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

Patent metadata

Field	Value
Publication number	US-10752599-B2
Application number	US-201916582051-A
Country	US
Kind code	B2
Filing date	Sep 25, 2019
Priority date	Mar 8, 2016
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

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.

First claim

What is claimed is:

1. A process for preparing (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (I), the process comprising:
(a) coupling benzyl (2S,4R)-4-amino-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-2-methylpentanoate hydrochloride with 3-((4-methoxybenzyl)oxy)isoxazole-5-carboxylic acid in a solvent in approximately a 1:1 molar ratio to give benzyl (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-((4-methoxybenzyl)oxy)isoxazole-5-carboxamido)-2-methylpentanoate; and
(b) deprotecting benzyl (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-((4-methoxybenzyl)oxy)isoxazole-5-carboxamido)-2-methylpentanoate to form (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (I).

2. The process of claim 1 , wherein (a) further comprises a peptide coupling agent and a base in approximately a 1:3:1:1 molar ratio of coupling agent to base to benzyl (2S,4R)-4-amino-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-2-methylpentanoate hydrochloride to 3-((4-methoxybenzyl)oxy)isoxazole-5-carboxylic acid.

3. The process of claim 2 , wherein the coupling agent is 2-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) and the base is N,N-diisopropylethylamine.

4. The process of claim 1 , wherein (b) is performed with a palladium catalyst and hydrogen gas.

5. The process of claim 1 , wherein (a) further comprises a peptide coupling agent.

6. The process of claim 5 , wherein the peptide coupling agent is selected from O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, and O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetra methyluronium tetrafluoroborate.

7. The process of claim 6 , wherein the peptide coupling agent is selected from O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, and O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.

8. The process of claim 7 , wherein the peptide coupling agent is O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.

9. The process of claim 1 , wherein (a) further comprises a base.

10. The process of claim 9 , wherein the base is N,N-diisopropylethylamine.

11. The process of claim 1 , wherein the solvent of (a) is tetrahydrofuran.

12. The process of claim 1 , wherein the deprotecting of (b) comprises adding a palladium catalyst.

13. The process of claim 1 , wherein the deprotecting of (b) comprises adding hydrogen.

14. The process of claim 1 , wherein the deprotecting of (b) comprises adding ethanol.

15. The process of claim 12 , further comprising removing the palladium catalyst following the deprotecting of (b).

16. The process of claim 15 , further comprising adding an oxidizing agent following the removing of the palladium catalyst.

17. The process of claim 16 , wherein the oxidizing agent is hydrogen peroxide.

18. The process of claim 8 , wherein (a) further comprises N,N-diisopropylethylamine.

19. The process of claim 18 , wherein the deprotecting of (b) comprises adding a palladium catalyst and hydrogen.

20. The process of claim 1 , further comprising isolating (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (I).

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Hughes Adam D
• Fleury Melissa
• Rapta Miroslav
• Thalladi Venkat R
• Fass Gene Timothy
• Simeone Michael

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61K31/42 Primary

  Oxazoles · CPC title

• C07D261/18 Primary

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title