenBio, containing isobutylmethylxanthine, insulin, dexamethasone, and a PPAR agonist. After a minimum of 7 days, the cells will differentiate into adipocytes. Then, mature adipocytes were maintained in adipocyte maintenance medium (AM) for 4 to 6 days. Cells were then placed in steroid-deficient conditions for 48 h in the presence of ...

Embodiment 2

[0053] Example 2: Single oral administration of different type 1 11β-HS in C57BL / 6N mice D. Inhibitor compounds post blood Evaluation of pulp bioactivity (bioavailability / strength / efficacy)

[0054] plan

[0055] Evaluations were performed in non-fasted male C57BL / 6N strain mice aged 4 to 6 weeks. Compounds to be tested or vehicle (0.5% methylcellulose in water, 10 ml / kg) were administered orally; n=3 mice per treatment.

[0056] Blood samples were collected 1 h and 4 h after administration; tubes were centrifuged to obtain plasma and frozen at -70°C until bioanalysis. Plasma bioactivity (2% final volume) was analyzed at each dose tested by using inhibition of human type 1 11[beta]-HSD as the detection system for each compound (SPA technology). The percent inhibition (compared to vehicle-treated mice) was calculated for each dose.

[0057] Compounds tested:

[0058] Compound 1: (4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalene-2-yl)methanone;

...

Embodiment 3

[0070] Example 3: Single oral administration of different type 1 11β-HS in C57BL / 6N mice D. Inhibitor Compound Whitening Evaluation of bioactivity of adipose tissue (distribution / intensity / efficacy)

[0071] plan

[0072] Four hours after administration, mice were euthanized and inguinal white adipose tissue was removed and frozen at -70°C until the day of bioanalysis. White adipose tissue was homogenized in liquid nitrogen and then treated with acetonitrile (1 ml distilled water corresponds to 4 ml acetonitrile and 200 mg inguinal white adipose tissue) to extract soluble material. The acetonitrile fractions were collected, then dried, and the residue was dissolved in 1 ml DMSO (corresponding to 300 mg white adipose tissue). Inguinal white adipose tissue (equivalent to 150 μg tissue per well, 1% DMSO) was analyzed for bioactivity by using inhibition of human type 1 11β-HSD as a detection system (SPA technology) for each compound and each dose tested.

[0073] Compounds...

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PUM

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Abstract

The present invention relates to (4-hydroxy-2-methyl-1,1-dioxido-2H-benzo [e][1,2]thiazine-3-yl)(naphthalen-2-yl)methanone or one of the salts thereof, pharmaceutically acceptable for use in the prevention and / or treatment of hepatic steatosis, including non-alcoholic steatohepatitis or one of the complications of same.

Description

technical field [0001] The present invention relates to (4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalene-2-yl)methanone or its A pharmaceutically acceptable salt for use in the prevention and / or treatment of fatty liver (hepatic steatosis), including nonalcoholic steatohepatitis or its complications. Background technique [0002] (4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl represented by the formula )(naphthalene-2-yl)methanone: [0003] [0004] and pharmaceutically acceptable salts thereof, and their use in type 2 diabetes, obesity, dyslipidemia, arterial hypertension, atherosclerosis and the resulting clinical pathology such as coronary events, cerebrovascular accidents or lower extremity arteritis , hyperglycemia, glucose intolerance, insulin resistance, hypertriglyceridemia, hypercholesterolemia, restenosis, pancreatitis, retinopathy, nephropathy, neuropathy, certain types of cancer, and glaucoma, both therapeutically and proph...

Claims

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Application Information

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IPC IPC(8): A61K31/5415A61P1/16
CPCA61K31/5415A61P1/00A61P1/16A61P3/06A61P43/00A61K45/06
Inventor M·拉莫特D·洪克罗B·勒格朗
Owner PIERRE FABRE MEDICAMENT SAS
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