Salts with CRTH2 antagonist activity

A technology of potassium salt and sodium salt, applied in the field of preparation of these salts, can solve the problem of high solubility without expansion

Inactive Publication Date: 2009-05-13
OXAGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is also unexpected that this high solubility does not extend to all salts of the selected compounds

Method used

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  • Salts with CRTH2 antagonist activity
  • Salts with CRTH2 antagonist activity
  • Salts with CRTH2 antagonist activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Embodiment 1: Synthesis of (5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)acetic acid (compound 1)

[0096] Step 1: Synthesis of (5-fluoro-2-methylindole-1-acetic acid) ethyl ester

[0097]

[0098] Put 5-fluoro-2-methylindole (0.45Kg, 3.017mol, 1.0 weight), powdered potassium carbonate (1.251Kg, 9.05mol, 2.78 weight) and acetonitrile (9.0L, 20 volumes) at 15-25°C into a 20L flanged flask. Ethyl bromoacetate (0.671 L, 2.67 mol, 1.49 vol) was added and the resulting suspension was heated to reflux for 18 hours, after which 1 H NMR in-progress check analysis (reaction sampling, sample concentration, addition of D to residue 6 -DMSO, filter and log 1 H NMR spectrum) indicated 87% conversion. Ethyl bromoacetate (0.333 L, 1.32 mol, 0.74 vol) and powdered potassium carbonate (0.626 Kg, 4.53 mol, 1.39 wt) were further added and refluxed for another 6 hours. 1 H NMR progress check analysis indicated 98.4% conversion. The contents of the flask were allowed to cool ...

Embodiment 2

[0106] Example 2: Solubility of Compound 1 Free Acid

[0107] A basic solubility screen was performed in order to provide information on the intrinsic solubility of the non-ionized form of Compound 1 and the potential increase / decrease in solubility resulting from salt formation. 50 mg of Compound 1 was charged into a vial along with 20 volumes of the indicated solvent. The mixture was stirred at 15-25°C, and if a clear solution was obtained, more solids were added until the solution was fully saturated. If no solution was obtained, the mixture was heated to reflux with stirring and an additional 20 volumes of solvent were added if necessary. The DMSO, NMP and DMF mixture was heated to 100 °C. The mixture was then cooled to 15-25°C. Table 1 below summarizes the experimental results.

[0108] Table 1

[0109]

[0110] The results indicated that Compound 1 was very insoluble ( 50 mg / ml) at 20 volumes at 15-25°C (after obtaining a solution at 100°C).

Embodiment 4

[0143] Example 4: Formation of Salt of Compound 1

[0144] As shown in Example 1, the synthesis of compound 1 involves ester hydrolysis in the final step to generate the carboxylic acid. This was done using 3 equivalents of potassium hydroxide in THF / water as base. Obviously, potassium salts must be formed during the hydrolysis. With this in mind, a vial was charged with 1 g of compound 1 along with 3 equivalents of potassium hydroxide. Water (20 vols) was added and the mixture was heated to 50°C to almost give solution. After cooling to 15-25°C, a solid precipitates and can be collected by filtration. 1 H NMR analysis confirmed that a salt had been formed. The experiment was repeated using 3 equivalents of sodium hydroxide, but after separation a sticky solid was collected which dissolved when washed with ethanol.

[0145] The experiment was repeated using acetonitrile as solvent with a few drops of water to help dissolve the base. This time using 2 equivalents of base,...

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Abstract

The potassium, sodium, ammonium, lysine, diethylamine, tromethamine (TRIS), piperazine, ethylenediamine and ethanolamine salt of a compound of general formula (I): wherein R<1> is halo or cyano; R<2> is C1-C4 alkyl; and R<3> is quinolyl or phenyl substituted with methane sulfonyl; can be synthesised by a novel method and are substantially more soluble than the parent free acids in a range of solvents.

Description

technical field [0001] The present invention relates to compounds for use as medicines. In particular, the present invention relates to salts which are especially soluble in a range of solvents. The present invention also relates to methods for preparing these salts, compositions containing them and their usefulness in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and by prostaglandins acting on CRTH2 receptors on cells D. 2 (PGD 2 ) mediated purposes in other inflammatory diseases, wherein the cells include eosinophils, basophils and Th2 lymphocytes. Background technique [0002] PGD 2 It is a kind of eicosanoid, which is a kind of chemical medium synthesized by cells in response to local tissue damage, normal stimulation or hormone stimulation or activation pathway of cells. Eicosanoids bind to specific cell surface receptors in various tissues throughout the body and mediate various effects in these tissues....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10C07D401/06A61K31/405A61P29/00
CPCC07D209/10C07D401/06A61P1/04A61P9/08A61P9/10A61P11/00A61P11/02A61P11/06A61P17/00A61P17/06A61P17/10A61P19/02A61P21/00A61P25/00A61P25/16A61P25/28A61P27/02A61P27/14A61P29/00A61P37/02A61P37/06A61P37/08A61P43/00A61K31/405
Inventor J·M·洛弗尔
Owner OXAGEN
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