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Crystalline(2s,4r)-5-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid and uses thereof

A technology of ethoxymethyl and formylamino, which is used in the treatment of diseases such as hypertension, heart failure and kidney disease, and can solve the problem of unpredictability of the formation of crystal forms of organic compounds

Pending Publication Date: 2018-11-09
THERAVANCE BIOPHARMA R&D IP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the formation of crystalline forms of organic compounds is extremely difficult to predict
No reliable method exists to predict which form, if any, of an organic compound will crystallize
Furthermore, no method exists to predict which crystalline form, if any, has the desired physical properties for use as a pharmaceutical

Method used

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  • Crystalline(2s,4r)-5-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid and uses thereof
  • Crystalline(2s,4r)-5-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid and uses thereof
  • Crystalline(2s,4r)-5-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid and uses thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0049] The preparation of crystalline Form I' is generally carried out in a suitable inert diluent, examples of which include, but are not limited to, acetone, acetonitrile, ethyl acetate, methyl ethyl ketone, methanol, ethanol, isopropanol, isobutanol, Dichloromethane, methyl t-butyl ether, cyclopentyl methyl ether, hexane, etc., and mixtures thereof, optionally containing water. Mixtures of inert diluents (also known as solvent systems) include acetone and water, acetonitrile and water, ethanol and ethyl acetate, ethyl acetate and hexane, and lower alcohols (C 1-6 Alkyl-OH) and water, such as methanol and water and isopropanol and water. A particularly suitable solvent system includes ethyl acetate and water. After crystallization is complete, the crystalline compound can be separated from the reaction mixture by any conventional method, such as precipitation, filtration, concentration, centrifugation, drying in vacuo, and the like.

[0050] In one embodiment, crystalline ...

example A

[0208] Freezing solutions suitable for the preparation of injectable solutions are prepared as follows:

[0209]

[0210] Representative procedure: Dissolve excipients (if present) in about 80% water for injection, add active compound I or I' and dissolve. The pH was adjusted to 3 to 4.5 with 1M sodium hydroxide, and then the volume was adjusted to 95% of the final volume with water for injection. Check pH and adjust if necessary, and adjust volume to final volume with water for injection. The formulation is then sterile filtered through a 0.22 micron filter and placed into sterile vials under aseptic conditions. Vials were capped, labeled and stored frozen.

example B

[0212] Lyophilized powders or crystalline solids suitable for the preparation of injectable solutions are prepared as follows:

[0213]

[0214] Representative procedure: Dissolve excipients and / or buffers (if present) in about 60% water for injection. Add active compound I or I', dissolve, adjust pH to 3 to 4.5 with 1M sodium hydroxide and adjust volume to 95% of final volume with water for injection. Check pH and adjust if necessary, and adjust volume to final volume with water for injection. The formulation is then sterile filtered through a 0.22 micron filter and placed into sterile vials under aseptic conditions. The formulation is then lyophilized using an appropriate lyophilization cycle. Will be capped (optionally under partial vacuum or dry nitrogen), labeled and stored frozen.

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Abstract

In one aspect, the invention relates to a crystalline form of the structure: or a pharmaceutically acceptable salt thereof, having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising this crystalline form; methods of using this crystalline form and its soluble form (I); and processes for preparing soluble (I) and crystalline (I') forms.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application Nos. 62 / 305,393 and 62 / 346,336, filed March 8, 2016, and June 6, 2016, respectively, the entire disclosures of which are incorporated herein by reference. technical field [0003] The present invention relates to novel crystalline forms having enkephalinase inhibitory activity. The invention also relates to pharmaceutical compositions comprising the compounds, methods of preparing the compounds and methods of using the compounds to treat diseases such as hypertension, heart failure and kidney disease. Background technique [0004] Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP) is an endothelial membrane found in several organs and tissues, including the brain, kidney, lung, gastrointestinal tract, heart, and peripheral vasculature Combined with Zn 2+ metallopeptidase. NEP degrades and inactivates a variety of endogenous peptides such as enkep...

Claims

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Application Information

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IPC IPC(8): C07D261/18A61K31/42A61P9/00
CPCC07D261/18A61K31/415A61P13/12A61P43/00A61P9/00A61P9/04A61P9/12A61K45/06C07B2200/13A61K31/42A61K9/4816A61K9/0053
Inventor 亚当·D·休斯梅丽莎·弗勒里米罗斯拉夫·拉普塔文卡特·R·萨兰迪吉恩·蒂莫西·法斯迈克尔·西梅奥内R·迈克尔·鲍德温戴维·L·布尔代特
Owner THERAVANCE BIOPHARMA R&D IP LLC
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