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Substituted phenylphosphates as mutual prodrugs of steroids and beta-agonists for the treatment of pulmonary inflammation and bronchoconstriction

A phosphate ester, alkyl technology, applied in the field of new synergistic prodrugs, can solve the problem of not getting a completely satisfactory substitute for glucocorticoid therapy and the like

Inactive Publication Date: 2008-07-23
GILEAD SCI INC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, until today, there is no fully satisfactory alternative to glucocorticoid therapy

Method used

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  • Substituted phenylphosphates as mutual prodrugs of steroids and beta-agonists for the treatment of pulmonary inflammation and bronchoconstriction
  • Substituted phenylphosphates as mutual prodrugs of steroids and beta-agonists for the treatment of pulmonary inflammation and bronchoconstriction
  • Substituted phenylphosphates as mutual prodrugs of steroids and beta-agonists for the treatment of pulmonary inflammation and bronchoconstriction

Examples

Experimental program
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preparation example Construction

[0081] I. Preparation of Compounds of the Invention

[0082] Compounds of the invention can be prepared by the methods illustrated in Figures I-VII.

[0083] Concentrated routes to synergistic corticosteroid-β-agonist prodrugs include:

[0084] a) Synthesis of active phosphate-β-agonist derivatives (Figures I, II and III);

[0085] b) Preparation of steroid analogs (Figures IV and V);

[0086] c) Alkylation of steroid analogs with active β-agonist derivatives followed by final deprotection (Figures VI and VII).

[0087]

[0088] Figure II

[0089]

[0090] Figure III

[0091]

[0092] Figure IV

[0093]

[0094] Figure V

[0095]

[0096] Figure VI

[0097]

[0098] Figure VII

[0099]

[0100] For example, synergistic prodrug 17 (Example 133)

[0101] R 3 =(CH 2 ) 6 O(CH 2 ) 4 Ph

[0102] R 4 = F; R 5 = H;

[0103] Y-X(R 1 R 2 ) = 3-pyridinium

[0104] The synthesis of phosphate functionalized protected β-agonist derivatives is shown ...

Embodiment 1

[0127] Di-tert-butyl bromophosphate

[0128]

[0129] The title phosphorylation reagent was prepared following conditions modified from those described by Gajda and Zwierzak (1976). By lowering the reaction temperature to 15°C and reducing the reaction time to 2.5 hours, we obtained the title compound with better purity than when applying literature conditions (4 hours at 25°C). The title phosphorobromoester was unstable and was used immediately in the phosphorylation reaction (see Examples 4, 11 and 14).

Embodiment 2

[0132] [2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethyl]-[6-(4-phenyl-butoxy)-hexyl-ammonia tert-butyl carbamate

[0133]

[0134] Commercially available salmeterol xinafoate (6.04 g, 10 mmol) and potassium carbonate (1.39 g, 10 mmol) were suspended in 1,4-dioxane / water mixture (1:1, 80 mL) with stirring middle. Then, di-tert-butyl dicarbonate (2.40 g, 11 mmol) dissolved in 1,4-dioxane (10 mL) was added dropwise while stirring was continued at room temperature. TLC analysis after 30 minutes showed only traces of starting material. After 2 hours, 1,4-dioxane was evaporated 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 and evaporation is purified by chromatography on silica gel eluting with an ethyl acetate / hexane mixture (1:1). The title com...

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Abstract

A mutual prodrug of a corticosteroid and a substituted phenylphosphate (ss-agonist derivative) for 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 L) dissolved in a quarter normal saline having pH between 5.0 and 7.0 for the treatment of respiratory tract inflammation and bronchoconstriction by an aerosol having mass median average diameter predominantly between 1 to 5 , produced by nebulization or by dry powder inhaler.

Description

field of invention [0001] The present invention relates to the preparation of novel synergistic prodrugs of corticosteroids and beta-agonists delivered to the lung by aerosolization. In particular, the present invention relates to the synthesis, formulation and administration of substituted phenylphosphate steroids as synergistic steroid-beta-agonist prodrugs so that when administered to the lungs, endogenous enzymes present in the lung tissue and airways degrade Prodrugs, which release the corticosteroid and beta-agonist at the site of administration (eg, salmeterol, albuterol). The synergistic prodrug is formulated as a liquid or dry powder, and the formulation allows and is suitable for administration of the prodrug to the pulmonary bronchial space of the airways in an aerosol with a mass median mean diameter mainly between 1-5 μ. An effective amount of the substituted phenyl phosphate prodrug formulated and administered is sufficient to deliver a therapeutic amount of the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/58C07J71/00
CPCA61K9/0075A61K31/58C07J71/00A61P11/00A61P11/06A61P11/08A61P29/00A61P43/00C07J73/00C07F9/12
Inventor W·R·贝克M·斯塔西亚克B·C·吉尔顿
Owner GILEAD SCI INC
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