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Solid forms of antiviral compound

A compound and crystal form technology, applied in antiviral agents, drug combinations, organic chemistry, etc., can solve unknown problems

Inactive Publication Date: 2015-02-25
GILEAD PHARMASSET LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, any solid crystalline form of Compound I is so far unknown

Method used

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  • Solid forms of antiviral compound
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0180] Example 1: (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-nitrogen Hetero-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzimidazol-2-yl]-2-aza-bicyclo[ 2.2.1] Preparation of heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester diacetone solvate (Compound I Form I).

[0181] Weigh approximately 15-60 mg of amorphous (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl) )-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzimidazol-2-yl]-2- Aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (99.3% HPLC purity) and transferred to a vial equipped with a mini magnetic stir bar . Acetone was added in 200 μL increments, resulting in the formation of a slurry. The slurry was stirred at room temperature (~22°C) for two weeks and checked periodically.

[0182]Two weeks later, a 300 μL sample of the slurry was removed from the vial, transferred to a centrif...

Embodiment 2

[0189] Example 2: (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-nitrogen Hetero-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzimidazol-2-yl]-2-aza-bicyclo[ 2.2.1] Preparation of heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester monoacetone solvate (compound I type II).

[0190] Compound I Form II was prepared by partial desolvation of Form I as described more fully below. Methods of desolvation are well known to those skilled in the art. These include, for example, the application of vacuum, prolonged exposure to ambient conditions, subjecting Form I to elevated temperatures, and subjecting Form I to a gas stream, such as air or nitrogen, and any combination thereof. In some embodiments, the preparation of Compound 1 Form I described in Example 1 above results in the formation of a detectable amount of Compound 1 Form II. Thus, in these embodiments, a mixture of Form I and Form II can be prepared.

[0191] As an e...

Embodiment 3

[0197] Example 3: (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-nitrogen Hetero-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzimidazol-2-yl]-2-aza-bicyclo[ 2.2.1] Preparation of heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (compound I type III).

[0198] Although Form II confers surprising advantages over amorphous compound I, it still has a significant content of tightly bound acetone in its structure. The purpose of this example was to break the solvate and produce the anhydrous crystalline form.

[0199] Therefore, the Form II crystals were heated to complete dryness or desolvated at -115°C, which led to the discovery of a third crystal form, Form III.

[0200] Form III was revealed by variable temperature XRPD experiments. In this experiment, samples of Form II were heated at 10°C / min starting at 25°C. After each 10°C temperature increase, the samples were held at the elevated temperature for 20 min to al...

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Abstract

Amorphous and crystalline solid forms of the anti-HCV compound (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Compound I) were prepared and characterized in the solid state: Also provided are processes of manufacture and methods of using the amorphous and crystalline forms.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims US Provisional Application Serial No. 61 / 655,934, filed June 5, 2012, US Provisional Application Serial No. 61 / 759,295, filed January 31, 2013, and US Application Serial No. 13, filed March 13, 2013 / 800,374, the entire contents of these applications are incorporated herein by reference. Background technique [0003] The present invention generally relates to antiviral compounds (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl) -5-Aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzimidazol-2-yl]-2-nitrogen Crystalline solid form of methyl hetero-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamate, methods for preparing the same and methods of treatment using the same. [0004] Hepatitis C is considered a chronic viral disease of the liver characterized by liver disease. Although drugs targeting the liver are widely available and have shown efficacy...

Claims

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Application Information

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IPC IPC(8): C07D471/08A61K31/4178A61P31/12
CPCA61K31/7056A61K31/381C07D471/08C07D403/14A61K31/4184C07B2200/13C07D487/08A61P1/16A61P31/12A61P31/14
Inventor 罗伯特·威廉·斯科特王芳施兵埃里克·莫格里安
Owner GILEAD PHARMASSET LLC
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