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Morphic forms of complement factor d inhibitors

A Form, Dosage Technology Applied in the Field of Morphological Forms of Complement Factor D Inhibitors

Pending Publication Date: 2021-05-25
ACHILLION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While current hypotheses suggest that most IC-MPGNs are attributable to overactivity of the classical pathway, those patients with low C3 and normal C4 may have significant overactivity of the alternative pathway

Method used

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  • Morphic forms of complement factor d inhibitors
  • Morphic forms of complement factor d inhibitors
  • Morphic forms of complement factor d inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0167] a) Isolated crystalline form I of compound 2, characterized in that it comprises XRPD pattern of at least three 2θ values ​​of °, 17.4±0.2°, 18.0±0.2°, 18.4±0.2°, 21.1±0.2°, 22.0±0.2°, 22.6±0.2°, 23.8±0.2° and 27.4±0.2° ;

[0168] b) isolated crystalline form I of compound 2 of embodiment (a), characterized in that it comprises At least four of 0.2°, 16.2±0.2°, 17.4±0.2°, 18.0±0.2°, 18.4±0.2°, 21.1±0.2°, 22.0±0.2°, 22.6±0.2°, 23.8±0.2° and 27.4±0.2° XRPD patterns of 2θ values;

[0169] c) isolated crystalline form I of compound 2 of embodiment (a), characterized in that it comprises At least five of 0.2°, 16.2±0.2°, 17.4±0.2°, 18.0±0.2°, 18.4±0.2°, 21.1±0.2°, 22.0±0.2°, 22.6±0.2°, 23.8±0.2° and 27.4±0.2° XRPD patterns of 2θ values;

[0170] d) Isolated crystalline form I of compound 2 of embodiment (a), characterized in that it comprises At least six of 0.2°, 16.2±0.2°, 17.4±0.2°, 18.0±0.2°, 18.4±0.2°, 21.1±0.2°, 22.0±0.2°, 22.6±0.2°, 23.8±0.2° and 27.4±0.2° XRPD...

Embodiment

[0428] Scheme 1. Compound 1 ((2S,4R)-1-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)- Synthesis of N-(-6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide) Form II

[0429]

[0430] Step 1: Synthesis of tert-butyl (2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (3): under nitrogen atmosphere , N-Boc-trans-4-fluoro-L-proline (50.8 kg) was added to DCM (1000 L) in a glass-lined reactor. The reaction mixture was cooled to 0±5°C and N-methylimidazole (44.7 kg) was added while maintaining the temperature at 0±5°C. Methanesulfonyl chloride (29.97 kg) was slowly added to the reaction mixture followed by 2-amino-6-bromopyridine (2). The reaction temperature was warmed to room temperature and stirred for 12 h. The reaction was monitored by HPLC. After the reaction was complete, water (2,000 kg) was added, the reaction was stirred and the DCM layer was separated. The aqueous layer was extracted again with DCM (1000L). The combin...

Embodiment 2

[0436] Example 2. Solubility Evaluation of Amorphous Compound 1

[0437] Through FT Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), TGA combined with infrared exhaust gas detection (TGA-IR), polarized light microscopy (PLM), powder X-ray diffraction (PXRD) , Dynamic Vapor Sorption (DVS) and Modulated DSC Analysis of Amorphous Compound 1. Selected physicochemical data for amorphous compound 1 are shown in Figure 1A , Figure 1B , Figure 1C , Figure 1D , Figure 1E and Figure 1F middle. These figures indicate that the material is a light brown powder, which was tested by PXRD ( Figure 1C ) and PLM ( Figure 1D ) is determined to be amorphous. DSC data show low energy broad endotherms at 37.3°C and 113.4°C ( Figure 1B ). TGA-IR data ( Figure 1B ) indicates that the material contained residual water (2.0%) and DCM (1.8%). DVS analysis performed on the amorphous form indicated a water uptake of 4.0% from 0%-90% RH (...

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Abstract

This invention provides stable, highly crystalline forms of Complement factor D inhibitors Compound 1 and Compound 2 for advantageous therapeutic pharmaceutical efficacy and dosage form stability.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Application No. 62 / 727,954, filed September 6, 2018. The entire content of said application is incorporated herein. technical field [0003] The present invention provides advantageous isolated morphological forms of the complement factor D inhibitors Compound 1 and Compound 2. Background technique [0004] The complement system is part of the innate immune system that does not adapt to changes in the host's life course, but is recruited and used by the adaptive immune system. For example, it assists or complements the ability of antibodies and phagocytes to clear pathogens. This complex regulatory pathway allows rapid responses to pathogenic organisms while protecting host cells from destruction. More than thirty proteins and protein fragments make up the complement system. These proteins act by opsonization (enhancing phagocytosis of antigens), chemotaxis (a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/00C07D471/04C07D487/00C07D487/02
CPCC07D401/14A61K31/506A61K45/06A61P21/00A61P27/02A61P37/00A61P29/00C07B2200/13
Inventor 阿维纳什·法德克秋广·桥本伟·马李·M·卡特里契奇
Owner ACHILLION PHARMA INC
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