November 1, 2018
The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of…
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4- methylbenzenesulfonate. SALT
|Molecular Weight:||565.704 g/mol|
Lumateperone (INN; developmental code names ITI-007, ITI-722) is an investigational atypical antipsychotic which is currently under development by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb, for the treatment of schizophrenia. It is also being developed by Intra-Cellular Therapies for the treatment of bipolar disorder, depression, and sleep and behavioral disturbance in dementia, autism, and other neuropsychiatric disorders. As of September 2015, lumateperone has passed the first of two phase IIIclinical trials for schizophrenia. In November 2017 the US FDA awarded Intra-Cellular Therapies Fast Track designation for lumateperone.
Relative to presently-available antipsychotics, lumateperone possesses a unique and novel mechanism of action. It acts as a 5-HT2A receptor antagonist (Ki = 0.54 nM), a partial agonist of presynaptic D2 receptors and an antagonist of postsynaptic D2 receptors (Ki = 32 nM), and a serotonin transporter blocker (Ki = 61 nM). It also possesses affinity for the D1 receptor (Ki = 52 nM) and lower affinity for the α1A– and α1B-adrenergic receptors (Ki = 73 nM at α1), 5-HT2C receptor (Ki = 173 nM), and D4 receptor. Lumateperone does not significantly bind to the 5-HT2B, H1 (Ki > 1,000 nM), muscarinic acetylcholine receptors, or many other sites (Ki > 100 nM).
Lumateperone shows a 60-fold difference in its affinities for the 5-HT2A and D2 receptors, which is far greater than that of most or all existing atypical antipsychotics, such as risperidone (12-fold), olanzapine (12.4-fold), and aripiprazole (0.18-fold). It is thought that this property may improve the effectiveness and reduce the side effect profile of lumateperone relative to currently-available antipsychotics, a hypothesis which is supported by the observation of minimal catalepsy in mice treated with the drug. Moreover, it has been expressed that this property could result in full occupancy and blockade of the 5-HT2A at low doses, with dose-dependent adjustable modulation of the D2 receptor, as well as the SERT, possible with increasing doses, which would uniquely allow for clinical optimization of efficacy and side effect incidence.
Unlike most current antipsychotics, such as haloperidol, risperidone, and olanzapine, lumateperone does not disrupt striatal dopamine signaling, a property which is likely due to its partial agonism of presynaptic D2 receptors. In accordance, similarly to aripiprazole, which is also a partial agonist of presynaptic D2 receptors, lumateperone showed no striatum-based motor side effects (i.e., catalepsy) in animals.
In phase II clinical trials, lumateperone showed statistically-significant efficacy in improvement of psychosis at a dose of 60 mg daily. In addition, it distinguished itself from its comparator risperidone in reducing negative symptoms, including improvement in social function, as well as in alleviating depressive symptoms in schizophrenia patients with comorbid depression, whereas risperidone had no effect. Lumateperone also distinguished itself from risperidone in that it produced little or no weight gain, did not negatively affect metabolic parameters (i.e., insulin, glucose, triglyceride, and cholesterol levels), did not increase prolactin levels, and did not show a rate of the side effect of akathisia that differed from placebo. In addition, lumateperone did not produce any changes in cardiovascular function, such as QTc prolongation, and unlike risperidone, it did not produce a measurable increase heart rate. Due to its favorable influence on metabolic parameters, it was concluded that lumateperone, unlike many other available antipsychotics such as risperidone, may not cause an increase in the risk of diabetes or cardiovascular disease, and hence may prove to be a significant improvement relative to many existing antipsychotic drugs in terms of long-term safety and tolerability.
Lumateperone, at a dose of 60 mg per day, was not found to be associated with any statistically significant treatment-emergent side effects relative to placebo. At a dose of 120 mg daily, the most frequent adverse effect observed was sedation/somnolence, reported by 32.5% of patients. There was no evidence of extrapyramidal symptoms or increase in suicidal ideation or behavior.
dx.doi.org/10.1021/jm401958n | J. Med. Chem. 2014, 57, 2670−2682
5 (367 mg, 53%yield) as a gray solid.
1H NMR (DMSO-d6, 500 MHz) δ 9.10 (br, 1H),8.10−8.01 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.42−7.33 (m, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.65−6.57 (m, 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 3.59 (dd, J = 12.2, 6.5 Hz, 1H), 3.52−3.37 (m, 3H), 3.37−3.28 (m, 2H), 3.25−3.20 (m, 1H), 3.18−2.99 (m, 5H), 2.81 (s, 3H), 2.71 (td, J = 10.2, 3.0 Hz, 1H), 2.63−2.52 (m, 1H), 2.28 (s, 3H), 2.27−2.22 (m, 1H), 2.15−1.93 (m, 3H).
13C NMR (DMSOd6, 126 MHz) δ 197.2, 165.1 (d, JCF = 252 Hz), 145.6, 137.6, 137.3, 135.2, 133.1, 130.9 (d, JCF = 10 Hz), 128.1, 126.7, 125.5, 120.6, 115.7 (d, JCF = 22 Hz), 112.5, 109.3, 62.2, 55.5, 52.5, 49.8, 47.8, 43.7, 38.6, 37.0, 34.9, 21.7, 20.8, 18.0.
MS (ESI) m/z 394.2 [M + H]+.
HRMS (ESI) m/z calcd for C24H29FN3O [M + H]+, 394.2295; found, 394.2292. UPLC purity, 97.7%; retention time, 2.06 min (method A).
0003] l-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H- pyrido[3′,4′:4,5]pyrrolo[l,2,3-de]quinoxalin-8-yl)-butan-l-one (sometimes referred to as 4- ((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3′,4′:4,5]pyrrolo[l,2,3- de]quinoxalin-8(7H)-yl)-l-(4-fluorophenyl)-l-butanone, or as ITI-007), has the following structure:
 ITI-007 is a potent 5-HT2A receptor ligand (Ki=0.5 nM) with strong affinity for dopamine (DA) D2 receptors (Ki=32 nM) and the serotonin transporter (SERT) (Ki=62 nM) but negligible binding to receptors (e.g., HI histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. ΠΊ-007 is currently in clinical trials, i.a., for treatment of schizophrenia. While ITI-007 is a promising drug, its production and formulation present challenges. In free base form, ITI-007 is an oily, sticky solid, with poor solubility, not only in water but also in many organic solvents. Making salts of the compound has proven to be unusually difficult. A hydrochloride salt form of ITI-007 was disclosed in US 7183282, but this salt is hygroscopic and shows poor stability. A toluenesulfonic acid addition salt (tosylate) of ITI- 007 was finally identified and described in WO 2009/114181.
 There is a need for alternative stable, pharmaceutically acceptable solid forms of ITI-007, which can be readily incorporated into galenic formulations.
 The following equipment and methods are used to isolate and characterize the exemplified co-crystal forms:
 X-ray powder diffraction (XRPD): The X-ray powder diffraction studies are performed using a Bruker AXS D2 PHASER in Bragg-Brentano configuration, equipment #1549 / #2353. The equipment uses a Cu anode at 30kV, 10 mA; sample stage standard rotating; monochromatization by a Κβ-filter (0.5% Ni). Slits: fixed divergence slits 1.0mm (=0.61°), primary axial Soller slit 2.5°, secondary axial Soller slit 2.5°. Detector: Linear detector LYNXEYE with receiving slit 5° detector opening. The standard sample holder (0.1 mm cavity in (510) silicon wafer) has a minimal contribution to the background signal. Measurement conditions: scan range 5 – 45° 2Θ, sample rotation 5 rpm, 0.5s/step, 0.010°/step, 3.0mm detector slit; and all measuring conditions are logged in the instrument control file. As system suitability, corundum sample A26- B26-S (NIST standard) is measured daily. The software used for data collection is Diffrac. Commander v2.0.26. Data analysis is done using Diffrac.Eva vl.4. No background correction or smoothing is applied to the patterns.
 Simultaneous thermogravimetry (TGA) and differential scanning calorimetry (DSC) or TGA/DSC analysis: The TGA/DSC studies are performed using a Mettler Toledo TGA/DSC 1 Stare System, equipment #1547, auto-sampler equipped, using pin-holed Al- crucibles of 40 μΐ. Measurement conditions: 5 min 30.0 °C, 30.0 – 350.0 °C with 10 °C/min., N2 flow of 40 ml/min. The software used for instrument control and data analysis is STARe vl2.10.
 Differential scanning calorimetry (DSC): The DSC studies are performed using a Mettler Toledo DSC1 STARe System, equipment #1564. The samples are made using Al crucibles (40 μΐ; pierced). Typically 1 – 8 mg of sample is loaded onto a pre- weighed Al crucible and is kept at 30°C for 5 minutes, after which it is heated at 10°C/min from 30°C to 350 °C and kept at 350°C for 1 minute. A nitrogen purge of 40 ml/min is maintained over the sample. As system suitability check Indium and Zinc are used as references. The software used for data collection and evaluation is STARe Software vl2.10 build 5937. No corrections are applied to the thermogram.
 Polarized light microscopy (PLM): The microscopy studies are performed using an Axio Vert 35M, equipped with an AxioCamERc 5s, equipment #1612. The microscope is equipped with four lenses: Zeiss A-Plan 5x/0.12, Zeiss A-Plan lOx/0.25, LD A-Plan 20x/0.30 and Achros TIGMAT 32x/0.40. Data collection and evaluation is performed using Carl Zeiss Zen Axio Vision Blue Edition Lite 2011 vl.0.0.0 software. A small amount of sample is loaded on an object glass and carefully spread until a thin layer is obtained.
 Dynamic Vapour Sorption (DVS): The Dynamic Vapour Sorption studies are performed using a Surface Measurement Systems Ltd. DVS-1 No Video, equipment #2126. The sample is loaded into a balance pan, typically 20-30 mg, and equilibrated at 0% RH. After the material was dried, the RH is increased with 10% per step for 1 hour per increment, ending at 95% RH. After completion of the sorption cycle, the sample was dried using the same method. The software used for data collection is DVSWin v3.01 No Video. Data analysis is performed using DVS Standard Analysis Suite v6.3.0 (Standard).
 Particle size distribution (PSD): The particle size distribution studies are performed using a Malvern Instruments Mastersizer, equipment #1712. The Mastersizer uses a 300RF lens range of 0.05 μηι – 900 mm. Polydisperse is used as analysis model. Measurement conditions: before each sample measurement a background measurement is performed, the background scan time is 12 seconds (12000 snaps). Each sample is dispersed in Multipar G, refractive index of 1.42. The obscuration range on sample dispersion is between 10%-30%. Each sample is measured 6 times at t=0 and t=30 minutes and the measurement scan time is 10 seconds (10000 snaps). The targeted stirring speed of the sample dispersion unit is 2000+10 rpm. Data collection and evaluation is performed using Mastersizer S Version 2.19 software.  Capillary Melting Point: The capillary melting point is determined on a Biichi Melting Point B-545, equipment #000011, conform USP guidelines.
 X-ray fluorescence (XRF): The X-ray fluorescence studies are performed using a Bruker AXS S2 RANGER, equipment #2006. Using an end-window X-ray tube with Palladium anode and an ultra-thin Beryllium window (75 μιη) for superior light element analysis. As detector the Xflash V5 detector with Cr, Ti, Al, Ta collimator (energy resolution < 129 eV FWHM at 100 000 cps Mnka) is used. The S2 Ranger is equipped with an autosampler with integrated 28 position X- Y automatic sample changer with exchangeable tray, which allows maximum sample diameter of 40 mm. Samples are mounted in steel rings of 51.5 mm diameter for automatic operation. Measurement conditions: disposable liquid cups (35 mm inner diameter, 40 mm outer diameter) with polypropylene foil 5 μιη. As system suitability check a copper disk is measured daily and a glass disk, containing several elements, is measured weekly. The software used for data collection is S2 Ranger Control Software V4.1.0. Data analysis is performed using SPECTRA EDX V2.4.3 evaluation software. No background correction or smoothing is applied to the patterns.
 Fourier transform infrared spectroscopy (FT-IR): The FT-IR studies are performed using a Thermo Scientific Nicolet iS50, equipment # 2357. An attenuated total reflectance (ATR) technique was used with a beam splitter of KBr. Experiment setup of the collected sample is used number of scans 16 with a resolution of 4from 400 cm“1 to 4000 cm“1. The software OMNIC version 9.2 is used for data collection and evaluation.
 Thermogravimetric analysis (TGA) with infrared spectroscopy (TGA-IR):
In TGA-IR, the off-gassing materials are directed through a transfer line to a gas cell, where the infrared light interacts with the gases. The temperature ramp and first derivative weight loss information from the TGA is shown as a Gram-Schmidt (GS) profile; the GS profile essentially shows the total change in the IR signal relative to the initial state. In most cases, the GS and the derivative weight loss will be similar in shape, although the intensity of the two can differ. For this experiment are two devices coupled to each other. The TGA studies are performed using a Mettler Toledo TGA/DSCl STARe System with a 34-position auto sampler, equipment #1547. The samples are made using Al crucibles (100 μΐ; pierced). Typically 20-50 mg of sample is loaded into a pre- weighed Al crucible and is kept at 30°C for 5 minutes after which it is heated at 10°C/min from 30°C to 350°C. A nitrogen purge of 40 ml/min is maintained over the sample. The TGA-IR module of the Nicolet iS50 is coupled to the TGA/DSCl. The IR studies were performed using a Thermo Scientific Nicolet iS50, equipment # 2357. Experiment setup of the collected series, the profile Gram-Schmidt is used number of scans 10 with a resolution of 4. The software OMNIC version 9.2 is used for data collection and evaluation.
 High performance liquid chromatography (HPLC): The high performance liquid chromatography analyses are performed on LC-31, equipped with an Agilent 1100 series G1322A degasser equipment #1894, an Agilent 1100 series G1311A quaternary pump equipment #1895, an Agilent 1100 series G1313A ALS equipment #1896, an Agilent 1100 series G1318A column equipment #1897 and an Agilent 1100 series G1314A VWD equipment #1898 / LC-34, equipped with an Agilent 1200 series G1379B degasser equipment #2254, an Agilent 1100 series G1311A quaternary pump equipment #2255, Agilent 1100 series G1367A WPALS equipment #1656, an Agilent 1100 series G1316A column equipment #2257 and an Agilent 1100 series G1315B DAD equipment #2258. Data is collected and evaluated using Agilent ChemStation for LC systems Rev. B.04.02. Solutions are prepared as follows: Mobile phase A: Add 800 ml of MilliQ water to a 1L volumetric flask. Add 1 ml of TFA and homogenize. Fill up to the mark with MilliQ; Mobile phase B: Add 800 ml of Acetonitrile to a 1L volumetric flask. Add 1 ml of TFA and homogenize. Fill up to the mark with Acetonitrile; Diluent: 50/50 MeOH/ACN.
Example 1: Co-crystal screen
 Solubility of free base in various solvents is evaluated, and based on the results of the solubility range, suitable solvents are selected for the co-crystal screen. Co-crystal formation is based on hydrogen bonding and stacking of the molecules, meaning the co-former selection is based on active groups. Grinding is a method to form co-crystals, however the free base itself is an oil/ sticky solid and therefore not suitable for this method. The free base and counter ion are added to a solution in a certain ratio to give the chance to form a co-crystal, similar to salt formation. We found the best method is to add a saturated solution of the co-former to that of the free base to find an optimal ratio for co-crystal formation.
 Three different experiments are performed with each of 26 candidate co-formers, which include sugar alcohols, amino acids, and other compounds identified as having potential to for co- crystals; adding solutions stepwise, slurry experiments and cooling crystallization experiments. The free base and co-former are dissolved prior to adding to each other. Co-formers are added in a 1 : 1 , 2: 1 and 1 :2 ratio to the free base. All experiments are performed using four different solvents, methanol, acetonitrile, ethyl acetate and toluene. All solids are characterized by XRPD. Two different ITI-007 free base co-crystals formed, with nicotinamide and with isonicotinamide. Both co-crystals were obtained by slurry experiments in methanol.
Example 2: Isonicotinamide co-crystal
 Isonicotinamide forms a possible co-crystal with ITI-007 free base by slurrying the mixture in methanol and ethyl acetate, appearing as a red/brown and yellow solid respectively. TGA-DSC analysis of the experiment using isonicotinamide in methanol results in two endothermic events,
Both endothermic events do not correspond to the free base or the co-former, which means ITI-007 free base-isonicotinamide co-crystal is formed. HPLC and Ή-ΝΜΡ analyses confirm both of the free base and the co-former to be present. Using isonicotinamide in ethyl acetate, however, does not result in a co-crystal and, no endothermic event is present in the TGA/DSC analysis.
 The slurry experiment in methanol is repeated at a gram scale. First, ITI-007 free base and isonicotinamide are each dissolved in methanol. Subsequently, the obtained solutions are mixed in a 1: 1 ratio and the resulting mixture is stirred at room temperature for 2 hours. The mixture remains a clear solution, which is evaporated under vacuum to give a brown sticky solid. XRPD analysis shows the brown sticky solid to be crystalline, as shown in Figure 1, ITI-007 free base-isonicotinamide co-crystal has formed. The corresponding peak list is showing in Table 1. The XRPD shows clustered peaks which is likely due to preferred orientation.
The present application relates to solid state forms of Lumateperone p-Tosylate and processes for preparation thereof.
The drug compound is having the adopted name “Lumateperone” and it has chemical name: l-(4-fluorophenyl)-4-[(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-3-methyl-lH-pyrido[3′,4′:4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl] 1-Butanone; and a structure depicted by Formula I.
International Patent Application Publication Nos. WO2000077002A1, WO2009145900 A 1 and WO2013155504A1 which are incorporated herein in their entirety reported Lumateperone and its related compounds. These compounds have been found to be useful as 5-HT2 receptor agonists and antagonists used in treating disorders of the central nervous system including a disorder associated with 5HT2C or 5HT2A receptor modulation selected from obesity, anorexia, bulemia, depression, a anxiety, psychosis, schizophrenia, migraine, obsessive -compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility. International Patent Application Publication No. WO2008112280A1 disclose process(es) for preparing Lumateperone and its salts.
International Patent Application Publication No. WO2009114181A2 disclose crystalline forms of the p-Tosylate salt of compound of Formula (I), WO 2017172784 Al disclose oxalate, aminosalicylate, cyclamate salts of Lumateperone, WO 2017172811 Al
disclose co-crystal of Lumateperone with iso-nicotinamide, nicotinatinamide, WO 2018031535 Al disclose crystalline Form Fl of Lumateperone ditosylate.
Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form. For some therapeutic indications, one bioavailability pattern may be favored over another. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.
In view of the above, it is therefore, desirable to stable amorphous form of Lumateperone j?-tosylate. The amorphous form provided herein is at least stable under ordinary stability conditions with respect to purity, storage and is free flowing powder.
Amorphous solid dispersions of drugs are generally known to improve the stability and solubility of drug products. However, some of such amorphous solid dispersions are found to be unstable over time. Amorphous solid dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material. The present invention, however provides stable amorphous solid dispersions of Lumateperone j?-tosylate with improved solubility. Moreover, the present invention provides solid dispersions of Lumateperone j?-tosylate which may be reproduced easily and is amenable for processing into a dosage form
EXAMPLE 1 : PREPARATION OF AMORPHOUS LUMATEPERONE p-TOSYLATE
Lumateperone j?-tosylate (500 mg) was dissolved in methanol (25 mL) at room temperature for clear solution and filtered to remove undissolved particles. The resultant filtrate was subjected to fast solvent evaporation using rotavapor at about 55°C to afford the solid compound. The said solid was dried under vacuum at about 45°C to afford the amorphous Lumateperone p-tosylate according to Figure 1.
|Chemical and physical data|
|3D model (JSmol)|
|Patent ID||Title||Submitted Date||Granted Date|
|US8648077||SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SOLID||
|US9586960||SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SOLID||
|US9199995||SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SOLID||
////// Lumateperone, PHASE 3, ITI-007, ITI-722
November 16, 2018
The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.
“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.
Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by having three or more unformed stools in 24 hours, in a person who is traveling. It is caused by a variety of pathogens, but most commonly bacteria found in food and water. The highest-risk destinations are in most of Asia as well as the Middle East, Africa, Mexico, and Central and South America.
The efficacy of Aemcolo was demonstrated in a randomized, placebo-controlled clinical trial in 264 adults with travelers’ diarrhea in Guatemala and Mexico. It showed that Aemcolo significantly reduced symptoms of travelers’ diarrhea compared to the placebo.
The safety of Aemcolo, taken orally over three or four days, was evaluated in 619 adults with travelers’ diarrhea in two controlled clinical trials. The most common adverse reactions with Aemcolo were headache and constipation.
Aemcolo was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients. Aemcolo should not be used in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components in Aemcolo.
The FDA granted Aemcolo a Qualified Infectious Disease Product (QIDP)designation. QIDP designation is given to antibacterial and antifungal drug products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, the Aemcolo marketing application was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.
The FDA granted approval of Aemcolo to Cosmo Technologies, Ltd.
ACT-541468, UNII LMQ24G57E9
Nemorexant (developmental code name ACT-541468) is a dual orexin receptor antagonist (DORA) which was originated by Actelion Pharmaceuticals and is under development by Idorsia Pharmaceuticals for the treatment of insomnia. It acts as a selective dual antagonist of the orexin receptors OX1 and OX2. As of June 2018, nemorexant is in phase III clinical trials for the treatment of insomnia.
Idorsia is developing nemorexant, a dual orexin receptor antagonist (DORA), for the oral treatment of insomnia and investigating the program for the treatment of COPD. In May 2018, a phase III study was initiated in subjects with insomnia disorder and in September 2018, a phase I trial was initiated in COPD.
Synthesis of nemorexant, using 2-methyl-L-proline hydrochloride as the starting material
N-Protection of 2-methyl-L-proline hydrochloride with Boc2O gives N-Boc-2-methyl-L-proline,
Which upon condensation with 4-chloro-3-methylbenzene-1,2-diamine using HATU and DIEA in CH2Cl2 affords the corresponding amide.
Cyclization of diamine in the presence of AcOH at 100 °C provides imidazole derivative,
Whose Boc moiety is removed by means of HCl in dioxane to yield 5-chloro-4-methyl-2-[2(S)-methylpyrrolidin-2-yl]benzimidazole hydrochloride.
N-Acylation of pyrrolidine derivative with 5-methoxy-2-(1,2,3-triazol-2-yl)benzoic acid using HATU and DIEA in CH2Cl2 produces Nemorexant
5-methoxy-2-(1,2,3-triazol-2-yl)benzoic acid (prepared by the coupling of 2-iodo-5-methoxybenzoic acid with 1,2,3-triazole using CuI and Cs2CO3 in DMF)
Reference Example 1
1) Synthesis of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid
2-lodo-5-methoxy benzoic acid (15.0 g; 53.9 mmol) is dissolved in anhydrous DMF (45 ml) followed by the addition of 1 H-1 ,2,3-triazole (7.452 g; 108 mmol) and cesium carbonate (35.155 g; 108 mmol). By the addition of cesium carbonate the temperature of the reaction mixture increases to 40°C and gas evolved from the reaction mixture. Copper(l)iodide (514 mg; 2.7 mmol) is added. This triggers a strongly exothermic reaction and the temperature of the reaction mixture reaches 70°C within a few seconds. Stirring is continued for 30 minutes. Then the DMF is evaporated under reduced pressure followed by the addition of water (170 ml) and EtOAc (90 ml). The mixture is vigorously stirred and by the addition of citric acid monohydrate the pH is adjusted to 3-4. The precipitate is filtered off and washed with water and EtOAc and discarded. The filtrate is poured into a separation funnel and the phases are separated. The water phase is extracted again with EtOAc. The combined organic layers are dried over MgS04, filtered and the solvent is evaporated to give 7.1 g of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid as a white powder of 94% purity (6 % impurity is the regioisomerically N1-linked triazolo-derivative); tR [min] = 0.60; [M+H]+ = 220.21
2) Synthesis of (S)-1 -(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid
2-Methyl-L-proline hydrochloride (99.7 g; 602 mmol) is dissolved in a 1/1-mixture of MeCN and water (800 ml) and triethylamine (254 ml; 1810 mmol) is added. The temperature of the reaction mixture slightly rises. The reaction mixture is cooled to 10°C to 15°C followed by careful addition of a solution of Boc20 (145 g; 662 mmol) in MeCN (200 ml) over 10 minutes.
Stirring at RT is continued for 2 hours. The MeCN is evaporated under reduced pressure and aq. NaOH solution (2M; 250 ml) is added to the residual aq. part of the reaction mixture. The water layer is washed with Et20 (2x 300 ml) then cooled to 0°C followed by slow and careful addition of aq. HCI (25%) to adjust the pH to 2. During this procedure a suspension forms.
The precipitate is filtered off and dried at HV to give 1 10.9 g of the title compound as a beige powder; tR [min] = 0.68; [M+H]+ = 230.14
3) Synthesis of (S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-
(S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (60 g; 262 mmol) and HATU (100 g; 264 mmol) is suspended in DCM (600 ml) followed by the addition of DIPEA (84.6 g; 654 mmol) and 6-chloro-2,3-diaminotoluene (41 g; 262 mmol). The reaction mixture is stirred at rt for 14 hours then concentrated under reduced pressure and to the residue is added water followed by the extraction of the product with EtOAc (3x). The combined organic layers are washed with brine, dried over MgS04, filtered and the solvent is evaporated under
reduced pressure to give 185 g of the title compound as a dark brownish oil, which is used in the next step without further purification; tR [min] = 0.89; [M+H]+ = 368.01
4) Synthesis of (S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1 -carboxylate
(S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-methylpyrrolidine-1-carboxylate (185 g; 427 mmol) are dissolved in AcOH (100%; 611 ml), heated to 100°C and stirring continued for 90 minutes. The AcOH is evaporated under reduced pressure and the residue is dissolved in DCM followed by careful addition of saturated sodium bicarbonate solution. The phases are separated, the aq. phase is extracted once more with DCM, the combined aq. phases are dried over MgS04, filtered and the solvent is evaporated under reduced pressure to give 142.92 g of the title compound as a dark brown oil which is used in the next step without further purification; tR [min] = 0.69; [M+H]+ = 350.04
5) Synthesis of (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride
(S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (355.53 g; 1.02 mol) are dissolved in dioxane (750 ml) followed by careful addition of HCI solution in dioxane (4M; 750 ml; 3.05 mol). The reaction mixture is stirred for 3 hours followed by the addition of Et20 (800 ml) which triggered precipitation of the product. The solid is filtered off and dried at high vacuum to give 298.84 g of the title compound as a redish powder; tR [min] = 0.59; [M+H]+ = 250.23
6) Synthesis of [(S)-2-(5-chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-pyrrolidin-1- -(5-methoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone
(S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride (62.8 g; 121 mmol) is dissolved in DCM (750 ml) followed by the addition of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (62.8 g; 121 mmol) and DIPEA (103 ml; 603 mmol). Stirring is continued for 10 minutes followed by the addition of HATU (47 g; 124 mmol). The reaction mixture is stirred for 16 hours at RT. The solvents are evaporated under reduced pressure and the residue is dissolved in EtOAc (1000 ml) and washed with water (3x 750 ml). The organic phase is dried over MgS04, filtered and the solvent is evaporated under reduced pressure. The residue is purified by CC with EtOAc / hexane = 2 / 1to give 36.68 g of the title compound as an amorphous white powder. tR [min] = 0.73; [M+H]+ = 450.96
Table 1 : Characterisation data for COMPOUND as free base in amorphous form
II. Preparation of crystalline forms of COMPOUND
Example 1 :
Preparation of seeding material of COMPOUND hydrochloride in crystalline Form 1
10 mg COMPOUND is mixed with 0.2 mL 0.1 M aq. HCI and 0.8 mL EtOH. The solvent is fully evaporated and 0.05 mL isopropanol is added. Alternatively 0.05 mL methyl-isobutylketone can be added. The sample is stored closed at room temperature for 4 days and crystalline material of COMPOUND hydrochloride in crystalline Form 1 is obtained. This material can be used as seeding material for further crystallization of COMPOUND hydrochloride in crystalline Form 1.
Example 2: Preparation and characterization of COMPOUND hydrochloride in crystalline form 1
5g COMPOUND is mixed with 0.9 mL 1 M aq. HCI and 20 mL EtOH. The solvent is evaporated and 25 mL isopropanol is added. Seeds of COMPOUND hydrochloride are added and the sample is allowed to stand at room temperature. After about 2 days the suspension is filtered and the solid residue is dried at reduced pressure (2 mbar for 1 hour) and allowed to equilibrate open for 2 hours at 24°C/46% relative humidity. The obtained solid is COMPOUND hydrochloride in crystalline Form 1
Table 2: Characterisation data for COMPOUND hydrochloride in crystalline form 1
Process for the preparation of a crystalline potassium salt of a 2-(2H-[1,2,3]triazol-2-yl)-benzoic acid derivatives is claimed. Compound is disclosed to be useful for the preparation of pharmaceuticals, especially certain orexin receptor antagonists such as nemorexant .
|Patent ID||Title||Submitted Date||Granted Date|
|US9790208||CRYSTALLINE SALT FORM OF (S)-(2-(6-CHLORO-7-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1-YL)(5-METHOXY-2-(2H-1, 2, 3-TRIAZOL-2-YL)PHENYL)METHANONE AS OREXIN RECEPTOR ANTAGONIST||
|US2016368901||CRYSTALLINE FORM OF (S)-(2-(6-CHLORO-7-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1 -YL)(5-METHOXY-2-(2H-1, 2, 3-TRIAZOL-2-YL)PHENYL)METHANONE AND ITS USE AS OREXIN RECEPTOR ANTAGONISTS||
|Drug class||Orexin antagonist|
|Chemical and physical data|
|Molar mass||450.927 g/mol|
|3D model (JSmol)|
///////////////Nemorexant, ACT-541468, Phase III, Insomnia
Eflornithine, also known as α-difluoromethylornithine (DFMO), is an Active Pharmaceutical Ingredient (API) on the World Health Organization’s list of essential medicines. DFMO is used to treat the second stage of African trypanosomiasis (sleeping sickness). In addition, DFMO is also used to treat opportunistic infections with Pneumocystis carinii pneumonia, a form of pneumonia found in people with a weak immune system suffering from conditions such as acquired immunodeficiency syndrome (AIDS) It has also been explored as chemopreventive agent in cancer therapy with minor success. Today, its main use is to treat excessive facial hair growth on women (hirsutism). The topical cream (Vaniqa) significantly reduces the psychological burden of those affected.\
Eflornithine is a prescription drug indicated in the treatment of facial hirsutism (excessive hair growth). Eflornithine hydrochloride cream for topical application is intended for use in women suffering from facial hirsutism and is sold by Allergan, Inc. under the brand name Vaniqa. Besides being a non-mechanical and non-cosmetic treatment, eflornithine is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism. Eflornithine for injection against sleeping sickness was manufactured by Sanofi Aventis and sold under the brand name Ornidyl in the USA. It is now discontinued. Eflornithine is on the World Health Organization’s List of Essential Medicines.
Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women. Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is used by injection or applied to the skin.
Common side effects when applied as a cream include rash, redness, and burning. Side effects of the injectable form include bone marrow suppression, vomiting, and seizures. It is unclear if it is safe to use during pregnancy or breastfeeding. It is recommended typically for children over the age of 12.
Eflornithine was developed in the 1970s and came into medical use in 1990. It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system. There is no generic version as of 2015 in the United States. In the United States the injectable form can be obtained from the Centers for Disease Control and Prevention. In the 1990s the cost of a course of treatment in Africa was 210 USD. In regions of the world where the disease is common eflornithine is provided for free by the World Health Organization.
Sleeping sickness, or trypanosomiasis, is treated with pentamidine or suramin (depending on subspecies of parasite) delivered by intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine intravenous injection in the second phase of the disease. Efornithine is commonly given in combination with nifurtimox, which reduces the treatment time to 7 days of eflornithine infusions plus 10 days of oral nifurtimox tablets.
Eflornithine is also effective in combination with other drugs, such as melarsoprol and nifurtimox. A study in 2005 compared the safety of eflornithine alone to melarsoprol and found eflornithine to be more effective and safe in treating second-stage sleeping sickness Trypanosoma brucei gambiense. Eflornithine is not effective in the treatment of Trypanosoma brucei rhodesiense due to the parasite’s low sensitivity to the drug. Instead, melarsoprol is used to treat Trypanosoma brucei rhodesiense. Another randomized control trial in Uganda compared the efficacy of various combinations of these drugs and found that the nifurtimox-eflornithine combination was the most promising first-line theory regimen.
A randomized control trial was conducted in Congo, Côte d’Ivoire, the Democratic Republic of the Congo, and Uganda to determine if a 7-day intravenous regimen was as efficient as the standard 14-day regimen for new and relapsing cases. The results showed that the shortened regimen was efficacious in relapse cases, but was inferior to the standard regimen for new cases of the disease.
After its introduction to the market in the 1980s, eflornithine has replaced melarsoprol as the first line medication against Human African trypanosomiasis (HAT) due to its reduced toxicity to the host. Trypanosoma brucei resistant to eflornithine has been reported as early as the mid-1980s.
The gene TbAAT6, conserved in the genome of Trypanosomes, is believed to be responsible for the transmembrane transporter that brings eflornithine into the cell. The loss of this gene due to specific mutations causes resistance to eflornithine in several trypanosomes. If eflornithine is prescribed to a patient with Human African trypanosomiasis caused by a trypanosome that contains a mutated or ineffective TbAAT6 gene, then the medication will be ineffective against the disease. Resistance to eflornithine has increased the use of melarsoprol despite its toxicity, which has been linked to the deaths of 5% of recipient HAT patients.
The topical cream is indicated for treatment of facial hirsutism in women. It is the only topical prescription treatment that slows the growth of facial hair. It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment. Positive results were seen after eight weeks. However, discontinuation of the cream caused regrowth of hair back to baseline levels within 8 weeks.
Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.
It has been noted that ornithine decarboxylase (ODC) exhibits high activity in tumor cells, promoting cell growth and division, while absence of ODC activity leads to depletion of putrescine, causing impairment of RNA and DNA synthesis. Typically, drugs that inhibit cell growth are considered candidates for cancer therapy, so eflornithine was naturally believed to have potential utility as an anti-cancer agent. By inhibiting ODC, eflornithine inhibits cell growth and division of both cancerous and noncancerous cells.
However, several clinical trials demonstrated minor results. It was found that inhibition of ODC by eflornithine does not kill proliferating cells, making eflornithine ineffective as a chemotherapeutic agent. The inhibition of the formation of polyamines by ODC activity can be ameliorated by dietary and bacterial means because high concentrations are found in cheese, red meat, and some intestinal bacteria, providing reserves if ODC is inhibited. Although the role of polyamines in carcinogenesis is still unclear, polyamine synthesis has been supported to be more of a causative agent rather than an associative effect in cancer.
Other studies have suggested that eflornithine can still aid in some chemoprevention by lowering polyamine levels in colorectal mucosa, with additional strong preclinical evidence available for application of eflornithine in colorectal and skin carcinogenesis. This has made eflornithine a supported chemopreventive therapy specifically for colon cancer in combination with other medications. Several additional studies have found that eflornithine in combination with other compounds decreases the carcinogen concentrations of ethylnitrosourea, dimethylhydrazine, azoxymethane, methylnitrosourea, and hydroxybutylnitrosamine in the brain, spinal cord, intestine, mammary gland, and urinary bladder.
Topical use is contraindicated in people hypersensitive to eflornithine or to any of the excipients.
Throughout clinical trials, data from a limited number of exposed pregnancies indicate that there is no clinical evidence that treatment with Vaniqa adversely affects pregnant women or fetuses.
When taken by mouth the risk-benefit should be assessed in people with impaired renal function or pre-existing hematologic abnormalities, as well as those with eighth-cranial-nerve impairment. Adequate and well-controlled studies with eflornithine have not been performed regarding pregnancy in humans. Eflornithine should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. However, since African trypanosomiasis has a high mortality rate if left untreated, treatment with eflornithine may justify any potential risk to the fetus.
The topical form of elflornithine is sold under the brand name Vaniqa . The most frequently reported side effect is acne (7–14%). Other side effects commonly (> 1%) reported are skin problems, such as skin reactions from in-growing hair, hair loss, burning, stinging or tingling sensations, dry skin, itching, redness or rash.
The intravenous dosage form of eflornithine is sold under the brand name Ornidyl. Most side effects related to systemic use through injection are transient and reversible by discontinuing the drug or decreasing the dose. Hematologic abnormalities occur frequently, ranging from 10–55%. These abnormalities are dose-related and are usually reversible. Thrombocytopenia is thought to be due to a production defect rather than to peripheral destruction. Seizures were seen in approximately 8% of patients, but may be related to the disease state rather than the drug. Reversible hearing loss has occurred in 30–70% of patients receiving long-term therapy (more than 4–8 weeks of therapy or a total dose of >300 grams); high-frequency hearing is lost first, followed by middle- and low-frequency hearing. Because treatment for African trypanosomiasis is short-term, patients are unlikely to experience hearing loss.
No interaction studies with the topical form have been performed.
Eflornithine is a “suicide inhibitor,” irreversibly binding to ornithine decarboxylase (ODC) and preventing the natural substrate ornithine from accessing the active site (Figure 1). Within the active site of ODC, eflornithine undergoes decarboxylation with the aid of cofactor pyridoxal 5’-phosphate (PLP). Because of its additional difluoromethyl group in comparison to ornithine, eflornithine is able to bind to a neighboring Cys-360 residue, permanently remaining fixated within the active site.
During the reaction, eflornithine’s decarboxylation mechanism is analogous to that of ornithine in the active site, where transamination occurs with PLP followed by decarboxylation. During the event of decarboxylation, the fluoride atoms attached to the additional methyl group pull the resulting negative charge from the release of carbon dioxide, causing a fluoride ion to be released. In the natural substrate of ODC, the ring of PLP accepts the electrons that result from the release of CO2.
The remaining fluoride atom that resides attached to the additional methyl group creates an electrophilic carbon that is attacked by the nearby thiol group of Cys-360, allowing eflornithine to remain permanently attached to the enzyme following the release of the second fluoride atom and transimination.
The reaction mechanism of Trypanosoma brucei‘s ODC with ornithine was characterized by UV-VIS spectroscopy in order to identify unique intermediates that occurred during the reaction. The specific method of multiwavelength stopped-flow spectroscopy utilized monochromatic light and fluorescence to identify five specific intermediates due to changes in absorbance measurements. The steady-state turnover number, kcat, of ODC was calculated to be 0.5 s-1 at 4 °C. From this characterization, the rate-limiting step was determined to be the release of the product putrescine from ODC’s reaction with ornithine. In studying the hypothetical reaction mechanism for eflornithine, information collected from radioactive peptide and eflornithine mapping, high pressure liquid chromatography, and gas phase peptide sequencing suggested that Lys-69 and Cys-360 are covalently bound to eflornithine in T. brucei ODC’s active site. Utilizing fast-atom bombardment mass spectrometry (FAB-MS), the structural conformation of eflornithine following its interaction with ODC was determined to be S-((2-(1-pyrroline-methyl) cysteine, a cyclic imine adduct. Presence of this particular product was supported by the possibility to further reduce the end product to S-((2-pyrrole) methyl) cysteine in the presence of NaBH4 and oxidize the end product to S-((2-pyrrolidine) methyl) cysteine (Figure 2).
Eflornithine’s suicide inhibition of ODC physically blocks the natural substrate ornithine from accessing the active site of the enzyme (Figure 3). There are two distinct active sites formed by the homodimerization of ornithine decarboxylase. The size of the opening to the active site is approximately 13.6 Å. When these openings to the active site are blocked, there are no other ways through which ornithine can enter the active site. During the intermediate stage of eflornithine with PLP, its position near Cys-360 allows an interaction to occur. As the phosphate of PLP is stabilized by Arg 277 and a Gly-rich loop (235-237), the difluoromethyl group of eflornithine is able to interact and remain fixated to both Cys-360 and PLP prior to transimination. As shown in the figure, the pyrroline ring interferes with ornithine’s entry (Figure 4). Eflornithine will remain permanently bound in this position to Cys-360. As ODC has two active sites, two eflornithine molecules are required to completely inhibit ODC from ornithine decarboxylation.
Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but was found to be ineffective in treating malignancies. However, it was discovered to be highly effective in reducing hair growth, as well as in the treatment of African trypanosomiasis (sleeping sickness), especially the West African form (Trypanosoma brucei gambiense).
In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the U.S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation.
The drug was registered for the treatment of gambiense sleeping sickness on November 28, 1990. However, in 1995 Aventis (now Sanofi-Aventis) stopped producing the drug, whose main market was African countries, because it did not make a profit.
In 2001, Aventis and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders) in countries where sleeping sickness is endemic.
According to Médecins sans Frontières, this only happened after “years of international pressure,” and coinciding with the period when media attention was generated because of the launch of another eflornithine-based product (Vaniqa, for the prevention of facial-hair in women),while its life-saving formulation (for sleeping sickness) was not being produced.
From 2001 (when production was restarted) through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives.
Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe. Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.
Ornidyl, intended for injection, was supplied in the strength of 200 mg eflornithine hydrochloride per ml.
In 2000, the cost for the 14-day regimen was US $500; a price that many in countries where the disease is common cannot afford.
Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission among others, is currently the only topical prescription treatment that slows the growth of facial hair. Besides being a non-mechanical and non-cosmetic treatment, it is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism. Vaniqa is marketed by Almirall in Europe, SkinMedica in the USA, Triton in Canada, Medison in Israel, and Menarini in Australia.
Ornidyl, the injectable form of eflornithine hydrochloride, is licensed by Sanofi-Aventis, but is currently discontinued in the US.
Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source
The development of a scalable telescoped continuous flow procedure for difluoromethylation of a protected amino acid with fluoroform (CHF3, R-23) gas and subsequent high temperature deprotection to provide eflornithine, an important Active Pharmaceutical Ingredient (API), is described. Eflornithine is used for the treatment of sleeping sickness and hirsutism, and it is on the World Health Organization’s list of essential medicines. Fluoroform is produced in large quantities as a side product in the manufacture of polytetrafluoroethylene (PTFE, Teflon). Fluoroform is an ozone-benign and nontoxic gas, but its release into the environment is forbidden under the Kyoto protocol owing to its high global warming potential. The existing manufacturing route to eflornithine uses chlorodifluoromethane (CHClF2, R-22) which will be phased out under the Montreal protocol; therefore, the use of the fluoroform presents a viable cost-effective and more sustainable alternative. The process parameters and equipment setup were optimized on laboratory scale for the two reaction steps to improve product yield and scalability. The telescoped flow process utilizing fluoroform gas was operated for 4 h to afford the target molecule in 86% isolated yield over two steps with a throughput of 24 mmol/h.
1hydrochloride monohydrate as colorless powder. (17.05 g, 72.3 mmol, 86% yield). Mp. 228 °C;
1H NMR (300.36 MHz, D2O): δ = 6.46 (t, 2JHF = 52.8 Hz, 1H), 3.05 (t,3JHH = 7.6 Hz, 2H), 2.25–1.97 (m, 2H), 1.96–1.79 (m, 1H), 1.76–1.59 (m, 1H) ppm.
13C NMR (75 MHz, D2O): δ = 167.8 (d, 3JCF = 6.4 Hz), 114.0 (dd, 1JCF = 249.7 Hz, 1JCF = 247.0 Hz), 64.5 (dd, 2JCF = 20.4 Hz, 2JCF = 18.7 Hz), 38.8 (d, 3JCF = 7.3 Hz), 31.6 (d, 4JCF = 3.2 Hz), 20.8 ppm.
19F NMR (282 MHz, D2O): δ = −126.28 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz), – 131.76 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz) ppm.
|Trade names||Vaniqa, others|
|Synonyms||α-difluoromethylornithine or DFMO|
|Elimination half-life||8 hours|
|Chemical and physical data|
|Molar mass||182.17 g·mol−1|
|3D model (JSmol)|
/////////////ZQN1G5V6SR, эфлорнитин , إيفلورنيثين , 依氟鸟氨酸 , Eflornithine, エフロルニチン
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FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin
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November 1, 2018
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Pirlindole (Lifril, Pyrazidol) is a reversible inhibitor of monoamine oxidase A (RIMA) which was developed and is used in Russia as an antidepressant.:337 It is structurally and pharmacologically related to metralindole.
Biovista is investigating BVA-201, a repurposed oral formulation of pirlindole mesylate, for the potential treatment of multiple sclerosis
Khimiko-Farmatsevticheskii Zhurnal (1986), 20(3), 300-3.
U.S.S.R. (1986), SU 276060
Sudebno-meditsinskaia ekspertiza (1989), 32(4), 49-50
claiming method for resolving racemic mixture of pirlindole hydrochloride into enantiomerically pure (S)-pirlindole and/or (R)-pirlindole,
Pirlindole, 2, 3, 3a, 4, 5, 6-hexahydro-lH-8-methyl-pyrazine
[3, 2, 1-j , k] carbazole, is a tetracyclic compound of the formula I
Pirlindole is a reversible monoamine oxidase A inhibitor being up to date useful as a medicament in the treatment of depression.
Pirlindole has an asymmetric carbon atom which implies that there are two enantiomers, (S) -pirlindole and (R) -pirlindole .
The state of the art teaches several methods for the enantiomeric separation of pirlindole. For example, The Journal of Pharmaceutical and Biomedical Analysis, 18(1998) 605- 614, “Enantiomeric separation of pirlindole by liquid chromatography using different types of chiral stationary phases”, Ceccato et al, discloses the enantiomeric separation of pirlindole by liquid chromatography (LC) using three different chiral stationary phases.
Further, The Journal of Pharmaceutical and Biomedical Analysis 27(2002) 447-455, “Automated determination of pirlindole enantiomers in plasma by on-line coupling of a pre-column packed with restricted access material to a chiral liquid chromatographic column”, Chiap et al., discloses the use of a pre-column packed with restricted access material for sample clean up coupled to a column containing a cellulose based chiral stationary phase for separation and quantitative analysis of the enantiomers .
According to the prior art, Chirality 11:261-266 (1999) all attempts to obtain the enantiomers of pirlindole by selective crystallization with optically active acids failed, and it was only possible to obtain at laboratory scale (few grams) as hydrochloride salt, using derivatization technique in conjunction with preparative chromatography.
The characteristics of the process disclosed in the state of the art limit in a definitive way, its implementation on an industrial or semi-industrial scale due to the necessity to use a separation by chromatography on a large scale which makes the process very costly, difficult to implement and with poor reproducibility. .
(R) -Pirlindole mesylate
Starting from 10 g of (R) -pirlindole (S) -mandelate obtained in Example 1 and following the procedure described in Example 5 using methanesulfonic acid as pharmaceutical acceptable acid, ,
7.4 g (0.023 mole) of (R) -pirlindole mesylate were obtained (yield = 85.2% ). Chiral HPLC (enantiomeric purity = 98.0%).
(S) -pirlindole mesylate
Starting from 10 g of (S) -pirlindole (R) -mandelate obtained in Example 2 and following the procedure described in Example 6 using methanesulfonic acid as pharmaceutical acceptable acid, 6.8 g (0.021 mole) of (S) -pirlindole mesylate were obtained (yield = 77.8%). Chiral HPLC (enantiomeric purity = 98.0%).
Process for the preparation of pirlindole . useful for treating depression.
Pirlindole (8-methyl-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole) of formula I
Compound Formula I
also described as Pyrazidole™ represents a new class of original tetracyclic antidepressants, the pyrazinocarbazole derivatives. The drug was synthesized and characterized at the end of the 1960s and was marketed as an anti-depressant in 1975. Current clinical trials have demonstrated to be a highly effective short-acting and safe drug.
 Pirlindole is a selective, reversible inhibitor of MAO-A. In-vitro evidence suggest the catalytic oxidation of Pirlindole into dehydro-pirlindole by MAO-A. Dehydro-pirlindole may be a more potent slowly reversible inhibitor of MAO-A and this might explain the persistence of MAO-A inhibition in-vivo (MAO-The mother of all amine oxidases, John P.M. Finberg et al. 1998, Springer).
 Pirlindole chemical structure is composed of one stereogenic centre which indicates the existence of two enantiomers, the ( ?)-Pirlindole and the (S)-Pirlindole.
 Although Pirlindole pharmacological data and the clinical use were performed on the racemate, recently there have been increasing interest in the pharmacological profile of each enantiomer (WO 2015/171005 Al).
 International patent publication WO 2015/171003A1 filed 9th May 2014 discloses a resolution of racemic pirlindole into optically active pirlindole. The Resolution-Racemization-Recycle (RRR) synthesis described involves derivatization by preparation of pairs of diastereomers in the form of salts from an optically active organic acid. These diastereomers can be separated by conventional techniques such as crystallisation. Although it is a very efficient procedure to prepare laboratorial scale or pre-clinical batch of (/?)- or (S)-Pirlindole, it is not economically convenient at an industrial scale because the process relies on Pirlindole racemate as the starting material.
 Andreeva et al. (Pharmaceutical Chemistry 1992, 26., 365-369) discloses the first isolation of Pirlindole enantiomers in isolated form. ( ?)-Pirlindole of formula II
was isolated as an hydrochloride salt from a racemic base by the fractional crystallization of racemic pirlindole salt with (+)-camphor-10-sulfonic acid. (S)-Pirlindole formula III
was also isolated as an hydrochloride salt although via asymmetric synthesis from the 6-methyl-2,3,4,9-tetrahydro-lH-carbazol-l-one IV
 Compound of formula IV was reacted with chiral auxiliary (S)-(-)-a-methylbenzylamine to afford asymmetric (S)-6-methyl-N-(l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-imine V
 Compound of formula V was subjected to stereoselective reduction with sodium borohydride in ethanol. According to Andreeva et al. the reaction might occur through directed intramolecular hydride transfer after formation of a complex between compound of formula V and reducing agent to afford (S)-6-methyl-N-((S)-l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-amine VI
 Compound of formula VI is reacted with ethylene glycol ditosylate by ethylene bridge formation under alkaline conditions to yield (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole VII.
 Alkaline agent is sodium hydride (NaH), in the presence of dimethyl sulfoxide (DMSO) or dimethylformamide (DMF).
 The ratio between alkaline agent, compound of formula VI and ethylene glycol ditosylate is 1.2:1:1.
 The cyclization reaction occurs at room temperature for a period of 4.5 hours.  Compound of formula VII was subjected to catalytic hydrogenolysis conditions to afford the desired hydrochloride salt of compound of formula III.
 The hydrogenolysis reaction was catalysed by Palladium on charcoal (Pd content 0.1 g, 9 mol%) and was conducted in methanol. The conversion of compound of formula VII into compound of formula III was performed under a hydrogen pressure of 1.8-2.0 MPa at 22 °C for a period of 17h.
 The work-up conditions for the hydrogenolysis reaction involved neutralization with ammonia solution followed by benzene recrystallization. The hydrochloride salt of compound of formula III was formed from addition of hydrochloric acid to a solution of free base in ethanol.
 The process yielded (S)-Pirlindole hydrochloride with a final yield of 10% with respect to the intermediate VI.
 The mixture of sodium hydride with DMSO generates dimsyl anion. This anion is very often used in laboratory scale, but because it is unstable its use on large scale should be under specific precautions. Dimsyl anion decomposition is exotermic. It is reported that dimsyl anion decomposition starts even at 20 °C, and above 40 °C it decomposes at an appreciable rate (Lyness, W. I. et ai, U.S. 3,288,860 1966, CI. 260-607).
 The mixture of DMF and sodium hydride is reported in ‘Sax & Lewis’s Dangerous Properties of Industrial Materials’ to give a violent reaction with ignition above 50 °C. Buckey, J. et ai, Chem. Eng. News 1982, 60(28), 5, describes the thermal runaway of a pilot plant reactor containing sodium hydride and DMF from 50 °C. Accelerated Rate Calorimetry (ARC) tests showed exothermic activity as low as 26 °C. Similar behaviour was also seen with DMA. De Wall, G. et ai, Chem. Eng. News 1982, 60(37), 5, reports a similar incident, wherein runaway started at 40 °C, and rose 100 °C in less than 10 minutes, boiling off most of the DMF.
 There exists a need for safe, industrial- and eco-friendly processes for the preparation of Pirlindole enantiomers. These facts are disclosed in order to illustrate the technical problem addressed by the present disclosure.
 In an embodiment, the preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole, compound of formula VII was carried out as follow.
 In an embodiment, in a 2 L three necked round bottomed flask equipped with magnetic stirrer, ethylene glycol ditosylate (73 g, 197 mmol) and DMI (240 mL) were loaded. To the resulting clear solution, NaH (60% suspension in mineral oil, 15.8 g, 394 mmol) was added carefully. To the resulting suspension a solution of VI ((S)-6-methyl-N-((S)-l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-amine) (30 g, 98.5 mmol) in DMI (60 mL) was added dropwise at 60 °C. The mixture was stirred for 1 h at 60 °C. The mixture was cooled down to room temperature, then MeOH was added slowly with ice-water cooling. A white precipitation appeared, and the resulting suspension was stirred and then filtered. The filtered product was washed with water-MeOH. The product was dried under vacuum to give 24.9 g of compound of formula VII (75.2 mmol, yield: 76%). Purity >99.9area% (HPLC).
 In an embodiment, the preparation of hydrochloride salt of (S)-Pirlindole, compound of formula III, was performed as follow.
 In an embodiment, the free amine VII ((S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole) (8,32 g, 25 mmol) was dissolved in DCM (42 mL) and excess of HCI in MeOH (42 mL) was added. The solvents were evaporated under reduced pressure to dryness to give a yellow oil. The residue was dissolved in MeOH (120 mL) and was added to the dispersion of Pd/C (1,74 g, -50% water) in MeOH (20 mL). The reaction mixture was stirred at 50 °C under a 750 KPa (7.5 bar) pressure of hydrogen for 5h. After completion (HPLC) the suspension was filtered through a celite pad, and the filter cake was washed with MeOH. The pH of the resulting solution was checked (<3) and it was evaporated to give the crude hydrochloride salt of compound of formula III. To the crude material iPrOH was added and the suspension was allowed to stir at reflux. The suspensions were filtered, and the product was dried under vacuum to give the hydrochloride salt of (S)-Pirlindole, compound of formula III (5.11 g, 19.5 mmol, yield: 77%). Purity > 99.5% (HPLC). Enantiomeric purity 99.5% (Chiral HPLC). MS (ESI): m/z 227.2 (M+H)+.
Process for the preparation of piperazine ring for the synthesis of pyrazinocarbazole derivatives, such as the antidepressant pirlindole .
Pirlindole hydrochloride is the compound represented in formula I
 It is the common name of 8-methyl-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole hydrochloride which is an active pharmaceutical ingredient marketed with the name Pyrazidol™. The compound is effective as an anti-depressant agent.
 Pirlindole chemical structure belongs to the pyrazinocarbazole group. It is composed of one stereogenic centre which anticipate the existence of two enantiomers, the ( ?)-Pirlindole of formula II and the (S)-Pirlindole of formula III.
 Although Pirlindole pharmacological data and the clinical use were performed on the racemate, recently there have been increasing interest in the pharmacological profile of each enantiomer (WO 2015/171005 Al).
 The document WO 2015/171003Al(Tecnimede group) filed 9th May 2014 discloses a resolution of racemic pirlindole into optically active pirlindole. The Resolution-Racemization-Recycle (RRR) synthesis described involves derivatization by preparation of pairs of diastereomers in the form of salts from an optically active organic acid. These diastereomers can be separated by conventional techniques such as crystallisation. Although it is a very efficient procedure to prepare laboratorial scale or pre-clinical batch of (/?)- or (S)-Pirlindole, it is not economically convenient at an industrial scale because the process relies on Pirlindole racemate as the starting material.
 Processes to prepare Pirlindole involve the formation of a piperazine ring. The state of the art discloses different processes for piperazine ring formation but they are generally a multistep approach, and they are hampered by low yields, expensive reagents, or are reported as unsuccessful (Roderick et al. Journal of Medicinal Chemistry 1966, 9, 181-185).
 The first asymmetric synthesis of Pirlindole enantiomers described by Andreeva et al. (Pharmaceutical Chemistry 1992, 26, 365-369) discloses a one-step process to prepare pyrazinocarbazole piperazine ring system from a tetrahydrocarbazole-amine. The process discloses a very low yield (23.8 %) and employs the use of sodium hydride (NaH) in the presence of dimethyl sulfoxide (DMSO) or dimethyl formamide (DMF), both conditions described as generating exothermic decomposition that can cause reaction ignition or reaction thermal runaway.
 The mixture of sodium hydride with DMSO generates dimsyl anion. This anion is very often used in laboratory scale, but because it is unstable its use on large scale should be under specific precautions. The dimsyl anion decomposition is exothermic. It is reported that dimsyl anion decomposition starts even at 20 °C, and above 40 °C it decomposes at an appreciable rate (Lyness et al. US 3288860).
 The mixture of DMF and sodium hydride is reported in Sax & Lewis’s Dangerous Properties of Industrial Materials to give a violent reaction with ignition above 50 °C. Buckey et al., (Chemical & Engineering News, 1982, 60(28), 5) describes the thermal runaway of a pilot plant reactor containing sodium hydride and DMF from 50 °C. Accelerated Rate Calorimetry (ARC) tests showed exothermic activity as low as 26 °C.
Similar behaviour was also seen with DMA. De Wall et al. (Chem. Eng. News, 1982, 60(37), 5) reports a similar incident, wherein runaway started at 40 °C, and rose 100 °C in less than 10 minutes, boiling off most of the DMF.
 An alternative process for the preparation of a piperazine ring system of a pyrazinocarbazole derivative can involve the formation of a lactam ring in a three steps approach:
1. N-acylation reaction;
2. intramolecular indole acetamide cyclisation to afford a lactam ring;
3. lactam reduction.
 Intramolecular indole chloroacetamide cyclization to yield a lactam ring has been described by Bokanov et al. (Pharmaceutical Chemistry Journal 1988, 23, 12, 1311-1315) particularly in the non-enantioselective synthesis of pyrazinocarbazolone derivatives. Bokanov et al. did not describe the lactam reduction into a piperazine ring.
 Intramolecular indole chloroacetamide cyclization to yield a lactam ring has also been described both by Rubiralta et al. (Journal of Organic Chemistry 54, 23, 5591-5597) and Bennasar, et al. (Journal of Organic Chemistry 1996., 61, 4, 1239-1251), as an unexpected outcome of a photocyclization reaction. The lactam conversion was low (<11% yield).
 Lactam reduction of a pyrazinone into piperazine ring systems is disclosed both by Aubry et al. (Biorganic Medicinal Chemistry Letters 2007, 17, 2598-2602) and Saito et al. (Tetrahedron 1995, 51, 30, 8213-8230) in the total synthesis of alkaloid natural products.
 There exists the need for improved processes for the preparation of piperazine ring derivatives in particular enantioselective processes for the preparation of pyrazinocarbazole intermediates precursors of Pirlindole enantiomers compounds of formula II and III.
Example 1 – Preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one – Formula IV
 In an embodiment, the preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one (Formula IV) was carried out as follows. To the solution of VI (S)-6-methyl-N-((S)-l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-amine (30 g, 98.5 mmol) in toluene (300 mL), 50 % (w/v) aqueous NaOH (79 g) was added dropwise at 0-5 °C, then the solution of chloroacetyl
chloride (12 mL, 148 mmol, 1.5 equiv.) in toluene (15 mL) was added dropwise at 0-5 °C. The mixture was stirred at 0-5 °C for approximately 2.5 h, and additional chloroacetyl chloride (12 mL, 148 mmol, 1.5 equiv.) in toluene (15 mL) was added dropwise at 0-5 °C. The mixture was stirred at 0-5 °C for approximately 1.5 h. Water was added to the reaction mixture keeping the temperature below 5 °C. The phases were separated, and the aqueous phase was extracted with toluene. The organic phase was treated with 2M aqueous HCI. The resulting suspension was filtered. The filtered solid was identified as the HCI salt of VI, which can be liberated and driven back to the chloroacetylation step. The phases of the mother liquor were separated, and the aqueous phase was extracted with toluene. The organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to about 350 mL as a solution in toluene. The toluene solution of the crude product compound of formula X was reacted in the next step.
 In an embodiment, in the same reaction vessel to the toluene solution of crude intermediate obtained in previous step were added TBAB (0.394 g, 1.22 mmol, 1 w/w% for the theoretical yield of prev. step) and 50 % (w/v) aqueous NaOH (8.1 g, 10 equiv.). The reaction mixture was stirred for 1 h at 65 °C, while the reaction was complete. Water was added to the mixture at 0 °C, and the phases were separated, the organic phase was washed with aqueous HCI, and with water, then dried over Na2S04, filtered and evaporated to give 32.87 g of compound IV (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one (yield: 97% for the two steps) as a brown solid. The crude product was reacted in the next step without further purification.
Example 2 – Preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole _ Formula V
 In an embodiment, the preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole (Formula V) was performed as follows. To the stirred solution of 32.87 g of IV, (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one (95.4 mmol) in dry THF (170 mL) 66 mL solution of sodium bis(2-methoxyethoxy)aluminium hydride in toluene (70 w/w%, 237 mmol, 2.5 equiv.) was added dropwise. The reaction mixture was warmed to 40 °C, and the end of the addition the mixture was stirred at 50 °C until the total consumption of the starting material. Additional 22 mL of sodium bis(2-methoxyethoxy)aluminium hydride solution (70 w/w%, 79 mmol, 0.8 equiv.) was added dropwise. After completion the mixture was cooled to room temperature and 5% aqueous NaOH was added carefully. Water and DCM were added to the mixture, the phases were separated, and the aqueous phase was extracted with DCM. The organic phase was dried over Na2S04, filtered and the solvent was evaporated to get a brown solid (28.8 g). This crude product was dissolved in DCM and MeOH was added. White solid precipitated. The solid was filtered and washed with MeOH to give V (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-j‘k]carbazole 14.6 g (yield: 46%) as an off-white cotton-like solid.
Example 3 – Preparation of (S)-Pirlindole Hydrochloride – Formula III
 In an embodiment, the preparation of (S)-Pirlindole hydrochloride III was carried out as follows. The free amine V ((S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a, 4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole) (8.32 g, 25 mmol) was dissolved in DCM (42 mL) and excess of HCI in MeOH (42 mL) was added. The solvents were evaporated under reduced pressure to dryness to give a yellow oil. The residue was dissolved in MeOH (120 mL) and was added to the dispersion of Pd/C (1.74 g, -50% water) in MeOH (20 mL). The reaction mixture was stirred at 50 °C under 750 KPa (7.5 bar) pressure of hydrogen for 5h. After completion (HPLC) the suspension was filtered through a celite pad, and the filter cake was washed with MeOH. The pH of the resulting solution was checked (<3) and it was evaporated to give the crude hydrochloride salt of compound of formula III. To the crude material iPrOH was added and the suspension was allowed to stir at reflux. The suspensions were filtered, and the product was dried under vacuum to give the hydrochloride salt of (S)-Pirlindole, compound of formula III (5.11 g, 19.5 mmol, yield: 77%). Purity > 99.5% (HPLC). Enantiomeric purity 99.5% (Chiral HPLC). MS (ESI): m/z 227.2 (M+H)+.
 Table 1. Comparative yields
|Onset of action||2 to 8 hours|
|Elimination half-life||185 hours|
|Excretion||urine (50–70%), feces (25–45%)|
|Chemical and physical data|
|Molar mass||226.32 g/mol|
|3D model (JSmol)|
//////////////Pirlindole, Lifril, Pyrazidol, 60762-57-4, DEPRESSION
Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder
On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP 1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.
About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP 2.
Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019
EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA ISRTGGSTYY
PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG VRAEDGRVRT LPSEYTFWGQ
GTQVTVSSAA AEVQLVESGG GLVQPGGSLR LSCAASGRTF SYNPMGWFRQ APGKGRELVA
AISRTGGSTY YPDSVEGRFT ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR
(disulfide bridge: 22-96, 153-227)
EU 2018/8/31 APPROVED, Cablivi
Treatment of thrombotic thrombocytopenic purpura, thrombosis
This drug was developed by Ablynx NV. On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.
It is an anti-von Willebrand factor humanized immunoglobulin. It acts by blocking platelet aggregation to reduce organ injury due to ischemia. Results of the phase II TITAN trial have been reported.
|Type||Single domain antibody|
|Chemical and physical data|
|Molar mass||27.88 kg/mol|
/////////////eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ , PEPTIDE, ALX 0081
October 24, 2018
Today, the U.S. Food and Drug Administration approved Xofluza (baloxavir marboxil) for the treatment of acute uncomplicated influenza (flu) in patients 12 years of age and older who have been symptomatic for no more than 48 hours.
“This is the first new antiviral flu treatment with a novel mechanism of action approved by the FDA in nearly 20 years. With thousands of people getting the flu every year, and many people becoming seriously ill, having safe and effective treatment alternatives is critical. This novel drug provides an important, additional treatment option,” said FDA Commissioner Scott Gottlieb, M.D. “While there are several FDA-approved antiviral drugs to treat flu, they’re not a substitute for yearly vaccination. Flu season is already well underway, and the U.S. Centers for Disease Control and Prevention recommends getting vaccinated by the end of October, as seasonal flu vaccine is one of the most effective and safest ways to protect yourself, your family and your community from the flu and serious flu-related complications, which can result in hospitalizations. Yearly vaccination is the primary means of preventing and controlling flu outbreaks.”
Flu is a contagious respiratory illness caused by influenza viruses. When patients with the flu are treated within 48 hours of becoming sick, antiviral drugs can reduce symptoms and duration of the illness.
“When treatment is started within 48 hours of becoming sick with flu symptoms, antiviral drugs can lessen symptoms and shorten the time patients feel sick,” said Debra Birnkrant, M.D., director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Having more treatment options that work in different ways to attack the virus is important because flu viruses can become resistant to antiviral drugs.”
The safety and efficacy of Xofluza, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 patients where participants were assigned to receive either Xofluza, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms. In both trials, patients treated with Xofluza had a shorter time to alleviation of symptoms compared with patients who took the placebo. In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received Xofluza and those who received the other flu treatment.
The most common adverse reactions in patients taking Xofluza included diarrhea and bronchitis.
Xofluza was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.
The FDA granted approval of Xofluza to Shionogi & Co., Ltd.