Monophosphates as mutual prodrugs of anti-inflammatory signal transduction modulators (AISTM's) and ss-agonists for the treatment of pulmonary inflammation and bronchoconstriction

A technology for signal transduction and regulators, which can be used in drug combinations, pharmaceutical formulations, organic active ingredients, etc., and can solve problems such as systemic exposure

Inactive Publication Date: 2010-02-24
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many existing drugs have been developed for oral delivery and therefore have good absorption properties which may lead to undesired systemic exposure via pulmonary absorption into the circulatory system.

Method used

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  • Monophosphates as mutual prodrugs of anti-inflammatory signal transduction modulators (AISTM's) and ss-agonists for the treatment of pulmonary inflammation and bronchoconstriction
  • Monophosphates as mutual prodrugs of anti-inflammatory signal transduction modulators (AISTM's) and ss-agonists for the treatment of pulmonary inflammation and bronchoconstriction
  • Monophosphates as mutual prodrugs of anti-inflammatory signal transduction modulators (AISTM's) and ss-agonists for the treatment of pulmonary inflammation and bronchoconstriction

Examples

Experimental program
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preparation example Construction

[0072] I. Preparation of compounds of the present invention

[0073] Compounds of the present invention can be prepared by the methods described in Reaction Schemes I-VI.

[0074] A comprehensive approach to compounds of formula A includes:

[0075] a) Synthesis of phosphorylated β-agonist derivatives activated towards alkylation (Schemes I-V); and

[0076] b) Quaternization (alkylation) of AISTM molecules carrying "quaternizable moieties" or their physiologically cleavable esters with activated β-agonist derivatives, followed by final deprotection (Scheme VI).

[0077] Reaction scheme I

[0078]

[0079] Reaction Scheme II

[0080]

[0081] Reaction Scheme III

[0082]

[0083] Reaction Scheme IV

[0084]

[0085] Reaction Scheme V

[0086]

[0087] Reaction Scheme VI

[0088]

[0089] The synthesis of phosphate-functionalized protected β-agonist derivatives is shown in Reaction Schemes I-V.

[0090] Commercially available racemic salmeterol xinafo...

Embodiment 1

[0114] Phosphorobromidic acid di-tert-butyl ester

[0115]

[0116] The title phosphorylating reagent was prepared according to conditions modified from those described by Gajda and Zwierzak (1976). By reducing the reaction temperature to 15°C and shortening the reaction time to 2.5 hours, we obtained the title compound with better purity than when using literature conditions (25°C, 4 hours). The title phosphobromidate was unstable and was therefore immediately used in the phosphorylation reaction (see Examples 4 and 10).

Embodiment 2

[0119] [2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethyl]-[6-(4-phenyl-butoxy)-hexyl-ammonia tert-butyl carbamate

[0120]

[0121] Suspend commercially available salmeterol xinafoate (6.04 g, 10 mmol) and potassium carbonate (1.39 g, 10 mmol) in a 1,4-dioxane / water mixture (1:1, 80 mL) with stirring )middle. Di-tert-butyl dicarbonate (2.40 g, 11 mmol) dissolved in 1,4-dioxane (10 mL) was then added dropwise at room temperature while stirring. TLC analysis after 30 minutes showed only a small amount of starting material. After 2 hours, 1,4-dioxane was evaporated off and the resulting suspension was diluted with water and extracted twice with chloroform (total 125 mL). Then, the organic layer was washed with saturated sodium bicarbonate, brine, and dried over anhydrous magnesium sulfate. The crude material obtained after decantation or evaporation was purified by chromatography on silica gel, eluting with an ethyl acetate / hexane mixture (1:1). The title compound ...

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Abstract

A mutual prodrug of an AISTM and a ss-agonist in formulation for delivery by aerosolization to inhibit pulmonary inflammation and bronchoconstriction is described. The mutual prodrug is preferably formulated in a small volume solution (10-500 [mu]L) dissolved in a quarter normal saline having pH between about 5.0 and 7.0 for the treatment of respiratory tract inflammation and bronchoconstriction by an aerosol having mass median average diameter predominantly between about 1 to 5 [mu], produced by nebulization or by dry powder inhaler.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 60 / 874,543, filed December 13, 2006. field of invention [0003] The present invention relates to the preparation of novel mutual prodrugs of anti-inflammatory signaling modulators (AISTM's) and beta-agonists for delivery to the lung by nebulization. In particular, the present invention relates to the synthesis, formulation and delivery of monophosphate esters as mutual prodrugs of AISTM-β-agonists which, when delivered to the lung, are degraded by endogenous enzymes present in the lung tissue and airways and released in AISTM and beta-agonists (eg salmeterol, albuterol) are released at the site of administration. The reciprocal prodrugs are formulated as liquids or dry powders and form formulations and are suitable for delivering the prodrugs to the pulmonary bronchial site of the respiratory tract as an aerosol having a mass median mean diameter of pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/12C07F9/58C07F9/6503C07F9/6558A61K31/661A61K31/665A61K31/675A61P11/06
CPCC07F9/12C07F9/581C07F9/65586C07F9/65038C07F9/65583A61P11/00A61P11/06A61P11/08A61P43/00C07F9/58
Inventor W·R·巴克M·斯塔西亚克S·斯瓦米纳坦金武成
Owner GILEAD SCI INC
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