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Crystalline forms of a lta4h inhibitor

A technology of crystal form and amino group, which is applied in the field of crystal form of LTA4H inhibitors, can solve the problem of toxicity of polymorphs

Pending Publication Date: 2021-03-16
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In extreme cases, undesired polymorphs may even show toxicity

Method used

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  • Crystalline forms of a lta4h inhibitor
  • Crystalline forms of a lta4h inhibitor
  • Crystalline forms of a lta4h inhibitor

Examples

Experimental program
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example

[0203] abbreviation:

[0204] IT: internal temperature

[0205] Tj: reactor jacket temperature

[0206] Tr: reaction temperature

[0207] THF: Tetrahydrofuran

[0208] Rpm: revolutions per minute

example 1

[0209] Example 1: Form H B preparation of

[0210]

[0211] Into a 2500 L glass-lined reactor was charged Int-1 (55 kg) and toluene (810 kg) and the mixture was stirred (55 rpm, anchored). 31% HCl (232 kg) was added. The discharge pressure of the reactor was set at 2000 mbar. The internal temperature was adjusted to 65 °C and stirred (60 rpm) for 11 h 29 min at an internal temperature (IT) between 65 °C and 66 °C. The internal temperature was then adjusted to 35°C. Then through the Dean-Stark separator-like device (IT max =44° C.) 82 kg of aqueous solution were separated under reduced pressure and the internal temperature was adjusted to about 20°C. The system was stirred at 19°C to 24°C for 80 min. The solid was collected by centrifugation. The wet cake was washed with toluene (50 kg, 20 mL of antistatic agent added) and dichloromethane (50 kg). The solid was dried at 195 mbar for 8 h 26 min with a solution of sodium bisulfite from the company JT Baker set at 60°...

example 2

[0217] Example 2: Preparation of Hydrate Form B

[0218]

[0219] The first method: 505mg H B Weigh into a 20ml glass vial and add 6mL of methanol. The slurry was heated to 50 °C and stirred using a magnetic stirrer for 4 days. The suspension was cooled to room temperature and filtered. The recovered solid was dried under vacuum at 40 °C for 2.5 h. The white solid was analyzed by XRPD, DSC and TGA (respectively Figure 1-3 ).

[0220] The second method: stirring H in water / MeOH (2:8, 1:9, 1:2 v / v) at a temperature above 60 °C B Type B will also lead to Type B. For example, 20.7g H B type (dry weight) was added to the solution containing 810mL MeOH and 90mL H 2 O in a premixed solvent mixture. The resulting mixture was heated to 68 °C for 36 h, then cooled to 25 °C. The mixture was stirred for another 2h and filtered. The filter cake was dried under vacuum to give Form B (15.8 g, 76% yield) as a white powder.

[0221] M / z=393.1[M+H] + , Rt=2.47min (UPLC-MS con...

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Abstract

This application relates to various crystalline forms of (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in its free form, as well as compositions, method of making and methods of using the same. In some embodiments the crystalline forms also contain water ("hydrates"). These materials are useful in the treatment of diseases and disorders which are typically ameliorated by the inhibition of LTA4H. Such diseases and disorders may include inflammatory and autoimmune disorders and pulmonary and respiratory tract inflammation.

Description

technical field [0001] The present disclosure generally relates to (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazole-2- base) crystal form of butyric acid. The present disclosure also generally relates to pharmaceutical compositions comprising these crystalline forms, as well as methods for obtaining such crystalline forms and methods of using such crystalline forms in the treatment of diseases and conditions that are typically ameliorated by inhibition of LTA4H. Such diseases and disorders may include inflammatory and autoimmune disorders as well as lung and airway inflammation. Background technique [0002] (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid in First disclosed as an HCl salt in WO2015 / 092740, filed December 18, 2014, which is incorporated by reference in its entirety, and is an LTA4H inhibitor having the structure of formula (I): [0003] [0004] Compounds of formula (I) are usefu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P29/00A61K31/4439
CPCC07D401/12A61P29/00A61K31/4439A61P37/00A61P11/00C07B2200/13A61K45/06
Inventor A·柯迪考斯基吴艳香
Owner NOVARTIS AG
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