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Tartrate of isofagomine and use thereof

A technology of isofagomine and tartrate, applied in organic chemistry, drug combination, active ingredients of heterocyclic compounds, etc., can solve the problems of poor solid properties, shortened life, and difficult large-scale purification of free bases

Inactive Publication Date: 2008-02-06
AMICUS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

People with type 3 Gaucher disease live to adulthood, but may have a shortened lifespan
For example, the hydrochloride salt of isfargomine (isofargomine-HCl) has been disclosed in U.S. Patent 5,844,102, however, isfargomine-HCl and isfargomine free base are not easily purified on a large scale, and they are not Unfavorable solid properties for industrial scale production methods and applications in pharmaceutical formulation

Method used

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  • Tartrate of isofagomine and use thereof
  • Tartrate of isofagomine and use thereof
  • Tartrate of isofagomine and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] Example 1: Synthesis of Isofargomine Tartrate from D-(-)-Arabinose

[0121] The reaction was monitored by TLC with 5% H 2 SO 4 / methanol, phosphomolybdic acid solution or 254nm UV color development.

[0122] step 1 : D-arabinose (50 kg, 330.04 moles) and benzyl alcohol (132.2 kg, 4.33 equiv) were stirred and heated to 35°C. Acetyl chloride (10.9 kg, 0.42 equiv) was added, keeping the temperature <45°C, then stirred at 50°C overnight. The mixture was cooled to 20 °C and diluted with MTBE (600 kg). The mixture was stirred for 0.5-5 hours. The solid was collected by filtration and washed with MTBE (2 x 40 kg). The product was dried in a filter drier. 2-Phenyl-D-arabinose was obtained as an off-white solid, 70.9 kg (88.6%).

[0123] 1 H NMR (300MHz, DMSO-d 6 ): δ7.32(m, 5H), 4.76(s, 1H), 4.66(d, J=12Hz, 1H), 4.59(m, 3H), 4.45(d, J=12Hz, 1H), 3.70(m , 4H), 3.47 (dd, J=12, 3Hz, 1H).

[0124] step 2 : 2-Benzyl-D-arabinose (73.5 kg, 305.92 moles) was mixed with...

Embodiment 2

[0139] Example 2: Recrystallization of isofagomine tartrate

[0140] Isofagomine tartrate (1,767 g) was dissolved in water (1.767 L) at ambient temperature. Absolute ethanol (1.767 L) was added and stirred for 30 minutes. Another aliquot of absolute ethanol (1.767 L) was added dropwise at a slow flow rate and stirred for 30 minutes. This process was repeated twice (including 30 minutes of stirring) to obtain a 4:1 ethanol / water solution. The solid was filtered, washed with ethanol / water (4:1), and dried in a vacuum oven at 43° C. overnight to constant weight (ie net weight loss <1% after re-drying for another 2 hours). The yield of recrystallization was 91%. The sample was found to contain 1.3% impurities according to HPLC. The NMR spectrum of the recrystallized product is shown in Fig. 3 and Fig. 4 . The melting point is 168-169°C.

Embodiment 3

[0141] Example 3: Synthesis of Isofargomine Tartrate

[0142] Isofargamine L(+)-tartrate (2:1)

[0143] A solution of L(+)-tartaric acid (102 mg, 0.679 mmol) in deionized water (1.0 mL) was added to a solution of isofagomin (200 mg, 2.0 equiv) in deionized water (2.0 mL) at room temperature. The solution was stirred for 10 minutes and lyophilized overnight. The residue was further dried in vacuo at 45°C for 3 days to afford the desired salt (275.6 mg, 91%). Melting point 92-93°C,

[0144] 1H NMR (300MHz, D 2 O): δ4.22(s, 2H), 3.71(dd, J=12, 3.6Hz, 1H), 3.67-3.59(m, 2H), 3.44-3.37(m, 3H), 2.85(t, J= 12Hz, 1H), 2.75(t, J=12Hz, 1H), 1.85(m, 1H) (Fig. 8A)

[0145] Isofagomin D-(-)-tartrate (2:1)

[0146] A solution of D-(-)-tartaric acid (102 mg, 0.679 mmol) in deionized water (1.0 mL) was added to a solution of isofagomin (200 mg, 2.0 equiv) in deionized water (2.0 mL) at room temperature . The solution was stirred for 10 minutes and lyophilized overnight. The res...

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Abstract

A novel tartaric acid salt of Isafagomine (Isofagomine tartrate) that can be used for the treatment of Gaucher disease is provided. The invention also provides a crystalline form of isofagomine tartrate, method for preparing the salt, a pharmaceutical composition containing the salt, and a method of treating Gaucher disease.

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 60 / 808020, filed May 24, 2006, and U.S. Provisional Patent Application No. 60 / 890719, filed February 20, 2007. patent application, the above application is incorporated herein by reference in its entirety. Background of the invention [0002] Gaucher disease is a lysosomal storage disorder associated with the accumulation of glycosphingolipids (GSL) in patient cells, especially monocytes and macrophages. This abnormal accumulation of glycosphingolipids results from a genetic defect (mutation) in the gene encoding the lysosomal enzyme acid β-glucosidase (glucocerebrosidase, GCase), acid β-glucosidase Glucosidase is a lysosomal hydrolase that breaks down GSL glucosylceramide (GluCer). Most glucocerebrosidase gene (Gba) mutations lead to GCase misfolding in the endoplasmic reticulum (ER). This misfolded GCase is recognized by the ER quality control system and subsequently degraded rather than pro...

Claims

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Application Information

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IPC IPC(8): C07D211/40A61K31/445A61P43/00
Inventor B·穆格拉格K·A·谢特D·帕林P·J·雷布琴斯基
Owner AMICUS THERAPEUTICS INC
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