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Morphic forms of complement factor d inhibitors

A form and crystallization technology, applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc.

Pending Publication Date: 2021-06-18
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
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  • Morphic forms of complement factor d inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0106] a) an isolated crystalline form A of compound 3, characterized in that it comprises XRPD patterns of at least three 2θ values ​​of ±0.2°, 5.7±0.2°, 5.6±0.2°, 5.4±0.2° and 4.2±0.2°;

[0107] b) isolated crystalline form A of compound 3 of embodiment (a), characterized in that it comprises XRPD patterns of at least four 2θ values ​​of 0.2°, 6.0±0.2°, 5.7±0.2°, 5.6±0.2°, 5.4±0.2° and 4.2±0.2°;

[0108] c) isolated crystalline Form A of Compound 3 according to embodiment (a) or (b), characterized by an XRPD pattern comprising at least a 2Θ value of 3.7 ± 0.2°;

[0109] d) isolated crystalline Form A of Compound 3 of embodiment (a), (b) or (c), characterized by an XRPD pattern comprising at least a 2Θ value of 9.3±0.2°;

[0110] e) Isolated crystalline Form A of Compound 3 according to any one of embodiments (a)-(d), wherein the XRPD pattern has image 3 The characteristic 2θ value of ;

[0111] f) A pharmaceutical composition comprising an isolated crystalline Form A of...

Embodiment 1

[0423] Scheme 1. Synthesis of compound 3

[0424]

[0425] To a solution of intermediate 10 and intermediate 33 in DMF was added N,N-diisopropylethylamine. TBTU was added while maintaining the reaction temperature. The reaction was warmed to room temperature and stirred for 4-8 hours. The reaction was diluted with water and the resulting solid formed was collected by centrifugation. The solid was washed twice with water, then dissolved in DCM and treated with Siliabondthiol resin and activated carbon to remove Pd-based impurities. The resin and charcoal were removed by filtration and washed with MeOH / DCM. The filtrate was evaporated to dryness and the residue was purified by silica gel chromatography using methanol / DCM. Pure fractions were combined and evaporated to dryness.

Embodiment 2

[0426] Example 2. Polymorph experiment of compound 3

[0427] Table 1. Polymorph studies of compound 3, starting material is disordered compound 3 unless otherwise indicated.

[0428]

[0429]

[0430]

[0431]

[0432] *Graph successfully indexed

[0433] FE: fast evaporation

[0434] ET: rapid evaporation at elevated temperature

[0435] SE: slow evaporation

[0436] VR: Volume reduction

[0437] SC: slow cooling

[0438] RT ppt: ambient temperature precipitation

[0439] CP: sharp precipitation

[0440] SVD: Solid-Vapor Diffusion

[0441] Roto-vap: rotary evaporation

[0442] The procedure for the conditions in Table 1 is discussed below.

[0443] Fast Evaporation (FE)

[0444] Prepare solutions of compound 3 and the solvent / solvent system of interest. Samples were filtered and placed at ambient conditions until dry.

[0445] Slow evaporation (SE)

[0446] Prepare solutions of compound 3 and the solvent / solvent system of interest. Filter the sample. ...

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Abstract

This invention provides stable, highly crystalline forms of Complement Factor D inhibitor Compound 3 for therapeutic applications.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Application No. 62 / 736,294, filed September 25, 2018; U.S. Application No. 62 / 757,565, filed November 8, 2018; U.S. Application No. 62 / 760,520, filed November 13, 2018; and 2019 Priority benefit of U.S. Application No. 62 / 796,776, filed January 25. Each of these applications is incorporated herein by reference in its entirety. technical field [0003] The invention provides a complement factor D inhibitor (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl ) Acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide Favorable separation Morphological form. 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 cl...

Claims

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Application Information

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IPC IPC(8): A61K31/167A61K31/395A61K31/40
CPCA61K31/506C07D401/14A61P37/00A61P29/00A61P25/00A61P35/00C07B2200/13
Inventor 阿维纳什·法德克秋广·桥本马克·安德烈斯
Owner ACHILLION PHARMA INC
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