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Polymorph of SYK inhibitors

A polymorphic, dimesylate technology, applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve problems such as different pharmacodynamic reactions

Inactive Publication Date: 2016-03-30
GILEAD CONNENTICUT INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, different challenges were observed in early clinical studies when administering this oral formulation to human subjects
First, high inter-individual variability was observed, which could result in differential pharmacodynamic responses among subjects

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0315] Example 1: Synthesis of polymorph 3

[0316] General methods for preparing the different forms of the compound of formula I can be found in US Patent Nos. 8,450,321 and 8,455,493. The following is a process for the preparation of polymorph 3, which is the polymorph of the dimesylate salt monohydrate of the compound of formula I (and can also be described as the monohydrate of the compound of formula IA shown in the following embodiments. polymorphic form).

[0317]

[0318] To Reactor A was charged compound of Formula I (1.0X). To Reactor B was added methanesulfonic acid (0.56X, 2.40eq), water (4X, 4V) and acetone (3.2X, 4V). The contents of Reactor B were added to Reactor A while maintaining the temperature in Reactor A below 35°C. After the solids had dissolved, the contents of Reactor A were transferred to Reactor B. Reactor A was rinsed with water (1X, 1V) and acetone (0.8X, 1V) and transferred to Reactor B. The temperature of Reactor B was adjusted to 19-25...

Embodiment 2

[0320] Embodiment 2: another synthesis method of polymorph 3

[0321] The following is a method for preparing polymorph 3 of the dimesylate salt monohydrate of the compound of formula I (which may also be described as a polymorph of the monohydrate of the compound of formula IA shown in the following reaction schemes).

[0322]

[0323] Polymorph 7 was obtained as described in Example 1.

[0324] The isolated polymorph 7 was seeded in reactor B with polymorph 3 of the compound of formula IA (0.01X, 1 mol%). Acetone (15.0X, 19.0V) and water (1.0X, 1.0V) were added to Reactor B. The contents of Reactor B were heated to reflux (about 55°C) until polymorph Form 7 was converted to Form 3. The conversion was monitored by XRPD or DSC. The contents of Reactor B were a slurry and were cooled to 19-25°C, then filtered, rinsed with acetone (2.4X, 3V) and dried in vacuo at 60°C until constant weight was reached to provide polymorph 3 . exist Figure 1A and 3A Representative XRPD ...

Embodiment 3

[0325] Example 3: One-pot synthesis of polymorph 3

[0326] The following is the preparation of polymorph 3 of the dimesylate salt monohydrate of the compound of formula I (which can also be described as the monohydrate of the compound of formula IA shown in the reaction scheme below) from the compound of formula I (as the free base) polymorphic form) method. The process uses a single reactor in the conversion of the compound of formula I to polymorph 3 and does not require the isolation of compound intermediates.

[0327]

[0328] Compound of Formula I (1.0X) was added to acetone (14.2X, 18V) in Reactor A and mixed. Water (0.8X, 0.8V) was charged to Reactor A, followed by methanesulfonic acid (0.48X, 2.05eq). Acetone (0.9X, 1.2V) was pumped in, flushing the tubing to Reactor A with acetone. The contents of Reactor A were heated to reflux (about 55°C) for about 2 hours. Reactor A was seeded with polymorph 3 (0.015X, 1 mol%) and the contents mixed at reflux to convert th...

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Abstract

Polymorphs of a bis-mesylate salt of a compound of Formula (I), or a hydrate thereof, are provided. The bis-mesylate salt may also be depicted as a compound of Formula (IA): Provided herein are also compositions thereof, methods for their preparation and methods for such polymorphs.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Patent Application 61 / 860,197, filed July 30, 2013, the entire disclosure of which is incorporated herein by reference. technical field [0003] The present disclosure relates to polymorphic forms of compounds that inhibit spleen tyrosine kinase (Syk) activity and pharmaceutical compositions of the polymorphic forms. The present disclosure also relates to methods of preparing said polymorphs and polymorphic pharmaceutical compositions, and the use of said polymorphs and pharmaceutical compositions in the treatment of subjects suffering from various diseases, including cancer and inflammatory disorders. Background technique [0004] Inhibition of spleen tyrosine kinase (Syk) activity is useful in the treatment of certain types of cancer and autoimmune diseases. One of the compounds found to inhibit Syk activity is represented by formula I, or a pharmaceutically acc...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519
CPCC07D487/04A61P11/06A61P19/02A61P25/00A61P25/02A61P29/00A61P35/00A61P35/02A61P37/00A61P37/06C07C309/04
Inventor P.C.冯D.斯蒂芬迪斯D.维齐蒂乌T.G.埃尔福德M.L.赫里
Owner GILEAD CONNENTICUT INC
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