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Pharmaceutical composition comprising a 4-hydroxy-2-oxo-2, 3- dihydro-1, 3-benzothiazol-7-yl compound for modulation of beta2-adrenoreceptor activity

A technology of cycloheptane carbonyloxy and hydroxyl, which is applied in the field of intermediates for the preparation of the pharmaceutical active substance and its salt, and can solve problems such as unsatisfactory efficacy

Inactive Publication Date: 2011-07-20
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although corticosteroid therapy can yield important benefits, the efficacy of these agents is often far from satisfactory, especially in the treatment of COPD

Method used

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  • Pharmaceutical composition comprising a 4-hydroxy-2-oxo-2, 3- dihydro-1, 3-benzothiazol-7-yl compound for modulation of beta2-adrenoreceptor activity
  • Pharmaceutical composition comprising a 4-hydroxy-2-oxo-2, 3- dihydro-1, 3-benzothiazol-7-yl compound for modulation of beta2-adrenoreceptor activity
  • Pharmaceutical composition comprising a 4-hydroxy-2-oxo-2, 3- dihydro-1, 3-benzothiazol-7-yl compound for modulation of beta2-adrenoreceptor activity

Examples

Experimental program
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Effect test

preparation example Construction

[0509] Samples of material obtained by preparation 16 as described above in this application were analyzed by XRPD (PANalytical X'Pert or Cubix system), GVS and DSC. Melting point by DSC was 189°C (onset) (±2°C), GVS determined at 0.1% weight gain (%w / w) at 80% relative humidity (±0.2%).

[0510] (R)-1-(4-fluorophenethyl)-3-((S)-2-phenyl-2-(piperidin-1-yl)propionyloxy)-1- prepared according to Preparation 16 The XRPD spectrum of azonia bicyclo[2.2.2]octane 4-methylbenzenesulfonate is shown in FIG. 28 .

[0511] Figure 28

[0512]

[0513] cAMP production mediated by adrenergic β2

[0514] cell preparation

[0515] at 225cm 2 Flask incubator (37°C and 5% CO 2 ) in RPMI medium (containing 10% (v / v) FBS (fetal bovine serum) and 2 mM L-glutamine).

[0516] experimental method

[0517] Attached H292 cells were removed from tissue culture flasks as follows: with Accutase TM Cell detachment solution was treated for 15 minutes. Place the flask in a humidified incub...

Embodiment 1

[0543] Evaluation of compound activity on intraalveolar neutrophil migration following aerosol challenge with lipopolysaccharide (LPS) in CRL:CD rats

[0544] LPS challenge in CRL:CD rats brought inflammatory cells into the lungs. Rats were challenged with 0.9% w / v saline aerosol for 30 minutes or with 0.1 mg / ml [LPS] / [0.9% saline] aerosol challenge for 30 minutes or intratracheal administration of 0.1-10 μg / kg. This was repeated up to 8 times according to the experimental protocol. Based on the experimental protocol, rats are dosed with vehicle, standard compound or test compound by appropriate route and frequency at different time points pre-challenge and post-challenge. Panels of test compounds can be different doses of the same compound or single doses of different compounds or a combination of both. Test compounds are administered by intraperitoneal, intravenous or subcutaneous injection or by inhalation or intratracheal administration.

[0545] Depending on the nature...

Embodiment 2

[0548] Evaluation of compound activity on intraalveolar neutrophil migration following aerosol challenge with lipopolysaccharide (LPS) in guinea pigs

[0549] Male Dunkin-Hartley guinea pigs (300-600 g) were placed in open-fronted guinea pig holding cones connected randomly around a cylindrical aerosol chamber. Each group of guinea pigs was maintained in a challenge cone and exposed to either a vehicle aerosol or a 0.1-30 [mu]g / ml [LPS] / [0.9% saline] aerosol. Aerosols were generated using 2 jet nebulizers per column with a flow rate of 12 L / min. 10ml of elicitor was placed in each nebulizer. Alternatively, 0.1-10 [mu]g / kg is administered intratracheally to the animal. This was repeated up to 8 times according to the experimental protocol.

[0550] Based on the experimental protocol, guinea pigs are dosed with vehicle, standard compound or test compound at the appropriate route and frequency at different time points before and after challenge. Panels of test compounds can b...

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Abstract

The invention provides a pharmaceutical product, kit or composition comprising a first active ingredient which is N-Cyclohexyl-N3-(2-(3-fluorophenyl)ethyl)-N-(2-[(2-(4- hydroxy-2-oxo-2,3-dihydro- 1,3-benzothiazol-7-yl)ethyl)amino] ethyl)-beta-alaninamide or a salt thereof, and a second active ingredient selected from: a non-steroidal Glucocorticoid Receptor (GR Receptor) Agonist; an antioxidant; a CCRl antagonist; a chemokine antagonist (not CCRl); a corticosteroid; a CRTh2 antagonist; a DPI antagonist; an Histone Deacetylase Inducer; an IKK2 inhibitor; a COX inhibitor; a lipoxygenase inhibitor; a leukotriene receptor antagonist; an MPO inhibitor; a muscarinic antagonist; a p38 inhibitor; a PDE inhibitor; a PPAR<gamma> 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 (for example chronic obstructive pulmonary disease (COPD) or asthma); to certain salts of N-Cyclohexyl-N3-(2-(3-fluorophenyl)ethyl)- N-(2-[(2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7-yl)ethyl)amino]ethyl)-beta- alaninamide and to an intermediate useful in the manufacture of this pharmaceutically active substance and salts thereof.

Description

technical field [0001] The present invention relates to combinations of two or more pharmaceutically active substances, N-cyclohexyl-N 3 -[2-(3-fluorophenyl)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazole-7 Some salts of -yl)ethyl]amino}ethyl)-β-aminopropanamide and intermediates that can be used to prepare the pharmaceutically active substance and its salts. Background technique [0002] The primary function of the lung requires extensive exposure of a fragile structure to an environment including pollutants, microorganisms, allergens, and carcinogens. Host factors stemming from the interaction of lifestyle choices and genetic makeup influence responses to the above exposures. Lung injury or infection can lead to many respiratory diseases. Many of these diseases are of great public health importance. Respiratory diseases include acute lung injury, acute respiratory distress syndrome (ARDS), occupational lung disease, lung cancer, tuberculosis, fibrosis, p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/428A61P11/06A61P11/08
CPCA61K45/06A61K31/428A61P11/00A61P11/02A61P11/06A61P11/08A61P11/16A61P43/00A61K2300/00
Inventor 斯蒂芬.康诺利阿德里安.费希尔亚历山大.汉弗莱斯安德鲁.J.沃茨凯瑟琳.E.威利
Owner ASTRAZENECA AB
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