Process for the production of 2-[4-(3- and 2-fluorobenzyloxy) benzylamino] propanamides
Inventors
Barbanti, Elena • Caccia, Carla • Salvati, Patricia • Velardi, Francesco • Ruffilli, Tiziano • BOGOGNA, Luigi
Assignees
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Publication Number
US-8278485-B2
Publication Date
2012-10-02
Expiration Date
Abstract
A process for obtaining therapeutically active 2-[4-(3- and 2-(fluorobenzyloxy)benzylamino]propanamides and their salts with pharmaceutically acceptable acids with high purity degree, in particular, with a content of dibenzyl derivatives impurities lower than 0.03%, preferably lower than 0.01% by weight.The process is carried out by submitting the Schiff bases intermediates 2-[4-(3- and 2-fluorobenzyloxy)benzylideneamino]propanamides to catalytic hydrogenation in the presence of a heterogeneous catalyst in a protic organic solvent.
Core Innovation
The disclosed subject matter provides high purity safinamide ((S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide) or ralfinamide ((S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide), and pharmaceutically acceptable acid salts thereof, including methanesulfonate salts. The document describes scalable manufacture and preparation routes that convert fluorobenzyloxybenzaldehyde intermediates into Schiff base intermediates, followed by catalytic hydrogenation with hydrogen gas in the presence of a heterogeneous catalyst in a protic organic solvent, and optional conversion of the free base to a pharmaceutically acceptable acid salt.
The document focuses on controlled removal and quantitation of two toxic dibenzyl derivative impurities, especially as methanesulfonates, identified as (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzylamino]propanamide (IIa) and (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzylamino]propanamide (IIb). It states impurity control targets for the final product at or below 0.03 wt% and preferably at or below 0.01 wt%, and characterizes compound purity and impurity levels using GC/HPLC, NMR data, chiral/enantiomeric purity determination, and crystallization studies.
The problem addressed is that prior large-scale methods yield these dibenzyl derivative impurities above 0.03 wt% and they are difficult to purify to lower levels. The document links the impurities to strong inhibition of CYP3A4, CYP2D6, CYP2C19, and CYP2C9 and HERG currents, and to high cytotoxicity, while comparative data are reported to support a safety advantage associated with high-purity methanesulfonate salts.
Claims Coverage
The provided claim set includes one independent manufacturing/process claim and multiple independent treatment claims. The independent claims center on catalytic hydrogenation of Schiff base intermediates in a protic organic solvent with a heterogeneous catalyst, optional conversion to pharmaceutically acceptable acid salts, and therapeutic administration of high purity safinamide or ralfinamide defined by impurity limits below 0.03% by weight.
High purity safinamide or ralfinamide from Schiff base catalytic hydrogenation
Producing high purity safinamide ((S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide) or ralfinamide ((S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide) or pharmaceutically acceptable acid salts thereof by submitting a Schiff base intermediate to catalytic hydrogenation with hydrogen gas in the presence of a heterogeneous catalyst in a protic organic solvent.
Optional conversion to pharmaceutically acceptable acid salt
When safinamide or ralfinamide are obtained in free base form, optionally converting the free base form to a salt thereof with a pharmaceutically acceptable acid.
Treating epilepsy using safinamide with limited impurity IIa
Treating epilepsy by administering an effective amount of high purity safinamide or a pharmaceutically acceptable acid salt thereof wherein the content of impurity (IIa) is lower than 0.03% by weight.
Treating Parkinson’s disease using safinamide with limited impurity IIa
Treating Parkinson’s disease by administering an effective amount of high purity safinamide or a pharmaceutically acceptable acid salt thereof wherein the content of impurity (IIa) is lower than 0.03% by weight.
Treating Alzheimer’s disease using safinamide with limited impurity IIa
Treating Alzheimer’s disease by administering an effective amount of high purity safinamide or a pharmaceutically acceptable acid salt thereof wherein the content of impurity (IIa) is lower than 0.03% by weight.
Treating depression using safinamide with limited impurity IIa
Treating depression by administering an effective amount of high purity safinamide or a pharmaceutically acceptable acid salt thereof wherein the content of impurity (IIa) is lower than 0.03% by weight.
Treating restless legs syndrome using safinamide with limited impurity IIa
Treating restless legs syndrome by administering an effective amount of high purity safinamide or a pharmaceutically acceptable acid salt thereof wherein the content of impurity (IIa) is lower than 0.03% by weight.
Treating migraine using safinamide with limited impurity IIa
Treating migraine by administering an effective amount of high purity safinamide or a pharmaceutically acceptable acid salt thereof wherein the content of impurity (IIa) is lower than 0.03% by weight.
Treating pain conditions using ralfinamide with limited impurity IIb
Treating pain conditions by administering an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of impurity (IIb) is lower than 0.03% by weight.
Treating migraine using ralfinamide with limited impurity IIb
Treating migraine by administering an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of impurity (IIb) is lower than 0.03% by weight.
Treating bipolar disorders using ralfinamide with limited impurity IIb
Treating bipolar disorders by administering an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of impurity (IIb) is lower than 0.03% by weight.
Treating depressions using ralfinamide with limited impurity IIb
Treating depressions by administering an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of impurity (IIb) is lower than 0.03% by weight.
Treating cardiovascular disorders using ralfinamide with limited impurity IIb
Treating cardiovascular disorders by administering an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of impurity (IIb) is lower than 0.03% by weight.
Treating inflammatory disorders using ralfinamide with limited impurity IIb
Treating inflammatory disorders by administering an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of impurity (IIb) is lower than 0.03% by weight.
Treating urogenital disorders using ralfinamide with limited impurity IIb
Treating urogenital disorders by administering an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of impurity (IIb) is lower than 0.03% by weight.
Treating metabolic disorders using ralfinamide with limited impurity IIb
Treating metabolic disorders by administering an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of impurity (IIb) is lower than 0.03% by weight.
Treating gastrointestinal disorders using ralfinamide with limited impurity IIb
Treating gastrointestinal disorders by administering an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of impurity (IIb) is lower than 0.03% by weight.
The claims cover production of high purity safinamide or ralfinamide by catalytic hydrogenation of Schiff base intermediates with heterogeneous catalysts in a protic organic solvent, with optional conversion to pharmaceutically acceptable acid salts. They also cover therapeutic administration for multiple indications using products defined by impurity thresholds: safinamide with impurity (IIa) below 0.03% by weight, and ralfinamide with impurity (IIb) below 0.03% by weight.
Stated Advantages
Improved safety associated with high-purity methanesulfonate salts.
Reduced exposure to impurities that are linked to strong inhibition of CYP3A4, CYP2D6, CYP2C19, CYP2C9, and HERG currents and high cytotoxicity.
Documented Applications
Treating epilepsy by administering high purity safinamide or a pharmaceutically acceptable acid salt thereof with impurity (IIa) below 0.03% by weight.
Treating Parkinson's disease by administering high purity safinamide or a pharmaceutically acceptable acid salt thereof with impurity (IIa) below 0.03% by weight.
Treating Alzheimer's disease by administering high purity safinamide or a pharmaceutically acceptable acid salt thereof with impurity (IIa) below 0.03% by weight.
Treating depression by administering high purity safinamide or a pharmaceutically acceptable acid salt thereof with impurity (IIa) below 0.03% by weight.
Treating restless legs syndrome by administering high purity safinamide or a pharmaceutically acceptable acid salt thereof with impurity (IIa) below 0.03% by weight.
Treating migraine by administering high purity safinamide or a pharmaceutically acceptable acid salt thereof with impurity (IIa) below 0.03% by weight.
Treating pain conditions by administering high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid with impurity (IIb) below 0.03% by weight.
Treating migraine by administering high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid with impurity (IIb) below 0.03% by weight.
Treating bipolar disorders by administering high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid with impurity (IIb) below 0.03% by weight.
Treating depressions by administering high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid with impurity (IIb) below 0.03% by weight.
Treating cardiovascular disorders by administering high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid with impurity (IIb) below 0.03% by weight.
Treating inflammatory disorders by administering high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid with impurity (IIb) below 0.03% by weight.
Treating urogenital disorders by administering high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid with impurity (IIb) below 0.03% by weight.
Treating metabolic disorders by administering high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid with impurity (IIb) below 0.03% by weight.
Treating gastrointestinal disorders by administering high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid with impurity (IIb) below 0.03% by weight.
A mouse behavioral model result indicating ralfinamide reduces Amph/CDP-induced hyperactivity.
Assay-described assessment for pharmacology including Cytochrome P450 inhibition assay, cytotoxicity in SH-SY5Y with Alamar Blue, and HERG current inhibition in CHO cells.
In vitro/in vivo pharmacology assay descriptions and associated results are documented for the methanesulfonate forms.
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