Drugs comprising combination of triazaspiro [5.5] undecane derivative with cytochrome p450 isozyme 3A4 inhibitor and/or P-glycoprotein inhibitor

A technology of triazaspiro and its derivatives, applied in the field of pharmaceuticals containing triazaspiro[5.5]undecane derivatives combined with cytochrome P450 isoenzyme 3A4 inhibitors and/or P-glycoprotein inhibitors , can solve problems such as no records, and achieve the effect of effective treatment methods

Inactive Publication Date: 2005-01-26
ONO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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Method used

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  • Drugs comprising combination of triazaspiro [5.5] undecane derivative with cytochrome p450 isozyme 3A4 inhibitor and/or P-glycoprotein inhibitor
  • Drugs comprising combination of triazaspiro [5.5] undecane derivative with cytochrome p450 isozyme 3A4 inhibitor and/or P-glycoprotein inhibitor
  • Drugs comprising combination of triazaspiro [5.5] undecane derivative with cytochrome p450 isozyme 3A4 inhibitor and/or P-glycoprotein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1754] Evaluation of Metabolized CYP Molecular Species Using Human Liver Microsomes and CYP Inhibitors:

[1755] Metabolic responses of test compounds were evaluated in pooled human liver microsomes (Zenotec) in the presence of inhibitors specific to each CYP molecular species, and the CYP molecular species involved in metabolism were evaluated according to the effect of each inhibitor.

[1756] The following inhibitors are used as specific inhibitors of CYP molecular species:

[1757] α-naphthalene brass (CYP1A2 inhibitor) 1 μmol / L (final concentration)

[1758] Sulfabenzopyrazole (CYP2C9 inhibitor) 1μmol / L (final concentration)

[1759] S-Mephenytoin (CYP2C19 inhibitor) 1 μmol / L (final concentration)

[1760] Quinidine (CYP2D6 inhibitor) 1 μmol / L (final concentration)

[1761] Ketoconazole (CYP3A4 inhibitor) 1μmol / L (final concentration)

[1762] Contain 100mmol / L phosphate buffer (pH7.4), 0.05mmol / L edetate disodium, 5mmol / L magnesium chloride, 1μmol / L test compound, 0....

Embodiment 2

[1769] Compound plasma concentrations in rats administered intravenously in the presence of CYP3A4 inhibitors:

[1770] method

[1771] Ketoconazole (50 mg / kg), an inhibitor of CYP3A4, was intraperitoneally administered to male SD rats. One hour thereafter, the test compound (3 mg / kg) was intravenously administered. At 2, 5, 15, 30, 60, 120, and 240 minutes after administration of the test compound, blood was collected from the jugular vein of the rat, and centrifuged at 3,000 rpm for 10 minutes to obtain plasma. To 150 μL of the resulting plasma was added 5 ng of 2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butylamino]-5-ethoxycarbonyl-4,6-di Methylpyrimidine trihydrochloride was used as an internal standard, from which protein was removed with ethanol, and the plasma concentration of the test compound was determined by high pressure liquid chromatography. From the obtained plasma concentrations of the test compounds, the area under the plasma concentration-time curve (AUC, μg·...

Embodiment 3

[1775] Determination of membrane permeability of P-gp expressing cells:

[1776] method

[1777] Human MDR1-expressing cells (LLC-GA-5-COL 150) and their parent cells (LLC-PK1) were cultured in 12-well transwell plates until confluent to prepare monolayer membranes. Compound 75(54) was treated with assay buffer (M 199, 26.2mM NaHCO 3 , 10% FBS, 0.03% L-glutamine; pH 7.4) adjusted to 10 μM. In the determination of membrane permeability from lumen to vessel, the drug solution is loaded into the lumen, whereas in the determination of membrane permeability from vessel to lumen, it is loaded into the blood vessel and incubated at 37°C, 5% CO 2 and incubated at 90% relative humidity. After a certain period of time, the sample solutions were collected, and in order to maintain the respective volumes, the assay buffer was supplemented to reach the collection volume range. Likewise, the membrane permeability of compound 75 (54) was also observed in the presence of cyclosporine A (...

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PUM

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Abstract

Drugs comprising a combination of triazaspiro[5,5]undecane derivatives represented by the following general formula I: I wherein each symbol is as will be defined hereinafter quaternary ammonium salts thereof, N-oxides of the same or nontoxic salts of the same with at least one cytochrome P450 isozyme 3A4 inhibitor and/or at least one P-glycoprotein inhibitor. The drugs comprising such a combination, wherein the bioavailability of the compounds represented by the general formula I is elevated, are efficaciously usable as oral preparations in treating various diseases.

Description

field of invention [0001] The present invention relates to [0002] (1) A pharmaceutical composition comprising a triazaspiro[5.5]undecane derivative of formula (I) as an active ingredient: [0003] [0004] (wherein all symbols have the same meaning as defined below), its quaternary ammonium salt, or its N-oxide, or its non-toxic salt and cytochrome P450 isozyme 3A4 inhibitor and / or P-glycoprotein inhibitor combinations of agents; and [0005] (2) For the prevention and / or treatment of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic diseases (allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis ), nephritis, kidney disease, hepatitis, arthritis, chronic joint rheumatism, psoriasis, rhinitis, conjunctivitis, ischemia-reperfusion injury, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, concomitant bacterial infection Agents for shock, diabetes, autoimmune diseases, transplant rejection, im...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/499A61K31/5377A61K45/00A61K45/06A61P43/00C07D471/10
CPCC07D471/10A61K31/499A61K45/06A61P1/04A61P1/16A61P11/00A61P11/06A61P11/10A61P11/14A61P13/12A61P15/10A61P17/00A61P17/06A61P19/02A61P19/06A61P23/00A61P25/18A61P25/22A61P25/24A61P25/28A61P27/02A61P27/16A61P29/00A61P3/10A61P31/04A61P31/08A61P31/10A61P31/18A61P35/00A61P3/06A61P35/04A61P37/06A61P37/08A61P43/00A61P5/38A61P9/04A61P9/06A61K2300/00
Inventor 今若治夫柴山史朗高冈义和
Owner ONO PHARMA CO LTD
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