Combinations of beta- 2 -adrenoceptor agonistic benzothiazolone

A receptor antagonist and receptor technology, applied in the field of combination of beta-2 adrenergic receptor antagonistic benzothiazolones, can solve the problems of unsatisfactory efficacy and the like

Inactive Publication Date: 2010-02-17
ASTRAZENECA AB
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although glucocorticoid therapy can yield important benefits, the efficacy of ...

Method used

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  • Combinations of beta- 2 -adrenoceptor agonistic benzothiazolone
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0241] For the effect of compounds on lung after intratracheal challenge with lipopolysaccharide (LPS) in CRL:CD rats Evaluation of activity of neutrophil migration in vesicles

[0242] LPS challenge in CRL:CD rats induces neutrophil influx into the lungs. Under recoverable gas (5% isoflurane / oxygen) anesthesia, rats were administered vehicle (0.05M phosphate, 0.1% Tween 80, 0.6% saline, pH 6) or compound via the intratracheal route , challenged 30 minutes later with LPS at an intratracheal dose of 10 μg / kg.

[0243] Rats (250-400 g) were euthanized with 1 mL sodium pentobarbital 4 hours after LPS challenge. A tracheostomy was performed and intubated. The airways were then lavaged with 3 mL of Isoton at room temperature. Isoton (Beckman Coulter, High Wycombe, UK) was left in the airway for 10 seconds and then removed. Bronchiolo-alveolar lavage (BAL) fluid containing inflammatory cells was placed in a 15 mL centrifuge tube and kept on ice. This operation was repeated ...

Embodiment 2

[0251] For compounding after aerosol challenge with lipopolysaccharide (LPS) in guinea pigs Evaluation of the Activity of Drugs on the Migration of Intraalveolar Neutrophils

[0252] Male Dunkin-Hartley guinea pigs (300-600 g) were placed in an open-fronted guinea pig holding cone attached randomly around the perimeter of a cylindrical aerosol chamber. Each group of guinea pigs was maintained in a challenge cone and exposed to vehicle spray or LPS at a concentration of 0.1-30 [mu]g / ml in 0.9% saline. Two sprayers per column were used to generate the spray with a flow rate of 12 L / m. 10ml of challenger was placed in each nebulizer. Alternatively animals receive an intratracheal dose of 0.1-10 [mu]g / kg. This was repeated up to 8 times according to the experimental protocol.

[0253] Depending on the experimental protocol, guinea pigs are dosed with vehicle, standard compound or test compound at the appropriate route and frequency at various time points before and after ch...

Embodiment 3

[0255] Effects of compounds on alveolar neutrophils after aerosol challenge with lipopolysaccharide (LPS) in mice Evaluation of Cell Migration Activity

[0256] Male C57BL / 6 / J or BALB / C mice (20-35 g) were housed in groups of up to 20 in Perspex exposure boxes and exposed to 0.3 mg / ml LPS spray or 0.9% w / v In saline spray. LPS (Sigma, E. coli, reference L-3755, serotype 026:B6, lot 111k4078) was made in 0.9% w / v saline. Nebulization was generated using two nebulizers operating at a flow rate of 12 L / min (6 L / min for each nebulizer) for 15 minutes. Alternatively animals receive an intratracheal dose of 0.1-10 [mu]g / kg. This was repeated up to 8 times according to the experimental protocol.

[0257] Depending on the experimental protocol, mice are dosed with vehicle, standard compound or test compound by appropriate route and frequency at various time points before and after challenge. The test compound panel can be different doses of the same compound or a single dose o...

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Abstract

The invention provides a pharmaceutical product comprising a first active ingredient which is N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-naphthyl)ethoxy]propan amide or a salt thereof, and a second active ingredient selected from: a non-steroidal Glucocorticoid Receptor (GR Receptor) Agonist; an antioxidant; a CCR1 antagonist; achemokine antagonist (not CCR1); a corticosteroid; a CRTh2 antagonist; a DP1 antagonist; an Histone Deacetylase Inducer; an IKK2 inhibitor; a COX inhibitor; a lipoxygenase inhibitor; a leukotriene receptor antagonist; an MPO inhibitor; a muscarinic antagonist which is Aclidinium bromide, Glycopyrrolate, Oxitropium bromide, Pirenzepine, telenzepine, Tiotropium bromide,3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide,3(R)-1-phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane bromide or (3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]actane bromide; a p38 inhibitor; a PDE inhibitor; a PPARy agonist; a protease inhibitor; a Statin; a thromboxane antagonist; a vasodilator; or, an ENAC blocker (Epithelial Sodium-channel blocker); and its use in the treatment of respiratory disease.

Description

technical field [0001] The present invention relates to combinations of two or more pharmaceutically active substances for use in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma. Background technique [0002] The essential function of the lung requires a delicate structure to be exposed extensively to the environment including pollutants, microorganisms, allergens and carcinogens. Host factors arising from the interplay of lifestyle choices and genetic makeup influence the response to this exposure. Injury or infection to the lungs can produce a wide range of respiratory diseases (or respiratory diseases). Many of these diseases are of enormous public health importance. Respiratory diseases include acute lung injury, acute respiratory distress syndrome (ARDS), occupational lung disease, lung cancer, tuberculosis, fibrosis, pneumoconiosis, pneumonia, emphysema, chronic obstructive pulmonary disease (COPD), and asthma . ...

Claims

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Application Information

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IPC IPC(8): A61K31/428
CPCA61K45/06A61K31/428A61P11/00A61P11/02A61P11/06A61P11/08A61P43/00A61K2300/00A61K31/573
Inventor 伊莱恩·B·卡多根斯蒂芬·康诺利戴维·J·尼科尔斯凯瑟琳·E·威利艾伦·扬
Owner ASTRAZENECA AB
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