Patent Grant
11014925
This disclosure relates to certain novel co-crystal forms of a substituted heterocycle fused gamma-carboline together with nicotinamide or isonicotinamide, the manufacture of such co-crystals, pharmaceutical compositions thereof, and use thereof, e.g., in the treatment of diseases or abnormal conditions involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways.
1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (sometimes referred to as 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-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., H1 histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. ITI-007 is currently in clinical trials, i.e., 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 U.S. Pat. No. 7,183,282, 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.
Given the difficulties involved in making salts of ITI-007, it was decided to explore whether the compound was capable of forming co-crystals. An extensive co-crystal screen was undertaken, using 24 potential co-crystal formers and a variety of solvents and crystallization conditions. Two different ITI-007 free base co-crystals were discovered, with nicotinamide and with isonicotinamide. Both co-crystals were obtained by slurry experiments in methanol.
The disclosure thus provides novel co-crystal forms of ITI-007 and nicotinamide and of ITI-007 and isonicotinamide, which co-crystals are especially advantageous for use in the preparation of galenic formulations, together with methods of making and using the same.
Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The present invention will become more fully understood from the detailed description and the accompanying drawings, wherein:
The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by referenced in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification should be understood to refer to percentages by weight. The amounts given are based on the active weight of the material.
In a first embodiment, the invention provides 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base in the form of a co-crystal (Co-crystal 1). The invention therefore provides the following:
In another embodiment, the invention provides a process (Process 1) for the production of Co-crystal 1, comprising
In another embodiment, the invention provides a method of purifying 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) in free or salt form, comprising combining crude ITI-007 with a second compound selected from nicotinamide and isonicotinamide, in the presence of a solvent, e.g., comprising methanol, removing the solvent and recovering the Co-crystal thus formed, e.g., in accordance with Process 1, and optionally converting the Co-crystal back to ITI-007 free base or to a desired salt form.
In another embodiment, the invention provides the use of a compound selected from nicotinamide and isonicotinamide in a method of isolating and/or purifying ITI-007.
In another embodiment, the invention provides a pharmaceutical composition comprising Co-crystal 1, e.g., any of Co-crystal 1.1-1.20, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
In another embodiment, the invention provides a pharmaceutical composition comprising Co-crystal 1, e.g., any of Co-crystal 1.1-1.20, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Co-crystal 1 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
Co-crystal 1, e.g., any of Co-crystal 1.1-1.20, are found to be relatively insoluble. While the free base is poorly soluble, it does not form crystals and is difficult to formulate. Salt forms are quite soluble, but may provide undesirably fast dissolution in extended release formulations. In a particular embodiment, therefore, the invention provides a pharmaceutical composition for extended release of ITI-007, comprising Co-crystal 1, e.g., any of Co-crystal 1.1-1.20, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, e.g., wherein the pharmaceutical composition is in the form of an injectable depot for extended release.
In another embodiment, the invention provides Co-crystal 1, e.g., any of Co-crystal 1.1-1.20, or a pharmaceutical composition comprising Co-crystal 1, e.g., any of Co-crystal 1.1-1.20, for use in treating a disease or abnormal condition involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression, 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, or dementia.
In another embodiment, the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression, 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, or dementia, comprising administering to a patient in need thereof a therapeutically effective amount of any of Co-crystal 1-1.20.
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 30 kV, 10 mA; sample stage standard rotating; monochromatization by a Kβ-filter (0.5% Ni). Slits: fixed divergence slits 1.0 mm (=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, 0.5 s/step, 0.010°/step, 3.0 mm 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 v1.4. 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/DSC1 Stare System, equipment #1547, auto-sampler equipped, using pin-holed A1-crucibles of 40 μl. 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 v12.10.
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 μl; pierced). Typically 1-8 mg of sample is loaded onto a pre-weighed A1 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 v12.10 build 5937. No corrections are applied to the thermogram.
Polarized light microscopy (PLM): The microscopy studies are performed using an AxioVert 35M, equipped with an AxioCamERc 5s, equipment #1612. The microscope is equipped with four lenses: Zeiss A-Plan 5×/0.12, Zeiss A-Plan 10×/0.25, LD A-Plan 20×/0.30 and Achros TIGMAT 32×/0.40. Data collection and evaluation is performed using Carl Zeiss Zen AxioVision Blue Edition Lite 2011 v1.0.0.0 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 μm-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 Büchi 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 μm) for superior light element analysis. As detector the Xflash V5 detector with Cr, Ti, Al, Ta collimator (energy resolution <129 eV FWHM at 100000 cps Mnkα) 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 μm. 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 4 from 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/DSC1 STARe System with a 34-position auto sampler, equipment #1547. The samples are made using Al crucibles (100 μl; 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/DSC1. 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[96]. Solutions are prepared as follows: Mobile phase A: Add 800 ml of MilliQ water to a 1 L 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 1 L volumetric flask. Add 1 ml of TFA and homogenize. Fill up to the mark with Acetonitrile; Diluent: 50/50 MeOH/ACN.
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.
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, Tpeak=145° C. and Tpeak=185° C. 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 1H-NMR 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
The free base-isonicotinamide co-crystal is also analyzed by DVS, DSC/TGA and HPLC. The results are summarized in Table 2. DSC/TGA analysis shows one endothermic event at Tonset=136.7° C., Tpeak=149.5° C. and ΔE=−38.1 J/g. TGA shows three different mass losses, 2.4% in a temperature range of 40° C.-140° C., 12.4% in a temperature range of 150° C.-240° C. and 49.33%, decomposition, in a temperature range of 250° C.-330° C. Analysis of the HPLC data shows both the free base (70 area %) and isonicotinamide (24%) to be present. Analysis of the 1H-NMR data shows the free base and isonicotinamide to be present, no shifts are observed, meaning a co-crystal has been formed. FT-IR confirms the chemical structure. Analysis of the DVS data shows a long drying curve for the co-crystal. Only 0.2% mass uptake can be observed at 95 RH %, indicating the co-crystal is not hygroscopic.
In second and third experiments employing substantially similar conditions for co-crystal formation, each at a 1-gram scale, second batch and third batches of ITI-007 free base-isonicotinamide co-crystal are obtained having the XPRD Peak list shown in Tables 3 and 4, and the XPRD patterns shown in overlay in
Using the third batch of ITI-007 free base-isonicotinamide co-crystal, solubility studies are performed using the shake flask method. About 10 mg of co-crystal is weighed into a vial and solvent is added stepwise. As some solvents are added, crystallization is observed. The use of methanol, acetone or ethanol results in dissolution of the co-crystal to yield a solution. Subsequent evaporation produces solids which are analyzed by XPRD. In contrast, the use of dichloromethane, methyl t-butyl ether, ethyl acetate, acetonitrile or toluene results in the immediate formation of crystals as the solvent is added. Obtained crystals are isolated and are also analyzed by XRPD. XRPD patterns for the material obtained from methanol, dichloromethane, methyl t-butyl ether, acetone, ethyl acetate, ethanol, acetonitrile and toluene all show a common new XPRD pattern with the dominant peak offset from the original co-crystal major peak. These XPRD patterns are shown in overlay in
For the slurry experiment with nicotinamide in methanol, a solid is formed, for which TGA-DSC shows an endothermic event of Tpeak=120° C. This event is similar to the endothermic event of the free base (Tpeak=120.9° C.), therefore HPLC and 1H-NMR analysis are performed. HPLC shows both the free base and the co-former are present, also 1H-NMR shows both to be present, meaning a free base-nicotinamide co-crystal is formed. XRPD analysis of the material is depicted in
TGA-DSC analysis of the other slurry experiments using nicotinamide does not show any melting events, meaning the experiments conducted in acetonitrile or ethyl acetate do not form a co-crystal. This experiment is repeated at a gram scale. First, ITI-007 free base and nicotinamide are each dissolved in methanol. Subsequently, the obtained solutions were added in a 1:1 ratio to a vial. The mixture is stirred at room temperature for 2 hours, but no precipitation is observed. The solution is evaporated under vacuum to give a brown sticky solid. XRPD analysis of this brown sticky solid shows this to be nicotinamide itself.
Further experiments are conducted to evaluate other solvent systems for the production and scale-up of the nicotinamide co-crystal. Slurry experiments are performed using a 25 mg of ITI-007 free base and 8.6 mg of nicotinamide co-former in 100 μL of solvent with 24 hours of stirring. The results show that when methanol or ethanol is used, the ITI-007 free base and nicotinamide both dissolve to yield a solution. When attempts are made using isopropanol, 2-butanol, acetonitrile, ethyl acetate, 2-butanone, tetrahydrofuran, or di-isopropyl ether, dissolution does not occur and a white/brown sticky solid is seen to be suspended in the solvent. When water is used, dissolution also does not occur, and a sticky brown solid is seen to be suspended in the water. The solids are filtered and analyzed by XRPD. XRPD analysis for the organic solvents show the presence of nicotinamide, while for the aqueous solution, the solid is amorphous. This shows that of these ten solvents, only methanol or ethanol appear to potentially show the formation of a co-crystal. Evaporation of the methanol and ethanol solutions results in sticky solids. The solid obtained from ethanol evaporation is analyzed by XRPD and shows peaks corresponding to nicotinamide. In contrast, the solid obtained from methanol evaporation is analyzed by XPRD and is consistent with the formation of a co-crystal. XRPD Spectra are shown in
Co-crystals are also attempted using a cooling crystallization method. 25 mg of ITI-007 free base and 8.6 mg of nicotinamide co-former are combined in 200 μL of solvent and heated to 50° C. The mixtures are kept at 50° C. for one hour, then cooled to 5° C. at a rate of 5° C. per hour. The results show that when methanol, ethanol, isopropanol or 2-butanol is used, the ITI-007 free base and nicotinamide both dissolve to yield a solution which remains a solution on cooling. In contrast, the use of acetonitrile, ethyl acetate, 2-butanone, tetrahydrofuran, or di-isopropyl ether does not result in dissolution, and instead, after cooling a white/brown sticky solid is recovered. When water is used, dissolution also does not occur, and a sticky brown solid is recovered. The solids are filtered and analyzed by XRPD. XRPD analysis for the non-alcoholic organic solvents shows the presence of nicotinamide, while for the aqueous solution, the solid is amorphous. This shows that of these ten solvents, only the alcohols appear to potentially show the formation of a co-crystal. Evaporation of the alcoholic solutions results in sticky solids for each. The solids obtained from isopropanol and 2-butanol evaporation are analyzed by XRPD and show peaks corresponding to nicotinamide. In contrast, the solids obtained from methanol and ethanol evaporation are analyzed by XPRD and are shown to be consistent with the formation of a co-crystal. XRPD Spectra are shown in
This application is a United States Application under 35 U.S.C. § 371 claiming priority to and the benefit of PCT Application No. PCT/US2017/024597, filed Mar. 28, 2017, which claims priority to and the benefit of U.S. Provisional Application Ser. No. 62/314,339, filed on Mar. 28, 2016, the contents of each of which are hereby incorporated by reference in their entireties.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2017/024597 | 3/28/2017 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2017/172811 | 10/5/2017 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 2490813 | Hughes et al. | Dec 1949 | A |
| 3299078 | Pachter | Jan 1967 | A |
| 3813392 | Sellstedt et al. | May 1974 | A |
| 3914421 | Rajagopalan | Oct 1975 | A |
| 4115577 | Rajagopalan | Sep 1978 | A |
| 4183936 | Rajagopalan | Jan 1980 | A |
| 4219550 | Rajagopalan | Aug 1980 | A |
| 4238607 | Rajagopalan | Dec 1980 | A |
| 4522944 | Doria et al. | Jun 1985 | A |
| 4971971 | Tokunaga et al. | Nov 1990 | A |
| 4985432 | Tokunaga et al. | Jan 1991 | A |
| 5114976 | Norden | May 1992 | A |
| 5151419 | Perenyi et al. | Sep 1992 | A |
| 5576460 | Buchwald et al. | Nov 1996 | A |
| 5648539 | Goodbrand et al. | Jul 1997 | A |
| 5648542 | Goodbrand et al. | Jul 1997 | A |
| 5654482 | Goodbrand et al. | Aug 1997 | A |
| 5705697 | Goodbrand et al. | Jan 1998 | A |
| 5723669 | Goodbrand et al. | Mar 1998 | A |
| 5723671 | Goodbrand et al. | Mar 1998 | A |
| 5847166 | Buchwald et al. | Dec 1998 | A |
| 5902901 | Goodbrand et al. | May 1999 | A |
| 6043370 | Kubo et al. | Mar 2000 | A |
| 6166226 | Buchwald et al. | Dec 2000 | A |
| 6235936 | Buchwald et al. | May 2001 | B1 |
| 6307087 | Buchwald et al. | Oct 2001 | B1 |
| 6323366 | Wolfe et al. | Nov 2001 | B1 |
| 6395916 | Buchwald et al. | May 2002 | B1 |
| 6407092 | Hester et al. | Jun 2002 | B1 |
| 6465693 | Buchwald et al. | Oct 2002 | B2 |
| 6541639 | Zhou et al. | Apr 2003 | B2 |
| 6548493 | Robichaud et al. | Apr 2003 | B1 |
| 6552017 | Robichaud et al. | Apr 2003 | B1 |
| 6699852 | Robichaud et al. | Mar 2004 | B2 |
| 6713471 | Robichaud et al. | Mar 2004 | B1 |
| 6759554 | Buchwald et al. | Jul 2004 | B2 |
| 6762329 | Marcoux et al. | Jul 2004 | B2 |
| 6849619 | Robichaud et al. | Feb 2005 | B2 |
| 6867298 | Buchwald et al. | Mar 2005 | B2 |
| 6888032 | Buchwald et al. | May 2005 | B2 |
| 6946560 | Buchwald et al. | Sep 2005 | B2 |
| 7026498 | Buchwald et al. | Apr 2006 | B2 |
| 7071186 | Robichaud et al. | Jul 2006 | B2 |
| 7081455 | Robichaud et al. | Jul 2006 | B2 |
| 7109339 | Lee et al. | Sep 2006 | B2 |
| 7115784 | Buchwald et al. | Oct 2006 | B2 |
| 7183282 | Robichaud et al. | Feb 2007 | B2 |
| 7223879 | Buchwald et al. | May 2007 | B2 |
| RE39679 | Robichaud et al. | Jun 2007 | E |
| RE39680 | Robichaud et al. | Jun 2007 | E |
| 7238690 | Robichaud et al. | Jul 2007 | B2 |
| 7247731 | Buchwald et al. | Jul 2007 | B2 |
| 7323608 | Buchwald et al. | Jan 2008 | B2 |
| 7375226 | Jolidon et al. | May 2008 | B2 |
| 7462641 | Igo et al. | Dec 2008 | B2 |
| 7592454 | Lee et al. | Sep 2009 | B2 |
| 7645752 | McDevitt et al. | Jan 2010 | B2 |
| 7998971 | Barlow et al. | Aug 2011 | B2 |
| 8309722 | Tomesch et al. | Nov 2012 | B2 |
| 8598119 | Mates et al. | Dec 2013 | B2 |
| 8648077 | Tomesch et al. | Feb 2014 | B2 |
| 8779139 | Tomesch et al. | Jul 2014 | B2 |
| 8993572 | Mates et al. | Mar 2015 | B2 |
| 9168258 | Mates et al. | Oct 2015 | B2 |
| 9199995 | Tomesch | Dec 2015 | B2 |
| 9315504 | Tomesch et al. | Apr 2016 | B2 |
| 9371324 | Mates et al. | Jun 2016 | B2 |
| 9428506 | Mates et al. | Aug 2016 | B2 |
| 9616061 | Mates et al. | Apr 2017 | B2 |
| 9708322 | Li et al. | Jul 2017 | B2 |
| 9751883 | Tomesch et al. | Sep 2017 | B2 |
| 9956227 | Vanover et al. | May 2018 | B2 |
| 10117867 | Mates et al. | Nov 2018 | B2 |
| 20010008942 | Buchwald et al. | Jul 2001 | A1 |
| 20040034015 | Robichaud et al. | Feb 2004 | A1 |
| 20040127482 | Robichaud et al. | Jul 2004 | A1 |
| 20040186094 | Robichaud et al. | Sep 2004 | A1 |
| 20040220178 | Robichaud et al. | Nov 2004 | A1 |
| 20050127482 | Fauty et al. | Jun 2005 | A1 |
| 20050222209 | Zeldis et al. | Oct 2005 | A1 |
| 20050239768 | Lee et al. | Oct 2005 | A1 |
| 20060128713 | Jolidon et al. | Jun 2006 | A1 |
| 20060148808 | Robichaud et al. | Jul 2006 | A1 |
| 20060205787 | Muller et al. | Sep 2006 | A1 |
| 20070066677 | Igo et al. | Mar 2007 | A1 |
| 20070203120 | McDevitt et al. | Aug 2007 | A1 |
| 20140050783 | Mates et al. | Feb 2014 | A1 |
| 20140323491 | Tomesch et al. | Oct 2014 | A1 |
| 20140364609 | Tomesch et al. | Dec 2014 | A1 |
| 20150072964 | Mates et al. | Mar 2015 | A1 |
| 20150079172 | Mates et al. | Mar 2015 | A1 |
| 20150080404 | Mates et al. | Mar 2015 | A1 |
| 20150166540 | Mates et al. | Jun 2015 | A1 |
| 20160031885 | Li et al. | Feb 2016 | A1 |
| 20160194326 | Tomesch et al. | Jul 2016 | A1 |
| 20160310502 | Vanover et al. | Oct 2016 | A1 |
| 20180271862 | Li | Sep 2018 | A1 |
| Number | Date | Country |
|---|---|---|
| 0856508 | Aug 1998 | EP |
| 1245553 | Oct 2002 | EP |
| 1254884 | Nov 2002 | EP |
| 1564671 | Aug 2005 | EP |
| WO 1998015515 | Apr 1998 | WO |
| WO 1999043643 | Sep 1999 | WO |
| WO 2000002887 | Jan 2000 | WO |
| WO 2000064899 | Nov 2000 | WO |
| WO 2000077001 | Dec 2000 | WO |
| WO 2000077002 | Dec 2000 | WO |
| WO 2000077010 | Dec 2000 | WO |
| WO 2002085838 | Oct 2002 | WO |
| WO 2004013094 | Feb 2004 | WO |
| WO 2004039788 | May 2004 | WO |
| WO 2004056324 | Jul 2004 | WO |
| WO 2006081251 | Aug 2006 | WO |
| WO 2007025103 | Mar 2007 | WO |
| WO 2007084841 | Jul 2007 | WO |
| WO 2008112280 | Sep 2008 | WO |
| WO 2009017836 | Feb 2009 | WO |
| WO 2009100324 | Aug 2009 | WO |
| WO 2009114181 | Sep 2009 | WO |
| WO 2009145900 | Dec 2009 | WO |
| WO 2011133224 | Oct 2011 | WO |
| WO 2013155504 | Oct 2013 | WO |
| WO 2013155506 | Oct 2013 | WO |
| WO 2014145192 | Sep 2014 | WO |
| WO 2015085004 | Jun 2015 | WO |
| Entry |
|---|
| Li, J., et al. “New polymorphs of isonicotinamide and nicotinamide.” Chem. Commun. (2011), vol. 47, pp. 1530-1532. (Year: 2011). |
| International Search Report for International Application No. PCT/US2018/052922, dated Nov. 26, 2018, 3 pages. |
| Alvir, J., et al., “Clozapine-Induced Agranulocytosis. Incidence and Risk Factors in the United States,” The New England Journal of Medicine, 329(3): 162-167 (1993). |
| Angst, J., et al., “Prevalence and Characteristics of Undiagnosed Bipolar Disorders in Patients With a Major Depressive Episode,” Arch. Gen. Psychiatry, 68(8): 701-709 (2011). |
| Avendaño, C., et al., “The Problem of the Existence of C(Ar)-H . . . N Intramolecular Hydrogen Bonds in a Family of 9-Azaphenyl-9H-carbazoles,” J. Chem. Soc. Perkin. Trans., 2: 1547-1555 (1993). |
| Balbach, S., et al., “Pharmaceutical evaluation of early development candidates ‘the 100 mg-approach,’” International Journal of Pharmaceutics, 275: 1-12 (2004). |
| Bastin, R.J., et al., “Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research & Development, 4(5):427-435 (2000). |
| Beletskaya, I., et al., “Pd- and Cu-catalyzed selective Arylation of Benzotriazole,” Tetrahedron Letters, 39: 5617-5620 (1998). |
| Berger, J., et al., “Synthesis of Some Conformationally Restricted Analogues of Fentanyl,” Journal of Medicinal Chemistry, 20(4): 600-602 (1977). |
| Boger, D., et al., “Inverse Electron Demand Diels-Alder Reactions of Heterocyclic Aza Dienes. Studies on the Total Synthesis of Lavendamycin: Investigative Studies on the Preperation of the CDE β-Carboline Ring System and AB Quinoline-5,8-quinone Ring System,” J. Org. Chem., 50:5782-5789 (1985). |
| Bowman, W.R., et al., “Copper(1) Catalysed Aromatic Nucleophilic Substitution: A Mechanistic and Synthetic Comparison with the SRN1 Reaction,” Tetrahedron Letters, 25(50): 5821-5824 (1984). |
| Bowman, W.R., et al., “Intramolecular Aromatic Substitution (SRN1) Reactions, Use of Entrainment for the Preparation of Benzothiazoles,” Tetrahedron Letters, 23(48): 5093-5096 (1982). |
| Bowman, W.R., et al., “Synthesis of 1H-quinazoline-4-ones using intramolecular aromatic nucleophilic substitution,” ARKIVOC, x: 434-442 (2003). |
| Byrn, S., et al., “Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations,” Pharmaceutical Research, 12(7): 945-954 (1995). |
| Crawford, K., et al., “Copper-catalyzed amidations of bromo substituted furans and thiophenes,” Tetrahedron Letters, 43: 7365-7368 (2002). |
| Davis, R., et al., “ITI-007 demonstrates brain occupancy at sertonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers,” Psychopharmacology, Published Online Apr. 7, 2015, pp. 1-10. |
| Davis, R., et al., “ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes,” Expert Review of Neurotherapeutics, 16(6): 601-614 (2016). |
| Evindar, G., et al., “Copper- and Palladium-Catalyzed Intramolecular Aryl Guanidinylation: An Efficient Method for the Synthesis of 2-Aminobenzimidazoles,” Organic Letters, 5(2): 133-136 (2003). |
| Ezquerra, J., et al., “Efficient Reagents for the Synthesis of 5-, 7-, and 5,7-Substituted Indoles Starting from Aromatic Amines: Scope and Limitations,” J. Org. Chem., 61: 5804-5812 (1996). |
| Fee, W.W., et al., “Copper (II)-Promoted Solvolyses of Nickel(II) Complexes III. Tetradentate Schiff Base Ligands Containing Various Diamine Segments,” Aust. J. Chem., 26: 1475-1485 (1973). |
| Ferreira, I., et al., “Novel synthetic routes to thienocarbazoles via palladium or copper catalyzed amination or amidation of arylhalides and intramolecular cyclizaiton,” Tetrahedron, 58: 7943-7949 (2002). |
| Finet, J., et al., “Recent Advances in Ullmann Reaction: Copper(II) Diacetate Catalysed N-, O- and S-Arylation Involving Polycoordinate Heteroatomic Derivatives,” Current Organic Chemistry, 6: 597-626 (2002). |
| Fitzgerald, R., et al., “Inhibition of Caries in Hamsters by 2-Deoxy-D-Glucose,” J. Dent. Res., 56(11): 1431 (1977). |
| Goodbrand, H.B., et al., “Ligand-Accelerated Catalysis of the Ullmann Condensation: Application to Hole Conducting Triarylamines,” J. Org. Chem., 64:670-674 (1999). |
| Grant, “Polymorphism in Pharmaceutical Solids,” Chapter 1, 1-10 (1999). |
| Guillory, “Polymorphism in Pharmaceutical Solids,” Chapter 5, 183-226 (1999). |
| Hackam, D., et al., “Translation of Research Evidence From Animals to Humans,” JAMA, 296(14): 1731-1732 (2006). |
| Hamann, B., et al., “Systematic Variation of Bidentate Ligands Used in Aryl Halide Amination. Unexpected Effects of Steric, Electronic, and Geometric Perturbations,” J. Am. Chem. Soc., 120: 3694-3703 (1998). |
| Hartwig, J.F., “Palladium-Catalyzed Amination of Aryl Halides: Mechanism and Rational Catalyst Design,” Synlett, 329-340 (1996). |
| Hassan, J., et al., “Aryl-aryl bond formation one century after the discovery of the ullmann reaction,” Chem. Rev., 102: 1359-1469 (2002). |
| Haynes, D., et al., “Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database,” Journal of Pharmaceutical Sciences, 94(10): 2111-2120 (2005). |
| International Search Report for International Application No. PCT/US2009/003261, dated Jul. 16, 2009, 3 pages. |
| International Search Report for International Application No. PCT/US2017/024562, dated Jun. 27, 2017, 2 pages. |
| International Search Report for International Application No. PCT/US2017/024597, dated Jun. 27, 2017, 3 pages. |
| Ito, T., et al., “Studies of Organic Catalytic Reactions. VI. The Function of Pyridine and Copper in the Rosenmund-von Braun reaction,” Bulletin of the Chemical Society of Japan, 41: 419-423 (1968). |
| Jain, N.K., et al., “Polymorphism in Pharmacy,” Indian Drugs, 23(6): 315-316 (1986). |
| Ji, J. “Selective in of Polyhalpyridines Catalyzed by a Palladium-Xantphos Complex,” Organic Letters, 5(24): 4611-4614 (2003). |
| Jordan, V.C., “Tamoxifen: A Most Unlikely Pioneering Medicine,” Nature Reviews: Drug Discovery, 2: 205-213 (2003). |
| Kametani, T., et al., “A Novel Synthesis of Indole Derivatives,” Heterocycles, 14(3): 277-280 (1980). |
| Kang, S.K., “Copper-catalyzed N-Arylation of Aryl Iodides with Benzamides or Nitrogen Heterocycles in the Presence of Ethylenediamine,” Synlett, 3: 427-430 (2002). |
| Kiyomori A., et al “An Efficient Copper-Catalyzed Coupling of Aryl Halides with Imidazoles,” Tetrahedron Letters, 40: 2657-2660 (1999). |
| Klapars, A., et al., “A General and Efficient Copper Catalyst for the Amidation of Aryl Halides,” J. Am. Chem. Soc., 124: 7421-7428 (2002). |
| Klapars, A., et al., “A General and Efficient Copper Catalyst for the Amidation of Aryl Halides and the N-Arylation of Nitrogen Heterocycles,” J. Am. Chem. Soc., 123: 7727-7729 (2001). |
| Kondratov, S.A., et al., “Nucleophilic Substitution in the Aromatic Series. LV. Reaction of o-Nitrochlorobenzene with Ammonia in the Presence of Copper Compouds,” Zhurnal Oranidreskoi Khimii, 51(11): 2387-2390 (1979). |
| Kwong, F., et al., “Mild and Efficient Copper-Catalyzed Amination of Aryl Bromides with Primary Alkylamines,” Organic Letters, 5(6): 793-796 (2003). |
| Lee, T., et al., “Novel, Highly Potent, Selective 5-HT2A/D2 Receptor Antagonists as Potential Atypical Antipsychotics,” Bioorganic & Medicinal Chemistry Letters, 13: 767-770 (2003). |
| Li, J., et al., “New polymorphs of isonicotinamide and nicotinamide,” Chem. Commun., 47: 1530-1532 (2011). |
| Li, P., et al., “Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders,” Journal of Medicinal Chemistry, 57: 2670-2682 (2014). |
| Louie, J., et al., “Palladium-Catalyzed Synthesis of Arylamines from Aryl Halides. Mechanistic Studies Lead to Coupling in the Absence of Tin Reagents,” Tetrahedron Letters, 36(21): 3609-3612 (1995). |
| Marcoux, J., et al., “A General Copper-Catalyzed Synthesis of Diaryl Ethers,” J. Am. Chem. Soc., 119: 10539-10540 (1997). |
| Marek, G., et al., “Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders,” Neuropsychopharmacology, 28: 402-412 (2003). |
| Mulrooney, C.A., “Recent Developments in Copper-Catalyzed N-Arylation with Aryl Halides,” Essay—University of Pennsylvania. |
| Murakami, et al., Chem. Pharm. Bull., 43(8): 1281-1286 (1995). |
| Nagai, Y., et al., “Synthesis of 2,3,4,4a,5,9b-Hexahydro-1H-prido[4,3-b]indole Derivatives and Their Central Nervous System Activities,” Journal of Medicinal Chemistry, 22(6): 677-683 (1979). |
| Newman, A., et al., “Solid-state analysis of the active pharmaceutical ingredient in drug products,” Drug Discovery Today, 8(9): 898-903 (2003). |
| Perlis, R., et al., “Clinical Features of Bipolar Depression Versus Major Depressive Disorder in Large Multicenter Trials,” Am. J. Psychiatry, 163: 225-231 (2006). |
| “Protection for the Amino Group,” Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, Inc., 494-505 (1999). |
| Rackova, L., et al., “Free Radical Scavenging and Antioxidant Activities of Substituted Hexahydropyridoindoles. Quantitative Structure—Activity Relationships,” J. Med. Chem., 49: 2543-2548 (2006). |
| Rye, D.B., “Sleep Disorders and Parkinson's Disease,” American Parkinson Disease Association, 2000, 2 pages, URL: <http://www.waparkinsons.org/edu_research/articles/Sleep_Disorders.html>. |
| Sadighi, J., et al “A Highly Active Palladium Catalyst System for the Arylation of Anilines,” Tetrahedron Letters, 39: 5327-5330 (1998). |
| Savjani, K., et al., “Drug Solubility: Importance and Enhancement Techniques,” International Scholarly Research Network Pharmaceutics, 2012: 1-10 (2012). |
| Sigel, H., et al., “Ternary Complexes in Solution. XVI. Influence of the Size of the Chelate Rings on the Stability of Mixed-Ligand Copper(II) Complexes Containing Aliphatic Ligands,” Inorganic Chemistry, 13(2): 462-465 (1974). |
| Singhal, D., et al., “Drug polymorphism and dosage form design: a practical perspective,” Advanced Drug Delivery Reviews, 56: 335-347 (2004). |
| Skoog, “Principles of Instrumental Analysis, 4th Edition,” 577 (1992). |
| Smith, A.D., et al., “Oxford Dictionary of Biochemistry and Molecular Biology,” Oxford University Press, 145 (1997). |
| Snyder, G., et al., “Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission,” Psychopharmacology, 232: 605-621 (2015). |
| Sugahara, M., et al., “A Facile Copper-Catalyzed Ullmann Condensation: N-Arylation of Heterocyclic Compounds Containing an —NHCO—Moiety,”Chem. Pharm. Bull., 45(4):719-721 (1997). |
| Wagaw, S., et al., “A Palldium-Catalyzed Method for the Preparation of Indoles via the Fischer Indole Synthesis,” Journal of the American Chemical Society, 121(44): 10251-10263 (1999). |
| Wolfe, J., et al., “An Improved Catalyst System for Aromatic Carbon-Nitrogen Bond Formation: The Possible Involvement of Bis(Phosphine) Palladium Complexes as Key Intermediates,” J. Am. Chem. Soc., 118: 7215-7216 (1996). |
| Wolfe, J., et al “Intramolecular Palladium-Catalyzed Aryl Amination and Aryl Amidation,” Tetrahedron, 52(21): 7525-7546 (1996). |
| Wolter, M., et al., “Synthesis of N-Aryl Hydrazides by Copper-Catalyzed Coupling of Hydrazides with Aryl Iodides,” Organic Letters, 3(23): 3803-3805 (2001). |
| Yamada, K., et al., “A Mild Copper-mediated Intramolecular Amination of Aryl Halides,” Synlett, 2: 231-234 (2002). |
| Yang, B., et al., “The development of efficient protocols for the palladium-catalyzed cyclization reactions of secondary amides and carbamates,” Organic Letters, 1(1): 35-37 (1999). |
| Zhang, Z., et al., “Highly efficient copper-catalyzed N-arylation of alkylamines with aryl iodides using phosphoramidite as ligand,” Catalysis Communications, 6: 784-787 (2005). |
| Yadav, et al., “Co-Crystals: A Novel Approach to Modify Physicochemical Properities of Active Pharmaceutical Ingredients,” Indian J. Pharm. Sci., 71(4):359-370 (2009). |
| Number | Date | Country | |
|---|---|---|---|
| 20190112310 A1 | Apr 2019 | US | |
| 20200017500 A9 | Jan 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62314339 | Mar 2016 | US |
